Glucokinase activators and pharmaceutical compositions containing them as active ingredient

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula (I) X represents NH, n means a number equal to 0-3, Y represents a direct bond, -(CH2)pO-, -(CH2)q- or -(CH2)qSO2-, p means a number equal to 0-2, q means a number equal to 1-3, R1 represents hydrogen, -(CR4R5)P-A-R6 or -(CR4R5)q-R6, R2 represents halogen, C1-C3-alkyl or trifluoromethyl, or represents 5~6-member heteroaryl or heterocyclyl each of which has 1 -3 heteroatoms selected from N and O, or represents optionally substituted C1-C3-alkylsulphonyl 6~12-member aryl, R3 represents R7-X-B-X'-, B represents a direct bond or represents 5~6-member heterocyclyl or heteroaryl each of which optionally contains oxo, optionally condensed and has 1-4 heteroatoms selected from N, O and S. Also the invention refers to a pharmaceutical composition for glucokinase activation and a method for preparing it.

EFFECT: use of the compounds of formula (I) as glucokinase activators.

22 cl, 11 dwg, 3 tbl, 222 ex

 

[Technical field to which the invention relates]

the present invention relates to new compounds exhibiting excellent activity against glucokinase (activator of glucokinase, GKA), and pharmaceutical compositions containing them as active ingredient.

[The prior art]

Diabetes has a deleterious effect on human health, causing various complications. Diabetes can be classified as type 1 diabetes, in which insulin is not reproduced due to destruction of pancreatic cells, and type 2 diabetes, in which insulin is not produced due to other conditions or the body does not respond to insulin. Type 2 diabetes has 90% or more of the total number of patients suffering from diabetes. Typical complications that accompany diabetes, including hyperlipidemia, hypertension, retinas, renal failure, etc. (P. Zimmer et al., Nature, 2001, 414, 782). As therapeutic agents for diabetes was used sulfonylureas (promoting insulin secretion in pankreaticheskikh cells), biguanides (suppressing the production of glucose in the liver), inhibitors of α-glucosidase (inhibit glucose uptake in the intestine) and so on, among which in recent times the focus is on agonist-activated proliferation gamma receptor peroxisomes (PPARγ) (thiazolidin the ions, increases insulin sensitivity). However, these agents find some side effects, such as increased body weight, according to the relevant mechanism of action (Moller D.E., Nature, 2001, 414, 821). There is therefore a need to develop agent for treating diabetes, which does not cause such side effects.

In a person with normal health of glucose in the blood is reliably regulated in the safe and narrow physiological range using various endocrine glycolytically systems. If such gluconatesee system does not operate, first occurs intolerance to glucose, which gradually turns into type 2 diabetes. Dysfunction of such a control mechanism is the result of (i) reducing the secretion of insulin from pancreatic cells, (ii) increase insulin resistance in liver cells of adipose tissue and skeletal muscle cells, and (iii) excessive production of glucose by the liver.

According to many research results obtained over the last forty years, glucokinase, which belongs to a number of hexokinase IV, takes part in the first stage of glucose metabolism for direct regulation of glucose levels in the blood, and therefore it plays an important role in maintenance of homeostasis of glucose in the body.

Glucokinase in pancreatic cells m which may determine the threshold for stimulated glucose insulin secretion (GSIR) act as a glucose sensor. Glucokinase reduces the content of glucose phosphorylation of glucose to glucose-6-phosphate, consuming ATP, and maintaining the glucose-6-phosphate in cells (Meglasson MD and F.M. Matschinsky, Diabetes Metab Rev, 1986, 2, 163).

On the other hand, glucokinase in hepatocytes has the ability to briefly governed by the regulatory protein of glucokinase. The regulatory protein of glucokinase forms a complex with 1:1 with glucokinase and acts as a competitive inhibitor against glucose to limit inactivated glucokinase in the nucleus and to protect and stabilize it from the actions of other proteins, such as enzymes decomposition, etc. Described that fructose-6-phosphate additionally stabilizes the regulatory protein of glucokinase, whereas fructose-1-phosphate isolates glucokinase from the regulatory protein of glucokinase and transfers it from the nucleus to the cytoplasm to maintain its activated state (Van Schaftingen E., Eur J Biochem, 1989, 179). Glucokinase in hepatocytes appropriately regulates glucose metabolism in the liver. That is, the absorption and the production of glucose effectively regulated at the state of satiety or hunger (Agius L. et al., J. Biol Chem, 1996, 271, 30479).

As explained above, glucokinase activates two functions: (i) direct regulation of blood glucose in the liver and (ii) facilitating the secretion of insulin in the physiological range after detection to the ncentratio glucose in the pancreas, and, thus, plays a very important role in maintaining glucose homeostasis.

Experimental results on many rodent models suggest that glucokinase is a key regulator in the maintenance of glucose homeostasis. Rats lacking the gene function of glucokinase in pancreatic beta-cells, to find a significant hyperglycemic symptoms and rats lacking the gene function of glucokinase in hepatocytes, detect impaired glucose uptake and hyperglycemic symptoms. On the other hand, when the gene for glucokinase sverkhekspressiya in hepatocytes of normal rats, found an effect of improving glucose tolerance (Rossetti L. et al., Am J Physiol, 1997, 273, E743). But overexpression of glucokinase in diabetic rats causes an improvement in glucose tolerance and the effect of reducing the amount of glucose in the blood in the hungry state (Desai U.J. et al., Am J Diabetes, 2001, 50, 2285).

To date clinically described approximately 200 mutant glucokinase gene of the person. Patients with MODY-2 (early developed diabetes of the young patient)-2, a subtype of type 2 diabetes, found a decrease in glucokinase due to loss of function mutations and hyperglycemia due to reduced insulin secretion. On the contrary, patients with PNDM (permanent neonatal diabetes) is PHHI (persistent hyperinsulinemia, hypoglycemia infants) found severe hypoglycemia due to activation of glucokinase on the basis of a gain of function mutation (Matsinsky F.M. et al., Frontiers in Daibetes, 2004, 16, chapter 4-7). Such phenotypes associated with glucokinase diseases suggest that glucokinase plays an important role in maintaining glucose homeostasis in the body, and this assumption provides the key to drug development for increasing the activity of glucokinase.

According to recent studies (Nakamura A. et al., Impact of small molecule glucokinase activator on glucose metabolism and beta cell mass, Endocrinology, 2008, Nov.), activators of glucokinase facilitate the division of the pancreatic beta cells, thereby improving glucose metabolism by maintaining the mass of pancreatic cells. In addition, it was described that glucose metabolism and hyperglycemia can normalize the recovery of hepatocellular glucokinase model only 20 weeks of ZDF rats with (rats, obesity and diabetes) (Torres T.P. et al., Restoration of hepatic glucokinase expression corrects hepatic glucose flux and normalize plasma glucose in zucker diabetic fatty rats, 2008, Endocrinology, Oct.), this suggests that hepatocyte-specific activators of glucokinase and can be developed as therapeutic agents that can be applied to type 1 diabetes, and, in the future, chronic type 2 diabetes.

Describes a lot of the research is to work on glucokinase activators. As of recently published patents, you can specify WO 2007/007910 A1, WO 2006/112549 A1, WO 2007/031739, WO 2007/037534, WO 2007/043638, WO 2007/028135, US 20070099930, WO 2007/041365, WO 2007/051847, WO 2007/053345, WO 2007/007910, WO 2006/049304 etc.

The authors of the present invention conducted extensive studies on the activators of glucokinase and the result confirmed that the indole derivatives of formula (I) are useful as glucokinase activators. Thus, they completed the present invention relates to activators of glucokinase based on the structure of indole.

[Detailed description of the invention]

[Technical problem that needs to be solved]

The present invention is the provision of activators of glucokinase, which is the indole derivatives of formula (I). Another objective of the present invention is the provision of compositions for the prevention or treatment of diseases caused by decreased activity of glucokinase, which contain these compounds as the active ingredient.

[Means for solving technical tasks]

The present invention relates to compounds of the following formula (1)

[Formula 1]

in which

X represents O or NH,

n denotes a number equal to 0 to 3,

Y represents a direct bond, -(CH2)pO-, -(CH2)qor (CH 2)qSO2-,

p denotes a number equal to 0-2,

q denotes a number equal to 1-3,

R1 represents hydrogen, -(CR4R5)p-A-R6 or -(CR4R5)q-R6

p and q have the meanings indicated above,

R4 and R5 independently of one another represent hydrogen or C1-C5-alkyl,

A represents a 6~12-membered aryl or optionally oxosteroid C3-C8-cycloalkyl or 3~10-membered heterocyclyl or heteroaryl, each of which has 1-3 heteroatoms selected from O, S and N,

R6 represents hydrogen, hydroxy, halogen, nitro, C1-C6-alkylsulphonyl, C1-C6-alkylsulfonyl, C1-C6-alkoxycarbonyl or carboxy,

R2 represents hydrogen, nitro, halogen, C1-C6-alkyl or trifluoromethyl, or represents a 5~12-membered heteroaryl or heterocyclyl, each of which has 1-3 heteroatoms selected from N and O, or represents an optional C1-C6-alkylsulfonamides 6~12-membered aryl,

R3 represents R7-X-B-X'-,

B represents a direct bond or represents a 3~10-membered heterocyclyl or heteroaryl, each of which optionally contains oxo, optionally condensed and has 1-4 heteroatoms selected from N, O and S,

X and X' independently of one another represent a direct the Yu bond or selected from the group consisting of-CO-, -(CH2)q-, -NR4C(O)-, -NR4-, -OC(O)-, -O-, -(CH2)pC(O)-, -(CH2)pO-, -(CH2)pNR4-, -C(O)NR4 and-S(O)rwhere p and q have the meanings stated above, r denotes a number equal to 0 to 2, and R4 represents hydrogen or C1-C5-alkyl,

R7 represents hydrogen, hydroxy, C1-C6-alkyl, C1-C6-alkoxy, halogen-(C1-C6-alkyl or C3-C6-cycloalkyl represents 6~12-membered aryl or represents a 4~8-membered heteroaryl or heterocyclyl, each of which has 1 to 4 heteroatom selected from N and O,

where alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl and heteroaryl can be optionally substituted and the substituents are one or more substituents selected from the group consisting of hydroxy, halogen, nitrile, amino, C1-C6-alkylamino, di(C1-C6-alkyl)amino, C1-C6-alkyl, halogen-(C1-C6-alkyl, C1-C6-alkylsulfonyl, aryl-C1-C6-alkoxy and oxo,

their pharmaceutically acceptable salts or isomers.

In the above definitions for compounds of formula (1), the term “alkyl” means an aliphatic hydrocarbon radical. The alkyl may be saturated alkyl, which does not contain alkenylphenol or alkenylphenol part, or unsaturated alkyl, which sod is RIT at least one alkenylphenol or alkenylphenol part. “Alkenyl” means a group containing at least one carbon-carbon double bond, and “quinil” means a group containing at least one carbon-carbon triple bond. The alkyl may be branched or unbranched chain when applied separately or in a mixed form, such as alkoxy.

The alkyl group can have 1 to 20 carbon atoms, unless otherwise specified. The alkyl group may be an alkyl group of medium size, having 1-10 carbon atoms. Otherwise, the alkyl group can be lower alkyl having 1-6 carbon atoms. Typical examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, ethynyl, propenyl, butenyl etc. for Example, With1-C4the alkyl has 1-4 carbon atoms in the alkyl chain and selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

The term “alkoxy” means alkyloxy having 1-10 carbon atoms, unless otherwise specified.

The term “cycloalkyl” means a saturated aliphatic 3~10-membered cycle, unless otherwise specified. Typical examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

The term “aryl” includes at least adekola, having a system of covalent π-electrons, for example, monocyclic or condensed polycyclic (i.e. cycles that share a pair of carbon atoms) group. In the present description of the invention the aryl means aromatic 4~10-membered, preferably 6~10-membered monocyclic or polycyclic ring comprising phenyl, naphthyl, etc. unless otherwise stated.

The term “heteroaryl” means aromatic 3~10-membered, preferably 4~8-membered, more preferably 5~6-membered cycle, which has 1-3 heteroatoms selected from N, O and S, and may be condensed with benzo or3-C8cycloalkyl, unless otherwise noted. Monocyclic heteroaryl includes, but is not limited to, thiazole, oxazole, thiophene, furan, pyrrole, imidazole, isoxazol, isothiazol, pyrazole, triazole, triazine, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrimidine, pyrazin and the like. Bicyclic heteroaryl includes, but is not limited to, indole, indoline, benzothiophen, benzofuran, benzimidazole, benzoxazole, benzisoxazole, benzthiazole, benzothiadiazole, benzotriazole, quinoline, isoquinoline, purine, properidine and the like.

The term “heterocycle” means 3~10-membered, preferably 4~8-membered, more preferably 5~6-membered cycle, which has 1-3 heteroatoms selected the s from N, O and S, can be condensed with benzo or3-C8cycloalkyl and is saturated or contains 1 or 2 double bonds, unless otherwise noted. The heterocycle includes, but is not limited to, pyrrolin, pyrrolidin, imidazolin, imidazolidin, pyrazoline, pyrazolidine, Piran, piperidine, morpholine, thiomorpholine, piperazine, hydrofuran and the like.

It should be clear that other terms and abbreviations in the present description of the invention shall have the meanings commonly used in this field specialist, unless otherwise specified.

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

X represents O or NH,

n denotes a number equal to 0 to 3,

Y represents a direct bond, -(CH2)pO-, -(CH2)q- or -(CH2)qSO2-,

p denotes a number equal to 0-2,

q denotes a number equal to 1-3,

R1 represents -(CR4R5)p-A-R6 or -(CR4R5)q-R6

p and q have the meanings indicated above,

R4 and R5 independently of one another represent hydrogen or C1-C5-alkyl,

A represents a 6~12-membered aryl or optionally oxosteroid C3-C7-cycloalkyl or represents a 4~8-membered heterocyclyl or heteroaryl, each of which has 1-3 heteroatoms selected from O, S, ie,

R6 represents hydrogen, hydroxy, halogen, nitro, C1-C6-alkylsulphonyl, C1-C6-alkylsulfonyl, C1-C6-alkoxycarbonyl or carboxy,

R2 represents hydrogen, halogen, C1-C6-alkyl or trifluoromethyl, represents 5~8-membered heteroaryl or heterocyclyl, each of which has 1-3 heteroatoms selected from N and O, or represents an optional C1-C6-alkylsulfonamides 6~10-membered aryl,

R3 represents R7-X-B-X'-,

B represents a direct bond or represents a 4~10-membered heterocyclyl or heteroaryl, each of which optionally contains oxo, optionally condensed and has 1-4 heteroatoms selected from N, O and S,

X and X' independently of one another represent a direct bond or is selected from the group consisting of-CO-, -(CH2)q-, -NR4C(O)-, -NR4-, -OC(O)-, -O-, -(CH2)pC(O)-, -C(O)NR4 and-S(O)rwhere p and q have the meanings stated above, r denotes a number equal to 0 to 2, and R4 represents hydrogen or C1-C5-alkyl,

R7 represents hydrogen, hydroxy, C1-C6-alkyl, halogen-(C1-C6-alkyl or C3-C6-cycloalkyl represents 6~12-membered aryl or represents a 4~8-membered heteroaryl or heterocyclyl, each of which has 1 to 4 heteroatoms, selected the data from N and O,

where alkyl, alkoxy, aryl, cycloalkyl, heterocyclyl and heteroaryl can be optionally substituted and the substituents are one or more substituents selected from the group consisting of hydroxy, halogen, nitrile, amino, C1-C6-alkylamino, di(C1-C6-alkyl)amino, C1-C6-alkyl, halogen-(C1-C6-alkyl, C1-C6-alkylsulfonyl, aryl-C1-C6-alkoxy and oxo.

In the compounds of formula (1) according to the present invention Deputy Y preferably represents a direct bond, -O-, -(CH2)O-, -(CH2)- or -(CH2)SO2-.

Deputy R1 more preferably represents -(CH2)p-A-R6 or -(CR4R5)q-R6, where p denotes a number equal to 0 to 2, q denotes a number equal to 1-3, R4 and R5 independently of one another represent hydrogen or C1-C5-alkyl, A represents a 6~12-membered aryl or optionally oxosteroid C3-C6-cycloalkyl or represents a 5~6-membered heterocyclyl, which has 1 or 2 heteroatoms selected from O, S and N, and R6 represents hydrogen, halogen, nitro, C1-C6-alkylsulphonyl, C1-C6-alkylsulfonyl, C1-C6-alkoxycarbonyl or carboxy. More preferably, R1 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl,diverticulosis, tetrahydrofuran (THF), tetrahydropyran, (tetrahydropyran-4-yl)methyl, tetrahydrothiopyran, 4-oxocyclohexyl, (1-methanesulfonyl)pyrrolidine, (1-acetyl)piperidine, 4-nitrophenyl and methylpropionate.

Deputy R2 more preferably represents hydrogen, halogen, C1-C3-alkyl or trifluoromethyl, represents 5~6-membered heteroaryl or heterocyclyl, each of which has 1-3 heteroatoms selected from N and O, or represents optionally methanesulfonamide 6~10-membered aryl. More preferably, R2 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, phenyl, methansulfonate, pyridine, research, 1,2-imidazole, 1,3-imidazole, pyrrolidine and pyrrole.

In the group R7-X-B-X' substituent R3 Deputy more preferably represents a direct bond, represents a pyrazole, imidazole or oxadiazole, each of which is optionally substituted C1-C6-alkyl, or represents 5~9-membered heterocycle, which optionally contains oxo, optionally is condensed and has 1-4 heteroatoms selected from N, S and O. preferably, represents a direct link or may be a structure selected from the following formulas (i) to (xi):

in which R7 has the value of the order the items above.

Deputy X' preferably represents a direct bond or is selected from the group consisting of-CO-, - NR4CO-, -SO2- and-O-.

Deputy X more preferably represents a direct bond or is selected from the group consisting of-C(O)NR4-, -NR4-, -OC(O)-, -NR4C(O)-, -(CH2)C(O)-, -S(O)2and-C(O)-. More preferably, X represents a direct bond or is selected from the group consisting of-C(O)NH-, -C(O)N(Me)-, -NH-, -N(Me)-, -OC(O)-, -N(Me)C(O)-, -(CH2)C(O)-, -S(O)2and-C(O)-.

More preferably, the Deputy R7 represents hydrogen, hydroxy, C1-C6-alkyl, halogen-C1-C6-alkyl or C4-C6-cycloalkyl, represents optionally halogen-substituted 6~10-membered aryl or a 5~6-membered heteroaryl or heterocyclyl, each of which has 1 to 4 heteroatom selected from N and O. More preferably, R7 is selected from the group consisting of hydrogen, hydroxy, methyl, trifloromethyl, ethyl, tert-butyl, cyclohexyl, pyrrolidine, phenyl, 2-ftoheia, piperidine, pyridine, 1,3-pyrazine, 1,4-pyrazine, furan, trifloromethyl, 1,2,3,4-tetrazole and tetrahydrofuran.

Typical compounds among the compounds of formula (1) are compounds selected from

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

{(R)-2-[7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-ylmethanol;

{(R)-2-[7-(tetrahydrofuran-3-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;

{(R)-2-[7-(1-methanesulfonanilide-3-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;

[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol;

{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;

[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol;

{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;

{(R)-2-[5-chloro-7-(tetrahydrothiopyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;

[(R)-2-(5-bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol;

{(R)-2-[5-bromo-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;

[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol;

{(R)-2-[7-cyclopentylamine-5-(pyridine-3-yloxy)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;

{(R)-2-[5-(pyridine-3-yloxy)-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;

cyclopentyl-[2-((R)-4-pyrrolidin-1-ylmethyl-4,5-dihydrothiazolo-2-yl)-1H-indol-7-yl]amine;

cyclopentyl-[2-((R)-4-morpholine-4-ylmethyl-4,5-dihydrothiazolo-2-yl)-1H-indol-7-yl]amine;

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

{(R)-2-[5-morpholine-4-ylmethyl-7-(tetrahydropyran-4-yl) - Rev. Ino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;

[(R)-2-[7-cyclopentylamine-5-pyrazole-1-ylmethyl-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;

[(R)-2-(7-cyclopentylamine-5-imidazol-1-ylmethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl}methanol;

{(R)-2-[7-cyclopentylamine-5-(1H-pyrrol-3-ylmethyl)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;

[(R)-2-(7-cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol;

[7 cyclopentylamine-2-((R)-4-hydroxymethyl-4,5-dihydrothiazolo-2-yl)-1H-indol-5-yl]methanol;

methyl ester [(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

ethyl ester [(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]ethanol;

methyl ester {(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanol;

[(R)-2-(5-bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

2-[(R)-2-(5-bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]ethanol;

{(R)-2-[5-bromo-7-(tetrahydropyran-4-yl) - Rev. Ino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

2-{(R)-2-[5-bromo-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanol;

[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

ethyl ester [(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanol;

{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanol;

[(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

ethyl ester [(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

2-[(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanol;

{(R)-2-[7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

2-{(R)-2-[7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanol;

methyl ester [(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

ethyl ester [(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

methyl ester {(R)-2-[5-methoxy-7-(tetrahydropyran-4-ylamino)-1H-indole-2-the l]-4,5-dihydrothiazolo-4-yl}acetic acid;

{(R)-2-[5-methoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

[(R)-2-(7-cyclopentylamine-5-ethoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

[(R)-2-(7-cyclopentylamine-5-propoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

[(R)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

{(R)-2-[5-phenoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

methyl ester {(R)-2-[7-cyclopentylamine-5-(pyridine-3-yloxy)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

{(R)-2-[7-cyclopentylamine-5-(pyridine-3-yloxy)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

methyl ester {(R)-2-[5-(pyridine-3-yloxy)-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

{(R)-2-[5-(pyridine-3-yloxy)-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

methyl ester [(R)-2-(7-cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

[(R)-2-(7-cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

{(R)-2-[5-methyl-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

{(R)-2-[5-methyl-7-(4-oxocyclohexyl)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

{(R)-2-[7-cyclopentylamine-5-(4-IU is analpornos)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

methyl ester [(R)-2-(7-cyclopentylamine-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

[(R)-2-(7-cyclopentylamine-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

methyl ester [(R)-2-(7-cyclopentylamine-5-pyrrolidin-1-ylmethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

methyl ester [(R)-2-(7-cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

[(R)-2-(7-cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

2-[(R)-2-(7-cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanol;

cyclopentyl-{5-methanesulfonyl-2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}amine;

1-(4-{2-[(R)-2-(7-cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)ethanone;

2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-morpholine-4-ratanana;

2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-(2-morpholine-4-retil)ndimethylacetamide;

2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-(3-morpholine-4-ylpropyl)ndimethylacetamide;

2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-methylacetamide;

2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N,N-DIMET is acetamido;

2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(4-methylpiperazin-1-yl)ethanone;

2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(3-dimethylaminopropan-1-yl)ethanone;

2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(3-hydroxypyrrolidine-1-yl)ethanone;

2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-piperidine-1-ratanana;

2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}-N-methylacetamide;

2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}-1-morpholine-4-ratanana;

2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(4-methylpiperazin-1-yl)ethanone;

2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-(2-morpholine-4-retil)ndimethylacetamide;

1-(4-acetylpiperidine-1-yl)-2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanone;

2-[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-methylacetamide;

2-[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-morpholine-4-ratanana;

2-[(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-ethylacetamide;

2-[(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-methylacetamide;

2-[(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-m is Holin-4-ratanana;

N-methyl-2-{(R)-2-[7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ndimethylacetamide;

1-morpholine-4-yl-2-{(R)-2-[7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanone;

{5-chloro-2-[(R)-4-(2-dimethylaminoethyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine;

{5-chloro-2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine;

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

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

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

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

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

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

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

(5-chloro-2-{(R)-4-[2-(3-dimethylaminopropan-1-yl)-ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)cyclopentylamine;

{5-chloro-2-[(R)-4-(2-piperidine-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine;

(5-chloro-2-{(R)-4-[2-(1,1-diocletianopolis-4-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indole-yl)cyclopentylamine;

{5-chloro-2-[(R)-4-(2-pyrazole-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine;

(S)-1-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}pyrrolidin-2-carboxylic acid;

{5-chloro-2-[(R)-4-(2-methansulfonate)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine;

ethyl ester of 3-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}-5-methyl-3H-imidazole-4-carboxylic acid;

3-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}-5-methyl-3H-imidazole-4-carboxylic acid;

1-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}pyrrolidin-2-it;

1-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperidine-3-carboxylic acid;

dimethylamide 1-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperidine-3-carboxylic acid;

tert-butyl ester [(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)pyrrolidin-3-yl]carbamino acids;

(2-{(R)-4-[2-((S)-3-aminopyrrolidine-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-chloro-1H-indol-7-yl)-(tetrahydropyran-4-yl)amine;

N-[(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)pyrrolidin-3-yl]ndimethylacetamide;

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

1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]-2-hydroxyethane;

1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]-2-tetrazol-1 ratanana;

1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]-3,3,3-cryptochrome-1-it;

[4-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]furan-2-ylmethanone;

(5-chloro-2-{(R)-4-[2-(2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)-(tetrahydropyran-4-yl)amine;

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

{2-[(R)-4-(2-amino-ethyl)-4,5-dihydrothieno-2-yl]-5-fluoro-1H-indol-7-yl}cyclopentylamine;

1-(4-{2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)ethanone;

cyclopentyl-{5-fluoro-2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}amine;

cyclopentyl-{2-[(R)-4-(2-dimethylaminoethyl)-4,5-dihydrothieno-2-yl]-5-fluoro-1H-indol-7-yl}amine;

cyclopentyl-{5-fluoro-2-[(R)-4-(2-pyrrolidin-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}amine;

cyclopentyl-(2-{(R)-4-[2-(1,1-diocletianopolis-4-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-fluoro-1H-indol-7-yl)amine;

4-{2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indole-2-the l)-4,5-dihydrothieno-4-yl]ethyl}piperazine-2-it;

1-(4-{2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)-2-hydroxyethane;

cyclopentyl-{5-fluoro-2-[(R)-4-(2-methansulfonate)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}amine;

{2-[(R)-4-(2-dimethylaminoethyl)-4,5-dihydrothieno-2-yl]-5-fluoro-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine;

{5-fluoro-2-[(R)-4-(2-pyrrolidin-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine;

{5-fluoro-2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine;

1-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethylpiperazin-1-yl)ethanone;

(2-{(R)-4-[2-(1,1-diocletianopolis-4-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-fluoro-1H-indol-7-yl)-(tetrahydropyran-4-yl)amine;

(5-fluoro-2-[(R)-4-(2-methansulfonate)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl)-(tetrahydropyran-4-yl)amine;

4-(2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-2-it;

1-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]-2-hydroxyethane;

cyclopentyl-{2-[(R)-4-(2-methoxyethyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}amine;

cyclopentyl-{2-[(R)-4-(2-dimethylaminoethyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}amine;

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

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

{2-[(R)-4-(2-methansulfonate)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine;

1-(4-{2-[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)-2-hydroxyethane;

2-hydroxy-1-[4-(2-{(R)-2-[5-methoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]ethanone;

ethyl ester of 3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;

3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;

3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propan-1-ol;

3-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}propionic acid;

3-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}propan-1-ol;

3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-(2-morpholine-4-retil)propionamide;

3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(4-methylpiperazin-1-yl)propane-1-it;

1-(4-{3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propyl}piperazine-1-yl)ethanone;

{5-chloro-2-[(R)-4-(3-morpholine-4-ylpropyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine;

ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;

3-[(R)-2-(7-what kilometraje-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;

3-[(R)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;

ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;

3-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;

ethyl ester of 3-[(R)-2-(5-bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;

3-[(R)-2-(5-bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;

3-[(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;

3-[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;

ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-ethoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;

3-[(R)-2-(7-cyclopentylamine-5-ethoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;

ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-triptoreline-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;

3-[(R)-2-(7-cyclopentylamine-5-triptoreline-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;

ethyl ester [(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-ylethoxy]acetic acid;

[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-ylethoxy]acetic acid;

cyclopentyl-{2-[(R)-4-(3-Cyclops is ntil-[1,2,4]oxadiazol-5-ylmethyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}amine;

cyclopentyl-{2-[(R)-4-(3-piperidine-1-yl-[1,2,4]oxadiazol-5-ylmethyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}amine;

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

1-(4-{2-[(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)ethanone;

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

7 phenoxy-2-[(R)-4-(2-pyrrolidin-1-retil)-4,5-dihydrothieno-2-yl]-1H-indole;

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

[(S)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

{(S)-2-[7-(1-acetylpiperidine-4-ylamino)-5-methyl-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

((S)-2-{7-[(tetrahydropyran-2-ylmethyl)amino]-1H-indol-2-yl}-4,5-dihydrothieno-4-yl)acetic acid;

((S)-2-{7-[(tetrahydropyran-4-ylmethyl)amino]-1H-indol-2-yl}-4,5-dihydrothieno-4-yl)acetic acid;

{(S)-2-[7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

{(S)-2-[7-(1-acetylpyrrolidine-3-ylamino)-5-methyl-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

[(S)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

((S)-2-{5-phenoxy-7-[(tetrahydropyran-4-ylmethyl)amino]-1H-indol-2-yl}-4,5-dihydrothieno-4-yl)acetic acid;

{(S)-2-[5-phenoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

{(S)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

[(S)-2-(7-cyclobutylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

{(S)-2-[5-methyl-7-(tetrahydrofuran-3-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

{(S)-2-[7-(cyclopropylamino)-5-methyl-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

((S)-2-{5-methyl-7-[(tetrahydropyran-4-ylmethyl)amino]-1H-indol-2-yl}-4,5-dihydrothieno-4-yl)acetic acid;

{(S)-2-[5-methyl-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

methyl ester [(S)-2-(7-cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

[(S)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;

{(S)-2-[7-(4,4-diverticulectomy)-5-methyl-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;

(2-{(S)-4-[2-((R)-3-aminopyrrolidine-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-chloro-1H-indol-7-yl)-cyclopentylamine;

(5-chloro-2-{(S)-4-[2-((R)-3-dimethylaminopropan-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)cyclopentylamine;

1-(4-{2-[(S)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)ethanone;

1-(4-{2-[(S)-2-(7-amino-5-chloro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)ethanone;

1-(4-{2-[(S)-2-(5-methyl-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl)-4,5-Digi retisol-4-yl]ethyl}piperazine-1-yl)ethanone;

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

1-(4-{2-[(S)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)-2-hydroxyethane;

cyclopentyl-{5-phenoxy-2-[(S)-4-(2-piperazine-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}amine;

tert-butyl ester 4-{2-[(S)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-carboxylic acid;

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

4-{2-[(S)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-2-it;

(4-{2-[(S)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)(tetrahydrofuran-2-yl)methanone;

cyclopentyl-(5-phenoxy-2-{(S)-4-[2-(4-pyridine-2-reparation-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)amine;

cyclopentyl-[2-((S)-4-{2-[4-(2-forfinal)piperazine-1-yl]ethyl}-4,5-dihydrothieno-2-yl)-5-phenoxy-1H-indol-7-yl)amine;

1-(4-{2-[(S)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)ethanone;

{(R)-1-[2-[(S)-2-{5-methyl-7-[(tetrahydropyran-4-ylmethyl)amino]-1H-indol-2-yl}-4,5-dihydrothieno-4-yl]ethyl]pyrrolidin-2-yl}methanol;

N-((R)-1-{2-[(S)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}pyrrolidin-3 is)ndimethylacetamide;

(2-{(S)-4-[2-(4-benzylpiperazine-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-phenoxy-1H-indol-7-yl)cyclopentylamine;

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

{2-[(S)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-5-phenoxy-1H-indol-7-yl}-(tetrahydropyran-4-ylmethyl)amine;

4-[2-((S)-2-{5-phenoxy-7-[(tetrahydropyran-4-ylmethyl)amino]-1H-indol-2-yl}-4,5-dihydrothieno-4-yl)ethyl]piperazine-2-it;

cyclopentyl-{5-phenoxy-2-[(S)-4-(2-pyrrolidin-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl)amine;

(4,4-diverticulosis)-{2-[(S)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl)amine;

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

4-[2-((S)-2-{5-phenoxy-7-[(tetrahydropyran-4-ylmethyl)amino]-1H-indol-2-yl}-4,5-dihydrothieno-4-yl)ethyl]piperazine-2-she

4-(2-{(S)-2-[7-(4,4-diverticulectomy)-5-phenoxy-7-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-2-it.

It should be clear that other terms and abbreviations in the present description have the meanings commonly used in this field specialist, unless otherwise specified.

The compounds of formula (1) according to the present invention can also form pharmaceutically acceptable salt. Such pharmaceutically acceptable salt includes detoxi the strong acid additive salt, containing pharmaceutically acceptable anion, for example, salts with inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, Hydrobromic acid, uudistoodetena acid etc; salts with organic acids such as tartaric acid, formic acid, citric acid, acetic acid, trichloroacetic acid, triperoxonane acid, gluconic acid, benzoic acid, lactic acid, fumaric acid, maleic acid, salicylic acid and so on; or a salt with sulfonic acids such as methanesulfonate acid, econsultancy acid, benzolsulfonat acid, p-toluensulfonate acid etc. in Addition, pharmaceutically acceptable salt of the carboxylic acid includes, for example, salts 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 dicyclohexylamine, N-methyl-D-glucamine, Tris(hydroxymethyl)methylamine, diethanolamine, choline, triethylamine, etc. of Compounds of formula (1) according to the present invention can be converted into their salts in accordance with any of the conventional ways.

The compounds of formula (1) according to the present invention may have an asymmetric center(s) in the volume(s) of carbon in its structure and can therefore exist in the form of R - or S-isomer, the racemate, mixture of diastereomers or of an individual diastereoisomer, etc. All isomers are also included in the present invention.

The present invention relates also to methods of preparing compounds of formula (1). Further, with the aim of better understanding the ways of obtaining compounds of formula (1) below illustrates the approximate schemes reactions. However, a specialist in the field to which the present invention can obtain the compounds of formula (1) through a variety of ways according to their structures, and it should be clear that such methods are within the scope of the present invention. In other words, the compounds of formula (1) can be obtained optional combination of different synthetic methods described in the present description or described in the prior art. Methods for obtaining compounds of formula (1) include even such ways and is not limited to the methods explained below.

The compounds of formula (1) can be obtained according to the following reaction scheme (1) the restoration of the nitro group of the compound (2) obtaining the amino compounds (3) and the introduction of the substituent R1 in the formed amino group. Alternative compounds of formula (1) can be obtained according to the following schemes of the reactions from (2) to (7) modification of the substituents R1, R2 and R3 in the compound (4).

The compound (5) can be obtained according to issleduyuschimi schemes of reactions (8) and (9). Compound (7) can be obtained according to the following reaction scheme (10), the compound (20) can be obtained according to the following reaction scheme (11).

The scheme of reactions 1

In the above reaction scheme (1)

and means Fe, Zn, Pd/C, and so on,

b means ketone compound in the form R1=O, triacetoxyborohydride sodium {NaBH(OAc)3}, cyanoborohydride sodium (NaBH3CN) and so on,

R1, R2 and R3 have the meanings indicated in the formula (1), and

R8 represents a Y-R2, where Y and R2 have the values listed in the formula (1).

Compound (2) can be obtained according to the following schemes of the reactions from (2) to (9).

The compound (3) can be obtained by reduction of compound (2). Response recovery can be performed using an acid catalyst and a metal or metal catalyst in the presence of gaseous hydrogen.

Acids which can be used in the reaction of recovery with the use of an acid catalyst and a metal include, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc. and organic carboxylic acids such as acetic acid, triperoxonane acid, etc., Aminata, such as ammonium chloride, preferably hydrochloric acid, acetic acid, chloride Ammon who I am etc. The acid is usually used in an amount of 0.01~10 EQ., preferably of 0.1~5 EQ., relative to 1 EQ. compounds (2). Metals that can be used include, for example, iron, zinc, lithium, sodium, tin (usually the chloride of tin, and so on, particularly preferably iron, zinc, tin chloride, etc. Metal typically used in quantities of 1~20 equiv., preferably 1~10 EQ., relative to 1 EQ. compounds (2). The reaction of the metal in the presence of acid catalyst can be carried out in an inert solvent. As the inert solvent can be, for example, enter alkalemia alcohols, such as methanol, ethanol and so on, ethers such as tetrahydrofuran, diethyl ether, etc., alkalemia esters, such as ethyl acetate, etc., preferably methanol, ethanol, tetrahydrofuran, ethyl acetate, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 25~120°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

Metal catalysts that can be used in the reaction of recovery with the use of metal catalyst in the presence of gaseous hydrogen, include palladium, Nickel, platinum, ruthenium, rhodium, etc., particularly preferably palladium, Nickel, etc. Metal catalyst is usually used in amounts of 0.001~2 EQ., preferably 0,01~1 EQ., relative to 1 EQ. is soedineniya (2). The pressure of the hydrogen gas is usually in the range of 101325~1013250 PA (1~10 ATM), preferably 101325~303977 PA (1~3 ATM). The reaction can be carried out in an inert solvent, for example, alilovic alcohols, such as methanol, ethanol and so on, ethers such as tetrahydrofuran, diethyl ether, etc., allylacetate, such as methyl acetate, ethyl acetate, etc., preferably in methanol, ethanol, ethyl acetate, etc. the Temperature of the reaction using a metal catalyst is usually in the range of -10~200°C, preferably 25~50°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

The compound (4) can be obtained by the reaction of reductive alkylation of the compound (3).

Reductive alkylation of the amino group of compound (3) can be a ketone using the recovery agent and, if necessary, with the use of an acid catalyst. The ketone is usually used in quantities of 1~10 EQ., preferably 1-3 equiv., relative to 1 EQ. compounds (3). Restorative agents that can be used include borohydride sodium, cyanoborohydride sodium, triacetoxyborohydride sodium, etc. reduction agent is usually used in quantities of 1~10 EQ., preferably 1~3 EQ., relative to 1 EQ. compounds (3). Acid catalysts that can be applied, including the t, for example, inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, etc. and organic carboxylic acids such as acetic acid, triperoxonane acid, etc., Aminata, such as ammonium chloride, particularly preferably hydrochloric acid, acetic acid, etc. Acid is usually used in an amount of 0.1~10 EQ., preferably 1~5 EQ., relative to 1 EQ. compounds (3). The reaction can be carried out in an inert solvent selected, for example, from ethers such as tetrahydrofuran, diethyl ether, etc., chloroalkanes, such as dichloromethane, chloroform, dichloroethane, etc., preferably dichloroethane, chloroform, etc. the reaction Temperature is usually in the range of 10~100°C, preferably -10~50°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

The compound (1) or (2) of the present invention can be obtained according to methods which, in particular, are cited as examples in the following schemes of the reactions from (2) to (9).

The scheme of reactions 2

In the above reaction scheme (2)

and means metal hydroxide (such as NaOH, LiOH),

b means of the condensing agent (e.g., EDC, CDI, BOP-Cl) and the compound (7),

c means PCl5or Tf2O and Ph3PO,

d means con is entirely agent (for example, EDC, CDI, BOP-Cl) and the compound (11),

R8 have the meanings indicated in the reaction scheme (1),

R9 represents C1-C6-alkyl,

R10 represents NO2or R1-X, where X and R1 have the meanings indicated in the formula (1),

R11 represents a p-MeOBn or Ph3C, and

R3' and R3” are independently from each other represent R7-X-B-, where R7, X and V have the meanings indicated in the formula (1).

The compound (5) can be obtained according to the schemes of reactions (8) and (9).

The compound (6) can be obtained by hydrolysis of compound (5) with the use of reason. The Foundation, which can be used include lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. the Base is usually used in quantities of 1~10 EQ., preferably 1~5 EQ., relative to 1 EQ. compounds (5). The hydrolysis reaction can be carried out in an inert solvent selected from, for example, water, alilovic alcohols, such as methanol, ethanol and so on, ethers such as tetrahydrofuran, diethyl ether, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 25~120°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

Compound (7) can be obtained according to the following schemes of reactions (10) and (11).

Compound (8) can be obtained by the condensation reaction of compound (6), which is the carboxylic acid, with AMI what agropol connection (7). Known condensing agents which can be used in the condensation reaction include, but are not limited to, carbimide, such as dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), 1,1'-dicarbonitriles (CDI), etc. mixed with 1-hydroxybenzotriazole (NOVT) or 1-hydroxy-7-isobenzofuranone (NAAT), or the acid chloride of bis-(2-oxo-3-oxazolidinyl)phosphinic acid (THIEF-Cl), diphenylphosphoryl (DPPA), N-[dimethylamino-1H-1,2,3-triazole[4,5-b]pyridine-1-ylmethylene]-N-methylmethanamine (HATU), etc. Condensing agent is usually used in quantities of 1~10 EQ., preferably 1~3 EQ., relative to 1 EQ. compounds (6). The number used NOWT or NOT is usually in the range of 1~10 EQ., preferably 1~3 EQ., relative to 1 EQ. compounds (6). When the condensation reaction is used hydrochloride amine, the acid should be removed with the use of reason. The Foundation, which can be used include organic bases such as triethylamine, diisopropylethylamine. The base is usually used in quantities of 1~10 EQ., preferably 1~3 EQ., relative to 1 EQ. compounds (7). The reaction mix can be carried out in an inert solvent selected from tetrahydrofuran, diethyl ether, N,N-dimethylformamide, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 25~120°C,and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

Compound (9) can be obtained by cyclization of compound (8)as described in Journal of Organic Chemistry, 68(24), 2003, 9506-9509, Tetrahedron, 55(34), 1999, 10271-10282, etc.

When R11 represents a p-methoxybenzyloxy group (p-MeOBn), the cyclization reaction is carried out in the solvent dichloromethane using pentachloride phosphorus (PCl5). PCl5usually used in quantities of 1~10 EQ., preferably 1~3 EQ., relative to 1 EQ. compounds (8). The reaction temperature is usually in the range of -10~50°C, preferably 0~25°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

When R11 represents triphenylmethyl group (Ph3C), the cyclization reaction is carried out in the solvent dichloromethane using triftormetilfullerenov anhydride (Tf2O) and triphenylphosphine oxide (Ph3PO), which is typically used in quantities of 1~10 EQ., preferably 1~3 EQ., relative to 1 EQ. compounds (8). The reaction temperature is usually in the range of -10~50°C, preferably 0~25°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

The compound (11) is aminoguanidinium, which is commercially available.

The compound (12) can be obtained by the condensation reaction of the compound (10), which is a carboxylic acid with compound (11) according to the method is Holocene connection (8).

The reaction scheme 3

In the above reaction scheme (3)

and means reducing agent (e.g., NaBH4, LiAlH4),

b means I2or MsCl, etc.,

by means of a base and the compound (11),

d means the base and the compound (15),

R8 has the values shown in the reaction scheme (1),

R9 represents C1-C6-alkyl,

R10 represents NO2or R1-X, where X and R1 have the meanings indicated in the formula (1),

R12 represents a C1-C6-alkoxy, cyano or 5~6-membered heteroaryl,

R' and R” have the meanings given in the reaction scheme (2), and

W represents a leaving group, for example, halides such as chloride, bromide, iodide, etc., or sulfonates, such as methanesulfonate, p-toluensulfonate etc.

The compound (13) can be obtained by conversion of the ester group of compound (9) in the alcohol group. Reducing agents that can be used for recovery of the ester group to an alcohol group, include, for example, borohydride sodium, borohydride lithium, borane, sociallyengaged, diisobutylaluminium (DIBAL-H), etc. reducing agent is usually used in quantities of 1~10 EQ., preferably 1~3 EQ., relative to 1 EQ. compounds (9). The reaction can be carried out in an inert solvent, selected, voltage is emer, of the alcohols, such as methanol, ethanol and so on, ethers such as tetrahydrofuran, diethyl ether, etc., preferably tetrahydrofuran, diethyl ether, etc. the reaction Temperature is usually in the range of -78~100°C., preferably -78~50°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

The compound (14) can be obtained by conversion of the alcohol group of compound (13) in the stretching group W. the Leaving group W can be introduced through reaction of halogenation or sulfonation. The halogenation reaction can be carried out with the use of halogenation agent selected from iodine, bromine, N-jodatime (NIS), N-bromosuccinimide (NBS), carbon tetrachloride (CCl4), tetrabromide carbon (CBr4and so, in the presence of a base such as imidazole, dimethylaminopyridine (DMAP) and so on, and phosphines such as triphenylphosphine (Ph3P), tributylphosphine (Bu3P), etc. Each of halogenation agent, the base and phosphine is usually used in quantities of 1~10 EQ., preferably 1~3 EQ., relative to 1 EQ. compounds (13). This reaction can be carried out in an inert solvent selected, for example, from ethers such as tetrahydrofuran, diethyl ether, etc. and dichloromethane, chloroform, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 0~50°C, and time reacts and is usually in the range of 10 min~60 h, preferably 10 min~12 hours

The reaction of sulfonation can be performed using sulfurous agent selected from methanesulfonamido, p-toluensulfonate, etc. in the presence of organic bases such as pyridine, triethylamine, etc. Each of sulfurous agent and the base is usually used in quantities of 1~10 EQ., preferably 1~5 EQ., relative to 1 EQ. compounds (13). This reaction can be carried out in an inert solvent selected, for example, from ethers such as tetrahydrofuran, diethyl ether, etc., chloroalkanes, such as dichloromethane, dichloroethane, chloroform, etc., preferably in dichloromethane, dichloroethane, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 0~50°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

Compound (16) can be obtained by condensation reaction of compound (11) with compound (14) with the use of reason. As a basis you can specify, for example, inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate, etc. and organic bases such as triethylamine, diisopropylethylamine, 1,8-diazabicyclo[5,4,0]undeca-7-ene (DBU), etc. the Base is usually used in quantities of 1~10 EQ., preferably 1~5 EQ., relative to 1 EQ. connection (14). This reaction can be carried out in a trade is nom solvent, selected, for example, from ethers such as tetrahydrofuran, diethyl ether, etc., alkylation, such as acetonitrile, propionitrile etc., amides such as N,N-dimethylformamide, etc., preferably tetrahydrofuran, acetonitrile, N,N-dimethylformamide, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 25~120°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

The compound (17) can be obtained by the condensation reaction of compound (14) with compound (15) according to the production method of compound (16).

The reaction scheme 4

In the above reaction scheme (4)

and means condensing agent (e.g., EDC, CDI, BOP-Cl) and the compound (18),

R8 has the values shown in the reaction scheme (1),

R10 represents NO2or R1-X, where X and R1 have the meanings indicated in the formula (1), and

R13 represents a C3-C6-cycloalkyl or piperidinyl.

The compound (18) can be obtained according to the method described in Heterocycles, 60(10), 2087, 2003 or Bioorganic & Medicinal Chemistry Letters, 11(24), 3164, 2001.

The compound (19) can be obtained by the condensation reaction of the compound (10) with compound (18). As agent combination can be applied dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), 1,1'-dicarbonitrile the ol (CDI), etc., but not limited to. The condensing agent is usually used in quantities of 1~10 EQ., preferably 1~3 EQ., relative to 1 EQ. compounds (10). This reaction can be carried out in an inert solvent selected from tetrahydrofuran, diethyl ether, N,N-dimethylformamide, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 25~120°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

The reaction scheme 5

In the above reaction scheme (5)

and means condensing agent (e.g., EDC, CDI, BOP-Cl),

b represents PCl5or Tf2O and Ph3PO,

c is a metal hydroxide (such as NaOH, LiOH),

d represents the I2or MsCl, etc.,

e represents the base of the compound (11),

R8 has the values shown in the reaction scheme (1),

R10 represents NO2or R1-X, where X and R1 have the meanings indicated in the formula (1),

R11 represents a p-MeOBn or Ph3C,

R14 represents a C1-C6-alkyl,

R' and R” have the meanings given in the reaction scheme (2), and

W represents a leaving group, for example, halides such as chloride, bromide, iodide, etc., or sulfonates, such as methanesulfonate, p-toluensulfonate etc.

The compound (20) can be obtained which according to the reaction scheme (11).

The compound (21) can be obtained with the use of compounds (6) and (20) according to the method of producing compound (8) in the reaction scheme (2).

Compound (22) can be obtained by using the compound (21) according to the production method of compound (9) in reaction scheme (2).

The compound (23) can be obtained by using the compound (22) according to the production method of compound (6) in the reaction scheme (2).

The compound (24) can be obtained by using the compound (23) according to the production method of compound (14) in the reaction scheme (3).

The compound (25) can be obtained by using the compound (24) according to the production method of compound (16) in the reaction scheme (3).

The scheme of reactions 6

In the above reaction scheme (6)

rather it represents a di-tert-butyloxycarbonyl (Re2On), base (for example, NaOH, K2CO3),

b represents pomeroyi agent (for example, N-bromosuccinimide (NBS)),

c represents sodium acetate (NaOAc),

d represents an acid (e.g. hydrochloric acid, triperoxonane acid)

e represents a metal hydroxide (such as NaOH, LiOH),

f represents a condensing agent (e.g., EDC, CDI, BOP-Cl) and the compound (33),

g represents a PCl5,

h is a base and the compound (33),

R2 have the values listed in the Le (1),

R9 represents C1-C6-alkyl,

R11 represents a p-MeOBn, and

R15 represents a C1-C6-alkoxycarbonyl and C1-C6-alkylcarboxylic.

The compound (26) can be obtained according to reaction scheme (9).

Compound (27) can be obtained sequentially by protecting the amino group of compound (26) with the use of Vos2In the presence of a base and the transformation of the methyl group in bromatology group using brainwashes agent.

Vos2Oh, used in the reaction for the protection of amino groups, typically used in quantities of 1~10 EQ., preferably 1~3 EQ., relative to 1 EQ. compound (26). The base is usually used in quantities of 1~10 EQ., preferably 1~3 EQ., relative to 1 EQ. compound (26). To facilitate the reaction, it is possible to apply the catalyst. Used catalyst is dimethylaminopyridine (DMAP) and it is usually used in an amount of 0.01~2 EQ., preferably of 0.1~0.3 EQ., relative to 1 EQ. compound (26). This reaction can be carried out in an inert solvent selected from tetrahydrofuran, diethyl ether, N,N-dimethylformamide, dichloromethane, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 25~120°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

Brainwashee agents used in the reaction of bromm is melirovanie, include N-bromosuccinimide (NBS) and 1,3-dibromo-5,5-dimethylhydantoin and they are usually used in quantities of 1~10 EQ., preferably 1~3 EQ., relative to 1 EQ. compound (26). To facilitate the reaction, it is possible to apply the catalyst. Used catalyst is 2,2'-azinobis-(2-methylpropionitrile) (AIBN) or benzoyl peroxide, and it is usually used in amounts of 0.001~2 EQ., preferably of 0.01~0.3 EQ., relative to 1 EQ. compound (26). This reaction can be carried out in an inert solvent selected from benzene, toluene, carbon tetrachloride, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 25~120°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

Compound (28) can be obtained by the reaction of sodium acetate (NaOAc) with compound (27). Sodium acetate is typically used in quantities of 1~10 EQ., preferably 1~5 EQ., relative to 1 EQ. compound (27). This reaction can be carried out in an inert solvent, for example, chosen from ethers such as tetrahydrofuran, diethyl ether, etc., alkylation, such as acetonitrile, propionitrile etc., amides such as N,N-dimethylformamide, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 25~120°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

Compound (29) can be obtained is sledovatelno removing groups VOS using acid hydrolysis using Foundation. Used acid group when you delete a VOS is hydrochloric acid, triperoxonane acid, etc. Acid is usually used in quantities of 1~10 EQ., preferably 2~5 EQ., relative to 1 EQ. compound (28). This reaction can be carried out in an inert solvent, for example, chosen from ethers such as tetrahydrofuran, diethyl ether, dioxane, etc., alilovic alcohols, such as methanol, ethanol, etc., chloroalkanes, such as dichloromethane, chloroform, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 25~120°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

The base used in the hydrolysis reaction include lithium hydroxide, sodium hydroxide, potassium hydroxide, etc. the Base is usually used in the amount of 2~20 equiv., preferably 2~10 EQ., relative to 1 EQ. compound (28). This hydrolysis reaction can be carried out in an inert solvent, for example, selected from alilovic alcohols, such as methanol, ethanol and so on, ethers such as tetrahydrofuran, diethyl ether, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 25~120°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

The compound (30) can be obtained according to the schemes of reactions (10) and (11).

The compound (31) can get the ü by the condensation reaction of the compound (29) with compound (30) according to the method of producing compound (8) in the reaction scheme (2).

Compound (32) can be obtained by the reaction of PCl5with the connection (31). In this reaction using PCl5simultaneous cyclization and chlorination of the alcohol group. PCl5usually used in quantities of 1~10 EQ., preferably 1~3 EQ., relative to 1 EQ. compound (31). This reaction can be carried out in a solvent selected from dichloromethane, chloroform, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 0~50°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

The compound (33) is commercially available.

Compound (34) can be obtained by the condensation reaction of the compound (32) with compound (33) according to the production method of compound (16).

The scheme of reactions 7

In the above reaction scheme (7)

but allerease agent [for example, R11-CO-Cl (R11-CO)2O]

b represents PCl5,

with is a metal hydroxide (such as NaOH, LiOH),

R11 represents a p-MeOBn,

R14 represents a C1-C6-alkyl, and

R15 represents a C1-C6-alkoxycarbonyl or1-C6-alkylcarboxylic.

Compound (35) can be obtained by protection of the alcohol group of compound (31) acyl group and cyclization using PCl5. Rea is on the protection of the alcohol group is carried out with application of Foundation and Alliluyeva agent. Used bases include organic bases, such as triethylamine, diisopropylethylamine, pyridine, etc. the Base is usually used in quantities of 1~10 EQ., preferably 1~5 EQ. relative to 1 EQ. compound (31). Used allermuir agent is a compound in the form R14-CO-Cl or (R14-CO)2O (R14=C1-C6-alkyl). Allerease agent is usually used in quantities of 1~10 EQ., preferably 1~3 EQ., relative to 1 EQ. compound (31). This reaction can be carried out in a solvent selected from dichloromethane, chloroform, dichloroethane, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 0~50°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

For the reaction of cyclization apply PCl5. PCl5usually used in quantities of 1~10 EQ., preferably 2~5 EQ., relative to 1 EQ. compound (31). This reaction can be carried out in a solvent selected from dichloromethane, chloroform, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 0~50°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

Compound (36) can be obtained by reaction of removal of protecting the hydroxyl group of compound (35) with the use of reason. Used in the reaction, removal of the protecting bases include hydroxide l is ment, sodium hydroxide, potassium hydroxide, etc. the Base is usually used in quantities of 1~10 EQ., preferably 1~5 EQ., relative to 1 EQ. compounds (35). This reaction can be carried out in an inert solvent, for example, selected from water, alilovic alcohols, such as methanol, ethanol and so on, ethers such as tetrahydrofuran, diethyl ether, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 25~120°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

The scheme of reactions 8

In the above reaction scheme (8)

and represents sodium nitrite (NaNO2); tin chloride (SnCl2),

b is a ketone compound (39), a base (for example, NaOAc),

c is an acid (for example, polyphosphoric acid, PPA),

d is a NaNO2,

e represents a connection (42), a base (such as NaOH),

R8 has the values shown in the reaction scheme (1), and

R9 and R10 have the meanings indicated in the reaction scheme (2).

The compound (37) is commercially available or can be obtained by the method described in Heterocycles, 68(11), 2285-99, 2006, or Bioorganic & Medicinal Chemistry Letters, 14(19), 4903-4906, 2004.

Compound (38) is commercially available or can be obtained by conversion of the amino group of compound (37) in Hijazi is Gruppo according to the method, described in the Journal of the American Chemical Society, 198(48), 15374-75, 2006.

Alternative hydrazinonicotinamide (38) can be obtained by reaction of an amino group of compound (37) with NaNO2in the presence of hydrochloric acid to obtain diazonium salt (41), which without isolation restore using SnCl2. NaNO2usually used in quantities of 1~10 EQ., preferably 2~5 EQ., relative to 1 EQ. compound (37). SnCl2usually used in quantities of 1~10 EQ., preferably 2~5 EQ., relative to 1 EQ. compound (37). This reaction is carried out in 1~12 N., preferably 4~8 N. aqueous solution of hydrochloric acid. The reaction temperature is in the range of -10~50°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~6 hours

Compound (39) is commercially available.

Hydrazono connection (40) can be obtained by the condensation reaction of the compound (38) with a ketone compound (39). The base is not used, when the compound (38) is in the neutral form, but it should be used when the compound (38) is in the form of a salt of the acid, to obtain a neutral form. As a basis you can apply, for example, metal hydroxides such as sodium hydroxide, lithium hydroxide, etc., metal carbonates, such as sodium bicarbonate, potassium carbonate, etc., acetates of metals, such as AOC is tat sodium, etc., organic bases such as triethylamine, pyridine, etc., preferably sodium acetate, sodium bicarbonate, etc. the Base is usually used in quantities of 1~5 EQ., preferably 1~2 EQ., relative to 1 EQ. compounds (38). This reaction can be carried out in an inert solvent selected from tetrahydrofuran, methanol, ethanol, etc. the reaction Temperature is in the range of -10~100°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

The compound (40) can also be obtained by reaction of the diazonium salt (41) with compound (42) in the presence of a base according to the method of rearrangement Japp-Klingemann described in Organic Process Research & Development, 2, 1988, 214-220. Upon receipt of diazonium salt (41) using hydrochloric acid, usually in quantities of 1~10 EQ., preferably 2~4 EQ., relative to 1 EQ. compound (37). The base used in the reaction of compounds (41) and (42)is sodium hydroxide, which is usually used in quantities of 1~20 equiv., preferably 1~10 EQ., relative to 1 EQ. compound (42). As the solvent used 80% aqueous solution of ethanol, and the reaction temperature is in the range of -10~50°C. the reaction Time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

The compound (5) can be obtained by using an acid catalyst and a compound (40). Acid applied p and synthesis, is polyphosphoric acid, hydrochloric acid, p-toluensulfonate acid, sulfuric acid, acetic acid, etc., preferably polyphosphoric acid. Polyphosphoric acid is used alone or in a mixture with aromatic hydrocarbons such as benzene, toluene and so on, the reaction Temperature is in the range of 25~150°C, and the reaction time is usually in the range of 5 min~60 h, preferably 5 min~12 hours

The reaction scheme 9

In the above reaction scheme (9)

and is a sodium alkoxide (e.g. sodium methoxide),

b means to heat,

R1 has the values listed in the formula (1),

R8 has the values shown in the reaction scheme (1), and

R9 represents C1-C6-alkyl.

Compound (43) is commercially available.

Compound (44) can be obtained by the method described in Journal of Medicinal Chemistry, 31(11), 2145, 1988.

The compound (45) is commercially available or can be obtained by the method described in WO 2007040289, WO 200601079 or Organic Letters 9(3), 397-400, 2007.

The alternate connection (45) can be obtained by the condensation reaction of the compound (43) with compound (44) in the presence of a base. Apply the base is sodium methoxide, ethoxide sodium, etc. the Base is usually used in quantities of 1~10 EQ., preferably 1~3 EQ. about the relative 1 EQ. compound (43). This reaction can be carried out in an inert solvent, for example, selected from alilovic alcohols, such as methanol, ethanol and so on, ethers such as tetrahydrofuran, diethyl ether, etc. the reaction Temperature is usually in the range of -10~200°C, preferably -10~25°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

Compound (46) can be obtained by cyclization of compound (45). The cyclization reaction can be carried out by dissolving compound (45) in an inert solvent and heating the solution. Inert solvents which can be used include tetrahydrofuran, benzene, toluene, etc. the reaction Temperature is usually in the range of 25~200°C, preferably 50~120°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

The reaction scheme 10

In the above reaction scheme (10)

and represents the p-methoxybenzylamine (PMBCl) or triphenylmethylchloride (TrCl), a base (such as NaOH),

b is a di-tert-butyloxycarbonyl (Re2On), base (for example, NaOH, K2CO3),

with is alkylchloride (for example, EtOCOCl), a base (for example, N-methylmorpholine),

d represents diazomethane (CH2N2), a base (such as KOH),

e represents the ion with the ribs (for example, benzoate silver),

f is an acid,

g represents MsCl, Et3N

h is a p-methoxybenzylthio (PMBSH), NaH,

R9 represents C1-C6-alkyl, and

R11 represents a p-MeOBn or Ph3C.

The compound (47) can be obtained protection Tilney group of cysteine using p-methoxybenzylamine (PMBCl) or triphenylmethylchloride (TrCl) in the presence of a base.

PMBCl or TrCl used in the reaction protection Tilney group, usually used in quantities of 1~5 EQ., preferably 1~2 EQ., relative to 1 EQ. cysteine. Apply the base is sodium hydroxide, potassium carbonate, etc. and it is usually used in quantities of 1~5 EQ., preferably 1~2 EQ., relative to 1 EQ. cysteine. This reaction can be carried out in an inert solvent selected from tetrahydrofuran, methanol, ethanol, water, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 0~50°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

Compound (48) can be obtained by protecting the amino group of compound (47) using group VOS.

Vos2Oh, used in the reaction for the protection of amino groups, typically used in quantities of 1~5 EQ., preferably 1~2 EQ., relative to 1 EQ. cysteine. Apply a base selected from, for example, hydroxides such as guide the oxide of sodium, the lithium hydroxide, etc., carbonates such as sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, etc. and organic bases such as diisopropylethylamine, triethylamine, etc., preferably potassium carbonate, triethylamine, etc. This reaction can be carried out in an inert solvent selected from tetrahydrofuran, methanol, ethanol, water, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 0~50°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

Compound (49) can be obtained by the method described in Helvetica Chimica Acta, 87, 2004, 3131-3159.

1 EQ. compound (48) is subjected to reaction with 1~2 EQ. ethylchloride (EtOCOCl) or isobutylphthalate (iBuOCOCl) in the solvent tetrahydrofuran maintained at room temperature, in the presence of 1~2 EQ. reason {for example, N-methylmorpholine (NMM), triethylamine etc.}, while receiving anhydrite connection. The resulting anhydrous compound is subjected to reaction with 1-5 EQ. diazomethane and 1~5 EQ. an aqueous solution of potassium hydroxide in a solvent diethyl ether maintained at 0°C, and then subjected to reaction with 0.1~2 EQ. ion Ag (for example, triptoreline silver (CF3CO2Ag), silver benzoate, etc.) and 1~10 EQ. Olkiluoto alcohol (e.g. methanol, ethanol etc) in the dark at room temperature, the floor is tea alkilany ester.

Response delete a group, VOS can be performed with the use of acid. Apply the acid includes hydrochloric acid, triperoxonane acid, etc. Acid is usually used in quantities of 1~10 EQ., preferably 2~5 EQ., relative to 1 EQ. connection (48). This reaction can be carried out in an inert solvent, for example, chosen from ethers such as tetrahydrofuran, diethyl ether, dioxane, etc., alilovic alcohols, such as methanol, ethanol, etc., chloroalkanes, such as dichloromethane, chloroform, etc. the reaction Temperature is usually in the range of -10~200°C, preferably 25~120°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

Connection (50) can be obtained from glutamic acid or aspartic acid by the method described in Synlett, 15, 2005, 2397-2399, Journal of Organic Chemistry, 66(5), 2001, 1919-1923, etc.

The compound (51) can be obtained by sulfonation of the compound (50). The reaction of sulfonation can be performed using methanesulfonanilide in the presence of organic bases such as pyridine, triethylamine, etc. Each of sulfurous agent and the base are used in amounts of 1~10 EQ., preferably 1~5 EQ., relative to 1 EQ. connection (50). This reaction can be carried out in an inert solvent selected from dichloromethane, dichloroethane, etc. the reaction Temperature is usually b is pointed in the range of -10~200°C, preferably 0~50°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

Compound (7) can be obtained by the reaction of p-methoxybenzylthio (PMBSH) with compound (51) in the presence of a base and removing groups VOS using acid. Apply the base is sodium hydride, potassium carbonate, cesium carbonate, etc., preferably sodium hydride. The base is usually used in quantities of 1~10 EQ., preferably 2~5 EQ., relative to 1 EQ. compounds (51). p-Methoxybenzylthio (PMBSH) is usually used in quantities of 1~10 EQ., preferably 2~5 EQ., relative to 1 EQ. compounds (51). This reaction can be carried out in an inert solvent selected from tetrahydrofuran, dimethylformamide, N-methylpyrrolidinone etc. the reaction Temperature is usually in the range of -10~200°C, preferably 25~100°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

The reaction for removal of the group VOS can be performed in the same way as deleting groups VOS, described in the production method of compound (49).

The reaction scheme 11

In the above reaction scheme (11)

but alkilany alcohol (e.g. methanol, ethanol), acetylchloride or thionyl chloride,

b is a di-tert-butyloxycarbonyl (Re2On), base (nab, the emer, NaOH, K2CO3),

c is a reducing agent (e.g., NaBH4),

d represents alkylcarboxylic (for example, tert-BUTYLCARBAMATE (tBuCOCl), base (e.g., Et3N),

e represents an acid,

R9 represents C1-C6-alkyl,

R11 represents a p-MeOBn or Ph3C, and

R14 represents a C1-C6-alkyl.

Compound (52) can be obtained by esterification of the carboxyl group of the compound (47) and the protection of the amino group of the BOC. The esterification reaction can be carried out with the use of acetylchloride or thionyl chloride in a solvent Akilova alcohol. Acetylchloride or thionyl chloride is used in quantities of 1~10 EQ., preferably 1~5 EQ., relative to 1 EQ. compound (47). The reaction temperature is usually in the range of 25~200°C, preferably 25~100°C, and the reaction time is usually in the range of 10 min~60 h, preferably 10 min~12 hours

The reaction of the protection of the amino group can be performed in the same manner as the production method of compound (48).

The compound (20) can be obtained from the starting compound (52) by sequentially recovery ester groups, protection of the alcohol group and removal of the BOC. The reduction of the ester group can be carried out by reaction with alkylchlorosilanes (for example, ethylchloride is, isobutylparaben) in the solvent tetrahydrofuran at room temperature in the presence of 1~5 EQ. base (e.g. triethylamine, diisopropylethylamine, N-methylmorpholine and so on) to obtain the anhydride, which is then subjected to reaction with 1~5 EQ. of lithium borohydride or sodium borohydride in an aqueous solution of tetrahydrofuran at 0~25°C for 10 min~12 hours

The response of the protection of the alcohol group can be carried out by reaction with alkylcarboxylic, for example, t-BuCOCl in the solvent dichloromethane at 0~25°C in the presence of 1~5 EQ. base selected from triethylamine, pyridine, etc. for 10 min~12 hours

Response delete a group, VOS can be carried out by dissolving the reagent in an inert solvent selected from tetrahydrofuran, dioxane, ethyl acetate, dichloromethane, etc. and the reaction with 1~10 EQ. hydrochloric acid or triperoxonane acid at 0~50°C for 10 min~12 hours

Compounds, methods of production which are not specifically described in the present description, are known per se or can be obtained from known compounds according to known method or a similar method.

The compounds of formula (1)obtained by the above methods can be isolated from the reaction product or to clean a variety of ways, such as recrystallization, iontophoresis, column chromatography on silica gel, ion the exchange chromatography, etc.

As indicated above, the compounds according to the present invention, the starting materials, intermediate products, etc. for their production can be obtained in various ways, and we must assume that such methods of obtaining compounds of formula (1) are within the scope of the present invention.

[Activity]

The present invention further relates to a pharmaceutical composition for activating glucokinase, which contains compounds of the formula (1), their pharmaceutically acceptable salts or isomers as an active ingredient together with pharmaceutically acceptable carriers.

Diseases caused by deactivation of glucokinase or which can be prevented or treated by the pharmaceutical composition of the present invention, include, but are not limited to, diabetes, complications of diabetes, obesity, etc. Pharmaceutical composition of the present invention can be used to prevent or treat type 1 diabetes or type 2 diabetes and particularly preferably of type 2 diabetes. Complications from diabetes can be prevented or treated by the pharmaceutical composition of the present invention, include, but are not limited to, hyperlipidemia, hypertension, retinas, renal failure, etc.

The present invention further relates to hipoglicemia eskay composition, which contains compounds of the formula (1), their pharmaceutically acceptable salts or isomers as an active ingredient together with pharmaceutically acceptable carriers.

The present invention further relates to a method for producing a pharmaceutical composition for activating glucokinase, more specifically, for the prevention or treatment of diabetes, complications of diabetes or obesity, which includes a step of mixing the compounds of formula (1), their pharmaceutically acceptable salts or isomers as the active ingredient with pharmaceutically acceptable carriers.

The above “pharmaceutical composition” or “hypoglycemic composition may contain pharmaceutically acceptable carriers, diluents, excipients or combinations thereof, if necessary, together with the compounds of the present invention. The pharmaceutical composition facilitates the introduction of the compound in a living organism. There are several ways of introducing connections, and they include, but are not limited to, oral, injection, aerosol, parenteral and local introduction.

Used in context, the term “carrier” means a substance that facilitates the incorporation of compounds into cells or tissues. For example, dimethylsulfoxide (DMSO) is a typical media used to facilitate entered the I various organic compounds in cells or tissues of living organisms.

Used in the context of the term “diluent” is defined as a substance that is diluted with water, which dissolves the connection, and which stabilizes the biologically active form of the considered connection. As diluents in this area apply salt dissolved in the buffer solution. Commonly used buffer solution is a phosphate buffered saline solution, which mimics a physiological fluid of a person. Buffer diluents rarely alter the biological activity of the compounds, whereas the buffer salts to adjust the pH of the solution at low concentration.

Used in context, the term “pharmaceutically acceptable” means a property that does not impair the biological activity and physical properties of the compound.

Compounds of the present invention can be applied in various types, used in pharmaceutical dosage forms according to the purpose of use. Upon receipt of the pharmaceutical compositions of the present invention the active ingredient, in particular, the compounds of formula (1), their pharmaceutically acceptable salts or isomers mixed with various pharmaceutically acceptable carriers that can be selected according to the obtained product. For example, the pharmaceutical composition of the present invention can be spotovi the ü in the form of injectable preparation, oral drug etc. according to the purpose of use.

Preparations of the compounds of the present invention can be manufactured by methods known in this field, which is used pharmaceutical carriers and excipients known in this field, and can be included in the container for the dosage form or forms of many doses. Form of the medication can be solutions, suspensions or emulsions in oily or aqueous medium, which may contain the usual dispersing agents, suspendresume agents or stabilizers. In addition, the drug can be, for example, in the form of a dry powder, which is supposed to restore dissolved in sterile pyrogen-free water before use. Compounds of the present invention can also be used in preparations in the form of suppositories, which apply the usual bases for suppositories, such as cocoa butter or other glycerides. As solid dosage forms for oral administration can be produced capsules, tablets, pills, powders and granules, especially applicable are capsules and tablets. Pills and tablets preferably manufactured in the form of covered intersolubility shell. Solid dosage forms can be obtained by mixing the compounds of the present invention with the media, for example, one or n is the number of diluents, such as sucrose, lactose, starch, etc., lubricating agents such as magnesium stearate, dezintegriraat substance, a binder, etc.

If necessary, the compounds of the present invention or containing pharmaceutical compositions can also type in combination with other active agents, for example, other agents for the treatment of diabetes.

The dose of the compounds of formula (1) depends on the prescription of a physician, considering factors such as body weight or age of the patient, the specific nature of the disease and the severity of the disease, etc. But the dose required for treatment of an adult patient, usually from about 1 to 500 mg per day, depending on the efficiency and frequency of administration. With the introduction of the adult patient by intramuscular or intravenous routes total dose is usually from about 5 to 300 mg per day will be sufficient when introduced separately as a single dose, but for some patients it may be desirable higher daily dose.

The present invention further relates to a method for prevention or treatment of diseases caused by deactivation of glucokinase, by applying an effective amount of compounds of formula (1), their pharmaceutically acceptable salts or isomers as the active ingredient.

The present invention dal is relates to a method for producing a pharmaceutical composition for the prevention or treatment of diseases, caused by deactivation of glucokinase, which contains the stage of mixing the compounds of formula (1), their pharmaceutically acceptable salts or isomers as the active ingredient with pharmaceutically acceptable carriers.

Used in context, the term “treatment” means the termination or delay of disease development in the application for the subject, which manifests the beginning of symptoms, and the term “prevention” means the termination or delay of symptom onset of the disease when applied to the subject, who do not manifest such symptoms, but there is a risk of the onset of symptoms.

The present invention will be described more specifically by the following receipts and examples. However, it should be clear that they are intended to illustrate the present invention but in no way to limit the scope of the present invention. The following receipts and examples, M means molar concentration, and N. mean normal concentration.

[Best mode for carrying out the invention]

Getting 1: synthesis of ethyl ester of 2-[(4-fluoro-2-nitrophenyl)hydrazono]propionic acid

Ethyl ester of 2-[(4-fluoro-2-n is trienyl)hydrazono]propionic acid

4-fluoro-2-nitroaniline (10 g, 64 mmol) was dissolved in 6 N. hydrochloric acid (64 ml, 0.27 mol)is slowly added dropwise to the solution at 0°C was added sodium nitrate (4.4 g, 64 mmol)dissolved in water (50 ml)and the mixture was stirred for 30 min at a temperature of 0°C~room temperature. Simultaneously ethyl-2-methylacetoacetate (9,2 ml, 64 mmol) and sodium hydroxide (19 g, 0.34 mol) was dissolved in 80% aqueous ethanol (95 ml) and the solution was stirred for 10 min at 0°C. the thus Obtained two solutions were mixed and stirred for 8 h at a temperature of 0°C~room temperature. To the reaction solution were added water and the insoluble solid was collected. The solid is washed with water and dried, thus obtaining specified in the title compound (7.9 g, yield 46%).

1H NMR (400 MHz, CDCl3); δ 10,81 (user. c, 1H), with 8.05 (m, 1H), of 7.90 (m, 1H), 7,41 (m, 1H), 4,36 (square, 2H), 2,22 (s, 3H), of 1.38 (t, 3H).

Getting 2: synthesis of ethyl ester of 5-fluoro-7-nitro-1H-indole-2-carboxylic acid

Ethyl ester of 5-fluoro-7-nitro-1H-indole-2-carboxylic acid

The compound (8.8 g, 33 mmol), obtained in the obtaining 1, was mixed with polyphosphoric acid (50 ml) and the mixture was stirred for 7 h at 60°C. To the reaction is th solution was added water and the insoluble solid was collected. The solid is washed with water and dried, thus obtaining specified in the title compound (3.4 g, yield 41%).

1H NMR (400 MHz, DMSO-d6); δ 11,55 (user. c, 1H), 8,16 (m, 1H), 8,10 (m, 1H), 7,42 (s, 1H), 4,40 (square, 2H), of 1.36 (t, 3H).

Getting 3: synthesis of hydrochloride (4-chloro-2-nitrophenyl)hydrazine

(4-Chloro-2-nitrophenyl)hydrazine

4-Chloro-2-nitroaniline (40 g, 0.23 mol) was dissolved in 12 N. hydrochloric acid (100 ml). At 0°C slowly, dropwise to the solution was added sodium nitrate (16 g, 0.23 mol)dissolved in water (50 ml)and the mixture was stirred for 30 min at a temperature of 0°C~room temperature. The temperature was lowered to 0°C. and to the mixture slowly, dropwise, was added tin chloride (II) (132 g, 0.70 mol), dissolved in 12 N. hydrochloric acid (100 ml). The mixture was stirred for 3 hours at a temperature of 0°C~room temperature. The resulting yellow solid was separated by filtration, washed with a small amount of 6 N. HCl and dried, thus obtaining specified in the title compound (30 g, yield 63%).

1H NMR (400 MHz, DMSO-d6); δ of 9.21 (s, 1H), 7,98 (d, J=2.4 Hz, 1H), 7,66 (d, J=9.6 Hz, 1H), 7,55 (DD, J=2,4, 9.6 Hz, 1H), 4,74 (user. s, 2H).

Getting 4: synthesis of methyl ester of 2-[(4-chloro-2-nitrophenyl)hydrazono]pianoboy acid

Methyl ester 2-[(4-chloro-2-nitrophenyl)hydrazono]propionic acid

Hydrazine (30 g, 0.14 mol), obtained in the obtaining 3, and methylpiruvate (14.4 ml, 0.16 mol) was dissolved in methanol (300 ml) and to the solution was added sodium acetate (14.2 g, to 0.17 mol). The mixture was stirred for 8 h at room temperature. The resulting yellow solid was separated by filtration, washed with water and methanol and dried, thus obtaining specified in the title compound (30 g, yield 82%).

1H NMR (400 MHz, CDCl3); δ 10,88 (c, 1H), 8,21 (d, J=2.4 Hz, 1H), 8,01 (d, J=9,2 Hz, 1H), 7,56 (DD, J=2,4, and 9.2 Hz, 1H), 3,90 (s, 3H), of 2.23 (s, 3H).

Mass spectrum (ESI, m/z): calculated for C10H10ClN3O4271,04 found 271,66.

Getting 5: synthesis of methyl ester of 5-chloro-7-nitro-1H-indole-2-carboxylic acid

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

To the compound (13 g, 46 mmol), obtained in the obtaining 4, was added polyphosphoric acid (100 ml), the mixture then was heated at 100°C for 4 hours After completion of the reaction to the reaction solution were added water and the insoluble solid is the second substance was collected. The solid is washed with water and dried, thus obtaining specified in the title compound (6.0 g, yield 49%).

1H NMR (400 MHz, CDCl3); δ 10,32 (user. s, 1H), 8,29 (d, 1H), 8,03 (d, J=2.4 Hz, 1H), 7,31 (d, J=2.0 Hz, 1H), 4,01 (s, 3H).

Mass spectrum (ESI, m/z): calculated 254,01 found 254,63.

Getting 6: synthesis of methyl ester of 5-bromo-7-nitro-1H-indole-2-carboxylic acid

Methyl ester of 5-bromo-7-nitro-1H-indole-2-carboxylic acid

4-Bromo-2-nitroaniline (15.6 g, to 71.9 mmol) was subjected to reaction according to the same methods as in the receive 3-5, while receiving specified in the title compound (7.2 g, yield 73%).

1H NMR (400 MHz, CDCl3); δ 10,33 (user. s, 1H), to 8.41 (s, 1H), 8,18 (s, 1H), 7,30 (d, J=4.0 Hz, 1H), 4,01 (s, 3H).

Getting 7: synthesis of methyl ester of 5-methyl-7-nitro-1H-indole-2-carboxylic acid

Methyl ester 5-methyl-7-nitro-1H-indole-2-carboxylic acid

4-Methyl-2-nitroaniline (40 g, 0.26 mol) was subjected to reaction according to the same methods as in the receive 3-5, while receiving specified in the title compound (20 g, yield 32%).

1H NMR (500 MHz, DMSO-d6); δ 1,25 (user. s, 1H), 8,08 (3, 1H), of 7.96 (s, 1H), 7,32 (s, 1H), a 3.87 (s, 3H), of 2.44 (s, 3H).

Getting 8: synthesis of methyl ester of 7-nitro-1H-indole-2-carboxylic acid

Methyl ester of 7-nitro-1H-indole-2-carboxylic acid

2-Nitroaniline (30 g, 0.21 mol) was subjected to reaction according to the same methods as in the receive 3-5, while receiving specified in the title compound (11 g, yield 23%).

1H NMR (500 MHz, DMSO-d6); δ 11,36 (user. s, 1H), 8,23 (d, 1H), 8,17 (d, 1H), 7,42 (s, 1H), 7,32 (m, 1H), 3,88 (s, 3H).

9: synthesis of methyl ester of 5-methoxy-7-nitro-1H-indole-2-carboxylic acid

Methyl ester of 5-methoxy-7-nitro-1H-indole-2-carboxylic acid

4-Methoxy-2-nitrophenylamino (30 g, 0.18 mol) was subjected to reaction according to the same methods as in the receive 3-5, while receiving specified in the title compound (12 g, yield 27%).

10: synthesis of 4-ethoxy-2-nitrophenylamino

4-Ethoxyphenylurea4 Ethoxy--nitrophenylamino

4-Ethoxyaniline (40 g, 0.29 mol) and triethylamine (61 ml, 0.44 mol) was dissolved in dichloromethane (200 ml). Dropwise to the solution was added acetic anhydride (30 ml, 0.32 mmol) and the mixture was stirred for 1 h at a temperature of 0°C~room temperature. To the mixture was added 1 n hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate.

The resulting derived ndimethylacetamide was dissolved in dichloromethane (200 ml) and added dropwise at 0°C. to the solution was added fuming nitric acid (13 ml, 0.29 mol). The mixture was stirred for 1 h at a temperature of 0°C~room temperature. Was added a saturated aqueous solution of sodium bicarbonate and the mixture was extracted with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate.

The formed nitrate compound was dissolved in methanol (100 ml) and tetrahydrofuran (100 ml) and added dropwise to the solution was added 6 n sodium hydride. The mixture was stirred for 6 h at room temperature. After completion of the reaction, the reaction solution was neutralized to approximately pH 7 using 6 n hydrochloric acid and was extracted with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and dried over b is wodnym magnesium sulfate, while receiving specified in the title compound (44 g, yield 83%).

Obtaining 11: synthesis of methyl ester 5-ethoxy-7-nitro-1H-indole-2-carboxylic acid

Methyl ester 5-ethoxy-7-nitro-1H-indole-2-carboxylic acid

4 Ethoxy-2-nitroaniline (40 g, 0.22 mol), obtained in the obtaining 10 were subjected to reaction according to the same methods as in the receive 3-5, while receiving specified in the title compound (13 g, yield 22%).

1H NMR (400 MHz, DMSO-d6); δ 10,20 (user. s, 1H), 7,86 (s, 1H), 7,51 (s, 1H), 7,26 (s, 1H), 4,13 (m, 2H), 3,98 (s, 3H), 1,47 (m, 3H).

Obtaining 12: synthesis of methyl ester of 7-nitro-5-phenoxy-1H-indole-2-carboxylic acid

Methyl ester of 7-nitro-5-phenoxy-1H-indole-2-carboxylic acid

4-Aminophenylamino simple ether (20 g, 0.11 mol) was subjected sequentially to the reaction according to the same methods as in getting 10 and receive 3-5, while receiving specified in the title compound (5 g, yield 15%).

1H NMR (400 MHz, CDCl3); δ 10,26 (user. s, 1H), with 8.05 (s, 1H), 7,69 (s, 1H), 7,39 (m, 2H), 7,26 (s, 1H), 7,15 (m, 1H), 7,01 (m, 2H), 4.00 points (s, 3H).

13: synthesis of these the new ester of 7-nitro-5-(pyridine-3-yloxy)-1H-indole-2-carboxylic acid

Ethyl ester of 7-nitro-5-(pyridine-3-yloxy)-1H-indole-2-carboxylic acid

(Stage 1)

1-Chloro-4-nitrobenzene (40 g, 0.25 mol) and 3-hydroxypyridine (36 g, 0.38 mol) was dissolved in N,N-dimethylformamide (100 ml). To the solution was added potassium carbonate (52,6 g, 0.38 mol) and the mixture was stirred for 20 h at 100°C. To the reaction solution were added water and then extracted it with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate, thus obtaining 3-(4-nitrophenoxy)pyridine.

Thus obtained compound was dissolved with water (100 ml), tetrahydrofuran (100 ml) and methanol (100 ml). To the solution was added iron powder (103 g of 1.84 mol) and ammonium chloride (99 g of 1.84 mol) and the mixture was stirred using a mechanical stirrer for 3 h at 80°C. After completion of the reaction, the reaction solution was filtered through celite, washed with methanol and concentrated. The formed solid substance was separated by filtration, washed with simple ether and dried, thus obtaining 4-(pyridine-3-yloxy)phenylamine (17 g, yield 36%).

(Stage 2)

Ethyl ester of 7-nitro-5-(pyridine-3-yloxy)-1H-indole-2-carboxylic acid

4-(Pyridine-3-yloxy)phenylamine (25 g, of 0.13 mol), obtained in stage 1 were subjected to reaction according to the same methods as in getting 10 and receive 3-5, while receiving specified in the header connection (4,2 g, yield 10%).

1H NMR (400 MHz, CDCl3); δ 10,32 (user. s, 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 (square, 2H), 1,47 (t, 3H).

Obtaining 14: synthesis of methyl ester of 5-(4-methysulfonylmethane)-7-nitro-1H-indole-2-carboxylic acid

Methyl ester 5-(4-methysulfonylmethane)-7-nitro-1H-indole-2-carboxylic acid

(Stage 1)

1-Chloro-4-nitrobenzene (15 g, 95 mmol) and 4-(methylmercapto)phenol (13.3 g, 95 mmol) was dissolved in dimethyl sulfoxide (100 ml). To the solution was added potassium carbonate (15,8 g, 134 mmol) and the mixture was stirred for 12 h at 100°C. After completion of the reaction was added to excess water, while receiving the precipitated solid. A solid substance was separated by filtration and dried, thus obtaining 1-(4-methylsulfinylphenyl)-4-nitrobenz the L.

Thus obtained compound was dissolved in dichloromethane (500 ml). To the solution was added mCPBA (3-chloroperbenzoic acid) (83 g, 330 mmol) and the mixture was stirred for 2 hours at a temperature of 0°C~room temperature. After completion of the reaction was added to excess aqueous 6 n sodium hydroxide solution and the mixture was extracted with ethyl acetate and dichloromethane. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate, thus obtaining 1-(4-methylsulfinylphenyl)-4-nitrobenzene (28 g, yield 100%).

(Stage 2)

4-(4-Methysulfonylmethane)phenylamine

1-(4-Methylsulfinylphenyl)-4-nitrobenzene (28 g)obtained in stage 1, was dissolved in methanol (500 ml) and ethyl acetate (500 ml). To the solution was added 10% Pd/C (1.0 g) and the mixture was stirred for 3 h in an atmosphere of hydrogen gas under normal pressure. After completion of the reaction, the reaction solution was filtered through celite, washed with methanol, concentrated and dried, thus obtaining 4-(4-methysulfonylmethane)phenylamine (25 g, yield 100%).

(Stage 3)

4-(4-Methysulfonylmethane)phenylamine (25 g, 95 mmol) was subjected R. the shares according to the same methods, both get 10 and receive 3-5, while receiving specified in the title compound (0.9 g, yield of 2.4%).

Obtaining 15: synthesis of methyl ester hydrochloride (R)-3-amino-4-(4-methoxybenzenesulfonyl)butyric acid

Methyl ester of (R)-3-amino-4-(4-methoxybenzenesulfonyl)butyric acid

(Stage 1)

(R)-2-Amino-3-(4-methoxybenzenesulfonyl)propionic acid

To a solvent mixture of diethyl ether (400 ml) and conc. hydrochloric acid (400 ml) was added dropwise within 2 h 4-methoxybenzyloxy alcohol (280 g, 1780 mmol)dissolved in diethyl ether (400 ml)and the mixture was stirred for 1 h the Organic layer was separated and added to a solution obtained by dissolving L-cysteine (197 g, 1625 mmol), and 2 N. aqueous sodium hydroxide solution (980 ml) in ethanol (1890 ml). The mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction solution was cooled to 0°C. and neutralized to pH 7 using 3 N. aqueous solution of hydrochloric acid. The formed solid substance was separated by filtration and the left the house taking, thus the (R)-2-amino-3-(4-methoxybenzenesulfonyl)propionic acid (250 g, 1035 mmol, yield 64%).

(Stage 2)

(R)-2-tert-butoxycarbonylamino-3-(4-methoxybenzenesulfonyl)propionic acid

Connection (30,7 g, RUB 127.3 mmol)obtained in stage 1, was dissolved in tetrahydrofuran (150 ml) and water (150 ml). To the solution was added potassium carbonate (26,4 g, 190 mmol) and di-tert-butyloxycarbonyl (27.7 g, RUB 127.3 mmol) and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove tetrahydrofuran. The residue was cooled to 0°C and acidified to pH 3 using 3 N. aqueous solution of hydrochloric acid. The resulting solid was washed with water and dried, thus obtaining (R)-2-tert-butoxycarbonylamino-3-(4-methoxybenzenesulfonyl)propionic acid (43 g, 126 mmol, yield 99%).

(Stage 3)

tert-Butyl ester[(R)-3-diazo-1-(4-methoxybenzenesulfonyl)-2-oxopropyl]carbamino acid

Compound (43 g), obtained in stage 2, 1 methylmorpholin (14,5 ml, 13 mmol) and ethylchloride (14.1 ml, 132 mmol) was dissolved in tetrahydrofuran (500 ml) and was stirred for 1 h at -25°C. Simultaneously, the potassium hydroxide (75 g, 1336 mmol) was dissolved in water (75 ml) and diethyl ether (750 ml)to the solution dropwise over 2 h at 0°C was added N-methylnitrosamino (26 g, 252 mmol) and the mixture was stirred for 30 minutes thus Obtained two solutions were mixed and stirred for 3 h at 25°C~room temperature. After completion of the reaction was added water and the mixture is then washed with a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of ammonium chloride. The organic layer was concentrated, thus obtaining tert-butyl ester [(R)-3-diazo-1-(4-methoxybenzenesulfonyl)-2-oxopropyl]carbamino acid.

1H NMR (400 MHz, CDCl3); δ is 7.25 (d, J=8,8 Hz, m, 2H), 6,86 (d, J=8,8 Hz, 2H), 5,48 (user. s, 1H), from 5.29 (m, 1H), or 4.31 (m, 1H), 3,79 (s, 3H), of 3.69 (s, 2H), was 2.76 (d, J=6.0 Hz, 2H), 1,45 (s, 9H).

(Stage 4)

Methyl ester of (R)-3-tert-butoxycarbonylamino-4-(4-methoxybenzenesulfonyl)butyric acid

The compound obtained in stage 3, was dissolved in methanol (1000 ml), the solution was added silver benzoate (7,1 g, and 31.1 mmol) and the mixture was treated with ultrasound for 1 h After the head is Rhenia reaction, the reaction solution was concentrated and separated column chromatography, thus the methyl ester of (R)-3-tert-butoxycarbonylamino-4-(4-methoxybenzenesulfonyl)butyric acid (35.2 g, to 95.3 mmol, yield 76%).

1H NMR (500 MHz, CDCl3); δ from 7.24 (d, J=8.6 Hz, 2H), 6,83 (d, J=8.6 Hz, 2H), 5,09 (m, 1H), 4,08 (m, 1H), 3,79 (s, 3H), 3,68 (s, 2H), 3,66 (s, 3H), 2,70~2,52 (m, 4H), of 1.44 (s, 9H).

(Stage 5)

Connection (35.2 g)obtained in stage 4, was dissolved in dichloromethane (70 ml), to the solution was added a solution of 4 N. hydrochloric acid/1,4-dioxane (71 ml) and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction solution was concentrated. To the residue was added dichloromethane (30 ml) and diethyl ether (150 ml)and the formed solid substance was separated by filtration and dried, thus obtaining specified in the header connection (25,5 g, and 83.3 mmol, yield 87%).

1H NMR (400 MHz, DMSO-d6); δ 8,21 (user. s, 3H), 7,25 (d, 2H), 6,83 (d, 2H), of 3.78 (s, 3H), 3,68 (s, 2H), the 3.65 (s, 3H), 3,29 (m, 1H), of 2.51-2,48 (m, 2H), 2,35-2,31 (m, 2H).

Obtaining 16: synthesis of the hydrochloride of the ethyl ester of (R)-3-amino-4-(4-methoxybenzenesulfonyl)butyric acid

Ethyl ester of (R)-3-amino-4-(4-methoxybenzenesulfonyl)butyric acid

L-Cysteine (50 g, 0.41 mol) was subjected to reaction according to the same procedure as in obtaining 15, excluded the eat that ethanol was used instead of methanol in stage 4 get 15, while receiving specified in the title compound (5.2 g, yield 40%).

1H NMR (400 MHz, CDCl3); δ of 8.37 (user. c, 3H), 7,28 (d, J=8.0 Hz, 2H), 6.87 in (d, J=8.0 Hz, 2H), 4,11 (m, 2H), of 3.73 (s, 3H), 3,70 (s, 2H), 2,81~to 2.67 (m, 4H), of 1.18 (t, 3H).

Obtaining 17: synthesis of ethyl ester hydrochloride (R)-4-amino-5-(4-methoxybenzenesulfonyl)pentanol acid

Ethyl ester of (R)-4-amino-5-(4-methoxybenzenesulfonyl)pentanol acid

(Stage 1)

Ethyl ester of (R)-4-tert-butoxycarbonylamino-5-hydroxypentanal acidEthyl ester of (R)-4-tert-butoxycarbonylamino-5-methysulfonylmethane acid

Ethyl ester of (R)-4-tert-butoxycarbonylamino-5-hydroxypentanal acid (36 g, 137,8 mmol), which can be obtained in a known manner, and triethylamine (38,4 ml, 275,5 mol) was dissolved in dichloromethane (200 ml). Dropwise to the solution was added methanesulfonamide (11.7 ml, 151,5 mmol) and the mixture was stirred for 1 h at a temperature of 0°C~room temperature. To it was added 1 n solution of chlorine is stevedorage acid and the mixture was extracted with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate, thus obtaining the ethyl ester of (R)-4-tert-butoxycarbonylamino-5-methysulfonylmethane acid.

(Stage 2)

Ethyl ester of (R)-4-tert-butoxycarbonylamino-5-(4-methoxybenzenesulfonyl)
pentanol acid

Sodium hydride (5.5 g, 137,8 mmol) and 4-methoxybenzylamine (15,4 ml, 110,2 mmol) was dissolved in N,N-dimethylformamide (150 ml) and the solution was stirred for 10 min at 0°C. To the thus obtained solution was added dropwise methanesulfonate obtained in stage 1. The mixture was stirred for 4 h at 0°C. After completion of the reaction was added water and the reaction solution was extracted with ethyl acetate. The extract was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and were divided by column chromatography, thus obtaining the ethyl ester of (R)-4-tert-butoxycarbonylamino-5-(4-methoxybenzenesulfonyl)pentanol acid (21,0 g, yield 38%).

1H NMR (400 MHz, CDCl3); δ is 7.25 (d, J=8,8 Hz, 2H), 6,85 (d, J=8,8 Hz, 2H), 4,56 (m, 1H), 4,12 (m, 2H), 3,79 (s, 3H), of 3.69 (s, 2H), 2,53 (m, 2H), 2,33 (t, 2H), 1.93 and (m, 1H), 1,70 (m, 1H), of 1.44 (s, 9H), 1,25 (t, 3H).

(Stage 3)

Connect the s (11 g, 62,7 mmol), obtained in stage 2, was dissolved in dichloromethane (200 ml) and to the solution was added a solution of 4 N. hydrochloric acid/ethyl acetate (20 ml). The mixture was stirred for 2 h at room temperature. After completion of the reaction, the reaction solution was concentrated and thereto was added diethyl ether (150 ml). The formed solid substance was separated by filtration and dried, thus obtaining specified in the title compound (20 g, yield 96%).

1H NMR (400 MHz, DMSO-d6); δ 8,69 (user. s, 3H), 7,29 (d, J=8.0 Hz, 2H), 6.89 in (d, J=8.0 Hz, 2H), 4,08 (m, 2H), 3,74 (m, 5H), 3,26 (m, 1H), was 2.76~2,63 (m, 2H), 2.49 USD~to 2.40 (m, 2H), 1,89 (m, 2H), 1,20 (t, 3H).

Obtaining 18: synthesis of (R)-2-amino-3-(4-methoxybenzenesulfonyl)propyl ether of 2,2-dimethylpropionic acid

(R)-2-Amino-3-(4-methoxybenzenesulfonyl)propyl ether of 2,2-dimethylpropionic acid

(Stage 1)

Methyl ester of (R)-2-amino-3-(4-methoxybenzenesulfonyl)propionic acid

The compound (50 g, 207,2 mmol)obtained in stage 1 receiving 15, was dissolved in methanol (300 ml). According to plan to the solution was added acetylchloride (21 ml, 207,2 mmol) and the mixture was stirred for 12 h at 50°C. After completion of the reaction, the reaction solution was concentrated, was added diethyl ether. The formed solid substance was separated by filtration and dried, thus obtaining methyl ester (R)-2-amino-3-(4-methoxybenzenesulfonyl)propionic acid.

1H NMR (400 MHz, DMSO-d6, HCl salt)δ 8,81 (user. s, 3H), 7,29 (d, J=8,4 Hz, 2H), 6,91 (d, J=8,4 Hz, 2H), 4,28 (m, 1H), 3,18 (user. s, 8H), 2.95 and (m, 2H).

(Stage 2)

Methyl ester of (R)-2-tert-butoxycarbonylamino-3-(4-methoxybenzenesulfonyl)propionic acid

The compound obtained in stage 1, was dissolved in tetrahydrofuran (200 ml) and water (200 ml). To the solution was added triethylamine (87 ml, 621,6 mmol), and stirring was added dropwise di-tert-butyloxycarbonyl (43,0 g, 196,8 mmol)dissolved in tetrahydrofuran (100 ml). The mixture was stirred for 8 h at room temperature. After completion of the reaction to the reaction solution was added water, and the solution was then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate, thus the methyl ester of (R)-2-tert-butoxycarbonylamino-3-(4-methoxybenzenesulfonyl)impregnated the new acid.

(Stage 3)

tert-Butyl ester [(R)-2-hydroxy-1-(4-methoxybenzenesulfonyl)ethyl]-carbamino acid

The compound obtained in stage 2, was dissolved in tetrahydrofuran (300 ml). To the solution was added borohydride lithium (9.0 g, 414,4 mmol) and the mixture was stirred for 3 h at 0°C. After completion of the reaction was added water, and the reaction solution was extracted with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate, while receiving tert-butyl ester [(R)-2-hydroxy-1-(4-methoxybenzenesulfonyl)ethyl]carbamino acid

1H NMR (500 MHz, DMSO-d6); δ from 7.24 (d, J=8.6 Hz, 2H), at 6.84 (d, J=8.6 Hz, 2H), 4,96 (user. s, 1H), of 3.78 (s, 3H), 3,76 (user. s, 1H), 3,70 (s, 2H), 3,7~3,66 (m, 3H), 2,58 (m, 2H), of 1.44 (s, 9H).

(Stage 4)

(R)-2-tert-Butoxycarbonylamino-3-(4-methoxybenzenesulfonyl)propyl ether of 2,2-dimethylpropionic acid

The compound obtained in stage 3, was dissolved in dichloromethane (300 ml). To the solution was added triethylamine (58 ml, 414,4 mmol) and trimethylacetylchloride (28 ml, 227,9 mmol) and the mixture was stirred during the 6 h at 0°C. After completion of the reaction was added water and the reaction solution was extracted with ethyl acetate. The extract was washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and were divided by column chromatography, thus obtaining (R)-2-tert-butoxycarbonylamino-3-(4-methoxybenzenesulfonyl)propyl ether of 2,2-dimethylpropionic acid (81,0 g, yield 95%).

1H NMR (400 MHz, CDCl3); δ is 7.25 (d, J=8,8 Hz, 2H), 6,85 (d, J=8,8 Hz, 2H), 4,71 (m, 1H), 4,11 (m, 2H), 3,79 (s, 3H), 3,70 (s, 2H), by 2.55 (d, J=6,4 Hz, 2H), of 1.52 (s, H)of 1.27 (s, 9H).

(Stage 5)

Compound (81 g, 196 mmol), obtained in stage 4, was dissolved in dichloromethane (300 ml), the solution was added a solution of 4 N. hydrochloric acid/1,4-dioxane (100 ml) and the mixture was stirred for 8 h at room temperature. After completion of the reaction, the reaction solution was concentrated and added to diethyl ether. The formed solid substance was separated by filtration and dried, thus obtaining specified in the title compound (68 g, yield 95%).

1H NMR (400 MHz, DMSO-d6free form)δ from 7.24 (d, J=12.0 Hz, 2H), 6,85 (DD, J=4,0, 8.0 Hz, 2H), Android 4.04 (m, 1H), 3,95 (m, 1H), 3,80 (s, 3H), 3,68 (s, 2H), 3,10 (m, 1H), 2,60 (m, 1H), a 2.36 (m, 1H), 1,18 (s, 9H).

Obtaining 19: synthesis of (R)-2-(7-amino-1H-indol-2-yl)-4,5-dihydrothieno-4-Eletropaulo ether of 2,2-dimethylpropionic acid

(R)-2-(7-Amino-1H-indol-2-yl)-4,5-dihydrothieno-4-ymetray ether of 2,2-dimethylpropionic acid

(Stage 1)

Methyl-7-nitroindole-2-carboxylate (13 g, 59 mmol), obtained in the obtaining 8, was dissolved in solvent mixture of tetrahydrofuran and water (1:1, 300 ml) and to the solution was added 1 N. aqueous sodium hydroxide solution (180 ml, 177 mmol). The mixture was stirred for 3 h at room temperature, was added an excess of 6 n hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure, thus obtaining 7-nitro-1H-indole-2-carboxylic acid (12 g, yield 99%).

(Stage 2)

(R)-3-(4-methoxybenzenesulfonyl)-2-[(7-nitro-1H-indole-2-carbonyl)amino]propyl ether of 2,2-dimethylpropionic acid

The compound 7-Nitroindole-1H-carboxylic acid (8.2 g, 22.7 mmol), obtained in stage 1, and aminosidine (13,2 g of 27.2 mmol)obtained in the obtaining 18, was dissolved in N,N-dimethylformamide (100 ml) and to the solution was added EDC (6.6 g, 25,mmol) and NOT (4.6 g, 25,0 mmol). The mixture was stirred for 8 h at room temperature and the solution was added a saturated solution of sodium bicarbonate. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure, concentrated and the residue was purified column chromatography, thus obtaining (R)-3-(4-methoxybenzenesulfonyl)-2-[(7-nitro-1H-indole-2-carbonyl)amino]propyl ether of 2,2-dimethylpropionic acid (8.1 g, yield 71%).

1H NMR (400 MHz, CDCl3); δ 10,47 (user. s, 1H), 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), of 4.44 (m, 1H), 4,24 (m, 1H), 3,74 (m, 5H), 2,77 (m, 1H), 2,62 (m, 1H), 1,18 (s, 9H).

(Stage 3)

(R)-2-(7-nitro-1H-indol-2-yl)-4,5-dihydrothieno-4-ymetray ether of 2,2-dimethylpropionic acid

The compound (1.6 g, 3.2 mmol)obtained in stage 2, was dissolved in dichloromethane (50 ml). To the solution was added pentachloride phosphorus (1.3 g, 6.4 mmol) and the mixture was stirred for 5 h at room temperature. After completion of the reaction, to the mixture was added a saturated solution of sodium bicarbonate. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled at ponie nom pressure, concentrated and the residue was purified column chromatography, thus obtaining (R)-2-(7-nitro-1H-indol-2-yl)-4,5-dihydrothieno-4-ymetray ether of 2,2-dimethylpropionic acid (0.8 g, yield 69%).

1H NMR (400 MHz, CDCl3); δ 10,53 (user. s, 1H), compared to 8.26 (d, J=8.0 Hz, 1H), to 7.99 (d, J=8.0 Hz, 1H),? 7.04 baby mortality (d, J=2.0 Hz, 1H), make 6.90 (d, J=7,6 Hz, 1H), 4,78 (m, 1H), 4,46 (m, 1H), 4,30 (m, 1H)and 3.59 (m, 1H), 3,36 (m, 1H), 1,20 (s, 9H).

(Stage 4)

(R)-2-(7-amino-1H-indol-2-yl)-4,5-dihydrothieno-4-ymetray ether of 2,2-dimethylpropionic acid

The compound (2.7 g, 7.5 mmol), obtained in stage 3, was dissolved in solvent mixture of tetrahydrofuran, methanol and water (1:1:1, 150 ml). Added iron powder (4,2 g, to 74.7 mmol) and ammonium chloride (4.0 g, to 74.7 mmol) and the mixture was stirred for 30 min at 60°C with the use of mechanical stirrers. After completion of the reaction, to the mixture was added water. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (2.0 g, yield 81%).

1H NMR (400 MHz, CDCl3); δ 9,86 (user. s, 1H), 7,30 (d, J=7,6 Hz, 1H), 7,14 (d, J=8.0 Hz, 1H), 6.89 in (d, J=2.0 Hz, 1H), is 6.61 (DD, J=0,8, 7.2 Hz, 1H), 4,96 (m, 1H), 4,36 (m, 2H), 3,55 (m, 1H), 3.33 and (m, 1 is), of 1.18 (s, 9H).

20: synthesis of (R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-Eletropaulo ether of 2,2-dimethylpropionic acid

(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-ymetray ether of 2,2-dimethylpropionic acid

The compound (2.0 g, 5.0 mmol)obtained in the obtaining 19, was dissolved in 1,2-dichloroethane (100 ml). To the solution was added Cyclopentanone (0.8 g, 7.5 mmol) and triacetoxyborohydride sodium (1.9 g, 7.5 mmol) and the mixture was stirred for 8 h at room temperature. After completion of the reaction, to the mixture was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure, and the residue was purified column chromatography, thus obtaining specified in the title compound (1.3 g, yield 54%).

Example 1: synthesis of [(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]methanol

[(R)-2-(7-Cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol

The compound (1.3 g, 3.3 mmol)obtained in the obtaining 20, was dissolved in tetrahydrofuran 10 ml), methanol (10 ml) and water (10 ml). To the solution was added a hydrate of lithium hydroxide (0.4 g, 9.8 mmol) and the mixture was stirred for 4 h at room temperature. The reaction solution was concentrated by distillation under reduced pressure. To the residue was added 1 N. hydrochloric acid and the mixture was then extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (820 mg, yield 80%).

1H NMR (500 MHz, CDCl3); δ 11,17~11,08 (m, 1H), to 7.09 (m, 1H), 6,99 (t, 1H), of 6.96 (s, 1H), of 6.52 (m, 1H), 4.72 in (m, 1H), Android 4.04 (m, 1H), 3,75 (m, 1H), 3,65 (m, 1H), 3,51 (m, 1H), 3,40 (m, 1H), 1,90 (m, 2H), 1,60~for 1.49 (m, 4H), 1,41~1,24 (m, 2H).

Mass spectrum (ESI, m/z): calculated 315,14 found 315,44.

Example 2: synthesis of {(R)-2-[7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

{(R)-2-[7-(Tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

(Stage 1)

(R)-2-[7-(Tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-ymetray ether of 2,2-dimethylpropionic acid

The compound (900 mg, 2.7 mmol), obtained in the obtaining 19, was dissolved in 1,2-dichloroethane (100 ml). To the solution was added tetrahydro-4H-Piran-4-one (0.8 ml, 8,13 mmol), triacetoxyborohydride sodium (1,72 g, 8,13 mmol) and acetic acid (0,47 ml, 8,13 mmol) and the mixture was stirred for 48 h at room temperature. After completion of the reaction, the reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining (R)-2-[7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-ymetray ether of 2,2-dimethylpropionic acid.

1H NMR (400 MHz, CDCl3); δ 10,91 (user. s, 1H), 7,01~6,91 (m, 3H), 6.48 in (d, J=7.2 Hz, 1H), a 4.86 (m, 1H), 4,34 (m, 2H), 4.00 points (m, 2H), 3,61 (m, 1H), 3,54 (m, 3H), and 3.31 (m, 1H), 2.05 is (m, 2H), 1.55V (m, 2H), 1,16 (s, 9H).

(Stage 2)

The compound obtained in stage 1, was dissolved in methanol (32 ml), tetrahydrofuran (32 ml) and water (16 ml). To the solution was added 1 n sodium hydroxide (7 ml) and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure was extracted with dichloromethane, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filter the Wali. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (700 mg, yield 78%).

1H NMR (500 MHz, CDCl3); δ 11,04~10,95 (m, 1H), 7,11 (m, 1H), 6,99 (t, 1H), of 6.96 (s, 1H), of 6.52 (m, 1H), 4,74 (m, 1H), was 4.02 (m, 1H), 3,92 (m, 2H), 3,68 (m, 1H), 3.46 in~3,30 (m, 5H), at 1.91 (m, 2H), 1.28 (in m, 2H).

Mass spectrum (ESI, m/z): calculated 331,14 found 331,44.

Example 3: synthesis of {(R)-2-[7-(tetrahydrofuran-3-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

{(R)-2-[7-(Tetrahydrofuran-3-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}-methanol

The compound (940 mg, 2.9 mmol)obtained in the obtaining 19, and tetrahydrofuran-3-he used instead of tetrahydro-4H-Piran-5-she was subjected to reaction according to the same procedure as in example 2, thus obtaining specified in the title compound (650 mg, yield 69%).

1H NMR (500 MHz, CDCl3); δ of 10.58 (user. s, 1H), 7,14 (d, J=7,95 Hz, 1H), 7,00 (m, 1H), 6,94 (m, 1H), 6.48 in (d, J=7,35 Hz, 1H), 4,79 (m, 1H), 4,15~3,95 (m, 3H), 3,90~the 3.65 (m, 4H), 3,50~3,39 (m, 2H), measuring 2.20 (m, 1H)and 1.83 (m, 1H).

Example 4: synthesis of {(R)-2-[7-(1-methanesulfonanilide-3-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

{(R)-2-[7-(1-Methanesulfonanilide-3-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

(Stage 1)

tert-Butyl ether 3-{2-[(R)-4-(2,2-dimethylphenylacetic)-4,5-dihydrothieno-2-yl]-1H-indole-7-ylamino}pyrrolidin-1-carboxylic acid

The compound (1.0 mg, 3.0 mmol)obtained in the obtaining 19, and tert-butyl methyl ether 3-oxopyrrolidin-1-carboxylic acid (1.1 g, 6.0 mmol)is used instead of tetrahydro-4H-Piran-5-she was subjected to reaction according to the same procedure as in stage 1 of example 2, thus obtaining the derived pyrrolidine (853 mg, yield 57%).

(Stage 2)

(R)-2-[7-(1-Methanesulfonanilide-3-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-ymetray ether of 2,2-dimethylpropionic acid

The compound (460 mg, 0.9 mmol), obtained in stage 1, was dissolved in methanol (50 ml) and to the solution was added a 4 n solution of hydrochloric acid (0.8 ml, 2.7 mmol). The mixture was stirred for 8 h at room temperature, distilled under reduced pressure and was purified column chromatography.

Thus obtained compound (313 mg, 0.8 mmol) races shall varali in dichloromethane (50 ml). Was added triethylamine (158 mg, 1.6 mmol) and methanesulfonamide (90 mg, 0.8 mmol) and the mixture was stirred for 30 min at a temperature of 0°C~room temperature. After completion of the reaction to the reaction solution was added water, the solution then was extracted with dichloromethane, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining sulfonamidnuyu compound (223 mg, yield 58%).

(Stage 3)

The compound (223 mg, 0.47 mmol)obtained in stage 2, were subjected to reaction according to the same procedure as in example 1, thus obtaining specified in the title compound (152 mg, yield 82%).

1H NMR (500 MHz, CDCl3); δ 10,50 (user. s, 1H), 7,15 (d, J=7,95 Hz, 1H), 7,00 (DD, 1H), 6,93 (s, 1H), 6,46 (d, J=7,35 Hz, 1H), 4,77 (m, 1H), 4,18 (m, 1H), 4,08 (DD, 1H), 3,75 (DD, 1H), 3,59~to 3.36 (m, 6H), of 3.48 (s, 3H), and 2.27 (m, 1H), 1,95 (m, 1H).

Getting 21: synthesis of (R)-2-[7-amino-5-fluoro-1H-indol-2-yl]-4,5-dihydrothiazolo-4-Eletropaulo ether of 2,2-dimethylpropionic acid

(R)-2-[7-Amino-5-fluoro-1H-indol-2-yl]-4,5-dihydrothiazolo-4-ymetray ether of 2,2-dimethylpropionic acid

Ethyl-5-fluoro-7-nitro-1H-indole-2-carboxylate (6.0 g, to 23.8 mmol), the floor is built in the receiving 2, was subjected to reaction according to the same procedure as in obtaining 19, while receiving specified in the title compound (2.3 g, yield 28%).

Example 5: synthesis of [(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol

[(R)-2-(7-Cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol

Aminosidine (1.1 g, 3.1 mmol), obtained in the obtaining 21 were subjected to reaction according to the same methods as in obtaining 20 and example 1, thus obtaining specified in the title compound (600 mg, yield 58%).

1H NMR (400 MHz, CDCl3); δ of 10.73 (user. s, 1H), 6,91 (s, 1H), 6,72 (m, 1H), 6,33 (m, 1H), 4,78 (m, 1H), 4,12 (m, 1H), 3,97 (user. s, 1H), 3,79 (m, 1H), 3,75 (m, 1H), 3,49 (m, 2H), 2,01 (m, 2H), 1,62 (m, 4H), of 1.41 (m, 2H).

Example 6: synthesis of {(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

Aminosidine (1.1 g, 3.1 mmol), obtained in the obtaining 21, was subjected to reaction according to the same procedure as in example 2, thus obtaining specified in the title compound (750 m is, yield 68%).

1H NMR (400 MHz, CDCl3); δ 10,45 (user. s, 1H), 6.90 to (s, 1H), 6.75 in (m, 1H), 6,34 (m, 1H), 4,82 (m, 1H), 4,12 (m, 1H), 4,01 (m, 2H), 3,94 (m, 1H), 3,78 (m, 1H), 3,54~of 3.43 (m, 5H), 2,03 (m, 2H), 1,50 (m, 2H).

Example 7: synthesis of [(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol

[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol

(Stage 1)

(R)-2-(7-amino-5-chloro-1H-indol-2-yl)-4,5-dihydrothieno-4-ymetray ether of 2,2-dimethylpropionic acid

Methyl-5-chloro-7-nitro-1H-indole-2-carboxylate (3.0 g, to 11.8 mmol)obtained in the obtaining 5, were subjected to reaction according to the same procedure as in example 19, while receiving aminosidine (2.4 g, yield 56%).

(Stage 2)

Aminosidine (150 mg, 0.4 mmol), obtained in stage 1 were subjected to reaction according to the same methods as in obtaining 20 and example 1, thus obtaining specified in the title compound (50 mg, yield 36%).

1H NMR (500 MHz, CDCl3); δ 10,53 (user. s, 1H), 7,24 (s, 1H), at 6.84 (d, 1H), 6,45 (s, 1H), 4,74 (m, 1H), 4,06 (m, 1H), 3,81 (m, 1H), 3,71 (m, 1H), of 3.45 (DD, 2H), 1,99 (m, 2H), 1,60 (m, 4H), to 1.37 (m, 2H).

Example 8: synthesis of {(R)-2-[5-chloro--(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

{(R)-2-[5-Chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

Aminosidine (150 mg, 0.4 mmol), obtained in stage 1 of example 7 was subjected to reaction according to the same procedure as in example 2, thus obtaining specified in the title compound (40 mg, yield 27%).

Example 9: synthesis of {(R)-2-[5-chloro-7-(tetrahydrothiopyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

{(R)-2-[5-Chloro-7-(tetrahydrothiopyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

Aminosidine (150 mg, 0.4 mmol), obtained in stage 1 of example 7, and tetrahydrothiopyran-4-one, used instead of tetrahydro-4H-Piran-4-she was subjected to reaction according to the same procedure as in example 2, thus obtaining specified in the title compound (130 mg, yield 85%).

1H NMR (400 MHz, CDCl3); δ 10,87 (user. s, 1H), 7,01 (s, 1H), 6.89 in (s, 1H), 6,40 (s, 1H), 4,80 (m, 1H), 4,10 (m, 1H), 3,80 (m, 1H), 3,50 (m, 2H), 3,32 (m, 1H), was 2.76 (m, 4H), to 2.29 (m, 2H), and 1.56 (m, 2H).

Example 10: synthesis of [(R)-2-(5-bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol

[(R)-2-(5-Bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol

Methyl-5-bromo-7-nitro-1H-indole-2-carboxylate (1.3 g, 4.3 mmol), obtained in the obtaining 6 were subjected sequentially to the reaction according to the same methods as in obtaining 19, 20 and example 1, thus obtaining specified in the title compound (100 mg, yield 6%).

1H NMR (400 MHz, CDCl3); δ 10,59 (user. s, 1H), 7.23 percent (s, 1H), to 6.88 (s, 1H), only 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), of 1.65 (m, 4H), of 1.41 (m, 2H).

Example 11: synthesis of {(R)-2-[5-bromo-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

{(R)-2-[5-Bromo-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

Methyl-5-bromo-7-nitro-1H-indole-2-carboxylate (1.3 g, 4.3 mmol), obtained in the obtaining 6 were subjected sequentially to the reaction according to the same methods as in getting 19 and example 2, thus obtaining specified in the title compound (70 mg, yield 4%).

1H NMR (400 MHz, CDCl3); δ 10,53 (user. s, 1H), 7,25 (s, 1H), 6.87 in (s, 1H), 6,63 (d, 1H), 4,80 (m, 1H), 4,14 (m, 1H), a 4.03 (m, 2H), 3,79 (m, 1H), 3,56-,3,44 (m, 4H), 2,02 (m, 2H), 1,45 (m, 2H).

Example 12: synthesis of [(R)-2-(7-what kilometraje-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol

[(R)-2-(7-Cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol

Methyl-5-methoxy-7-nitro-1H-indole-2-carboxylate (700 mg, 2.8 mmol)obtained in the obtaining 9, was subjected sequentially to the reaction according to the same methods as in obtaining 19, 20 and example 1, thus obtaining specified in the title compound (80 mg, yield 8%).

1H NMR (500 MHz, DMSO-d6); δ 11,23 (user. s, 1H), 6,60 (s, 1H), 6,23 (s, 1H), of 5.89 (m, 1H), of 5.84 (m, 1H), 4,96 (m, 1H)and 4.65 (m, 1H), of 3.77 (m, 1H), 3,70 (m, 1H), of 3.45 (m, 1H), 3.33 and (m, 1H), 3,29 (s, 3H), 1.91 a (m, 2H), 1,67 (m, 2H), 1,53 (m, 4H).

Example 13: synthesis of {(R)-2-[7-cyclopentylamine-5-(pyridine-3-yloxy)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

{(R)-2-[7-Cyclopentylamine-5-(pyridine-3-yloxy)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

Ethyl ester of 7-nitro-5-(pyridine-3-yloxy)-1H-indole-2-carboxylic acid (500 mg, 1.5 mmol)obtained in the obtaining 13, subjected sequentially to the reaction according to the same methods as in obtaining 19, 20 and example 1, thus obtaining specified in the title compound (35 mg, yield 6%).

1H NMR (400 MHz, CDCl3); the 11,16 (user. s, 1H), 8,42 (d, 1H), 8,28 (m, 1H), 7,30 (m, 1H), 7,22 (m, 1H), to 6.88 (s, 1H), to 6.67 (d, 1H), 6,28 (d, 1H), a 4.83 (m, 1H), was 4.02 (m, 1H), 3,75 (m, 2H), 3.46 in (m, 2H), of 1.97 (m, 2H), and 1.63 (m, 4H), USD 1.43 (m, 2H).

Example 14: synthesis of {(R)-2-[5-(pyridine-3-yloxy)-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

{(R)-2-[5-(Pyridine-3-yloxy)-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

Ethyl ester of 7-nitro-5-(pyridine-3-yloxy)-1H-indole-2-carboxylic acid (500 mg, 1.5 mmol)obtained in the obtaining 13, subjected sequentially to the reaction according to the same methods as in getting 19 and example 2, thus obtaining specified in the title compound (40 mg, yield 6%).

1H NMR (400 MHz, CDCl3); δ 10,96 (user. s, 1H), at 8.36 (d, J=2.4 Hz, 1H), compared to 8.26 (m, 1H), 7,27 (m, 1H), 7,19 (m, 1H), 6,83 (s, 1H), 6,63 (d, J=1.6 Hz, 1H), 6,24 (d, J=1.6 Hz, 1H), to 4.81 (m, 1H), 4,01~of 3.94 (m, 3H), of 3.75 (m, 1H), 3,47 (s, 3H), 3,48~3,29 (m, 5H), of 1.93 (m, 2H), of 1.52 (m, 2H).

Obtaining 22: synthesis of (R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-Eletropaulo ether methanesulfonate acid

(R)-2-(7-Cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-ymetray ether methanesulfonate acid

The compound (820 mg, 2.6 mmol)obtained in example 1 was dissolved in dichloromethane (50 ml). To the solution was added methanesulfonamide (of 0.24 ml, 3.1 mmol) and triethylamine (0,81 ml, 3.1 mmol) and the mixture was stirred for 30 min at 0°C. After completion of the reaction was added saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (600 mg, yield 60%).

Example 15: synthesis of cyclopentyl-[2-((R)-4-pyrrolidin-1-ylmethyl-4,5-dihydrothiazolo-2-yl)-1H-indol-7-yl]amine

Cyclopentyl-[2-((R)-4-pyrrolidin-1-ylmethyl-4,5-dihydrothiazolo-2-yl)-1H-indol-7-yl]amine

The compound (150 mg, 0.38 mmol)obtained in the obtaining 22, was dissolved in N,N-dimethylformamide (5 ml). To the solution was added pyrrolidine (of 0.08 ml, 1.1 mmol) and the mixture was stirred for 4 h at 70°C. After completion of the reaction was added water and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (20 mg, yield 14%).

1H NMR (400 MHz, DMSO-d6); δ 11,37 (user. s, 1H), 6,83 (m, 1H), 6.75 in (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), a 3.87 (m, 1H), 3,52 (m, 1H), 3.43 points (m, 1H), 3.33 and (m, 2H), 2,78 (m, 2H), 2,61 (m, 2H), 1,99 (m, 2H), 1,72 (m, 6H), to 1.60 (m, 4H).

Example 16: Synthesis of cyclopentyl-[2-((R)-4-morpholine-4-ylmethyl-4,5-dihydrothiazolo-2-yl)-1H-indol-7-yl]amine

Cyclopentyl-[2-((R)-4-morpholine-4-ylmethyl-4,5-dihydrothiazolo-2-yl)-1H-indol-7-yl]amine

The compound (150 mg, 0.38 mmol)obtained in the obtaining 22, and morpholine used instead of pyrrolidine, is subjected to reaction according to the same procedure as in example 15, while receiving specified in the title compound (50 mg, yield 34%).

1H NMR (400 MHz, DMSO-d6); δ 11,37 (user. s, 1H), 6,83 (m, 1H), 6.75 in (m, 1H), 6,29 (d, J=8.0 Hz, 1H), 5,85 (d, J=8.0 Hz, 1H), 4,87 (m, 1H), a 3.87 (m, 1H), 3,61 (m, 4H), to 3.35 (m, 3H), 2,71 (m, 1H), 2,54 (m, 2H), 2,44 (m, 2H), 1,99 (m, 2H), 1,74 (m, 6H), to 1.59 (m, 4H).

Example 17: synthesis of cyclopentyl-[2-((R)-4-dimethylaminomethyl-4,5-dihydrothiazolo-2-yl)-1H-indol-7-yl]amine

Cyclopentyl-[2-((R)-4-dimethylaminomethyl-4,5-dihydrothiazolo-2-yl)-1H-indol-7-yl]amine

The compound (150 mg, 0.38 mmol)obtained in the obtaining 22,and dimethylamine, used instead of pyrrolidine, were subjected to reaction according to the same procedure as in example 15, while receiving specified in the title compound (20 mg, yield 15%).

1H NMR (400 MHz, CDCl3); δ 9,87 (user., 1H), 7,05 (d, J=8.0 Hz, 1H), 6,99 (t, 1H), 6.89 in (s, 1H), of 6.52 (d, J=8.0 Hz, 1H), a 4.83 (m, 1H), 3,91 (m, 1H), 3,50 (t, 1H), 3,29 (t, 1H), 2.63 in (m, 1H), 2,44 (m, 1H), to 2.29 (s, 6H), 2,04 (m, 2H), 1.70 to (m, 2H), 1,50 (m, 4H).

Example 18: synthesis of 2-[2-((R)-4-hydroxymethyl-4,5-dihydrothiazolo-2-yl)-1H-indole-7-ylamino]propionic acid

2-[2-((R)-4-Hydroxymethyl-4,5-dihydrothiazolo-2-yl)-1H-indole-7-ylamino]propionic acid

The compound obtained in the obtaining 19, and methylpiruvate subjected sequentially to the reaction according to the same methods as in obtaining 20 and example 1, thus obtaining specified in the header of the connection.

1H NMR (400 MHz, CDCl3); δ 11,16 (m, 1H), 10,43 (user., 1H),? 7.04 baby mortality (m, 1H), 7,00 (m, 1H), 6,97 (m, 1H), 6,53 (m, 1H), 4,74 (m, 1H), 4,14 (m, 1H), of 4.05 (m, 1H), of 3.77 (m, 1H), only 3.57 (m, 1H), 3,42 (m, 1H), USD 1.43 (d, 3H).

Example 19: Synthesis of {(R)-2-[7-(4-nitrophenylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

The compound obtained in the obtaining 19, and 4-ftorirovannom were subjected to reaction in the presence of a base Cs2CO3according to the same procedure to the to in example 15, while receiving specified in the header of the connection.

1H NMR (400 MHz, CDCl3); δ of 11.15 (user., 1H), a 7.85 (d, 2H),? 7.04 baby mortality (m, 1H), 6,97 (m, 1H), of 6.96 (m, 1H), 6,65 (d, 2H), 6,53 (m, 1H), 4,73 (m, 1H), 4,10 (m, 1H), 3,78 (m, 1H), 3,52 (m, 1H), 3,38 (m, 1H).

23: synthesis of 1-tert-butyl ester-2-methyl ester 5-methyl-7-nitroindole-1,2-dicarboxylic acid

1-tert-Butyl ether-2-methyl ester 5-methyl-7-nitroindole-1,2-dicarboxylic acid

Connection (24,0 g, 100 mmol), obtained in the obtaining 7, was dissolved in dichloromethane (500 ml). To the solution was added triethylamine (84 ml, 601 mmol) and 4-(dimethylamino)pyridine (600 mg, 5 mmol) and was added dropwise di-tert-butyloxycarbonyl (43,7 g, 200 mmol)dissolved in dichloromethane (100 ml). The mixture was stirred for 8 h at room temperature. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, washed with a saturated solution of sodium chloride and dried over anhydrous sodium sulfate, while receiving specified in the header connection (34,0 g, yield 100%).

1H NMR (500 MHz, CDCl3); δ 7,80 (s, 1H), to 7.67 (s, 1H), 7,15 (s, 1H), 3,93 (s, 3H), of 2.51 (s, 3H), of 1.62 (s, 9H).

Obtaining 24: synthesis of 1-tert-butyl ester-2-methyl ester 5-methyl bromide-7-nitroindole-1,2-dicarboxylic acid

1-tert-Butyl ether-2-methyl ester 5-methyl bromide-7-nitroindole-1,2-dicarboxylic acid

Compound (34 g, of 101.7 mmol)obtained in the obtaining 23, was dissolved in carbon tetrachloride (100 ml). To the solution was added N-bromosuccinimide (27,2 g, 152,6 mmol) and AIBN (1.7 g, 10.2 mmol) and the mixture was stirred for 5 h at 80°C. After completion of the reaction, the reaction solution was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the header connection (48,0 g, yield 100%).

1H NMR (500 MHz, CDCl3); δ 8,01 (s, 1H), of 7.90 (s, 1H), 7,21 (s, 1H), 4,60 (s, 2H), 3,93 (s, 3H), of 1.62 (s, 9H).

Obtaining 25: synthesis of 1-tert-butyl-2-methyl ester 5-acetoxymethyl-7-nitroindole-1,2-dicarboxylic acid

1-tert-Butyl-2-methyl ester 5-acetoxymethyl-7-nitroindole-1,2-dicarboxylic acid

The compound (10.0 g, and 24.2 mmol)obtained in the obtaining 24, was dissolved in N,N-dimethylformamide (50 ml). To the solution was added sodium acetate (2.4 g, 29,0 mmol) and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the reaction restoreregistry under reduced pressure. Added water and the mixture was extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and purified column chromatography, thus obtaining specified in the title compound (4.7 g, yield 50%).

1H NMR (500 MHz, CDCl3); δ to 7.99 (s, 1H), of 7.90 (s, 1H), 7,21 (s, 1H), 5,22 (s, 2H), of 3.94 (s, 3H), 2,12 (s, 3H), and 1.63 (s, 9H).

Receiving 26: synthesis of methyl ester of 5-acetoxymethyl-7-nitro-1H-indole-2-carboxylic acid

Methyl ester 5-acetoxymethyl-7-nitro-1H-indole-2-carboxylic acid

The compound (4.7 g, 12,0 mmol)obtained in the obtaining 25, was dissolved in dichloromethane (50 ml). To the solution was added 2 n hydrochloric acid (30 ml, 60 mmol) and the mixture was stirred for 12 h at room temperature and distilled under reduced pressure, thus obtaining specified in the title compound (3.5 g, yield 100%) as a solid.

1H NMR (500 MHz, CDCl3); δ 10,33 (user. s, 1H), 8,32 (s, 1H), of 8.06 (s, 1H), 7,34 (s, 1H), 5,24 (s, 2H), 3,99 (s, 3H), 2,12 (s, 3H).

Receive 27: synthesis of 5-hydroxymethyl-7-nitro-1H-indole-2-carboxylic acid

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

The compound (3.5 g, 12,0 mmol)obtained in the obtaining 26, was dissolved in a solvent mixture of tetrahydrofuran, methanol and water (1:1:1, 100 ml). To the solution was added a hydrate of lithium hydroxide (1.5 g, or 35.9 mmol) and the mixture was stirred for 3 h at room temperature. After distillation of the mixture under reduced pressure, to the residue was added 1 N. hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (2.3 g, yield 81%).

1H NMR (500 MHz, DMSO-d6); δ 11,02 (user. s, 1H), 8,21 (s, 1H), 8,10 (s, 1H), 7,34 (s, 1H), 5,43 (user. s, 1H), with 4.64 (s, 2H).

Receive 28: synthesis of (R)-2-[(5-hydroxymethyl-7-nitro-1H-indole-2-carbonyl)amino]-3-(4-methoxybenzenesulfonyl)propyl ether of 2,2-dimethylpropionic acid

(R)-2-[(5-Hydroxymethyl-7-nitro-1H-indole-2-carbonyl)amino]-3-(4-methoxybenzenesulfonyl)propyl ether of 2,2-dimethylpropionic acid

Compound (2.2 g, 9.3 mmol), obtained in the obtaining 27, was subjected to reaction according to the same procedure as in stage 2 get 9, while receiving specified in the title compound (4.0 g, yield 84%).

Receiving 29: synthesis of (R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydrothieno-4-Eletropaulo ether of 2,2-dimethylpropionic acid

(R)-2-(5-Chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydrothieno-4-ymetray ether of 2,2-dimethylpropionic acid

The compound (1.0 g, 1.9 mmol)obtained in the obtaining 28, was dissolved in dichloromethane (30 ml). To the solution was added pentachloride phosphorus (0.8 g, 3.9 mmol) and the mixture was stirred for 6 h at room temperature. After completion of the reaction was added saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure, thus obtaining specified in the title compound (0.7 g, yield 90%).

1H NMR (500 MHz, CDCl3); δ 12,89 (user. s, 1H), 8,40 (s, 1H), 7,98 (s, 1H), 7,42 (s, 1H), and 5.30 (m, 1H), to 4.73 (s, 2H), br4.61 (m, 1H), 4,54 (m, 1H), 3,97 (m, 1H), 3,62 (m, 1H), 1,20 (s, 9H).

Example 20: synthesis of {(R)-2-[5-morpholine-4-ylmethyl-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

{(R)2-[5-Morpholine-4-ylmethyl-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

The compound obtained in the obtaining 29, morpholine and tetrahydropyran-4-one was subjected sequentially to the reaction according to the same procedures as in example 15, 20 and example 1, thus obtaining specified in the title compound (20 mg, yield 12%).

1H NMR (400 MHz, CDCl3); δ 10,77 (user. s, 1H), 7,06 (s, 1H), 6,95 (s, 1H), 6,62 (s, 1H), 4,80 (m, 1H), 4,11 (m, 1H), 3,99 (m, 2H), 3,76 (m, 1H), 3,75 (m, 4H), 3,51 (s, 2H), 3.45 points (m, 5H), of 2.51 (user. s, 4H), 2,00 (m, 2H), 1,45 (m, 2H).

Example 21: Synthesis of {(R)-2-[7-cyclopentylamine-5-pyrazole-1-ylmethyl-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

{(R)-2-[7-Cyclopentylamine-5-pyrazole-1-ylmethyl-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

(Stage 1)

(R)-2-(7-Nitro-5-pyrazole-1-ylmethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-ymetray ether of 2,2-dimethylpropionic acid

The compound (300 mg, 0.73 mmol)obtained in the obtaining 29, was dissolved in N,N-dimethylformamide (10 ml). To the solution was added potassium carbonate (300 mg, 2.2 mmol) and pyrazole (149 mg, 2.2 mmol) and the mixture was stirred for 1 h at room temperature. After completion of the reaction was added water, and the mixture extrage is ovali with ethyl acetate, was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure, thus obtaining a derivative of pyrazole (225 mg, yield 70%).

(Stage 2)

The compound (300 mg, of 0.68 mmol)obtained in stage 1, was subjected sequentially to the reaction according to the same methods as in stage 4 of receipt 19, 20 and example 1, thus obtaining specified in the title compound (42 mg, yield 24%).

1H NMR (500 MHz, CDCl3); δ 11,05 (user. s, 1H), 7,52 (s, 1H), 7,34 (s, 1H), 6,93 (s, 1H), 6.87 in (s, 1H), 6,34 (s, 1H), 6,23 (m, 1H), and 5.30 (s, 2H), 4,71 (m, 1H), 3,99 (m, 1H), 3,66 (m, 2H), 3,42 (m, 2H), to 1.86 (m, 2H), of 1.52 (m, 4H), 1.26 in (m, 2H).

Example 22: synthesis of [(R)-2-(7-cyclopentylamine-5-imidazol-1-ylmethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol

[(R)-2-(7-Cyclopentylamine-5-imidazol-1-ylmethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol

The compound (300 mg, 0.73 mmol)obtained in the obtaining 29, and imidazole instead of pyrazole was subjected to reaction according to the same procedure as in example 21, while receiving specified in the title compound (65 mg, yield 23%).

1H NMR (500 MHz, CDCl3); δ 11,10 (user. s, 1H), to 8.20 (s, 1H), 7,25 (s, 1H), 7.23 percent (s, 1H), 6.87 in (m, 2H), 6,16 (s, 1H), of 5.05 (s, 2H), 4,77 (m, 1H), 3.96 points (m, 1H), to 3.73 (m, 2H), 3.43 points (m, 2H), 1,92 (m, 2H), 1,59 (m, 4H), to 1.38 (m, 2H).

Example 23: synthesis of {(R)-2-[7-cyclopentylamine-5-(1H-pyrrol-3-ylmethyl)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

{(R)-2-[7-Cyclopentylamine-5-(1H-pyrrol-3-ylmethyl)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol

The compound (300 mg, 0.73 mmol)obtained in the obtaining 29, and pyrrole used instead of pyrazole was subjected to reaction according to the same procedure as in example 21, while receiving specified in the title compound (65 mg, 23%).

1H NMR (500 MHz, CDCl3); δ 11,04 (user. s, 1H), a 7.85 (s, 1H), to 6.88 (m, 2H), is 6.61 (s, 1H), 6,36 (s, 1H), 6,13 (m, 1H), 6,00 (s, 1H), 4,71 (m, 1H), Android 4.04 (m, 1H), 3,99 (s, 2H), 3,69 (m, 2H), of 3.45 (m, 2H), 1,90 (m, 2H), 1.55V (m, 4H), 1,32 (m, 2H).

Example 24: synthesis of [(R)-2-(7-cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol

[(R)-2-(7-Cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol

The compound (330 mg, 0.81 mmol)obtained in the obtaining 29, and methanesulfonate sodium used instead of pyrazole was subjected to reaction according to the same procedure as in example 21, while receiving specified in the title compound (152 mg, 46%).

1H NMR (500 MHz, CDCl3); δ 11,10 (user. s, 1H), 7,01 (s, 1H), to 6.88 (m, 1H), of 6.49 (s, 1H), amounts to 4.76 (m, 1H), 4.26 deaths (s, 2H), 3,99 (m, 1H), 3,79 (m, 1H), 3,68 (who, 1H), 3.43 points (m, 2H), by 2.73 (s, 3H), a 1.96 (m, 2H), 1.57 in (m, 4H), of 1.35 (m, 2H).

30: synthesis of (R)-2-{[5-(2,2-dimethylphenylacetic)-7-nitro-1H-indole-2-carbonyl]amino}-3-(4-methoxybenzenesulfonyl)propyl ether of 2,2-dimethylpropionic acid

(R)-2-{[5-(2,2-Dimethylphenylacetic)-7-nitro-1H-indole-2-carbonyl]-amino}-3-(4-methoxybenzenesulfonyl)-propyl ester of 2,2-dimethylpropionic acid

The compound (3.1 g, 6.0 mmol), obtained in the obtaining 28, was dissolved in dichloromethane (50 ml). To the solution was added triethylamine (1.2 g, 12,0 mmol) and pivaloate (0.8 g, 6.6 mmol) and the mixture was stirred for 8 h at 0°C. After completion of the reaction was added water, and the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (3.6 g, yield 98%).

1H NMR (400 MHz, CDCl3); δ 10,47 (user. s, 1H), of 8.27 (s, 1H), 8,01 (s, 1H), 7,27 (d, J=8.0 Hz, 2H), 6,92 (s, 1H), 6,83 (d, J=8.0 Hz, 2H), 6,76 (d, J=8.0 Hz, 1H), 5.25 in (s, 2H), 4,56 (m, 1H), 4,42 (m, 1H), 4,22 (m, 1H), 3,75 (s, 3H), 3,74 (, 2H), 2,82 (m, 1H), 2,69 (m, 1H), 1,25 (s, 9H), of 1.20 (s, 9H).

Getting 31: synthesis of (R)-2-[5-(2,2-dimethylphenylacetic)-7-nitro-1H-indol-2-yl]-4,5-dihydrothiazolo-4-Ismailovo what about the ether of 2,2-dimethylpropionic acid

(R)-2-[5-(2,2-Dimethylphenylacetic)-7-nitro-1H-indol-2-yl]-4,5-dihydrothiazolo-4-ymetray ether of 2,2-dimethylpropionic acid

The compound (3.6 g, 5.9 mmol), obtained in the obtaining 30, was subjected to reaction according to the same procedure as in stage 3 of receipt 19, while receiving specified in the title compound (2.0 g, yield 72%).

1H NMR (400 MHz, CDCl3); δ 12,91 (user. s, 1H), 8,35 (s, 1H), of 7.96 (s, 1H), 7,46 (s, 1H), 5.40 to (m, 1H), 5,23 (s, 2H), with 4.64 (m, 2H), 4.09 to (m, 1H), to 3.64 (m, 1H), 1.27mm (s, 9H), to 1.19 (s, 9H).

Obtaining 32: synthesis of (R)-2-[7-amino-5-(2,2-dimethylphenylacetic)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-Eletropaulo ether of 2,2-dimethylpropionic acid

(R)-2-[7-Amino-5-(2,2-dimethylphenylacetic)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-ymetray ether of 2,2-dimethylpropionic acid

The compound (2.0 g, 4.2 mmol), obtained in the obtaining 31, was subjected to reaction according to the same procedure as in stage 4 of receipt 19, while receiving specified in the title compound (1.0 g, yield 53%).

1H NMR (400 MHz, CDCl3); δ 10,08 (user. s, 1H), 7,26 (s, 1H), 6.87 in (s, 1H), 6,60 (s, 1H), 5,09 (s, 2H), 4.95 points (m, 1H), and 4.40 (m, 2H), to 3.58 m, 1H), the 3.35 (m, 1H), 1,20 (s, 9H), of 1.12 (s, 9H).

Example 25: synthesis of [7-cyclopentylamine-2-((R)-4-hydroxymethyl-4,5-dihydrothiazolo-2-yl)-1H-indol-5-yl]methanol

[7 Cyclopentylamine-2-((R)-4-hydroxymethyl-4,5-dihydrothiazolo-2-yl)-1H-indol-5-yl]methanol

The compound (100 mg, 0.22 mmol)obtained in the obtaining 34 were subjected to reaction according to the same methods as in obtaining 20 and example 1, thus obtaining specified in the title compound (10 mg, yield 13%).

1H NMR (400 MHz, CDCl3); δ 9,63 (user. s, 1H), 7,40 (s, 1H), 7,18 (s, 1H), 6.90 to (s, 1H), 4,80 (m, 1H), to 4.73 (s, 2H), 4,06 (m, 1H), 3,84 (m, 1H), 3,66 (m, 2H), 3,48 (m, 1H), and 3.31 (m, 1H), 1,79 (m, 2H), USD 1.43 (m, 4H), 1.26 in (m, 2H).

Receive 35: synthesis of 1-tert-butyl ester-2-ethyl ester 5-methyl bromide-7-nitroindole-1,2-dicarboxylic acid

1-tert-Butyl ether-2-ethyl ester 5-methyl bromide-7-nitroindole-1,2-dicarboxylic acid

(Stage 1)

Ethyl ester 5-methyl-7-nitro-1H-indole-2-carboxylic acid

4-Methyl-2-nitroaniline (20 g, 131 mmol who) was subjected to reaction according to the same methods, as in the receive 1 and receive 2, thus obtaining the ethyl ester of 5-methyl-7-nitro-1H-indole-2-carboxylic acid (16 g, yield 49%).

(Stage 2)

The compound (15.1 g, of 60.8 mmol)obtained in stage 1 were subjected to reaction according to the same methods as in getting 23 and receiving 24, while receiving specified in the title compound (6.3 g, yield 24%).

Receive 33: Synthesis of 5-chloro-7-nitro-1H-indolocarbazoles acid

5-Chloro-7-nitro-1H-indolocarbazole acid

The compound (15.0 g, 59,1 mmol)obtained in the obtaining 5, was dissolved in tetrahydrofuran (300 ml) and methanol (100 ml). The monohydrate of lithium hydroxide (7,43 g, 177 mmol) was dissolved in water (100 ml) and the solution was added to the reaction solution which was then stirred for 3 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove tetrahydrofuran and methanol. The residue was neutralized to a pH of about 6 with the use of 3 N. hydrochloric acid. The formed solid substance was separated by filtration and dried, thus obtaining specified in the title compound (13.1 g, yield 92%).

Receive 34: synthesis of methyl ester [(R)-2-(7-amino-5-chloro-1H-indol-2-yl-4,5-dihydrothiazolo-4-yl]acetic acid

Methyl ester [(R)-2-(7-amino-5-chloro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

(Stage 1)

Methyl ester of (R)-3-[(5-chloro-7-nitro-1H-indole-2-carbonyl)amino]-4-(4-methoxybenzenesulfonyl)butyric acid

Compound (12.5 g, with 52.0 mmol)obtained in the obtaining 33, and the connection of 19.1 g of 62.4 mmol)obtained in the obtaining 15, was dissolved in N,N-dimethylformamide (200 ml). To the solution was added triethylamine (8.7 ml of 62.4 mmol), NOT (14.0 g, 104 mmol) and EDC (16,9 g, to 88.4 mmol) and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the reaction solution was concentrated, extracted with ethyl acetate and washed using a saturated solution of sodium bicarbonate and a saturated aqueous solution of ammonium chloride, respectively. The organic layer was concentrated and separated column chromatography, thus obtaining methyl ester (R)-3-[(5-chloro-7-nitro-1H-indole-2-carbonyl)amino]-4-(4-methoxybenzenesulfonyl)butyric acid (20.2 g, 41,0 mmol, yield 79%).

1H NMR (500 MHz, CDCl3); δ 10,47 (user. s, 1H), 8,24 (d, J=1.9 Hz, 1H), of 7.96 (d, J=1.9 Hz, 1H), 7,24(d, J=8.6 Hz, 2H), 6.89 in (s, 1H), for 6.81 (d, J=8.6 Hz, 2H), 4,58 (m, 1H), 3,75 (s, 3H), of 3.73 (s, 2H), 3,71 (s, 3H), of 2.86 (m, 1H), 2,80 (m, 1H), 2,73 (m, 1H), 2,70 (m, 1H).

(Stage 2)

Methyl ester [(R)-2-(5-chloro-7-nitro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound obtained in stage 1, was dissolved in dichloromethane (200 ml). To the solution was added pentachloride phosphorus (17.1 g, 82 mmol) and the mixture was stirred for 1 h at room temperature. After completion of the reaction, the reaction solution was concentrated and added to diethyl ether (200 ml). The formed solid substance was separated by filtration and dried, thus obtaining methyl ester [(R)-2-(5-chloro-7-nitro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid.

1H NMR (500 MHz, CDCl3); δ 10,48 (user. s, 1H), they were 8.22 (d, J=1.8 Hz, 1H), 7,94 (d, J=1.8 Hz, 1H), 7,29 (d, J=8.6 Hz, 2H), of 6.96 (d, J=2.5 Hz, 1H), 6.89 in (d, J=8.6 Hz, 2H), 5,00 (m, 1H), 3,76 (s, 3H), 3,71 (m, 1H), 3,26 (m, 1H), 2,99 (m, 1H), to 2.67 (m, 1H).

(Stage 3)

Methyl ester [(R)-2-(7-amino-5-chloro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound obtained in stage 2, was dissolved in tetrahydrofuran (200 ml), methanol (200 ml) and water (00 ml). To the solution was added iron powder (22.9 g, 410 mmol) and ammonium chloride (21,9 g, 410 mmol) and the mixture was stirred for 1 h at 60°C with the use of mechanical stirrers. After completion of the reaction, to the mixture was added tetrahydrofuran (300 ml). The mixture was filtered through celite, washed with tetrahydrofuran (100 ml), distilled under reduced pressure and concentrated. The residue was extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (9.0 g, yield 68%).

Example 26: synthesis of methyl ester [(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (4.9 g, 15.1 mmol), obtained in the obtaining 34, was dissolved in dichloroethane (100 ml). To the solution was added Cyclopentanone (2.7 ml, 30.3 mmol), acetic acid (0,86 ml, 15.1 mmol) and triacetoxyborohydride sodium (6.42 per g, 30.3 mmol) and the mixture was stirred for 36 h at room temperature. After completion of the reaction actionnow the mixture was washed with a saturated aqueous solution of sodium bicarbonate (200 ml), concentrated and separated column chromatography, thus obtaining specified in the header connection (5,15 g, yield 87%).

1H NMR (DMSO-d6, ppm)δ 11,51 (s, 1H), 6,79 (s, 1H), 6,79 (s, 1H), 6,16 (s, 1H), 6,13 (d, 1H), around 4.85 (m, 1H), 3,80 (m, 1H), 3,62 (m, 1H), to 3.58 (s, 3H), 3,19 (m, 1H), 2,71 (m, 1H), 2.63 in (m, 1H), 1.93 and (m, 2H), 1.69 in (m, 2H), and 1.56 (m, 4H).

FAB-MS(m/e) = 392.

Example 27: synthesis of [(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (1.5 g, a 3.83 mmol)obtained in example 26 was dissolved in tetrahydrofuran (100 ml) and methanol (50 ml). The monohydrate of lithium hydroxide (640 mg, and 15.3 mmol) was dissolved in water (50 ml) and the solution was added to the reaction solution which was then stirred for 4 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove tetrahydrofuran and methanol. To the residue was added 1 n hydrochloric acid and the mixture was extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated colonoscopy because it allows the Noah chromatography, while receiving specified in the title compound (13.1 g, yield 92%).

1H NMR (DMSO-d6, ppm)δ 12,51 (user. s, 1H), 11,51 (s, 1H), 6,79 (s, 1H), 6,79 (s, 1H), 6,16 (s, 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 and (m, 2H), 1.69 in (m, 2H), and 1.56 (m, 4H).

FAB-MS (m/e) = 378.

Example 28: synthesis of ethyl ester [(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Ethyl ester [(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (4.5 g, to 18.7 mmol)obtained in the obtaining 33, the compound (6.3 g, of 19.7 mmol), obtained in the obtaining 16 were subjected to reaction according to the same methods as in getting 34 and example 26, while receiving specified in the title compound (840 mg, yield 11%).

1H NMR (500 MHz, CDCl3); δ 10,01 (user. s, 1H), 6,99 (s, 1H), 6,80 (s, 2H), to 6.43 (s, 1H), to 5.03 (m, 1H), 4,07 (square, 2H), 3,81 (m, 1H), to 3.64 (m, 1H), 3,21 (m, 1H), 2,81 (m, 1H), to 2.67 (m, 1H), 2,04 (m, 2H), 1,64 (m, 4H), for 1.49 (m, 2H), 1,20 (t, 3H).

Example 29: synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]ethanol

2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indole-yl)-4,5-dihydro-1,3-thiazol-4-yl]ethanol

The compound (550 mg, 1.4 mmol)obtained in example 26 was dissolved in tetrahydrofuran (50 ml). To the solution was added 1 M solution of lithium borohydride in tetrahydrofuran (2,11 ml, 2,11 mmol) and the mixture was stirred for 1 h with increasing reaction temperature from -60°C to 0°C. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated column chromatography, thus obtaining specified in the title compound (510 mg, yield 100%).

1H NMR (DMSO-d6, ppm)δ 11,47 (1H, s), 6,79 (1H, s), to 6.67 (1H, s), 6,11 (1H, s)6,09 (1H, m)and 4.65 (1H, t), of 4.54 (1H, m), 3,80 (2H, m), 3,61 (2H, m), 3,52 (1H, m)and 3.15 (1H, m), 2,47 (1H, m)of 1.97 (2H, m), 1,68 (2H, m), and 1.54 (4H, m).

FAB-MS (m/e) = 364.

Example 30: synthesis of methyl ester {(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

Methyl ester {(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

The compound (1.0 g, 3.1 mmol), obtained in the obtaining 34, was dissolved in 1,2-dichloroethane (100 ml). To the solution was added tetrahydro-4H-Piran-4-one (or 0.57 ml, 6,18 mmol), Tr is acetoxyvalerenic sodium (1.31 g, 6,18 mmol) and acetic acid (0.18 to ml, to 3.09 mmol) and the mixture was stirred for 24 h at room temperature. After completion of the reaction, the reaction solution was diluted with dichloromethane, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (0.5 g, yield 40%).

1H NMR (DMSO-d6, ppm)δ to 11.52 (1H, s), for 6.81 (1H, s)of 6.71 (1H, s), 6,28 (1H, s), 6,07 (1H, d), the 4.90 (1H, m), 3,86 (2H, m)to 3.64 (3H, s), 3,62 (2H, m), 3,44 (2H, t), 2,82-a 2.71 (2H, m), of 1.94 (2H, m)of 1.40 (2H, m).

FAB-MS (m/e) = 408.

Example 31: synthesis of {(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

{(R)-2-[5-Chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

The compound (400 mg, 1.0 mmol)obtained in example 30 was subjected to reaction according to the same procedure as in example 27, while receiving specified in the title compound (360 mg, yield 92%).

1H NMR (DMSO-d6, ppm)δ 12,43 (1H, s, of usher.), 11,53 (1H, s), for 6.81 (1H, s)of 6.71 (1H, s), 6,28 (1H, s), the 6.06 (1H, d), to 4.87 (1H, m), a 3.87 (2H, m), 3,62 (2H, m), 3,44 (2H, t), 3,19 (1H, m), 3,74 (1H, m), 2.63 in (1H, m), of 1.94 (2H, m)of 1.41 (2H, m).

FAB-MS (m/e) = 39.

Example 32: synthesis of 2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanol

2-{(R)-2-[5-Chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanol

Compound (2.5 g, 6.12 mmol)obtained in example 30 was subjected to reaction according to the same procedure as in example 29, while receiving specified in the header connection (2,19 g, USD 5.76 mmol, yield 94%).

1H NMR (DMSO-d6, ppm)δ of $ 11.48 (1H, s), for 6.81 (1H, s), of 6.68 (1H, s), 6,28 (1H, s), equal to 6.05 (1H, d), of 4.66 (1H, Quinn.), of 4.54 (1H, t), a 3.87 (2H, m), 3,61-of 3.54 (3H, m), 3,44 (2H, t)and 3.15 (1H, m), 1,99-of 1.93 (3H, m)of 1.73 (1H, m)of 1.40 (2H, m), 1,20 (1H, m).

FAB-MS (m/e) = 380.

Receive 35: synthesis of methyl ester [(R)-2-(7-amino-5-bromo-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(7-amino-5-bromo-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl-5-bromo-7-nitro-1H-indole-2-carboxylate (2.7 g, 9.0 mmol), obtained in the obtaining 6 were subjected to reaction according to the same methods as in obtaining 33 and receiving 34, while receiving specified in the title compound (585 mg, yield 18%).

Example 33: synthesis of [(R)-2-(5-bromo-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

[(R)-2-(5-Bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (340 mg, 0.9 mmol), obtained in the obtaining 35 were subjected to reaction according to the same procedures as in example 26 and example 27, while receiving specified in the title compound (250 mg, yield 66%).

1H NMR (400 MHz, CDCl3); δ 12,50 (user. s, 1H), 7,10 (see 1H), 7,06 (s, 1H), 6,56 (s, 1H), 5,31 (m, 1H), 3,89 (m, 2H), 3,40 (m, 1H), 2,99 (m, 1H), and 2.83 (m, 1H), 2,08 (m, 2H), to 1.86 (m, 2H), of 1.66 (m, 4H).

Example 34: synthesis of 2-[(R)-2-(5-bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]ethanol

2-[(R)-2-(5-Bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]ethanol

(Stage 1)

The compound (582 mg, was 1.58 mmol)obtained in the obtaining 35, was subjected to reaction according to the same procedure as in example 26, while receiving cyclopentanedione (430 mg, yield 62%).

(Stage 2)

The compound (150 mg, 0.34 mmol)obtained in stage 1, was dissolved in tetrahydrofuran (8 ml). To the solution was added borohydride lithium (15 mg, 0.69 mmol) and the mixture was stirred for 1 h at room temperature. After the end the of the reaction was added water. The mixture was extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated column chromatography, thus obtaining specified in the title compound (135 mg, yield 96%).

1H NMR (400 MHz, CDCl3); δ 10,42 (user. s, 1H), 7,18 (s, 1H), 6.87 in (s, 1H), 6,59 (d, 1H), 4,67 (m, 2H), was 4.02 (m, 2H), 3,91 (m, 1H), 3,63 (m, 1H), and 3.16 (t, 1H), 2,10 (m, 4H), of 1.74 (m, 2H), 1,4 (m, 4H).

Example 35: synthesis of {(R)-2-[5-bromo-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

{(R)-2-[5-Bromo-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

The compound (50 mg, 0.14 mmol)obtained in the obtaining 44 were subjected to reaction according to the same procedures as in example 30 and example 27, while receiving specified in the title compound (54 mg, yield 88%).

1H NMR (400 MHz, CDCl3); δ 7,07 (m, 2H), 6,50 (s, 1H), 5,10 (m, 1H), a 4.03 (m, 2H), 3,91 (m, 1H), 3,70-to 3.41 (m, 4H), 3,11 (m, 1H), and 2.83 (m, 2H), 2,52 (m, 1H), 2,04 (m, 2H), 1.69 in (m, 2H).

Example 36: Synthesis of 2-{(R)-2-[5-bromo-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanol

2-{(R)-2-[5-Bromo-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanol

The compound (50 mg, 0.14 mmol)obtained in the obtaining 35 were subjected to reaction according to the same procedures as in example 30 and stage 2 of example 34, while receiving specified in the title compound (35 mg, yield 59%).

1H NMR (400 MHz, CDCl3); δ 10,50 (user. s, 1H), 7,19 (s, 1H), 6.89 in (s, 1H), 6,59 (d, 1H), 4,67 (m, 2H), of 4.05 (m, 4H), 3,63 (m, 4H), 3,18 (t, 1H), 2,12 (m, 4H), of 1.64 (m, 4H).

Receive 36: synthesis of methyl ester [(R)-2-(7-amino-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(7-amino-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Ethyl-5-fluoro-7-nitro-1H-indole-2-carboxylate (2.3 g, 9.1 mmol), obtained in the obtaining 2 were subjected to reaction according to the same methods as in obtaining 33 and receiving 34, while receiving specified in the title compound (650 mg, yield 23%).

Example 37: synthesis of [(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

[(R)-2-(7-Cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydr is a thiazol-4-yl]acetic acid

The compound (361 mg, 1.2 mmol)obtained in the obtaining 36 were subjected to reaction according to the same procedures as in example 26 and example 27, while receiving specified in the title compound (189 mg, yield 44%).

1H NMR (400 MHz, CDCl3); δ 11,09 (user. s, 1H), 6.73 x (s, 1H), 6,45 (DD, 1H), 6,07 (DD, 1H), to 4.98 (m, 1H), 3,79 (m, 1H)and 3.59 (m, 1H), and 3.16 (m, 1H), and 2.79 (m, 1H), 2,60 (m, 1H), 1,96 (m, 2H), 1,71 (m, 2H), 1,58 (m, 4H).

Example 38: Synthesis of ethyl ester [(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Ethyl ester [(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (80 mg, 0.22 mmol)obtained in example 37 was dissolved in ethanol (2 ml). To the solution was added acetylchloride (0.1 ml) and the mixture was stirred for 8 h at room temperature. After completion of the reaction, the reaction solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate solution, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (50 mg, yield 58%).

1H NMR (400 MHz, CDCl3); δ 10,71 (user. s, 1H), 6,86 (s, 1H), only 6.64 (DD, 1H), 6,23 (DD 1H), 5,07 (m, 1H), 3,99 (square, 2H), 3,91 (m, 1H), 3,76 (m, 1H), to 3.64 (m, 1H), up 3.22 (m, 1H), 2,88 (m, 1H), 2,65 (m, 1H), 2,00 (m, 2H), and 1.63 (m, 4H), of 1.40 (m, 2H), 1,12 (t, 3H).

Example 39: synthesis of 2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanol

2-[(R)-2-(7-Cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanol

Compound (90 mg, 0.29 mmol)obtained in the obtaining 36 were subjected to reaction according to the same procedures as in example 26 and stage 2 of example 34, while receiving specified in the title compound (46 mg, yield 46%).

1H NMR (400 MHz, CDCl3); δ 10,90 (user. s, 1H), 6,91 (s, 1H), 6,65 (DD, 1H), of 6.26 (DD, 1H), and 4.68 (m, 1H), 4,08 (m, 2H), 3,88 (m, 1H), 3,62 (m, 1H), 3.15 in (t, 1H), 2,10 (m, 4H), of 1.74 (m, 2H), 1,62 (m, 4H).

Example 40: synthesis of {(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

Connection (852 mg, 2.8 mmol)obtained in the obtaining 36 were subjected to reaction according to the same procedures as in example 30 and example 27, while receiving specified in the title compound (970 mg, yield 92).

1H NMR (400 MHz, DMSO-d6); δ of 11.45 (s, 1H), 6.75 in (d, 1H), from 6.22 (DD, 1H), 6,16 (d, J=6,8 Hz, 1H), 4,91 (m, 1H), 3,88 (m, 2H), 3,66 (m, 1H), 3,61 (m, 1H), 3,48 (m, 2H), up 3.22 (m, 1H), 2,80 (m, 1H), 2,65 (m, 1H), 2,99 (m, 2H), 1,40 (m, 2H).

Example 41: synthesis of 2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanol

2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanol

The compound (1.24 g, 4.0 mmol)obtained in the obtaining 36 were subjected to reaction according to the same procedures as in example 30 and stage 2 of example 34, while receiving specified in the title compound (810 mg, yield 55%).

1H NMR (400 MHz, CDCl3); δ 10,69 (user. s, 1H), 6.87 in (s, 1H), 6,63 (d, 1H), from 6.22 (d, 1H), 4,87 (m, 1H), of 4.66 (m, 1H), was 4.02 (m, 4H), 3,55 (m, 4H), 3.15 in (m, 1H), 2,04 (m, 4H), and 1.54 (m, 2H).

Receive 37: synthesis of methyl ester [(R)-2-(7-amino-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(7-amino-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl-7-nitro-1H-indole-2-carboxylate (14.0 g, of 63.6 mmol)obtained in the obtaining 8 were subjected to reaction according to the same methods as in gaining the 33 and receiving 34, while receiving specified in the title compound (6.5 g, yield 35%).

Example 42: synthesis of [(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

[(R)-2-(7-Cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

(Stage 1)

The compound (5.0 g, 17.3 mmol), obtained in the obtaining 37, was subjected to reaction according to the same procedure as in example 26, while receiving methyl ester.

(Stage 2)

The compound obtained in stage 1, were subjected to reaction according to the same procedure as in example 27, while receiving specified in the header connection (5,44 g, 2 stage, yield 91%).

1H NMR (400 MHz, CDCl3); δ 11,77 (user. s, 1H),? 7.04 baby mortality (d, 1H), 6,97 (m, 2H), to 6.43 (d, 1H), of 5.34 (m, 1H), 3,88 (m, 1H), 3,69 (m, 1H), 3,19 (m, 1H), 2,72 (m, 1H), 2,60 (m, 1H), 2,01 (m, 2H), 1,74 (m, 2H), 1,59 (m, 4H).

Example 43: synthesis of ethyl ester [(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Ethyl ester [(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (500 mg, of 1.46 mmol)obtained in example 42 was subjected reactionalso the same procedure as in example 38, while receiving specified in the title compound (420 mg, yield 78%).

1H NMR (400 MHz, CDCl3); δ 10,12 (user. s, 1H), 7,05 (m, 1H), 6,99 (m, 1H), 6,91 (d, 1H), 6,51 (d, 1H), 5,07 (m, 1H), 4.09 to (square, 2H), a 3.87 (m, 1H), 3,65 (m, 1H), 3,21 (m, 1H), 2,86 (m, 1H), 2,65 (m, 1H), 2,01 (m, 2H), 1,74 (m, 2H), 1,62 (m, 4H), of 1.46 (m, 2H), 1,81 (t, 3H).

Example 44: synthesis of 2-[(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanol

2-[(R)-2-(7-Cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanol

Connection (1,46 g of 5.06 mmol), obtained in the obtaining 37 were subjected to reaction according to the same procedures as in example 26 and stage 2 of example 34, while receiving specified in the title compound (1.44 g, yield 78%).

1H NMR (DMSO-d6, ppm)δ to 11.28 (1H, s), 6,77-6,74 (2H, m), 6,69 (1H, s), and 6.25 (1H, d), 5,78 (1H, d)and 4.65 (1H, Quinn.), a 4.53 (1H, t), 3,82 (1H, m), of 3.60 (2H, m), 3,51 (1H, m), 3,11 (1H, m), 1,99 is 1.91 (3H, m), a 1.75-to 1.67 (3H, m), 1.56 to and 1.54 (4H, m).

FAB-MS (m/e) = 330.

Example 45: synthesis of {(R)-2-[7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

{(R)-2-[7-(Tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

Connection(1,32 g, 4,58 mmol)obtained in the obtaining 37 were subjected to reaction according to the same procedures as in example 30 and example 27, while receiving specified in the title compound (1.25 g, yield 76%).

1H NMR (DMSO-d6, ppm)δ 12,42 (1H, s, of usher.), 11,34 (1H, s), to 6.80 (1H, d), 6,72 (1H, s), 6,33 (1H, d), 5,79 (1H, d), a 4.86 (1H, Quinn.), 3,88 (2H, m), 3,60-to 3.52 (2H, m), 3,42 (2H, t), 3,17 (1H, m), is 2.74 (1H, m), 2,59 (1H, m), of 1.94 (2H, m)of 1.39 (2H, m).

FAB-MS (m/e) = 360.

Example 46: synthesis of 2-{(R)-2-[7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanol

2-{(R)-2-[7-(Tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanol

The compound (529 mg, to 1.83 mmol)obtained in the obtaining 37 were subjected to reaction according to the same procedures as in example 30 and stage 1 of example 34, while receiving specified in the title compound (340 mg, yield 54%).

1H NMR (DMSO-d6, ppm)δ of 11.29 (1H, s), 6,79 (2H, m), 6,70 (1H, s), 6,33 (1H, m), USD 5.76 (1H, d), of 4.66 (1H, Quinn.), of 4.54 (1H, t), 3,88 (2H, m), 3,62-3,59 (3H, m), 3,53 (1H, t), of 3.43 (2H, m), of 3.12 (1H, m), a 1.96 (3H, m)of 1.75 (1H, m)of 1.40 (2H, m).

FAB-MS (m/e) = 346.

Obtaining 38: synthesis of methyl ester [(R)-2-(7-amino-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(7-amino-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl-5-methoxy-7-nitro-1H-indole-2-carboxylate (2.5 g, 6.0 mmol), obtained in the obtaining 9 were subjected to reaction according to the same methods as in obtaining 33 and receiving 34, while receiving specified in the title compound (1.0 g, yield 52%).

Example 47: synthesis of methyl ester [(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (1.0 g, 3,13 mmol)obtained in the obtaining 38, was subjected to reaction according to the same procedure as in example 26, while receiving specified in the title compound (490 mg, yield 40%).

1H NMR (DMSO-d6, ppm)δ 11,24 (1H, s), 6,62 (1H, s), from 6.22 (1H, s), of 5.89 (1H, d), of 5.84 (1H, s), a 4.83 (1H, Quinn.), of 3.77 (1H, m)to 3.64 (3H, s)and 3.59 (3H, s), of 3.56 (1H, m)and 3.15 (1H, m), 2,69 (1H, m), 2,58 (1H, m), 1,90 (2H, m)to 1.67 (2H, m)and 1.51 (4H, m).

FAB-MS (m/e) = 388.

Example 48: synthesis of [(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

[(R)-2-(7-Cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (300 mg, 0.78 mmol)obtained in example 47 was subjected to reaction according to the same procedure as in example 27, while receiving specified in the title compound (240 mg, yield 82%).

1H NMR (DMSO-d6, ppm)δ 12,54 (1H, s, of usher.), 11,21 (1H, s), 6,63 (1H, s), 6,23 (1H, s), of 5.89 (1H, d), of 5.84 (1H, s), 4,84 (1H, Quinn.), of 3.77 (1H, m)to 3.64 (3H, s), of 3.56 (1H, m)and 3.15 (1H, m), 2,69 (1H, m), 2,58 (1H, m), 1,90 (2H, m)to 1.67 (2H, m), of 1.52 (4H, m).

FAB-MS (m/e) = 374.

Example 49: Synthesis of ethyl ester [(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Ethyl ester [(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (200 mg, 0.54 mmol)obtained in example 48 was subjected to reaction according to the same procedure as in example 38, while receiving specified in the title compound (124 mg, yield 57%).

1H NMR (400 MHz, CDCl3); δ of 10.73 (user. s, 1H), 6,83 (s, 1H), gold 6.43 (s, 1H), 6,16 (s, 1H), 5,07 (m, 1H), 4,00-3,88 (m, 3H), of 3.80 (s, 3H), 3,76 (m, 1H), 3,62 (m, 1H), 3,20 (m, 1H), and 2.83 (m, 1H), 2.63 in (m, 1H), up to 1.98 (m, 2H), 1.61 of (m, 4H), 1,40 (m, 2H), 1,12 (t, 3H).

Example 50: synthesis of methyl ester {(R)-2-[5-methoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihyd thiazol-4-yl}acetic acid

Methyl ester {(R)-2-[5-methoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

The compound (4.8 g, of 14.8 mmol)obtained in the obtaining 38, was subjected to reaction according to the same procedure as in example 30, while receiving specified in the title compound (2.5 g, yield 42%).

Example 51:synthesis of {(R)-2-[5-methoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

{(R)-2-[5-Methoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

The compound (30 mg, 0.07 mmol)obtained in example 50 was subjected to reaction according to the same procedure as in example 27, while receiving specified in the title compound (8.7 g, 30%yield).

1H NMR (500 MHz, DMSO-d6); δ 11,21 (user. s, 1H), only 6.64 (m, 1H), of 6.26 (m, 1H), 5,95 (m, 1H), of 5.84 (m, 1H), around 4.85 (m, 1H), 3,85 (m, 1H), to 3.64 (s, 3H), 3,63-to 3.49 (m, 2H), 3.43 points (m, 2H), 3,17 (m, 1H), 2,73 (m, 1H), 2,62 (m, 1H), was 1.94 (m, 2H), 1,72 (m, 1H), 1,38 (m, 2H).

Example 52: synthesis of [(R)-2-(7-cyclopentylamine-5-ethoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

[(R)-2-(7-Cyclopentylamine-5-ethoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl-5-ethoxy-7-nitro-1H-indole-2-carboxylate (1.5 g, 5.7 mmol)obtained in 11 were subjected sequentially to the reaction according to the same methods as in obtaining 33, receiving 34, example 26 and example 27, while receiving specified in the title compound (150 mg, yield 7%).

1H NMR (400 MHz, DMSO-d6); δ 11,24 (user. s, 1H), 6,65 (d, J=2.0 Hz, 1H), of 6.26 (d, J=2.0 Hz, 1H), of 5.92 (d, J=6.0 Hz, 1H), 5,88 (d, J=2.0 Hz, 1H), 4,89 (m, 1H), 3,94 (square, 2H), 3,81 (m, 1H), 3,65 (m, 1H), 3,20 (m, 1H), 2,74 (m, 1H), 2,62 (m, 1H), was 1.94 (m, 2H), 1,72 (m, 2H), 1.61 of (m, 4H), to 1.31 (t, 3H).

Obtaining 39: synthesis of ethyl ester of 7-nitro-5-propoxy-1H-indole-2-carboxylic acid

Ethyl ester of 7-nitro-5-propoxy-1H-indole-2-carboxylic acid

2-Nitro-4-propoxyphenyl (20 g, 102 mmol) was subjected to reaction according to the same methods as in receive 1 and receive 2, while receiving specified in the title compound (1.5 g, yield 5%).

Example 53: synthesis of [(R)-2-(7-cyclopentylamine-5-propoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

[(R)-2-(7-Cyclopentylamine-5-propoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Ethyl-5-propoxy-7-nitro-1H-indole-2-carboxylate (1.4 g, 4,82 mmol)obtained in example 39 was subjected sequentially to the reaction according to the same methods as in obtaining 33, receiving 34, example 26 and receiving 27, while receiving specified in the title compound (70 mg, yield 4%).

1H NMR (500 MHz, CDCl3); δ 12,79 (user. s, 1H), 7,05 (s, 1H), of 6.26 (s, 1H), from 6.22 (s, 1H), 5,14 (user. s, 1H), 3,88 (m, 3H), 3,41 (m, 2H), of 3.07 (m, 1H), and 2.83 (m, 1H), 2,03 (m, 2H), equal to 1.82 (m, 3H), 1.69 in (m, 2H), 1,60 (m, 2H), was 1.04 (t, 3H).

Obtaining 40: Synthesis of methyl ester [(R)-2-(7-amino-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(7-amino-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl-5-phenoxy-7-nitro-1H-indole-2-carboxylate (550 mg, of 1.84 mmol), obtained in the obtaining 12 were subjected to reaction according to the same methods as in obtaining 33 and receiving 34, while receiving specified in the title compound (150 mg, yield 16%).

Example 54: synthesis of [(R)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

[(R)-2-(7-Cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Compound (65 mg, 0.13 mmol)obtained in the obtaining 40 were subjected to reaction according to the same procedures as in example 26 and example 27, while receiving specified in the title compound (20 mg, yield 35%).

1H NMR (400 MHz, CDCl3); δ 11,92 (user. s, 1H), 7,28 (m, 2H), 7,00 (m, 4H), 6,56 (s, 1H), from 6.22 (s, 1H), 5,34 (user. s, 1H), 3,81 (user. s, 1H), 3,70 (m, 1H), up 3.22 (d, J=12.0 Hz, 1H), was 2.76~2,62 (m, 2H), 1,96 (m, 2H), 1,73 (m, 2H), 1,58 (m, 4H).

Example 55: synthesis of {(R)-2-[5-phenoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

{(R)-2-[5-Phenoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

Compound (65 mg, 0.13 mmol)obtained in the obtaining 40 were subjected to reaction according to the same procedures as in example 30 and example 27, while receiving specified in the title compound (13 mg, yield 22%).

1H NMR (400 MHz, CDCl3); δ 11,98 (user. s, 1H), 7,28 (m, 2H), 7,00 (m, 4H), to 6.58 (s, 1H), from 6.22 (s, 1H), 5,34 (user. s, 1H), 3,98 (user. s, 2H), 3,70 (m, 1H), 3,50 (m, 3H), 3,21 (m, 2H), 2,74 (m, 1H), 2,66 (m, 1H), 2.05 is (m, 2H), 1,58 (m, 2H).

Getting 41: synthesis of methyl what about the ether {(R)-2-[7-amino-5-(pyridine-3-yloxy)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

Methyl ester {(R)-2-[7-amino-5-(pyridine-3-yloxy)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

Ethyl ester of 7-nitro-5-(pyridine-3-yloxy)-1H-indole-2-carboxylic acid (1.0 g, 3.1 mmol), obtained in the obtaining 13 were subjected to reaction according to the same methods as in obtaining 33 and receiving 34, while receiving specified in the title compound (160 mg, yield 14%).

Example 56: synthesis of methyl ester {(R)-2-[7-cyclopentylamine-5-(pyridine-3-yloxy)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

Methyl ester {(R)-2-[7-cyclopentylamine-5-(pyridine-3-yloxy)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

The compound (80 mg, 0.21 mmol)obtained in the obtaining 41, was subjected to reaction according to the same procedure as in example 26, while receiving specified in the title compound (45 mg, yield 48%).

1H NMR (400 MHz, CDCl3); δ 10,89 (user. s, 1H), to 8.41 (d, 1H), compared to 8.26 (m, 1H), 7,27 (m, 1H), 7,19 (m, 1H), 6,85 (s, 1H), 6,62 (d, 1H), from 6.22 (m, 1H), 5,04 (m, 1H), 4,13 (user. s, 1H), 3,78 (m, 1H), 3,65 (m, 1H)and 3.59 (s, 3H), 3,20 (m, 1H), and 2.83 (m, 1H), to 2.67 (m, 1H), up to 1.98 (m, 2H), 1.61 of (m, 4H), of 1.46 (m, 2H).

Example 57: synthesis of {(R)-2-[7-C is chlopheniramine-5-(pyridine-3-yloxy)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

{(R)-2-[7-Cyclopentylamine-5-(pyridine-3-yloxy)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

Compound (35 mg, 0.08 mmol)obtained in example 56 was subjected to reaction according to the same procedure as in example 27, while receiving specified in the title compound (15 mg, yield 44%).

1H NMR (400 MHz, CDCl3); δ up 11,86 (user. s, 1H), 8,40 (d, 1H), compared to 8.26 (m, 1H), 7,25 (m, 1H), 7,17 (m, 1H), of 6.96 (s, 1H), to 6.57 (d, 1H), 6,18 (d, 1H), 5,33 (user. s, 1H), 3,80 (user. s, 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), 1,58 (m, 4H).

Example 58: synthesis of methyl ester {(R)-2-[5-(pyridine-3-yloxy)-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

Methyl ester {(R)-2-[5-(pyridine-3-yloxy)-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

The compound (480 mg, 0.21 mmol)obtained in the obtaining 41, was subjected to reaction according to the same procedure as in example 30, while receiving specified in the title compound (35 mg, yield 36%).

1H NMR (400 MHz, DMSO-d6); δ 11,48 (user. s, 1H), 8.30 to (d, 1H), 8,25 (m, 1H), 7,34 (m, 1H), 7,29 (m, 1H), 6,76 (d, 1H), 6,46 (who, 1H), 6,18 (d, 1H), is 4.93 (m, 1H), a 3.87 (m, 3H), 3,66 (s, 3H)and 3.59 (m, 1H), 3,44 (m, 2H), 3,23 (m, 1H), 2,81 (m, 2H), 1,95 (m, 2H), USD 1.43 (m, 2H).

Example 59: synthesis of {(R)-2-[5-(pyridine-3-yloxy)-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

{(R)-2-[5-(Pyridine-3-yloxy)-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

Compound (25 mg, 0.05 mmol)obtained in example 58, was subjected to reaction according to the same procedure as in example 27, while receiving specified in the title compound (15 mg, yield 58%).

1H NMR (400 MHz, Meon-d4); δ to 8.14 (s, 1H), 8,07 (s, 1H), 7,25 (m, 2H), 6,76 (s, 1H), 6,45 (s, 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 and (m, 2H), 1,46 (m, 2H).

Obtaining 42: synthesis of methyl ester [(R)-2-(7-amino-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(7-amino-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl-5-methyl-7-nitro-1H-indole-2-carboxylate (3.4 g, 14.5 mmol), obtained in the obtaining 7 were subjected to reaction according to the same methods as in the poluchenii 33 and receiving 34, while receiving specified in the title compound (1.7 g, yield 39%).

Example 60: synthesis of methyl ester [(R)-2-(7-cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(7-cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Compound (1.7 g, 5,67 mmol)obtained in the obtaining 42, was subjected to reaction according to the same procedure as in example 26, while receiving specified in the title compound (1.2 g, yield 58%).

1H NMR (DMSO-d6, ppm)δ 11,19 (1H, s), 6,62 (1H, s), 6,55 (1H, s), 6,07 (1H, s), of 5.75 (1H, d), 4,88 (1H, Quinn.), with 3.79 (1H, m), 3,63 is 3.57 (5H, m), 3,17 (1H, m), 2,82-by 2.73 (2H, m), of 2.23 (3H, s), of 1.94 (2H, m), by 1.68 (2H, m)of 1.55 (3H, m).

FAB-MS (m/e) = 372.

Example 61: synthesis of [(R)-2-(7-cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

[(R)-2-(7-Cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (12 mg, 0.03 mmol)obtained in example 60 was subjected to reaction according to the same procedure as in example 27, while receiving specified in the title compound (5 mg, yield 43%).

H NMR (DMSO-d6, ppm)δ 12,42 (1H, s, of usher.), 11,21 (1H, s), is 6.61 (1H, s), is 6.54 (1H, s), of 6.02 (1H, s), USD 5.76 (1H, d), to 4.87 (1H, Quinn.), of 3.77 (1H, m), 3,62 (2H, t), and 3.16 (1H, m), 2,81-of 2.72 (2H, m), of 2.23 (3H, s), of 1.94 (2H, m), by 1.68 (2H, m)of 1.55 (3H, m).

FAB-MS (m/e) = 358.

Example 62: synthesis of {(R)-2-[5-methyl-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

{(R)-2-[5-Methyl-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

Compound (55 mg, 0.18 mmol)obtained in the obtaining 42 were subjected to reaction according to the same procedures as in example 30 and example 27, while receiving specified in the title compound (47 mg, yield 70%).

1H NMR (500 MHz, CDCl3); δ 11,85 (user. s, 1H), 6,97 (d, 1H), 6,76 (s, 1H), of 6.26 (s, 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), was 2.76 (m, 1H), 2,64 (m, 1H), 2,31 (s, 3H), of 2.06 (m, 2H), 1,58 (m, 2H).

Receive 43: synthesis of methyl ester {(R)-2-[7-(1,4-dioxaspiro[4,5]Dec-8-ylamino)-5-methyl-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

Methyl ester {(R)-2-[7-(1,4-dioxaspiro[4,5]Aug-8-ylamino)-5-methyl-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

The compound (9 mg, 0.32 mmol), obtained in the obtaining 42, and monoethyleneglycol 1,4-cyclohexandione used instead of Cyclopentanone, was subjected to reaction according to the same procedure as in example 26, while receiving specified in the title compound (31 mg, yield 23%).

1H NMR (500 MHz, CDCl3); δ to 10.62 (user. s, 1H), 6,85 (s, 1H), 6,77 (s, 1H), of 6.31 (s, 1H), to 4.98 (m, 1H), 3.96 points (m, 4H), and 3.72 (s, 3H), of 3.64 (m, 1H), 3,55 (m, 1H), 3,21 (m, 1H), 2,89 (m, 1H), 2,66 (m, 1H), is 2.37 (s, 3H), of 2.08 (m, 2H), 1,99 (m, 2H), 1.69 in (m, 4H).

Example 63: synthesis of {(R)-2-[5-methyl-7-(4-oxocyclohexyl)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

{(R)-2-[5-Methyl-7-(4-oxocyclohexyl)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

The compound (40 mg, 0.09 mmol)obtained in the obtaining 43, was dissolved in tetrahydrofuran (2 ml), methanol (2 ml) and water (2 ml). To the solution was added monohydrate of lithium hydroxide (8 mg, 0.18 mmol) and the mixture was stirred for 4 h at room temperature. After completion of the reaction was added 1 n hydrochloric acid. The mixture was extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography.

the shelled thus the compound was dissolved in acetone (5 ml). To the solution was added p-toluensulfonate acid (5 mg) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated column chromatography, thus obtaining specified in the title compound (7 mg, yield 20%).

1H NMR (500 MHz, CDCl3); δ 11,99 (user. s, 1H), 7,00 (s, 1H), 6,79 (s, 1H), 6.30-in (s, 1H), of 5.34 (m, 1H), with 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), and 2.26 (m, 2H), of 1.97 (m, 2H).

Receiving 44: synthesis of methyl ester {(R)-2-[7-amino-5-(4-methysulfonylmethane)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

Methyl ester {(R)-2-[7-amino-5-(4-methysulfonylmethane)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

The compound (900 mg, 2,30 mmol)obtained in the obtaining 14 were subjected to reaction according to the same methods as in obtaining 33 and receiving 34, while receiving specified in the title compound (328 mg, yield 31%).

Example 64: synthesis of {(R)-2-[7-cyclopentylamine-5-(4-methysulfonylmethane)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid the

{(R)-2-[7-Cyclopentylamine-5-(4-methysulfonylmethane)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid

The compound (320 mg, 0.7 mmol), obtained in the obtaining 44 were subjected to reaction according to the same procedures as in example 26 and example 27, while receiving specified in the title compound (45 mg, yield 13%).

1H NMR (500 MHz, DMSO-d6); δ 11,71 (user. s, 1H), 7,81 (d, 2H), 7,05 (m, 2H), 6,65 (s, 1H), of 6.49 (s, 1H), 6.35mm (m, 1H), 5,96 (s, 1H), a 4.86 (m, 1H), 3,75 (m, 1H), 3,52 (m, 1H), 3,17 (m, 1H), 3,12 (s, 3H), of 1.87 (m, 2H), 1,67 (m, 2H), 1,53 (m, 4H).

45: synthesis of methyl ester of (R)-3-[(5-hydroxymethyl-7-nitro-1H-indole-2-carbonyl)amino]-4-(4-methoxybenzenesulfonyl)butyric acid

Methyl ester of (R)-3-[(5-hydroxymethyl-7-nitro-1H-indole-2-carbonyl)amino]-4-(4-methoxybenzenesulfonyl)butyric acid

The compound (12.9 g, of 54.8 mmol)obtained in the obtaining 27, was subjected to reaction according to the same procedure as in stage 1 receive 34, while receiving specified in the title compound (15.3 g, yield 57%).

1H NMR (500 MHz, CDCl3); δ 10,43 (user. s, 1H), 8,28 (s, 1H), 8,00 (s, 1H), 7,25 (m, 2H), 6,92 (d, 1H), 6,84 (s, 1H), PC 6.82 (s, 1 is), a 4.86 (m, 2H), 4,59 (m, 1H), 3,76 (s, 3H), of 3.73 (s, 2H), 3,69 (s, 3H), 2,88 (m, 1H), 2,82 (m, 2H), 2,73 (m, 1H), 2,69 (m, 1H).

Receive 46: synthesis of methyl ester [(R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(5-chloromethyl-7-nitro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (4.8 g, 0.8 mmol), obtained in the obtaining 45, was subjected to reaction according to the same procedure as in receiving 29, while receiving specified in the title compound (3.2 g, yield 88%).

1H NMR (500 MHz, CDCl3); δ 12,82 (user. s, 1H), 8,43 (s, 1H), 8,04 (s, 1H), 7,49 (s, 1H), 5.25 in (m, 1H), 4,74 (s, 2H), a 4.03 (m, 1H), only 3.57 (m, 1H), of 3.45 (m, 1H), 2,99 (m, 1H).

Getting 47: synthesis of methyl ester [(R)-2-(7-nitro-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(7-nitro-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (500 mg, 1.4 mmol)obtained in the obtaining 46, was dissolved in N,N-dimethylformamide (10 ml). To the solution was added potassium hydride (82 mg, 2.0 mmol) and phenol (192 mg, 2.0 mmol) and the mixture was stirred for 8 h at tempera is ur 0°C~room temperature. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure, thus obtaining specified in the title compound (55 mg, yield 6%).

1H NMR (500 MHz, CDCl3); δ 10,46 (user. s, 1H), 8.34 per (s, 1H), of 8.06 (s, 1H), 7,31 (m, 2H), 7,25 (s, 1H), 7,00 (m, 3H), 5,19 (s, 2H), is 5.06 (m, 1H), of 3.77 (s, 3H), 3,71 (m, 1H), 3,26 (m, 1H), 2,97 (m, 1H), 2,69 (m, 1H).

Example 65: synthesis of methyl ester [(R)-2-(7-cyclopentylamine-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(7-cyclopentylamine-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (33 mg, 0.08 mmol), obtained in the obtaining 47, was subjected to reaction according to the same methods as in stage 3 of receipt 34 and example 26, while receiving specified in the title compound (16 mg, yield 43%).

1H NMR (500 MHz, CDCl3); δ 9,49 (user. s, 1H), 7,27 (m, 2H), 7,10 (s, 1H), 7,01 (m, 2H), 6,93 (m, 1H), 6.89 in (s, 1H), 6,59 (s, 1H), 5,07 (s, 2H), 5,02 (m, 1H), 3,93 (m, 1H), 3,71 (s, 3H), of 3.65 (m, 1H), 3,21 (m, 1H), 2,88 (m, 1H), 2,68 (m, 1H), 2,04 (m, 2H), of 1.75 (m, 2H), 1,58 (m, 4H).

Example 66: synthesis of [(R)-2-(7-cyclopentylamine-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

[(R)-2-(7-Cyclopentylamine-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (11 mg, 0.02 mmol)obtained in example 65, was subjected to reaction according to the same procedure as in example 27, while receiving specified in the title compound (5 mg, yield 45%).

1H NMR (500 MHz, CDCl3); δ to 11.79 (user. s, 1H), 7,26 (m, 2H), 7,02 (m, 2H), 6,99 (s, 1H), 6,92 (m, 1H), 6.48 in (s, 1H), 5,35 (m, 1H), 5,07 (s, 2H), with 3.89 (m, 1H), 3,71 (m, 1H), 3,21 (m, 1H), 2,75 (m, 1H), 2.63 in (m, 1H), 2,00 (m, 2H), 1,73 (m, 2H), 1,59 (m, 4H), of 1.75 (m, 2H).

Receive 48: synthesis of methyl ester [(R)-2-(7-nitro-5-pyrrolidin-1-ylmethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(7-nitro-5-pyrrolidin-1-ylmethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Compound (87 mg, 0.24 mmol)obtained in the obtaining 46, and pyrrolidin used instead of dimethylamine, was subjected to reaction according to the same procedure as in example 15, while receiving specified in the title compound (56 mg, yield 58%).

1H NMR (500 MHz, CDCl3); δ of 8.28 (s, 1H), compared to 8.26 (s, 1H), 7,00 (s, 1H), to 5.03 (m, 1H), 4,10 (s, 2H), 3,74 (s, 3H), 3,68 (m, 1H), equal to 2.94 (m, 1H), 2,92 (m, 4H), to 2.66 (m, 1H), up to 1.98 (m, 4H).

Example 67: SinTe the methyl ester [(R)-2-(7-cyclopentylamine-5-pyrrolidin-1-ylmethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(7-cyclopentylamine-5-pyrrolidin-1-ylmethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Compound (56 mg, 0.14 mmol)obtained in the obtaining 48, was subjected to reaction according to the same methods as in stage 3 of receipt 34 and example 26, while receiving specified in the title compound (13 mg, yield 21%).

1H NMR (400 MHz, CDCl3); δ 10,20 (user. s, 1H), 6,97 (s, 1H), to 6.88 (s, 1H), 6.73 x (s, 1H), free 5.01 (m, 1H), Android 4.04 (s, 2H), was 4.02 (m, 1H), of 3.73 (s, 3H), of 3.65 (m, 1H), up 3.22 (m, 1H), 3,10 (m, 4H), 2,87 (m, 1H), 2,68 (m, 1H), 2.06 to (m, 3H), of 1.95 (m, 4H), of 1.65 (m, 3H), of 1.47 (m, 2H).

Getting 49: synthesis of methyl ester [(R)-2-(5-methanesulfonyl-7-nitro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(5-methanesulfonyl-7-nitro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Compound (110 mg, 0.30 mmol)obtained in the obtaining 55, and methansulfonate used instead of dimethylamine were subjected to reaction according to the same procedure as in example 15, while receiving specified in the title compound (92 mg, yield 74%).

1H NMR (500 MHz, CDCl3); δ 10,55 (user. with, 1 is), compared to 8.26 (s, 1H), 8,08 (s, 1H),? 7.04 baby mortality (s, 1H), is 5.06 (m, 1H), and 4.40 (s, 2H), of 3.77 (s, 3H), of 3.48 (m, 1H), 3.27 to (m, 1H), 2,99 (m, 1H), 2,86 (s, 3H), 2,71 (m, 1H).

Example 68: synthesis of methyl ester [(R)-2-(7-cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(7-cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (92 mg, 0.22 mmol)obtained in the obtaining 49, was subjected to reaction according to the same methods as in stage 3 of receipt 34 and example 26, while receiving specified in the title compound (31 mg, yield 31%).

1H NMR (500 MHz, CDCl3); δ 10,22 (user. s, 1H), 7,00 (s, 1H), 6.87 in (s, 1H), 6,50 (s, 1H), of 5.05 (m, 1H), 4,27 (s, 2H), a 3.87 (m, 1H), 3,61 (s, 3H), up 3.22 (m, 1H), and 2.83 (m, 1H), 2,72 (s, 3H), of 2.66 (m, 1H), 2,03 (m, 2H), 1,64 (m, 4H), of 1.46 (m, 2H).

Example 69: synthesis of [(R)-2-(7-cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

[(R)-2-(7-Cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Compound (29 mg, 0.07 mmol)obtained in example 68 was subjected to reaction according to the same procedure as in example 27, while receiving specified in the title compound (19 mg, yield 67%).

1H NMR (400 MHz, DMSO-d6); δ 11,68 (user. s, 1H), 6,85 (s, 1H), of 6.71 (s, 1H), 6,33 (s, 1H), 6,18 (m, 1H), 4,88 (m, 1H), 4,35 (s, 2H), 3,84 (m, 1H), of 3.56 (m, 1H), 3,20 (m, 1H), 2,84 (s, 3H), by 2.55 (m, 1H), 2,09 (m, 1H), of 1.97 (m, 2H), 1,73 (m, 2H), 1,58 (m, 4H).

Example 70 synthesis of 2-[(R)-2-(7-cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanol

2-[(R)-2-(7-Cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanol

The compound (720 mg, to 1.60 mmol)obtained in example 68 was dissolved in tetrahydrofuran (20 ml). To the solution was added 2 M solution of lithium borohydride in tetrahydrofuran (1.6 ml, 3.2 mmol) and the mixture was stirred for 3 h at room temperature. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated column chromatography, thus obtaining specified in the title compound (292 mg, yield 43%).

1H NMR (500 MHz, CDCl3); δ 10,41 (user. s, 1H), 6,98 (s, 1H), 6.90 to (s, 1H), of 6.49 (s, 1H), and 4.68 (m, 1H), 4,28 (s, 2H), 3.96 points (m, 3H)and 3.59 (m, 1H), 3,13 (m, 1H), 2.05 is (m, 4H), 1,72 (m,2H), to 1.60 (m, 4H).

Obtaining 50: synthesis cyclopentyl-{2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-5-methanesulfonyl-1H-indol-7-yl}Amin

Cyclopentyl-{2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-5-methanesulfonyl-1H-indol-7-yl}Amin

The compound (178 mg, 0.42 mmol)obtained in example 70, was dissolved in tetrahydrofuran (10 ml). To the solution was added iodine (161 mg, 0,63 mmol), triphenylphosphine (166 mg, 0,63 mmol) and imidazole (86 mg, of 1.23 mmol) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and separated column chromatography, thus obtaining specified in the title compound (120 mg, yield 54%).

Example 71: Synthesis cyclopentyl-{5-methanesulfonyl-2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

Cyclopentyl-{5-methanesulfonyl-2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

The connection is giving (116 mg, 0.22 mmol)obtained in the obtaining 50, was dissolved in N,N-dimethylformamide (4 ml). To the solution was added morpholine (57 mg, 0.66 mmol) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure, thus obtaining specified in the title compound (68 mg, yield 64%).

1H NMR (500 MHz, CDCl3); δ or 10.60 (user. s, 1H), 6,99 (s, 1H), 6.89 in (s, 1H), of 6.49 (s, 1H), 4,79 (m, 1H), 4.26 deaths (s, 2H), 3,86 (m, 1H), 3,57 (m, 5H), 3,19 (m, 1H), 2,72 (s, 3H), of 2.45 (m, 2H), 2,32 (m, 2H), and 2.26 (m, 2H), 2,04 (m, 2H), 1,80 (m, 2H), of 1.66 (m, 4H), of 1.41 (m, 2H).

Example 72: synthesis of 1-(4-{2-[(R)-2-(7-cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)ethanone

1-(4-{2-[(R)-2-(7-Cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)alanon

The compound (129 mg, 0.24 mmol)obtained in receipt of 50, and 1-acetylpiperidine used instead of the research, were subjected to reaction according to the same procedure as in example 71, while receiving specified in the title compound (54 mg, yield 42%).

1H NMR (500 MHz, CDCl3); δ to 10.62 (user. s, 1H), 6,99 (s, 1H), 6.89 in (s, 1H), 6,46 (s, 1H, of 4.77 (m, 1H), 4.26 deaths (s, 2H), a 3.87 (m, 1H), only 3.57 (m, 1H), 3,30 (m, 2H), and 3.16 (m, 1H), 2,72 (s, 3H), 2,46 (m, 2H), 2,31 (m, 2H), of 2.21 (m, 2H), 2,04 (s, 3H), 2,03 (m, 2H), 1,79 (m, 2H), 1,64 (m, 4H), 1,45 (m, 2H).

Example 73: synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-morpholine-4-ratanana

2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-morpholine-4-ylatason

The compound (50 mg, 0.13 mmol)obtained in example 27 was dissolved in N,N-dimethylformamide (2 ml). To the solution was added morpholine (17 mg, 0.20 mmol), EDC (43 mg, 0.23 mmol) and NOT (36 mg, 0.26 mmol) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and concentrated. The residue was purified column chromatography, thus obtaining specified in the title compound (22 mg, yield 37%).

1H NMR (500 MHz, DMSO-d6); δ to 11.52 (user. s, 1H), 6,80 (s, 1H), 6,69 (s, 1H), 6,16 (s, 1H), 6,12 (m, 1H), 4.95 points (m, 1H), 3,81 (m, 1H), 3,63 (m, 1H), 3,41 (m, 8H), of 3.12 (m, 1H), 2,85 (m, 1H), 2,69 (m, 1H), 1.93 and (m, 2H), by 1.68 (m, 2H), and 1.56 (m, 4H).

Example 74: synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-(2-Mor the Olin-4-retil)ndimethylacetamide

2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-(2-morpholine-4-retil)ndimethylacetamide

The compound (50 mg, 0.13 mmol)obtained in example 27, 4-(2-amino-ethyl)morpholine, used instead of the research, were subjected to reaction according to the same procedure as in example 73, while receiving specified in the title compound (22 mg, yield 34%).

1H NMR (500 MHz, DMSO-d6); δ 11,53 (user. s, 1H), to $ 7.91 (m, 1H), 6,80 (s, 1H), 6,70 (s, 1H), 6,16 (s, 1H), 6,12 (m, 1H), is 4.93 (m, 1H), 3,80 (m, 1H), 3,53 (m, 5H), 3,20 (m, 3H), 2,60 (m, 1H), 2,32 (m, 7H), of 1.93 (m, 2H), by 1.68 (m, 2H), 1,53 (m, 4H).

Example 75: synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-(3-morpholine-4-ylpropyl)ndimethylacetamide

2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-(3-morpholine-4-ylpropyl)ndimethylacetamide

The compound (50 mg, 0.13 mmol)obtained in example 27, 4-(3-aminopropyl)morpholine, used instead of the research, were subjected to reaction according to the same procedure as in example 73, while receiving specified in the title compound (23 mg, yield 35%).

1H NMR (500 MHz, DMSO-d6); δ to 11.52 (user. s, 1H), 7,94 (m, 1 is), 6,79 (s, 1H), 6,70 (s, 1H), 6,16 (s, 1H), 6,12 (m, 1H), is 4.93 (m, 1H), 3,80 (m, 1H), 3,51 (m, 5H), 3,10 (m, 3H), at 2.59 (m, 1H), 2,37 (m, 1H), 2,25 (m, 6H), 1.93 and (m, 2H), by 1.68 (m, 2H), 1,53 (m, 6H).

Example 76: synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-methylacetamide

2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-methylacetamide

The compound (50 mg, 0.13 mmol)obtained in example 27, and the methylamine used instead of the research, were subjected to reaction according to the same procedure as in example 73, while receiving specified in the title compound (45 mg, yield 87%).

1H NMR (500 MHz, DMSO-d6); δ to 11.52 (user. s, 1H), of 7.90 (m, 1H), 6,80 (s, 1H), 6,69 (s, 1H), 6,16 (s, 1H), 6,13 (m, 1H), is 4.93 (m, 1H), 3,80 (m, 1H), 3,55 (m, 1H), 3.15 in (m, 1H), 2,58 (m, 4H), 2,39 (m, 1H), 1.93 and (m, 2H), by 1.68 (m, 2H), and 1.56 (m, 4H).

Example 77: synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N,N-dimethylacetamide

2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N,N-dimethylacetamide

The compound (50 mg, 0.13 mmol)obtained in example 27, and the dimethylamine used instead of the research, were subjected to reaction according to the same procedure as in example 73, while receiving specified in the title compound (26 mg, yield 49%).

1H NMR (500 MHz, DMSO-d6); δ 11,53 (user. s, 1H), 6,79 (s, 1H), 6,69 (s, 1H), 6,16 (s, 1H), 6,12 (m, 1H), is 4.93 (m, 1H), 3,81 (m, 1H), 3,63 (m, 1H), 3.15 in (m, 1H), 2.95 and (s, 3H), 2,87 (m, 1H), and 2.83 (s, 3H), 2,65 (m, 1H), 1.93 and (m, 2H), 1.69 in (m, 2H), 1,53 (m, 4H).

Example 78: synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(4-methylpiperazin-1-yl)ethanone

2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(4-methylpiperazin-1-yl)alanon

The compound (40 mg, 0.11 mmol)obtained in example 27, 1-methylpiperazin used instead of the research, were subjected to reaction according to the same procedure as in example 73, while receiving specified in the title compound (21 mg, yield 43%).

1H NMR (500 MHz, DMSO-d6); δ to 11.52 (user. s, 1H), 6,80 (s, 1H), 6,69 (s, 1H), 6,16 (s, 1H), 6,12 (m, 1H), 4,94 (m, 1H), 3,80 (m, 1H), 3,62 (m, 1H), 3,42 (m, 4H), to 3.35 (m, 1H), 3.15 in (m, 1H), 2,85 (m, 1H), 2,66 (m, 1H), 2,24 (m, 4H), 2.13 in (C, 3H), of 1.93 (m, 2H), by 1.68 (m, 2H), 1.55V (m, 4H).

Example 79: synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(3-dimethylaminopropan-1-yl)ethanone

2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(3-dimethylaminopropan-1-yl)alanon

The compound (40 mg, 0.11 mmol)obtained in example 27, and 3-dimethylaminopyridine used instead of the research, were subjected to reaction according to the same procedure as in example 73, while receiving specified in the title compound (24 mg, yield 48%).

1H NMR (500 MHz, DMSO-d6); δ 11,53 (user. s, 1H), 6,80 (s, 1H), 6,69 (s, 1H), 6,16 (s, 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 (s, 3H), 2,07 (s, 3H), of 1.93 (m, 2H), 1.69 in (m, 3H), of 1.59 (m, 5H).

Example 80: synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(3-hydroxypyrrolidine-1-yl)ethanone

2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(3-hydroxypyrrolidine-1-yl)alanon

The compound (40 mg, 0.11 mmol)obtained in example 27, and 3-pyrrolidino used instead of the research, were subjected to reaction according to the same procedure as in example 73, while receiving specified in the title compound (19 mg, yield 40%).

1H NMR (500 MHz, DMSO-d6); δ 11,54 (user. s, 1H), 6,80 (s, 1H), 6,69 (s, 1H), 6,16 (s, 1H), 6,12 (m, 1H), is 4.93 (m, 1H), 4,25 (m, 1H), 3,81 (m, 1H), 3,63 (m, 3H), 3,47 (m, 2H), 3,32 (m, 2H), 3,17 (m, 1H), and 2.79 (m, 1H), 2,59 (m, 1H), 1,3 (m, 3H), of 1.80 (m, 1H), 1,68 (m, 2H), 1,53 (m, 4H).

Example 81: synthesis of 2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-piperidine-1-ratanana

2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-piperidine-1-ylatason

The compound (40 mg, 0.11 mmol)obtained in example 27, and the piperidine used instead of the research, were subjected to reaction according to the same procedure as in example 73, while receiving specified in the title compound (27 mg, yield 57%).

1H NMR (500 MHz, DMSO-d6); δ to 11.52 (user. s, 1H), 6,80 (s, 1H), 6,69 (s, 1H), 6,16 (s, 1H), 6,12 (m, 1H), 4,94 (m, 1H), 3,81 (m, 1H), 3,63 (m, 1H), of 3.45 (m, 1H), 3,38 (m, 3H), 3,14 (m, 1H), 2,85 (m, 1H), 1.93 and (m, 2H), by 1.68 (m, 2H), 1,48 (m, 10H).

Example 82: synthesis of 2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}-N-methylacetamide

2-{(R)-2-[5-Chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}-N-methylacetamide

Compound (44 mg, 0.11 mmol)obtained in example 31 was dissolved in N,N-dimethylformamide (2 ml). To the solution was added methylamine (0,08 ml, 2 M solution in THF, 0,17 mmol), EDC (36 mg, 0,19 mmol) and NOT (30 mg, 0,22 IMO the b) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and concentrated. The residue was purified column chromatography, thus obtaining specified in the title compound (18 mg, yield 37%).

1H NMR (500 MHz, DMSO-d6); δ 11,54 (user. s, 1H), to $ 7.91 (m, 1H), for 6.81 (s, 1H), 6,70 (s, 1H), 6,28 (s, 1H), between 6.08 (m, 1H), is 4.93 (m, 1H), 3,85 (m, 2H), of 3.56 (m, 2H), 3,44 (m, 2H), 3.15 in (m, 1H), 2.06 to (m, 4H), is 2.37 (m, 1H), 1.93 and (m, 2H), 1.39 in (m, 2H).

Example 83: synthesis of 2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}-1-morpholine-4-ratanana

2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}-1-morpholine-4-ylatason

Compound (44 mg, 0.11 mmol)obtained in example 31, and morpholine used instead of methylamine, was subjected to reaction according to the same procedure as in example 82, while receiving specified in the title compound (35 mg, yield 68%).

1H NMR (500 MHz, DMSO-d6); δ 11,53 (user. s, 1H), for 6.81 (s, 1H), 6,70 (s, 1H), 6,28 (s, 1H), between 6.08 (m, 1H), 4,96 (m, 1H), 3,86 (m, 2H), 3,47 (m, 12H), 3.15 in (m, 1H), 2,85 (m, 1H), 2,69 (m, 1H), was 1.94 (m, 2H), 1.39 in (m, 2H).

Example 84: synthesis of 2-[(R)-2-(7-cyclopentylamine-5-fluoro-1 is-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(4-methylpiperazin-1-yl)ethanone

2-[(R)-2-(7-Cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(4-methylpiperazin-1-yl)alanon

The compound (100 mg, 0.28 mmol)obtained in example 37 was dissolved in N,N-dimethylformamide (3 ml). To the solution was added 1-methylpiperazine (36 mg, 0.36 mmol), EDC (90 mg, 0.47 mmol) and NOT (75 mg, 0.55 mmol) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and concentrated. The residue was purified column chromatography, thus obtaining specified in the title compound (78 mg, yield 64%).

1H NMR (400 MHz, DMSO-d6); δ 11,44 (user. s, 1H), 6.73 x (s, 1H), of 6.52 (DD, 1H), to 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 (m, 4H), 2,17 (s, 3H), to 1.98 (m, 2H), 1,72 (m, 2H), 1,58 (m, 4H).

Example 85: synthesis of 2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-(2-morpholine-4-retil)ndimethylacetamide

2-[(R)-2-(7-Cyclopentylamine-5-fluoro-1H-indol-yl)-4,5-dihydrothieno-4-yl]-N-(2-morpholine-4-retil)ndimethylacetamide

The compound (100 mg, 0.28 mmol)obtained in example 37, 4-(2-amino-ethyl)morpholine, used instead of 1-methylpiperazine, were subjected to reaction according to the same procedure as in example 84, while receiving specified in the title compound (80 mg, yield 60%).

1H NMR (400 MHz, DMSO-d6); δ 11,46 (user. s, 1H), 7,95 (m, 1H), 6.75 in (s, 1H), 6.73 x (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), of 2.34 (m, 4H), to 1.98 (m, 2H), 1,72 (m, 2H), 1,59 (m, 4H).

Example 86: synthesis of 1-(4-acetylpiperidine-1-yl)-2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanone

1-(4-Acetylpiperidine-1-yl)-2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]alanon

The compound (100 mg, 0.28 mmol)obtained in example 37 and 1-acetylpiperidine used instead of 1-methylpiperazine, were subjected to reaction according to the same procedure as in example 84, while receiving specified in the title compound (60 mg, yield 55%).

Example 87: synthesis of 2-[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-methylacetamide

2-[(R)-2-(7-Cyclopen is ylamino-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-methylacetamide

Compound (83 mg, 0.22 mmol)obtained in example 48 was dissolved in N,N-dimethylformamide (3 ml). To the solution was added methylamine (0.17 ml, 2 M solution in THF, 0.33 mmol), EDC (72 mg, 0.38 mmol) and NOT (60 mg, 0.44 mmol) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and concentrated. The residue was purified column chromatography, thus obtaining specified in the title compound (39 mg, yield 46%).

1H NMR (500 MHz, DMSO-d6); δ 11,22 (user. s, 1H), of 7.90 (m, 1H), is 6.61 (s, 1H), 6,23 (s, 1H), by 5.87 (m, 1H), to 5.85 (s, 1H), 4,90 (m, 1H), 3,76 (m, 1H), to 3.64 (s, 3H), 3,52 (m, 1H), 3,12 (m, 1H), 2,58 (m, 4H), to 2.35 (m, 1H), 1.91 a (m, 2H), 1,67 (m, 2H), 1,53 (m, 4H).

Example 88: synthesis of 2-[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-morpholine-4-ratanana

2-[(R)-2-(7-Cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-morpholine-4-ylatason

Compound (83 mg, 0.22 mmol)obtained in example 48, and morpholine used instead of methylamine, was subjected to reaction according to the same procedure as in example 87, while et is m specified in the title compound (24 mg, yield 24%).

1H NMR (500 MHz, DMSO-d6); δ 11,21 (user. s, 1H), 6,62 (s, 1H), 6,24 (s, 1H), by 5.87 (m, 1H), to 5.85 (s, 1H), 4.92 in (m, 1H), of 3.77 (m, 1H), the 3.65 (s, 3H), of 3.60 (m, 1H), to 3.58-to 3.33 (m, 8H), of 3.13 (m, 1H), 2,84 (m, 1H), 2,66 (m, 1H), 1.91 a (m, 2H), 1,67 (m, 2H), 1,53 (m, 4H).

Example 89: synthesis of 2-[(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-ethylacetamide

2-[(R)-2-(7-Cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-ethylacetamide

The compound (9 mg, 0.03 mmol)obtained in example 42 was dissolved in N,N-dimethylformamide (1 ml). To the solution was added ethylamine hydrochloride (3 mg, 0.03 mmol), EDC (8 mg, 0.04 mmol), NOT (5 mg, 0.04 mmol) and triethylamine (8 mg, 0.08 mmol) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and concentrated. The residue was purified column chromatography, thus obtaining specified in the title compound (4 mg, yield 41%).

1H NMR (400 MHz, CDCl3); δ 9,66, 7,08~of 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), to 2.67 (1H, m), 2,52 (m, 1H), 2,04 (m, 1H), 1,72~of 1.53 (m, 6H), a 1.08 (m, 3H).

Example 90: C the MES 2-[(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-methylacetamide

2-[(R)-2-(7-Cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-methylacetamide

Compound (97 mg, 0.28 mmol)obtained in example 42, and the methylamine used instead of ethylamine, was subjected to reaction according to the same procedure as in example 89, while receiving specified in the title compound (34 mg, yield 34%).

1H NMR (500 MHz, DMSO-d6); δ 11,33 (user. s, 1H), of 7.90 (m, 1H), 6,78 (m, 1H), of 6.71 (s, 1H), 6,24 (s, 1H), 5,80 (m, 1H), is 4.93 (m, 1H), 3,81 (m, 1H), 3,54 (m, 1H), 3,14 (m, 1H), 2,62 (m, 1H), 2,58 (m, 3H), of 2.38 (m, 1H), 1.93 and (m, 2H), 1.69 in (m, 2H), and 1.54 (m, 4H).

Example 91: synthesis of 2-[(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-morpholine-4-ratanana

2-[(R)-2-(7-Cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-morpholine-4-ylatason

Compound (97 mg, 0.28 mmol)obtained in example 42, and morpholine used instead of ethylamine, was subjected to reaction according to the same procedure as in example 89, while receiving specified in the title compound (19 mg, yield 16%).

1H NMR (500 MHz, DMSO-d6); δ 11,32 (user. s, 1H), 6,78 (m, 1H), of 6.71 (s, 1H), 6,24 (s, 1H), of 5.81 (m, 1H), 4.95 points (m, 1H), 3,81 (m, 1H), 3,61 (m, 1H), 3,59-3,39 (m, 8H), 3.15 in (m, N), 2,87 (m, 1H), 2,68 (m, 1H), 1.93 and (m, 2H), by 1.68 (m, 2H), and 1.54 (m, 4H).

Example 92: synthesis of N-methyl-2-{(R)-2-[7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ndimethylacetamide

N-Methyl-2-{(R)-2-[7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ndimethylacetamide

The compound (80 mg, 0.22 mmol)obtained in example 45 and used instead of the compound obtained in example 48 was subjected to reaction according to the same procedure as in example 87, while receiving specified in the title compound (17 mg, yield 20%).

1H NMR (500 MHz, DMSO-d6); δ 11,34 (user. s, 1H), of 7.90 (m, 1H), 6,79 (m, 1H), 6,72 (s, 1H), 6,33 (m, 1H), USD 5.76 (m, 1H), is 4.93 (m, 1H), 3,86 (m, 1H), 3,54 (m, 2H), 3.43 points (m, 2H), 3,14 (m, 1H), 2,61 (m, 1H), 2,59 (m, 3H), of 2.38 (m, 1H), 1,95 (m, 2H), 1,40 (m, 2H).

Example 93: synthesis of 1-morpholine-4-yl-2-{(R)-2-[7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanone

1-Morpholine-4-yl-2-{(R)-2-[7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}alanon

The compound (80 mg, 0.22 mmol)obtained in example 45 and used instead of the compound obtained in example 42 was subjected to reaction according to the same procedure as in the example 91, while receiving specified in the title compound (12 mg, yield 13%).

1H NMR (500 MHz, DMSO-d6); δ 11,34 (user. s, 1H), 6,79 (m, 1H), 6,72 (s, 1H), 6,33 (m, 1H), 5,77 (m, 1H), 4.95 points (m, 1H), a 3.87 (m, 1H), 3,61 (m, 1H), 3,57-to 3.38 (m, 11H)and 3.15 (m, 1H), 2,87 (m, 1H), 2,68 (m, 1H), 1,95 (m, 2H), 1,40 (m, 2H).

Getting 51: synthesis of {5-chloro-2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine

{5-Chloro-2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine

The compound (520 mg, of 1.43 mmol)obtained in example 28 was subjected to reaction according to the same procedure as in receipt of 50, while receiving specified in the title compound (524 mg, yield 77%).

Example 94: synthesis of {5-chloro-2-[(R)-4-(2-dimethylaminoethyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine

{5-Chloro-2-[(R)-4-(2-dimethylaminoethyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine

Compound (52 mg, 0.11 mmol)obtained in the obtaining 51, was dissolved in N,N-dimethylformamide (4 ml). To the solution was added dimethylamine (1.1 ml, 2 M solution in THF, 2.2 mmol) and potassium carbonate (300 mg, 2,17 mmol) and the mixture was stirred for 8 h at room is the temperature. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and concentrated. The residue was purified column chromatography, thus obtaining specified in the title compound (29 mg, yield 68%).

1H NMR (500 MHz, CDCl3); δ 10,07 (user. s, 1H), 6,99 (s, 1H), 6,80 (s, 1H), 6.42 per (s, 1H), 4,67 (m, 1H), 3,54 (m, 1H), and 3.16 (m, 1H), 2,46 (m, 1H), 2,37 (m, 1H), 2,19 (s, 6H), 2,02 (m, 3H), of 1.81 (m, 4H), 1.69 in (m, 4H).

Example 95: synthesis of {5-chloro-2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine

{5-Chloro-2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine

Compound (52 mg, 0.11 mmol)obtained in the obtaining 51, and morpholine used instead of dimethylamine, was subjected to reaction according to the same procedure as in example 94, while receiving specified in the title compound (18 mg, yield 38%).

1H NMR (DMSO-d6, ppm)δ 11,46 (1H, s), 6,79 (1H, s), of 6.68 (1H, s), 6,11 (1H, s)6,09 (1H, d), br4.61 (1H, Quinn.), 3,81 (1H, m), of 3.57 (4H, m)and 3.15 (1H, m), 2,50 is 2.43 (3H, m), 2,35 (4H, m), of 1.95 (2H, m), of 1.80 (1H, m), by 1.68 (2H, m), 1,57-1,49 (4H, m), 1,21 (1H, m).

FAB-MS (m/e) = 434.

Example 96: synthesis of {5-chloro-2-[(R)-4-(2-piperazine-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclo is entellina

{5-Chloro-2-[(R)-4-(2-piperazine-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine

The compound (250 mg, of 0.53 mmol)obtained in the obtaining 51, was dissolved in tetrahydrofuran (10 ml). To the solution was added 1-tert-butoxycarbonylmethyl (980 mg, 5,28 mmol) and potassium carbonate (730 mg, 5,28 mmol) and the mixture was stirred for 8 h at 80°C. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure.

Thus obtained compound was dissolved in dichloromethane (50 ml) and to the solution was added a 4 n solution of hydrochloric acid in ethyl acetate (1.3 ml, 5,28 mmol). The mixture was stirred for 4 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure, thus obtaining a solid substance. The solid is washed with ethyl simple with ether, and dried, thus obtaining specified in the title compound (125 mg, yield 55%).

1H NMR (DMSO-d6, ppm)δ of $ 11.48 (1H, s), 6,79 (1H, s), to 6.67 (1H, s), 6,11 (1H, s), 6,10 (1H, d), br4.61 (1H, m), 3,80 (1H, m), of 3.54 (1H, m)and 3.15 (1H, m), with 2.93 (2H, m), 2,50-to 2.41 (2H, m), 2,31 (3H, m), of 1.95 (4H, m), 1,79 (1H, m), by 1.68 (3H, m), 1,57 of 1.50 (4H, m), 1,20 (1H, m).

FAB-MS (m/e) = 432

Example 97: synthesis of 1-(4-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)ethanone

1-(4-{2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)alanon

The compound (80 mg, 0.22 mmol)obtained in the obtaining 51, and 1-acetylpiperidine used instead of dimethylamine, was subjected to reaction according to the same procedure as in example 94, while receiving specified in the title compound (26 mg, yield 33%).

1H NMR (500 MHz, DMSO-d6); δ 11,47 (user. s, 1H), 6,79 (s, 1H), of 6.68 (s, 1H), 6,16 (s, 1H), 6,11 (m, 1H), to 4.62 (m, 1H), 3,80 (m, 1H), 3,55 (m, 1H), 3,39 (m, 4H), 3.15 in (m, 1H), 2,46 (m, 1H), 2,32 (m, 4H), of 1.95 (m, 4H), of 1.80 (m, 1H), 1,68 (m, 2H), 1,53 (m, 4H).

Example 98: synthesis of (5-chloro-2-{(R)-4-[2-(4-acanaloniidae-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)cyclopentylamine

(5-Chloro-2-{(R)-4-[2-(4-acanaloniidae-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)cyclopentylamine

The compound (40 mg, 0.11 mmol)obtained in the obtaining 51, and 1-ethylsulphuric used instead of dimethylamine, was subjected to reaction according to the same procedure as the example 94, while receiving specified in the title compound (17 mg, yield 39%).

1H NMR (500 MHz, CDCl3); δ 11,29 (user. s, 1H), 6,97 (s, 1H), 6,86 (s, 1H), 6,37 (s, 1H), is 4.93 (m, 1H), 3,92 (user. s, 1H), of 3.77 (m, 1H), only 3.57 (m, 1H), and 3.16 (m, 1H), 2.95 and (m, 2H), 2,80 (m, 4H), 2,42-of 2.28 (m, 4H), 2,03 (m, 4H), of 1.74 (m, 3H), and 1.63 (m, 4H), USD 1.43 (m, 1H), 1,32 (t, 3H).

Example 99: synthesis of 1-(4-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)-2-hydroxyethane

1-(4-{2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)-2-hydroxyethane

Compound (85 mg, 0.20 mmol)obtained in example 96 was dissolved in N,N-dimethylformamide (1 ml). To the solution was added glycolic acid (22 mg, 0.30 mmol), EDC (64 mg, 033 mmol) and NOT (53 mg, 0,39 mmol) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and concentrated. The residue was purified column chromatography, thus obtaining specified in the title compound (41 mg, yield 44%).

1H NMR (500 MHz, DMSO-d6); δ 11,47 (user. s, 1H), 6,79 (s, 1H), of 6.68 (s, 1H), 6,16 (s, 1H), 6,10 (who, 1H), 4,63 (m, 1H), 4,50 (m, 1H), Android 4.04 (m, 2H), 3,81 (m, 1H), 3,55 (m, 1H), 3.43 points (m, 2H), and 3.16 (m, 1H), 2,52 (m, 2H), 2,35 (m, 4H), of 1.95 (m, 3H), of 1.81 (m, 1H), 1,68 (m, 2H), 1,53 (m, 4H).

Example 100: synthesis of (5-chloro-2-{(R)-4-[2-(4-methylpiperazin-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)cyclopentylamine

(5-Chloro-2-{(R)-4-[2-(4-methylpiperazin-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)cyclopentylamine

The compound (80 mg, 0.22 mmol)obtained in the obtaining 51, and 1-methylpiperazin used instead of dimethylamine, was subjected to reaction according to the same procedure as in example 94, while receiving specified in the title compound (24 mg, yield 32%).

1H NMR (500 MHz, DMSO-d6); δ 11,47 (user. s, 1H), 6,79 (s, 1H), to 6.67 (s, 1H), 6,16 (s, 1H), 6,10 (m, 1H), 4,59 (m, 1H), 3,80 (m, 1H), 3,54 (m, 1H), 3.15 in (m, 1H), 2.40 a (m, 10H)to 2.13 (s, 3H), of 1.95 (m, 3H), of 1.78 (m, 1H), 1,68 (m, 2H), 1,53 (m, 4H).

Example 101: the synthesis of 1-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperidine-4-ol

1-{2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperidine-4-ol

The compound (80 mg, 0.22 mmol)obtained in the obtaining 51, and 4-hydroxypiperidine, used mistadobalina, was subjected to reaction according to the same procedure as in example 94, while receiving specified in the title compound (28 mg, yield 37%).

1H NMR (500 MHz, DMSO-d6); δ 11,48 (user. s, 1H), 6,79 (s, 1H), of 6.68 (s, 1H), 6,16 (s, 1H), 6,10 (m, 1H), 4,60 (m, 1H), 3,80 (m, 1H), 3,54 (m, 1H), 3,32 (m, 4H), and 3.16 (m, 1H), 2,71 (m, 1H), 2,60 (m, 1H), 2,32 (m, 5H), 1,71 (m, 5H), of 1.57 (m, 5H).

Example 102: synthesis of (4-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-2-it

(4-{2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-2-he

The compound (80 mg, 0.22 mmol)obtained in the obtaining 51, and 2-oxopiperidin used instead of dimethylamine, was subjected to reaction according to the same procedure as in example 94, while receiving specified in the title compound (38 mg, 51%yield).

1H NMR (500 MHz, DMSO-d6); δ 11,48 (user. s, 1H), 7,71 (s, 1H), 6,79 (s, 1H), of 6.68 (s, 1H), 6,16 (s, 1H), 6,10 (m, 1H), br4.61 (m, 1H), 3,81 (m, 1H), 3,55 (m, 1H), 3,13 (m, 3H), of 2.92 (m, 2H), 2,56 (m, 3H), 1,96 (m, 3H), of 1.80 (m, 1H), 1,68 (m, 2H), 1,53 (m, 4H).

Example 103: synthesis of (5-chloro-2-{(R)-4-[2-(3-dimethylaminopropan-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)cyclopentylamine

The compound (80 mg, 0.22 mmol)obtained in the obtaining 51, and 3-dimethylaminopyridine used instead of dimethylamine, was subjected to reaction according to the same procedure as in example 94, while receiving specified in the title compound (21 mg, yield 27%).

1H NMR (500 MHz, DMSO-d6); δ 11,47 (user. s, 1H), 6,79 (s, 1H), to 6.67 (s, 1H), 6,16 (s, 1H), 6,11 (m, 1H), to 4.62 (m, 1H), 3,80 (m, 1H), 3,52 (m, 1H), 3.15 in (m, 1H), 2,66 (m, 2H), has 2.56 (m, 2H), 2,41 (m, 2H), and 2.27 (m, 1H), 1.93 and (m, 3H), 1,71 (m, 4H), of 1.53 (m, 4H).

Example 104: synthesis of {5-chloro-2-[(R)-4-(2-piperidine-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine

{5-Chloro-2-[(R)-4-(2-piperidine-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine

The compound (80 mg, 0.22 mmol)obtained in the obtaining 51, and the piperidine used instead of dimethylamine, was subjected to reaction according to the same procedure as in example 94, while receiving specified in the title compound (30 mg, yield 41%).

1H NMR (500 MHz, DMSO-d6); δ to 11.52 (user. s, 1H), 6,80 (s, 1H), 6,70 (s, 1H), 6,16 (s, 1H), 6,12 (m, 1H), 4,63 (m, 1H), 3,80 (m, 1H), only 3.57 (m, 1H), 3,29 (m, 4H), 3,17 (m, 1H), 2,60 (m, 4H), of 1.95 (m, 3H), by 1.68 (m, 2H), 1,58 (m, 9H).

Example 105: synthesis of (5-chloro-2-{(R)-4-[2-(1,-diocletianopolis-4-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)cyclopentylamine

(5-Chloro-2-{(R)-4-[2-(1,1-diocletianopolis-4-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)cyclopentylamine

The compound (80 mg, 0.22 mmol)obtained in the obtaining 51, and 1,1-dioxide thiomorpholine used instead of dimethylamine, was subjected to reaction according to the same procedure as in example 94, while receiving specified in the title compound (31 mg, yield 38%).

1H NMR (500 MHz, DMSO-d6); δ 11,48 (user. s, 1H), 6,79 (s, 1H), of 6.68 (s, 1H), 6,16 (s, 1H), 6,09 (m, 1H), br4.61 (m, 1H), 3,80 (m, 1H), of 3.56 (m, 1H), and 3.16 (m, 1H), of 3.07 (m, 4H), 2,89 (m, 4H), to 2.67 (m, 2H), was 1.94 (m, 3H), of 1.81 (m, 1H), 1,68 (m, 2H), 1,53 (m, 4H).

Example 106: synthesis of {5-chloro-2-[(R)-4-(2-pyrazole-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine

{5-Chloro-2-[(R)-4-(2-pyrazole-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine

Compound (81 mg, 0.11 mmol)obtained in example 51 was dissolved in tetrahydrofuran (4 ml). To the solution was added pyrazole (58 mg, 0.85 mmol) and sodium hydride (21 mg, 60%, 0.85 mmol) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried nadaswaram magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and concentrated. The residue was purified column chromatography, thus obtaining specified in the title compound (24 mg, yield 34%).

1H NMR (DMSO-d6, ppm)δ 11,50 (1H, s), 7,76 (1H, s), 7,42 (1H, s), to 6.80 (1H, s)6,70 (1H, s), from 6.22 (1H, s), 6,17 (1H, s), 6,11 (1H, d), of 4.49 (1H, Quinn.), 4,32 (2H, m), 3,80 (1H, m), 3,53 (1H, t), of 3.12 (1H, t), of 2.38 (1H, m), and 2.14 (1H, m), with 1.92 (2H, m), by 1.68 (2H, m), 1,59 of 1.50 (4H, m).

FAB-MS (m/e) = 414.

Example 107: synthesis of (S)-1-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}pyrrolidin-2-carboxylic acid

(S)-1-{2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}pyrrolidin-2-carboxylic acid

The compound (200 mg, 0.42 mmol)obtained in example 51 was dissolved in tetrahydrofuran (20 ml). To the solution was added the hydrochloride of the methyl ether pyrrolidin-2-carboxylic acid (700 mg, 4,22 mmol) and potassium carbonate (1.2 g, 8,44 mmol) and the mixture was stirred for 8 h at 80°C. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure.

Thus obtained compound was dissolved in tetrahydrofuran (10 ml), methanol (10 ml) and water (10 ml). K R is the target monohydrate was added lithium hydroxide (71 mg, 1.70 mmol) and the mixture was stirred for 4 h at room temperature. After completion of the reaction was added 1 n hydrochloric acid. The mixture was extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (34 mg, yield 18%).

1H NMR (CDCl3, ppm)δ 12,04 (1H, s), 11,02 (1H, s), 6,85 (1H, s), 6,69 (1H, s), of 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), or 3.28 (1H, m), 3,17 (1H, m), is 2.88 (2H, m)at 2.59 (1H, m), of 2.21 (1H, m), 2.06 to 1,59 (11H, m)of 1.23 (1H, m).

FAB-MS (m/e) = 461.

Example 108: synthesis of {5-chloro-2-[(R)-4-(2-methansulfonate)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine

{5-Chloro-2-[(R)-4-(2-methansulfonate)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine

The compound (50 mg, 0.11 mmol)obtained in example 51 was dissolved in N,N-dimethylformamide (2 ml). To the solution was added methanesulfonic sodium (54 mg, 0.55 mmol) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtration is ovale. The filtrate was distilled under reduced pressure and concentrated. The residue was purified column chromatography, thus obtaining specified in the title compound (19 mg, yield 45%).

1H NMR (400 MHz, CDCl3); δ accounted for 10.39 (user. s, 1H), 7,03 (s, 1H), 6.89 in (s, 1H), 6.48 in (s, 1H), 6,17 (s, 1H), 4,77 (m, 1H), a 3.87 (m, 1H)and 3.59 (m, 1H), 3,29 (m, 1H), 3,17 (m, 2H), 2,86 (s, 3H), and 2.26 (m, 2H), 2,10 (m, 2H), 1.70 to (m, 4H)and 1.51 (m, 2H).

Example 109: synthesis of ethyl ester of 3-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}-5-methyl-3H-imidazole-4-carboxylic acid

Ethyl ester of 3-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}-5-methyl-3H-imidazole-4-carboxylic acid

The compound (150 mg, 0.31 mmol)obtained in the obtaining 51, and ethyl ester 5-methyl-3H-imidazole-4-carboxylic acid used instead of pyrazole was subjected to reaction according to the same procedure as in example 106, while receiving specified in the title compound (74 mg, yield 47%).

1H NMR (500 MHz, DMSO-d6); δ 11,49 (user. s, 1H), 7,71 (s, 1H), 6,80 (s, 1H), 6,72 (s, 1H), 6,17 (s, 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 (s, 3H), 2,11 (m, 2H), 1,95 (m, 2H), by 1.68 (m, 2H), 1,53 (m, 4H), 1,22 (m, 3H).

Example 110: synthesis of 3-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-yl]ethyl}-5-methyl-3H-imidazole-4-carboxylic acid

3-{2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}-5-methyl-3H-imidazole-4-carboxylic acid

Compound (35 mg, 0.07 mmol)obtained in example 109 was dissolved in tetrahydrofuran (10 ml), methanol (10 ml) and water (10 ml). To the solution was added monohydrate of lithium hydroxide (29 mg, 0.70 mmol) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added 1 n hydrochloric acid. The mixture was extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (17 mg, yield 52%).

1H NMR (DMSO-d6, ppm)δ 11,50 (1H, s), 7,71 (1H, s), to 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-of 2.15 (2H, m), of 1.95 (3H, m), by 1.68 (3H, m)and 1.51 (5H, m).

FAB-MS (m/e) = 472.

Example 111: synthesis of 1-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}pyrrolidin-2-it

1-{2-[(R)-2-(5-Chloro-7-cyclopentylamine-1H and the Dol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}pyrrolidin-2-he

The compound (80 mg, 0.22 mmol)obtained in the obtaining 51, and pyrrolidine used instead of dimethylamine, was subjected to reaction according to the same procedure as in example 94, while receiving specified in the title compound (17 mg, yield 36%).

1H NMR (500 MHz, DMSO-d6); δ 11,49 (user. s, 1H), 6,80 (s, 1H), 6,69 (s, 1H), 6,16 (s, 1H), 4,51 (m, 1H), 3,80 (m, 1H), only 3.57 (m, 1H), 3.46 in (m, 1H), 3,32 (m, 1H), 3.15 in (m, 1H), 2,18 (m, 2H), 1.91 a (m, 5H), of 1.80 (m, 1H), 1,68 (m, 2H), 1,53 (m, 4H).

Getting 52: synthesis of {5-chloro-2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine

{5-Chloro-2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)Amin

The compound (3.7 g, 10.2 mmol)obtained in example 32 was dissolved in tetrahydrofuran (10 ml). To the solution was added imidazole (2.1 g, 30,6 mmol), triphenylphosphine (4.0 g, of 15.3 mmol) and iodine (3,9 g of 15.3 mmol) and the mixture was stirred for 8 hours at a temperature of 0°C~room temperature. After completion of the reaction was added ethyl acetate (100 ml) and the mixture was washed with water (2×100 ml). The organic layer was concentrated and the residue was divided by column chromatography, thus obtaining specified in the title compound (2.0 g, 4.07 mmol, yield 40%).

Getting 53: synthesis of ethyl ester of 1-(2-{(R)-2-5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperidine-3-carboxylic acid

Ethyl ester of 1-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperidine-3-carboxylic acid

The compound (300 mg, to 0.63 mmol)obtained in the obtaining 52, was dissolved in N,N-dimethylformamide (20 ml). To the solution was added ethyl ether piperidine-3-carboxylic acid (1.97 ml, 12.7 mmol) and potassium carbonate (1.75 g, 12.7 mmol) and the mixture was stirred for 4 h at room temperature. After completion of the reaction was added 1 n hydrochloric acid. The mixture was extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (150 mg, yield 46%).

1H NMR (DMSO-d6, ppm)δ of $ 11.48 (1H, s), PC 6.82 (1H, s), to 6.67 (1H, s)of 6.29 (1H, s), 6,04 (1H, d), br4.61 (1H, Quinn.), 4,47 (1H, m), a 3.87 (2H, m), 3,62 (2H, square), of 3.56 (2H, m), 3,44-3,39 (4H, m), 3,14 (2H, m), 2,52 (1H, m), 2,37-of 2.30 (6H, m), 1,96-of 1.92 (3H, m), is 1.81 (1H, m)of 1.42 (2H, m)of 1.28 (3H, t).

FAB-MS (m/e) = 519.

Example 112: synthesis of 1-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperidine-3-carboxylic acid

1-(2-{(R)-2-[5-Chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperidine-3-carboxylic acid

The compound (135 mg, 0.28 mmol)obtained in the obtaining 53, was subjected to reaction according to the same procedure as in example 110, while receiving specified in the title compound (90 mg, yield 58%).

1H NMR (DMSO-d6, ppm)δ 13,17 (1H, s)11,94 (1H, s), to 6.80 (1H, s), of 6.68 (1H, s), 6,28 (1H, s), 6,04 (1H, d), to 4.62 (1H, Quinn.), 4,47 (1H, m), a 3.87 (2H, m), of 3.56 (2H, m), 3,44-3,39 (4H, m), 3,14 (2H, m), 2,52 (1H, m), 2,37-of 2.30 (6H, m), 1,96-of 1.92 (3H, m), of 1.80 (1H, m)of 1.40 (2H, m).

FAB-MS (m/e) = 491.

Example 113: synthesis of dimethylamide 1-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperidine-3-carboxylic acid

Dimethylamide 1-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperidine-3-carboxylic acid

Compound (84 mg, 0.18 mmol)obtained in example 112 was dissolved in N,N-dimethylformamide (4 ml). To the solution was added dimethylamine (0,13 ml, 2 M solution in THF, 0.27 mmol), EDC (58 mg, 0.30 mmol) and NOT (48 mg, 0.35 mmol) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added a saturated solution of bicarb the Nata sodium. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and concentrated. The residue was purified column chromatography, thus obtaining specified in the title compound (18 mg, yield 20%).

1H NMR (DMSO-d6, ppm)δ of $ 11.48 (1H, s), for 6.81 (1H, s), 6,69 (1H, s), 6,28 (1H, s), 6,04 (1H, d), 4,60 (1H, Quinn.), a 3.87 (2H, m), of 3.56 (2H, m), 3,44 (2H, t), and 3.16 (1H, m), of 2.97 (3H, s), 2,95 (1H, m), 2,88 was 2.76 (2H, m), is 2.74 (5H, m)a 1.96 (4H, m), of 1.80 (2H, m)of 1.66 (2H, m), 1,50 to 1.37 (3H, m)of 1.23 (1H, m).

FAB-MS (m/e) = 518.

Example 114: synthesis of tert-butyl ester [(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)pyrrolidin-3-yl]carbamino acid

tert-Butyl ester [(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)pyrrolidin-3-yl]carbamino acid

The compound (300 mg, to 0.63 mmol)obtained in the obtaining 52, and tert-butyl methyl ether (S)-pyrrolidin-3-ylcarbamate acid is used instead of the ethyl ester piperidine-3-carboxylic acid, was subjected to reaction according to the same procedure as in example 53, while receiving specified in the title compound (210 mg, yield 61%).

1H NMR (500 MHz, DMSO-d6); δ 11,48 (user. s, 1H), 6,92 (m, 1 is), for 6.81 (s, 1H), of 6.68 (s, 1H), 6,28 (m, 1H), equal to 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 to of 2.58 (m, 2H, in), 2.25 (m, 1H), 1,95 (m, 4H), of 1.75 (m, 1H), of 1.52 (m, 1H), 1.39 in (m, 2H), 1,37-1,32 (m, 11H).

Example 115: synthesis of (2-{(R)-4-[2-((S)-3-aminopyrrolidine-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-chloro-1H-indol-7-yl)-(tetrahydropyran-4-yl)amine

(2-{(R)-4-[2-((S)-3-Aminopyrrolidine-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-chloro-1H-indol-7-yl)-(tetrahydropyran-4-yl)Amin

The compound (150 mg, 0.27 mmol)obtained in example 114 was dissolved in dichloromethane (30 ml). To the solution was added a 4 n solution of hydrochloric acid in dioxane (0,34 ml, 1.35 mmol) and the mixture was stirred for 4 h at room temperature. After completion of the reaction, the reaction solution was distilled under reduced pressure to obtain a solid substance. The solid is washed with ethyl simple with ether, and dried, thus obtaining specified in the title compound (92 mg, yield 75%).

1H NMR (DMSO-d6, ppm) δ 10,92 (1H, s), 8,63 (2H, s, of usher.), 6,86 (1H, s), 6,83 (1H, s), to 6.43 (1H, s), 6,11 (1H, m), 4.72 in (1H, m), the 3.65 (5H, m), of 3.45 (5H, m), up 3.22 (3H, m), is 2.37 (2H, m), 2,19 (3H, m), 1,90 (2H, m), for 1.49 (2H, m).

FAB-MS (m/e) = 448.

Example 116: synthesis of N-[(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)pyrrolidin-3-yl]acetone is Yes

N-[(S)-1-(2-{(R)-2-[5-Chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)pyrrolidin-3-yl]ndimethylacetamide

Compound (85 mg, 0,19 mmol)obtained in example 115 was dissolved in dichloromethane (10 ml). To the solution was added diisopropylethylamine made (0.13 ml, 0.75 mmol) and acetylchloride (0,013 ml to 0.19 mmol) and the mixture was stirred for 30 min at room temperature. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and concentrated. The residue was purified column chromatography, thus obtaining specified in the title compound (39 mg, yield 42%).

1H NMR (DMSO-d6, ppm) δ 11,49 (1H, s), of 7.97 (1H, s), for 6.81 (1H, s), 6,69 (1H, s), 6,28 (1H, s), equal to 6.05 (1H, d), with 4.64 (1H, Quinn.), of 4.12 (1H, m), 3,85 (2H, m), 3,53 (2H, m), 3,44 (2H, t)to 3.34 (2H, m)and 3.15 (1H, t), 2,72-2,60 (3H, m), 2,39 (1H, m), 2.05 is-to 1.87 (4H, m), 1,80-1,72 (4H, m)of 1.53 (1H, m)to 1.37 (2H, m).

FAB-MS (m/e) = 490.

Example 117: synthesis of {5-chloro-2-[(R)-4-(2-piperazine-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine

{5-Chloro-2-[(R)-4-(2-piperazine-1-retil)-4,5-dihydro shall eazol-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)Amin

The compound (100 mg, 0.2 mmol), obtained in the obtaining 52, was subjected to reaction according to the same procedure as in example 96, while receiving specified in the title compound (25 mg, 30%yield).

1H NMR (DMSO-d6, ppm)δ 11,42 (1H, s), 6,83 (1H, s), 6,74 (1H, s), 6.30-in H, (C), of 6.02 (1H, d), 4,69 (1H, m), 3,85 (1H, m), 3,52-of 3.42 (6H, m)to 3.35 (3H, m), 3,20 (2H, m)of 2.16 (2H, m), with 1.92 (3H, m)of 1.42 (3H, m).

FAB MS (m/e) = 448.

Example 118: synthesis of 1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]-2-hydroxyethane

1-[4-(2-{(R)-2-[5-Chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]-2-hydroxyethane

The compound (23 mg, 0.05 mmol)obtained in example 117 was dissolved in N,N-dimethylformamide (5 ml). To the solution was added glycolic acid (15.1 mg, 0.2 mmol), triethylamine (28 μl, 0.2 mmol), EDC (45 mg, 0.23 mmol) and NOT (40 mg, 0.29 mmol) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added 1 n hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in is the head of the compound (5 mg, yield 19%).

1H NMR (500 MHz, DMSO-d6); δ 11,48 (user. s, 1H), for 6.81 (s, 1H), 6,69 (d, J=1.8 Hz, 1H), 6,29 (s, 1H), equal to 6.05 (d, J=7,4 Hz, 1H), to 4.62 (m, 1H), 4,49 (t, 1H), Android 4.04 (m, 2H), a 3.87 (m, 2H), of 3.56 (m, 1H), of 3.45 (m, 4H), 3,29 (m, 4H), and 3.16 (m, 1H), 2,36 (m, 4H), to 1.96 (m, 3H), of 1.80 (m, 1H), 1,40 (m, 2H).

Example 119: synthesis of 1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]-2-tetrazol-1 ratanana

1-[4-(2-{(R)-2-[5-Chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]-2-tetrazol-1-ylatason

Compound (61 mg, 0.14 mmol)obtained in example 117, and 1H-tetrazol-1-acetic acid is used instead of glycolic acid was subjected to reaction according to the same procedure as in example 118, while receiving specified in the title compound (31 mg, yield 48%).

1H NMR (DMSO-d6, ppm)δ of $ 11.48 (1H, s), 9,26 (1H, s), for 6.81 (1H, s)6,70 (1H, s)of 6.29 (1H, s), 6,04 (1H, d), the ceiling of 5.60 (2H, s), with 4.64 (1H, Quinn.), a 3.87 (2H, m), of 3.57 (2H, m), 3,47-3,41 (7H, m), 3,17 (2H, m), 2,58 (1H, m), 2,39 (2H, m), 1,99-of 1.93 (4H, m), is 1.81 (1H, m)of 1.40 (2H, m).

FAB-MS (m/e) = 558.

Example 120: synthesis of 1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]-3,3,3-cryptochrome-1-it

1-[4-(2-{(R)-2-[5-Chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]-3,3,3-cryptochrome-1-he

Compound (66 mg, 0.15 mmol)obtained in example 117 was dissolved in dichloromethane (10 ml). To the solution was added diisopropylethylamine (0,08 ml, 0.44 mmol) and 2,5-dioxopiperidin-1 silt ester of 3,3,3-triptocaine acid (29 mg, 0.13 mmol) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (6 mg, yield 9%).

1H NMR (DMSO-d6, ppm)δ 11,47 (1H, s), for 6.81 (1H, s), 6,69 (1H, s), 6,28 (1H, s)6,09 (1H, d), to 4.62 (1H, Quinn.), a 3.87 (2H, m), of 3.56 (4H, m), 3,47-3,38 (7H, m), and 3.16 (1H, m), 2,53 (1H, m), 2,37-of 2.30 (4H, m), of 1.94 (3H, m), is 1.81 (1H, m)of 1.40 (2H, m).

FAB-MS (m/e) = 558.

Example 121: synthesis of [4-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]furan-2-ylmethanone

[4-(2-{(R)-2-[5-Chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]furan-2-ylmethanol

With the unity (100 mg, 0.20 mmol)obtained in the obtaining 52, and paranoidparanoid used instead of the ethyl ester piperidine-3-carboxylic acid, was subjected to reaction according to the same procedure as in example 53, while receiving specified in the title compound (19 mg, yield 17%).

1H NMR (500 MHz, DMSO-d6); δ 11,48 (user. s, 1H), 7,79 (s, 1H), for 6.81 (s, 1H), 6,69 (s, 1H), 6,59 (m, 1H), 6,28 (s, 1H), equal to 6.05 (m, 1H), 4,63 (m, 1H), 3,86 (m, 2H), 3,57 (m, 6H), 3,44 (m, 2H), and 3.16 (m, 2H), has 2.56 (m, 1H), 1,96 (m, 3H)and 1.83 (m, 1H), 1,41 (m, 2H).

Example 122: synthesis of (5-chloro-2-{(R)-4-[2-(2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)-(tetrahydropyran-4-yl)amine

(5-Chloro-2-{(R)-4-[2-(2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)-(tetrahydropyran-4-yl)Amin

The compound (100 mg, 0.20 mmol)obtained in the obtaining 52, and 1-(2-pyrazinyl)piperazine used instead of the ethyl ester piperidine-3-carboxylic acid, was subjected to reaction according to the same procedure as in obtaining 53, while receiving specified in the title compound (13 mg, yield 12%).

1H NMR (500 MHz, DMSO-d6); δ 11,48 (user. s, 1H), of 8.27 (s, 1H), 8,04 (s, 1H), 7,80 (s, 1H), for 6.81 (s, 1H), 6,69 (s, 1H), 6,29 (s, 1H), equal to 6.05 (m, 1H), with 4.64 (m, 1H), 3,86 (m, 2H), only 3.57 (m, 2H), 3,53 (m, 4H), 3,18 (m, 1H), 2.57 m (m, 1H), 1,99 (m, 1H), 1,95 (m, 2H)and 1.83 (m, 1H), 1,4 (m, 2H).

Example 123: synthesis of (5-chloro-2-{(R)-4-[2-(4-(pyrimidine-2-reparation-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)-(tetrahydropyran-4-yl)amine

(5-Chloro-2-{(R)-4-[2-(4-(pyrimidine-2-reparation-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)-(tetrahydropyran-4-yl)Amin

The compound (100 mg, 0.20 mmol)obtained in the obtaining 52, and 1-(2-pyrimidyl)piperazine used instead of the ethyl ester piperidine-3-carboxylic acid, was subjected to reaction according to the same procedure as in obtaining 53, while receiving specified in the title compound (10 mg, yield 9%).

1H NMR (500 MHz, DMSO-d6); δ 11,49 (user. s, 1H), 8,31 (m, 1H), for 6.81 (s, 1H), 6,69 (s, 1H), return of 6.58 (m, 1H), 6,28 (s, 1H), the 6.06 (m, 1H)and 4.65 (m, 1H), 3,86 (m, 2H), 3,69 (m, 4H), to 3.58 (m, 2H), of 3.45 (m, 2H), 3,35 (m, 1H), 3,18 (m, 1H), has 2.56 (m, 1H), 2,43 (m, 3H), 2,00 (m, 1H), 1,96 (m, 2H), 1,40 (m, 2H).

Getting 54: Synthesis cyclopentyl-{5-fluoro-2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

Cyclopentyl-{5-fluoro-2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

The compound (120 mg, 0.35 mmol)obtained in example 39 was subjected to reaction according to the same procedure as in example 50, olucha when this is mentioned in the title compound (110 mg, yield 70%).

Example 124: synthesis of {2-[(R)-4-(2-amino-ethyl)-4,5-dihydrothieno-2-yl]-5-fluoro-1H-indol-7-yl}cyclopentylamine

{2-[(R)-4-(2-amino-ethyl)-4,5-dihydrothieno-2-yl]-5-fluoro-1H-indol-7-yl}cyclopentylamine

(Stage 1)

{2-[(R)-4-(2-Azidoethyl)-4,5-dihydrothieno-2-yl]-5-fluoro-1H-indol-7-yl}cyclopentylamine

The compound (100 mg, 0.22 mmol)obtained in example 54 was dissolved in N,N-dimethylformamide (2 ml). To the solution was added sodium azide (43 mg, 0.66 mmol) and the mixture was stirred for 1 h at 70°C. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining etidocaine (75 mg, yield 9%).

(Stage 2)

The compound (70 mg, 0,19 mmol)obtained in stage 1, was dissolved in tetrahydrofuran (3 ml). To the solution was added water (4 μl, 0.21 mmol) and triphenylphosphine (55 mg, 0.31 mmol) and the mixture was stirred for 2 h at 80°C. After completion of the reaction, the reaction solution was distilled under reduced pressure and was purified in the column chromatography, while receiving specified in the title compound (45 mg, yield 69%).

1H NMR (400 MHz, CDCl3/DMSO-d6); δ 11,28 (user. s, 1H), 6,80 (user. s, 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), to 3.02 (m, 1H), 2,13~of 1.55 (m, 10H).

Receive 55: synthesis of 2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl ester methanesulfonic acid

2-[(R)-2-(7-Cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl ester methanesulfonic acid

The compound (1.0 g, 2,87 mmol)obtained in example 39 was subjected to reaction according to the same procedure as in obtaining 22, while receiving specified in the title compound (1.1 g, yield 90%).

Example 125: synthesis of 1-(4-{2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)ethanone

1-(4-{2-[(R)-2-(7-Cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)alanon

The compound (100 mg, 0.23 mmol)obtained in the obtaining 55, was dissolved in N,N-dimethylformamide (10 ml). To the solution was added triethylamine (48 mg, 0.47 mmol) and 1-acetylide asin (92 mg, 0.70 mmol) and the mixture was stirred for 8 h at 50°C. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (60 mg, yield 56%).

1H NMR (400 MHz, CDCl3); δ 10,47 (user. s, 1H), 6.87 in (s, 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)and 3.59 (m, 2H), 3,49 (m, 1H), or 3.28 (m, 1H), 3,18 (m, 1H), 2,44 (m, 2H), 2,34 (m, 1H), 2.23 to (m, 2H), and 2.14 (m, 1H), 2.05 is (s, 3H), 1.93 and (m, 1H), is 1.81 (m, 1H), 1,71 (m, 5H), to 1.48 (m, 2H).

Example 126: synthesis cyclopentyl-{5-fluoro-2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

Cyclopentyl-{5-fluoro-2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

The compound (100 mg, 0.23 mmol)obtained in the obtaining 55, and morpholine used instead of 1-acetylpiperidine, were subjected to reaction according to the same procedure as in example 125, while receiving specified in the title compound (50 mg, yield 52%).

1H NMR (400 MHz, CDCl3); δ 10,92 (user. s, 1H), 6.87 in (s, 1H), only 6.64 (d, J=8.0 Hz, 1H), 6,24 (d, J=12.0 Hz, 1H), a 4.83 (m, 1H), 3,93 (m, 1H), of 3.77 (m, 1H), 3,54 (m, 4H), 3,47 (m, 1H), 3,17 (m, 1H), of 2.38 (m, 1H), 2,33 (m, 2H), 2,16 (m, 2H), 2,04 (m, 3H), 1.77 in (m, 1H), of 1.65 (m, 4H), 1,47 (m, 1H), 1,35 (m, 1H).

Example 127: synthesis cyclopentyl-{2-[(R)-4-(2-dimethylaminoethyl)-4,5-dihydrothieno-2-yl]-5-fluoro-1H-indol-7-yl}Amin

Cyclopentyl-{2-[(R)-4-(2-dimethylaminoethyl)-4,5-dihydrothieno-2-yl]-5-fluoro-1H-indol-7-yl}Amin

The compound (100 mg, 0.23 mmol)obtained in the obtaining 55, and dimethylamine used instead of 1-acetylpiperidine, were subjected to reaction according to the same procedure as in example 125, while receiving specified in the title compound (40 mg, yield 47%).

1H NMR (400 MHz, CDCl3); δ 10,99 (user. s, 1H), 6,80 (s, 1H), 6,60 (d, J=8.0 Hz, 1H), from 6.22 (d, J=12.0 Hz, 1H), 4,59 (m, 1H), 4,13 (m, 1H), 3,47 (m, 1H), 3,03 (m, 1H), 2,90 (m, 1H), to 2.55 (m, 1H), 2,42 (s, 6H), for 2.01 (m, 3H), of 1.81 (m, 1H), 1,62 (m, 2H), 1.55V (m, 4H).

Example 128: synthesis cyclopentyl-{5-fluoro-2-[(R)-4-(2-pyrrolidin-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

Cyclopentyl-{5-fluoro-2-[(R)-4-(2-pyrrolidin-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

The compound (100 mg, 0.23 mmol)obtained in the obtaining 55, and pyrrolidin used instead of 1-acetylpiperidine, were subjected to reaction according to the same procedure as in example 125, while this is mentioned in the title compound (30 mg, yield 33%).

1H NMR (400 MHz, CDCl3); δ is 11.39 (user. s, 1H), for 6.81 (s, 1H), 6,63 (DD, 1H), and 6.25 (DD, 1H), 4,59 (m, 1H), 4,17 (m, 1H), with 3.89 (m, 1H), 3,32 (m, 1H), of 3.07 (m, 3H), 2,71 (m, 1H), 2,09 (m, 2H), 1,95 (m, 4H), 1.77 in (m, 2H), of 1.65 (m, 4H).

Example 129: synthesis cyclopentyl-(2-{(R)-4-[2-(1,1-diocletianopolis-4-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-fluoro-1H-indol-7-yl)amine

Cyclopentyl-(2-{(R)-4-[2-(1,1-dioxo-1-lambda*6*-thiomorpholine-4-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-fluoro-1H-indol-7-yl)Amin

The compound (100 mg, 0.23 mmol)obtained in the obtaining 55, and 1,1-dioxide thiomorpholine used instead of 1-acetylpiperidine, were subjected to reaction according to the same procedure as in example 125, while receiving specified in the title compound (10 mg, yield 9%).

1H NMR (400 MHz, CDCl3); δ 11,05 (user. s, 1H), 6,94 (s, 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 (square, 1H), 3,18 (square, 1H), 3,00 (m, 8H), is 2.74 (m, 2H), 2.05 is (m, 3H), 1,79 (m, 2H), 1,63 (m, 4H).

Example 130: synthesis of 4-{2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-2-it

4-{2-[(R)-2-(7-Cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-2-he

The compound (200 mg, 0.44 mmol)obtained in the obtaining 55, was dissolved in tetrahydrofuran (5 ml). To the solution was added 2-oxopiperidin (87 mg, 0.88 mmol) and potassium carbonate (118 mg, 0.88 mmol) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (650 mg, yield 27%).

1H NMR (400 MHz, CDCl3); δ of 11.26 (user. s, 1H), 7,26 (user. s, 1H), 6.87 in (s, 1H), return of 6.58 (d, J=8.0 Hz, 1H), from 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), of 1.95 (m, 1H), 1,74 (m, 2H), 1,62 (m, 2H).

Example 131: synthesis of 1-(4-{2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)-2-hydroxyethane

1-(4-{2-[(R)-2-(7-Cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)-2-hydroxyethane

The compound (500 mg, of 1.09 mmol)obtained in the obtaining 55 were subjected to reaction according to the same methods as in example 96 and example 99, while receiving specified in the title compound (100 mg, yield 19%).

1H NMR (400 MHz, CDCl3) of 11.26 δ (user. s, 1H), 6.89 in (s, 1H), 6,63 (d, J=8.0 Hz, 1H), from 6.22 (d, J=12.0 Hz, 1H), around 4.85 (m, 1H), 4,10 (s, 2H), of 3.77 (m, 1H), only 3.57 (m, 2H), 3,41 (m, 1H), 3,14 (square, 1H), 3,00 (m, 1H), 2.91 in (m, 1H), of 2.38 (m, 3H), 2,12 (m, 2H), 2,02 (m, 4H), of 1.85 (m, 1H), 1.77 in (m, 1H), and 1.63 (m, 4H), of 1.36 (m, 1H), 1.26 in (m, 1H).

Example 132: synthesis cyclopentyl-{5-fluoro-2-[(R)-4-(2-methansulfonate)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

Cyclopentyl-{5-fluoro-2-[(R)-4-(2-methansulfonate)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

The compound (50 mg, 0.12 mmol)obtained in the obtaining 55, and sodium iodide (88 mg, 0.59 mmol) was dissolved in N,N-dimethylformamide (5 ml) and the solution was stirred for 6 h at 50°C. To the solution was added methanesulfonic sodium (60 mg, 0.59 mmol) and the mixture was stirred for 8 h at room temperature. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (14 mg, yield 29%).

1H NMR (400 MHz, CDCl3); δ 9,89 (user. s, 1H), 6.87 in (s, 1H), to 6.67 (DD, 1H), 6,28 (DD, 1H), 4,77 (m, 1H), 3,83 (t, 1H)and 3.59 (m, 1H), and 3.31 (m, 1H), 3,13 (m, 2H), 2,84 (s, 3H), and 2.27 (m, 2H), 2,04 (m, 2H), by 1.68 (m, 6H)and 1.51 (m, 2H).

Getting 56: synthesis of 2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-the laminitis)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl ester methanesulfonic acid

2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl ester methanesulfonic acid

The compound (740 mg, 2.03 mol)obtained in example 44 was subjected to a reaction by the same procedure as in obtaining 22, while receiving specified in the title compound (750 mg, yield 84%).

Example 133: synthesis of {2-[(R)-4-dimethylaminoethyl)-4,5-dihydrothieno-2-yl]-5-fluoro-1H-indol-7-yl}(tetrahydropyran-4-yl)amine

{2-[(R)-4-Dimethylaminoethyl)-4,5-dihydrothieno-2-yl]-5-fluoro-1H-indol-7-yl}(tetrahydropyran-4-yl)Amin

The compound (100 mg, 0.23 mmol)obtained in the obtaining 56, and dimethylamine used instead of 1-acetylpiperidine, were subjected to reaction according to the same procedure as in example 125, while receiving specified in the title compound (21 mg, yield 23%).

1H NMR (400 MHz, CDCl3); δ 11,27 (user. s, 1H), 6,79 (s, 1H), 6,60 (d, J=8.0 Hz, 1H), from 6.22 (d, J=12.0 Hz, 1H), br4.61 (m, 1H), 4,13 (m, 2H)and 3.59 (m, 4H), 3.04 from (m, 1H), to 2.55 (s, 4H), 2,04 (m, 6H), of 1.65 (m, 2H), 1.26 in (m, 2H).

Example 134: synthesis of {5-fluoro-2-[(R)-4-(2-pyrrolidin-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine

{5-fluoro-2-[(R)-4-(2-pyrrolidin-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)Amin

The compound (100 mg, 0.23 mmol)obtained in the obtaining 56, and pyrrolidin used instead of 1-acetylpiperidine, were subjected to reaction according to the same procedure as in example 125, while receiving specified in the title compound (29 mg, 30%yield).

1H NMR (400 MHz, CDCl3); δ 11,16 (user. s, 1H), 6.87 in (s, 1H), of 6.68 (d, J=8.0 Hz, 1H), of 6.26 (d, J=12.0 Hz, 1H), 4,69 (m, 1H), 4,17 (d, J=8.0 Hz, 2H), 3,60 (m, 5H), 3,17 (m, 1H), 2,90 (m, 1H), to 2.67 (m, 5H), is 2.09 (m, 3H), 1,90 (m, 4H), 1.57 in (m, 2H).

Example 135: synthesis of {5-fluoro-2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine

{5-fluoro-2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)Amin

The compound (100 mg, 0.23 mmol)obtained in the obtaining 56, and morpholine used instead of 1-acetylpiperidine, were subjected to reaction according to the same procedure as in example 125, while receiving specified in the title compound (16 mg, yield 16%).

1H NMR (400 MHz, CDCl3); δ 11,16 (user. s, 1H), 6,86 (s, 1H), only 6.64 (d, J=8.0 Hz, 1H), 6,23 (d, J=12.0 Hz, 1H), and 4.75 (m, 1H), was 4.02 (m, 1H), 3,66 (m, 4H), 3,51 (who, 4H), 3,18 (m, 1H), 2,60 (m, 1H), 2.49 USD (m, 4H), 2,07 (m, 4H), of 1.80 (m, 1H), and 1.54 (m, 2H).

Example 136: synthesis of 1-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethylpiperazin-1-yl)ethanone

1-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]alanon

The compound (100 mg, 0.23 mmol)obtained in the obtaining 56, and 1-acetylpiperidine was subjected to reaction according to the same procedure as in example 125, while receiving specified in the title compound (24 mg, yield 22%).

1H NMR (400 MHz, CDCl3); δ 10,20 (user. s, 1H), 6.87 in (s, 1H), of 6.68 (d, J=8.0 Hz, 1H), 6,27 (d, J=12.0 Hz, 1H), amounts to 4.76 (m, 1H), 4,01 (m, 3H), 3,61 (m, 4H), 3,30 (m, 2H), 3,20 (m, 1H), of 2.51 (m, 2H), 2,33 (m, 4H), to 2.06 (m, 7H), 1,99 (m, 1H), 1,49 (m, 2H).

Example 137: synthesis of (2-{(R)-4-[2-(1,1-diocletianopolis-4-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-fluoro-1H-indol-7-yl)-(tetrahydropyran-4-yl)amine

(2-{(R)-4-[2-(1,1-Dioxo-lambda-*6*-thiomorpholine-4-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-fluoro-1H-indol-7-yl)-(tetrahydropyran-4-yl)Amin

The compound (100 mg, 0.23 mmol)obtained in the obtaining 56, and 1,1-dioxide thiomorpholine used instead of 1-acetylide the azina, was subjected to reaction according to the same procedure as in example 125, while receiving specified in the title compound (28 mg, yield 25%).

1H NMR (400 MHz, CDCl3); δ 6,93 (s, 1H), only 6.64 (d, J=8.0 Hz, 1H), 6,28 (d, J=12.0 Hz, 1H), and 4.68 (m, 1H), a 4.03 (m, 2H), 3,55 (m, 3H), 3,26 (m, 2H), 3,17 (m, 3H), 3,05 (m, 4H), 2.95 and (m, 1H), 2,82 (m, 1H), 2,09 (m, 4H), 1,82 (m, 1H), 1,65 (m, 2H).

Example 138: synthesis of (5-fluoro-2-[(R)-4-(2-methansulfonate)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl)-(tetrahydropyran-4-yl)amine

(5-fluoro-2-[(R)-4-(2-methansulfonate)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl)-(tetrahydropyran-4-yl)Amin

The compound (50 mg, 0.11 mmol)obtained in the obtaining 56, was subjected to reaction according to the same procedure as in example 132, while receiving specified in the title compound (18 mg, yield 38%).

1H NMR (400 MHz, CDCl3); δ 10,15 (user. s, 1H), 6,86 (s, 1H), 6,65 (DD, 1H), of 6.26 (DD, 1H), 4,77 (m, 1H), of 4.05 (m, 1H), of 3.56 (m, 4H), to 3.36 (m, 1H), 3,24 (m, 2H), 3,12 (m, 1H), 2.91 in (s, 3H), 2,32 (m, 1H), 2,22 (m, 1H), 2,13 (m, 1H), 2,02 (m, 1H), and 1.54 (m, 2H).

Getting 57: synthesis of {5-fluoro-2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine

{5-fluoro-2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-1H-shall ndol-7-yl}-(tetrahydropyran-4-yl)Amin

Compound (3.2 g, 8,82 mol)obtained in example 41 was subjected to reaction according to the same procedure as in receipt of 50, while receiving specified in the title compound (1.9 g, yield 46%).

Example 139: synthesis of 4-(2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-2-it

4-(2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-2-he

The compound (200 mg, 0.44 mmol)obtained in the obtaining 57, was subjected to reaction according to the same procedure as in example 130, while receiving specified in the title compound (50 mg, 51%yield).

1H NMR (400 MHz, CDCl3); δ 11,07 (user. s, 1H), 7,70 (user. s, 1H), 6,83 (s, 1H), is 6.61 (d, J=8.0 Hz, 1H), from 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), to 3.33 (m, 3H), 3,14 (m, 1H), 2,73 (m, 4H), 2,10 (m, 2H), 1,98 (m, 2H), 1,58 (m, 4H).

Example 140: synthesis of 1-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]-2-hydroxyethane

1-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]-2-hydroxyethane is n

The compound (500 mg, 1.06 mmol)obtained in the obtaining 57, was subjected to reaction according to the same methods as in example 96 example 97, while receiving specified in the title compound (100 mg, yield 19%).

1H NMR (400 MHz, CDCl3); δ 11,19 (user. s, 1H), 6.89 in (s, 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 (s, 2H), 3,98 (m, 2H), 3,61 (m, 2H), 3,47 (m, 4H), and 3.16 (m, 3H), 2,42 (m, 3H), 2,17 (m, 5H), 1,90 (m, 2H), 1,40 (m, 2H).

Getting 58: synthesis cyclopentyl-{2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

Cyclopentyl-{2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

The compound (1.68 g, 5,10 mol)obtained in example 44 was subjected to reaction according to the same procedure as in receipt of 50, while receiving specified in the title compound (1.75 g, yield 78%).

Example 141: synthesis cyclopentyl-{2-[(R)-4-(2-methoxyethyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

Cyclopentyl-{2-[(R)-4-(2-methoxyethyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

The compound (100 mg, 0.23 mmol)obtained in the obtaining 58, was dissolved in tetrahydrofuran (20 ml). To the solution was added met XID sodium (61 mg, 1.15 mmol) and the mixture was stirred for 8 h at 80°C. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (154 mg, yield 19%).

1H NMR (500 MHz, DMSO-d6); δ to 10.62 (user. s, 1H), 7,03 (d, J=7,95 Hz, 1H), 6,99 (t, 1H), 6,93 (s, 1H), 6.48 in (d, J=7,35 Hz, 1H), a 4.83 (m, 1H), 3,83 (m, 1H), of 3.56 (m, 1H), 3.46 in (m, 2H), 3,20 (m, 4H), 2.05 is~to 1.87 (m, 4H), 1.70 to~to 1.38 (m, 6H).

Example 142: synthesis cyclopentyl-{2-[(R)-4-(2-dimethylaminoethyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

Cyclopentyl-{2-[(R)-4-(2-dimethylaminoethyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

The compound (150 mg, 0.34 mmol)obtained in the obtaining 58, and dimethylamine used instead of 2-oxopiperidine, were subjected to reaction according to the same procedure as in example 130, while receiving specified in the title compound (38 mg, yield 31%).

1H NMR (500 MHz, DMSO-d6); δ 11,28 (user. s, 1H), 6,78 (m, 2H), 6,24 (m, 2H), 5,80 (m, 1H), 4,59 (m, 1H), 3,81 (m, 1H), 3,51 (m, 1H), 3,13 (m, 1H), 2,50 (m, 1H), 2,37 (m, 1H), 2,17 (s, 6H), 1.93 and (m, 3H), 1,79-of 1.65 (m, 3H), and 1.54 (m, 4H).

Example 143: synthesis cyclopentyl-{2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1 is-indol-7-yl}Amin

Cyclopentyl-{2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

The compound (150 mg, 0.34 mmol)obtained in the obtaining 58, and morpholine used instead of 2-oxopiperidine, were subjected to reaction according to the same procedure as in example 130, while receiving specified in the title compound (48 mg, yield 35%).

1H NMR (500 MHz, DMSO-d6); δ 11,27 (user. s, 1H), 6,78 (m, 2H), 6,70 (m, 1H), 6,24 (m, 1H), 5,80 (m, 1H), 4,60 (m, 1H), 3,81 (m, 1H), 3,55-to 3.49 (m, 4H), of 3.13 (m, 1H), 2,46 (m, 1H), a 2.36 (m, 4H), to 1.96 (m, 3H), of 1.80 (m, 1H), 1,68 (m, 2H), and 1.54 (m, 4H).

Example 144: synthesis cyclopentyl-{2-[(R)-4-(2-piperidine-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

Cyclopentyl-{2-[(R)-4-(2-piperidine-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

(Stage 1)

Connection methyl ether complex (68 mg, 0,19 mmol)obtained in stage 1 of example 42 was dissolved in dichloromethane (4 ml). At -78°C was added diisobutylaluminium made (0.13 ml, 1.5 M solution in CH2Cl2, 0.21 mmol) and the mixture was stirred for 2 hours After completion of the reaction solution was added potassium tartrate sodium. The mixture was extracted with ethyl what Etat, was dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure, thus obtaining aldehyde compound (62 mg, yield 100%).

(Stage 2)

Aldehyde compound (23 mg, 0.07 mmol), obtained in stage 1, was dissolved in dichloroethane (2 ml). To the solution was added piperidine (9 mg, 0.11 mmol) and triacetoxyborohydride sodium (19 mg, 0.09 mmol) and the mixture was stirred for 30 min at room temperature. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (10 mg, yield 36%).

1H NMR (400 MHz, CDCl3); δ 10,34 (user. s, 1H),? 7.04 baby mortality (d, 1H), 6,99 (t, 1H), of 6.49 (d, 1H), 4.72 in (m, 1H), 3,86 (m, 1H), 3,51 (m, 1H), 3.15 in (m, 1H), 2,30~2,00 (m, 8H), 2,69~of 1.40 (m, 14H).

Getting 59: synthesis of {2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine

{2-[(R)-4-(2-Codetel)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)Amin

The compound (340 mg, 0.98 mol)obtained in example 46 was subjected to reaction according to the same procedure as in receipt of 50, while receiving specified in the agolove compound (370 mg, yield 83%).

Example 145: synthesis of {2-[(R)-4-(2-methansulfonate)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine

{2-[(R)-4-(2-Methansulfonate)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)Amin

The compound (50 mg, 0.11 mmol)obtained in the obtaining 59, was subjected to reaction according to the same procedure as in example 108, while receiving specified in the title compound (18 mg, yield %).

1H NMR (400 MHz, CDCl3); δ 10,02 (user. s, 1H), was 7.08 (d, 1H), 7,00 (t, 1H), 6,95 (s, 1H), is 6.54 (d, 1H), 4,78 (m, 1H), 4,01 (m, 2H), 3,61-3,47 (m, 4H), to 3.33 (m, 1H), 3.15 in (m, 2H), 2,85 (s, 3H), of 2.25 (m, 2H), 2.05 is (m, 2H)and 1.51 (m, 2H).

Getting 60: synthesis of 2-[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanol

2-[(R)-2-(7-Cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanol

Connection (2,40 g, to 6.19 mmol)obtained in example 47 was subjected to reaction according to the same procedure as in example 70, while receiving specified in the title compound (1.20 g, yield 54%).

Getting 61: synthesis cyclopentyl-{2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-5-methoxy-1H-indol-7-yl}Amin/p>

Cyclopentyl-{2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-5-methoxy-1H-indol-7-yl}Amin

The compound (1.20 g, to 3.34 mmol), obtained in the obtaining of 60, were subjected to reaction according to the same procedure as in receipt of 50, while receiving specified in the title compound (1.23 g, yield 78%).

Example 146: synthesis of 1-(4-{2-[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)-2-hydroxyethane

1-(4-{2-[(R)-2-(7-Cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)-2-hydroxyethane

The compound (500 mg, 1.07 mmol)obtained in the obtaining 61, was subjected to reaction according to the same methods as in example 96 example 97, while receiving specified in the title compound (20 mg, yield 4%).

1H NMR (400 MHz, CDCl3); δ 11,13 (user. s, 1H), 6,98 (s, 1H), 6.42 per (s, 1H), 6,13 (d, 1H), around 4.85 (m, 1H), 4,07 (s, 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), of 1.84 (m, 1H), 1,75 (m, 1H), 1,62 (m, 4H), of 1.44 (m, 1H), 1,35 (m, 1H).

Getting 62: synthesis of 2-{(R)-2-[5-methoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanol/p>

2-{(R)-2-[5-Methoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanol

Connection (4,00 g to 9.91 mmol)obtained in example 50 was subjected to reaction according to the same procedure as in example 70, while receiving specified in the header connection (2,80 g, 75%yield).

Getting 63: synthesis of {2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-5-methoxy-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine

{2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-5-methoxy-1H-indol-7-yl}-(tetrahydropyran-4-yl)Amin

Connection (2,80 g, 7,46 mmol)obtained in the obtaining 62, was subjected to reaction according to the same procedure as in receipt of 50, while receiving specified in the title compound (2.65 g, yield 73%).

Example 147: synthesis of 2-hydroxy-1-[4-(2-{(R)-2-[5-methoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]ethanone

2-Hydroxy-1-[4-(2-{(R)-2-[5-methoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazin the-1-yl]alanon

The compound (500 mg, of 1.03 mmol)obtained in the obtaining 63, was subjected to reaction according to the same methods as in example 96 example 97, while receiving specified in the title compound (50 mg, yield 10%).

1H NMR (400 MHz, CDCl3); δ 11,13 (user. s, 1H), 6,91 (s, 1H), 6,47 (s, 1H), 6,17 (s, 1H), a 4.86 (m, 1H), 4,13 (m, 2H), 3,97 (m, 3H), of 3.84 (m, 3H), 3,62 (m, 2H), 3,47 (m, 4H), 3,03 (m, 3H), 2,43 (m, 3H), 2,17 (m, 5H), to 1.98 (m, 3H), of 1.44 (m, 2H).

Getting 64: synthesis of ethyl ester of 3-[(R)-2-(7-amino-5-chloro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Ethyl ester of 3-[(R)-2-(7-amino-5-chloro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Which is the acid compound (2.0 g, 8.3 mmol), obtained in the obtaining 33, and the connection hydrochloride ethyl ester (R)-4-amino-5-(4-methoxybenzenesulfonyl)pentanol acid (3.4 g, 10.2 mmol), obtained in the obtaining 17, were subjected to reaction according to the same procedure as in obtaining 34, while receiving specified in the header connection (0,76 g, yield 26%).

1H NMR (400 MHz, CDCl3); δ 10,00 (user. s, 1H), was 7.08 (s, 1H), 6,80 (s, 1H), to 6.57 (s, 1H), 4,71 (m, 1H), 4,07 (m, 2H), 3,88 (user. s, 2H), 3,55 (m, 1H), 3,11 (m, 1H), 2,50 (t, 2H), 2.05 is (m, 2H), 1,22 (t, 3H).

Example 148: Synthesis of ethyl ester of 3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-Digue is kotesol-4-yl]propionic acid

Ethyl ester of 3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

The compound (760 mg, 2.1 mmol)obtained in obtaining 64, was subjected to reaction according to the same procedure as in example 26, while receiving specified in the title compound (450 mg, yield 51%).

Getting 65: synthesis of hydrochloride of cyclohexylurea ether (R)-4-amino-5-(4-methoxybenzenesulfonyl)pentanol acid

Cyclohexyloxy ether (R)-4-amino-5-(4-methoxybenzenesulfonyl)pentanol acid

Cyclohexyloxy ether (R)-4-tert-butoxycarbonylamino-5-hydroxypentanal acid (6.5 g, to 20.6 mmol) was subjected to reaction according to the same procedure as in obtaining 17, while receiving specified in the title compound (7.5 g, yield 97%).

Getting 66: synthesis of cyclohexylurea ester 3-[(R)-2-(7-amino-5-chloro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Cyclohexyloxy ester of 3-[(R)-2-(7-amino-5-chloro-1H-indol-2-yl)-4,5-di is erotical-4-yl]propionic acid

The compound (3.9 g, 16.2 mmol), obtained in the obtaining 33, the compound (7.5 g, a 19.5 mmol)obtained in getting 65, was subjected to reaction according to the same procedure as in obtaining 34, while receiving specified in the title compound (2.6 mg, yield 40%).

Getting 67: synthesis of cyclohexylurea ester 3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Cyclohexyloxy ester of 3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

The compound (1.30 grams, 3,20 mmol)obtained in the obtaining 66, was subjected to reaction according to the same procedure as in example 29, while receiving specified in the header connection (1,15 mg, yield 76%).

Example 149: synthesis of 3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

3-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Ester compound (500 mg, 1.05 mmol)obtained in the obtaining 67, was subjected to reaction according to the same procedure as in example 27, while receiving is shown in the title compound (400 mg, yield 97%).

1H NMR (400 MHz, DMSO-d6, Na salt); δ of 11.69 (user. s, 1H), PC 6.82 (d, J=4.0 Hz, 1H), of 6.68 (s, 1H), 6,27 (s, 1H), 6,18 (s, 1H), 4,63 (m, 1H), 3,83 (m, 1H), 3,50 (m, 1H), 3,13 (m, 1H), 2,08~a 1.96 (m, 6H), 1,72 (m, 2H), 1,58 (m, 4H).

Example 150: synthesis of 3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propan-1-ol

3-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propan-1-ol

The compound (650 mg, 1.37 mmol)obtained in the obtaining 67, was subjected to reaction according to the same procedure as in example 70, while receiving specified in the title compound (210 mg, yield 41%).

1H NMR (400 MHz, CDCl3); δ 10,42 (user. s, 1H), 6,94 (s, 1H), PC 6.82 (s, 1H), 6,37 (s, 1H), 4,58 (m, 1H), 4,56 (m, 1H), 3,75 (m, 2H), 3,65 (m, 1H), 1,95 (m, 7H)and 1.51 (m, 4H), to 1.31 (m, 2H).

Getting 68: synthesis of cyclohexylurea ester 3-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}propionic acid

Cyclohexyloxy ester of 3-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}propionic acid

The compound (1.30 grams, 3,20 mmol)obtained in the obtaining 66, was subjected to reaction according to tako the same method, as in example 30, while receiving specified in the title compound (1.24 g, yield 79%).

Example 151: synthesis of 3-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}propionic acid

3-{(R)-2-[5-Chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}propionic acid

Ester compound (500 mg, 1.05 mmol)obtained in the obtaining 68, was subjected to reaction according to the same procedure as in example 27, while receiving specified in the title compound (250 mg, yield 59%).

1H NMR (400 MHz, DMSO-d6, Na salt); δ 11,53 (user. s, 1H), 6,86 (s, 1H), 6,76 (s, 1H), 6,34 (s, 1H), 4,67 (m, 1H), 3,91 (m, 2H), 3,49 (m, 4H), 3,21 (m, 1H), 2,50 (m, 2H), 2,01 (m, 4H), USD 1.43 (m, 2H).

Example 152: synthesis of 3-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}propan-1-ol

3-{(R)-2-[5-Chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}propan-1-ol

The compound (650 mg, of 1.33 mmol), obtained in the obtaining 68, was subjected to reaction according to the same procedure as in example 70, while receiving specified in the title compound (150 mg, yield 29%).

sup> 1H NMR (400 MHz, CDCl3), δ 11,00 (user. s, 1H), 6,93 (s, 1H), PC 6.82 (s, 1H), of 6.31 (s, 1H), 4,89 (user. s, 1H), 4,56 (m, 1H), 3,95 (m, 1H), 3,85 (m, 1H), of 3.77 (m, 1H), 3,65 (m, 1H), 3,51 (m, 4H), 3,10 (m, 1H), of 1.97 (m, 2H)and 1.83 (m, 3H), of 1.74 (m, 1H), 1,44 (m, 1H), 1,40 (m, 1H).

Example 153: synthesis of 3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-(2-morpholine-4-retil)propionamide

3-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-(2-morpholine-4-retil)propionamide

The compound (150 mg, 0.38 mmol)obtained in example 149, and 4-(2-amino-ethyl)morpholine, used instead of the research, were subjected to reaction according to the same procedure as in example 70, while receiving specified in the title compound (50 mg, yield 26%).

1H NMR (400 MHz, CDCl3); δ 11,13 (user. s, 1H), 7,06 (user. s, 1H), 6,93 (s, 1H), PC 6.82 (s, 1H), to 6.39 (s, 1H), br4.61 (m, 1H), 3,88 (m, 2H), of 3.77 (s, 4H), of 3.45 (m, 2H), of 3.07 (m, 1H), 2,70 (m, 6H), 2,44 (m, 2H), 2,10 (m, 3H), of 1.95 (m, 1H), 1,71 (m, 2H), 1,64 (m, 2H), and 1.54 (m, 2H).

Example 154: synthesis of 3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(4-methylpiperazin-1-yl)propane-1-it

3-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(4-methylp perazin-1-yl)propane-1-he

The compound (150 mg, 0.38 mmol)obtained in example 149, and 1-methylpiperazin used along the research, were subjected to reaction according to the same procedure as in example 73, while receiving specified in the title compound (50 mg, yield 28%).

1H NMR (400 MHz, CDCl3); δ of 11.26 (user. s, 1H), 6,93 (s, 1H), 6,85 (s, 1H), 6,38 (s, 1H), 4,73 (m, 1H), 3,83 (m, 1H)and 3.59 (m, 3H), 3,30 (m, 2H), 3,14 (m, 1H), 2,45 (m, 4H), 2,30 (m, 5H), 2,04 (m, 4H), to 1.70 (m, 4H), of 1.52 (m, 2H).

Getting 69: synthesis of 3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propyl ester methanesulfonic acid

3-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propyl ether methanesulfonate acid

Compound (140 mg, of 0.37 mmol)obtained in example 154 was subjected to reaction according to the same procedure as in obtaining 22, while receiving specified in the title compound (120 mg, 71%yield).

Example 155: synthesis of 1-(4-{3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propyl}piperazine-1-yl)ethanone

1-(4-{3-[(R)-2-(5-Chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propyl}the Pipera the Jn-1-yl)alanon

The compound (100 mg, 0.22 mmol)obtained in the obtaining 69, was subjected to reaction according to the same procedure as in example 125, while receiving specified in the title compound (49 mg, yield 46%).

1H NMR (400 MHz, CDCl3); δ 10,33 (user. s, 1H), 6,97 (s, 1H), for 6.81 (s, 1H), 6.42 per (s, 1H), with 4.64 (m, 1H), 3,85 (m, 1H), 3,65 (m, 2H), of 3.56 (m, 1H), of 3.45 (m, 2H), 3,13 (m, 1H), 2,43 (m, 6H), 2,04 (m, 2H), 1,72 (m, 8H), and 1.54 (m, 2H).

Example 156: synthesis of {5-chloro-2-[(R)-4-(3-morpholine-4-ylpropyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine

{5-Chloro-2-[(R)-4-(3-morpholine-4-ylpropyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine

The compound (100 mg, 0.22 mmol)obtained in the obtaining 69, and morpholine used instead of 1-acetylpiperidine, were subjected to reaction according to the same procedure as in example 125, while receiving specified in the title compound (43 mg, yield 44%).

1H NMR (400 MHz, CDCl3); δ 11,07 (user. s, 1H), 6.90 to (s, 1H), 6,74 (s, 1H), 6,36 (s, 1H), br4.61 (m, 1H), 3,94 (m, 4H), 3,55 (m, 1H), 3.04 from (m, 3H), 2,04 (m, 7H), 1,71 (m, 3H), of 1.61 (m, 4H), 1.26 in (m, 3H).

Example 157: synthesis of ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

The compound (2.0 g, 8.6 mmol), obtained in the obtaining 7, the compound (3.4 g, 10.2 mmol), obtained in the obtaining 17, subjected sequentially to the reaction according to the same methods as in obtaining 33, receiving 34 and example 26, while receiving specified in the title compound (500 mg, yield 15%).

1H NMR (400 MHz, CDCl3); δ 10,75 (user. s, 1H), PC 6.82 (d, 2H), 6,32 (s, 1H), 4,71 (m, 1H), 4,01 (square, 2H), 3,83 (m, 1H), 3,53 (m, 1H), 3,11 (m, 1H), 2,44 (m, 2H), is 2.37 (s, 3H), a 2.01 (m, 4H), of 1.64 (m, 4H), of 1.40 (m, 2H).

Example 158: Synthesis of 3-[(R)-2-(7-cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

3-[(R)-2-(7-Cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

The compound (300 mg, 0.75 mmol)obtained in example 157, was dissolved in tetrahydrofuran (25 ml) and methanol (25 ml). To the solution was added 1 N. aqueous sodium hydroxide solution (4.0 ml, 4 mmol) and the mixture was stirred for 3 h at room temperature. After completion of the reaction was added 1 N. hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled p and reduced pressure and was purified column chromatography, while receiving specified in the title compound (235 mg, yield 84%).

1H NMR (400 MHz, CDCl3); δ 11,34 (user. s, 1H), 6,56 (s, 1H), is 6.54 (s, 1H), the 6.06 (s, 1H), of 5.05 (user. d, 1H), 4,60 (m, 1H), 3,81 (m, 1H), of 3.45 (m, 1H), 3,06 (m, 1H), 2,28 (s, 3H), 2,09~of 1.93 (m, 5H), 1,78~and 1.54 (m, 7H).

Getting 70: synthesis of ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Compound (2.6 g, 8.4 mmol), obtained in the obtaining 12, the compound (3.4 g, 10.2 mmol), obtained in the obtaining 17, subjected sequentially to the reaction according to the same methods as in obtaining 33, receiving 34 and example 26, while receiving specified in the title compound (1.0 g, yield 25%).

Example 159: synthesis of 3-[(R)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

3-[(R)-2-(7-Cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

The compound (600 mg, of 1.26 mmol)obtained in the obtaining 70, was subjected to reaction with soglasnogo same method, as in example 158, while receiving specified in the title compound (430 mg, yield 76%).

1H NMR (400 MHz, DMSO-d6); δ 11,59 (user. s, 1H), 7,29 (m, 2H), 7,01 (m, 1H), 6,92 (m, 2H), to 6.67 (s, 1H), 6,40 (d, 1H), 6,21 (d, 1H), of 5.99 (d, 1H), 4,63 (m, 1H), 3,75 (m, 1H), 3,50 (m, 1H), 3,11 (m, 1H), 2,08 (m, 2H), 2,03 (m, 1H), 1,90 (m, 2H), is 1.81 (m, 1H), 1,71 (m, 2H), and 1.56 (m, 4H).

Example 160: synthesis of ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Compound (2.2 g, 8.9 mmol), obtained in the obtaining 2, the compound (3.6 g, is 10.7 mmol)obtained in the obtaining 17, subjected sequentially to the reaction according to the same methods as in obtaining 33, receiving 34 and example 26, while receiving specified in the title compound (1.1 g, yield 31%).

1H NMR (400 MHz, CDCl3); δ 10,48 (user. s, 1H), 6,91 (s, 1H), 6,69 (m, 1H), 6.30-in (m, 1H), 4,77 (m, 1H), 4,19~was 4.02 (m, 3H), of 3.84 (m, 1H), 3,60 (m, 1H), 3,18 (m, 1H), of 2.51 (m, 2H), 2,07 (m, 4H), 1,74~of 1.46 (m, 6H), to 1.21 (m, 3H).

Example 161: synthesis of 3-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

3-[(R)-2-(7-Cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

The compound (1.0 g, 2.48 mmol)obtained in example 160 was subjected to reaction according to the same procedure as in example 158, while receiving specified in the title compound (430 mg, yield 46%).

1H NMR (400 MHz, DMSO-d6); δ 11,63 (user. s, 1H), of 6.49 (m, 1H), 6,33 (m, 1H), 6,09 (m, 1H), 6,66 (m, 1H), br4.61 (m, 1H), 3,85 (m, 1H), 3,52 (m, 1H), 3,11 (m, 1H), 2,09~of 1.74 (m, 12H).

Example 162: synthesis of ethyl ester of 3-[(R)-2-(5-bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Ethyl ester of 3-[(R)-2-(5-bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Compound (2.1 g, 7,01 mmol)obtained in the obtaining 6, the compound (2.3 g, 6,89 mmol)obtained in the obtaining 17, subjected sequentially to the reaction according to the same methods as in obtaining 33, receiving 34 and example 26, while receiving specified in the title compound (530 mg, yield 16%).

1H NMR (400 MHz, CDCl3); δ 10,02 (user. s, 1H), 7,16 (s, 1H), for 6.81 (s, 1H), to 6.57 (s, 1H), 4,74 (m, 1H), 4,11 (m, 2H), was 4.02 (m, 2H), 3,59 (square, 1H), and 3.16 (square, 1H), 2,52 (m, 2H), 2.06 to (m, 4H), 1,72 (m, 3H), 1,49 (m, 2H), 1,19 (t, 3H).

Example 163: synthesis of 3-[(R)-2-(5-bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydro shall eazol-4-yl]propionic acid

3-[(R)-2-(5-Bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

The compound (420 mg, 0.88 mmol)obtained in example 162, were subjected to reaction according to the same procedure as in example 158, while receiving specified in the title compound (350 mg, yield 91%).

1H NMR (400 MHz, DMSO-d6); δ 11,77 (user. s, 1H), of 6.96 (s, 1H), of 6.68 (s, 1H), of 6.31 (m, 1H), 6,29 (s, 1H), with 4.64 (m, 1H), 3,82 (m, 1H), 3,53 (m, 1H), 3,13 (m, 1H), 2.05 is (m, 2H), of 1.97 (m, 2H), 1.77 in (m, 3H), 1,58 (m, 4H).

Getting 71: synthesis of ethyl ester of 3-[(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Ethyl ester of 3-[(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

The compound (1.64 g, 7,49 mmol)obtained in the obtaining 8, the compound (3.50 g, 10,46 mmol)obtained in the obtaining 17, subjected sequentially to the reaction according to the same methods as in obtaining 33, receiving 34 and example 26, while receiving specified in the title compound (1.23 g, yield 43%).

Example 164: synthesis of 3-[(R)-2-(7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid is you

3-[(R)-2-(7-Cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

The compound (1.0 g, at 2.59 mmol), obtained in the obtaining 71, was subjected to reaction according to the same procedure as in example 158, while receiving specified in the title compound (560 mg, yield 60%).

1H NMR (400 MHz, DMSO-d6); δ 11,46 (user. s, 1H), 6,85 (m, 2H), 6,70 (s, 1H), 6,27 (d, J=4.0 Hz, 1H), 5,94 (d, J=8.0 Hz, 1H)and 4.65 (m, 1H), 3,86 (m, 1H), 3,52 (m, 1H), 3,11 (m, 1H), 2.05 is (m, 2H), of 1.97 (m, 3H), of 1.78 (m, 3H), and 1.56 (m, 4H).

Getting 72: synthesis of ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Compound (2.1 g, 8.5 mmol), obtained in the obtaining 9, the compound (3.4 g, 10.2 mmol), obtained in the obtaining 17, subjected sequentially to the reaction according to the same methods as in obtaining 33, receiving 34 and example 26, while receiving specified in the title compound (700 mg, yield 20%).

Example 165: synthesis of 3-[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-di is erotical-4-yl]propionic acid

3-[(R)-2-(7-Cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

The compound (700 mg, was 1.69 mmol)obtained in the obtaining 72, was subjected to reaction according to the same procedure as in example 158, while receiving specified in the title compound (430 mg, yield 66%).

1H NMR (400 MHz, DMSO-d6); δ 11,28 (user. s, 1H), is 6.61 (s, 1H), 6,27 (s, 1H), 5,97 (m, 1H), 5,88 (s, 1H), 4,59 (m, 1H), 3,75 (m, 1H), 3,68 (s, 3H), of 3.48 (m, 2H), is 3.08 (m, 1H), 2,00 (m, 5H), of 1.75 (m, 3H), of 1.57 (m, 4H).

Example 166: synthesis of ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-ethoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-ethoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Compound (2.4 g, 9.0 mmol)obtained in 11, the compound (3.0 g, 8.98 mmol), obtained in the obtaining 17, subjected sequentially to the reaction according to the same methods as in obtaining 33, receiving 34 and example 26, while receiving specified in the title compound (600 mg, yield 16%).

1H NMR (500 MHz, CDCl3); δ 9,79 (user. s, 1H), 6,80 (s, 1H), 6,44 (s, 1H), to 6.19 (s, 1H), 4,69 (who, 1H), 4,11 (square, 2H), 4,03 (square, 2H), 3,83 (m, 1H), 3,54 (m, 1H), 3,11 (m, 1H), 2.49 USD (m, 2H), 2,02 (m, 4H), 1.69 in (m, 2H), 1,60 (m, 2H), 1,48 (m, 2H), 1,25 (t, 3H), 1,19 (t, 3H).

Example 167: synthesis of 3-[(R)-2-(7-cyclopentylamine-5-ethoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

3-[(R)-2-(7-Cyclopentylamine-5-ethoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

The compound (300 mg, 0.70 mmol)obtained in example 166 was subjected to reaction according to the same procedure as in example 158, while receiving specified in the title compound (210 mg, 71%yield).

1H NMR (400 MHz, DMSO-d6); δ 11,37 (user. s, 1H), 6,78 (s, 1H), 6.30-in (s, 1H), 5,94 (s, 1H), with 4.64 (m, 1H), 3,93 (square, 2H), 3,82 (m, 1H), 3,60 (m, 1H), 3,21 (m, 1H), 2,44 (m, 2H), of 1.97 (m, 4H), 1,71 (m, 2H), 1.57 in (m, 4H), of 1.32 (t, 3H).

Getting 73: synthesis of methyl ester of 7-nitro-5-triptoreline-1H-indolocarbazoles acid

Methyl ester of 7-nitro-5-triptoreline-1H-indole-2-carboxylic acid

4 Triptoreline-2-nitroaniline (10.0 g, 45,0 mmol) was subjected to reaction according to the same methods as in the receive 3-5, while receiving specified in the title compound (3.0 g, yield 22%).

Example 168: Shin is ez ethyl ester 3-[(R)-2-(7-cyclopentylamine-5-triptoreline-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

Ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-triptoreline-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

The compound (2.7 g, 8,96 mmol)obtained in getting 73, and the compound (3.0 g, 8.98 mmol), obtained in the obtaining 17, subjected sequentially to the reaction according to the same methods as in obtaining 33, receiving 34 and example 26, while receiving specified in the title compound (900 mg, yield 21%).

1H NMR (500 MHz, CDCl3); δ 10,97 (user. s, 1H), 6,93 (s, 1H), 6,86 (s, 1H), 6.30-in (s, 1H), amounts to 4.76 (m, 1H), 4,05-to 3.89 (m, 3H), of 3.78 (m, 1H), only 3.57 (m, 1H), and 3.16 (m, 2H), 2,42 (m, 2H), 2,00 (m, 4H), and 1.63 (m, 2H), 1,45 (m, 1H), 1,34 (m, 1H).

Example 169: synthesis of 3-[(R)-2-(7-cyclopentylamine-5-triptoreline-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

3-[(R)-2-(7-Cyclopentylamine-5-triptoreline-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid

The compound (750 mg, to 1.60 mmol)obtained in example 168, were subjected to reaction according to the same procedure as in example 158, while receiving specified in the title compound (600 mg, yield 5%).

1H NMR (40 MHz, DMSO-d6); δ of 11.61 (user. s, 1H), 6,85 (d, 1H), 6,77 with, 1H), 6,16 (s, 1H), of 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), 1,58 (m, 4H).

Example 170: synthesis of ethyl ester [(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-ylethoxy]acetic acid

Ethyl ester [(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-ylethoxy]acetic acid

The compound (50 mg, 0.15 mmol)obtained example 5, was dissolved in tetrahydrofuran (5 ml). To the solution was added ethyl ether bromoxynil acid (30 mg, 0.18 mmol) and sodium hydride (8 mg, 0.18 mmol) and the mixture was stirred for 3 h at room temperature. After completion of the reaction was added 1 N. hydrochloric acid. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (15 mg, yield 24%) and which is the acid compound (40 mg, yield 68%) of example 171.

1H NMR (400 MHz, CDCl3); δ 10,16 (user. s, 1H), 6.87 in (s, 1H), 6,66 (DD, J=2,4, and 9.2 Hz, 1H), 6.30-in (DD, J=2,4, and 11.8 Hz, 1H), 4,94 (m, 1H), 4,25 (square, 2H), 4,13 (d, J=5.6 Hz, 2H), a 3.87 (m, 1H), 3,76 (d, J=6,4 Hz, 2H), of 3.56 (m, 1H), 3,44 (m, 1H), 2,07 (m, 2H), 1,67 (m, 4H)and 1.51 (m, 2H), of 1.30 (t, 3H).

Example 171: synthesis of [(R)-2-(7-cyclo is enteramine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-ylethoxy]acetic acid

[(R)-2-(7-Cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-ylethoxy]acetic acid

Specified in the title compound was additionally obtained in example 170.

1H NMR (400 MHz, DMSO-d6); δ 12,70 (user. s, 1H), 7,07 (s, 1H), to 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), with 3.89 (m, 1H), 3,63 (m, 3H), 2,03 (m, 2H), 1,58 (m, 6H).

Example 172: synthesis cyclopentyl-{2-[(R)-4-(3-cyclopentyl-[1,2,4]oxadiazol-5-ylmethyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

Cyclopentyl-{2-[(R)-4-(3-cyclopentyl-[1,2,4]oxadiazol-5-ylmethyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

Compound (140 mg, 0.41 mmol)obtained in example 42 was dissolved in N,N-dimethylformamide (5 ml). To the solution was added 1,1'-dicarbonitriles (73 mg, 0.45 mmol) and the mixture was stirred for 30 min at room temperature. To the mixture was added N-hydroxycyclohexanecarboxylate (260 mg, 2.03 mmol) and the mixture was stirred for 5 h at 80°C. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced is the first pressure and was purified column chromatography, while receiving specified in the title compound (100 mg, yield 56%).

1H NMR (400 MHz, CDCl3); δ to 10.62 (user. s, 1H),? 7.04 baby mortality (d, 1H), 6,97 (t, 1H), 6,92 (d, 1H), of 6.49 (d, 1H), 5,20 (m, 1H), 3,83 (m, 2H), to 3.64 (m, 1H), 3,39 (m, 1H), and 3.31 (m, 1H), 3,17 (m, 1H), 3,01 (m, 1H), of 1.97 (m, 4H), at 1.73 (m, 4H), to 1.60 (m, 6H), of 1.46 (m, 2H), of 1.34 (m, 2H).

Example 173: synthesis cyclopentyl-{2-[(R)-4-(3-piperidine-1-yl-[1,2,4]oxadiazol-5-ylmethyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

Cyclopentyl-{2-[(R)-4-(3-piperidine-1-yl-[1,2,4]oxadiazol-5-ylmethyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}Amin

Compound (140 mg, 0.41 mmol)obtained in example 42, and N-hydroxypiperidine used instead of N-hydroxycyclohexanecarboxylate, were subjected to reaction according to the same procedure as in example 172, while receiving specified in the title compound (100 mg, yield 54%).

1H NMR (400 MHz, CDCl3); δ 10,56 (user. s, 1H), 7,01 (d, 1H), of 6.96 (t, 1H), 6.90 to (d, 1H), 6,46 (d, 1H), 5,23 (m, 1H), 3,83 (m, 2H), to 3.64 (m, 1H), 3,36 (m, 1H), and 3.31 (m, 1H), 3,17 (m, 2H), 3,01 (m, 1H), 1,95 (m, 2H), 1,68 was 1.43 (m, 11H), 1,35 (m, 1H).

Getting 74: synthesis of methyl ester of 7-phenoxy-1H-indole-2-carboxylic acid

Methyl ether 7-phenoxy-H-indole-2-carboxylic acid

(Stage 1)

Methyl ester (Z)-2-azido-3-(3-phenoxyphenyl)acrylic acid

3-Phenoxybenzaldehyde (16,1 g, 81,3 mmol) was dissolved in methanol (300 ml). To the solution was added sodium methoxide (70,3 g, 25%, 325,3 mmol) and methylacetoacetate (42,0 g, 325,3 mmol) and the mixture was stirred for 5 h at -10°C. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (18.5 g, yield 77%).

(Stage 2)

The compound (18.5 g, and 62.6 mmol)obtained in stage 1, was dissolved in xylene (100 ml) and was stirred for 4 h at 120°C. After completion of the reaction, the reaction solution was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (4.9 g, yield 29%).

Getting 75: synthesis of methyl ester hydrochloride (R)-3-amino-4-criticalinformation acid

Methyl ester of (R)-3-amino-4-criticalinformation KIS is the notes

(Stage 1)

Hydrochloride L-cysteine (50 g, 284,7 mmol) was dissolved in N,N-dimethylformamide (200 ml). To the solution was added trailhead (119 g, 427,0 mmol) and the mixture was stirred for 48 h at room temperature. After completion of the reaction was added 10% sodium acetate (1.5 l). The mixture was filtered to obtain a solid substance, which was then added to an acetone (1.5 l) and stirred for 30 min at 50°C. the Insoluble solid was separated by filtration and dried, thus obtaining titelseite (80 mg, yield 78%).

(Stage 2)

Compound (34 g, 154 mmol), obtained in stage 1 were subjected to reaction according to the same methods as in stages 2 to 5 get 15, while receiving specified in the title compound (26 g, yield 39%).

Getting 76: synthesis of methyl ester [(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

Methyl ester [(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (4.9 g, and 18.3 mmol)obtained in getting 74, the compound (10.4 g, a 24.3 mmol)obtained in the obtaining 75, was subjected sequentially to the reaction according to the same methods as in obtaining 33, receiving 34 and example 26, while receiving specified in the header is VCE connection (4,48 g, yield 57%).

Example 174: synthesis of [(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

[(R)-2-(7-Phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid

The compound (500 mg, of 1.36 mmol)obtained in getting 76, was subjected to reaction according to the same procedure as in example 27, while receiving specified in the title compound (300 mg, yield 63%).

1H NMR (400 MHz, DMSO-d6); δ 12,17 (user. s, 1H), 7,51 (d, J=8.0 Hz, 1H), 7,41 (t, 1H), 7,28 (user. s, 1H), 7,16 (m, 2H), was 7.08 (m, 2H), at 6.84 (d, J=8.0 Hz, 1H), 4.95 points (m, 1H), of 3.77 (m, 1H), 3,37 (m, 1H), 2,86 (m, 1H), 2,75 (m, 1H).

Getting 77: synthesis of 2-[(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanol

2-[(R)-2-(7-Phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanol

Connection (2,56 g of 6.99 mmol)obtained in getting 76, was dissolved in tetrahydrofuran (20 ml). To the solution was added borohydride lithium (7 ml, 2.0 M solution in THF, 14.0 mmol) and the mixture was stirred for 4 h at 0°C. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (2.20 g, yield 93%).

Getting 78: synthesis of 2-[(R)-4-(2-codetel)-4,5-dihydrothieno-2-yl]-7-phenoxy-1H-indole

2-[(R)-4-(2-Codetel)-4,5-dihydrothieno-2-yl]-7-phenoxy-1H-indol

The compound (2.20 g, 6,50 mmol)obtained in getting 77, was subjected to reaction according to the same procedure as in receipt of 50, while receiving specified in the title compound (1.80 g, yield 62%).

Example 175: synthesis of 1-(4-{2-[(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)ethanone

1-(4-{2-[(R)-2-(7-Phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)alanon

The compound (100 mg, 0.22 mmol)obtained in getting 78, was dissolved in acetonitrile (3 ml). To the solution was added 1-acetylpiperidine (29 mg, 2.2 mmol) and potassium carbonate (93 mg, 0.67 mmol) and the mixture was stirred for 8 h at 80°C. After completion of the reaction was added water. The mixture was extracted with ethyl acetate, washed with a saturated solution of sodium chloride, dried over anhydrous sulfate is magnesium and filtered. The filtrate was distilled under reduced pressure and was purified column chromatography, thus obtaining specified in the title compound (40 mg, yield 41%).

1H NMR (400 MHz, CDCl3); δ 9,73 (user. s, 1H), 7,55 (d, J=8.0 Hz, 1H), 7,41 (m, 2H), 7,11 (t, 1H), 7,07 (m, 3H), 6,91 (s, 1H), 6,78 (d, J=8.0 Hz, 2H), 4,71 (m, 1H), to 3.58 (m, 2H), 3,48 (m, 1H), 3,38 (m, 2H), 3,11 (t, 1H), has 2.56 (m, 2H), 2,50 (m, 4H), to 2.06 (s, 3H), of 1.98 (m, 1H), equal to 1.82 (m, 1H).

Example 176: synthesis of 2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-7-phenoxy-1H-indole

2-[(R)-4-(2-Morpholine-4-retil)-4,5-dihydrothieno-2-yl]-7-phenoxy-1H-indol

The compound (100 mg, 0.22 mmol)obtained in getting 78, and morpholine used instead of 1-acetylpiperidine, were subjected to reaction according to the same procedure as in example 175, while receiving specified in the title compound (40 mg, yield 45%).

1H NMR (400 MHz, CDCl3); δ 9,17 (user. s, 1H), 7,42 (d, J=8.0 Hz, 1H), 7,34 (t, 2H), 7,13 (t, 1H), 7,05 (m, 3H), 6,93 (s, 1H), 6,80 (d, J=8.0 Hz, 2H), and 4.68 (m, 1H), and 3.72 (m, 4H), 3,70 (t, 1H), 3,14 (t, 1H), 2,62 (m, 2H), of 2.51 (m, 4H), 2,07 (m, 1H), of 1.85 (m, 1H).

Example 177: synthesis of 7-phenoxy-2-[(R)-4-(2-pyrrolidin-1-retil)-4,5-dihydrothieno-2-yl]-1H-indole

7 Phenoxy-2-[(R)-4-(2-pyrrolin the n-1-retil)-4,5-dihydrothieno-2-yl]-1H-indole

The compound (100 mg, 0.22 mmol)obtained in getting 78, and pyrrolidin used instead of 1-acetylpiperidine, were subjected to reaction according to the same procedure as in example 175, while receiving specified in the title compound (80 mg, yield 93%).

1H NMR (400 MHz, CDCl3); δ 9,37 (user. s, 1H), 7,41 (d, J=8.0 Hz, 1H), 7,34 (t, 2H), 7,10 (t, 1H), 7,05 (m, 3H), 6,92 (s, 1H), 6,80 (d, J=8.0 Hz, 2H), 4,67 (m, 1H), 3,54 (t, 1H), 3,14 (t, 1H), 2.57 m (m, 2H), of 2.51 (m, 4H), 2,07 (m, 1H), 1,89 (m, 1H), 1.77 in (m, 4H).

Example 178: synthesis of dimethyl-{2-[(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}amine

Dimethyl-{2-[(R)-2-(7-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}amine

The compound (100 mg, 0.22 mmol)obtained in getting 78, and dimethylamine used instead of 1-acetylpiperidine, were subjected to reaction according to the same procedure as in example 175, while receiving specified in the title compound (70 mg, yield 87%).

1H NMR (400 MHz, CDCl3); δ 9,31 (user. s, 1H), 7,41 (d, J=8.0 Hz, 1H), 7,43 (t, 2H), 7,10 (t, 1H), 7,05 (m, 3H), 6,92 (s, 1H), 6,80 (d, J=8.0 Hz, 2H)and 4.65 (m, 1H), 3,54 (t, 1H), 3,14 (t, 1H), 2.57 m (m, 2H), and 2.27 (s, 6H), 2,04 (m, 1H), 1.85 to (m, 1H).

Getting 79: synthesis of isopropyl ester of (S)-3-amino-4-(4-methoxybenzenesulfonyl)butyric acid

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

(Stage 1)

Commercially available 1-methyl ester (S)-2-BOC-amino amber acid (2.4 g, 10 mmol) was dissolved in DCM (30 ml) and to the solution was added triethylamine (2.8 ml, 20 mmol). 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 h at room temperature. The reaction extinguished saturated aqueous NaHCO3. Organic matter was extracted with EtOAc, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified column chromatography, thus obtaining the compound (2.3 g, yield 87%).

(Stage 2)

Connection of 57.8 g, 200 mmol), obtained in stage 1, was dissolved in methanol (200 ml). To the solution was added LiBH4(1 n solution in THF, 400 ml) and the mixture was stirred for 2 h while maintaining the temperature of 10°C or below. After completion of the reaction, the reaction solution was cooled to 0°C. For quenching the reaction was slowly added water, and the methanol was removed under reduced pressure. The residue was diluted with saturated aqueous NaHCO3. Organic matter was extracted with EtOAc and dried over MgSO4. The solvent was removed when bonigen the m pressure and the residue was purified column chromatography, thus obtaining the compound (39 g, 75%yield).

(Stage 3)

Compound (36 g, 137,8 mmol), obtained in stage 2, and triethylamine (38,4 ml, 275,5 mmol) was dissolved in dichloromethane (200 ml). Dropwise to the solution was added methanesulfonamide (11.7 ml, 151,5 mmol) and the mixture was stirred for 1 h at a temperature of 0°C~room temperature. After completion of the reaction was added 1 n hydrochloric acid. Organic matter was extracted with ethyl acetate, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, while receiving the connection.

(Stage 4)

Sodium hydride (5.5 g, 137,8 mmol) and 4-methoxybenzylamine (15,4 ml, 110,2 mmol) was dissolved in N,N-dimethylformamide (150 ml) and the mixture was stirred for 10 min at 0°C. To the resulting solution was added dropwise the compound (46,7 g, 137,8 mmol), obtained in stage 3, and the mixture was stirred for 4 h at 0°C. For damping the response to the mixture was added water. Organic matter was extracted with ethyl acetate, washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure and the residue was purified column chromatography to obtain the connection.

(Stage 5)

The compound (24 g, 62,7 mmol)obtained in stage 4, was dissolved in dichloromethane (200 ml). The solution to allali a solution of 4 N. hydrochloric acid/ethyl acetate (20 ml) and the mixture was stirred for 2 h at room temperature. After completion of the reaction the solvent was completely removed under reduced pressure. The residue was recrystallized from diethyl ether (150 ml) and dried, thus obtaining specified in the title compound (20 g, yield 96%).

Examples 179-196

Indolocarbazole acid obtained in the receiving 5, 7, 8, and 12, and aminosidine received in the receiving 79, was subjected to reaction according to the same procedure as in obtaining 34, while receiving derivatives of indole, which are then subjected sequentially to the reaction with commercially available carbonylcyanide according to the same methods as in examples 26 and 27, thus obtaining the compounds of examples, as shown in the following table.

ExampleR3R2'R1
Data1H NMR
179carboxylchlorinecyclopentyl
(400 MHz, DMSO-d6, ppm)δ 12,51 (user. s, 1H), 11,51 (s, 1H), 6,79 (s, 1H), 6,7 (s, 1H), 6,16 (s, 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 and (m, 2H), 1.69 in (m, 2H), and 1.56 (m, 4H)

180carboxylmethyl1-(TRIFLUOROACETYL)piperidine-4-yl
(400 MHz, CDCl3); δ 11,94 (user. s, 1H), 6,98 (s, 1H), 6,78 (s, 1H), and 6.25 (s, 1H), 5,33 (m, 1H), 4,13 (m, 1H), 3,76-3,68 (m, 5H), 3,47-to 3.41 (m, 3H), 2,74-2,63 (m, 2H), a 2.36 (s, 3H), 2,04 (m, 2H), and 1.56 (m, 2H)
181CarboxylN(tetrahydropyran-2-yl)methyl
(400 MHz, CDCl3); δ 11,68 (user. s, 1H), 7,06-6,98 (m, 3H), of 6.45 (s, 1H), 5,32 (m, 1H), 3.96 points (m, 1H), of 3.77-3,61 (m, 2H), 3.43 points (m, 1H), 3,28-is 3.21 (m, 3H), 2,80 (m, 1H), 2,65 (m, 1H)and 1.83 (m, 1H), 1,71 (m, 1H), 1,62-of 1.42 (m, 4H)
182carboxylNtetrahydropyran-4-yl
(400 MHz, CDCl3); δ 11.87 per (user. s, 1H), 7,15 (s, 1H), 7,03 (m, 2H), 6,50 (m, 1H), 5,39 (m, 1H), 4,06 (m, 2H), 3,80-3,62 (m, 2H), only 3.57 (m, 2H), 3,29 (m, 1H), and 2.83 (m, 1H), 2,69 (m, 1H), 2,11 (m, 2H), 1,64 (m, 2H)

183 carboxylN(tetrahydropyran-4-yl)methyl
(400 MHz, CDCl3); δ 11,89 (user. s, 1H), 7,13 (s, 1H),? 7.04 baby mortality (m, 2H), 6,44 (m, 1H), 5,39 (m, 1H), 3,98 (m, 2H), of 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), 1,44 (m, 2N)
184carboxylmethyl1-acetylpyrrolidine-3-yl
(400 MHz, CDCl3); δ 10,13 (user. s, 1H), 6,93 (s, 1H), PC 6.82 (s, 1H), 6,38 (s, 1H), 5,09 (m, 1H), 4,16 (m, 1H), to 3.67 (m, 2H), 3,52 (m, 2H), 3,38 (m, 1H), 3,25 (m, 1H), 2.91 in (m, 1H), 2,66 (m, 1H), 2,48 (s, 3H), of 2.23 (m, 1H), 2,00 (m, 1H)
185carboxylNcyclopentyl
(400 MHz, CDCl3); δ 11,74 (user. s, 1H), 7,06 (s, 1H), 6,99 (m, 2H), 6,45 (s, 1H), 5,48 (m, 1H), 3,90 (m, 1H), 3,71 (m, 1H), 3,23 (m, 1H), 2,75 (m, 1H), to 2.67 (m, 1H), 2,04 (m, 2H), of 1.75 (m, 2H), 1,61 is 1.48 (m, 4H)
186carboxylphenoxy(tetrahydropyran-1-yl)methyl
(400 MHz, CDCl3); δ 11,95 (user. s, 1H), 7,28 (m, 2H), 7,06-of 6.96 (m, 4H), to 6.58 (s, 1H), 6,24 (s, 1H), 5,33 (m, 1H), 3,98 (m, 2H), ,75 (m, 1H), to 3.58-3,47 (m, 3H), of 2.23 (m, 1H), 2,78-2,62 (m, 2H), 2,04 (m, 2H), 1.26 in (m, 2H)

187carboxylphenoxytetrahydropyran-4-yl
(400 MHz, CDCl3); δ 11,94 (user. s, 1H), 7,00 (s, 1H), 6,78 (s, 1H), of 6.26 (s, 1H), 5,35 (m, 1H), 3,71 (m, 1H), 3,63 (m, 1H), up 3.22 (m, 1H), 2,75 (m, 1H), 2,62 (m, 1H), is 2.37 (s, 3H), of 2.25 (m, 1H), 2,09-of 1.73 (m, 7H)
188carboxylchlorinetetrahydropyran-4-yl
(400 MHz, CDCl3); δ 11,21 (user. s, 1H), 6,66 (s, 1H), is 6.61 (s, 1H), 6,00 (s, 1H), 4,89 (user. s, 1H), 3,95 (m, 1H), 3,63 (m, 1H), 3,35 (m, 2H), to 2.67 (m, 2H), 2,50 (s, 3H), 2,42 (m, 2H), 1,80 (m, 4H)
189carboxylmethylcyclobutyl
(400 MHz, CDCl3); δ 11,82 (d, 1H), 6,95 (s, 1H), 6,79 (s, 1H), of 6.20 (d, 1H), and 5.30 (user. s, 1H), 4,15 (m, 1H), 4,05~of 3.75 (m, 5H), 3,66 (m, 1H), 3,19 (s, 1H), 2,79-2,61 (m, 2H), is 2.37 (s, 3H), of 2.23 (m, 1H), up to 1.98 (m, 1H)
190carboxylmethyltetrahydrofuran-3-yl
(400 MHz, CDCl3/Meon-d4); δ 11,24 (user. s, 1H), 6,84 (s, 1H), 6,77 (s, 1H), and 6.25 (s, 1H), of 5.05 (m, 1H), of 3.56 (m, 1H), 3.15 in (m, 2H), 3,03 (m, 2H), 2,78 (m, 1H), 2.63 in (m, 1H), 2,34 (s, 3H), of 1.23 (m, 1H), 1,18 (m, 1H), 0,52 (m, 2H), 0,24 (m, 2N)

191carboxylmethylcyclopropylmethyl
(400 MHz, CDCl3); δ 11,92 (user. s, 1H), 6,98 (s, 1H), 6,77 (s, 1H), from 6.22 (s, 1H), 6,29 (user. s, 1H), 3.96 points (m, 2H), 3,70 (m, 1H), 3,37 (m, 2H), 3,18 (m, 1H), is 3.08 (m, 2H), 2,72 (m, 1H), has 2.56 (m, 1H), is 2.37 (s, 3H), 1.91 a (m, 1H), about 1.75 (m, 2H), 1,41 (m, 2H)
192carboxylmethyl(tetrahydropyran-4-yl)methyl
(400 MHz, DMSO-d6); δ 11,35 (user. s, 1H), to 6.67 (s, 1H), is 6.61 (s, 1H), 6,09 (s, 1H), 5,81 (user. s, 1H), 4,90 (m, 1H), to 3.64 (m, 1H), 3,21 (m, 1H), 3,05 (m, 2H), 2,77~2,69 (m, 2H), 2,28 (s, 3H), of 2.23 (m, 1H), of 1.85 (m, 2H), 1,65~1,58 (m, 4H), 1,32 (m, 2H)
193carboxylmethyltetrahydropyran-4-yl
(400 MHz, DMSO-d6); δ 11,88 (user. s, 1H), to 7.09 (s, 1H),? 7.04 baby mortality (s, 1H), 6,74 (s, 1H), 4,94 (m, 1H), 3,98 (m, 1 is), to 3.73 (m, 1H), 3,47 (m, 1H), 2,87~2,70 (m, 2H), of 2.51 (s, 3H), of 1.93 (m, 2H), 1,76~of 1.56 (m, 6N)
194MeO2With-methylcyclopentyl
(400 MHz, CDCl3); δ 10,66 (user. s, 1H), PC 6.82 (s, 1H), 6,41 (s, 1H), 6,17 (s, 1H), 5,08 (m, 1H), 4,01 (m, 2H), 3,80 (m, 1H), to 3.67 (m, 1H), 3,49 (s, 3H), 3,20 (DD, 1H), 2,85 (DD, 2H), 2,65 (DD, 1H), 2,02 (m, 1H), 1,66~of 1.53 (m, 4H), 1,45~of 1.33 (m, 5H)

195carboxylphenoxycyclopentyl
(400 MHz, DMSO-d6; Na salt); δ 11,85 (user. s, 1H), 7,31 (m, 2H), 7,01 (t, 1H), 6,93 (d, J=8 Hz, 2H), only 6.64 (s, 1H), 6.48 in (d, J=4 Hz, 1H), to 6.39 (s, 1H), 5,97 (s, 1H), is 4.93 (m, 1H), 3,75 (m, 1H), 3,55 (t, 1H), 3,20 (square, 1H), 2,62 (DD, 1H), 2,15 (square, 1H), 1,90 (m, 2H), 1,72 (m, 2H), 1,60 (m, 4H)
196carboxylmethyl4,4-diverticulosis-1-yl
(400 MHz, CDCl3); δ 11,94 (user. s, 1H), 7,00 (s, 1H), 6,78 (s, 1H), of 6.26 (s, 1H), 5,35 (m, 1H), 3,71 (m, 1H), 3,63 (m, 1H), up 3.22 (m, 1H), 2,75 (m, 1H), 2,62 (m, 1H), is 2.37 (s, 3H), of 2.25 (m, 1H), 2,09-of 1.73 (m, 7H)

Examples 197-222

Intermediate esters to receive the deposits of the compounds of examples 179, 185, 186, 192, 193, 195 and 196 and commercially available amino compounds were subjected sequentially to the reaction according to the same methods as in example 129, receiving 50 and example 71 to give the compounds of examples, as shown in the following table.

ExampleR3R2'R1
Data1H NMR
197(3S)-3-(amino)pyrrolidin-1-ylchlorinecyclopentyl
(400 MHz, MeOD); δ 7,51 (s, 1H), 7,28 (s, 1H), 7,06 (s, 1H), 4,27 (m, 1H), 4,15 (m, 1H), 3.95 to to 3.8 (m, 5H), to 3.67 (m, 3H), 3,44 (DD, 1H), 2,70 (m, 1H), 2,40 was 2.25 (m, 3H), 2,10 (m, 2H), 1.91 a (m, 4H), 1,71 (m, 2N)
198(3S)-3-(dimethylaminophenyl)-ethylamino-pyrrolidin-1-ylchlorinecyclopentyl
(500 Hz, CDCl3); δ 7,16 (t, 1H), 6.89 in (s, 1H), 6,74 (s, 1H), 6,61 (m, 3H), 6,34 (s, 1H), with 4.64 (m, 1H), 3,86 (m, 1H), 3,66 (m, 2H), 3,51 (m, 2H), 3,45-3,25 (user. s, 2H), 3.25 to 3,05 (user. s, 2H), 3,03 (t, 1H), 3,05-2,95 (user. s, 1H), 2,92 (C, 6N), 2,38 (user with, 1H), 2,05-of 1.85 (m, 5H), 1,80-of 1.65 (m, 4H), 1,58 (m, 1H)

199(1-(acetyl)piperazine-4-ylchlorinecyclopentyl
(500 Hz, CDCl3); δ 10,17 (user. s, 1H), 7,00 (s, 1H), 6,83 (s, 1H), gold 6.43 (s, 1H), and 4.75 (m, 1H), 3,83 (m, 2H), to 3.58 (m, 1H), of 3.56 (DD, 1H), 3,48 (m, 1H), 3,32 (m, 1H), 3,25 (m, 1H), 3.15 in (DD, 1H), 2,46 (m, 2H), a 2.36 (m, 1H), and 2.26 (m, 2H), measuring 2.20 (m, 1H), 2.05 is (s, 3H), 2,04 (m, 2H), 1,96 (m, 1H), 1,80 (m, 1H), of 1.66 (m, 3H), of 1.48 (m, 2H)
200(1-(acetyl)piperazine-4-ylchlorineN
(500 Hz, DMSO-d6); δ 11,70 (user. s, 1H), 10,41 (s, 1H), to $ 7.91 (s, 1H), 7,78 (d, 1H), 7,58 (s, 1H), 7,46 (s, 2H), was 7.36 (m, 3H), to 7.09 (t, 1H), 7,05 (s, 1H), 6,97 (d, 2H), 3,86 (s, 2H), 2,90 (user. s, 2H)
2012-oxopiperidin-4-ylmethyltetrahydropyran-4-yl
(500 MHz, CDCl3); δ 11,05 (s, 1H), 7,72 (s, 1H), PC 6.82 (s, 1H), 6,78 (s, 1H), 6,27 (s, 1H), 4,71-of 4.67 (m, 1H), 4,03-4,01 (m, 2H), 3,62-3,47 (m, 4H), 3,30-3,20 (m, 2H), 3.15 in (d, 2H), 3,11-is 3.08 (m, 1H), 2,59 of $ 2.53 (m, 4H), 2,42-a 2.36 (m, 3H), 2,09-2,04 (m, 2H), 1,95-of 1.92 (m, 1H), 1,84-of 1.81 (m, 1H), 1,59-is 1.51 (m, 2H)

202morpholine-4-ylmethyltetrahydropyran-4-yl
(400 MHz, CDCl3); δ 10,91 (s, 1H), 6,85 (s, 1H), 6,83 (s, 1H), 6,28 (s, 1H), to 4.81 (m, 1H), 3.96 points (m, 2H), 3,60-to 3.41 (m, 7H), 3,17 (, 1H), 2.40 a (m, 2H), a 2.36 (m, 3H), to 2.29 (m, 2H), 2,18 (m, 2H), 2,04~to 1.79 (m, 4H), 1.39 in (m 2N)
2031-(hydroxymethyl-carbonyl)piperazine-4-ylphenoxycyclopentyl
(400 MHz, CDCl3); δ is 10.7 (1H, user. C), 7,30-7,27 (2H, m),? 7.04 baby mortality-6,97 (3H, m)6,86 (1H, s), 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), 3,59-3,55 (2H, m), 3,49 is-3.45 (1H, m), 3,18-is 3.08 (2H, m), 3,03-3,01 (1H, m), 2,47-of 2.38 (3H, m), 2,24 with 2.14 (3H, m), 2.05 is-a 1.88 (4H, m), 1,84-of 1.55 (8H, m), 1,49-of 1.39 (2H, m)
204piperazine-1-Ilphenoxycyclopentyl
(400 MHz, CDCl3); δ 7,40 and 7.36 (4H, m), 7,16 for 7.12 (1H, m),? 7.04 baby mortality-7,02 (2H, m)6,94 (1H, s), 4,20-to 4.15 (1H, m), 3,99-of 3.94 (1H, m), 3,91-of 3.80 (5H, m), 3.75 to 3,63 (6N, m), to 3.58-of 3.48 (1H, m), 2,44-to 2.40 (2H, m), 2,09-2,07 (2H, m), 1,91-1,89 (4H, m), 1,71 was 1.69 (2H, m)

2051-BOC-Pieper is Zin-4-yl phenoxycyclopentyl
(400 MHz, CDCl3); δ is 10.7 (1H, s), 7,30-7,26 (2H, m), 7.03 is-6,98 (3H, m), 6,85 (1H, s), 6,62 (1H, d, J=2.0 Hz), of 6.26 (1H, d, J=2.4 Hz), 4,82-of 4.77 (1H, m), a 3.87 (1H, user. C), 3,78-3,74 (1H, m), 3,59-of 3.54 (1H, m), and 3.31 (4H, user. C)3,19-3,14 (1H, m), 2,48 to 2.35 (2H, m), and 2.26 (1H, user. C)2,17 (1H, user. C)2,03 is 1.91 (4H, m), of 1.84 and 1.75 (1H, m), 1,67-of 1.53 (4H, m), 1,45 (N, C)of 1.42 and 1.35 (1H, m)
206phenoxycyclopentyl
(400 MHz, CDCl3); δ 10,9 (1H, user. C), 7,32-7,28 (2H, m), 7,05-of 6.99 (3H, m), 6.90 to (1H, s), 6,59 (1H, d, J=1.6 Hz), of 6.29 (1H, d, J=2.0 Hz), 4,77-4,74 (1H, m), 4,06-to 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-to is 2.74 (1H, m), 2.00 in to 1.98 (4H, m), 1.69 in (2N, user. C)1,60-1,56 (6N, m)

2072-oxopiperidin-4-ylphenoxycyclopentyl
(400 MHz, CDCl3); δ is 10.7 (1H, user. C), 7,30-7,26 (2H, m), 7.03 is-to 7.00 (3H, m), PC 6.82 (1H, s), 6,60 (1H, d, J=2.0 Hz)at 3.25 (1H, d, J=2.0 Hz), 4,74-4,71 (2H, m), 3,83 (1H, user. C)3,56-to 3.52 (1H, m), 3,50-3,26 (2H, m), 3,20-3,10 (2H, m), 2,68-2,61 (4H, m), 2,01 is 1.86 (4H, m), 1,73 is 1.58 (8H, m)
208 1-[(tetrahydrofuran-2-yl)carbonyl]-piperazine-4-ylphenoxycyclopentyl
(400 MHz, CDCl3); δ 10,67-of 10.58 (1H, m), 7,30-7,27 (2H, m),? 7.04 baby mortality-6,98 (m, 3H), 6,85 (1H, d, J=1.2 Hz), 6,62 (1H, d, J=2.0 Hz), 6,27 (1H, user. C)4,84-4,78 (1H, m), 4,58-of 4.54 (m, 1H), 3.96 POINTS-3,91 (1H, m), a 3.87-3,71 (3H, m), 3,59-of 3.42 (3H, m), 3,19-3,14 (1H, m), 2,47-is 2.37 (2H, m), 2,33-of 2.16 (4H, m), 2,07-1,87 (6N, m), 1,83 is 1.75 (4H, m), 1,68-of 1.56 (1H, m,), 1,49-of 1.40 (2H, m)

2091-(pyridine-2-yl)piperazine-4-ylphenoxycyclopentyl
(400 MHz, CDCl3); δ of 10.3 (1H, s), 8,19-8,18 (1H, m), 7,49 was 7.45 (1H, m), 7,29-of 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, user. C)3,60-3,55 (1H, m), 3,49 is-3.45 (4H, m), 3,21-3,17 (1H, m), 2,55-2,41 (6N, m)to 1.99 (3H, user. C)1,88 is 1.86 (1H, m)1,70 (3H, user. C), 1,61 to 1.47 (3H, m)
2101-(2-forfinal)piperazine-4-ylphenoxycyclopentyl
(400 MHz, CDCl3); δ is 10.7 (1H, s), 7,29-of 7.25 (2H, m), 7,07-6,98 (5H, m), 6,95-to 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-to 4.81 (1H, m)to 3.89 (1H, user. C)3,60 of 3.56 (1H, m), 3,23-3,18 (1H, m), 2,99 (4 is, user. C)2,54-2,43 (5H, m), 2,04-of 1.94 (3H, m), 1,98-to 1.82 (2H, m), 1,68-1,37 (6N, m)

2111-(acetyl)piperazine-4-ylphenoxycyclopentyl
(400 MHz, CDCl3); δ is 10.6 (1H, s), 7,31-7,27 (2H, m),? 7.04 baby mortality-6,98 (3H, m), at 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, user. C)3,81 (1H, user. C), 3,74 (1H, user. C), 3,64-3,55 (2H, m)to 3.41 (1H, user. C), 3,17-3,10 (2H, m), 2,89 (1H, user. C)of 2.68 2.63 in (3H, m), 2,56-2,48 (2H, m)to 2.06 (3H, s), 2,03-1,90 (4H, m), 1,72 (2H, user. C)1,60-of 1.56 (4H, m)
212(2R)-2-(hydroxymethyl)-pyrrolidin-1-ylmethyl(tetrahydropyran-4-yl)methyl
(CDCl3, 400 MHz); δ of 10.25 (s, 1H), 6,76 (s, 1H), 6,74 (s, 1H), 6,23 (s, 1H), 4,67-4,58 (m, 2H), 4,16-4.09 to (m, 1H), 4,00-of 3.94 (m, 2H), of 3.73-3,68 (m, 1H), 3,50-to 3.36 (m, 2H), 3,11 (d, 2H), 2,99 vs. 2.94 (m, 2H), 2,32 (s, 3H)), 2,15-2,07 (m, 2H), 2,02-of 1.92 (m, 3H), 1,76-of 1.73 (m, 2H), 1,42-of 1.36 (m, 2H), 1,14-1,08 (m, 2H), 0,86 is 0.81 (m, 2H), 0,73 of-0.68 (m, 2H)

213(3R)-3-(acetylamino)-pyrrolidin-1-ylphenoxycyclopentyl
(500 Hz, CDCl3); δ of 11.45 (user. s, 1H), 8,14 (user. s, 1H), 6.90 to (s, 1H), 6,77 (s, 1H), 6,37 (s, 1H), a 4.83 (m, 1H), of 4.66 (m, 1H), of 4.05 (m, 1H), 3,91 (m, 1H), of 3.77 (m, 1H), 3,62-to 3.52 (m, 2H), 3,13 (m, 1H), is 3.08 3.00 for (m, 2H), 2,84 (m, 1H), 2,43 (m, 1H), of 2.23 (m, 1H), 2.05 is (m, 4H), from 2.00 (s, 3H), of 1.80 (m, 2H), 1,71 (m, 2H), and 1.63 (m, 2H)
214(4-(benzyl)piperazine-1-Ilphenoxycyclopentyl
(500 Hz, CDCl3); δ 7,32-7,24 (m, 7H), 7,01 (m, 3H), 6,77 (s, 1H), 6,59 (s, 1H), 6,29 (s, 1H), 4,71 (m, 1H), a 3.87 (m, 1H), of 3.56 (DD, 1H), 3,50 (s, 2H), is 3.08 (DD, 1H), 2,80 (user. s, 8H), 2,60 (user. s, 2H), 2,11 of 1.99 (m, 4H), of 1.80 (m, 2H), 1,71 (m, 2H), 1.61 of (m, 2H)

215morpholine-4-ylmethyl(tetrahydropyran-4-yl)methyl
(500 MHz, CDCl3); δ 11,13 (s, 1H), 6,84 (s, 1H), for 6.81 (s, 1H), 6,24 (s, 1H), 4,81-4,78 (m, 1H), a 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 (user., 2H), 2,38-of 2.36 (m, 7H), 2,14 (user., 2H), 1.91 a-a 1.88 (m, 1H), 1,75-1,71 (m, 2H), 1,28-to 1.21 (m, 2H)
216morpholine-4-ylphenoxy(tetrahydropyran-4-yl)methyl
(400 MHz, CDCl3); δ 10,19 (users, 1H), 7,29 (m, 2H), 7,01 (m, 3H), at 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, 6N), the 3.35 (m, 6N), 3,19 (m, 1H), 3.04 from (m, 2H), 2,46 (m, 2H), 2,34 (m, 4H), 2,00 (m, 1H)and 1.83 (m, 2H), 1,60 (m, 2H), 1,30 (m, 2H)
2172-oxopiperidin-4-ylphenoxy(tetrahydropyran-4-yl)methyl
(400 MHz, CDCl3); δ 10,7 (user. s, 1H), 7,28 (m, 2H), 7,00 (m, 3H), 6,85 (user. s, 1H), for 6.81 (d, 1H), 6,60 (d, J=1.6 Hz, 1H), 6,20 (d, J=2.0 Hz, 1H), to 5.03 (m, 1H), 4,70 (m, 1H), 3,98 (m, 2H), of 3.56 (m, 1H), 3,49-to 3.36 (m, 6N), 3,15-of 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)

218pyrrolidin-1-ylphenoxycyclopentyl
(500 MHz, CDCl3); δ 7,31-7,27 (2H, m), 7.03 is-7,00 (1H, m), of 6.96-6,94 (2H, m), 6,50 (1H, d, J=2.0 Hz), 6,17 (1H, d, J=2.0 Hz), 4,73-of 4.66 (1H, m), 3,86 (user. s, 1H), 3,74-TO 3.58 (2H, m), 3.46 in-3,37 (4H, m), 3,23-3,19 (1H, m), 2,24-2,10 (6N, m), 2,10 and 1.80 (2H, m), 1.70 to of 1.65 (5H, m)
219morpholine-4-ylN4,4-diverticulosis-1-yl
(400 MHz, CDCl3); δ 9,67 (user. s, 1H), 6.87 in (s, 1H), PC 6.82 (s, 1H), 6,34 (s, 1H), 4,71(m, 1H), the 3.65 (m, 6N), 3,55 (DD, J=8 Hz, 1H), 3,51 (m, 1H), 3.15 in (DD, J=8 Hz, 1H), 2,52-to 2.29 (m, N), 2,15-2,04 (m, 4H), 1,96-1,90 (m, 2H), 1,58-is 1.51 (m, 2H)
220phenoxy(tetrahydropyran-4-yl)methyl
(500 MHz, CDCl3); δ for 9.47 (user. C)to 6.88 (s, 1H), 6,47 (s, 1H), to 6.39 (s, 1H), by 5.87 (user. s, 1H), 4,12-4,00 (m, 2H), 3,85 (user. s, 4H), 3,66 (m, 1H), to 3.58 (t, 2H), is 3.08 (user. s, 4H), 2.95 and (m, 1H), 2,85-2,70 (m, 3H), 2,41 (s, 3H), 2,10 (m, 2H), 1,96 (m, 2H), 1,60 (m, 2H)

2212-oxopiperidin-4-ylphenoxy(tetrahydropyran-4-yl)methyl
(500 MHz, CDCl3); δ 11,03 (s, 1H), 8,19 (user. s, 1H), PC 6.82 (s, 1H), 6,79 (s, 1H), of 6.31 (s, 1H), 4,84 with 4.65 (m, 3H), 4,24 (m, 1H), 3,91 (m, 2H), 3,82-3,55 (m, 4H), and 3.31 (m, 2H), 3,19 (m, 1H), 3,14 (m, 2H), 2.95 and (m, 2H), 2,69 (m, 1H), measuring 2.20 (m, 1H), to 1.98 (m, 1H), 1,81 (d, 2H), 1.39 in (m, 2H)
2222-oxopiperidin-4-ylphenoxy4,4-diverticulosis-1-yl
(400 MHz, CDCl3); δ 10,14 (user. s, 1H), PC 6.82 (s, 1H), 6,80 (s, 1H), of 6.31 (s, 1H)and 4.65 (m, 1H), 3,54 (m, 1H, of 3.53 (DD, J=8 Hz, 1H), 3,39 (m, 2H), 3,30 (m, 1H), 3,22-is 3.08 (m, 4H), 2,78-to 2.65 (m, 4H), of 2.38 (s, 3H), 2,28-2,04 (m, 4H), 1,96 is 1.86 (m, 2H), 1,73 (m, 2H)

Compounds according to the present invention was tested in experiments on enzyme and animal models in the following experiments 1 and 2, in order to evaluate their effectiveness.

Experiment 1: analysis of the enzymatic activity of glucokinase

Glucokinase known as glucokinase IV (isoform 1 GK human pancreatic form, and isoform 2 GK human liver form)cloned into the expression vector RET fx (Novagen Co.), transformed into the strain E. coli BL21 (DE3) (Invitrogen Co.), expressed and purified using column containing Nickel sorbent. Then glucokinase obtained after dialysis was used in the following analysis.

Analysis of glucokinase was performed by absorption measurement according to the conventional method. In short, glucokinase converts glucose substrate glucose-6-phosphate in normal conditions, and glucose-6-phosphatedehydrogenase irreversibly converts glucose-6-phosphate gluconate-6-phosphate. During this procedure produces NADH and its absorption is measured to calculate the enzymatic activity.

When measuring the enzymatic activity of each compound 2-fold diluted from maximum to minimum concentrations, and 2 µl of each solution was added to 96-well UV-plan is o (BD bioscience). Added 60 μl of the first mixture (final concentration 25 mm Hepes, 25 mm KCl, 2 mm MgCl2, 1 mm DTT) and thoroughly mixed. Added 38 ál of enzyme mixture (final concentration 1 mm ATP, 1 mm NAD, 5 mm glucose, 0,85 Ed. G6PDH, 37 nm GK) (final volume 100 µl), and the mixture was subjected to reaction for 10 min at room temperature. The absorption of NADH was measured at 340 nm using a UV-spectrometer (Molecular Device).

The ability of compounds according to the present invention to activate this enzyme presents in the form AU1,5(the concentration at which enzyme activity is increased in 1.5 times, nm), which are in the range of from 0.001 μm to 30 μm or less, preferably from 0.001 μm to 10 μm, more preferably from 0.001 μm to 1 μm. The ability of representative compounds to activate the enzyme are shown in table 1.

Table 1
Connection exampleAU1,5
(nm)
Connection exampleAU1,5
(nm)
Connection exampleAU1,5
(nm)
Connection exampleAU1,5
(nm)
12224131844217
5763177832
92410611141225
1312148154001664
21152211223192432
267274288 3222
302831163218365
34113563612403
381839640174117
469647274894935
50285116752205397
541855 56175721
5814592860296111
62366311964176523
6964703271317251
7325741475217614
7727782579198021
1 6822283458427
8518862387108819
89329037917292112
9323994159511965
97698799510011
10110102710316 10413
1056106141076310815

10926110301111111281
12140122601236212424
12523126201272112816
12967130141311013213
137 23138361393814052
141241428514337144122
145138146291475214812
14912150101511415214
15312154141551215622
157241581615917 16012
1611016221163516425
16512166431672816815
16991701217123176178
173114178211757118056

Experiment 2: the Ability of activators of glucokinase to lower blood glucose level after a single oral administration to male mice C57BL/6

The glucokinase activators according to the present invention orally was administered as a single dose 30 mg/kg body weight to male mouseC57BL/6 to 24 hrs Wednesday for Akti is atarov selected depending on the solubility of distilled water, buffer solution of HCl with a pH of 1.2, 0.5% solution of methylcellulose in distilled water, a mixture of 10% gelucire/HCl buffer solution with a pH of 1.2 (1/1). Activators of glucokinase was dissolved in the chosen environment to an average volume of 0.1 ml/10 g of body weight based on the weight measured on the day of the experiment.

The blood glucose level was measured by cutting the tail vein for 1 h (time = -1) to measure blood glucose level, blood collection from the tail vein immediately before the introduction of the glucokinase activator (time = 0) and through 1, 2, 4, 8, 12, 24 h after injection, loading it into an automatic glucometer (Accu-Chek® Active, Roche, USA), precapitalism 5 µl of blood on the yellow strip strips Accu-Chek® Active glucose and registration of the measured value.

Mice who participated in the experiment, were divided into groups (n=0, in the case of a group with the introduction of the only environment n=4) the day before the experiment, so that each group has a constant mean and standard deviation of blood glucose level after 4 h of fasting. Mice fed the desire (ad libitum).

The area of blood glucose under the curve (AUC) relative to the control with the introduction of the medium was calculated for analysis within 24 h after injection of glucokinase activators. Reducing the blood glucose level of activity in % representative compounds relative to the control with the introduction of 100% environment shown in the following table 2.

Table 2
Connection exampleHypoglycemic ability (% protection)Wednesday
2775%Distilled water
3381%Distilled water
3767%Distilled water
3871%0.5% solution of methylcellulose in distilled water
4257%Distilled water
5262%Distilled water
5452%Distilled water
6154%Distilled water
9681%Distilled water
9972% Distilled water
15866%Distilled water
15963%Distilled water
16473%Distilled water
16764%Distilled water
17451%Distilled water

1. Derivatives of indole following formula (1):

in which X represents NH,
n denotes a number equal to 0 to 3,
Y represents a direct bond, -(CH2)pO-, -(CH2)q- or -(CH2)qSO2-,
R denotes a number equal to 0-2,
q denotes a number equal to 1-3,
R1 represents hydrogen, - (CR4R5)p-A-R6 or -(CR4R5)q-R6,
p and q have the meanings indicated above,
R4 and R5 independently of one another represent hydrogen or C1-C3-alkyl,
Rather it represents a phenyl or optional oxosteroid3-C6-cycloalkyl, which is optionally substituted by two halogen atoms, or is a 5-6-membered heterocyclyl, to the which is optionally substituted by 1 or 2 substituents and has 1 heteroatom, selected from O, S and N, where the substituents are selected from halogen atoms,
R6 represents hydrogen, nitro, C1-C3-alkylsulphonyl, which can be substituted by 1-3 halogen atoms, or a carboxy,
R2 represents halogen, C1-C3-alkyl or trifluoromethyl, or represents a 5-6-membered heteroaryl or heterocyclyl, each of which has 1-3 heteroatoms selected from N and O, or represents optionally substituted C1-C3-alkylsulfonyl 6-12 membered aryl,
R3 represents R7-X-B-X'-,
Represents a direct link or is a 5-6-membered heterocyclyl or heteroaryl, each of which optionally contains oxo, optionally condensed and has 1-4 heteroatoms selected from N, O and S,
X and X' independently of one another represent a direct bond or is selected from the group consisting of-CO-, -(CH2)q-, NR4C(O)-, -NR4-, -OC(O)-, -O-, - (CH2)pC(O)-, -(CH2)pO-, -(CH2)pNR4-, -C(O)NR4 and-S(O)r-where
p and q have the meanings stated above, r denotes a number equal to 2, and R4 represents hydrogen or C1-C3-alkyl,
R7 represents hydrogen, hydroxy, C1-C3alkyl, C1-C4-alkoxy, halogen-C1-C3is alkyl or cyclopentyl, represents phenyl, optionally substituted di(C 1-C3-alkyl)amino or halogen, or is a 5-6-membered heteroaryl, optionally substituted stands, or 5-6-membered heterocyclyl, optionally substituted 1 or 2 exography, each of which has 1 to 4 heteroatom selected from N and O,
or their isomers.

2. Compounds according to claim 1, where
X represents NH,
n denotes a number equal to 0 to 3,
Y represents a direct bond, -(CH2)pO-, -(CH2)q- or -(CH2)qSO2-,
R denotes a number equal to 0-2,
q denotes a number equal to 1-3,
R1 represents -(CR4R5)p-A-R6 or -(CR4R5)q-R6,
p and q have the meanings indicated above,
R4 and R5 independently of one another represent hydrogen or C1-C3-alkyl,
Rather it represents a phenyl or optional oxosteroid3-C6-cycloalkyl, which is optionally substituted by two halogen atoms, or is a 5-6-membered heterocyclyl, which is optionally substituted by 1 or 2 substituents and has 1 heteroatom selected from O, S and N, where the substituents are selected from halogen atoms,
R6 represents hydrogen, nitro, C1-C3-alkylsulphonyl or carboxy,
R2 represents halogen, C1-C3-alkyl or trifluoromethyl, a is a 5-6-membered heteroaryl or heterocyclyl, each of which has 1-3 gets is of rotoma, selected from N and O, or represents optionally substituted C1-C3-alkylsulfonyl 6-10-membered aryl,
R3 represents R7-X-B-X'-,
Represents a direct link or is a 5-6-membered heterocyclyl or heteroaryl, each of which optionally contains oxo, optionally condensed and has 1-4 heteroatoms selected from N, O and S,
X and X' independently of one another represent a direct bond or is selected from the group consisting of-CO-, -(CH2)q-, NR4C(O)-, -NR4-, -OC(O)-, -O-, -(CH2)pC(O)-, -C(O)NR4 and-S(O)rwhere p and q have the meanings stated above, r denotes a number equal to 2, and R4 represents hydrogen or C1-C3-alkyl, and
R7 represents hydrogen, hydroxy, C1-C4-alkyl, halogen-C1-C3is alkyl or cyclopentyl, represents phenyl, optionally substituted di(C1-C3-alkyl)amino or halogen, or is a 5-6-membered heteroaryl, optionally substituted stands, or 5-6-membered heterocyclyl, optionally substituted 1 or 2 exography, each of which has 1 to 4 heteroatom selected from N and O.

3. Compounds according to claim 2, in which R1 represents -(CH2)p-A-R6 or - (CR4R5)q-R6, where R denotes a number equal to 0 to 2, q denotes a number equal to 1-3, R4 and R5 independently from each other Pres who represent hydrogen or C 1-C3-alkyl, represents phenyl or optional oxosteroid3-C6-cycloalkyl, which can be substituted by two halogen atoms, or is a 5-6-membered heterocyclyl, which has 1 heteroatom selected from O, S and N, and R6 represents hydrogen, nitro, C1-C3-alkylsulphonyl or carboxy.

4. Compounds according to claim 3, in which R1 is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, diverticulosis, tetrahydrofuran, tetrahydropyran, (tetrahydropyran-4-yl)methyl, tetrahydrothiopyran, 4-oxocyclohexyl, (1-acetyl)piperidine and 4-nitrophenyl.

5. Compounds according to claim 2, in which Y represents a direct bond, -O-, - (CH2)Oh, -(CH2)- or -(CH2)SO2-.

6. Compounds according to claim 2, in which R2 represents halogen, C1-C3-alkyl or trifluoromethyl, a is a 5-6-membered heteroaryl or heterocyclyl, each of which has 1-3 heteroatoms selected from N and O, or represents optionally substituted by methanesulfonyl 6-10-membered aryl.

7. Compounds according to claim 6, in which R2 is selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, propyl, phenyl, methansulfonate, pyridine, research, 1,2-imidazole, 1,3-imidazole, pyrrolidine and pyrrole.

8. Compounds according to claim 2, which is a direct the second link, pyrazole, imidazole or oxadiazole or 5-6-membered heterocyclyl, which optionally contains oxo, optionally is condensed and has 1-4 heteroatoms selected from N, S and O.

9. Connection of claim 8, which represents a direct bond or is selected from the following formulas (i)to(xi):



in which R7 has the meanings indicated in claim 1 or 2.

10. Compounds according to claim 2, in which X' represents a direct bond or is selected from the group consisting of-CO-, - NR4CO-, -SO2- and-O-.

11. Compounds according to claim 2, in which X represents a direct bond or is selected from the group consisting of-C(O)NR4-, -NR4-, -OC(O)-, -NR4C(O)-, - (CH2)C(O)-, -S(O)2and-C(O)-.

12. Compounds according to claim 11, in which X represents a direct bond or is selected from the group consisting of-C(O)NH-, -C(O)N(Me)-, -NH-, -N(Me)-, - OC(O)-, - N(Me)C(O)-, -(CH2)C(O)-, -S(O)2and-C(O)-.

13. Compounds according to claim 2, in which R7 represents hydrogen, hydroxy, C1-C4-alkyl, halogen-C1-C3is alkyl or cyclopentyl, represents optionally halogen-substituted enyl or is a 5-6-membered heteroaryl, optionally substituted stands, or 5-6-membered heterocyclyl, optionally substituted 1 or 2 exography, each of which has 1 to 4 heteroatom selected from N and O.

14. Connection 13, in which R7 is selected from the group consisting of hydrogen, hydroxy, methyl, trifloromethyl, ethyl, tert-butyl, pyrrolidine, phenyl, 2-ftoheia, piperidine, pyridine, 1,3-pyrazine, 1,4-pyrazine, furan, 1,2,3,4-tetraselenafulvalene.

15. Compounds according to claim 2, selected from the group consisting of
[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol;
{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;
[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol;
{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;
{(R)-2-[5-chloro-7-(tetrahydrothiopyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;
[(R)-2-(5-bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol;
{(R)-2-[5-bromo-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl} methanol;
[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol;
{(R)-2-[7-cyclopentylamine-5-(pyridine-3-yloxy)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;
{(R)-2-[5-(pyridine-3-yloxy)-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol is;
{(R)-2-[5-morpholine-4-ylmethyl-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;
[(R)-2-[7-cyclopentylamine-5-pyrazole-1-ylmethyl-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}methanol;
[(R)-2-(7-cyclopentylamine-5-imidazol-1-ylmethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl} methanol;
{(R)-2-[7-cyclopentylamine-5-(1H-pyrrol-3-ylmethyl)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl} methanol;
[(R)-2-(7-cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]methanol;
[7 cyclopentylamine-2-((R)-4-hydroxymethyl-4,5-dihydrothiazolo-2-yl)-1H-indol-5-yl]methanol;
methyl ester [(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
ethyl ester [(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]ethanol;
methyl ester {(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl} ethanol;
[(R)-2-(5-bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
2-[(R)-2-(5-bromo-7-cyclopentylamine what-1H-indol-2-yl)-4,5-dihydro-1,3-thiazol-4-yl]ethanol;
{(R)-2-[5-bromo-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
2-{(R)-2-[5-bromo-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl} ethanol;
[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
ethyl ester [(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanol;
{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethanol;
methyl ester [(R)-2-(7-cyclopentylamine-5-methoxy-1 H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
ethyl ester [(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
methyl ester {(R)-2-[5-methoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
{(R)-2-[5-methoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
[(R)-2-(7-cyclopentylamine-5-ethoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
[(R)-2-(7-cyclopentylamine-5-propoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
[(R)-2-(7-cyclopen is ylamino-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
{(R)-2-[5-phenoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
methyl ester {(R)-2-[7-cyclopentylamine-5-(pyridine-3-yloxy)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
{(R)-2-[7-cyclopentylamine-5-(pyridine-3-yloxy)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
methyl ester {(R)-2-[5-(pyridine-3-yloxy)-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
{(R)-2-[5-(pyridine-3-yloxy)-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
methyl ester [(R)-2-(7-cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
[(R)-2-(7-cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
{(R)-2-[5-methyl-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
{(R)-2-[5-methyl-7-(4-oxocyclohexyl)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
{(R)-2-[7-cyclopentylamine-5-(4-methysulfonylmethane)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
methyl ester [(R)-2-(7-cyclopentylamine-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
[(R)-2-(7-cyclopentylamine-5-phenoxymethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
methyl ester [(R)-2-(7-cyclopentylamine-5-pyrrolidin-1-ylmethyl-1H-indol-2-yl)-4,5-dihydrothieno-4-and the]acetic acid;
methyl ester [(R)-2-(7-cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
[(R)-2-(7-cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
2-[(R)-2-(7-cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanol;
cyclopentyl-{5-methanesulfonyl-2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl} amine;
1-(4-{2-[(R)-2-(7-cyclopentylamine-5-methanesulfonyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)ethanone;
2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-morpholine-4-ratanana;
2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-(2-morpholine-4-retil)ndimethylacetamide;
2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-(3-morpholine-4-ylpropyl)ndimethylacetamide;
2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-methylacetamide;
2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N,N-dimethylacetamide;
2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(4-methylpiperazin-1-yl)ethanone;
2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(3-dimethylaminopropan-1-yl)ethanone;
2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(3-hydroxypyrrolidine-1-yl)ethanone;
2-[(R)-2-(5-chloro-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-piperidine-1-ratanana;
2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}-N-methylacetamide;
2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}-1-morpholine-4-ratanana;
2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(4-methylpiperazin-1-yl)ethanone;
2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-(2-morpholine-4-retil)ndimethylacetamide;
1-(4-acetylpiperidine-1-yl)-2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethanone;
2-[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-methylacetamide;
2-[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-morpholine-4-ratanana;
{5-chloro-2-[(R)-4-(2-dimethylaminoethyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine;
{5-chloro-2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine;
{5-chloro-2-[(R)-4-(2-piperazine-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine;
1-(4-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)ethanone;
(5-chloro-2-{(R)-4-[2-(4-acanaloniidae-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)cyclopentyl amine;
1-(4-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)-2-hydroxyethane;
(5-chloro-2-{(R)-4-[2-(4-methylpiperazin-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indole--yl)cyclopentyl amine;
1-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl} piperidine-4-ol;
(4-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-2-it;
(5-chloro-2-{(R)-4-[2-(3-dimethylaminopropan-1-yl)-ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)cyclopentylamine;
{5-chloro-2-[(R)-4-(2-piperidine-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine;
(5-chloro-2-{(R)-4-[2-(1,1-diocletianopolis-4-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)cyclopentylamine;
{5-chloro-2-[(R)-4-(2-pyrazole-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine;
(S)-1-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}pyrrolidin-2-carboxylic acid;
{5-chloro-2-[(R)-4-(2-methansulfonate)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine;
ethyl ester of 3-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}-5-methyl-3H-imidazole-4-carboxylic acid;
3-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}-5-methyl-3H-imidazole-4-carboxylic acid;
1-{2-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}pyrrolidin-2-it;
1-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperidine-3-carboxylic acid;
dimethylamide 1-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperidine-3-Carbo the OIC acid;
tert-butyl ester [(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)pyrrolidin-3-yl]carbamino acid;
(2-{(R)-4-[2-((S)-3-aminopyrrolidine-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-chloro-1H-indol-7-yl)-(tetrahydropyran-4-yl)amine;
N-[(S)-1-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)pyrrolidin-3-yl]ndimethylacetamide;
{5-chloro-2-[(R)-4-(2-piperazine-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine;
1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]-2-hydroxyethane;
1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]-2-tetrazol-1 ratanana;
1-[4-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]-3,3,3-cryptochrome-1-it;
[4-(2-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]furan-2-ylmethanone;
(5-chloro-2-{(R)-4-[2-(2,3,5,6-tetrahydro-[1,2']bipyridinyl-4-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)-(tetrahydropyran-4-yl)amine;
(5-chloro-2-{(R)-4-[2-(4-(pyrimidine-2-reparation-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)-(tetrahydropyran-4-yl)amine;
{2-[(R)-4-(2-amino-ethyl)-4,5-dihydrothieno-2-yl]-5-fluoro-1H-indol-7-yl}cyclopentylamine;
1-(4-{2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydro shall eazol-4-yl]ethyl}piperazine-1-yl)ethanone;
cyclopentyl-{5-fluoro-2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}amine;
cyclopentyl-{2-[(R)-4-(2-dimethylaminoethyl)-4,5-dihydrothieno-2-yl]-5-fluoro-1H-indol-7-yl}amine;
cyclopentyl-{5-fluoro-2-[(R)-4-(2-pyrrolidin-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl} amine;
cyclopentyl-(2-{(R)-4-[2-(1,1-diocletianopolis-4-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-fluoro-1H-indol-7-yl)amine;
4-{2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-2-it;
1-(4-{2-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)-2-hydroxyethane;
cyclopentyl-{5-fluoro-2-[(R)-4-(2-methansulfonate)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl} amine;
{2-[(R)-4-(2-dimethylaminoethyl)-4,5-dihydrothieno-2-yl]-5-fluoro-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine;
{5-fluoro-2-[(R)-4-(2-pyrrolidin-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine;
{5-fluoro-2-[(R)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine;
1-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethylpiperazin-1-yl)ethanone;
(2-{(R)-4-[2-(1,1-diocletianopolis-4-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-fluoro-1H-indol-7-yl)-(tetrahydropyran-4-yl)amine;
(5-fluoro-2-[(R)-4-(2-methansulfonate)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl)-(tetrahydropyran-4-yl)amine;
4-(2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-hydrational-4-yl}ethyl)piperazine-2-it;
1-[4-(2-{(R)-2-[5-fluoro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]-2-hydroxyethane;
1-(4-{2-[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)-2-hydroxyethane;
2-hydroxy-1-[4-(2-{(R)-2-[5-methoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-1-yl]ethanone;
ethyl ester of 3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;
3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;
3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propan-1-ol;
3-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}propionic acid;
3-{(R)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}propan-1-ol;
3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-N-(2-morpholine-4-retil)propionamide;
3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]-1-(4-methylpiperazin-1-yl)propane-1-it;
1-(4-{3-[(R)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propyl}piperazine-1-yl)ethanone;
{5-chloro-2-[(R)-4-(3-morpholine-4-ylpropyl)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}cyclopentylamine;
ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;
3-[(R)-2-7-cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;
3-[(R)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;
ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;
3-[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;
ethyl ester of 3-[(R)-2-(5-bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;
3-[(R)-2-(5-bromo-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;
3-[(R)-2-(7-cyclopentylamine-5-methoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;
ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-ethoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;
3-[(R)-2-(7-cyclopentylamine-5-ethoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;
ethyl ester of 3-[(R)-2-(7-cyclopentylamine-5-triptoreline-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;
3-[(R)-2-(7-cyclopentylamine-5-triptoreline-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]propionic acid;
ethyl ester [(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-ylethoxy]acetic acid;
[(R)-2-(7-cyclopentylamine-5-fluoro-1H-indol-2-yl)-4,5-dihydrothieno-4-ylethoxy]acetic acid;
[(S)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
{(S)-2-[7-(1-triftoratsetatov-4-ylamino)-5-METI what-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
{(S)-2-[7-(1-acetylpyrrolidine-3-ylamino)-5-methyl-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
((S)-2-{5-phenoxy-7-[(tetrahydropyran-4-ylmethyl)amino]-1H-indol-2-yl}-4,5-dihydrothieno-4-yl)acetic acid;
{(S)-2-[5-phenoxy-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
{(S)-2-[5-chloro-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
[(S)-2-(7-cyclobutylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
{(S)-2-[5-methyl-7-(tetrahydrofuran-3-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
{(S)-2-[7-(cyclopropylamino)-5-methyl-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
((S)-2-{5-methyl-7-[(tetrahydropyran-4-ylmethyl)amino]-1H-indol-2-yl}-4,5-dihydrothieno-4-yl)acetic acid;
{(S)-2-[5-methyl-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
methyl ester [(S)-2-(7-cyclopentylamine-5-methyl-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
[(S)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]acetic acid;
{(S)-2-[7-(4,4-diverticulectomy)-5-methyl-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}acetic acid;
(2-{(S)-4-[2-((R)-3-aminopyrrolidine-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-chloro-1H-indol-7-yl)-cyclopentylamine;
(5-chloro-2-{(S)-4-[2-((3S)-3-dimethylaminophenyl)-ethylamino-pyrrolidin-1-yl)ethyl]-4,5-Digi retisol-2-yl}-1H-indol-7-yl)cyclopentylamine;
1-(4-{2-[(S)-2-(5-chloro-7-cyclopentylamine-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)ethanone;
1-(4-{2-[(S)-2-(5-methyl-7-(tetrahydropyran-4-ylamino)-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-2-it;
{5-methyl-2-[(S)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl}-(tetrahydropyran-4-yl)amine;
1-(4-{2-[(S)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)-2-hydroxyethane;
cyclopentyl-{5-phenoxy-2-[(S)-4-(2-piperazine-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl} amine;
tert-butyl ester 4-{2-[(S)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-carboxylic acid;
cyclopentyl-(2-{(S)-4-[2-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-phenoxy-1H-indol-7-yl)amine;
4-{2-[(S)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-2-it;
(4-{2-[(S)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)(tetrahydrofuran-2-yl)methanone;
cyclopentyl-(5-phenoxy-2-{(S)-4-[2-(4-pyridine-2-reparation-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-1H-indol-7-yl)amine;
cyclopentyl-[2-((S)-4-{2-[4-(2-forfinal)piperazine-1-yl]ethyl}-4,5-dihydrothieno-2-yl)-5-phenoxy-1H-indol-7-yl)amine;
1-(4-{2-[(S)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}piperazine-1-yl)ethanone;
{(R)-1-[2-[(S)-2-{5-methyl-7-[(t is tragedian-4-ylmethyl)amino]-1H-indol-2-yl}-4,5-dihydrothieno-4-yl]ethyl]pyrrolidin-2-yl}methanol;
N-((R)-1-{2-[(S)-2-(7-cyclopentylamine-5-phenoxy-1H-indol-2-yl)-4,5-dihydrothieno-4-yl]ethyl}pyrrolidin-3-yl)ndimethylacetamide;
(2-{(S)-4-[2-(4-benzylpiperazine-1-yl)ethyl]-4,5-dihydrothiazolo-2-yl}-5-phenoxy-1H-indol-7-yl)cyclopentylamine;
4-[2-((S)-2-{5-phenoxy-7-[(tetrahydropyran-4-ylmethyl)amino]-1H-indol-2-yl}-4,5-dihydrothieno-4-yl)ethyl]piperazine-2-it;
cyclopentyl-{5-phenoxy-2-[(S)-4-(2-pyrrolidin-1-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl)amine;
(4,4-diverticulosis)-{2-[(S)-4-(2-morpholine-4-retil)-4,5-dihydrothieno-2-yl]-1H-indol-7-yl)amine;
(2-{(S)-4-[2-(3-trifluoromethyl-5,6-dihydro-8H-[1,2,4]triazolo[4,3-pyrazin-7-yl]ethyl)-4,5-dihydrothieno-2-yl}-5-phenoxy-1H-indol-7-yl)-(tetrahydropyran-4-ylmethyl)amine;
4-[2-((S)-2-{5-phenoxy-7-[(tetrahydropyran-4-ylmethyl)amino]-1H-indol-2-yl}-4,5-dihydrothieno-4-yl)ethyl]piperazine-2-it
4-(2-{(S)-2-[7-(4,4-diverticulectomy)-5-phenoxy-7-1H-indol-2-yl]-4,5-dihydrothiazolo-4-yl}ethyl)piperazine-2-it.

16. Pharmaceutical composition for activating glucokinase, which contains compounds of the formula (1) according to claim 1, pharmaceutically acceptable salts or isomers as an active ingredient together with pharmaceutically acceptable carriers.

17. The composition according to article 16, for the prevention or treatment of diabetes, complications of diabetes, diabetes-related diseases or obesity.

18. The composition according to 17, where the diabetes is type 1 diabetes.

19. Composition pop, where diabetes is type 2 diabetes.

20. The composition according to 17, where the complications of diabetes are a neurological disease, hyperlipidemia, hypertension, retinas or kidney failure.

21. The composition according to item 16, which is a hypoglycemic composition.

22. A method of obtaining a pharmaceutical composition for the prevention or treatment of diseases caused by deactivation of glucokinase, comprising a stage of mixing the compounds of formula (1) according to claim 1, pharmaceutically acceptable salts or isomers as the active ingredient with pharmaceutically acceptable carriers.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heteroaryl-substituted derivative of benzothiazole - 2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol where one or more atoms may be a detectable isotope, in form of a free base or pharmaceutically acceptable salt thereof, capable of binding with amyloid deposits, to pharmaceutical compositions based on the radioactive-labelled disclosed compound, to use of the detectable isotope-labelled disclosed compound for determining amyloid deposits, as well as use of the disclosed compound in producing a medicinal agent for preventing and/or treating Alzheimer's disease and familial Alzheimer's disease. The present invention also relates to a novel intermediate compound for producing the disclosed heteroaryl-substituted benzothiazole derivative

EFFECT: high efficiency of using the compounds during treatment.

15 cl, 1 tbl, 15 dwg, 82 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula

wherein R1, R2 and X are those as specified in cl.1 of the patent claim, or its pharmaceutically acceptable salt, as well as using such compound or its pharmaceutically acceptable salt for preparing a drug preparation for prevention and treatment of all types of sleeping, eating or drinking disorders.

EFFECT: preparing the new azetidine compounds showing activity of orexin receptor antagonists.

12 cl, 112 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 2-piperidino-5-(thienyl-2)-6H-1,3,4-thiadiazines, hydrobromides (of general formula I) and 2-piperidino-5-(thienyl-3)-6H-1,3,4-thiadiazines, hydrobromides (of general formula II) which possess antiaggregant action. wherein R=H; Cl; Br R1=H; Cl.

EFFECT: given compounds may be used for preparing cardiologic drugs and enable better treatment of various cardiovascular diseases, including myocardial infarction and thrombotic apoplexy.

1 cl, 2 tbl, 5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel purified compound PM 181104 of formula I

(with molecular weight 1514 and molecular formula C69H66N18O13S5), pharmaceutically acceptable salts thereof, methods for synthesis via fermentation of a microorganism of the type Kocuria (ZMA B-1 / MTCC 5269), as well as pharmaceutical compositions.

EFFECT: high efficiency of using the composition to produce a medicinal agent for treating bacterial infections.

20 cl, 4 dwg, 4 tbl, 16 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or tautomer thereof

or enantiomer or physiologically acceptable salt, where R1 is o-bromo, R2 is n-fluoro, R3 is C1-C4 alkyl, R6 is thiazolyl-2-yl, X is methylene and Z is morpholinyl. The invention also relates to methods of producing (versions) compounds of formula (I) and (Ia). The compound of formula (I) or (Ia) is used to prepare a pharmaceutical composition for treating or preventing HBV infections and HBV-induced diseases such as hepatitis B.

EFFECT: bromophenyl substituted thiazolyl dihydropyrimidines for HBV infection control.

20 cl, 7 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: invention refers to the compounds of formula (I): where R denotes cycloalkyl, heterocyclil, aryl, alkyl-O-C(O)-, alkanoyl or alkyl where each cycloalkyl, heterocyclil and aryl does not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, cyano group, alkoxy group, alkyl-O-C(O)-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil, and where each alkyl-O-C(O)-, alkyl, alkoxy group and heterocyclil does not necessarily have additional 1 to 3 substitutes chosen from the group including a hydroxy group, alkyl, halogen, carboxy group, alkoxy group, alkyl-O-C(O)-, alkanoyl, alkyl-SO2-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil; R2 denotes alkyl, cycloalkyl, cycloalkylalkyl- or alkoxy group where alkyl does not necessarily contain from 1 to 3 substitutes chosen from the alkoxy group or halogen; R3 denotes R8-O-C(O)-, (R8)(R9)N-C(O)-, R8-C(O)-, where R8 and R9 independently denote alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- or nonaromatic heterocyclil where each alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- and nonaromatic heterocyclil do not necessarily contain from 1 to 3 substitutes chosen from the group including a hydroxy group, carboxy group, alkyl-O-C(O)-, alkyl-C(O)-O- and alkanoyl; R4 and R5 independently denote hydrogen, alkyl, alkynyl, alkoxy group, cycloalkyl, arylalkyl-, cycloalkylalkyl-, heteroarylalkyl-, monoalkylamino-C(O)-, dialkylcmino-C(O)- or dialkylamino-C(O)-alkyl-, where both these alkyl groups do not necessarily form a ring and where each alkyl, alkynyl, cycloalkyl, arylalkyl-, cycloalkylalkyl- heteroarylalkyl-, monoalkylamino-C(O)-, dialkylamino-C(O)- or dialkylamino-C(O)-alkyl- do not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, carboxy group and alkoxy group; R6 and R7 independently denote hydrogen, halogenalkyl, halogen, dialkylamino group, alkoxy group, halogenalkoxy group, heteroaryl or alkyl-S(O)2- where each heteroaryl does not necessarily contain from 1 to 3 substitutes chosen from alkyl; where "heterocyclil" denotes fully saturated or nonsaturated aromatic or nonaromatic cyclic group that is represented by 5- or 6-membered monocyclic ring system containing at least one heteroatom chosen from nitrogen, oxygen and sulphur atoms; "heteroaryl" denotes 5- or 6-membered monocyclic ring system containing from 1 to 4 heteroatoms chosen from N, O and S; or to their pharmaceutically acceptable salts and their optical isomers, or to mixtures of the optical isomers. The invention also refers to the method of inhibition of the specimen's CETP activity, to the way of treatment of the specimen's abnormality or disease mediated by CETP or responsive to CETP inhibition, to the pharmaceutical composition, and to application of the formula (I) compounds.

EFFECT: production of new bioactive compounds that inhibit the CETP.

10 cl, 71 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new indazole derivants with the formula (1.0) or to their pharmaceutically acceptable salts and isomerides that act as inactivators in relation to ERK2. In formula (1.0): meanings of the chemical groups Q, R1, R2 are given in the invention formula. The invention also refers to the pharmaceutical composition containing the mentioned compounds and to application of the compounds with the formula (1.0) for production of crude drugs used in malignant growth treatment.

EFFECT: application of the compounds for production of crude drugs used in malignant growth treatment.

65 cl, 611 ex, 27 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): where R1 and R2 represent hydrogen and a group which is hydrolysed in a physiological environment, optionally substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents oxygen atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a group of pyridine N-oxide according to formula A, B or C which is attached as shown by an unmarked linking: where R4, R5, R6 and R7 independently represent aryl, heterocycle, hydrogen, C1-C6-alkyl, C1-C6-alkylthio, C6-C12-aryloxy or C6-C12-arylthio group, C1-C6-alkylsulphonyl or C6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, or heteroaryl group; or where two or more residues R4, R5, R6 and R7 taken together represent an aromatic ring, and where P represents a central part, preferentially chosen from regioisomers 1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazine-2,4-diyl, 1,2,4-triazine-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, 1-alkyl-3-(alkoxycarbonyl)-1R-pyrrol-2,5-diyl, where alkyl is presented by methyl, thiazol-2,4-diyl, 1H-pyrazol-1,5-diyl, pyrimidine-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl, furan-2,4-diyl, benzole-1,3-diyl and (Z)-1-cyanoethene-1,2-diyl, and where the regioisomers of the central part include both regioisomers produced by exchanging the nitrocatechol fragment and the -(X)n-(Y)m-R3 fragment. Also, the invention refers to a method for making a compound of formula I, as well as to a method for treating an individual suffering central and peripheral nervous system disorders, to a pharmaceutical composition based on the compounds of formula I, and also to their application for preparing the drug and as COMT inhibitor.

EFFECT: there are produced and described new compounds which show a potentially effective pharmaceutical properties in treating a number of central and peripheral nervous system disorders.

25 cl, 64 ex, 3 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazolidinone derivatives of formula and pharmaceutically acceptable salts thereof, where X denotes N or CH; R1 denotes a lower alkyl, fluoro-lower alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-lower alkyl, phenyl, naphthyl, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of a halide, lower alkyl, fluoro-lower alkyl, lower alkoxy group and fluoro-lower alkoxy group; R2 denotes lower alkyl, halide-lower alkyl, lower alkenyl, C3-C6-cycloalkyl, pheny, phenyl-lower alkyl, tetrahydropyran, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide; R3 denotes phenyl or heteroaryl (pyridinyl, thienopyridinyl, benzoisothiazolyl, benzooxazolyl, tetrahydropyrazinyl, pyrazinyl), where the phenyl or heteroaryl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide, CN, lower alkyl, fluoro-lower alkyl, lower alkoxy group; R4, R5, R6, R7, R8, R9, R10 and R11 independently denote hydrogen or lower alkyl. The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: obtaining novel imidazolidinone derivatives, having LXRalpha or LXRbeta receptor agonist activity.

26 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 3,3'-bi-1,5,3-dithiazepinane of formula (1) having fungicidal activity against Bipolaris sorokiniana, Aspergillus fumigates, Aspergillus niger and Paecilomyces variotii. The method involves reaction of a mixture of ethanedithiol and formaldehyde with hydrazine hydrate (60%) with molar ratio aldehyde: ethanedithiol: hydrazine = 40:20:10 at temperature 25°C and atmospheric pressure for 2-4 hours.

EFFECT: improved method.

2 cl, 2 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel heteroaryl-substituted derivative of benzothiazole - 2-[6-(methylamino)pyridin-3-yl]-1,3-benzothiazol-6-ol where one or more atoms may be a detectable isotope, in form of a free base or pharmaceutically acceptable salt thereof, capable of binding with amyloid deposits, to pharmaceutical compositions based on the radioactive-labelled disclosed compound, to use of the detectable isotope-labelled disclosed compound for determining amyloid deposits, as well as use of the disclosed compound in producing a medicinal agent for preventing and/or treating Alzheimer's disease and familial Alzheimer's disease. The present invention also relates to a novel intermediate compound for producing the disclosed heteroaryl-substituted benzothiazole derivative

EFFECT: high efficiency of using the compounds during treatment.

15 cl, 1 tbl, 15 dwg, 82 ex

FIELD: chemistry.

SUBSTANCE: invention relates to derivatives of 1,3,4-thiadiazolines (I), thiadiazinones (II) and thiadiazepines (III), obtained based on thiohydrazides of oxamic acids, which can be used to inhibit pathogenic bacteria, and can particularly affect type III secretion system in pathogens, having general formula:

, , ,

where R denotes H; R1 denotes H, pyridinyl; phenyl, substituted with alkyl C1-C5, Hal, CF3; a group , where X denotes S, substituted with alkyl C1-C5, COOR4; R2, R3 denotes alkyl C1-C5, pyridinyl, phenyl, substituted Hal, OH, OR4, a R4 denotes unsubstituted alkyl C1-C4.

EFFECT: obtaining compounds which can be used to inhibit pathogenic bacteria.

2 cl, 2 dwg, 6 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

,

where R denotes a substituted or unsubstituted thiazolyl group of formula or ; R4 and R5, each independently, are selected from i) hydrogen; ii) a substituted or unsubstituted C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl; iii) a substituted or unsubstituted phenyl; iv) a substituted or unsubstituted heteroaryl containing 5 or 6 ring atoms and 1 or 2 heteratoms, where the heteroatoms are selected from nitrogen, oxygen, sulphur and combination thereof; or R4 and R5 can be taken together to form a saturated or unsaturated ring, having 5-7 atoms; said substitutes are independently selected from one or more groups, selected from C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl, halogen, hydroxyl or cyano; R6 denotes a group selected from i) hydrogen; ii) a substituted or unsubstituted C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl; iii) a substituted or unsubstituted phenyl or iv) a substituted or unsubstituted heteroaryl containing 5 or 6 ring atoms and 1 or 2 heteroatoms, where the heteroatoms are selected from nitrogen, oxygen, sulphur and combination thereof; where said substitutes are independently selected from one or more groups selected from C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl, halogen, hydroxyl or cyano; R1 is selected from i) hydrogen; ii) C1-C6 linear or C3-C6 branched alkyl; iii) a substituted or unsubstituted phenyl or iv) a substituted or unsubstituted benzyl; where said substitutes are independently selected from one or more groups selected from C1-C6 linear, C3-C6 branched or C3-C6 cyclic alkyl, halogen, hydroxyl or cyano; R2 is selected from i) C1-C6 linear or C3-C6 branched alkyl or ii) C1-C6 linear or C3-C6 branched alkoxy; R3 denotes hydrogen or C1-C4 linear or C3-C6 branched alkyl.

EFFECT: compounds of formula (I) are effective as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

20 cl, 10 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present inventions refers to a new crystalline form of tetomilast hydrate of the X-ray powder diffraction spectrum having characteristic peaks at the angle 20=10.6°, 12.9°, 21.1°, 22.3° and 25.0°, to a new crystalline form of anhydrous tetomilast type C of the X-ray powder diffraction spectrum having characteristic peaks at the angle 2θ=4.2°, 8.2°, 12.0°, 16.4°, 24.7° and 25.9°, to a new crystalline form of acetonitrile tetomilast solvate of the X-ray powder diffraction spectrum having characteristic peaks at the angle 2θ=3.6°, 7.1°, 10.6°, 14.2° and 24.8°, to based pharmaceutical compositions and to methods for preparing.

EFFECT: new crystalline forms shows useful processing characteristics with relation to preparing pharmaceutical drugs of them.

13 cl, 14 dwg, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole and indazole compounds of formula in which n equals a whole number from 1 to 3, m equals 0 or 1, A denotes phenyl, X denotes C or N, R1 denotes hydrogen, alkyl, -(CH2)rNR7R8, where r equals a whole number from 1 to 5, and R7 and R8 independently denote hydrogen, alkyl or alkylcarbonyl, or can together form an optionally alkyl-substituted alkylene chain, where optionally one methylene is substituted with a N atom, R2 denotes hydrogen, halogen, cyano, nitro, hydroxy, alkyl, alkoxy or trialkylsilyl, denotes -(CH2)pCO2R7, -(CH2)pOR7, -(CH2)pNR7R8, -NHR10, -N(H)S(O)2R7, -NHC(O)R10, -(CH2)pS(O)2R7 or (CH2)p-heterocycle-R10, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, R10 denotes hydrogen, oxo, alkylsulphonyl, alkylcarbonyl, alkyloxycarbonyl, alkoxy, alkyl or heterocycle, R3 denotes hydrogen, cyano, halogen, alkyl or phenyl, or denoes -(CH2)n-heterocycle or -(CH2)n-aryl, where n equals a whole number from 0 to 3, provided that R3 denotes phenyl when X denotes C and m=0, R4 denotes -YR11, where Y denotes a direct bond or -(CR7R8)pY′-, where p equals a whole number from 0 to 3, R7 and R8 are as defined above, Y′ is selected from a group consisting of -O-, -S-, -NR12-, -NR12C(O)-, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)q- and -S(O)qNR12-, where R12 denotes hydrogen, alkyl, aryl or heteroaryl, q equals a whole number from 0 to 2, R11 is selected from a group consisting of hydrogen, cyano, halogen, hydroxy, thiol, carboxy, alkyl and -(CH2)tB-R13, where t equals a whole number from 0 to 3, B denotes heterocycle, heteroaryl or aryl, R13 denotes hydrogen, cyano, halogen, hydroxy, oxo, thiol, carboxy, carboxyalkyl, alkylcarbonyloxy, alkyl, alkoxy, alkylthio, alkylcarbonyl or alkylsulphonyl, R5 denotes hydrogen, alkyl, cycloalkyl, heterocycle or heterocyclylalkyl, R6 denotes (CR7R8)p-Z-D-W-R14, where Z denotes a direct bond, or is selected from a group consisting of -C(O)-, -C(O)O, -C(O)NR12- and -S(O)y-, y equals a whole number from 1 or 2, D denotes a direct bond, or denotes cycloalkyl, heteroaryl or heterocycle, W denotes a direct bond, or denotes -NR -, -C(O)-, -C(O)O-, -C(O)NR12-, -S(O)y-, -S(O)yNR12- or -NR12S(O)y, wherein R14 denotes hydrogen, hydroxy, alkyl, alkoxy, heterocycle, heteroaryl, aryl or aralkyl, R5 and R6 together denote an alkylene chain, provided that R6 denotes cycloalkyl or heterocyclyl when X denotes N, where the heteroaryl is a 5-6-member aromatic ring containing 1-2 heteroatoms selected from N, O and S, the heterocycle is a 3-8-member ring containing 1-3 heteroatoms selected from N, O and S, where the alkyl, alkoxy, aryl, cycloalky, heterocycle and heteroaryl can be optionally substituted, and the substitutes, one or more, are selected from a group consisting of hydroxy, halogen, nitrile, amino, alkylamino, dialkylamino, carboxy, alkyl, alkoxy, carboxyalkyl, alkylcarbonyloxy, alkylthio, alkyloxycarbonyl, alkylaminocarbonyl, arylalkoxy and oxo, and pharmaceutically acceptable salts or stereoisomers thereof. The invention also relates to a composition, as well as a method of preparing said composition.

EFFECT: obtaining novel biologically active compounds for preventing or treating necrosis and necrosis-associated diseases.

40 cl, 162 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R denotes a thiazolyl group of formula R2 and R3 are selected from: hydrogen, C1-C3linear alkyl; R4 is selected from: C1-C3linear or C3cyclic alkyl, phenyl and thiophenyl; Z denotes a group of formula: -(L)n-R1; R1 is selected from: i) C1-C3linear or branched alkyl, optionally substituted with C1-C4alkoxycarbonyl, halogen; ii) substituted phenyl or substituted with one or two substitutes selected from halogen, methoxy- or hydroxy group, C1-C4alkoxycarbonyl; iii) dioxopiperazinyl and 2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl, substituted with C1-C3alkyl; or iv) heteroaryl rings containing 5-10 atoms selected from thiazole, triazole, 1H-imidazole, thiadiazole, oxazole, isoxazole, oxadiazole, benzodioxole, benzo(1,4)dioxepanyl, pyridine, pyrimidine, 1H-indole, 2,3-dihydrobenzo[b][1,4]dioxynil, which can be substituted with oine or two substitutes selected from: a) hydroxy; b) C1-C3alkyl (which can be substituted with one more two substitutes selected from: ) phenyl; ii) C1-C4alkoxycarbonyl; iii) naphthalenyl; iv) 2-methylthiazolyl) ; c) NHC(O)C1-C3alkyl; d) C1-C4alkoxycarbonyl; e) 1 -(tert-butoxycarbonyl)-2-phenylethyl; f) methoxybenzyl; g) phenyl which can be substuted with C1-C4alkoxy, halogen, methoxycarbonyl or >NHC(O)CH3; h) (methoxy-2-oxoethyl)carbamoyl; L denotes a group selected from: i) C(O)NH[C(R5aR5b)]w-; ii) -C(O)[C(R6aR6b)]x-; iii) -C(O)[C(R7aR7b)]yC(O)-; iv) -SO2[C(R8aR8b)]z-; R5a, R5b, R6a, R6b, R7a, R7b, R8a and R8b, each independently denotes: i) hydrogen; ii) C1-C3 linear alkyl which can be substituted with 1 or 2 halogen atoms; iii) phenyl which can be substituted with 1-2 substitutes selected from halogen and lower alkoxy; iv) heteroaryl rings selected from imidazolyl, imidazolyl substituted with methyl, benzo(1,4)oxazinyl, oxadiazolyl substituted with methyl; index n equals 0 or 1; indices w, x, y and z are each independently equal to a number from 1 to 3. The invention also relates to pharmaceutically acceptable salts of compounds of formula (I) and use of compounds of formula (I) to prepare a medicinal agent for treating protein tyrosine phosphatase beta-mediated conditions.

EFFECT: obtaining compounds of formula (I) as human protein tyrosine phosphatase beta (HPTP-β) inhibitors.

15 cl, 17 dwg, 13 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 5-amino-3-(2-nitroxipropyl)-1,2,4-thiadiazoles of general formula , where R1, R2 can be similar or different and independently represent hydrogen, substituted or non-substituted aryl or heteroaryl or aralkyl, alkyl, cycloalkyl, and R1 + R2 can represent heteroaryl (optionally substituted piperasin and piperidin).

EFFECT: obtained are novel compounds, which can be applied in medicine for treatment of neurodegenerative diseases.

1 cl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel carbostyril compounds of general formula (1) or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds, having activity on promotion of TFF2 production, a pharmaceutical composition based on said compounds, an agent based on disclosed compounds used in case of a disorder where up-regulation of TFF has a prophylactic and/or therapeutic effect, use of disclosed compounds to prepare said agent and a method of producing disclosed compounds. The invention also relates to novel specific carbostyril compounds or salts thereof with common pharmaceutically acceptable acids or pharmaceutically acceptable basic compounds. In structural formula (1), A is a direct bond, a lower alkylene group or lower alkylidene group, X is an oxygen or sulphur atom, the bond between positions 3 and 4 of the carbostyril backbone is a single bond or a double bond, R4 and R5 each denotes a hydrogen atom provided that, when the bond between positions 3 and 4 of the carbostyril backbone is a double bond, R4 and R5 can instead be bonded to each other in form of a -CH=CH-CH=CH- group, and R1, R2 and R3 assume values given in the claims.

EFFECT: high efficiency of compositions based on said compounds.

32 cl, 23 dwg, 184 tbl, 1535 ex

Iap inhibitors // 2425838

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula

, which can inhibit binding of protein Smac with apoptosis protein inhibitor (IAP).

EFFECT: improved properties of the inhibitor.

4 cl, 198 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to N-(2-thiazolyl)amide derivatives of formula wherein R1 and R2 are independently selected from H, -NO2, fluorine, chlorine and iodine, provided at least one of R1 and R2 is different from H; m is equal to 1 or 2, or to its pharmaceutically acceptable salts.

EFFECT: invention refers to a method for preparing said compounds, based pharmaceutical composition and applying them for preparing a drug for treating or preventing GSK-3 mediated diseases or conditions, especially neurodegenerative diseases, such as Alzheimer's disease or insulin-independent diabetes.

24 cl, 3 tbl, 1 ex

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