6-(heterocyclyl-substituted benzyl)-4-oxoquinoline derivative and use thereof as hiv integrase inhibitor

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

or its pharmaceutically acceptable salt or its solvate, where ring A is a monocyclic heterocyclic group optionally substituted with 1-2 substitutes selected from the following group A, where the monocyclic heterocyclic group is selected from 1-pyrrolidinyl group, 2-oxopyrrolidin-1-yl group, piperidine group, 2-oxopiperidin-1-yl group, 1-piperazinyl group, morpholine group, 3-oxomorpholin-4-yl group, thiomorpholine group, 1,1-dioxoisothiazolin-2-yl group, 2-pyridyl group, 2-thiazolyl group and 1,2,4-oxadiazol-3-yl group; group A consists of a halogen atom, C1-4alkyl group, -(CH2)n-ORa1 and -CORa2, where Ra1 and Ra2 are identical or different and each of them is a hydrogen atom or a C1-4alkyl group and n equals 0; R1 is a C1-6alkyl group optionally substituted with 1 substitute selected from the following group B; group B consists of -ORb1, where Rb1 is a C1-4alkyl group; R2 is a hydrogen atom, C1-4alkyl group or -OR11, where R11 is an atom, C1-4alkyl group; R3 and R4 are identical or different and each is a halogen atom; R5 is a halogen atom; m equals 0 or 1; and R6 is a hydrogen atom. The invention also relates to a pharmaceutical composition, anti-HIV agent, HIV integrase inhibitor, anti-HIV compositions which contain an active ingredient in form of a formula I compound; to use of formula I compounds to prepare an anti-HIV agent and HIV integrase inhibitor; to a method of preventing or treating infectious diseases caused by HIV and to a method of inhibiting HIV integrase in mammals, involving administration of formula I compounds.

EFFECT: useful biological properties.

27 cl, 9 tbl, 67 ex

 

The technical field to which the invention relates

The present invention relates to a new derivative of 4-oxacilin, or its pharmaceutically acceptable salt, or MES, which is suitable as an anti-HIV agent. In addition, the present invention relates to pharmaceutical compositions containing a derivative of 4-oxacilin, or its pharmaceutically acceptable salt, or its MES and a pharmaceutically acceptable carrier; an anti-HIV agent and inhibitor of HIV integrase and the like, which contains a derivative of 4-oxacilin, or its pharmaceutically acceptable salt, or MES as an active ingredient; anti-HIV agent containing the derivative 4-oxacilin, or its pharmaceutically acceptable salt, or MES in combination with one or more other types of active anti-HIV agents; and the like.

The level of technology

HIV (the human immunodeficiency virus (type 1)), related to the retrovirus is a virus that causes AIDS (acquired immune deficiency syndrome human).

HIV attacks the group of CD4-positive cells, such as T-cell-helper cells, macrophage and dendritic cell and destroys these immunocompetent cells, causing immunodeficiency.

According to this pharmaceutical agent that destroys HIV in vivo or p is Dawley its growth, is effective for prevention or treatment of AIDS.

HIV has gene bimolecular RNA in the capsule, which is covered with a protein coat. RNA encodes several enzymes (protease, reverse transcriptase, integrase), characteristics of the virus, and the like. Translated, reverse transcriptase and integrase are present in the capsule, and the protease is present inside and outside the capsule.

HIV is in contact with the host-cell and is introduced into it, causing destruction of the membrane of the cells and releases the complex of RNA and integrase, and the like in the cytoplasm. From RNA to DNA is transcribed by reverse transcriptase, and produced a full-sized double-stranded DNA. DNA moves into the nucleus of the host cell and is activated by the integrase DNA of the host cell. Included DNA is transformed into mRNA by the polymerase of the host cell, such HIV protease mRNA synthesized various proteins needed for the formation of the virus, and the like, and, finally, is formed viral particle, which is then subjected to badinga and release.

It is believed that these specific virus enzymes are essential for the growth of HIV. These enzymes are attracting attention as a target for development of antiviral agents, and had already developed several antiviral agents.

For example, zidovudine, didanosin, lamivu is n and the like were already on sale as reverse transcriptase inhibitors and indinavir, nelfinavir and the like as protease inhibitors.

In addition, applied pallacanestro combination therapy (also frequently referred to as HAART (highly active antiretroviral therapy)), at the same time using these pharmaceutical agents. For example, clinically used a combination of three agents from two reverse transcriptase inhibitors (zidovudine and lamivudine or tenofovir and emtricitabine)and inhibitor nucleoside omnidirectional transcriptase inhibitor (efavirenz)or protease inhibitor (lopinavir, fosamprenavir or atazanavir), combined with ritonavir. This politikarena combination therapy becomes the main direction of the treatment of AIDS.

However, it is known that some of these pharmaceutical agents cause side effects, such as failure of the liver, disorders of the Central nervous system (e.g., dizziness), and the like. In addition, raises the issue of the acquisition of resistance to the pharmaceutical agent. Even worse was the news of the advent of HIV, which detects pallacanestro resistance when policecourtneu combination therapy.

In such circumstances, it was desirable to further the development of new pharmaceutical agents, especially anti-HIV agent-based but the second mechanism, moreover, it is planned to develop anti-HIV agent having the integrase inhibitory activity, as integrase characteristic of a retrovirus is an essential enzyme for growth of HIV.

However, an effective inhibitor integrase not found so far.

Connection with the integrase inhibitory activity, are described in the following publications.

In WO 2004/046115 (family of patent: US 2005/239819) describes the following compound [A] and the like as an anti-HIV agent having the integrase inhibitory activity (see patent document 1).

where the ring su represents optionally substituted C3-10carbocyclic group or optionally substituted heterocyclic group; R1represents an optionally substituted C1-10alkyl group, optionally substituted C3-10carbocyclic group or the like; R2represents a hydrogen atom or the like; R31represents a hydrogen atom or the like; X represents C-R32or a nitrogen atom and Y represents C-R33or nitrogen atom (where R32and R33independently represent a hydrogen atom or the like).

In WO 2004/046115 also describes the following compound [V] and similar to the operation of the anti-HIV agent, with the integrase inhibitory activity.

In WO 2005/087759 also describes the following compound [C] and the like as an anti-HIV agent having inhibitory retroviral integrase activity (see patent document 2)

where R1represents H, C1-6alkyl or substituted C1-6alkyl; Z represents-C(O)OR2or-C(O)CH2C(O)X; X represents a 5 - or 6-membered aromatic or heteroaromatic ring, or -- C(O)OR2; R2represents N or C1-6alkyl; R3, R4, R5and R6are each H, a halogen atom, a C1-6alkyloxy, -N(R8)(R9), -C(O)CH3, -C(O)CH2C(O)X, -S(O)n-R10where n is 0, 1 or 2, heteroalkyl, cycloalkyl, substituted cycloalkyl, heteroseksualci, substituted heteroseksualci, aryl, substituted aryl, heteroaryl or substituted heteroaryl; R8and R9is each H or C1-2alkyl, and R10represents a C1-6alkyl or the like, provided that when Z represents-C(O)OR2then at least one of R3, R4, R5and R6represents C(O)CH2C(O)X.

In addition, in WO 2005/113509 (family of patent: US 2006/019906) described Nigel is blowing the compound [D] and the like as an anti-HIV agent, with the integrase inhibitory activity (see patent document 3)

where the ring su represents a group selected from the group consisting of

R represents a hydrogen atom or the like; R1represents a

where R11represents -(CmH2m)-OR12, -(CmH2m)-SR12, -(CmH2m)-SO2R12(where R12represents a C1-4alkyl group and m is an integer from 1 to 4), saturated heterocyclic group, isopropyl group or tert-boutelou group or the like; R32represents a hydrogen atom, ethyl group, methoxy group or the like; R33represents a hydrogen atom or the like, and R7represents a hydrogen atom or a hydroxyl group.

However, in these publications are not described compound having a benzyl group, a substituted heterocyclic group in 6-position of ring 4-oxacilin, or even description, promising for this connection.

In addition, in WO 2006/033422 (family of patent: US 2006/084665) describes the following compound [E] and the like as an anti-HIV agent having the integrase inhibitory activity (see patent is a document 4)

where the ring su represents optionally substituted C3-10carbocyclic group or optionally substituted heterocyclic group; R1represents a hydrogen atom, optionally substituted C1-10alkyl group or the like; R2represents a hydrogen atom or the like; Z represents C-R31or nitrogen atom, where R31represents a hydrogen atom or the like; X represents C-R32or a nitrogen atom and Y represents C-R33or nitrogen atom, where R32and R33represent each a hydrogen atom or the like.

However, this publication does not include a derivative of 4-oxacilin described in the present description, or even description, promising for this connection.

Patent document 1: WO 2004/046115 (str, examples 1-88).

Patent document 2: WO 2005/087759.

Patent document 3: WO 2005/113509.

Patent document 4: WO 2006/033422.

Description of the invention

Problems that are resolved by the invention of

On the basis of the data obtained so far on the basis of pharmacological studies and clinical results, it was found that anti-HIV agent is effective for the prevention or treatment of AIDS and especially that the connection with ingibirujut the th integrase activity can be an effective anti-HIV agent.

Therefore, the present invention is to provide compounds with activity against HIV, especially in connection with the integrase inhibitory activity.

The way to overcome problems

The authors of the present invention conducted intensive studies in an attempt of finding compounds with activity against HIV, especially in connection with the integrase inhibitory activity, and completed the present invention.

That is, the present invention relates to a compound represented by the following formula [1]with the integrase inhibitory activity (sometimes commonly referred to in the present description connection [1]), its pharmaceutically acceptable salt, MES and their application.

[1] a Compound represented by the following formula [1]or its pharmaceutically acceptable salt, or its MES

where

ring a represents a monocyclic heterocyclic group, optionally substituted by 1-5 substituents selected from the following group a, where a monocyclic heterocyclic group contains, besides carbon atom, at least one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom;

the group And made the focus of a group, consisting of a halogen atom, a C1-4alkyl group, -(CH2)n-ORa1, -NRa3Ra4, -CORa2and-CONRa3Ra4where Ra1, Ra2, Ra3and Ra4are the same or different and each represents a hydrogen atom or a C1-4alkyl group and n is 0 or an integer from 1 to 4;

R1represents a hydrogen atom, a C1-6alkyl group, optionally substituted by 1-3 substituents selected from the following group b, C3-10carbocyclic group, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group, optionally substituted by 1-5 substituents selected from the aforementioned group a, heterocyclic group contains, besides carbon atom, at least one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom;

group b represents the group consisting of C3-10carbocyclic group, optionally substituted by 1-5 substituents selected from the above-mentioned group a, heterocyclic group optionally substituted by 1-5 substituents selected from the aforementioned group a, heterocyclic group has the above values, halogen atom, ceanography, -ORb1, -SRb1, -NRb2Rb3, -CONRb2Rb3, -SO2R b2Rb3, -CORb1, -NRb2CORb1, -SO2Rb1, -NRb2SO2Rb1, -COORb1, -NRb2COORb1and-NRb4CO-NRb2Rb3where Rb1, Rb2, Rb3and Rb4are the same or different and each represents a hydrogen atom, a C1-4alkyl group, a C3-10carbocyclic group, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group, optionally substituted by 1-5 substituents selected from the aforementioned group a, heterocyclic group has the values listed above;

R2represents a hydrogen atom, a C1-4alkyl group or-OR11where R11represents a hydrogen atom or a C1-4alkyl group;

R3and R4are the same or different and each represents a hydrogen atom, a halogen atom, a C1-4alkyl group or-OR12where R12represents a hydrogen atom or a C1-4alkyl group;

each R5independently represents a halogen atom, a C1-4alkyl group or-OR13where R13represents a hydrogen atom or a C1-4alkyl group;

m is 0, 1 or 2 and

R6represents a hydrogen atom, or R1and R6form together with the atoms ug is erode, associated With3-10cycloalkyl group, optionally substituted by 1-5 substituents selected from the above group A.

[2] the Compound of the above p.[1], where ring a is a monocyclic heterocyclic group containing at least one nitrogen atom, and mentioned monocyclic heterocyclic group optionally substituted by 1-5 substituents selected from group a, and is connected through the nitrogen atom from the benzene ring, or its pharmaceutically acceptable salt, or MES.

[3] the Compound of the above p.[2], where ring a is a heterocyclic group selected from 1-pyrrolidinyl group, 2-oxopyrrolidin-1-ilen group, piperidino, 2-oxopiperidin-1-ilen group, 1-piperazinilnom group, morpholinopropan, thiomorpholine, 3-exmortis-4-ilen group, 1,1-dioxothiazolidine-2-ilen group, 2-oxoacridine-3-ilen group and 3-oxopyrrolidin-1-ilen group, where the heterocyclic group is optionally substituted by 1-5 substituents selected from the group And, or its pharmaceutically acceptable salt, or MES.

[4] the Compound of the above p.[1], where R1represents a C1-6alkyl group, optionally substituted by 1-3 substituents selected from group b, and R6represents a hydrogen atom, or pharmaceuticas is acceptable salt, or MES.

[5] the Compound of the above p.[1], where R2represents a C1-4alkyl group or-OR11where R11represents a hydrogen atom or a C1-4alkyl group, or its pharmaceutically acceptable salt, or MES.

[6] the Compound of the above p.[1], where R2represents a hydrogen atom, or its pharmaceutically acceptable salt, or MES.

[7] the Compound of the above p.[1], where R3and R4are the same or different and each represents a halogen atom, or its pharmaceutically acceptable salt, or MES.

[8] the Compound of the above p.[1], where m is 1 and R5represents a halogen atom, or its pharmaceutically acceptable salt, or MES.

[9] the Compound of the above p.[1], where m is 0, or its pharmaceutically acceptable salt, or MES.

[10] the Compound of the above p.[1], which is selected from the group consisting of

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((R)-1-ethoxymethyl-2-hydroxyethyl)-7-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2),

6-[3-chloro-2-fluoro-5-(pyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3),

6-[3-chloro-2-fluoro-5-(2-oxoacridine-3-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 5),

6-[3-chloro-2-fluoro-5-(piperidine-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 6),

6-[3-chloro-2-fluoro-5-(2-oxopiperidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 7),

6-[3-chloro-2-fluoro-5-((R)-3-hydroxypyrrolidine-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 8),

6-[3-chloro-2-fluoro-5-((S)-3-hydroxypyrrolidine-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 9),

6-[3-chloro-2-fluoro-5-(2-methyl-3-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 10),

6-[5-(4-acetylpiperidine-1-yl)-3-chloro-2-terbisil]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 11),

6-[3-chloro-5-(3,3-debtorprovidian-1-yl)-2-terbisil]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic sour is s (example 12),

6-[3-chloro-2-fluoro-5-((R)-3-ftorpirimidinu-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 13),

6-[3-chloro-2-fluoro-5-((S)-3-ftorpirimidinu-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 14),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((1R,2R)-1-hydroxymethyl-2-methoxypropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 15),

6-[3-chloro-2,4-debtor-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 16),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 17),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 18),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((R)-1-ethoxymethyl-2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 19),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-[(R)-2-hydroxy-1-(methoxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 20),

6-[3-chloro-5-(1,1-dioxothiazolidine-2-yl)-2-terbisil]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 21),

6-[3-chloro-2-fluoro-5-(mo the folin-4-yl)benzyl]-1-[(R)-2-hydroxy-1-(methoxymethyl)ethyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 22),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 23),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 24),

6-[3-chloro-2,4-debtor-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 25),

6-[3-chloro-2,4-debtor-5-(2-oxopyrrolidin-1-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 26),

6-[3-chloro-2-fluoro-5-(thiomorpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 27),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((1R,2S)-1-hydroxymethyl-2-methoxypropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 28),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-3-methoxypropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 29),

6-[3-chloro-2-fluoro-5-(4-hydroxypiperidine-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 32),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-((1R,2R)-1-hydroxymethyl-2-methoxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 34),

6-[3-chloro-2-fluoro-5-(mo the folin-4-yl)benzyl]-7-ethyl-1-((1R,2S)-1-hydroxymethyl-2-methoxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 35),

6-[3-chloro-2-fluoro-5-(pyridin-2-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 36),

6-[3-chloro-2-fluoro-5-(thiazol-2-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 37),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-[(1R,2R)-2-ethoxy-1-(hydroxymethyl)propyl]-7-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 38),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((R)-1-ethoxymethyl-2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 39),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-[(1R,2R)-2-ethoxy-1-(hydroxymethyl)propyl]-7-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 40),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-7-ethyl-1- ((1R,2R)-1-hydroxymethyl-2-methoxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 41),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((R)-1-hydroxymethyl-2-methoxy-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 42),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-((R)-1-hydroxymethyl-2-methoxy-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 43),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-3-methoxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 44),

6-[3-chloro-2-fluoro-5-(2-Okapi Raiden-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 45),

6-[3-chloro-2,4-debtor-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 46),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-3-methoxypropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 47),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((1R,2R)-1-hydroxymethyl-2-methoxypropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 48),

6-[3-chloro-2,4-debtor-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 49),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-[(1R,2R)-2-ethoxy-1-(hydroxymethyl)propyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 50),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 51),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 52),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 53),

6-[3-chloro-2,4-debtor-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 54),

6-[3-the ers-2,4-debtor-5-(2-oxopyrrolidin-1-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 55),

6-[3-chloro-2,4-debtor-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 56),

6-[3-chloro-2-fluoro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 57),

6-[3-chloro-2,4-debtor-5-(3-exmortis-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 58), and

6-[3-chloro-2,4-debtor-5-(morpholine-4-yl)benzyl]-1-((R)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 59)

or its pharmaceutically acceptable salt, or MES.

[11] a Pharmaceutical composition comprising a compound of any of the above items [1] to [10], or its pharmaceutically acceptable salt, or its MES and a pharmaceutically acceptable carrier.

[12] Anti-HIV agent containing the compound of any of the above items [1] to [10], or its pharmaceutically acceptable salt, or MES as an active ingredient.

[13] the HIV integrase Inhibitor containing the compound of any of the above items [1] to [10], or its pharmaceutically acceptable salt, or MES as an active ingredient.

[14] the Anti-HIV agent containing the compound of any of the above items [1] to [10], or pharmaceuticas is acceptable salt, or MES in combination with one or more other types of substances that are active against HIV.

[15] the Use of compounds of any of the above items [1] to [10], or its pharmaceutically acceptable salt, or MES to obtain anti-HIV agent.

[16] the Use of compounds of any of the above items [1] to [10], or its pharmaceutically acceptable salt, or MES to get approved HIV integrase inhibitor.

[17] a Method of prevention or treatment due to HIV infectious disease in a mammal, which includes an introduction to the specified mammal an effective amount of a compound of any of the above items [1] to [10], or its pharmaceutically acceptable salt, or MES.

[18] the Method of the above item [17], which additionally includes an introduction to the mammal an effective amount of one or more other types of substances active against HIV.

[19] a Method of inhibiting HIV integrase in a mammal, which includes an introduction to the specified mammal an effective amount of a compound of any of the above items [1] to [10], or its pharmaceutically acceptable salt, or MES.

[20] the Composition against HIV-containing compound of any of the above items [1] to [10], or its pharmaceutically acceptable salt, Riego MES and a pharmaceutically acceptable carrier.

[21] the Pharmaceutical composition for inhibiting HIV integrase containing the compound of any of the above items [1] to [10], or its pharmaceutically acceptable salt, or its MES and a pharmaceutically acceptable carrier.

Compounds of the present invention exhibit high inhibitory activity against HIV integrase.

Therefore, these compounds may be pharmaceutical agents effective, for example, for prevention or treatment of AIDS, as integrase inhibitors, antiviral agents anti-HIV agents, and the like, possessing inhibiting the HIV integrase activity. In addition, in combined use with other anti-HIV agent(s), such as a protease inhibitor, a nucleoside reverse transcriptase inhibitor and the like, they can be more effective anti-HIV agents. In addition, having a high inhibitory activity-specific integrase, they can be pharmaceutical agents that are safe for humans and possess a weaker side effects.

The best way of carrying out the invention

Determine the appropriate substituents, the corresponding symbols and the corresponding parts used in the present description, are as follows.

“Halogen atom” is a fluorine atom, ATO is chlorine, the bromine atom or iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.

“C1-4alkyl group represents an alkyl group with unbranched or branched chain containing 1-4 carbon atoms, especially, you can specify a methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, sec-boutelou group and tert-boutelou group.

“C1-6alkyl group represents an alkyl group with unbranched or branched chain containing 1-6 carbon atoms, especially, you can specify a methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, pentelow group, isopentyl group, 1-methylbutyl group, 1-ethylpropyl group, 2-ethylpropyl group, 2,2-dimethylpropyl group, 1,2-dimethylpropylene group, tert-pentelow group, hexoloy group, isohexyl group, 1-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 1-ethylbutyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group and the like.

“C3-10cycloalkyl group” is with the battle cycloalkyl group, having 3-10 carbon atoms, preferably 3-6, and as such groups are especially you can specify cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group, cycloheptyl group, cyclooctyl group, cycloserine group and cyclodecyl group.

“C3-10carbocyclic group” is a saturated or unsaturated cyclic hydrocarbon group having 3-10 carbon atoms, and means aryl group, cycloalkyl group, cycloalkenyl group or a group with condensed rings.

As the “aryl group”, in particular, you can specify a phenyl group, naftalina group, pentylaniline group, azulinebloo group and the like, preferably phenyl group and naftalina group, particularly preferably phenyl group.

As cycloalkyl group” especially you can specify cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group, cycloheptyl group, cyclooctyl group, adamantly group, norbornylene group and the like, preferably cyclopropyl group, cyclobutyl group, cyclopentyl group and tsiklogeksilnogo group.

“Cycloalkenyl group contains at least one, preferably 1 or 2, double tie is, and as this group especially, you can specify cyclopropylamino group, cyclobutenyl group, cyclopentenyl group, cyclopentadienyls group, cyclohexenyl group, cyclohexadienyl group, (2,4-cyclohexadiene-1-ilen group, 2,5-cyclohexadiene-1-ilen group and the like), cycloheptenyl group, cyclooctyl group and the like.

The "aryl group", "cycloalkyl group" or "cycloalkenyl group" with condensed rings especially, you can specify indenolol group, indenolol group, 1,4-dihydronaphthalene group, 1,2,3,4-tetrahydronaphthalene group (1,2,3,4-tetrahydro-2-naftalina group, 5,6,7,8-tetrahydro-2-naftalina group, and so on), perhydroanthracene group and the like. Preferred is the group with condensed rings from the ring of the phenyl group and another ring, more preferably angenlina group, indayla group, 1,4-dihydronaphthalene group, 1,2,3,4-tetrahydronaphthalene group and the like, particularly preferably indayla group.

“C3-10carbocyclic group, optionally substituted by 1-5 substituents selected from group a”is above “C3-10carbocyclic group, optionally substituted by 1-5, preferably 1-3, substituents selected from the removal of the “group a”, and this group includes unsubstituted C3-10carbocyclic group”.

“Group a” represents a group consisting of the above-mentioned “halogen atom”, “C1-4alkyl group”, the values of which are specified above, -(CH2)n-ORa1, -NRa3Ra4, -CORa2and-CONRa3Ra4where Ra1, Ra2, Ra3and Ra4are the same or different and each represents a hydrogen atom or a C1-4alkyl group”, which has the values listed above, and n is 0 or an integer of 1-4.

As-(CH2)n-ORa1”in particular, you can specify a hydroxy-group, a methoxy group, ethoxypropan, propoxylate, isopropoxy, tert-butoxypropyl, hydroxymethylene group, methoxymethyl group, 2-(methoxy)ethyl group and the like.

As-NRa3Ra4”in particular, you can specify an amino group, methylaminopropyl, ethylamino, propylamino, isopropylamino, tert-butylamino, dimethylaminopropyl, diethylaminopropyl, N-ethyl-N-methylaminopropyl, N-methyl-N-propylamino, N-isopropyl-N-methylaminopropyl and the like.

As-CORa2”in particular, you can specify a formyl group, acetyl group, propionyl group, butyryloxy group, isobutyryloxy group, 2,2-dimethylpropyl the ilen group and the like.

As-CONRa3Ra4”in particular, you can specify karbamoilnuyu group, methylcarbamoyl group, ethylcarbitol group, profilirovannuju group, isopropylcarbamate group, tert-butylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group and the like.

As “C3-10carbocyclic group, optionally substituted by 1-5 substituents selected from group A”, in particular, you can specify a phenyl group, naftalina group, 2-florfenicol group, 2-chloraniline group, 2-bromperidol group, 3-florfenicol group, 3-chloraniline group, 3-bromperidol group, 4-florfenicol group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, 3-ethylphenyl group, 2-isopropylphenyl group, 3-isopropylphenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2-metoksifenilny group, 3-metoksifenilny group, 2-ethoxyphenyl group, 3-ethoxyphenyl group, 2-propoxyphenyl group, 3-propoxyphenyl group, 2-AMINOPHENYL group, 3-AMINOPHENYL group, 2-(methylamino)phenyl group, 3-(methylamino)phenyl group, 2-(dimethylamino)phenyl group, 3-(dimethylamino)phenyl group, 2-(diethylamino)f is niloy group, 2-(N-ethyl-N-methylamino)phenyl group, 2-(N-isopropyl-N-methylamino)phenyl group, 2-acetylphenyl group, 3-acetylphenyl group, 2-(carbarnoyl)phenyl group, 3-(carbarnoyl)phenyl group, 2-(methylcarbamoyl)phenyl group, 3-(methylcarbamoyl)phenyl group, 2-(dimethylcarbamoyl)phenyl group, 3-(dimethylcarbamoyl)phenyl group, 2,3-differenly group, 2,3-dichloraniline group, 3,4-dichloraniline group, 2,3-dibromophenyl group, 2,4-differenly group, 2,4-dichloraniline group, 2,5-dichloraniline group, 2,6-dichloraniline group, 2-chloro-3-florfenicol group, 2-chloro-4-florfenicol group, 2-chloro-5-florfenicol group, 2-chloro-6-florfenicol group, 3-chloro-2-florfenicol group, 5-chloro-2-florfenicol group, 5-bromo-2-chloraniline group, 2-chloro-3-methylphenyl group, 2-chloro-5-methylphenyl group, 3-chloro-2-methylphenyl group, 2-chloro-3-hydroxyphenyl group, 2-chloro-5-hydroxyphenyl group, 2-chloro-3-metoksifenilny group, 2-chloro-5-metoksifenilny group, 3-chloro-2-metoksifenilny group, 2-chloro-3-AMINOPHENYL group, 2-chloro-5-AMINOPHENYL group, 2-chloro-3-(methylamino)phenyl group, 2-chloro-5-(methylamino)phenyl group, 2-chloro-3-(dimethylamino)phenyl group, 2-chloro-5-(dimethylamino)phenyl group, 2,3,4-triptorelin group, 2-chloro-3,4-differenly group, 2-chloro-3,5-difthe ilen group, 2-chloro-3,6-differenly group, 2-chloro-4,5-differenly group, 2-chloro-4,6-differenly group, 3-chloro-2,4-differenly group, 3-chloro-2,5-differenly group, 3-chloro-2,6-differenly group, 2,3-dichloro-4-florfenicol group, 2-chloro-3,5,6-triptorelin group, 3-chloro-2,4,5-triptorelin group, 3-chloro-2,4,6-triptorelin group, 2,3-dichloro-4,5,6-triptorelin group, 3,5-dichloro-3,4,6-triptorelin group, 2,6-dichloro-3,4,5-triptorelin group, performancenow group, cyclopropyl group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group, 2-hydroxyisopropyl group, 2-hydroxyisobutyryl group, 3-hydroxyisobutyryl group, 2-hydroxycyclopent group, 3-hydroxycyclopent group, 2-hydroxycyclohexyl group, 3-hydroxycyclohexyl group, 4-hydroxycyclohexyl group, 4-indenolol group, 1H-inden-4-ilen group and the like.

“Heterocyclic group” is a saturated or unsaturated (including partially unsaturated and completely unsaturated) monocyclic 4-6-membered (preferably 5-membered or 6-membered) heterocyclic group containing, besides carbon atom, at least one, preferably 1 to 4 heteroatoms selected from nitrogen atoms, oxygen atom and sulfur atom, a group of kondensirovannye and rings of such heterocycles or condensed rings of the heterocycle and C 3-10carbocycle selected from benzene, cyclopentane and cyclohexane.

As the “saturated monocyclic heterocyclic group”, you can specify azetidinol group, pyrrolidinyl group, tetrahydrofuryl group, tetrahydrocannibinol group, imidazolidinyl group, pyrazolidine group, 1,3-DIOXOLANYL group, 1,3-oxathiolanes group, oxazolidinyl group, isoxazolidinone group, diazolidinyl group, isothiazolinone group, piperidinyl group, piperazinilnom group, tetrahydropyranyloxy group, tetrahydropyranyloxy group, dioxinlike group, morpholinyl group, 3-ecomorphology group, thiomorpholine group, 2-oxazolidinyl group, 2-oxopyrrolidin group, 3-oxadiazolyl group, 2-oxoacridine group, 1,1-dioxothiazolidine group, 2-oxopiperidine group, 4-oxopiperidine group, 2,6-dioxopiperidin group and the like.

As “unsaturated monocyclic heterocyclic group”, you can specify pyrrolidino group, follow group, thienyl group, imidazolidinyl group, 1,2-dihydro-2-Oxymetazoline group, pyrazolidine group, oxazolidinyl group, isoxazolyl group, thiazolidine group, isothiazolinone group, 1,2,4-triazole is the function group, 1,2,3-triazolyl group, tetrazolyl group, 1,3,4-oxadiazolyl group, 1,2,4-oxadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,4-thiadiazolyl group, foratenolol group, pyridyloxy group, pyramidalnou group, 3,4-dihydro-4-oxopyrimidine group, pyridazinyl group, personilnya group, 1,3,5-triazinyl group, imidazolidinyl group, pyrazolidine group, oxazolidinyl group (2-oxazolidinyl group, 3-oxazolidinyl group, 4-oxazolidinyl group), isoxazolyl group, thiazolidine group, isothiazolinone group, pyranyloxy group, 2-oxopyrrolo group 2-oxo-2,5-dihydropyrrolo group, 1,1-dioxo-1H-isothiazolinone group and the like.

As a condensed heterocyclic group, you can specify indolenine group (for example, 2-indolering group, 3-indolering group, 4-indolering group, 7-indolering group, and so on), isoindolyl group, 1,3-dihydro-1,3-dioxopiperidin group, benzofuranyl group (for example, 2-benzofuranyl group, 4-benzofuranyl group, 7-benzofuranyl group, and so on), indazolinone group, isobenzofuranyl group, benzothiazoline group (for example, 2-benzothiazoline group, 4-benzothiazoline group, 7-benzothiazoline group etc), benzoxazolyl group (for example, 2-benzoxazolyl the th group, 4-benzoxazolyl group, 7-benzoxazolyl group, and so on), benzimidazolyl group (for example, 2-benzimidazolyl group, 4-benzimidazolyl group, 7-benzimidazolyl group, and so on), benzothiazolyl group (for example, 2-benzothiazolylthio group, 4-benzothiazolyl group, 7-benzothiazolyl group, and so on), indolizinyl group, pinolillo group, izohinolinove group, 1,2-dihydro-2-oxopyridine group, chinazolinei group, khinoksalinona group, indolinyl group, talinolol group, hyalinella group, parinello group, pteridinyl group, indolinyl group, isoindolyl group, 5,6,7,8-tetrahydropyranyloxy group, 1,2,3,4-tetrahydropyrimidine group, 2-oxo-1,2,3,4-tetrahydropyrimidine group, benzo[1,3]dioxolo group, 3,4-methylenedioxyphenyl group, 4,5-ethylenediaminetetramethylene group, romanello group, romanello group, isopropanolol group and the like. Preferred is a condensed ring of a monocyclic 5-membered or 6-membered heterocycle and a benzene ring.

“Heterocyclic group optionally substituted by 1-5 substituents selected from group a”is the above “heterocyclic group”optionally substituted by 1-5, preferably 1-3, substituents selected from the above is shown “group a”, and this group includes unsubstituted “heterocyclic group”.

“Heterocyclic group” is preferably monocyclic heterocyclic group containing 1 or 2 heteroatoms or a heterocyclic group which has a condensed ring of the benzene ring.

As the “heterocyclic group optionally substituted by 1-5 substituents selected from group a”, in particular, you can specify 1-pyrrolidinyloxy group, 2-pyrrolidinyl group, 3-pyrrolidinyl group, 1-piperidinyloxy group, 2-piperidinyloxy group, 3-piperidinyl group, 4-piperidinyloxy group, morpholinopropan, 1-pyrrolidinyl group, 2-pyrrolidinyl group, 3-pyrrolidinyl group, 2-follow group, 3-follow group, 2-thienyl group, 3-thienyl group, 4,5-dichlorothiophene-3-ilen group, 2-oxo-2,5-dihydrofuran-3-ilen group, 1,1-dioxo-1H-isothiazol-5-ilen group, 4-methylthiazole-5-ilen group, 1-imidazolidinyl group, 2-imidazolidinyl group, 3-imidazolidinyl group, 4-imidazolidinyl group, 1-pyrazolidine group, 3-pyrazolidine group, 4-pyrazolidine group, 2-oxazolidinyl group, 3-isoxazolyl group, 2-thiazolidine group, 3-isothiazolinone group, 2-pyridyloxy group, 3-herperidin-2-ilen group, 3-chloropyridin-2-ilen group, 3-chloro-4-herperidin-2-ilen group, 3,5-dichloropurine the-2-ilen group, 3-pyridyloxy group, 2-herperidin-3-ilen group, 2-chloropyridin-3-ilen group, 2-chloro-4-herperidin-3-ilen group, 2-chloro-5-herperidin-3-ilen group, 2,5-dichloropyridine-3-ilen group, 2-chloro-6-herperidin-3-ilen group, 2,6-dichloropyridine-3-ilen group, 4-pyridyloxy group, 2-herperidin-4-ilen group, 2-chloropyridin-4-ilen group, 2-chloro-3-herperidin-4-ilen group, 2,3-differencein-4-ilen group, 2,3-dichloropyridine-4-ilen group, 2,5-dichloropyridine-4-ilen group, 2-chloro-6-herperidin-4-ilen group, 2,6-dichloropyridine-4-ilen group, 2-chloro-3,6-differencein-4-ilen group, 2-chloro-3,5-differencein-4-ilen group, 2,3,6-triptorelin-4-ilen group, 2,3,5,6-tetrafluoropyridine-4-ilen group, 2-indolering group, 3-indolering group, 4-indolering group, 7-indolering group, 2-benzofuranyl group, 4-benzofuranyl group, 7-benzofuranyl group, 2-benzothiazoline group, 4-benzothiazoline group, 7-benzothiazoline group, 2-benzimidazolyl group, 4-benzimidazolyl group, 2-benzoxazolyl group, 4-benzoxazolyl group, 7-benzoxazolyl group, 2-benzothiazolyl group, 4-benzothiazolyl group, 7-benzothiazolyl group 2-benzo[1,3]dioxolo group, 4-benzo[1,3]dioxolo group, 5-benzo[1,3]dioxolo group, tetrahydropyran-2-ilen group and the like.

“C1-6 alkyl group, optionally substituted by 1-3 substituents selected from group B”is above “C1-6alkyl group, optionally substituted by 1-3 substituents selected from the following “groups”, and such an alkyl group include unsubstituted “C1-6alkyl group”.

“Group B” is a group consisting of the above “C3-10carbocyclic group, optionally substituted by 1-5 substituents selected from group a”, the above-mentioned “heterocyclic group optionally substituted by 1-5 substituents selected from group a”, the above-mentioned “halogen atom”, ceanography, -ORb1, -SRb1, -NRb2Rb3, -CONRb2Rb3, -SO2NRb2Rb3, -CORb1, -NRb2CORb1, -SO2Rb1, -NRb2SO2Rb1, -COORb1, -NRb2COORb1and-NRb4CO-NRb2Rb3.

Rb1, Rb2, Rb3and Rb4are the same or different and each represents a hydrogen atom, the above-mentioned “C1-4alkyl group”, the aforementioned “C3-10carbocyclic group, optionally substituted by 1-5 substituents selected from group a”, or the above-mentioned “heterocyclic group optionally substituted by 1-5 substituents selected from group a”.

As “-ORb1”that frequent the spine, you can specify a hydroxy-group, a methoxy group, ethoxypropan, propoxylate, isopropoxy, butoxypropyl, isobutoxy, sec-butoxypropyl, tert-butoxypropyl, fenoxaprop, pyridine-2-lexigraphy, tetrahydropyran-2-lexigraphy and the like.

As-SRb1”in particular, you can specify mercaptopropyl, methylsulfanyl group, ethylsulfonyl group, propylsulfonyl group, isopropylphenyl group, tert-butylsulfonyl group and the like.

As-NRb2Rb3”in particular, you can specify an amino group, methylaminopropyl, ethylamino, propylamino, isopropylamino, tert-butylamino, dimethylaminopropyl, diethylaminopropyl, N-ethyl-N-methylaminopropyl, N-methyl-N-propylamino, N-isopropyl-N-methylaminopropyl, phenylaminopropyl, pyridine-2-luminograph, N-methyl-N-phenylaminopropyl and the like.

As-CONRb2Rb3”in particular, you can specify karbamoilnuyu group, methylcarbamoyl group, ethylcarbitol group, profilirovannuju group, isopropylcarbamate group, tert-butylcarbamoyl group, dimethylcarbamoyl group, diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, phenylcarbamoyl group and the like.

As “-SO2NRb2Rb3”cha is in the surrounding area, you can specify sulfamoyl group, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylamino group, tert-butylsulfonyl group, dimethylsulphamoyl group, diethylcarbamoyl group, N-ethyl-N-methylsulfonylamino group, phenylsulfonyl group and the like.

As-CORb1”in particular, you can specify a formyl group, acetyl group, propionyl group, butyryloxy group, isobutyryloxy group, 2,2-dimethylpropylene group, benzoyloxy group, pyrrolidin-1-ylcarbonyl group, 2-ftorpirimidinu-1-ylcarbonyl group, 2-oxopyrrolidin-1-ylcarbonyl group, piperidinylcarbonyl group, 4-oxopiperidin-1-ylcarbonyl group, 2,6-dimethylpiperidin-1-ylcarbonyl group, piperazine-1-ylcarbonyl group, morpholinomethyl group and the like.

As-NRb2CORb1”in particular, you can specify formylamino, acetylamino, propionamido, bucillamine, isobutylamino, 2,2-dimethylpropanolamine, N-acetyl-N-methylaminopropyl, benzoylamino, pyrrolidin-1-incorporatingthe, 2-ftorpirimidinu-1-incorporatingthe, 2-oxopyrrolidin-1-incorporatingthe, piperidinecarboxylate, 4-oxopiperidin-1-incorporating the PU, 2,6-dimethylpiperidin-1-incorporatingthe, piperazine-1-incorporatingthe, morpholinosydnonimine and the like.

As “-SO2Rb1”in particular, you can specify methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylphenyl group, tert-butylsulfonyl group and the like.

As-NRb2SO2Rb1”in particular, you can specify methylsulfonylamino, ethylsulfonylimidazo, propylsulfonyl, isopropylbenzylamine, tert-butylsulfonyl, N-methyl-N-(methylsulphonyl)amino group and the like.

As-COORb1”in particular, you can specify a carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, tert-butoxycarbonyl group and the like.

As-NRb2COORb1”in particular, you can specify methoxycarbonylamino, ethoxycarbonylmethoxy, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonylamino, N-(tert-butoxycarbonyl)-N-methylaminopropyl and the like.

As-NRb4CO-NRb2Rb3”in particular, you can specify raidgroup, 3-methyluridine, 3-ailuridae, 1,3-Dimethylol is idgruppo and the like.

As “C1-6alkyl group, optionally substituted by 1-3 substituents selected from group B”, in particular, you can specify a methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, sec-boutelou group, tert-boutelou group, pentelow group, isopentyl group, 1-methylbutyl group, 1-ethylpropyl group, 2-ethylpropyl group, 2,2-dimethylpropyl group, 1,2-dimethylpropylene group, tert-pentelow group, hexoloy group, isohexyl group, 1-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 1-ethylbutyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group, formeterol group, triptorelin group, 1-chlorethylene group, 2-foretelling group, 2-chloraniline group, 3-forproperty group, 2-chloropropylene group, 2,2,2-triptorelin group, hydroxymethylene group, methoxymethyl group, ethoxymethyl group, propoxymethyl group, isopropoxyethanol group, butoxymethyl group, isobutoxide group, Deut-butoxymethyl group, tert-butoxymethyl group, phenoxymethyl group, pyridine-2-roximately group, 1-hydroxic the optimum group, 2-hydroxyethyloxy group, 1-methoxyamino group, 2-methoxyaniline group, 1-ethoxyethylene group, 2-ethoxyethylene group, 1-methoxy-1-methylamino group, 2-propoxyethyl group, 2-isopropoxyethanol group, 2-butoxyethyl group, 2-isobutoxide group, 2-sec-butoxyethyl group, 2-tert-butoxyethyl group, 2-Phenoxyethanol group, 2-(pyridine-2-yloxy)ethyl group, 2-hydroxypropyl group, 2-hydroxy-1-methylamino group 2-hydroxy-1,1-dimethylethylene group, 1-(hydroxymethyl)sawn group, 3-hydroxypropyl group, 2-hydroxybutyl group, 4-hydroxybutyl group, 2-hydroxypentanal group, 5-hydroxypentanal group, 2,3-dihydroxypropyl group, 2,3-dihydroxybutyl group, 2-hydroxy-1-(hydroxymethyl)ethyl group, 2-hydroxy-2-methylpropyloxy group, 1-(hydroxymethyl)boutelou group, 1-(hydroxymethyl)-2-methylpropyl group, 1-(hydroxymethyl)-2,2-dimethylpropyl group, 1-(hydroxymethyl)-2-methylbutyl group, 2-hydroxy-1-phenylethylene group, 2-hydroxy-2-phenylethylene group, 1-(hydroxymethyl)-2-phenylethylene group, 1-(hydroxymethyl)-3-methylbutyl group, 3-hydroxy-1-methylpropyl group, 1,1-dimethyl-3-hydroxypropyl group, 1,2-dimethyl-3-hydroxypropyl group, 1-isopropyl-3-hydroxypropyl group, 1-ethyl-3-hydroxypropyl is the Rupp, 2-hydroxy-1-isopropylamino group, 1-ethyl-1-(hydroxymethyl)through the group, 1,1-dimethyl-2-hydroxypropyl group, 1,2-dimethyl-2-hydroxypropyl group, 1-ethyl-2-hydroxypropyl group, 4-hydroxy-1-methylbutyl group, 1-(hydroxymethyl)pentelow group, aminomethyl group, (methylamino)methyl group, (ethylamino)methyl group, (dimethylamino)methyl group, (N-ethyl-N-methylamino)methyl group, 1-aminoethyl group, 2-aminoethyl group, 1-(methylamino)ethyl group, 2-(methylamino)ethyl group, 1-(ethylamino)ethyl group, 2-(ethylamino)ethyl group, 2-(dimethylamino)ethyl group, methylsulfonylamino group, 2-(methylsulfanyl)ethyl group, carboxymethyl group, 2-carboxyaniline group, 2-carboxypropyl group, 3-carboxypropyl group, carbamoylmethyl group, 2-(carbarnoyl)ethyl group, methylcarbamoylmethyl group, dimethylcarbamoyl group, 2-(phenylcarbamoyl)ethyl group, 2-oxopropyl group, methylsulfonylamino group, 2-(methylsulphonyl)ethyl group, sulfamoylbenzoyl group, methylsulfonylamino group, dimethylaminomethyl group, tert-butylsulfonyl group, 2-(acetylamino)ethyl group, 2-(methylsulfonylamino)ethyl group, 2-(ethoxycarbonyl)ethyl group, benzyl gr the PPU, fenetylline group, 3-phenylpropyl group, 4-phenylbutyl group, 3,4-dichloraniline group, 2-hydroxy-2-phenylethylene group, cyclopentylmethyl group, cyclohexylmethyl group, 2-cyclohexylethyl group, 1-cyclohexyl-2-hydroxyethylene group, 1-cyclohexylmethyl-2-hydroxyethylene group, phenylcarbamoyl group, 2-(pyridin-2-yl)ethyl group, 2-(imidazol-1-yl)ethyl group, 2-(benzothiophen-2-yl)ethyl group, 2-morpholinoethyl group, 2-(4-methylthiazole-5-yl)ethyl group, 1-carboxyaniline group, 1-(carbarnoyl)ethyl group, 1-carboxy-2-methylpropyl group, 1-(carbarnoyl)-2-methylpropyloxy group, 2-hydroxy-1-(hydroxymethyl)sawn group, 1-(hydroxymethyl)-2-mercaptoethyl group, 1-(hydroxymethyl)-3-(methylsulfanyl), sawn group, 2-carboxy-1-(hydroxymethyl)ethyl group, 2-carbarnoyl-1-(hydroxymethyl)ethyl group, 2-(indol-3-yl)-1-(hydroxymethyl)ethyl group, 2-(imidazol-4-yl)-1-(hydroxymethyl)ethyl group, 2-(4-hydroxyphenyl)-1-(hydroxymethyl)ethyl group, 3-carbarnoyl-1-(hydroxymethyl)sawn group, 5-amino-1-(hydroxymethyl)pentelow group, 2-(tetrahydropyran-2-yloxy)ethyl group, acetamidomethyl group, methylsulfonylamino group, methoxycarbonylamino group, sulfamoylbenzoyl group, (tert-butoxycarbonylamino)is Milou group, (2,2-dimethylpropanolamine)methyl group, (N-tert-butoxycarbonyl-N-methylamino)methyl group, propionylthiocholine group, butyrylthiocholine group, isobutylamino group, benzylaminopurine group, ethoxycarbonylmethyl group (morpholinosydnonimine)methyl group, (3-methylurea)methyl group, (3-ethylurea)methyl group and the like.

As R1preferably, you can specify a methyl group, ethyl group, through the group, isopropyl group, tert-boutelou group, methoxymethyl group, ethoxymethyl group, 1-methoxyamino group, 2-methoxyaniline group, 1-ethoxyethylene group, 1-methoxy-1-methylamino group and the like.

“C3-10cycloalkyl group, optionally substituted by 1-5 substituents selected from group a”, which is formed of R1and R6together with the carbon atoms associated with them, is the aforementioned “3-10cycloalkyl group, optionally substituted by 1-5, preferably 1-3, substituents selected from the above-mentioned “group a”, and such group includes unsubstituted “C3-10cycloalkyl group.

As “C3-10cycloalkyl group, optionally substituted by 1-5 substituents selected from group a”, in particular, you can specify cycloprop the optimum group, cyclobutyl group, cyclopentyl group, tsiklogeksilnogo group, cycloheptyl group, cyclooctyl group, cycloserine group, cyclodecyl group and the like.

“Monocyclic heterocyclic group” of the “monocyclic heterocyclic group, optionally substituted by 1-5 substituents selected from group a”is a saturated or unsaturated (including partially unsaturated and completely unsaturated) monocyclic 4-6-membered (preferably 5-membered or 6-membered) heterocyclic group containing, besides carbon atom, at least one, preferably 1 to 4 heteroatoms selected from nitrogen atom, oxygen atom and sulfur atom.

As the “monocyclic heterocyclic group”, in particular, you can specify the following heterocyclic group.

“Monocyclic heterocyclic group, optionally substituted by 1-5 substituents selected from group a”is the above “monocyclic heterocyclic group”optionally substituted by 1-5, preferably 1-3, substituents selected from the above-mentioned “group a”, and such group includes unsubstituted “monocyclic heterocyclic group”.

As the e “monocyclic heterocyclic group”, optionally substituted by 1-5 substituents selected from group a”, the ring may be used, in particular, 1-pyrrolidinyl group, 2-oxopyrrolidin-1-ilen group, 3-hydroxypyrrolidine-1-ilen group, 3-ftorpirimidinu-1-ilen group, 3,3-debtorprovidian-1-ilen group, piperidino, 2-oxopiperidin-1-ilen group, 4-hydroxypiperidine-1-ilen group, 1-piperazinilnom group, 4-methylpiperazin-1-ilen group, 4-acetylpiperidine-1-strong group, morpholinopropan, 3-exmortis-4-ilen group, thiomorpholine, 1,1-dioxothiazolidine-2-ilen group, 2-oxoacridine-3-ilen group, 3-oxopyrrolidin-1-ilen group, 2-methyl-3-oxopyrrolidin-1-ilen group, 2-pyridyloxy group, 2-thiazolidine group, 1,2,4-oxadiazol-3-ilen group, 5-methyl-1,2,4-oxadiazol-3-ilen group and the like.

Ring And preferably represents a monocyclic carbocyclic group containing at least one nitrogen atom, and mentioned monocyclic heterocyclic group optionally substituted by 1-5 substituents selected from group a, and is connected through a nitrogen atom with the benzene ring represented by

in the formula [1].

As a ring, And more preferred is a heterocyclic group selected from 1-pyrrolidinyl group, 2-ocsober is lidin-1-ilen group, piperidino, 2-oxopiperidin-1-ilen group, 1-piperazinilnom group, morpholinopropan, 3-exmortis-4-ilen group, thiomorpholine, 1,1-dioxothiazolidine-2-ilen group, 2-oxoacridine-3-ilen group and 3-oxopyrrolidin-1-ilen group, where the heterocyclic group is optionally substituted by 1-5 substituents selected from group A. For ring A still more preferred is a heterocyclic group selected from 2-oxopyrrolidin-1-ilen group, 2-oxopiperidin-1-ilen group, and morpholinopropan 3-exmortis-4-ilen group, where the heterocyclic group is optionally substituted by 1-5 substituents selected from group A.

As rings And one of the most preferred embodiments is a 2-oxopyrrolidin-1-ilen group, another most preferred embodiment is morpholinopropan.

As another preferred option for implementation of the rings And you can specify a heterocyclic group selected from 1-pyrrolidinyl group, 2-oxopyrrolidin-1-ilen group, piperidino, 2-oxopiperidin-1-ilen group, 1-piperazinilnom group, morpholinopropan, 3-exmortis-4-ilen group, thiomorpholine, 1,1-dioxothiazolidine-2-ilen group, 2-oxoacridine-3-ilen group, 3-oxopyrrolidin-1-ilen group, 2-pyrid the school group, 2-thiazoline group and 1,2,4-oxadiazol-3-ilen group, where the heterocyclic group is optionally substituted by 1-5 substituents selected from group A.

As groups And rings And preferred are a halogen atom, a C1-4alkyl group, ORa1and-CORa2where Ra1and Ra2are the same or different and each represents a hydrogen atom or a C1-4alkyl group.

Preferably R1represents a C1-6alkyl group, optionally substituted by 1-3 substituents selected from group b, and R6represents a hydrogen atom. More preferably R1represents a C1-6alkyl group, optionally substituted by 1-3-ORb1where Rb1represents a hydrogen atom or a C1-4alkyl group, and R6represents a hydrogen atom.

R2represents preferably1-4alkyl group or-OR11where R11represents a hydrogen atom or a C1-4alkyl group. In another preferred variant implementation for R2you can specify a hydrogen atom.

Preferably R3and R4are the same or different, and each represents a halogen atom. More preferably R3represents a fluorine atom, and R4PR is dstanley a chlorine atom.

m is preferably 0 or 1, more preferably 1. When m is 1, R5preferably represents a halogen atom, more preferably a fluorine atom.

As the group represented by the formula

preferably, you can specify

and things like that. When R1is other than a hydrogen atom, R1preferably represents a group having the configuration illustrated

As compounds represented by the formula [1] or its pharmaceutically acceptable salt, preferred are the following compounds:

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((R)-1-ethoxymethyl-2-hydroxyethyl)-7-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2),

6-[3-chloro-2-fluoro-5-(pyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3),

6-[3-chloro-2-fluoro-5-(2-oxoacridine-3-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-meth is XI-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 5),

6-[3-chloro-2-fluoro-5-(piperidine-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 6),

6-[3-chloro-2-fluoro-5-(2-oxopiperidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 7),

6-[3-chloro-2-fluoro-5-((R)-3-hydroxypyrrolidine-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 8),

6-[3-chloro-2-fluoro-5-((S)-3-hydroxypyrrolidine-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 9),

6-[3-chloro-2-fluoro-5-(2-methyl-3-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 10),

6-[5-(4-acetylpiperidine-1-yl)-3-chloro-2-terbisil]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 11),

6-[3-chloro-5-(3,3-debtorprovidian-1-yl)-2-terbisil]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 12),

6-[3-chloro-2-fluoro-5-((R)-3-ftorpirimidinu-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 13),

6-[3-chloro-2-fluoro-5-((S)-3-ftorpirimidinu-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carb is a new acid (example 14),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((1R,2R)-1-hydroxymethyl-2-methoxypropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 15),

6-[3-chloro-2,4-debtor-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 16),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 17),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 18),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((R)-1-ethoxymethyl-2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 19),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-[(R)-2-hydroxy-1-(methoxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 20),

6-[3-chloro-5-(1,1-dioxothiazolidine-2-yl)-2-terbisil]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 21),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-[(R)-2-hydroxy-1-(methoxymethyl)ethyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 22),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 23),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)Ben who yl]-7-ethyl-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 24),

6-[3-chloro-2,4-debtor-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 25),

6-[3-chloro-2,4-debtor-5-(2-oxopyrrolidin-1-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 26),

6-[3-chloro-2-fluoro-5-(thiomorpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 27),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((1R,2S)-1-hydroxymethyl-2-methoxypropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 28),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-3-methoxypropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 29),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((R)-2-hydroxy-1-(methoxymethyl)ethyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 30),

6-[3-chloro-2,4-debtor-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((R)-2-hydroxy-1-(methoxymethyl)ethyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 31),

6-[3-chloro-2-fluoro-5-(4-hydroxypiperidine-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 32),

6-[3-chloro-2-fluoro-5-(4-methylpiperazin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example is 33),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-((1R,2R)-1-hydroxymethyl-2-methoxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 34),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-((1R,2S)-1-hydroxymethyl-2-methoxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 35),

6-[3-chloro-2-fluoro-5-(pyridin-2-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 36),

6-[3-chloro-2-fluoro-5-(thiazol-2-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 37),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-[(1R,2R)-2-ethoxy-1-(hydroxymethyl)propyl]-7-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 38),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((R)-1-ethoxymethyl-2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 39),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-[(1R,2R)-2-ethoxy-1-(hydroxymethyl)propyl]-7-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 40),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-7-ethyl-1-((1R,2R)-1-hydroxymethyl-2-methoxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 41),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((R)-1-hydroxymethyl-2-methoxy-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 42),

6-[3-chloro-2-fluoro-5-(morpholine-4-the l)benzyl]-7-ethyl-1-((R)-1-hydroxymethyl-2-methoxy-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 43),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-3-methoxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 44),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 45),

6-[3-chloro-2,4-debtor-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 46),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-3-methoxypropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 47),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((1R,2R)-1-hydroxymethyl-2-methoxypropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 48),

6-[3-chloro-2,4-debtor-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 49),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-[(1R,2R)-2-ethoxy-1-(hydroxymethyl)propyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 50),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 51),

6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 5),

6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 53),

6-[3-chloro-2,4-debtor-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 54),

6-[3-chloro-2,4-debtor-5-(2-oxopyrrolidin-1-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 55),

6-[3-chloro-2,4-debtor-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 56),

6-[3-chloro-2-fluoro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 57),

6-[3-chloro-2,4-debtor-5-(3-exmortis-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 58),

6-[3-chloro-2,4-debtor-5-(morpholine-4-yl)benzyl]-1-((R)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 59).

“Pharmaceutically acceptable salt” may be any salt as long as it is non-toxic salt formed by the connection represented by the above formula [1]. Examples of it include a salt with inorganic acid, salt with organic acid, salt with inorganic base, a salt with organic base, with the eh with amino acid and the like.

As a salt with inorganic acid, you can specify, for example, salts with hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, Hydrobromic acid and the like.

As a salt with organic acid, you can specify, for example, salts with oxalic acid, malonic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, triperoxonane acid, gluconic acid, ascorbic acid, methanesulfonic acid, benzosulfimide acid, p-toluensulfonate acid and the like.

As a salt with inorganic base, you can specify, for example, sodium salt, potassium salt, calcium salt, magnesium salt, ammonium salt and the like.

As a salt with an organic base, you can specify, for example, salts with methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, Ethylenediamine, Tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenziletilendiaminom, guanidine, pyridine, picoline, choline, cinchonine, morpholine, meglumine and the like.

As a salt with an amino acid can be specified, for example, salts with lysine, arginine, aspartic acid, glutamic what Isletas and the like.

Each salt can be obtained by reaction of the compound represented by the formula [1], with inorganic base, organic base, inorganic acid, organic acid or amino acid according to the known per se method.

In the present invention, the pharmaceutically acceptable salt of the compound represented by the formula [1], preferably is a sodium salt or potassium salt.

“MES” is a compound represented by formula [1]or its pharmaceutically acceptable salt, which coordinated solvent molecule, it also includes hydrates (also called water-containing compounds). The MES is preferably pharmaceutically acceptable MES, such as the monohydrate, 1/2-hydrate, dihydrate, monohydrate sodium salt, monoethanol, monoethanol, monoclonal, 2/3-ethanolate dihydrochloride compound represented by the formula [1], and the like.

MES compounds represented by the formula [1]or its pharmaceutically acceptable salt can be obtained according to a method known per se.

In addition, there are various isomers of the compounds represented by the above formula [1]. For example, when there is an asymmetric carbon atom, the enantiomer and the diastereoisomer may be present as stereoisomers based on them. Sootvetstvenno is that all such isomers and mixtures thereof are included in the scope of the present invention. As the compounds of the present invention, it is preferable compound isolated and purified from various isomers, by-products, metabolites or prodrugs, and preferred is a compound having a purity of at least 90%, and more preferred is a compound having a purity not less than 95%.

The compound represented by the formula [1]may have a crystalline or amorphous form.

In addition, the compound represented by the formula [1], can be labeled with an isotope (for example,3H,14C,35S and so on).

In the present invention is suitable pharmaceutical agent may also be a prodrug of the compound represented by the formula [1].

“Prodrug” means a derivative compound of the present invention, which has a chemically or metabolically degradable group and which, after introduction into the body turns into the initial connection, manifesting its inherent efficiency, including complex and a salt of such a compound, not including covalent bond.

The prodrug is used, for example, to increase absorption by oral administration or delivery to the place of the target.

As a part of that change, you can specify very reactive functional group in the compound of the present invention, such hydroxy the other group, carboxyl group, amino group, Tolna group and the like.

Examples hydroxymorphinone group include acetyl group, propionyl group, isobutyryl group, pivaloyl group, benzoyloxy group, 4-methylbenzoyl group, dimethylcarbamoyl group, alphagroup and the like. Examples carboxymethylcelluose group include ethyl group, pivaloyloxymethyl group, 1-(atomic charges)ethyl group, 1-(ethoxycarbonyl)ethyl group, 1-(cyclohexyloxycarbonyloxy)ethyl group, carboxymethyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group, phenyl group, o-taillow group and the like. Examples aminemodified groups include hexylberberine group, 3-methylthio-1-(acetylamino)propelleronline group, 1-sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl group and the like.

The compound of the present invention can be introduced mammal (human, mouse, rat, hamster, rabbit, cat, dog, bull, sheep, monkey, etc. and the like as an agent or composition against HIV integrase inhibitor, an antiviral agent, and the like.

When the compound of the present invention is used in the form of a pharmaceutical composition or drug, it is usually mixed with farmac whitesky acceptable carriers, the excipients, diluents, filling agents, dezinfeciruyuhimi agents, stabilizers, stabilizers, preservatives, buffers, emulsifiers, coloring agents, sweetening agents, thickeners, corrective agents, solubilizers agents and other additives which are known per se, such as water, vegetable oil, alcohol (for example, ethanol, benzyl alcohol, etc.), polyethylene glycol, glycerol triacetate, gelatin, carbohydrates (e.g. lactose, starch, etc.), magnesium stearate, talc, lanolin, petrolatum and the like into the form of tablets, pills, powder, granules, suppositories, injections, drops for eyes, liquids, capsules, tablets, aerosol, elixir, suspension, emulsion, syrup and the like accepted way and injected systemically or topically and orally or parenterally.

Although the dose varies depending on age, body weight, symptom, treatment effect, the route of administration and the like, it is usually from 0.01 mg to 1 g per time for an adult subject, and the dose is administered one to several times per day orally or in the form of dosage forms for injection, such as intravenous injection, and the like.

Usually requires rack to support the effect of anti-HIV agent over an extended period of time, so it was not effective is only for temporary suppression of viral growth but the obstacles to the resumption of viral growth. This means that prolonged introduction is necessary and that a single high dose can often be inevitable for steadfastly supported actions over a longer period of time throughout the night. The introduction of such prolonged and high doses increases the risk of side effects.

In view of this one of the preferred embodiments of the compounds of the present invention is a compound having a high absorption by oral administration, and such a connection with the introduction of can remain in the blood at high concentrations over a long period of time.

In addition to the above, the preferred embodiments of the compounds of the present invention it is possible to specify a connection having excellent pharmacological activity (e.g., a compound which has a strong inhibiting the HIV integrase activity, a compound which has a high activity against HIV), the compound which has excellent bioavailability (e.g., a compound which has a high permeability through the cell membrane), the connection is resistant to metabolic enzyme, a compound which has a low binding capacity in relation to the Bel is a, and the like), a compound with high security (for example, a compound exhibiting low inhibitory P450(CYP) activity, and the like) and the like.

Of the compounds of the present invention, more preferred is a compound which has a high pharmacological activity (specifically, inhibiting the HIV integrase activity in the form of the IC50less than 0.1 μm, preferably less than 0.01 μm) and high oral absorption, and concentration of such compounds in the blood is maintained for a long period of time after injection.

It is assumed that the application of the above compounds, the dose and/or frequency of introduction of the compounds of the present invention to a person decreases. The preferred frequency of injection is no more than twice per day, more preferably not more than once a day (for example, once a day, once in two days and so on).

A new derivative of 4-oxacilin of the present invention can be applied to achieve positive dynamics of viremia due to HIV and/or maintain the improved condition when viremia, the treatment of viral infections, especially of infectious diseases caused by HIV, and/or improved conservation status with this disease.

As an index of “treatment”, “positive dynamics” or “pieces which I can use to reduce the amount of virus or HIV RNA levels in the body, especially in the blood.

The term “prevention” means, for example, the introduction of a pharmaceutical agent to an individual whose positive HIV test, but has not yet developed a pathological condition of AIDS; the introduction of a pharmaceutical agent to an individual who has improved the pathological condition of AIDS after treatment, but which still contains in the body of HIV, which should be eliminated and which are worried about the recurrence of AIDS; the introduction of a pharmaceutical agent prior to HIV infection because of the risk of possible infection, and the like.

Examples of “other anti-HIV agents” and “other substances that are active against HIV”, which is used for policecourtneu combination therapy include antibody against HIV or other antibody, HIV vaccine or other vaccines, Immunostimulants, such as interferon, interferon agonist and the like, a ribozyme against HIV, HIV antisense drug, an inhibitor of HIV reverse transcriptase, protease inhibitor HIV integrase inhibitor HIV inhibitor accession receptor (CD4, CXCR4, CCR5, and the like) of the host cell, recognizable by a virus, the virus (CCR5 antagonist and the like), an inhibitor of DNA polymerase or an inhibitor of DNA synthesis, pharmaceutical agent, acting on Wicr, fusion inhibitor cells of HIV, the agonist or antagonist IL-2, antagonist of TNF-α, an inhibitor of α-glucosidase, an inhibitor polynucleotide, agonist or an inhibitor of apoptosis, a cholinesterase inhibitor, immunomodulator, and the like.

Specific examples of inhibitors of HIV reverse transcriptase include Retrovir(R) (zidovudine), Epivir(R) (lamivudine, stavudine, zerit(R) (senology), videx(R) (didanosine), hivid(R) (zalcitabine), Ziagen(R) (abacavir sulfate), viramune(R) (nevirapine), stocrin(R) (efavirenz), rescriptor(R), delavirdine mesilate), Combivir(R) (zidovudine + lamivudine), Trizivir(R) (abacavir sulfate + lamivudine + zidovudine), coaction(R) (emivirine), postanowi(R), coviracil(R), alovudine (3'-fluoro-3'-deoxythymidine), tower (thiophosphoramide acid), capravirine (5-[(3,5-dichlorophenyl)thio]-4-isopropyl-1-(4-pyridylmethyl)imidazol-2-metalcarbon acid), tenofovirdisproxil fumarate (fumarate bis((isopropoxycarbonyloxymethyl) ether (R)-[[2-(6-amino-N-purine-9-yl)-1-methylethoxy]methyl]phosphonic acid), DCP-083 ((4S)-6-chloro-4-[(1E)-cyclopropylethanol]-3,4-dihydro-4-trifluoromethyl-2(1H)-hintline), DPC-961 ((4S)-6-chloro-4-(cyclopropylamino)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-hintline), DAPD ((-)-β-D-2,6-diaminopyridine), Immunocal, MSK-055, MSA-254, MSH-143, NV-01, TMC-120, DPC-817, GS-7340 tel, TMC-125, SPD-754, D-A4FC, capravirine, UC-781, emtricitabine, alovudine, phosphated, VSN-10618, DCP-083, etravirine, VSN-13520, MIV-210, abacavir sulfate/lamivudine, GS-7340 tel, GM-5634, GM-695634 and t the th like, where (R) indicates registered trademark (hereinafter has the same meaning) and the names of other pharmaceutical agents are common names.

Specific examples of the inhibitor of HIV protease include Crixivan(R) (indinavir sulfate ethanolate), saquinavir, invirase(R) (saquinavir mesilate), norvir(R) (ritonavir), viracept(R) (nelfinavir mesilate), lopinavir, prosa(R) (APV), Kaletra(R) (ritonavir+lopinavir), mozenavir dimesylate (dimethanesulfonate [4R-(4α,5α,6β)]-1,3-bis-[(3-AMINOPHENYL)methyl]hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-it), tipranavir (3'-[(1R)-1-[(6R)-5,6-dihydro-4-hydroxy-2-oxo-6-phenylethyl-6-propyl-2H-Piran-3-yl]propyl]-5-(trifluoromethyl)-2-pyridinesulfonamide), latinovic (2-methoxyaniline N-[5(S)-(tert-butoxycarbonylamino)-4(S)-hydroxy-6-phenyl-2(R)-(2,3,4-trimethoxybenzyl)hexanoyl]-L-valine), INSTITUTE of 272 ((R)-N-tert-butyl-3-[(2S,3S)-2-hydroxy-3-N-[(R)-2-N-(isoquinoline-5-intoxicated)amino-3-methylthiophenol]amino-4-phenylbutane]-5,5-dimethyl-1,3-thiazolidin-4-carboxamide), GW-433908, TMC-126, DPC-681, buckminsterfullerene, MK-A (MK (N-(2(R)-hydroxy-1(S)-indanyl-2(R)-phenylmethyl-4(S)-hydroxy-5-[4-(2-benzo[b]furylmethyl)-2(S)-(tert-butylcarbamoyl)piperazine-1-yl]pentanone) + indinavir sulfate), JE-2147 ([2(S)-oxo-4-phenylmethyl-3(S)-[(2-methyl-3-oxy)phenylcarbonylamino]-1-oxobutyl]-4-[(2-were)methylamino]carbonyl-4(R)-5,5-dimethyl-1,3-thiazole), BMS-232632 (d is methyl-(3S,8S,9S,12S)-3,12-bis(1,1-dimethylethyl)-8-hydroxy-4,11-dioxo-9-(phenylmethyl)-6-[[4-(2-pyridinyl)phenyl]methyl]-2,5,6,10,13-pentasaccharideindependent), DMP-850 ((4R,5S,6S,7R)-1-(3-amino-1H-indazol-5-ylmethyl)-4,7-dibenzyl-3-butyl-5,6-dihydroxypregna-1,3-diazepin-2-one), DMP-851, RO-0334649, Nar-DG-35, R-944, VX-385, TMC-114, tipranavir, fosamprenavir sodium, fosamprenavir calcium, darunavir, GW-0385, R-944, RO-033-4649 and AG-1859, and the like.

Examples of approved HIV integrase inhibitor is S-1360, L-870810, and the like, examples of the inhibitor polymerase DNA or inhibit DNA synthesis are foscavir(R), ASN-126443 (L-2',3'-didehydrothymidine-5-perltidy), entecavir ((1S,3S,4S)-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecycloartanol]guanine), calanoid And ([10R-((10α,11β,12α)]-11,12-dihydro-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-2H,6N,10H-benzo[1,2-b:3,4-b':5,6-b”]Tripura-2-one), calanolide, NSC-674447 (1,1'-azobisformamide), iskador (extract of viscum alubm), rubitecan and the like, examples of drugs with antisense sequence against HIV are HGTV-43, GEM-92, and the like, examples of antibodies against HIV or other antibodies are NM-01, PRO-367, KD-247, cytolin(R), TNX-355 (CD4 antibody), AGT-1, PRO-140 (CCR5 antibody), anti-CTLA-4Mab and the like, examples of an HIV vaccine or other vaccines are ALVAC(R), AIDSVAX(R), remune(R), the vaccine HIV gp41 vaccine, the vaccine HIV gp120 vaccine HIV gp140 vaccine HIV gp160 vaccine HIV p17 vaccine HIV p24 vaccine HIV p55 system AlphaVax Vector, vaccine canarypox gp160, Tat, vaccine MVA-F6 Nef vaccine in HIV rev peptide C4-V3, p2249f, VIR-201, HGP-30W, TBC-3B, PARTICLE-3B, inteferon vaccine in which harperone-α), and the like, examples of interferon or interferon agonist are sumiferon(R), multiferon(R), interferon-τ, reticulose, interferon (of human leukocytes and the like, examples of the CCR5 antagonist is SCH-351125 and the like, an example of a pharmaceutical agent, acting on HIV P24 is GPG-NH2(glycyrrhizinate) and the like, examples of an inhibitor of the fusion of cells of HIV are FP-21399 (1,4-bis-[3-[(2,4-dichlorophenyl)carbylamine]-2-oxo-5,8-distribulion]naphthyl-2,5-acid-1,4-dihydrazone), T-1249, a synthetic polymer design No. 3, penthouse, FP-21399, PRO-542, enfuvirtide, and the like, examples of an agonist or antagonist of IL-2 are interleukin-2, Kunak(R), Proleukin(R), multicen(R), a touch of a button(R) and the like, examples of the TNF antagonist is(are THALOMID(R) (thalidomide), Remicade(R) (infliximab), Kurdian sulfate, examples of the inhibitor of α-glucosidase are balast(R), and the like, examples of the inhibitor polynucleotides are peltatin (2-amino-4-oxo-3H,5H-7-[(3-pyridyl)methyl]pyrrolo[3,2-d]pyrimidine and the like, examples of the agonist or inhibitor of apoptosis are Arkin Z(R), Panavir(R), coenzyme Q10 (2-DECA-(3-methyl-2-butylen)-5,6-dimethoxy-3-methyl-p-benzoquinone), and the like, examples of cholinesterase inhibitor are cognex(R), and the like, and examples of immunomodulator are R), the history(R), Met-enkephalin (6-de-L-arginine-7-de-L-arginine-8-de-L-filenamepattern), WF-10 (10-fold diluted solution of tetrachlorodecaoxide), perton, PRO-542, SCH-D, UK-427857, AMD-070, AK-602, and the like.

In addition, examples are neurotrophin(R), Ledokol(R), ancer 20(R), ampligen(R), anticort(R), inactive(R), Pro-2000, gene Rev M10, HIV-specific cytotoxic T cells (CTL immunotherapy, treatment Protocol 080 ACTG, gene therapy CD4-ζ, SCA-binding protein, complex RBC-CD4, motexafin gadolinium, GEM-92, CNI-1493, (±)-FTC, Ushercell, D2S, buffergel(R), vivagel(R), vaginal gel geminox, sodium lauryl sulfate, 2F5, 3F5/2G12, VRX-496, Ad5gag2, BG-777, IGIV-C, BILR-255, and the like.

“Other anti-HIV agents” and “other substances that are active against HIV”, which are used in policecourtneu combination therapy with a compound of the present invention, are preferably the inhibitor of HIV reverse transcriptase and HIV protease inhibitor. In combination it is possible to apply two or three or even more pharmaceutical agents where one of the preferred embodiments is a combination of pharmaceutical agents that have different mechanisms of action. In addition, the preferred choice of pharmaceutical agents without doubling side effects.

Specific examples of the combination pharmaceutical agents include a combination of the groups is, consisting of efavirenz, tenofovir, emtricitabine, indinavir, nelfinavir, atazanavir, ritonavir + indinavir, ritonavir + lopinavir, ritonavir + saquinavir, didanosine + lamivudine, zidovudine + didanosine, stavudine + didanosine, zidovudine + lamivudine, stavudine + lamivudine and tenofovir+emtricitabine and compounds [1] of the present invention (Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. August 13, 2001). Especially preferred is the combined use of two agents with efavirenz, indinavir, nelfinavir, tenofovir, emtricitabine, zidovudine or lamivudine and combined use of three agents with zidovudine + lamivudine, tenofovir + lamivudine, tenofovir + zidovudine, tenofovir + efavirenz, tenofovir + nelfinavir, tenofovir + indinavir, tenofovir + emtricitabine, emtricitabine + lamivudine, emtricitabine + zidovudine, emtricitabine + efavirenz, emtricitabine + nelfinavir, emtricitabine + indinavir, nelfinavir + lamivudine, nelfinavir + zidovudine, nelfinavir plus efavirenz, nelfinavir + indinavir, efavirenz + lamivudine, efavirenz + zidovudine or efavirenz + indinavir.

In case of a combined administration of the compound of the present invention can be administered simultaneously with the pharmaceutical agent to the th used in combination (hereinafter called drug combination) or you can enter at certain time intervals. In the case of combined introduction you can enter a pharmaceutical composition comprising the compound of the present invention and the drug combination. Alternatively, the pharmaceutical composition comprising the compound of the present invention, and a pharmaceutical composition comprising the drug combination can be entered separately. The way of administration of compounds of the present invention and the way the drug combination may be the same or different.

In case of a combined administration of the compound of the present invention can be injected once a day or several times a day in a dose of from 0.01 mg to 1 g, or you can enter at a lower dose. Drug combinations can be entered at the dose commonly used for prevention or treatment due to HIV infectious diseases, for example, when a single dose of 0.01 mg to 0.3, In the alternative case, it may be administered at a lower dose.

Some examples of the method for obtaining compounds used in the embodiment of the present invention, are shown below. However, the method of obtaining the compounds of the present invention is not limited to these examples.

Even in the absence of a description of the method of obtaining efficient production can be achieved by such developments as the entered the e, when necessary, the protective groups at the functional group with the subsequent removal of protection in a subsequent stage; retention of the functional group in each stage as predecessor and turning this group into the desired functional group in a suitable stage; changing the order of the corresponding production processes and stages; and the like.

The processing in each stage can be a typical way in which the selection and cleaning is performed by the selection means and, when necessary, by combining conventional methods such as crystallization, recrystallization, distillation, distribution, chromatography on silica gel, preparative HPLC and the like.

The method of obtaining 1

where Hal1represents a halogen atom, preferably a bromine atom or an iodine atom, Hal2represents a halogen atom, preferably a fluorine atom or a chlorine atom, RC1and RC2are the same or different and each represents a C1-4alkyl group such as methyl group, ethyl group and the like, R7Arepresents carboxylate group, such as1-4alkyl group (e.g. methyl group, ethyl group etc), benzyl group and the like, RP1is a Hydra is xidawang group, such as acetyl group, methoxycarbonyl group, methoxymethyl group, methoxyethoxymethyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group and the like, and other symbols have the meanings specified above.

Stage 1

Compound [3] can be obtained from compound [2] the common halogenoalkanes.

For example, the compound [3] can be obtained by reaction of the compound [2] with a halogenation agent such as bromine, N-bromosuccinimide, N-iodosuccinimide and the like in the condition from cooling to heating in a solvent such as triftormetilfullerenov acid, acetic acid, sulfuric acid, dimethylformamide and the like.

Stage 2

Gelegenheid acid can be obtained from compound [3] according to the conventional method, for example, by reaction of the compound [3] with a halogenation agent such as oxalicacid, thionyl chloride and the like, under conditions of from cooling to heating in a solvent such as a hydrocarbon solvent (e.g. toluene, xylene, etc.); halogenated hydrocarbon solvent (e.g. dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.); ester solvent (e.g. ethyl acetate, etc. and the like.

For example, when halogenic the existing agent used thionyl chloride, you can add a catalytic amount of dimethylformamide.

Connection [6] can be obtained by reaction of gelegenheid acid with the compound [4] in a solvent under conditions from room temperature to heating in the presence of a base, such as triethylamine, diisopropylethylamine, potassium carbonate, pyridine and the like, and reaction of the resulting compound with the compound [5] in terms of from room temperature to heating. Connection [6] can be E-form, Z-form or mixtures thereof.

As a solvent, you can specify a hydrocarbon solvent such as benzene, toluene, hexane, xylene and the like; halogenated hydrocarbon solvent, such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; the solvent in the form of simple ether such as 1,4-dioxane, diethyl simple ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; a polar solvent, such as acetonitrile and the like; ester solvent such as ethyl acetate and the like; and their mixed solvent, and the like.

Alternatively, the compound [6] can also be obtained by reaction of gelegenheid acid with ethylmalonate and dimethylacetal of dimethylformamide in two stages instead of the reaction with the compound [4] and reaction of the resulting compound with the compound [5].

Stage 3

The compound [7] can be obtained by cyclization of compound [6] in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, tert-piperonyl potassium, sodium hydride, potassium hydride and the like, in a solvent.

As one of the preferred methods of obtaining the compound [7] can be obtained by cyclization of compound [6] in terms of from room temperature to heating in a solvent in the presence of 1,8-diazabicyclo[5.4.0]-7-undecene.

As a solvent, you can specify a hydrocarbon solvent such as benzene, toluene, hexane, xylene and the like; halogenated hydrocarbon solvent, such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; the solvent in the form of simple ether such as 1,4-dioxane, diethyl simple ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; a polar solvent such as dimethylformamide, dimethylsulfoxide, acetonitrile and the like; and their mixed solvent, and the like.

Stage 4

The compound [8] can be obtained by transformation of compounds [7] reaction alkoxysilane introduction to R2according to the conventional method.

For example, when R2represents-OR11'(where R11'represents a C1-4Alki is inuu group), the compound [8] can be obtained by reaction of the compound [7] with the alkoxide of the metal when heated in an alcohol solvent such as methanol, ethanol, propanol, butanol and the like.

Apply the solvent and the metal alkoxide corresponding to the desired alkoxygroup. When R2represents a methoxy group, the reaction may be carried out with sodium methoxide or potassium methoxide in methanol solvent. When R2is ethoxypropan, the reaction may be carried out with ethoxide sodium or ethoxide potassium in the ethanol solvent.

The compound [8] can also be obtained without this stage the use of compounds in which the fluorine atom compounds [2] or the compound [3] is replaced by R2.

Stage 5

Compound [9] can be obtained by introducing a protective group into the hydroxyl group of compound [8] according to the conventional method.

Alternatively, compound [9] can also be obtained by introducing a protective group into the hydroxyl group of compound [6] according to the conventional method, by cyclization of the resulting compound in the same way as in stage 3, and alkoxysilanes formed the connection in the same way as in stage 4.

For example, when RP1represents a tert-butyldimethylsilyloxy group, compound [8] can be subjected to reaction with tert-butyl is metilsalicilata in the solvent dimethylformamide or toluene in the presence of imidazole at room temperature.

When RP1represents methoxycarbonyl group, compound [8] can be subjected to reaction with methylcarbonate in the solvent chloroform in the presence of pyridine while cooling to room temperature.

In the present production method of compound [3], compound [6], the compound [7], the compound [8] and the compound [9], in which R2represents a hydrogen atom or a methoxy group, can also be obtained by using compounds in which the fluorine atom of the compound [2] is replaced by a hydrogen atom or a methoxy group instead of compound [2].

The method of obtaining 2

where Hal represents a halogen atom such as chlorine atom, bromine atom and the like, -IN(ORC3)(ORC4) represents-B(OH)2In(och3)2- (Och(CH3)2, 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-ilen group, 5,5-dimethyl-1,3,2-dioxaborinane-2-ilen group and the like, and other symbols have the meanings specified above.

Stage 1

The compound [10] can be obtained by reaction of the compound [9] with pinacolborane, the ester of boric acid or ester derivative of Debora in the presence of a base and a catalyst in an atmosphere of argon or nitrogen and when heated.

As the ester derivative of Debora you can specify bis(neopentylglycol)dibor, bis(pinako is held)of LIBOR and the like.

As a catalyst it is possible to specify a palladium catalyst such as Pd(PPh3)4, PdCl2(dppb), PdCl2(dppf), PdCl2(dppf)CH2Cl2, PdCl2(PPh3)2Pd(OAc)2, PdCl2, palladium black, palladium on coal and the like.

As grounds usually indicate Ethylenediamine, sodium carbonate, barium hydroxide, potassium phosphate, cesium carbonate, sodium hydrogen carbonate, tert-piperonyl sodium tert-piperonyl potassium, triethylamine, potassium acetate and the like.

As a ligand can be added triphenylphosphine, tri-(2-tolyl)phosphine, 2-(dicyclohexylphosphino)biphenyl and the like.

Alternatively, compound [9] can be subjected to interaction with the ester of boric acid, such as triisopropylsilyl, trimethylboron and the like, in the presence of n-utility.

As a solvent, you can specify the sulfoxide, 1,4-dioxane, tetrahydrofuran, toluene, 1,2-dimethoxyethane, water and the like.

Stage 2

The compound [12] can be obtained by Suzuki reaction of compound [10] with the compound [11].

For example, compound [12] can be obtained by reaction of the compound [10] with the compound [11] in a solvent such as dimethylformamide, acetonitrile, an alcoholic solvent (e.g. methanol, ethanol etc), 1,2-dimethoxyethane, tetrahydrofuran, toluene, water and a mixed solution of the tel and the like, in the presence of a catalyst such as a palladium catalyst (e.g. tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium(II), palladium acetate-triphenylphosphine and so on), Nickel catalyst (e.g., of Nickel chloride, 1,3-bis(diphenylphosphino)propanolol(II)chloride, etc. and in the presence of a base such as sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, triethylamine, sodium phosphate, cesium carbonate and the like, in conditions from room temperature to heating.

Reactivity can be increased by adding lithium chloride and the like.

Stage 3

The compound [I-1] can be obtained by removing hydroxylamino group of compound [12] according to the conventional method.

For example, when RP1represents an acetyl group or methoxycarbonyl group, removing the protective group can be carried out by processing, such as heating compound [12] with concentrated hydrochloric acid; heating the compounds [12] in concentrated ammonium and the like.

For example, when RP1represents a tert-butyldimethylsilyloxy group, removing the protective group can be performed by means of the process of joining [12] tetrabutylammonium fluoride in tetrahydrofuran at room temperature is round; treatment of compound [12] with sodium hydroxide in tetrahydrofuran; treating compound [12] a mixture of acetic acid-water-tetrahydrofuran in conditions from room temperature to heating, and the like.

When RP1represents an acetyl group or methoxycarbonyl group, compound [I-2] can be obtained by reaction of the compound [12] with a base such as sodium hydroxide, potassium hydroxide and the like, under heating.

Stage 4

The compound [I-2] can be obtained by hydrolysis of compound [I-1] in a solvent under conditions from room temperature to heating in basic conditions, such as with the use of sodium hydroxide, potassium hydroxide, lithium hydroxide and the like, or in acidic conditions, such as with the use of hydrochloric acid, sulfuric acid, and the like.

As a solvent, you can specify an alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol and the like; a hydrocarbon solvent such as benzene, toluene, hexane, xylene and the like; the solvent in the form of simple ether such as 1,4-dioxane, diethyl simple ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; water; a mixed solvent and the like.

Stage 5

The compound [46] can be obtained by reaction of 1,2-dibromethane powder zinc dissolve in the when heated, reaction of the resulting compound with trimethylsilylpropyne and adding a solution of compound [11] to the reaction mixture for the reaction.

As a solvent, you can specify the solvent in the form of simple ether such as 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran and the like; a hydrocarbon solvent such as benzene, toluene, hexane, xylene and so on; and the like.

Stage 6

The compound [12] can be obtained by reaction of the compound [46] with the compound [9] in condition from cooling to heating in a solvent in the presence of a catalyst and, when necessary, in the presence of ligand, such as triphenylphosphine, tri-(2-furyl)phosphine and the like.

As a catalyst it is possible to specify a palladium catalyst such as bis(dibenzylideneacetone)palladium, Tris(dibenzylideneacetone)dipalladium, dichlorobis(triphenylphosphine)palladium, dichlorobis(benzonitrile)palladium, dichlorodimethylsilane, palladium acetate, tetrakis(triphenylphosphine)palladium and the like; Nickel catalyst and the like.

As a solvent, you can specify the solvent in the form of simple ether such as 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran and the like; a hydrocarbon solvent such as benzene, toluene, hexane, xylene and so on; and the like.

The method of obtaining 3

The example on the teachings of compound [11]

where Hal3represents a halogen atom, preferably a bromine atom or an iodine atom, RP2represents hydroxylamino group such as acetyl group, methoxycarbonyl group, methoxymethyl group, methoxyethoxymethyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group and the like; ring A' is a ring And containing NH as forming a ring component, such as pyrrolidine, piperidine, piperazine, morpholine, thiomorpholine, isothiazolin, oxazolidin, pyrazolidine and the like, and other symbols have the meanings stated above, provided that the substituent R5must not be associated with the position *.

Stage 1

In the same way as in stage 1 of the method of obtaining 1, the connection [14] can be obtained by halogenoalkanes compounds [13] according to the conventional method.

Stage 2

Connection [15] can be obtained by reduction of compound [14] according to the conventional method.

For example, compound [15] can be obtained by reaction of the compound [14] in condition from cooling to heating in a solvent such as tetrahydrofuran and the like, in the presence of a reducing agent, such as sociallyengaged, sodium borohydride, borane complex-then it is carbonated shall return and the like.

Recovery can also be a way through a mixed anhydride of the acid or way through gelegenheid acid.

Stage 3

In the same way as in stage 5 of the method of obtaining 1, compound [16] can be obtained by introducing a protective group into the hydroxyl group of compound [15] according to the conventional method.

Stage 4

Connection [18] can be obtained by reaction of the compound [16] with the compound [17].

For example, the connection [18] can be obtained by reaction of the compound [16] with the compound [17] in condition from cooling to heating in a solvent in the presence of catalyst and substrate in the atmosphere of argon or nitrogen.

As a catalyst it is possible to specify a palladium catalyst, such as Pd2(dba)3·CHCl3, tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium(II)acetate, palladium, etc.; copper catalyst such as copper chloride, copper(I)bromide copper(I)iodide copper(I) and so on; and the like.

As a basis you can specify the sodium carbonate, potassium carbonate, potassium bicarbonate, sodium bicarbonate, potassium phosphate, triethylamine, potassium fluoride, cesium fluoride, sodium phosphate, cesium carbonate and the like.

When using palladium catalyst, a ligand can be added triphenylphosphine, 2,2'-bis(diphenylphosphino)-1,1'-binaphthalene the like. As a solvent, you can specify dimethylformamide, acetonitrile, an alcoholic solvent (e.g. methanol, ethanol, isopropanol, tert-butanol etc), 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran, toluene, water, a mixed solvent and the like.

When using a copper catalyst, a ligand can be used ethylene glycol; (CH3)2N-(CH2)2-OH; a diamine such as (CH3)2N-(CH2)2-NH2, (CH3)2N-(CH2)2-N(CH3)2CH3NH-(CH2)2-NHCH3and things like that. As a solvent, you can specify dimethylformamide, acetonitrile, an alcoholic solvent (e.g. methanol, ethanol, isopropanol, tert-butanol etc), toluene, xylene and the like.

Stage 5

In the same way as in stage 3 of the method of obtaining 2, the compound [19] can be obtained by removing hydroxylamino group of compound [18] according to the conventional method.

Stage 6

Connection [20] can be obtained by halogenoalkanes hydroxyl group of compound [19] according to the conventional method.

For example, the connection [20] can be obtained by reaction of the compound [19] with a halogenation agent such as thionyl chloride, trichloride phosphorus, tribromide phosphorus complex tetrabromide carbon-triphenylphosphine, N-bromosuccinimide, and the like, the service is under from cooling to room temperature the solvent.

As a solvent, you can specify a halogenated hydrocarbon solvent, such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane, etc.; solvent type simple ether such as 1,4-dioxane, diethyl simple ether, 1,2-dimethoxyethane, tetrahydrofuran, etc.; and the like.

The method of obtaining 4

An example of obtaining compounds [11]

where each symbol has the values listed above.

Stage 1

In the same way as in step 2 of the method of obtaining 2, the connection [22] can be obtained by Suzuki reaction between the compound [16] and the compound [21].

Stage 2

In the same way as in stage 3 of the method of obtaining 2, the connection [23] can be obtained by removing hydroxylamino group compounds [22] according to the conventional method.

Stage 3

In the same way as in stage 6 ways to obtain 3, compound [24] can be obtained by halogenoalkanes hydroxyl group of compound [23] according to the conventional method.

The method of obtaining 5

An example of obtaining compounds [9], where R2represents an ethyl group

where RC5represents carboxylate group, such as1-4alkyl group (e.g. methyl group, ethyl group, etc. and the like, RP3 represents a protective group, such as trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group and the like, and other symbols have the meanings specified above.

Stage 1

Connection [26] can be obtained by introducing a protective group into the carboxyl group of compound [25] according to the conventional method.

For example, compound [26] can be obtained by reaction of the compound [25] with an alkylating agent such as methyliodide and the like, in a solvent such as dimethylformamide, tetrahydrofuran, toluene and the like, in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and the like.

Stage 2

Connection [28] can be obtained by reaction of the compound [26] with the compound [27] in terms of from room temperature to heating in a solvent such as dimethylformamide, acetonitrile, 1,4-dioxane, 1,2-dimethoxyethane, tetrahydrofuran, toluene, water and the like, in the presence of a catalyst such as a palladium catalyst (e.g. tetrakis(triphenylphosphine)palladium, dichlorobis(triphenylphosphine)palladium(II)complex of palladium acetate-triphenylphosphine and the like), a copper catalyst (e.g. copper chloride(I), and the like) or their mixture, in the presence of a base such as potassium carbonate, bicarbonate Kali is, sodium bicarbonate, potassium phosphate, triethylamine and the like.

Stage 3

Connection [29] can be obtained by removing the protective group RP3connections [28]according to the conventional method.

For example, when RP3represents trimethylsilyl group, tert-butyldimethylsilyloxy group or tert-butyldiphenylsilyl group, compound [29] can be obtained by means of processing compounds [28] tetrabutylammonium fluoride in tetrahydrofuran while cooling to room temperature, the processing of compounds [28] sodium hydroxide in tetrahydrofuran; treating compound [28] a mixture of acetic acid-water-tetrahydrofuran in conditions from room temperature to heating, and the like.

Stage 4

Connection [30] can be obtained by reduction of compound [29] according to the conventional method such as catalytic reduction in a hydrogen atmosphere, and the like.

For example, compound [30] can be obtained by reaction of the compound [29] in a solvent such as tetrahydrofuran, methanol, ethyl acetate, a mixed solvent and the like, in the presence of a catalyst such as palladium on coal and the like, in an atmosphere of hydrogen at room temperature.

Stage 5

In the same way as in stage 1 of the method of obtaining 1, compound [31] you will get what halogenoalkanes compounds [30] according to the conventional method.

Stage 6

In the same way as in stage 4 of the method of obtaining 2, compound [32] can be obtained by removing carboxylamide group compounds [31] according to the conventional method.

Stage 7

In the same way as in step 2 of the method of obtaining 1, compound [33] can be obtained by reaction of the compound [32] with the compound [4] and reaction of the resulting compound with the compound [5].

Stage 8

In the same way as in stage 3 of the method of obtaining 1, compound [34] can be obtained by cyclization of compounds [33].

Stage 9

In the same way as in stage 5 of the method of obtaining 1, compound [35] can be obtained by introducing a protective group into the hydroxyl group of compound [34].

The method of obtaining 6

where RP4represents aminosidine group, such as benzoline group, tert-bucilina group, tert-butylcellosolve group, tert-butoxycarbonyl group and the like, and other symbols have the meanings stated above, provided that the substituent R5must not be associated with the position *.

Stage 1

Connection [36] can be obtained by nitration of compounds [13] according to the conventional method.

For example, compound [36] can be obtained by nitration of compounds [13] nitrious agent (such as nitric acid, fuming nitric sour is Oh, concentrated nitric acid mixed with concentrated sulfuric acid, and the like) when cooled to room temperature.

Stage 2

In the same way as in step 2 of the method of obtaining 3, compound [37] can be obtained by reduction of compound [36] the common way.

Stage 3

Connection [38] can be obtained according to the conventional method, such as reconnection [37] zinc, or iron in a neutral or alkaline conditions; iron and acid; tin or tin chloride(II) and concentrated hydrochloric acid; the alkali metal sulfide; hydrosulfite in alkaline conditions, and the like, by the catalytic hydrogenation of compounds [37] in the atmosphere of hydrogen, and the like.

For example, compound [38] can be obtained by reaction of the compound [37] with reduced iron and ammonium chloride in a solvent such as ethanol, tetrahydrofuran, water, a mixed solvent and the like, in conditions from room temperature to heating. Alternatively, the compound [38] can be obtained by adding acetic acid and powdered zinc to the compound [37] when the cooling for the reaction at room temperature. Alternatively, the compound [38] can be obtained by reaction of the compound [37] in the presence of a catalyst, such as PA is lady coal and the like, in a solvent such as tetrahydrofuran, methanol, ethyl acetate, a mixed solvent and the like, in an atmosphere of hydrogen at room temperature.

Stage 4

Connection [39] can be obtained by introducing a protective group into the amino group of compound [38] according to the conventional method.

For example, when RP4represents a tert-butoxycarbonyl group, compound [39] can be obtained by reaction of the compound [38] with di-tert-BUTYLCARBAMATE in conditions from room temperature to heating in a solvent such as tetrahydrofuran and the like.

Stage 5

In the same way as in stage 6 ways to obtain 3, compound [40] can be obtained by halogenoalkanes hydroxyl group of compound [39] according to the conventional method.

The method of obtaining 7

where Q represents-CO-, -COO - or-SO2-, p is an integer 2-4, and other symbols have the meanings specified above.

Stage 1

In the same way as in step 2 of the method of obtaining 2, the compound [41] can be obtained by Suzuki reaction between the compound [10] and the compound [40].

Stage 2

Connection [42] can be obtained by removing aminosidine group of compound [41] according to the conventional method.

For example, when RP4present is employed, a tert-butoxycarbonyl group, the removal of the protective group can be performed by means of the treating compound [41] in ethyl acetate solution of hydrochloric acid in ethyl acetate at room temperature; processing the compound [41] hydrochloric acid in tetrahydrofuran at room temperature; processing the compound [41] in 1,4-dioxane solution of hydrochloric acid in 1,4-dioxane at room temperature; processing solution of compound [41] in chloroform triperoxonane acid and the like.

Stage 3

The compound [44] can be obtained by reaction of the compound [42] with the compound [43] in condition from cooling to heating in a solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, chloroform, ethyl acetate, toluene and the like, in the presence of a base, such as triethylamine, potassium carbonate, pyridine, 4-(dimethylamino)pyridine and the like.

Stage 4

Connection [45] can be obtained by cyclization of compounds [44] in condition from cooling to heating in a solvent such as dimethylformamide, acetonitrile, tetrahydrofuran, toluene and the like, in the presence of a base such as sodium carbonate, potassium carbonate, triethylamine, tert-piperonyl potassium, sodium hydride, potassium hydride and the like.

Stage 5

In the same way as in stage 3 receive mode 2, connect the s [I-3] can be obtained by removing hydroxylamino group of compound [45] according to the conventional method.

Stage 6

In the same way as in stage 4 of the method of obtaining 2, compound [I-4] can be obtained by removing carboxylamide group of compound [I-3] according to the conventional method.

EXAMPLES

Further, a derivative of 4-oxacilin represented by the formula [1] of the present invention, its pharmaceutically acceptable salt or MES and the retrieval method is specifically explained by means of examples, which should not be construed as restrictive.

Example 1

Stage 1

3-Chloro-2-fermenting acid (25,00 g, 143,21 mmol) is dissolved in concentrated sulfuric acid (100 ml) and at 5°C or lower portions add N-iodosuccinimide (32,20 g, 143,21 mmol). After complete addition, the mixture was stirred at the same temperature for 3 hours and at room temperature for 13 hours. The reaction mixture was poured into ice water (500 ml), add sodium sulfite (of 14.90 g, 143,19 mmol) and after stirring the precipitated solid is collected by filtration and washed with water. The obtained solid is dried under reduced pressure at 65°C for 8 hours, thus obtaining the target compound (41,02 g, yield 95%) as a light brown solid.

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: of 8.06 (1H, DD, J=6,1, 2.2 Hz), by 8.22 (1H, DD, J=6,4, 2,2 Hz).

MS (ESI): M - 299./p>

Stage 2

The compound (2.00 g, of 6.66 mmol), obtained in stage 1, was dissolved in tetrahydrofuran (10 ml). In a stream of nitrogen at 0°C is added dropwise a 1.0 M solution of the complex of borane-tetrahydrofuran in tetrahydrofuran (20,00 ml, 20.00 mmol). After completion of adding dropwise, the mixture is heated to room temperature, stirred for 2 hours and heated to boiling under reflux for 2 hours. Under ice cooling to the reaction mixture are added dropwise 2n. hydrochloric acid (11 ml) and after stirring the mixture extracted with ethyl acetate. The organic layer is washed with water, saturated aqueous sodium bicarbonate, water and saturated salt solution in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 6:1-5:1), thus obtaining the desired compound (1.70 g, yield 89%) as a white solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 1,83-of 1.84 (1H, m), 4,74 was 4.76 (2H, m), 7,65-of 7.70 (2H, m).

Stage 3

The compound (1.70 g, to 5.93 mmol), obtained in stage 2, was dissolved in dimethylformamide (17 ml), add imidazole (606 mg, of 8.90 mmol) and tert-butyldimethylsilyl (1.07 g, 7,10 m is ol) and the mixture is stirred at room temperature for 3 hours. To the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (only hexane), thus obtaining the desired compound (2,31 g, yield 97%) as a colourless oil.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 0,12 (6H, s)of 0.95 (9H, s), 4,74 (2H, s), 7,60 to 7.62 (1H, m), 7.68 per-of 7.69 (1H, m).

Stage 4

The palladium(II) acetate (448 mg, 2.00 mmol), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphthalene (2,49 g, 4.00 mmol) and cesium carbonate (9,76 g, 29,96 mmol) are added to 1,4-dioxane (40 ml) and a solution of the compound (8.00 g, 19,96 mmol), obtained in stage 3, and the research (2,62 ml, 29,95 mmol) in tert-butanol (40 ml) is added dropwise to the above mixture washed with 1,4-dioxane (40 ml)) in an argon atmosphere. The mixture is heated at the boil under reflux for 24 hours. After submitting the reaction mixture opportunities for cooling, water is added and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution in a specified sequence, and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure and obtained the STATCOM purify by chromatography on silica gel (hexane:ethyl acetate = 8:1), while receiving the desired compound (4,29 g, yield 60%).

1H NMR (CDCl3, 400 MHz) (δ) ppm: 0,12 (6H, s)of 0.95 (9H, s), is 3.08-3,10 (4H, m), 3,84-3,86 (4H, m), was 4.76 (2H, s), 6,79 (1H, DD, J=5,9, 3.1 Hz), to 6.95 (1H, DD, J=5,4, 3.1 Hz).

Stage 5

The compound (537 mg, 1,49 mmol)obtained in stage 4, was dissolved in tetrahydrofuran (1 ml), add 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (2,99 ml, 2,99 mmol) and the mixture is stirred at room temperature for 2 hours. To the reaction mixture are added water and ethyl acetate, the layers separated and the organic layer was washed with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 1:1), thus obtaining the desired compound (308 mg, yield 84%) as a beige solid.

1H NMR (CDCl3, 300 MHz) (δ) ppm: 1,90 (1H, t, J=6.0 Hz), is 3.08-of 3.12 (4H, m), 3,83-3,86 (4H, m), 4,74 (2H, d, J=6.0 Hz), 6,83 (1H, DD, J=6,0, 3.0 Hz), to 6.88 (1H, DD, J=5,3, 3,0 Hz).

MS (ESI): M+246.

Stage 6

Connection (1,00 g, 4.07 mmol), obtained in stage 5, is dissolved in chloroform (10 ml) and added 3 mmol/g of triphenylphosphine resin (2,04 g, 6,11 mmol). In addition, while cooling with ice add N-bromosuccinimide (2,03 g, 6,11 mmol) and the mixture was stirred at ControlTemplate for 40 minutes The reaction mixture is filtered and the filtrate concentrated under reduced pressure. The resulting residue is purified by chromatography on silica gel (hexane:ethyl acetate = 4:1), thus obtaining the desired compound (1.10 g, yield 88%) as a white solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 3,09-3,11 (4H, m), 3,83-3,86 (4H, m), 4,46 (2H, d, J=1.2 Hz), 6,79 (1H, DD, J=5,4, 3.1 Hz), 6,86 (1H, DD, J=6,0, 3,0 Hz).

Stage 7

Boc-D-Ser(Bzl)-ol (Boc-O-benzyl-D-serinol)(10,00 g, 35,54 mmol) dissolved in toluene (50 ml), add hydrosulphate of Tetra-n-butylamine (1.28 g, of 3.56 mmol), 8h. an aqueous solution of sodium hydroxide (50 ml) and bromate (of 7.96 ml, 106,65 mmol) and the mixture is stirred at room temperature for 20 hours. Add bromatan (2.65 ml, 35,54 mmol) and the mixture is additionally stirred at room temperature for 3.5 hours. The reaction mixture is extracted with toluene and the organic layer was washed with saturated salt solution and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 4:1), thus obtaining the desired compound (10,49 g, yield 95%).

1H NMR (CDCl3, 400 MHz) (δ) ppm: 1,17 (3H, t, J=7,1 Hz)of 1.44 (9H, s), 3,49 is 3.57 (6H, m), 3,90-to 3.92 (1H, m), a 4.53 (2H, s), 4.92 in-4,94 (1H, m), 7,27-7,37 (5H, m).

Stage 8

The connection is giving (10,49 g, 33,90 mmol)obtained in stage 7, is dissolved in methanol (100 ml), add 4,5% palladium on coal (1.10 g), under normal pressure is added to the hydrogen and the mixture is stirred at room temperature for 1.5 hour. The reaction mixture was filtered through celite and the filtrate concentrated under reduced pressure, thus obtaining the crude product (8.06 g).

1H NMR (CDCl3, 300 MHz) (δ) ppm: of 1.20 (3H, t, J=7.2 Hz), of 1.46 (9H, s), was 2.76-2,78 (1H, m), 3,47-3,84 (7H, m), 5,17-5,22 (1H, m).

Stage 9

The crude product (8.06 g)obtained in stage 8, was dissolved in 1,4-dioxane (20 ml), add 4n. a solution of hydrochloric acid in 1,4-dioxane (34 ml, 136 mmol) and the mixture is stirred at room temperature for 3.5 hours. The reaction mixture was concentrated under reduced pressure, thus obtaining the crude product (5,86 g).

1H NMR (CDCl3, 400 MHz) (δ) ppm: to 1.21 (3H, t, J=7.0 Hz), 3,53-3,61 (2H, m), 3,69-3,71 (3H, m), 3,89-of 3.94 (2H, m), 8,04 (3H, users).

MS (ESI): M+120 (free connection).

Stage 10

4-Bromo-2-fermenting acid (25,24 g, 115,24 mmol) dissolved in dimethylformamide (300 ml), add potassium carbonate (23,89 g, 172,86 mmol), followed by cooling with ice add itmean (was 9.33 ml, 149,81 mmol) and the mixture is stirred at room temperature for 4 hours. The reaction mixture is added to water, the content is soup acetic acid (15 ml), and the mixture is extracted three times with ethyl acetate. The organic layer was washed with water (four times) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining the crude product (of 24.90 g) as a pale yellow solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 3,93 (3H, s), 7,33-7,38 (2H, m), 7,82 (1H, DD, J=7,7, 8.6 Hz).

Stage 11

The crude product (2.50 g)obtained in stage 10, is dissolved in 1,4-dioxane (20 ml), add triethylamine (20 ml), trimethylsilylacetamide (1.97 ml, to 13.95 mmol), dichlorobis(triphenylphosphine)palladium(II) (377 mg, 0,537 mmol) and copper iodide(I) (61 mg, 0,322 mmol) in a specified sequence, and the mixture is further stirred under heating at 60°C for 1 hour. After allowing to cool, the reaction mixture was filtered through celite, washed with diethyl simple ether and the filtrate concentrated under reduced pressure. To the obtained residue is added ethyl acetate and water, the layers separated and the aqueous layer was extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified is by chromatography on silica gel (hexane:ethyl acetate = 15:1), while receiving the desired compound (3.04 from g, yield quantitative stage 2) in the form of a yellow oil.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 0,26 (9H, s), 3,93 (3H, s), 7,20-7,28 (2H, m), 7,87 (1H, DD, J=7,7, 7,7 Hz).

Stage 12

Connection (2,46 g, 9,81 mmol)obtained in stage 11, is dissolved in tetrahydrofuran (25 ml). At 0°C. add water (353 μl, being 9.61 mmol) and 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (490 μl, 0,490 mmol) and the mixture was stirred at the same temperature for 30 minutes To the reaction mixture are added water and ethyl acetate and the layers separated. The organic layer was washed with water (twice) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 10:1), thus obtaining the desired compound (1.52 g, yield 91%) as a light brown solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 3,26 (1H, s), of 3.94 (3H, s), 7.24 to 7,33 (2H, m), of 7.90 (1H, DD, J=7,8, 7,8 Hz).

Stage 13

Connection (2,23 g of 12.53 mmol)obtained in stage 12, dissolved in ethyl acetate (20 ml), add 5% palladium on coal (wet) (200 mg), introducing hydrogen at normal pressure and the mixture is stirred at room temperature is within 22 hours. The reaction mixture was filtered through celite, the filtrate concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 20:1 to 15:1), thus obtaining the desired compound (1,94 g, yield 85%) as a colourless oil.

1H NMR (CDCl3, 400 MHz) (δ) ppm: to 1.25 (3H, t, J=7,6 Hz), 2,69 (2H, q, J=7,6 Hz)to 3.92 (3H, s), 6,95? 7.04 baby mortality (2H, m), a 7.85 (1H, DD, J=7,8, 7,8 Hz).

Stage 14

Connection (1,94 g, 10,65 mmol)obtained in stage 13, is dissolved in concentrated sulfuric acid (15 ml) and under ice cooling in the form of portions add N-iodosuccinimide (2,40 g, 10,67 mmol). The mixture is stirred under ice cooling for 20 min and at room temperature for 2 hours. Add N-iodosuccinimide (120 mg, 0,532 mmol) and the mixture is stirred at room temperature for 30 minutes, the Reaction mixture was poured into ice water containing sodium sulfite (2.0 g, a trend of 15.87 mmol), and after mixing, the mixture is extracted with ethyl acetate. The organic layer was washed with water (three times) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane to a mixture of hexane:ethyl acetate = 15:1), thus obtaining the desired compound (3,20 g, yield 98%) in the ideal colorless solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: of 1.23 (3H, t, J=7.5 Hz), 2,73 (2H, q, J=7.5 Hz), to 3.92 (3H, s), 7,02 (1H, d, J=11.8 Hz), 8,35 (1H, d, J=7,2 Hz).

Stage 15

Connection (3,20 g, accounted for 10.39 mmol)obtained in stage 14, is dissolved in tetrahydrofuran (10 ml) and methanol (10 ml), add 4n. an aqueous solution of sodium hydroxide (5,20 ml, 20,77 mmol) and the mixture is stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, to the residue add 6N. hydrochloric acid and ethyl acetate and the layers separated. The aqueous layer was extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution in a specified sequence, and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining the crude product (3.03 g) as a white solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: to 1.25 (3H, t, J=7.5 Hz), was 2.76 (2H, q, J=7.5 Hz), 7,06 (1H, d, J=11.8 Hz), 8,44 (1H, d, J=7,2 Hz).

Stage 16

The crude product (2,84 g)obtained in stage 15, is dissolved in toluene (30 ml), add thionyl chloride (1,06 ml, 14,49 mmol) and dimethylformamide (catalytic amount) and the mixture is stirred under heating at 100°C for 2 hours. After allowing to cool, the reaction mixture is concentrated the ri reduced pressure and twice subjected to azeotropic distillation with toluene. The resulting residue is dissolved in toluene (15 ml) and the solution added dropwise to a solution of ethyl-3-(dimethylamino)acrylate (1.45 g, 10,14 mmol) and diisopropylethylamine (2,19 ml, 12,56 mmol) in toluene (15 ml) and the mixture is stirred under heating at 90°C for 14 hours. After allowing to cool to the reaction mixture, water is added, the layers separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water (twice) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 1:1-1:2), thus obtaining the desired compound (2.85 g, yield 70%, stage 2) in the form of a yellow-brown oil.

1H NMR (CDCl3, 400 MHz) (δ) ppm: to 0.96 (3H, t, J=7,1 Hz)of 1.20 (3H, t, J=7.5 Hz), 2,71 (2H, q, J=7.5 Hz), is 2.88 (3H, users), 3,29 (3H, users), of 4.00 (2H, q, J=7,1 Hz), make 6.90 (1H, d, J=11,4 Hz), 7,76 (1H, s), 8,02 (1H, users).

Stage 17

The triethylamine (349 μl, 2.51 mmol) and the crude product (312 mg)obtained in stage 9, dissolved in chloroform, add the compound (700 mg, 1,67 mmol)obtained in stage 16, and the mixture is stirred at room temperature for 1.5 hour. The reaction mixture was concentrated under reduced pressure. The resulting residue is dissolved is in ethylacetate, washed with water (twice) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining the crude product (898 mg) as a pale yellow oil.

Stage 18

The crude product (898 mg)obtained in stage 17, dissolved in dimethylformamide (8 ml), add potassium carbonate (692 mg, free 5.01 mmol) and the mixture is stirred under heating at 80°C for 21 hours. After allowing to cool to the reaction mixture are added water and ethyl acetate, the layers separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water (three times) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining the crude product (758 mg) as a white solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 1,17 (3H, t, J=6.9 Hz), is 1.31 (3H, t, J=7.5 Hz), of 1.40 (3H, t, J=7.2 Hz), 2,84-a 3.01 (2H, m), 3,50-3,62 (2H, m), 3,97-4,08 (2H, m), 4,11-4,18 (1H, m), 4.26 deaths-to 4.41 (3H, m), 4,81-4,88 (1H, m), 5,62 (1H, t, J=6.9 Hz), 7,37 (1H, s), 7,98 (1H, s), 8,61 (1H, s).

Stage 19

The crude product (758 mg)obtained in stage 18, is dissolved in dimethylformamide (8 ml), added imidazole (171 mg, 2.51 mmol) and tert-b is sildenafilcitrate (302 mg, 2.00 mmol) and the mixture is stirred at room temperature for 1 hour. To the reaction mixture are added water and ethyl acetate, the layers separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water (three times) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 2:3), thus obtaining the desired compound (820 mg, yield 84%, 3 phase) as a colourless oil.

1H NMR (CDCl3, 400 MHz) (δ) ppm: -0,02 (3H, s)-0,01 (3H, s)of 0.82 (9H, s)of 1.20 (3H, t, J=7,0 Hz)of 1.28 (3H, t, J=7.5 Hz), of 1.40 (3H, t, J=7.2 Hz), 2,85 (2H, q, J=7.5 Hz), of 3.54 (2H, q, J=7.0 Hz), with 3.89 (2H, d, J=5.3 Hz), Android 4.04 (2H, d, J=4.9 Hz), 4,34 was 4.42 (2H, m), 4.75 V-to 4.81 (1H, m), 7,38 (1H, s), a total of 8.74 (1H, s), of 8.95 (1H, s).

Stage 20

The compound (100 mg, 0,170 mmol)obtained in stage 19, was dissolved in 1,4-dioxane (1 ml), add palladium(II) acetate (2 mg, 0,0085 mmol), 2-(dicyclohexylphosphino)biphenyl (12 mg, 0,034 mmol), triethylamine (95 μl, of 0.68 mmol) and 1 M solution of pinacolborane in tetrahydrofuran (511 μl, 0,511 mmol) in a specified sequence, and the mixture is stirred under heating at 80°C for 1 hour. After submitting the reaction mixture opportunities for cooling there was added a saturated aqueous solution of chloride of shumilkin) and ethyl acetate the layers are separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water (three times) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 1:2), thus obtaining the desired compound (70 mg, yield 70%) as a colourless oil.

1H NMR (CDCl3, 400 MHz) (δ) ppm: -0,02 (6H, s), or 0.83 (9H, s)of 1.20 (3H, t, J=7,1 Hz)of 1.24 (3H, t, J=7.4 Hz), of 1.35 (12H, s)of 1.40 (3H, t, J=7.2 Hz), 3,03 (2H, DQC, J=1,6, 7,4 Hz), of 3.54 (2H, q, J=7,1 Hz), 3,90 (2H, d, J=5.6 Hz), 4,00-4,08 (2H, m), 4,37 (2H, DQC, J=2,0, 7,2 Hz), 4,79-is 4.85 (1H, m), 7,28 (1H, s), to 8.70 (1H, s), of 8.95 (1H, s).

Stage 21

The compound (70 mg, 0,119 mmol)obtained in stage 20, and the compound (44 mg, 0,143 mmol)obtained in stage 6, is dissolved in 1,2-dimethoxyethane (1.5 ml), added tetrakis(triphenylphosphine)palladium(0) (7 mg, 0,006 mmol) and 2 M aqueous sodium carbonate solution (240 μl, to 0.480 mmol) and the mixture is stirred under heating at 80°C for 50 minutes After submitting the reaction mixture opportunities for cooling there was added water and ethyl acetate and the layers separated. The organic layer was washed with water (three times) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate concentrate is their under reduced pressure and the resulting residue purified preparative thin-layer chromatography (PTSH) (hexane:ethyl acetate = 1:3), while receiving the desired compound (66 mg as not purified product as a colorless oil.

1H NMR (CDCl3, 400 MHz) (δ) ppm: -0,03 (3H, s)-0,02 (3H, s)of 0.82 (9H, s)to 1.21 (3H, t, J=7,0 Hz)of 1.23 (3H, t, J=7,6 Hz)of 1.40 (3H, t, J=7.0 Hz), 2,73 (2H, q, J=7,6 Hz), 2,96 (4H, t, J=4.9 Hz), of 3.56 (2H, q, J=7,0 Hz), 3,76 (4H, t, J=4.9 Hz), 3,91 (2H, d, J=5.3 Hz), of 4.05 (2H, d, J=4.9 Hz), 4.09 to (2H, s), 4,35 was 4.42 (2H, m), 4.80 to to 4.87 (1H, m), 6,40-6.42 per (1H, m), 6,74-6,76 (1H, m), of 7.36 (1H, s), 8,31 (1H, s), a total of 8.74 (1H, ).

Stage 22

Compound (66 mg)obtained in stage 21, dissolved in tetrahydrofuran (1 ml), add 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (144 μl, 0.144 mmol) and the mixture is stirred at room temperature for 40 minutes To the reaction mixture are added water and ethyl acetate, the layers separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water (three times) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified (PTSH) (chloroform:methanol = 15:1), thus obtaining the desired compound (53 mg, yield 77%, stage 2) in the form of a colorless oil.

1H NMR (CDCl3, 400 MHz) (δ) ppm: to 1.21 (3H, t, J=7.2 Hz), to 1.22 (3H, t, J=7.5 Hz), of 1.41 (3H, t, J=7,1 Hz), 2,63-of 2.81 (2H, m), is 2.88 (4H, t, J=4,7 Hz), 3,56-3,63 (2H, m), and 3.72 (4H, t, J=4,7 Hz), 3,98-was 4.02 (1H, m), 4,06-4,18 (4H, m), 4,28-4,43 (3H, m), 4,54-4,69 (1H, m), 4,86-492 (1H, m), 6,15-6,18 (1H, m), of 6.71-6.73 x (1H, m), 7,37 (1H, s), 7,66 (1H, s), 8,68 (1H, s).

Stage 23

Compound (53 mg, 0,092 mmol)obtained in stage 22, is dissolved in a mixed solvent of tetrahydrofuran (1 ml) and water (0.2 ml), add the monohydrate of lithium hydroxide (8 mg, 0.2 mmol) and the mixture is stirred at room temperature for 3 hours. The reaction mixture was acidified with aqueous citric acid solution. The precipitated solid is collected by filtration, washed with water and dried under reduced pressure, thus obtaining the desired compound (46 mg, yield 91%) as a white solid.

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: of 1.03 (3H, t, J=7,0 Hz)of 1.26 (3H, t, J=7.5 Hz), only 2.91 (2H, q, J=7.5 Hz), is 3.08 (4H, t, J=4.9 Hz), of 3.46 (2H, q, J=7.0 Hz), 3,71 (4H, t, J=4.9 Hz), 3,85-4,01 (4H, m), 4,20 (2H, s), 5,27 (1H, t, J=5.4 Hz), 5,33-5,41 (1H, m), 6,91-6,93 (1H, m), 7.03 is-7,05 (1H, m), of 7.96 (1H, s), 8,02 (1H, s), of 8.90 (1H, s), 15,21 (1H, s).

MS (ESI): M+547.

Example 2

Stage 1

3-Chloro-2-fermenting acid (5,00 g, 28,64 mmol) is dissolved in concentrated sulfuric acid (15 ml)under ice cooling are added dropwise nitric acid (1.50 ml, 31,50 mmol) and the mixture is stirred at room temperature for 19 hours. The reaction mixture was poured into ice water (200 ml) and after stirring the precipitated solid is collected by filtration and washed with water. P the obtained solid substance was dissolved in ethyl acetate, washed with water and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining the desired compound (4,81 g, yield 76%) as a pale orange solid.

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: 8,54 (1H, DD, J=5,7, 2,9 Hz), a total of 8.74 (1H, DD, J=5,8, 2,8 Hz), 14,25 (1H, users).

Stage 2

The compound (500 mg, 2.28 mmol), obtained in stage 1, was dissolved in tetrahydrofuran (5 ml)dropwise while cooling in a stream of argon added triethylamine (MX 0.317 ml, 2.28 mmol) and isobutylparaben (0,296 ml, 2.28 mmol) and the mixture was stirred at the same temperature for 25 minutes, the Reaction mixture was filtered and washed with tetrahydrofuran (5 ml). The filtrate is cooled with ice, add sodium borohydride (129 mg, of 3.42 mmol) and water (1.5 ml) and the mixture was stirred at the same temperature for 25 minutes To the reaction mixture is added saturated aqueous solution of ammonium chloride and a saturated salt solution, the layers separated and the organic layer was washed with saturated salt solution and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 4:1), thus obtaining the desired compound (357 mg, yield 76%) as a light brown oil.

1H NMR (CDCl3, 40 MHz) (δ) ppm: to 2.06 (1H, t, J=6.4 Hz), 4,88 (2H, d, J=6.0 Hz), of 8.27 (1H, DD, J=6,2, 2,9 Hz), at 8.36 (1H, DD, J=5,5, 2,9 Hz).

Stage 3

To a mixture of ethanol (10 ml) and water (5 ml) was added reduced iron (486 mg, to 8.70 mmol) and ammonium chloride (465 mg, to 8.70 mmol). Dropwise at 80°C. add a solution of the compound (357 mg, of 1.74 mmol)obtained in stage 2, in tetrahydrofuran (10 ml) and the mixture is stirred while heating at the same temperature for 20 minutes After allowing to cool, the reaction mixture was filtered through celite and washed with ethyl acetate. The filtrate is washed with water, saturated aqueous sodium hydrogen carbonate and a saturated solution of salt in sequence and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining the crude product (287 mg) as a yellow solid.

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: of 4.44 (2H, d, J=5.8 Hz), 5,20 (2H, users), 5,23 (1H, t, J=5.8 Hz), 6,53 (1H, DD, J=6,0, 2,8 Hz), is 6.61 (1H, DD, J=5,6, 2,8 Hz).

Stage 4

The crude product (287 mg), obtained in stage 3, was dissolved in tetrahydrofuran (3 ml), add di-tert-BUTYLCARBAMATE (418 mg, at 1.91 mmol) and the mixture heated to boiling under reflux for 6 hours. The reaction mixture was concentrated under reduced pressure and obtained the residue purified by chromatography on silica gel (hexane:ethyl acetate = 4:1), while receiving the desired compound (320 mg, yield 67%, stage 2) in the form of a white solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 1,53 (9H, s), 1,89 (1H, t, J=6.3 Hz), and 4.75 (2H, d, J=6.3 Hz), 6,46 (1H, s), 7,26-7,28 (4H, m), 7,51 (1H, DD, J=6.3, in the 2.6 Hz).

Stage 5

The compound (608 mg, 2.21 mmol), obtained in stage 4, is dissolved in chloroform (12 ml), while cooling with ice add 3 mmol/g of triphenylphosphine resin (1,11 g of 3.32 mmol) and N-bromosuccinimide (471 mg, to 2.65 mmol) in a specified sequence, and the mixture is stirred at room temperature for 1.5 hour. To the reaction mixture are added ethanol (26 ml) and the mixture is filtered and washed with chloroform. The filtrate is concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate, washed with water and saturated salt solution in a specified sequence, and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 4:1), thus obtaining the desired compound (369 mg, yield 49%) as a pale yellow solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: of 1.52 (9H, s), to 4.46 (2H, d, J=1.2 Hz), 6,45 (1H, users), 7,31 (1H, DD, J=5,8, 3.0 Hz), 7,46 (1H, DD, J=6,1, 2,4 Hz).

Stage 6

2,4-Differentyou acid (600,00 g of 3.80 mol) of rest the accelerate in concentrated sulfuric acid (2400 ml) and at 5°C or lower portions add N-iodosuccinimide (854,40 g, of 3.60 mol). After complete addition, the mixture was stirred at the same temperature for 3 hours. The reaction mixture was poured into ice-cold water (about 10 l), add 10% aqueous solution of sodium sulfite (40 ml) and the mixture is stirred for 30 minutes the Precipitated solid is collected by filtration, suspended in water (about 3 l) and washed suspensions repeat up until the pH would be 3 or higher. The obtained wet crystals (1677) is recrystallized from a 50% solution of EtOH/water (3000 ml), thus obtaining the desired compound (824,70 g, yield 76%) as a white solid.

1H NMR (CDCl3, 300 MHz) (δ) ppm: 6,94 (1H, DD, J=10,3, 10,3 Hz), 8,46 (1H, d, J=7.5 Hz).

Stage 7

Connection (650,57 g to 2.29 mol), obtained in stage 6, is dissolved in toluene (1300 ml), add thionyl chloride (184 ml, 2,52 mol) and dimethylformamide (catalytic amount) and the mixture was stirred at 90°C for 2 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure and subjected twice to azeotropic distillation with toluene (330 ml). The residue is dissolved in toluene (690 ml)and the solution added dropwise to a solution of ethyl-3-(dimethylamino)acrylate (361,52 g 2,525 mol) and diisopropylethylamine (480 ml of 2.75 mol) in toluene (690 ml), and the mixture is stirred under heating at 90°C for 3 caspase allow for cooling to the reaction mixture (S)-(+)-valinol (260,00 g, 2,52 mol) and the mixture is stirred at room temperature for 1 hour. To the reaction mixture are added water (2600 ml), the layers separated, and the aqueous layer was extracted with toluene (680 ml). The organic layer is washed twice with water (2000 ml) and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining the crude product (1180 g) as a brown oil.

Stage 8

The crude product (1180 g)obtained in stage 7, is dissolved in dimethylformamide (2500 ml), add powdered potassium carbonate (292,00 g, 1.06 mol) and the mixture is stirred at room temperature for 22 hours. The reaction mixture was added to ice water (10 l) and the mixture is stirred for 30 minutes the Precipitated solid is collected by filtration and washed with water (2000 ml). The obtained solid is dried under reduced pressure, suspended in ethyl acetate (5000 ml) and the suspension is subjected to washing. After filtration, the filtrate is dried under reduced pressure, thus obtaining the desired compound (774,63 g, yield 82%) as a yellow-white solid.

1H NMR (DMSO-d6, 300 MHz) (δ) ppm: to 0.72 (3H, d, J=6.6 Hz), 1,10 (3H, d, J=6.6 Hz), of 1.28 (3H, t, J=7,0 Hz), and 2.27 (1H, user), of 3.77 (1H, user), 3,86 (1H, user), to 4.23 (2H, usher, J=7,0 Hz), 4,56 (1H, user), 5,12 (1H, t, J=4.9 Hz), of 8.09 (1H, d, J=11,1 Hz), to 8.62 (1H, d, J=7.5 Hz), 8,68 (1H, s).

Stage 9

Connection (25,00 g, 55,90 mmol)obtained in stage 8, was dissolved in methanol (250 ml), add 28% solution of sodium methoxide in methanol (12.5 ml, 61,49 mol) and the mixture heated to boiling under reflux for 3 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure. The resulting residue is dissolved in dimethylformamide (125 ml), add potassium carbonate (7,72 g, 55,90 mmol) and itmean (3,48 ml, 55,90 mmol) and the mixture is stirred at room temperature for 2 hours. The reaction mixture was poured into ice water containing 6N. hydrochloric acid (12 ml)and the mixture is extracted twice with ethyl acetate. The organic layer was washed with water (three times) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining a yellow amorphous crude product (24,94 g).

Stage 10

The crude product (24,94 g)obtained in stage 9, is dissolved in dimethylformamide (125 ml), add imidazole (4,95 g, 72,66 mmol) and tert-butyldimethylsilyl (10,10 g, 67,07 mmol) and the mixture is stirred at room temperature for 15 hours. To the reaction mixture, water is added and the mixture extracted with on the every with ethyl acetate. The organic layer is washed four times with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 1:1-1:2), thus obtaining the desired compound (21,86 g, yield 70%, stage 2) as a pale yellow solid.

1H NMR (CDCl3, 300 MHz) (δ) ppm: -0,07 (3H, s)-0,04 (3H, s)to 0.78 (9H, s)is 0.84 (3H, d, J=6,8 Hz)to 1.19 (3H, d, J=6.8 Hz), 2,38-2,49 (1H, m), 3,91 (3H, s), 3,99-4,16 (6H, m), 6,76 (1H, s), 8,66 (1H, s), of 8.95 (1H, s).

Stage 11

The compound (3.50 g, 6.26 mmol), obtained in stage 10, is suspended in dimethyl sulfoxide (25 ml)in an argon flow add bis(pinacolato)LIBOR (1.75 g, 6,89 mmol), potassium acetate (1.84 g, 18,78 mmol) and the complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (1:1) (153 mg, 0,188 mmol) and the mixture is stirred under heating at 80°C for 1.5 hours. After allowing to cool to the reaction mixture are added water and ethyl acetate, the layers separated and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water (three times) and a saturated solution of salt in sequence and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining a brown amorphous crude p is oduct (3,45 g).

1H NMR (CDCl3, 300 MHz) (δ) ppm: -0,07 (3H, s), to-0.05 (3H, s)to 0.78 (9H, s)of 0.82 (3H, d, J=6.4 Hz), of 1.18 (3H, d, J=6.4 Hz), of 1.35 (12H, s), 2,36 is 2.51 (1H, m), 3,88 (3H, s), 3,93 (3H, s), a 4.03-to 4.23 (3H, m), of 6.73 (1H, s), 8,64 (1H, s), cent to 8.85 (1H, s).

Stage 12

The crude product (1.07 g)obtained in stage 11, the compound (433 mg, 1.28 mmol)obtained in stage 5, was dissolved in 1,2-dimethoxyethane add tetrakis(triphenylphosphine)palladium(0) (44 mg, of 0.038 mmol) and 2 M aqueous sodium carbonate solution (2,60 ml, 5,12 mmol) and the mixture is stirred under heating at 80°C for 30 minutes After submitting the reaction mixture opportunities for cooling add saturated aqueous solution of ammonium chloride and ethyl acetate and the layers separated. The organic layer is washed with water and saturated salt solution in a specified sequence, and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 1:1), thus obtaining a yellow amorphous connection required (1,21 g, 71%yield).

1H NMR (CDCl3, 400 MHz) (δ) ppm: 0,00 (6H, s)of 0.77 (9H, s)of 0.85 (3H, d, J=6,7 Hz)to 1.19 (3H, d, J=6.5 Hz), of 1.47 (9H, s), 2.40 a-2,50 (1H, m), 3,90 (3H, s), 3,91 (3H, s), of 3.95 (1H, DD, J=11,0, 2.7 Hz), was 4.02 (2H, s), a 4.03-4,06 (1H, m), 4,16-is 4.21 (1H, m), of 6.29 (1H, s), 6,72 (1H, DD, J=5,4, 2.7 Hz), 6,78 (1H, s), 7,53-7,58 (1H, m), 8,29 (1H, s), 8,65 (1H, s).

Stage 13

The compound (200 mg, 0,289 mmol)obtained in stage 12, dissolved in chloroform (1 ml), add triperoxonane acid (1 ml) and the mixture is stirred at room temperature for 30 minutes, the Reaction mixture was concentrated under reduced pressure and the resulting residue is dissolved in ethyl acetate. To the solution was added a saturated aqueous solution of sodium bicarbonate and the layers separated. The aqueous layer was extracted with ethyl acetate and the organic layer was washed with saturated salt solution and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining a yellow amorphous crude product (167 mg).

1H NMR (CDCl3, 400 MHz) (δ) ppm: 0,00 (6H, s)of 0.77 (9H, s)of 0.85 (3H, d, J=6.5 Hz), 1,19 (3H, d, J=6.5 Hz), 2,42-2,48 (1H, m), 3,90 (3H, s), 3,91 (3H, s), 3,93-of 3.96 (1H, m), 3,98 (2H, s), a 4.03-4,07 (1H, m), 4,15-is 4.21 (1H, m), 6,24 (1H, DD, J=5,4, 2,9 Hz), is 6.54 (1H, DD, J=5,7, 2,9 Hz), 6,78 (1H, s), 8,31 (1H, s), 8,65 (1H, s).

Stage 14

The compound (167 mg)obtained in stage 13, is dissolved in chloroform (1.7 ml), add pyridine (46 μl, 0,564 mmol) and 4-chlorobutyrate (38 μl, 0,338 mmol) and the mixture is stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue is dissolved in ethyl acetate. To the solution was added a saturated aqueous solution of sodium bicarbonate and the layers section is given. The aqueous layer was extracted with ethyl acetate and the organic layer washed with water, saturated aqueous sodium hydrogen carbonate and a saturated solution of salt in sequence and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (chloroform:methanol = 95:5), thus obtaining the desired compound (164 mg, yield 82%, stage 2) in the form of a light yellow resin.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 0,00 (6H, s)of 0.77 (9H, s)of 0.85 (3H, d, J=6,7 Hz)of 1.20 (3H, d, J=6.5 Hz), 2,11-to 2.18 (1H, m), 2.49 USD (2H, t, J=7,1 Hz), 3,61 (2H, t, J=6,1 Hz)to 3.89 (3H, s)to 3.92 (3H, s), 3,93-of 3.96 (1H, m), a 4.03 (2H, s), 4.04 the-4,08 (1H, m), 4,16-4,22 (1H, m), 6,79 (1H, s), to 6.95 (1H, DD, J=5,3, and 2.6 Hz), was 7.36 (1H, users), 7,73 (1H, DD, J=6,5, 2,8 Hz), of 8.28 (1H, s), 8,67 (1H, s).

Stage 15

The compound (164 mg, 0,236 mmol)obtained in stage 14, is dissolved in dimethylformamide (1.7 ml)at 0°C. add sodium hydride (14 mg, 0,354 mmol) and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture an aqueous solution of ammonium chloride and ethyl acetate and the layers separated. The aqueous layer was extracted with ethyl acetate and the organic layer washed with water (three times) and a saturated solution of salt in sequence and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure, olucha this crude product (152 mg) as a brown resin.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 0,00 (6H, s)of 0.77 (9H, s)of 0.85 (3H, d, J=6,7 Hz)to 1.19 (3H, d, J=6.5 Hz), 2,08-of 2.15 (2H, m), 2.40 a-2,50 (1H, m)to 2.55 (2H, t, J=8.1 Hz), 3,74 (2H, t, J=7,1 Hz), 3,90 (3H, s), 3,91-3,96 (1H, m), of 3.94 (3H, s), a 4.03-4,07 (1H, m), 4,07 (2H, s), 4,15-is 4.21 (1H, m), 6,78 (1H, s), 7,25-7,28 (1H, m), to 7.59 (1H, DD, J=6,0, 2,8 Hz), of 8.28 (1H, s), 8,65 (1H, s).

Stage 16

The crude product (152 mg)obtained in stage 15, is dissolved in tetrahydrofuran (3 ml), add 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (700 μl, 0,699 mmol) and the mixture is stirred at room temperature for 1 hour. To the reaction mixture are added water and ethyl acetate, the layers separated and the aqueous layer was extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified PTSH (chloroform:methanol = 9:1), thus obtaining the desired compound (98 mg, yield 76%, stage 2) in the form of a light yellow oil.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 0,76 (3H, d, J=6,5 Hz)of 1.23 (3H, d, J=6.5 Hz), 2,08-of 2.15 (2H, m), 2,43 is 2.51 (1H, m)to 2.55 (2H, t, J=8.1 Hz), 3,56-3,61 (1H, m), 3,69-3,74 (3H, m), 3,85 (3H, s), a 4.03 (3H, s), 4,12-4,27 (3H, m), 4,79-of 4.90 (1H, m), 6,92 (1H, s), 7,38 (1H, DD, J=5,7, 2.7 Hz), the 7.43 (1H, DD, J=6,0, 2,8 Hz), 7,58 (1H, users), to 8.57 (1H, users).

Stage 17

Compound (98 mg, 0.18 mmol), n is obtained at stage 16, dissolved in a mixed solvent of tetrahydrofuran (1 ml) and water (0.5 ml), add the monohydrate of lithium hydroxide (15 mg, 0.36 mmol) and the mixture is stirred at room temperature for 3 hours. The reaction mixture was acidified with 1N. hydrochloric acid and extracted with ethyl acetate. The organic layer is washed twice with water and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue is recrystallized from a mixture of acetone-hexane, thus obtaining the desired compound (61 mg, yield 64%) as a pale yellow solid.

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.72 (3H, d, J=6.6 Hz), of 1.16 (3H, d, J=6.4 Hz), 1,99-2,07 (2H, m), 2,31-to 2.41 (1H, m), 2,46-of 2.50 (2H, m), 3.75 to 3,82 (3H, m), 3.95 to 4,01 (1H, m), of 4.05 (3H, s), 4,11 (2H, s), to 4.87 (1H, users), 5,19 (1H, t, J=5,2 Hz), 7,46 (1H, s), a 7.62 (1H, DD, J=6,0, 2.6 Hz), 7,82 (1H, DD, J=6,4, and 2.6 Hz), 8,03 (1H, s), 8,88 (1H, s), 15,42 (1H, s).

MS (ESI): M+531.

Example 5

Stage 1

To a solution of compound (67 mg, 0.22 mmol)obtained in stage 6 of example 1, compound (182 mg, 0.33 mmol)obtained in stage 11 of example 2, tetrakis(triphenylphosphine)palladium(0) (7.5 mg, 0,0065 mmol) in 1,2-dimethoxyethane (2.1 ml) is added 2 M aqueous solution of sodium carbonate (434 μl, 0.87 mmol) and the mixture is stirred under heating at 80°C for 20 minutes After completion of the reaction, to the reaction mixture are added ethyl the Etat and water, the layers are separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer is washed twice with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified PTSH (chloroform:acetone = 6:1, are twice), while receiving not purified product (68 mg) as a pale brown amorphous solid.

Stage 2

Not purified product (68 mg)obtained in stage 1, is stirred in tetrahydrofuran (0.7 ml) with 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (154 μl, 0.15 mmol) at room temperature for 1.5 hour. To the reaction mixture are added ethyl acetate and a saturated salt solution, the layers separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer washed four times with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, the obtained residue is treated with ethyl acetate, the precipitated solid is collected by filtration and dried, thus obtaining the desired compound (30 mg, yield 25%, stage 2) in the form of a white solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 0,76 (3H, d, J=6,7 Hz)of 1.24 (3H, d, J=6.5 Hz), 2,42-2,52 (1H, m), 2,92 are 2.98 (4H, m), 3,57 (1H, d, J=15,0 Hz), 73-3,78 (4H, m)a 3.87 (3H, s), of 3.97 (3H, s)4,07 (1H, d, J=15,0 Hz), 4,13-4,30 (3H, m), 4.80 to 4,89 (1H, m), 6.42 per-6,46 (1H, m), 6,72 (1H, DD, J=5,9, 2,9 Hz), at 6.84 (1H, s), to 7.61 (1H, s), 8,56 (1H, s).

Stage 3

The compound (30 mg, by 0.055 mmol), obtained in stage 2, and the monohydrate of lithium hydroxide (3.5 mg, 0,082 mmol) is stirred in a mixed solvent of tetrahydrofuran (300 ml) and water (150 μl) at room temperature for 4 hours. To the reaction mixture are added 5% aqueous solution of potassium hydrosulfate and the mixture is extracted twice with ethyl acetate. The combined organic layer is washed twice with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, the obtained residue is treated with a mixed solvent of hexane-ethyl acetate and the precipitated solid is collected by filtration and dried under reduced pressure, thus obtaining the desired compound (28 mg, yield 96%) as a white solid.

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.72 (3H, d, J=6,8 Hz)of 1.16 (3H, d, J=6.8 Hz), 2,31 is 2.43 (1H, m), 3.04 from-3,10 (4H, m), 3,68-to 3.73 (4H, m), 3.75 to 3,82 (1H, m), 3,94-a 4.03 (1H, m), Android 4.04 (2H, s)4,06 (3H, s), a 4.83 to 4.92 (1H, m), 5,17-5,23 (1H, m), 6.90 to-6,95 (1H, m), 6,98-7,03 (1H, m), 7,46 (1H, s), 7,95 (1H, s), 8,87 (1H, s), 15,44 (1H, users).

MS (ESI): M+533.

Example 16

Stage 1

3-Chloro-2,4-differentyou acid (25 g, 130 mmol) is dissolved in concentrated is Oh sulfuric acid (250 ml) and for 10 min while cooling in an ice bath are added in several portions of N-iodosuccinimide (30,6 g, 136 mmol). After complete addition, the mixture was stirred at the same temperature for 30 min and at room temperature for 3.5 hours. The reaction mixture was poured into ice water (1000 ml)containing sodium sulfite (14.2 g, 136 mmol)and after stirring the precipitated solid is collected by filtration and washed with water. The obtained solid is dried under reduced pressure, thus obtaining the desired compound (40,4 g, yield 98%) as a white solid.

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: 8,21-of 8.27 (1H, m).

Stage 2

Connection (40,4 g, 127 mmol, obtained in stage 1, was dissolved in tetrahydrofuran (200 ml) and at 0°C for 20 min in an argon atmosphere is added dropwise a 1.0 M solution of the complex of borane-tetrahydrofuran in tetrahydrofuran (190 ml, 190 mmol). After completion of adding dropwise, the mixture is stirred at room temperature for 20 min and then heated at 50°C for 1 hour. After allowing to cool to the reaction mixture over 5 minutes under ice cooling are added dropwise 1.0 M solution of the complex of borane-tetrahydrofuran in tetrahydrofuran (100 ml, 100 mmol), after completion of adding dropwise, the mixture is stirred at room temperature for 15 min and then heated at 50°is within 1 hour. After completion of the reaction dropwise while cooling with ice add 1H. hydrochloric acid (300 ml). To the mixture are added ethyl acetate and a saturated salt solution, the layers separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated salt solution, saturated aqueous sodium hydrogen carbonate and a saturated solution of salt in the listed sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining the crude product (40,0 g) as a pale yellow solid.

Stage 3

The crude product (40,0 g)obtained in stage 2, was dissolved in dimethylformamide (200 ml) and added imidazole (11.2 g, 165 mmol). While cooling in an ice bath, add tert-butyldimethylsilyloxy (23,0 g, 152 mmol) and the mixture is stirred at room temperature for 1.3 hours. Additionally add imidazole (1.3 g, 7.9 mmol) and tert-butyldimethylsilyl (1,91 g, 12.5 mmol) and the mixture is stirred at room temperature for 0.7 hour. To the reaction mixture are added water and ethyl acetate, the layers separated and the aqueous layer was further extracted with ethyl acetate. The combined organic layer washed four times with saturated salt solution and dried over sodium sulfate. After filtering the project the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (only hexane), while receiving the desired compound (50.6 g, yield 95%, 2 stage) as a white solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 0,12 (6H, s)of 0.95 (9H, s), 4,70-4,74 (2H, m), 7,74-7,79 (1H, m).

Stage 4

The complex Tris(dibenzylideneacetone)diplegia(0) and chloroform (1:1) (12.5 g, 12.1 mmol), (±)-2,2'-bis(diphenylphosphino)-1,1'-binaphtyl of 15.3 g of 26.6 mmol) and cesium carbonate (66,9 g, 205 mmol) is added 1,4-dioxane (200 ml) and the mixture is stirred in an argon atmosphere at room temperature for 50 minutes To the mixture is added morpholine (of 14.8 ml, 169 mmol), add a solution of the compound (50.6 g, 121 mmol), obtained in stage 3, in 1,4-dioxane (300 ml) and the mixture heated to boiling under reflux for 20 hours. After allowing to cool to the reaction mixture hexane (400 ml) and the mixture is stirred. The resulting insoluble matter was separated by filtration through celite and the insoluble matter is washed with ethyl acetate. The combined filtrate is washed with water and saturated salt solution (twice) in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 50:1-30:1, then 20:1), thus obtaining the desired compound (22,8 g, yield 50%) in VI is e pale yellow oil.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 0,12 (6H, s)of 0.95 (9H, s), 3,02-of 3.06 (4H, m), 3,84-to 3.89 (4H, m), 4,74 (2H, s), 6,99-7,05 (1H, m).

Stage 5

Connection of 22.8 g of 60.2 mmol)obtained in stage 4, was dissolved in tetrahydrofuran (220 ml), add 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (90.3 per ml, of 90.3 mmol) and the mixture is stirred at room temperature for 1 hour. To the reaction mixture add a solution of salts and ethyl acetate, the layers separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer is washed with salt solution and a saturated salt solution in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 2:1-1:2), thus obtaining the desired compound (15.2 g yield 96%) as a pale yellow solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 1,79-of 1.84 (1H, m), 3,03-to 3.09 (4H, m), 3,84-to 3.89 (4H, m), 4,74 (2H, d, J=6.0 Hz), 6,92-6,99 (1H, m).

Stage 6

Compound (2 g, 7.6 mmol), obtained in stage 5, is dissolved in chloroform (20 ml)while cooling with ice, add triphenylphosphine (2,39 g, 9,10 mmol) and tetrabromide carbon (3,02 g, 9,10 mmol) and the mixture is stirred at room temperature for 20 minutes Add triphen fastin (0,597 g, 2.28 mmol) and tetrabromide carbon (0,754 g of 2.27 mmol) and the mixture is stirred at room temperature for 5 minutes After completion of the reaction the mixture was concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 50:1 to 2:1), thus obtaining the desired compound (2.20 g, yield 89%) as a white solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 3,02-is 3.08 (4H, m), 3,83-to 3.89 (4H, m), to 4.46 (2H, s), 6,82-to 6.88 (1H, m).

Stage 7

To a solution of compound (55 mg, 0,17 mmol)obtained in stage 6, and the compound (141 mg, 0.25 mmol)obtained in stage 11 of example 2, 1.2-dimethoxyethane (1.7 ml) is added tetrakis(triphenylphosphine)palladium(0) (6 mg, of 0.005 mmol) and 2 M aqueous sodium carbonate (337 μl, 0.67 mmol) and the mixture is stirred in an argon atmosphere by heating at 80°C for 20 minutes After completion of the reaction, to the reaction mixture are added ethyl acetate and a saturated solution of salt, the layers are separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer is washed twice with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (chloroform:acetone = 5:1), thus obtaining the desired compound (96 mg, yield 84%) as a yellow is isomorphous solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: -0,09 (3H, s), to-0.05 (3H, s)0,76 (9H, s)is 0.84 (3H, d, J=6,7 Hz)to 1.19 (3H, d, J=6.5 Hz), 2,39-of 2.50 (1H, m), 2.93 which are 2.98 (4H, m), 3,79-a 3.83 (4H, m), 3,89-4,08 (10H, m), 4,15-4,22 (1H, m), 6,60 of 6.66 (1H, m), 6,79 (1H, s), of 8.27 (1H, s), 8,65 (1H, s).

Stage 8

Compound (96 mg, 0.14 mmol)obtained in stage 7, is stirred in tetrahydrofuran (1 ml) with 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (212 μl, 0.21 mmol) and the mixture is stirred at room temperature for 1.8 hours. To the reaction mixture are added ethyl acetate and the salt solution, the layers separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer is washed twice with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (from a mixture of chloroform:acetone = 2:1 to a mixture of chloroform:methanol = 10:1), thus obtaining the desired compound (73 mg, yield 91%) as a pale yellow solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: of 0.77 (3H, d, J=6,7 Hz)of 1.23 (3H, d, J=6.5 Hz), 2.40 a is 2.51 (1H, m), 2,88-of 2.93 (4H, m), 3,62 (1H, d, J=14,2 Hz), 3,76-3,81 (4H, m), a 3.87 (3H, s), 3.96 points-Android 4.04 (4H, m), 4,15-to 4.28 (3H, m), to 4.52-br4.61 (1H, m), of 6.49-6,56 (1H, m)6,86 (1H, s), 7,66 (1H, s), 8,56 (1H, s).

Stage 9

Compound (73 mg, 0.13 mmol)obtained in stage 8, and the monohydrate of lithium hydroxide (11 m is, 0.26 mmol) is stirred in a mixed solvent of tetrahydrofuran (740 μl) and water (370 ml) at room temperature for 2.3 hours. To the reaction mixture are added ethyl acetate and 5% aqueous solution of potassium hydrosulfate, the layers separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer is washed twice with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue is treated with a mixed solvent of hexane-ethyl acetate. The precipitated solid is collected by filtration and dried, thus obtaining the desired compound (60 mg, yield 84%) as a light brown solid.

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.72 (3H, d, J=6,8 Hz)of 1.16 (3H, d, J=6.8 Hz), 2,31 at 2.45 (1H, m), 2.93 which is 3.00 (4H, m), 3,70 of 3.75 (4H, m), 3.75 to 3,82 (1H, m), 3.95 to as 4.02 (1H, m)4,06 (3H, s)4,07 (2H, s), a 4.83 to 4.92 (1H, m), 5,17-5,23 (1H, m), 7,05-7,11 (1H, m), 7,46 (1H, s), 8,01 (1H, s), 8,88 (1H, s), 15,44 (1H, users).

MS (ESI): M+551.

Example 17

Stage 1

2-Fluoro-4-methoxybenzoic acid (25,0 g, 147 mmol) was dissolved in concentrated sulfuric acid (175 ml) and cooled with ice for 30 min portions add N-iodosuccinimide (of 31.4 g, 140 mmol). After complete addition, the ice bath removed and the mixture is stirred at room temperature over night. Reaction the second mixture is then poured into ice water, contains sodium sulfite (1.9 g, 15 mmol)and the mixture stirred for 1 hour. The precipitated solid is collected by filtration and washed with water. The obtained solid is air-dried and stirred in ethanol (250 ml) at 90°C for 1 hour. After allowing to cool, the solid is collected by filtration, thus obtaining the desired compound (21,4 g, yield 49%) as a white solid.

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 3.92 (3H, s), 7,03 (1H, d, J=13,2 Hz), to 8.20 (1H, d, J=8,4 Hz), 13,12 (1H, users).

Stage 2

Connection (21,4 g, 72.2 mmol), obtained in stage 1, is suspended in toluene (42 ml), add thionyl chloride (15,8 ml, 217 mmol) and dimethylformamide (56 μl, to 0.72 mmol) and the mixture is stirred under heating at 75°C for 2.8 hours in nitrogen atmosphere. After allowing to cool, the reaction mixture was concentrated under reduced pressure and twice subjected to azeotropic distillation with toluene, thus obtaining the remainder.

To a mixture of ethylmalonate potassium (24.6 g, 145 mmol) and tetrahydrofuran (125 ml), add triethylamine (30,2 ml, 217 mmol) and magnesium chloride (1.45 g, 10,14 mmol) and the mixture is stirred in an argon atmosphere at room temperature for 1 hour and stirred at 70°C for 3.3 hours. To this mixture is added dropwise a solution obtained what about the above residue in tetrahydrofuran (50 ml) at the same temperature for 15 min and then stirred under heating for 30 minutes After allowing to cool to the reaction mixture in an ice bath are added dropwise 2n. hydrochloric acid (175 ml). To the mixture, the toluene and the layers separated. The organic layer is washed with water, aqueous sodium hydrogen carbonate solution (twice) and water in this sequence. The mixture is concentrated under reduced pressure and twice subjected to azeotropic distillation with toluene, thus obtaining the desired compound (26,0 g, yield 98%) as a pale yellow solid.

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: 1,17 (3H, t, J=7.0 Hz), of 3.94 (3H, s), 4.00 points (2H, d, J=3.3 Hz), 4,11 (2H, q, J=7.0 Hz), to 7.09 (1H, d, J=13,7 Hz), to 8.20 (1H, d, J=8,4 Hz).

Stage 3

Connection (26,0 g, 71,0 mmol), obtained in stage 2, are suspended in toluene (125 ml), add dimethylacetal of dimethylformamide (11.3 ml of 85.1 mmol) and the mixture is stirred under heating at 85°C for 3.8 hours. After allowing to cool, the reaction mixture was concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 1:1-1:2), thus obtaining the desired compound (25,0 g, yield 83%) as a pale yellow solid.

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: of 0.95 (3H, t, J=7,1 Hz), 2,73 (3H, users), 3,29 (3H, users), 3,84-of 3.96 (5H, m), 6,93 (1H, d, J=12,8 Hz), of 7.70 (1H, s), to 7.84 (1H, d, J=8,1 Hz).

Stage 4

The compound (700 mg, of 1.66 mmol)obtained in stage 3, and L-tert-leucinol (234 mg, 1,99 mmol) was stirred in chloroform (7 ml) at room temperature for 2.7 hours. The reaction mixture was concentrated under reduced pressure, to the residue is added ethyl acetate and water and the layers separated. The organic layer was washed with water (twice) and a solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining a white amorphous crude product (873 mg).

Stage 5

The crude product (873 mg)obtained in stage 4, is stirred with potassium carbonate (689 mg, 4,99 mmol) in dimethylformamide (8 ml) and heated at 80°C over night. After completion of the reaction, to the reaction mixture are added water and ethyl acetate, the layers separated and the organic layer washed twice with water. The aqueous layer was extracted again with ethyl acetate and the organic layers are combined and washed with a saturated solution of salt. The organic layer is dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining the crude product (931 mg) as a colourless oil.

Stage 6

The crude product (931 mg), n is obtained at stage 5, the imidazole (170 mg, 2.49 mmol) and tert-butyldimethylsilyl (301 mg, 1,99 mmol) is stirred in dimethylformamide (5 ml) at room temperature for 1 hour. To the reaction mixture are added water and ethyl acetate, the layers separated and the organic layer washed with water (twice) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 2:3), thus obtaining the desired compound (798 mg, yield 82%, stage 3) in the form of a white solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: -0,09 (3H, s)0,00 (3H, s)0,68 (9H, s)of 1.06 (9H, s)of 1.41 (3H, t, J=7,1 Hz)to 3.99 (3H, s), 4.09 to-4,20 (2H, m), 4,36-of 4.44 (2H, m)to 4.52 (1H, DD, J=8,7, and 4.5 Hz), 6,86 (1H, s), to 8.62 (1H, ), to 8.94 (1H, s).

Stage 7

A mixture of the compound (200 mg, 0,340 mmol)obtained in stage 6, bis(pinacolato)DIBORANE (95 mg, of 0.37 mmol), potassium acetate (100 mg, of 1.02 mmol) and complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (1:1) (8 mg, 0.01 mmol) in dimethyl sulfoxide (2 ml) is stirred under heating at 80°C for 1 hour. After allowing to cool to the reaction mixture are added ethyl acetate and water, the layers separated and the organic layer washed with water (twice) and a solution of salt in listed on the sledovatelnot and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining black-and-brown amorphous crude product (241 mg).

Stage 8

The crude product (241 mg)obtained in stage 7, the compound (126 mg, 0,408 mmol)obtained in stage 6 of example 1, and tetrakis(triphenylphosphine)palladium(0) (20 mg, is 0.017 mmol) is mixed with 1,2-dimethoxyethane (4 ml)is added 2 M aqueous solution of sodium carbonate (0.7 ml, 1.4 mmol) and the mixture is stirred under heating at 80°C for 30 minutes, After providing opportunity for cooling to the reaction mixture are added ethyl acetate and water, the layers separated and the organic layer washed with water (twice) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (chloroform:acetone = 5:1), thus obtaining the desired compound (217 mg, yield 93%, stage 2) in the form of a brown oil.

1H NMR (CDCl3, 400 MHz) (δ) ppm: -0,10 (3H, s)0,00 (3H, s)to 0.67 (9H, s)of 1.06 (9H, s)of 1.41 (3H, t, J=7.2 Hz), 2,96-a 3.01 (4H, m), 3,76-of 3.80 (4H, m), 3,91 (3H, s)to 3.99 (1H, d, J=15,5 Hz), Android 4.04 (1H, d, J=15,5 Hz), 4.09 to 4,20 (2H, m), 4,35-4,43 (2H, m), of 4.54 (1H, DD, J=8,8, 4,4 Hz), 6,51 (1H, DD, J=5,5, 2,9 Hz), to 6.75 (1H, DD, J=5,8, 2,9 Hz), 6.89 in (1H, s), of 8.28 (1H, s), to 8.62 (1H, s).

Stage 9

With the unity (217 mg, 0,315 mmol)obtained in stage 8, is stirred in tetrahydrofuran (2 ml) with 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (of 0.47 ml, 0.47 mmol) at room temperature over night. To the reaction mixture add water, then add ethyl acetate and the layers separated. The organic layer was washed with water (twice) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified PTSH (first appearance; hexane:ethyl acetate = 1:5, the second manifestation; chloroform:methanol = 20:1), thus obtaining the desired compound (166 mg, yield 92%) as a colourless oil.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 1.00 and (9H, s)of 1.40 (3H, t, J=6.8 Hz), 2.91 in-of 2.97 (4H, m), 3,62 (1H, d, J=14.4 Hz), 3.72 points-of 3.80 (4H, m), of 3.95 (3H, s), a 4.03 (1H, d, J=14.4 Hz), 4,20-4,43 (4H, m), 4,54 with 4.65 (2H, m), 6,39-to 6.43 (1H, m), 6,67-6,72 (1H, m)6,94 (1H, s), to 7.77 (1H, s), 8,61 (1H, s).

Stage 10

The compound (166 mg, 0,289 mmol)obtained in stage 9, and the monohydrate of lithium hydroxide (24 mg, of 0.58 mmol) is stirred in a mixed solvent of tetrahydrofuran (3 ml) and water (0.6 ml) at room temperature for 4 hours. To the reaction mixture is added an aqueous citric acid solution and ethyl acetate and the layers separated. The organic layer was washed with water (twice) and a saturated solution of salt in asanas sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining the desired compound (146 mg, yield 92%) as a white solid.

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: 0,99 (9H, s), is 3.08 (4H, t, J=4,8 Hz), 3,71 (4H, t, J=4,8 Hz), a 4.03-4,11 (2H, m), of 4.05 (2H, s)4,08 (3H, s)to 5.13 (1H, t, J=4.9 Hz), 5,17-5,20 (1H, m), 6.90 to-6,92 (1H, m), 7,01-7,03 (1H, m,), 7,54 (1H, s), of 7.96 (1H, s), 8,79 (1H, s), 15,39 (1H, s).

MS (ESI): M+547.

Example 25

Stage 1

3-Chloro-2,4-differentyou acid (5.0 g, 26 mmol) is dissolved in concentrated sulfuric acid (15 ml) and under ice cooling are added dropwise fuming nitric acid (1,43 ml, 33.8 mmol). After completion of adding dropwise, the mixture is stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and the mixture is stirred under ice cooling. The precipitated solid is collected by filtration and washed with water. The obtained solid is dried under reduced pressure and 50°C during the night, thus obtaining the desired compound (5,54 g, yield 90%).

1H NMR (CDCl3, 400 MHz) (δ) ppm: 8,78 (1H, DD, J=8,1, 7,2 Hz).

Stage 2

The compound (5.0 g, 21 mmol), obtained in stage 1, was dissolved in tetrahydrofuran (50 ml) and after cooling with ice, add triethylamine (is 3.08 ml, 22,1 mmol). Added dropwise isobutyl arbonet (2,87 ml, to 22.1 mmol) and the mixture was stirred at the same temperature for 40 minutes To the resulting mixture is added sodium borohydride (1.19 g, of 31.6 mmol) and dropwise over 15 min, add water (5 ml). The mixture was stirred at the same temperature for 30 min, to the reaction mixture, water is added and the mixture extracted with ethyl acetate. After distribution, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining the crude product (2,97 g).

Stage 3

To a mixture of ethanol (15 ml) and water (5 ml) was added reduced iron (of 3.56 g of 63.7 mmol) and ammonium chloride (3,41 g of 63.7 mmol). To the mixture is added dropwise a solution of the crude product (2.85 g), obtained in stage 2, in tetrahydrofuran (15 ml) at 70°C and the mixture is stirred under heating at 80°C for 30 min After allowing to cool, the reaction mixture was filtered through celite and to the filtrate is added ethyl acetate and a saturated aqueous solution of sodium bicarbonate, and the layers separated. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with saturated aqueous hydrocarb the Nata sodium and saturated salt solution and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 2:1), thus obtaining the desired compound (1.50 g, yield 38%, stage 2).

1H NMR (CDCl3, 400 MHz) (δ) ppm: 1,75 (1H, users), of 3.69 (2H, users), and 4.68 (2H, d, J=3,7 Hz), 6,76 (1H, DD, J=9,3, 7,0 Hz).

Stage 4

A solution of the compound (1.5 g, 7.8 mmol), obtained in stage 3, and di-tert-BUTYLCARBAMATE (2,54 g, 11.6 mmol) in tetrahydrofuran (10 ml) heated to boiling under reflux for 48 hours. To the reaction mixture are added di-tert-BUTYLCARBAMATE (508 mg, 2.32 mmol) and tetrahydrofuran (2 ml) and the mixture heated to boiling under reflux for 30,5 hour. Add di-tert-BUTYLCARBAMATE (2.0 g, 9.2 mmol) and the mixture heated to boiling under reflux for 16.5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate= 5:1, 4:1, 3:1-2:1), thus obtaining the desired compound (2.4 g, yield 95%).

1H NMR (CDCl3, 400 MHz) (δ) ppm: 1,53 (9H, s)to 1.98 (1H, t, J=6.4 Hz), to 4.73 (2H, d, J=6.4 Hz), 6,60 (1H, users), 8,08 (1H, t, J=7,8 Hz).

Stage 5

The compound (2.14 g, 7,29 mmol)obtained in stage 4, is dissolved in chloroform (20 ml), add trip nilpotent from 2.06 g, 7.87 mmol) and tetrabromide carbon (2.66 g, 8,02 mmol) and the mixture is stirred at room temperature. The reaction mixture was concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:chloroform = 1:1) and further treated with hexane. The precipitated solid is collected by filtration and dried under reduced pressure, thus obtaining the desired compound (1.54 g, yield 59%) as a solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 1,53 (9H, s), to 4.46 (2H, d, J=1.4 Hz), is 6.61 (1H, users), 7,88 (1H, t, J=7.9 Hz).

Stage 6

Argon is bubbled through a solution of the compound (497 mg, of 1.39 mmol)obtained in stage 5, the compound (600 mg, 1.07 mmol)obtained in stage 11 of example 2, tetrakis(triphenylphosphine)palladium(0) (62 mg, 0,054 mmol) and sodium carbonate (340 mg, is 3.21 mmol) in a mixture of 1,2-dimethoxyethane (4 ml) and water (2 ml) for 2 min and the solution stirred in an argon atmosphere by heating at 100°C for 0.5 hour. To the reaction mixture are added ethyl acetate and a saturated aqueous solution of sodium bicarbonate, the layers separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified chromate what graphy on silica gel (hexane:ethyl acetate = 2:1-1:1), while receiving the desired compound (649 mg, yield 85%).

1H NMR (CDCl3, 400 MHz) (δ) ppm: -0,08 (3H, s)-0,06 (3H, s)of 0.77 (9H, s)is 0.84 (3H, d, J=6,7 Hz)to 1.19 (3H, d, J=6.5 Hz), to 1.48 (9H, s), 2,38-of 2.50 (1H, m)to 3.89 (3H, s), 3,92-of 3.97 (4H, m), 4,00-4,08 (3H, m), 4,14-is 4.21 (1H, m), 6,50 (1H, users), was 6.73 (1H, s), 7,87 (1H, users), 8,18 (1H, s)8,64 (1H, s).

Stage 7

The compound (645 mg, 0,909 mmol)obtained in stage 6, is stirred in a mixed solvent of triperoxonane acid (2.5 ml) and chloroform (5 ml) at room temperature for 0.5 hour. The reaction mixture was concentrated under reduced pressure and to the residue is added ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate (twice) and a saturated solution of salt in sequence and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (chloroform:methanol = 10:1), thus obtaining the desired compound (454 mg, yield 82%).

1H NMR (CDCl3, 400 MHz) (δ) ppm: -0,08 (3H, s)-0,04 (3H, s)of 0.77 (9H, s)of 0.85 (3H, d, J=6.5 Hz), 1,19 (3H, d, J=6.5 Hz), 2.40 a is 2.51 (1H, m), 3,52 (2H, s), 3,88-3,98 (9H, m), to 4.01-4.09 to (1H, m), 4,14-4,22 (1H, m), 6,34-6,40 (1H, m), 6,78 (1H, s), 8,30 (1H, s), 8,65 (1H, s).

Stage 8

To a solution of compound (197 mg, 0,323 mmol)obtained in stage 7, and pyridine (53 μl, ,65 mmol) in chloroform (2 ml) is added 4-chlorobutyrate (44 μl, 0,39 mmol) and the mixture is stirred at room temperature for 4.3 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue is added ethyl acetate and a saturated aqueous solution of sodium bicarbonate and the layers separated. The organic layer was washed with saturated salt solution and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining the crude product (233 mg).

Stage 9

The crude product (233 mg)obtained in stage 8, was dissolved in dimethylformamide (2 ml)at 0°C. add sodium hydride (60%, and 19.4 mg, 0,485 mmol) and the mixture was stirred at the same temperature for 15 minutes To the reaction mixture an aqueous solution of potassium hydrosulfate and ethyl acetate and the layers separated. The organic layer is washed with water and saturated salt solution in a specified sequence, and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining the crude product.

Stage 10

The crude product obtained in stage 9, is stirred in tetrahydrofuran (3 ml) with 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (485 μl, 0,485 mmol) and acetic acid (55 μl, 0.97 mmol) at room temperature T. the value of 5 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (chloroform:methanol = 15:1), thus obtaining the desired compound (178 mg, yield 98%, stage 3).

1H NMR (CDCl3, 400 MHz) (δ) ppm: 0,76 (3H, d, J=6,7 Hz)of 1.24 (3H, d, J=6.0 Hz), 2,12-of 2.21 (2H, m), 2,43 of $ 2.53 (2H, m), of 3.54 (1H, d, J=14,8 Hz), 3,71 (2H, t, J=7,1 Hz), 3,86 (3H, s)to 3.99 (3H, s)4,08 (1H, d, J=14,8 Hz), 4,14-4,30 (3H, m), 6.87 in (1H, s), of 6.96-7,02 (1H, m), 7,58 (1H, s), 8,56 (1H, s).

Stage 11

The compound (175 mg, 0,311 mmol)obtained in stage 10, and the monohydrate of lithium hydroxide (26.1 mg, 0,622 mmol) is stirred in a mixed solvent of tetrahydrofuran (2 ml) and water (1 ml) at room temperature for 1 hour. The reaction mixture is neutralized 2n. hydrochloric acid and the mixture extracted with ethyl acetate. The organic layer was washed with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue is treated with a mixed solvent of hexane-ethyl acetate. The precipitated solid is collected by filtration and dried under reduced pressure, thus obtaining the desired compound (92 mg, yield 54%) as a solid.

1H NMR (DMSO-d6, 300 MHz) (δ) ppm: to 0.72 (3H, d, J=6.4 Hz), of 1.16 (3H, d, J=6.4 Hz), 2,10 (2H, TT, J=7,4, 7,4 Hz), 2,42 (2H, t, J=7.4 Hz), 2,31 is 2.44 (1H, m), 3,74 (2H, t, J=7.4 Hz), to 3.73-,83 (1H, m), 3.95 to 4,06 (1H, m), a 4.03 (3H, s), 4,10 (2H, s), a 4.83-4,91 (1H, m), 5,19 (1H, t, J=5.0 Hz), was 7.45 (1H, DD, J=7,6, 7,6 Hz), 7,45 (1H)to 8.12 (1H, s), 8,88 (1H, s), 15,45 (1H, s).

MS (ESI): M+549.

Example 49

Stage 1

A mixture of compound (217 mg, 0,369 mmol)obtained in stage 6 of example 17, bis(pinacolato)DIBORANE (103 mg, 0,406 mmol), potassium acetate (109 mg, 1.11 mmol) and complex [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) with dichloromethane (1:1) (60 mg, 0,074 mmol) in dimethyl sulfoxide (1.6 ml) is stirred in an argon atmosphere by heating at 80°C for 2 hours. After allowing to cool to the reaction mixture are added ethyl acetate and a saturated salt solution and the mixture is stirred at room temperature. The resulting insoluble matter was filtered through celite. The layers of the filtrate are separated and the organic layer washed four times with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining a brown amorphous crude product (230 mg).

Stage 2

The crude product (230 mg)obtained in stage 1, the compound (100 mg, 0,306 mmol)obtained in stage 6 of example 16, and tetrakis(triphenylphosphine)palladium(0) (10,6 mg, 0,0092 mmol) is mixed with 1,2-dimethoxyethane (2 ml). Add 2 M aqueous solution of the carbonate is sodium (612 μl, to 1.22 mmol) and the mixture is stirred under heating at 80°C for 25 minutes, After providing opportunity for cooling to the reaction mixture are added ethyl acetate and water, the layers separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer is washed twice with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue is purified twice by chromatography on silica gel (from a mixture of hexane:ethyl acetate = 1:2 to a mixture of chloroform:acetone = 5:1), while receiving a brown amorphous partially purified product (40 mg).

Stage 3

The partially purified product (40 mg)obtained in stage 2, is stirred in tetrahydrofuran (0.4 ml) with 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (85 μl, of 0.085 mmol) at room temperature for 5 minutes To the reaction mixture are added ethyl acetate and a saturated salt solution, the layers separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer is washed twice with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified PTSH (chloroform:acetone = 2:1), thus obtaining the desired compound (24 mg, yield 13%, stage 3) in the form of light to ichnevogo amorphous solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 1,02 (9H, s)of 1.41 (3H, t, J=7,3 Hz), 2,89-of 2.93 (4H, m), and 3.72 (1H, d, J=14,8 Hz), 3,76-3,82 (5H, m), 3,94-4,00 (4H, m), 4,20-of 4.44 (4H, m), 4,63 (1H, DD, J=9,4, 3.6 Hz), of 6.49-6,55 (1H, m), 6,95 (1H, s), 7,89 (1H, s), at 8.60 (1H, s).

Stage 4

To a mixture of compound (24 mg, 0.040 mmol), obtained in stage 3, tetrahydrofuran (240 ml) and water (120 μl) add the monohydrate of lithium hydroxide (3.4 mg, of 0.081 mmol) and the mixture is stirred at room temperature for 2.3 hours. To the reaction mixture are added 5% aqueous solution of potassium hydrosulfate and the mixture is extracted twice with ethyl acetate. The combined organic layer is washed twice with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, the obtained residue is treated with a mixed solvent of hexane-ethyl acetate and the precipitated solid is collected by filtration and dried, thus obtaining the desired compound (20 mg, yield 87%) as a white solid.

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: 0,98 (9H, s), 2.93 which are 2.98 (4H, m), 3,70-3,74 (4H, m), 4,00-4,14 (7H, m), 5,11 (1H, t, J=4,8 Hz), 5,13-5,19 (1H, m), 7,02-was 7.08 (1H, m), 7,52 (1H, s), 8,01 (1H, s), 8,78 (1H, s), shed 15.37 (1H, s).

MS (ESI): M+565.

Example 51

Stage 1

To a suspension of 2-fluoro-5-iodobenzoyl acid (4,79 g, 18.0 mmol) and dimethylformamide (69 μl, 0.90 mmol) in toluene (20 ml) d is billaut thionyl chloride (1.57 in ml, 21.6 mmol) and the mixture is stirred under heating at 110°C for 1 hour. The reaction mixture was concentrated under reduced pressure and twice subjected to azeotropic distillation with toluene. The resulting residue is dissolved in toluene (15 ml)and the solution added to a solution of ethyl-3-(dimethylamino)acrylate (2.83 g, and 19.8 mmol) and diisopropylethylamine (4,07 ml of 23.4 mmol) in toluene (15 ml) at 60°C for 5 min, and the mixture is stirred under heating at 100°C for 16 hours. To the reaction mixture are added water and ethyl acetate, the mixture is stirred and the layers separated. The obtained organic layer was washed with water and saturated salt solution in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 3:2-1:2), thus obtaining the desired compound (6,48 g, yield 85%) as a brown oil.

1H NMR (CDCl3, 400 MHz) (δ) ppm: of 0.95 (3H, t, J=7,1 Hz), 2,89 (3H, users), of 3.32 (3H, users), to 3.99 (2H, q, J=7,1 Hz), 6,79 (1H, DD, J=10,0, 8.5 Hz), 7,66 (1H, DDD, J=8,5, 4,6, 2.4 Hz), 7,78 (1H, s), 7,87 (1H, DD, J=6,6, 2,4 Hz).

Stage 2

Connection (3,20 g)obtained in stage 1, dissolved in tetrahydrofuran, add L-tert-leucinol (977 mg, to 8.34 mmol) and the mixture is stirred at room temperature for a 15.5 hour. The reaction is th mixture is concentrated under reduced pressure and to the residue is added ethyl acetate and water. The mixture is stirred and the layers separated. The organic layer is washed with water and saturated salt solution in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and subjected twice to azeotropic distillation with toluene, thus obtaining the crude product (to 4.41 g) as a brown oil which is a mixture of E-form, Z-form.

1H NMR (CDCl3, 300 MHz) (δ) ppm: 0,87-0,94 (1,6H, m), 0,99 was 1.06 (10,4H, m), 3,05-and 3.16 (1H, m), 3,64-to 3.73 (1H, m), 3,93-4,08 (3H, m), 6,74-6,84 (1H, m), to 7.59-7,74 (2H, m), 8,09-8,18 (1H, m).

Stage 3

A suspension of the crude product (to 4.41 g)obtained in stage 2, and potassium carbonate (1.57 in grams, or 11.4 mmol) in dimethylformamide (40 ml) is stirred under heating at 80°C for 6 hours. To the reaction mixture, water is added while cooling with ice and the precipitated solid is collected by filtration and washed with water. The obtained solid is dried in air at room temperature and dried under reduced pressure at 60°C, thus obtaining the crude product (3,23 g) as a brown solid.

1H NMR (CDCl3, 300 MHz) (δ) ppm: 0,98 (9H, s)of 1.41 (3H, t, J=7.2 Hz), 4,22 is 4.45 (4H, m), and 4.68 (1H, DD, J=8,9, 2,8 Hz), 5,14 (1H, users), 7,46 (1H, d, J=9.3 Hz), 7,89 (1H, DD, J=9,3, 2.2 Hz), 8,07 (1H, d, J=2.2 Hz), 8,69 (1H, C).

Stage 4

To a solution of neoch the seal of the product (3,23 g), obtained in stage 3, and imidazole (645 mg, 9,48 mmol) in dimethylformamide (30 ml) is added tert-butyldimethylsilyl (1,32 g is 8.75 mmol) and the mixture is stirred at room temperature for 1 hour in argon atmosphere. To the reaction mixture are added water and ethyl acetate, the layers separated and the organic layer washed with water (twice) and a saturated solution of salt in a specified sequence. The aqueous layer was extracted with ethyl acetate and the organic layer washed with water and saturated salt solution. The combined organic layer is dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 3:2-2:1), thus obtaining the desired compound (3,81 g, yield 90%, 3 phase) as a pale yellow amorphous solid.

1H NMR (CDCl3, 300 MHz) (δ) ppm: -0,10 (3H, s)-0,01 (3H, s)0,66 (9H, s), was 1.04 (9H, s)of 1.41 (3H, t, J=7.2 Hz), 4,06-4,19 (2H, m), 4,36 is 4.45 (2H, m), 4,60 (1H, DD, J=8,7, and 4.5 Hz), 7,39 (1H, d, J=9.4 Hz), 7,89 (1H, DD, J=9,4, 2.3 Hz), 8,67 (1H, s), 8,88 (1H, d, J=2.3 Hz).

Stage 5

A solution of the compound (300 mg, 0,538 mmol)obtained in stage 4, bis(pinacolato)DIBORANE (150 mg, 0,592 mmol), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) and dichloromethane (1:1) (22 mg, or 0.027 mmol) and potassium acetate (158 mg, of 1.61 mmol) in dimetilan is xide (3 ml) is stirred under heating at 80°C for 20 minutes After allowing to cool to the reaction mixture are added water and ethyl acetate and the resulting insoluble matter was separated by filtration through celite. The layers of the filtrate are separated and the organic layer washed with water (three times) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining the crude product (366 mg) as a brown amorphous solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: -0,10 (3H, s)-0,02 (3H, s), 0,65 (9H, s)of 1.03 (9H, s)of 1.35 (12H, s)of 1.41 (3H, t, J=7,1 Hz), 4.09 to 4,19 (2H, m), 4,36 is 4.45 (2H, m), 4,71 (1H, DD, J=8,2, 5.0 Hz), to 7.59 (1H, d, J=8,8 Hz), 8,01 (1H, DD, J=8,8, 1,63 Hz), 8,67 (1H, s), 9,03 (1H, d, J=1.6 Hz).

Stage 6

To a solution of the crude product (366 mg)obtained in stage 5, the compound (200 mg, 0,592 mmol)obtained in stage 5 of example 2 and tetrakis(triphenylphosphine)palladium(0) (31 mg, or 0.027 mmol) in 1,2-dimethoxyethane (6 ml) is added 2 M aqueous solution of sodium carbonate (1.1 ml, 2.2 mmol) and the mixture is stirred under heating at 80°C. After completion of the reaction the reaction mixture allow to cool and add ethyl acetate. The layers are separated and the organic layer washed with water (three times) and a saturated solution of salt in sequence and dried over sodium sulfate. On the Le filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 3:2), while receiving the desired compound (301 mg, yield 81%, stage 2) in the form of a white amorphous solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: -0,11 (3H, s)-0,02 (3H, s), 0,64 (9H, s)of 1.05 (9H, s)of 1.41 (3H, t, J=7.2 Hz), to 1.48 (9H, s), as 4.02-4,18 (4H, m), 4,36-of 4.44 (2H, m), with 4.64 (1H, DD, J=8,5, and 4.5 Hz), 6,34 (1H, s), at 6.84 (1H, DD, J=5,6, 2,8 Hz), 7,47 (1H, DD, J=8,9, and 2.1 Hz), 7,52-to 7.59 (2H, m), to 8.41 (1H, d, J=2.1 Hz), 8,69 (1H, s).

Stage 7

A solution of the compound (301 mg, 0,437 mmol)obtained in stage 6, in a mixture triperoxonane acid (3 ml) and chloroform (3 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and subjected to azeotropic distillation with toluene. To the obtained residue, add an aqueous solution of sodium bicarbonate and ethyl acetate and the layers separated. The organic layer was washed with water (twice) and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (from a mixture of hexane:ethyl acetate = 1:3 to a mixture of chloroform:methanol = 10:1), thus obtaining the desired compound (196 mg, yield 76%) as amorphous solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: -0,11 (3H, s)-0,02 (3H, s), 0,64 (9H, s)of 1.05 (9H, s)of 1.41 (3H, t, J=7,1 Hz), 3,50 (2H, users), 3,96-4,18 (4H, m), 4,36 is 4.45 (2H, m), with 4.64 (1H, DD, J=8,2, a 4.9 Hz), 6,32 (1H, DD, J=5,4, 2,8 Hz), 6,56 (1H, DD,J=5,6, 2,8 Hz), of 7.48 (1H, DD, J=9,0, 2.3 Hz), 7,56 (1H, d, J=9.0 Hz), 8,42 (1H, d, J=2.3 Hz), 8,69 (1H, s).

Stage 8

To a solution of the compound (100 mg, 0,170 mmol)obtained in stage 7, and pyridine (27 μl, 0.34 mmol) in chloroform (1 ml) is added 4-chlorobutyrate (44 μl, 0,39 mmol) and the mixture is stirred at room temperature for 20 minutes To the reaction mixture are added ethyl acetate and the mixture washed with water (twice) and a saturated solution of salt in a specified sequence. The organic layer is dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, thus obtaining a white amorphous crude product (122 mg).

Stage 9

The crude product (122 mg)obtained in stage 8, was dissolved in dimethylformamide (1 ml)at 0°C. add sodium hydride (60%, 10 mg, 0.25 mmol) and the mixture was stirred at the same temperature for 40 minutes To the reaction mixture an aqueous solution of ammonium chloride and the mixture extracted with ethyl acetate. The organic layer was washed with water (three times) and a saturated solution of salt in sequence and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (from a mixture of hexane:ethyl acetate 1:9 to a mixture of chloroform:meth is Nol = 10:1), while receiving the desired compound (98 mg, yield 88%) as a white amorphous solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: -0,11 (3H, s)-0,02 (3H, s)of 0.64 (s, 9H), OF 1.05 (9H, s)of 1.41 (3H, t, J=7,1 Hz), 2,09-to 2.18 (2H, m), to 2.57 (2H, t, J=8,2 Hz), to 3.73-with 3.79 (2H, m), 4,07-4,18 (4H, m), 4,36-of 4.44 (2H, m), br4.61-4,67 (1H, m), 7.23 percent-7,29 (1H, m), of 7.48-7,53 (1H, m), EUR 7.57 (1H, d, J=9,2 Hz), of 7.70 (1H, DD, J=6,3, 2,8 Hz), 8,40 (1H, d, J=2.2 Hz), 8,68 (1H, s).

Stage 10

Compound (98 mg, 0.15 mmol)obtained in stage 9, is stirred in tetrahydrofuran (1 ml) with 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (224 μl, 0,224 mmol) and the mixture is stirred at room temperature for 10 minutes To the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer was washed with water (three times) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified PTSH (chloroform:methanol = 15:1), thus obtaining the desired compound in quantitative yield (88 mg) as a solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 1.00 and (9H, s)of 1.40 (3H, t, J=7.2 Hz), 2,08-2,19 (2H, m), to 2.57 (2H, t, J=8.1 Hz), 3,76 (2H, t, J=7.5 Hz), 3,83 (1H, d, J=14.4 Hz), of 3.96 (1H, d, J=14.4 Hz), 4,16-4,27 (2H, m), 4,27-4,43 (3H, m), 4,69 was 4.76 (1H, m), 7,29 (1H, DD, J=5,8, 2,8 Hz), 7,42 (1H, DD, J=8,9, and 2.3 Hz), 7,60-7,66 (2H, m), 7,89 (1H, d, J=2.3 Hz), 8,68 (1H, s).

Stage 11

Compound (83 mg, 0.15 mmol)obtained in stage 10, and the monohydrate of lithium hydroxide (13 mg, 0.31 mmol) is stirred in a mixed solvent of tetrahydrofuran (1.5 ml) and water (0.3 ml) at room temperature for 2.7 hours. To the reaction mixture an aqueous solution of citric acid and the mixture extracted with ethyl acetate. The organic layer was washed with water (three times) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue is treated with a mixed solvent of hexane-ethyl acetate. The precipitated solid is collected by filtration and dried under reduced pressure, thus obtaining the desired compound (60 mg, yield 76%) as a white solid.

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.96 (9H, s), is 2.05 (2H, Quint, J=7.5 Hz), 2,45 is 2.55 (2H, m), 3,82 (2H, t, J=7,1 Hz), 4,00-4,12 (2H, m), 4.26 deaths (2H, s), 5,06-5,13 (2H, m), of 7.70 (1H, DD, J=6,1, 2.7 Hz), 7,83 (1H, DD, J=9,2, 2,2 Hz), 7,87 (1H, DD, J=6,4, 2.7 Hz), by 8.22 (1H, d, J=2.2 Hz), of 8.37 (1H, d, J=9,2 Hz), 8,82 (1H, s), 15,17 (1H, users).

MS (ESI): M+515.

Example 53

Stage 1

To a suspension of powdered zinc (0.793 g, 12.1 mmol) in tetrahydrofuran (10 ml) is added 1,2-dibromoethane (and 0.09 ml, 1.0 mmol) and trimethylsilane (with 0.27 ml, 2.1 mmol) by heating at 80°C in an oil bath and the mixture was stirred at so is th same temperature for 10 minutes After allowing to cool for 10 minutes under cooling in a water bath and add a solution of the compound (2,88 g, was 9.33 mmol)obtained in stage 6 of example 1, in tetrahydrofuran (20 ml) and the mixture is stirred at room temperature for 20 minutes To this mixture is added bis(triphenylphosphine)dichloropalladium(II) (252 mg, 0,359 mmol) and a solution of the compound (4.0 g, 7.2 mmol), obtained in stage 4 of example 51, in tetrahydrofuran (10 ml) in a specified sequence, and the mixture is stirred under heating at 80°C for 15 minutes After completion of the reaction the reaction mixture allow to cool and add an aqueous solution of ammonium chloride and ethyl acetate. The resulting insoluble matter was separated by filtration through celite. The layers of the filtrate are separated and the organic layer washed with water (twice) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 2:3-1:2), thus obtaining the desired compound (4.71 g, yield 99%) as a pale yellowish-white amorphous solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: -0,11 (3H, s)-0,02 (3H, s), 0,64 (9H, s)of 1.05 (9H, s)of 1.41 (3H, t, J=7,1 Hz), 2,99 was 3.05 (4H, m), of 3.77-a 3.83 (4H, m), as 4.02-4,18 (4H, m), 4,34-to 4.46 (2H, m), with 4.64 (1H, DD,J=8,5, 4,8 Hz), 6,59 (1H, DD, J=5,5, 3.1 Hz), 6,76 (1H, DD, J=6,0, 3.1 Hz), 7,49 (1H, DD, J=9,1, 2,1 Hz), EUR 7.57 (1H, d, J=9.1 Hz), 8,42 (1H, d, J=2.1 Hz), 8,68 (1H, s).

Stage 2

Connection (5,51 g, 8,35 mmol)obtained in stage 1, was dissolved in ethanol (16 ml), add 4n. an aqueous solution of sodium hydroxide (8 ml, 32 mmol) and the mixture is stirred under heating at 80°C for 2 hours. After providing cooling to the reaction mixture is added 10% aqueous citric acid solution and the mixture extracted with ethyl acetate. The organic layer was washed with water (three times) and a saturated solution of salt in the sequence, add sodium sulfate and activated charcoal and the mixture is diluted with chloroform. The mixture is stirred while heating at 45°C for 15 minutes After allowing to cool, the mixture is filtered through celite and concentrated under reduced pressure. The resulting residue is treated with a mixed solvent of hexane-ethyl acetate and the precipitated solid is collected by filtration and dried under reduced pressure, thus obtaining the desired compound (3,86 g, yield 89%) as a white solid.

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.96 (9H, s), 3,07-of 3.12 (4H, m), 3,69-3,74 (4H, m), 4,00-4,12 (2H, m), 4,18 (2H, s), of 5.05-5,13 (2H, m), 6,97 (1H, DD, J=5,8, 3.0 Hz), was 7.08 (1H, DD, J=5,7, 3.0 Hz), 7,88 (1H, DD, J=9,2, 2,1 Hz), 8,23 (1H, d, J=2.1 Hz), at 8.36 (1H, d, J=9,2 Hz), 8,82 (1H, s) 15,18 (1H, users).

MS (ESI): M+517.

Example 56

Stage 1

To a suspension of powdered zinc (0,572 g, 8,76 mmol) in tetrahydrofuran (7.5 ml) is added 1,2-dibromoethane (65 μl, 0.75 mmol) and trimethylsilane (195 μl, 1.54 mmol) in an argon atmosphere by heating at 80°C in an oil bath and the mixture was stirred at the same temperature for 5 minutes After allowing to cool for 10 minutes under cooling in a water bath and add a solution of the compound (2.20 g, 6,74 mmol)obtained in stage 6 of example 16 in tetrahydrofuran (15 ml) and the mixture stirred at room temperature for 15 minutes To this mixture is added bis(triphenylphosphine)dichloropalladium(II) (182 mg, 0,259 mmol) and a solution of the compound (2,89 g, 5.18 mmol), obtained in stage 4 of example 51, in tetrahydrofuran (7.5 ml) in a specified sequence, and the mixture is stirred under heating at 80°C for 15 minutes After completion of the reaction the reaction mixture allow to cool and add an aqueous solution of ammonium chloride and ethyl acetate. The resulting insoluble matter was separated by filtration through celite. The layers of the filtrate are separated and the aqueous layer was extracted with ethyl acetate. The combined organic layer is washed with salt solution and a saturated salt solution in sequence and dried over sulfate is m sodium. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (hexane:ethyl acetate = 3:4-3:5, then 1:2), thus obtaining the desired insufficiently purified product (3,39 g) as a pale yellow amorphous solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: -0,11 (3H, s)-0,02 (3H, s)0,63 (9H, s)of 1.05 (9H, s)of 1.41 (3H, t, J=7.2 Hz), 2,94-to 2.99 (4H, m), 3,79-a-3.84 (4H, m), as 4.02-4,18 (4H, m), 4,34-to 4.46 (2H, m)and 4.65 (1H, DD, J=8,5, and 4.5 Hz), 6,60-of 6.65 (1H, m), 7,47 (1H, DD, J=8,9, and 2.1 Hz), 7,58 (1H, d, J=8,9 Hz), 8,40 (1H, d, J=2.1 Hz), 8,69 (1H, s).

Stage 2

Not purified product (3,39 g)obtained in stage 1, was dissolved in tetrahydrofuran (34 ml), add 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (7.5 ml, 7.5 mmol) and the mixture is stirred at room temperature for 5 minutes To the reaction mixture is added a saturated solution of salt and the mixture is extracted twice with ethyl acetate. The combined organic layer is washed with salt solution (twice) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (from a mixture of hexane:ethyl acetate = 1:3 to a mixture of chloroform:acetone = 3:2)), thus obtaining the desired compound (2,81 g, yield 96%, stage 2) in wadesville-brown amorphous solid.

1H NMR (CDCl3, 400 MHz) (δ) ppm: 1.00 and (9H, s)of 1.41 (3H, t, J=7,1 Hz), 2.93 which is 3.00 (4H, m), 3,78-3,86 (6H, m), 3,95 (1H, d, J=15.3 Hz), 4,20 is 4.45 (4H, m), to 4.73 (1H, DD, J=9,4, 4,1 Hz), 6,54-6,60 (1H, m), 7,42 (1H, DD, J=8,9, 1.9 Hz), 7,63 (1H, d, J=8,9 Hz), of 7.96 (1H, d, J=1.9 Hz), 8,67 (1H, s).

Stage 3

Connection (2,81 g, 4,99 mmol), obtained in stage 2, was dissolved in a mixed solvent of tetrahydrofuran (1.5 ml) and water (0.3 ml), add the monohydrate of lithium hydroxide (418 mg, 9,98 mmol) and the mixture is stirred at room temperature for 2 hours. To the reaction mixture are added 5% aqueous solution of potassium hydrosulfate and the mixture is extracted twice with ethyl acetate. The combined organic layer is washed with salt solution (twice) and a saturated solution of salt in sequence and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue is treated with a mixed solvent of hexane-ethyl acetate. The precipitated solid is collected by filtration and dried under reduced pressure, thus obtaining the desired compound (2,43 g, yield 91%) as a white solid.

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.96 (9H, s), 2,97-a 3.01 (4H, m), 3,71 is 3.76 (4H, m), 4,00-4,12 (2H, m), is 4.21 (2H, s), 5,06-5,13 (2H, m), 7,24 (1H, DD, J=7,7, 7,7 Hz), 7,83 (1H, DD, J=9,2, and 2.1 Hz), 8,24 (1H, d, J=1.9 Hz), at 8.36 (1H, d, J=9.3 Hz), 8,81 (1H, s), 15,19 (1H, users).

MS (ESI): M+535.

Same the way, as in the above examples, and according to other conventional methods, when necessary, obtain compounds of examples 3, 4, 6-15, 18 to 24, 26-29, 32, 34-37, 38-48, 50, 52, 54, 55, 57-59. The chemical structural formulas of these compounds are shown in tables 1-7. In addition, the compounds of reference examples 30, 31 and 33, shown in table 4, can also be obtained in the same manner as in the above examples, and according to other conventional methods, when necessary.

Data of NMR and MS of the compounds of the examples described below.

Example 3

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.73 (3H, d, J=6.5 Hz), of 1.17 (3H, d, J=6.5 Hz), was 1.94 (4H, t, J=6.6 Hz), 2,33-to 2.42 (1H, m), 3,16-3,20 (4H, m), 3,76-a 3.83 (1H, m), 3.96 points-to 4.01 (1H, m), a 4.03 (2H, s)4,08 (3H, s), the 4.90 (1H, ), 5,20 (1H, t, J=5.0 Hz), 6,45 (1H, DD, J=5,4, 2,9 Hz), 6,53 (1H, DD, J=5,7, 2,9 Hz), 7,47 (1H, s), of 7.97 (1H, s)8,89 (1H, s), 15,44 (1H, s).

MS (ESI): M+517.

Example 4

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.72 (3H, d, J=6.4 Hz)and 1.15 (3H, d, J=6.6 Hz), 2,33-is 2.37 (1H, m), 3,78-of 3.80 (1H, m), 3.96 points-Android 4.04 (6H, m), 4,11 (2H, s), 4,42 (2H, DD, J=8,8, 7,1 Hz), 4,85-to 4.87 (1H, m), 5,19-5,20 (1H, m), 7,45 (1H, s), 7,55 (1H, DD, J=5,7, 2,9 Hz), to 7.68 (1H, DD, J=6,1, 2,8 Hz), of 8.04 (1H, s), 8,86 (1H, s), 15,43 (1H, s).

MS (ESI): M+533.

Example 5

1H NMR (DMSO-d6, 400 MHz) (δ) is d: to 0.72 (3H, d, J=6,8 Hz)of 1.16 (3H, d, J=6.8 Hz), 2,31 is 2.43 (1H, m), 3.04 from-3,10 (4H, m), 3,68-to 3.73 (4H, m), 3.75 to 3,82 (1H, m), 3,94-a 4.03 (1H, m), Android 4.04 (2H, s)4,06 (3H, s), a 4.83 to 4.92 (1H, m), 5,17-5,23 (1H, m), 6.90 to-6,95 (1H, m), 6,98-7,03 (1H, m), 7,46 (1H, s), 7,95 (1H, s), 8,87 (1H, s), 15,44 (1H, users).

MS (ESI): M+533.

Example 6

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.72 (3H, d, J=6,7 Hz)of 1.16 (3H, d, J=6,7 Hz), 1,46-to 1.63 (6H, m), 2,31 is 2.44 (1H, m), 3,05-of 3.12 (4H, m), 3.75 to a 3.83 (1H, m), 3.95 to as 4.02 (1H, m), was 4.02 (2H, s)4,06 (3H, s), a 4.83 to 4.92 (1H, m), 5,17-5,23 (1H, m), 6,86-of 6.90 (1H, m), 6,93-6,97 (1H, m), 7,46 (1H, s), of 7.96 (1H, s), 8,87 (1H, s), 15,44 (1H, users).

MS (ESI): M+531.

Example 7

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.72 (3H, d, J=6.5 Hz), of 1.16 (3H, d, J=6.5 Hz), 1,80 of-1.83 (4H, m), 2,33-2,39 (3H, m), of 3.57 (2H, t, J=5.6 Hz), of 3.77-of 3.80 (1H, m), 3,98-to 3.99 (1H, m), a 4.03 (3H, s), 4,10 (2H, s), a 4.86-4,88 (1H, m), 5,20 (1H, t, J=5,1 Hz), 7.23 percent (1H, DD, J=6,1, 2.4 Hz), 7,45-7,47 (2H, m), of 8.09 (1H, s), 8,88 (1H, s), 15,46 (1H, s).

MS (ESI): M+545.

Example 8

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.72 (3H, d, J=6,8 Hz)of 1.16 (3H, d, J=6.8 Hz), 1,82 is 1.91 (1H, m), 1,96-2,07 (1H, m), 2,31 is 2.43 (1H, m), 2,98-3,03 (1H, m), 3,17-to 3.38 (3H, m), 3.75 to a 3.83 (1H, m), 3,94-was 4.02 (1H, m), was 4.02 (2H, C)4,07 (3H, s), 4,33-and 4.40 (1H, m), 4,84 to 4.92 (1H, m), 4,96 (1H, d, J=3,7 Hz), 5,17-5,23 (1H, m), 6,39-6,44 (1H, m), 6,48-of 6.52 (1H, m), 7,46 (1H, s), of 7.96 (1H, s), 8,87 (1H, s), 15,44 (1H, users).

MS (ESI): M+533.

Example 9

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.72 (3H, d, J=6,8 Hz)of 1.16 (3H, d, J=6.8 Hz), 1,82 is 1.91 (1H, m), 1,96-2,07 (1H, m), 2,30 is 2.43 (1H, m), 2,97 totaling 3.04 (1H, m), 3,17-to 3.38 (3H, m), 3,74-a 3.83 (1H, m), 3,94-was 4.02 (1H, m), was 4.02 (2H, C)4,07 (3H, s), 4,33-and 4.40 (1H, m), 4,84 to 4.92 (1H, m), 4,96 (1H, d, J=3,9 Hz), 5,17-5,23 (1H, m), 6,40-6,44 (1H, m), 6,48-of 6.52 (1H, m), 7,46 (1H, s), of 7.96 (1H, s), 8,87 (1H, s), 15,44 (1H, ush the D.C).

MS (ESI): M+533.

Example 10

1H NMR (DMSO-d6, 300 MHz) (δ) ppm: to 0.72 (3H, d, J=6,8 Hz)and 1.15 (3H, d, J=6.4 Hz), 2,43 of $ 2.53 (3H, m), 2,89 (3H, s), 3.75 to of 3.80 (3H, m), 3.96 points-a 4.03 (4H, m), 4,10 (2H, s), 4,85-to 4.87 (1H, m), 5,18-5,19 (1H, m), 6.87 in (1H, DD, J=5,5, 2,8 Hz), 7,05 (1H, DD, J=6,0, 3.0 Hz), 7,45 (1H, s), of 8.09 (1H, s), 8,87 (1H, s), 15,44 (1H, s).

MS (ESI): M+546.

Example 11

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.72 (3H, d, J=6.5 Hz), of 1.16 (3H, d, J=6.5 Hz), 2,02 (3H, s), 2,31 is 2.46 (1H, m), 3.04 from-3,10 (2H, m), 3,11 -, and 3.16 (2H, m), 3,51-to 3.58 (4H, m), 3.75 to a 3.83 (1H, m), 3,94-a 4.03 (1H, m), Android 4.04 (2H, s), 4,06 (3H, s), 4,84 to 4.92 (1H, m), 5,17-5,23 (1H, m), 6,92-6,97 (1H, m), 7,00-7,05 (1H, m), 7,46 (1H, s), of 7.96 (1H, s), 8,88 (1H, s), 15,44 (1H, users).

MS (ESI): M+574.

Example 12

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.72 (3H, d, J=6.5 Hz), of 1.16 (3H, d, J=6.5 Hz), 2,34-is 2.37 (1H, m), 2,49-2,52 (2H, m), 3,44 (2H, t, J=7,1 Hz)to 3.67 (2H, t, J=13,2 Hz), of 3.77-of 3.80 (1H, m), 3,99-Android 4.04 (3H, m), 4,07 (3H, s), 4,87-4,89(1H, m), 5,20 (1H, t, J=5,2 Hz), to 6.57 (1H, DD, J=5,6, 3.0 Hz), 6,69 (1H, DD, J=5,7, 2,9 Hz), 7,46 (1H, s), 7,95 (1H, s), 8,88 (1H, s), 15,43 (1H, s).

MS (ESI): M+553.

Example 13

1H NMR (DMSO-d6, 300 MHz) (δ) ppm: to 0.72 (3H, d, J=6,8 Hz)of 1.16 (3H, d, J=6.4 Hz), 2,18 to 2.35 (3H, m), 3,28-to 3.58 (4H, m), 3.75 to-3,81 (1H, m), 3,97-was 4.02 (3H, m), 4,07 (3H, s), a 4.86-4,89 (1H, m), 5,20 (1H, t, J=5,1 Hz), 5,33-5,51 (1H, m), 6,50 (1H, DD, J=5,7, 3.0 Hz), 6,60 (1H, DD, J=5,8, 2,8 Hz), 7,46 (1H, s), of 7.96 (1H, s), 8,87 (1H, s), 15,43 (1H, s).

MS (ESI): M+535.

Example 14

1H NMR (DMSO-d6, 300 MHz) (δ) ppm: to 0.72 (3H, d, J=6.4 Hz), of 1.16 (3H, d, J=6.4 Hz), 2,20-2,31 (3H, m), 3,34-3,51 (4H, m), 3,76-3,82 (1H, m), 3.96 points-a 4.03 (3H, m), 4,07 (3H, s), 4,88-4,89 (1H, m), 5,20 (1H, t, J=4,7 Hz), 5,34-5,52 (1H, m), 6,50 (1H, DD, J=5,5, 2,8 Hz), 6,60 (1H, DD, J=5,8, 3,2 is C), 7,46 (1H, s), of 7.96 (1H, s), 8,87 (1H, s), 15,43 (1H, s).

MS (ESI): M+535.

Example 15

1H NMR (DMSO-d6, 300 MHz) (δ) ppm: of 1.18 (3H, d, J=6.0 Hz), of 3.07 (4H, t, J=4,7 Hz), 3,21 (3H, s), 3,71 (4H, t, J=4,7 Hz), 3,85-4,04 (8H, m), 5,18-5,23 (2H, m)6,91 (1H, DD, J=5,8, 2,8 Hz), 7,00 (1H, DD, J=5,7, 3.0 Hz), 7,44 (1H, s), 7,95 (1H, s), to 8.94 (1H, s), 15,41 (1H, s).

MS (ESI): M+549.

Example 16

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.72 (3H, d, J=6,8 Hz)of 1.16 (3H, d, J=6.8 Hz), 2,31 at 2.45 (1H, m), 2.93 which is 3.00 (4H, m), 3,70 of 3.75 (4H, m), 3.75 to 3,82 (1H, m), 3.95 to as 4.02 (1H, m)4,06 (3H, s)4,07 (2H, s), a 4.83 to 4.92 (1H, m), 5,17-5,23 (1H, m), 7,05-7,11 (1H, m), 7,46 (1H, s), 8,01 (1H, s), 8,88 (1H, s), 15,44 (1H, users).

MS (ESI): M+551.

Example 17

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: 0,99 (9H, s), is 3.08 (4H, t, J=4,8 Hz), 3,71 (4H, t, J=4,8 Hz), a 4.03-4,11 (2H, m), of 4.05 (2H, s)4,08 (3H, s)to 5.13 (1H, t, J=4.9 Hz), 5,17-5,20 (1H, m), 6.90 to-6,92 (1H, m), 7,01-7,03 (1H, m,), 7,54 (1H, s), of 7.96 (1H, s), 8,79 (1H, s), 15,39 (1H, s).

MS (ESI): M+547.

Example 18

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: 0,98 (9H, s), 1,25 (3H, t, J=7.4 Hz), 2,88-to 2.99 (2H, m), is 3.08 (4H, t, J=4,8 Hz), 3,71 (4H, t, J=4,8 Hz), a 4.03-4,13 (2H, m), 4,19 (2H, s), 5,14 (1H, t, J=4.9 Hz), 5,18-to 5.21 (1H, m), 6.89 in-6,91 (1H, m), 7.03 is-7,06 (1H, m), 7,94 (1H, s), 8,18 (1H, s), 8,80 (1H, s), 15,22 (1H, s).

MS (ESI): M+545.

Example 19

1H NMR (DMSO-d6, 300 MHz) (δ) ppm: of 1.03 (3H, t, J=7.0 Hz), of 3.07 (4H, t, J=4,7 Hz), of 3.45 (2H, q, J=6.9 Hz), 3,70 (4H, t, J=4,7 Hz), 3,88-4,00 (9H, m), a 5.25 (1H, t, J=5.3 Hz), 5,34 of 5.39 (1H, m)6,91 (1H, DD, J=5,7, 3,0 Hz), 7,00 (1H, DD, J=6,0, 3.0 Hz), 7,45 (1H, s), of 7.97 (1H, s), cent to 8.85 (1H, s), 15,39 (1H, s).

MS (ESI): M+549.

Example 20

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 1.25 (3H, t, J=7.5 Hz, 2,90 (2H, q, J=7.5 Hz), of 3.07 (4H, t, J=4,8 Hz), 3,26 (3H, s), 3,70 (4H, t, J=4,8 Hz), 3,80-of 3.96 (4H, m), 4,18 (2H, s), of 5.26 (1H, t, J=5.4 Hz), 5,35-5,42 (1H, m), 6.90 to-6,92 (1H, m), 7,01? 7.04 baby mortality (1H, m), 7,95 (1H, s), of 8.00 (1H, s), 8,86 (1H, s), 15,19 (1H, s).

MS (ESI): M+533.

Example 21

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.72 (3H, d, J=6,7 Hz)and 1.15 (3H, d, J=6.5 Hz), 2,34-to 2.41 (3H, m), 3,50-of 3.54 (2H, m), 3,70-to 3.73 (2H, m), 3,74-3,81 (1H, m), 3.95 to as 4.02 (1H, m), Android 4.04 (3H, s), 4,10 (2H, s), to 4.87 (1H, users), 5,18-5,20 (1H, m), 7,20 (1H, DD, J=5,7, 2,9 Hz), 7,25 (1H, DD, J=5,9, 2,9 Hz), 7,45 (1H, s), 8,08 (1H, s), 8,88 (1H, s), 15,44 (1H, s).

MS (ESI): M+567.

Example 22

1H NMR (DMSO-d6, 300 MHz) (δ) ppm: of 3.07 (4H, t, J=4,7 Hz), 3,26 (3H, s), 3,70 (4H, t, J=4,7 Hz), 3,83-of 3.94 (4H, m), as 4.02-Android 4.04 (5H, m), 5,27 (1H, t, J=5.5 Hz), 5,38-5,42 (1H, m)6,91 (1H, DD, J=5,7, 3.0 Hz), 7,00 (1H, DD, J=5,8, and 3.2 Hz), 7,45 (1H, s), of 7.97 (1H, s), 8,83 (1H, s)15,40 (1H, s).

MS (ESI): M+535.

Example 23

1H NMR (CDCl3400 MHz) (δ) ppm: or 0.83 (3H, d, J=6,5 Hz)of 1.23 (3H, d, J=6.5 Hz), is 1.31 (3H, t, J=7,6 Hz), 2,41-2,52 (1H, m), and 2.83 (2H, q, J=7,6 Hz)of 3.00 (4H, t, J=4.9 Hz), of 3.07 (1H, users), of 3.77 (4H, t, J=4.9 Hz), 4,12-4,27 (4H, m), 4,54-to 4.62 (1H, m), 6,44-of 6.49 (1H, m), 6,79 (1H, DD, J=2,8, 6,0 Hz), 7,58 (1H, s), 8,24 (1H, s), 8,86 (1H, s), 15,25 (1H, users).

MS (ESI): M+531.

Example 24

1H NMR (DMSO-d6, 300 MHz) (δ) ppm: to 0.72 (3H, d, J=7,0 Hz)and 1.15 (3H, d, J=7,0 Hz), 1,25 (3H, t, J=7.4 Hz), 2,03 (2H, TT, J=7,0, 7,0 Hz), 2,31 is 2.43 (1H, m), 2,47 (2H, t, J=7.0 Hz), 2,90 (2H, q, J=7.4 Hz), 3.75 to with 3.79 (1H, m), with 3.79 (2H, t, J=7.0 Hz), 3.95 to a 4.03 (1H, m), 4.26 deaths (2H, s), 4,88-of 4.95 (1H, m), 5,20 (1H, t, J=5,1 Hz), 7,60 (1H, DD, J=2,8, 6.2 Hz), 7,86 (1H, DD, J=2,8, 6.2 Hz), 7,95 (1H, s), of 8.09 (1H, s), 8,91 (1H, s), 15,23 (1H, s).

MS (ESI): M+529.

Example 25

1H I Is R (DMSO-d 6, 300 MHz) (δ) ppm: to 0.72 (3H, d, J=6.4 Hz), of 1.16 (3H, d, J=6.4 Hz), 2,10 (2H, TT, J=7,4, 7,4 Hz), 2,42 (2H, t, J=7.4 Hz), 2,31 is 2.44 (1H, m), 3,74 (2H, t, J=7.4 Hz), to 3.73-a 3.83 (1H, m), 3.95 to 4,06 (1H, m), 4,03 (3H, s), 4,10 (2H, s), a 4.83-4,91 (1H, m), 5,19 (1H, t, J=5.0 Hz), was 7.45 (1H, DD, J=7,6, 7,6 Hz), 7,45 (1H, s)to 8.12 (1H, s), 8,88(1H, s), 15,45 (1H, s).

MS (ESI): M+549.

Example 26

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: of 0.71 (3H, d, J=6.5 Hz), to 1.14 (3H, d, J=6.5 Hz), to 1.21 (3H, t, J=7.4 Hz), is 2.09 (2H, TT, J=7,4, 7,4 Hz), 2,31 is 2.43 (3H, m), 2,87 (2H, square, J=7,4 Hz), and 3.72 (2H, t, J=7.4 Hz), 3.75 to-3,81 (1H, m), 3,94-was 4.02 (1H, m), 4,24 (2H, s), the 4.90 (1H, users), 5,16 with 5.22 (1H, m), 7,41 (1H, t, J=7.8 Hz), 8,01 (1H, s), 8,08 (1H, s), of 8.90 (1H, s), 15,23 (1H, s).

MS (ESI): M+547.

Example 27

1H NMR (DMSO-d6, 300 MHz) (δ) ppm: to 0.72 (3H, d, J=6.4 Hz), of 1.16 (3H, d, J=6.4 Hz), 2,36 is 2.43 (1H, m), 2,63-of 2.66 (4H, m), 3,47-to 3.49 (4H, m), 3,76-a 3.83 (1H, m), 3,97-3,98 (1H, m), a 4.03 (2H, s)4,06 (3H, s), 4,85-of 4.90 (1H, m), 5,19 (1H, t, J=5,1 Hz), make 6.90 (1H, DD, J=5,7, 3.0 Hz), of 6.99 (1H, DD, J=6,0, 3.0 Hz), 7,46 (1H, s), of 7.97 (1H, s), 8,88 (1H, s), 15,43 (1H, s).

MS (ESI): M+549.

Example 28

1H NMR (CDCl3300 MHz) (δ) ppm: to 1.21 (3H, d, J=6.4 Hz), was 2.76-2,98 (1H, m), 3,03 (4H, t, J=4.5 Hz), 3.43 points (3H, s), 3,80 (4H, t, J=4,7 Hz), 3,83-3,93 (1H, m), 3,98 (3H, s), Android 4.04 (2H, s), 4,19 is 4.36 (2H, m), with 4.64 (1H, users), 6,57-only 6.64 (1H, m), 6,74-for 6.81 (1H, m), 6,98 (1H, s), 8,21 (1H, s), 8,84 (1H, s), 15,25 (1H, users).

MS (ESI): M+549.

Example 29

1H NMR (CDCl3300 MHz) (δ) ppm: 2,07-of 2.21 (1H, m), 2,22-is 2.37 (1H, m), 3,03 (4H, t, J=4,7 Hz), 3,22-3,31 (5H, m), 3.45 points-of 3.54 (1H, m), with 3.79 (4H, t, J=4,7 Hz)to 3.99 (3H, s), Android 4.04 (2H, s), 4,08-4,20 (2H, m), 5,09 (1H, users), 6,56-6,63 (1H, m), 6.75 in-to 6.80 (1H, m), 7,22 (1H, s), 8,18 (1H, s), 8,86 (1H, s), 15,46 (1H, users).

MS (ESI): M+549.

Example 2

1H NMR (DMSO-d6, 300 MHz) (δ) ppm: to 0.72 (3H, d, J=6,8 Hz)of 1.16 (3H, d, J=6.4 Hz), 1,39-1,49 (2H, m), of 1.78 and 1.80 (2H, m), a 2.36-to 2.41 (1H, m), 2,83-2,87 (2H, m), 3,42-3,82 (4H, m), 3,97-to 3.99 (1H, m), a 4.03 (2H, users), 4,06 (3H, s), 4,84-of 4.90 (1H, m), 6,88-6,94 (1H, m), 6,97-7,02 (1H, m), 7,46 (1H, users), of 7.97 (1H, users), 8,87 (1H, s).

MS (ESI): M+547.

Example 34

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: 1,17 (3H, d, J=6.2 Hz), 1,24 (3H, t, J=7.4 Hz), 2,90 (2H, q, J=7.4 Hz), 3,06-is 3.08 (4H, m), 3,19 (3H, s), 3,69-and 3.72 (4H, m), 3,83-are 3.90 (1H, m), 3,93-4,01 (2H, m), 4,18 (2H, s), 5,18-5,23 (2H,, m), 6.90 to (1H, DD, J=5,6, 3.0 Hz), 7,03 (1H, DD, J=6,0, 3.0 Hz), to 7.93 (1H, s), 8,02 (1H, s), 8,96 (1H, s), 15,21 (1H, s).

MS (ESI): M+547.

Example 35

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 1.16 (3H, d, J=6.5 Hz), 1,25 (3H, t, J=7.4 Hz), of 2.92 (2H, q, J=7.4 Hz), of 3.07 (4H, t, J=4,8 Hz)at 3.25 (3H, s), 3,70 (4H, t, J=4,8 Hz), 3,78-of 3.80 (1H, osirm), 3,98-4,07 (2H, m), 4,18 (2H, s), 5,12-5,19 (1H, m)to 5.17 (1H, t, J=5,1 Hz), 6,92 (1H, DD, J=5,8, 3.0 Hz), 7,03 (1H, DD, J=5,8, 3.0 Hz), 7,94 (1H, s), of 8.04 (1H, s), of 8.90 (1H, s), 15,18 (1H, s).

MS (ESI): M+547.

Example 36

1H NMR (DMSO-d6, 300 MHz) (δ) ppm: to 0.73 (3H, d, J=6.4 Hz), of 1.16 (3H, d, J=6.4 Hz), 2,34-2,39 (1H, m), 3,78-of 3.80 (1H, m), 3,98-4,00 (1H, m), of 4.05 (3H, s), is 4.21 (2H, s), a 4.86-4,89 (1H, m), 5,19 (1H, t, J=5,1 Hz), of 7.36-7,40 (1H, m), 7,47 (1H, users), 7,89 (1H, TD, J=7,7, 1.5 Hz), 8,01 (1H, d, J=8,3 Hz), 8,07 (1H, t, J=3.2 Hz), of 8.09 (1H, users), 8,19 (1H, DD, J=7,0, 2,1 Hz), 8,63-8,66 (1H, m), 8,88 (1H, s), 15,41 (1H, users).

MS (ESI): M+525.

Example 37

1H NMR (DMSO-d6, 300 MHz) (δ) ppm: to 0.73 (3H, d, J=6.4 Hz), of 1.16 (3H, d, J=6.8 Hz), 2,33-to 2.41 (1H, m), 3,76-3,82 (1H, m)to 3.99 (1H, t, J=7,7 Hz), of 4.05 (3H, s), is 4.21 (2H, s), 4,84-of 4.90 (1H, m), 5,19 (1H, t, J=4,7 Hz), of 7.48 (1H, users), 7,84 (1, d, J=3.0 Hz), of 7.90 (1H, DD, J=6,4, and 2.3 Hz), to 7.93 (1H, d, J=3,4 Hz), 8,02 (1H, DD, J=6,4, and 2.3 Hz), 8,13 (1H, s)8,89 (1H, s), 15,41 (1H, s).

MS (ESI): M+531.

Example 38

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: of 0.90 (3H, t, J=6.9 Hz), of 1.18 (3H, d, J=6.0 Hz), 1,24 (3H, t, J=7.4 Hz), 2,89 (2H, square, J=7,4 Hz), 3,05-is 3.08 (4H, m), 3,19 of 3.28 (1H, m), 3,50 is 3.57 (1H, m), 3,68-and 3.72 (4H, m), 3,84-3,91 (1H, m,), 3,94-4,08 (2H, m), 4,18 (2H, s), 5,15-5,24 (2H, m), to 6.88 (1H, DD, J=5,6, 3.0 Hz), 7,03 (1H, DD, J=5,8, 3.0 Hz), to 7.93 (1H, s), 8,02 (1H, s), 9,01 (1H, s), 15,21 (1H, s).

MS (ESI): M+561.

Example 39

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: of 1.03 (3H, t, J=7.0 Hz), 2,03 (2H, TT, J=7,8, 7.5 Hz), 2,48 (2H, t, J=7.8 Hz), 3,41-3,50 (2H, m), with 3.79 (2H, t, J=7.5 Hz), 3,83-was 4.02 (4H, m), a 4.03 (3H, s), 4,11 (2H, s), of 5.26 (1H, DD, J=5,1 at 5.1 Hz), 5,34-of 5.40 (1H, osirm), was 7.45 (1H, s), to 7.61 (1H, DD, J=6,1, 2,8 Hz), 7,80 (1H, DD, J=6,1, 2,8 Hz), of 8.04 (1H, s), 8,86 (1H, s), 15,39 (1H, s).

MS (ESI): M+547.

Example 40

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: of 0.91 (3H, t, J=7,0 Hz)of 1.18 (3H, d, J=6.0 Hz), 1,24 (3H, t, J=7.4 Hz), 2,02 (2H, TT, J=7,5, 7,7 Hz), 2,47 (2H, t, J=7,7 Hz), is 2.88 (2H, q, J=7.4 Hz), 3,20 to be 3.29 (1H, m), 3,50-to 3.58 (1H, m), of 3.78 (2H, t, J=7.5 Hz), a-3.84-4.09 to (3H, m), 4.26 deaths (2H, s), 5,16-to 5.21 (1H, m), 5,23 (1H, t, J=5.0 Hz), EUR 7.57 (1H, DD, J=6,2, 2.7 Hz), 7,86 (1H, DD, J=6,2, 2.7 Hz), 7,95 (1H, s), 8,03 (1H, s), 9,01 (1H, s), 15,21 (1H, s).

MS (ESI): M+559.

Example 41

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: 1,16-1,19 (3H, m)of 1.24 (3H, t, J=7.5 Hz), 2,03 (2H, TT, J=7,3, 7,3 Hz), 2,45 is 2.51 (2H, m), 2,89 (2H, q, J=7.5 Hz), 3,20 (3H, s), with 3.79 (2H, t, J=7,3 Hz), 3,83-are 3.90 (1H, m), 3,93-4,01 (2H, m,), 4,25 (2H, s), 5,18-a 5.25 (2H, m), 7,58 (1H, DD, J=6,4, 2.7 Hz), the 7.85 (1H, DD, J=6,4, 2.7 Hz), 7,95 (1H, s), 8,03 (1H, s), 8,96 (1H, s), 15,20 (1H, users).

MS (ESI): M+545.

Example 42/p>

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: of 0.91 (3H, s)of 1.45 (3H, s), 3.04 from-3,10 (4H, m), 3,14 (3H, s), 3,66 of 3.75 (4H, m), 3,94-of 4.05 (1H, m), a 4.03 (2H, s)4,06 (3H, s), 4,11-4,19 (1H, m), 4,95-free 5.01 (1H, m), 5,17-5,24 (1H, m), 6,88-6,94 (1H, m), 6,98-7,03 (1H, m), 7,49 (1H, s), 7,94 (1H, s), which is 9.09 (1H, s), 15,38 (1H, users).

MS (ESI): M+563.

Example 43

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,89 (3H, s)of 1.24 (3H, t, J=7,6 Hz)of 1.45 (3H, s), 2,85 are 2.98 (2H, m), 3.04 from-3,10 (4H, m), 3,14 (3H, s), 3,67-3,74 (4H, m), 3.95 to of 4.05 (1H, m), 4,10-4,20 (1H, m), 4,18 (2H, s), equal to 4.97-5,02 (1H, m,), to 5.21 at 5.27 (1H, m), 6,88-6,93 (1H, m), 7,01-7,05 (1H, m), to $ 7.91 (1H, s)to 8.14 (1H, s), the remaining 9.08 (1H, s), 15,21 (1H, users).

MS (ESI): M+561.

Example 44

1H NMR (DMSO-d6, 300 MHz) (δ) ppm: 1.26 in (3H, t, J=7.5 Hz), 2,11-of 2.27 (2H, m), 2,90 (2H, q, J=7.4 Hz), 3,06 (4H, t, J=4,7 Hz), 3,11 (3H, s), 3,19-up 3.22 (2H, m), 3,37-to 3.41 (2H, m), 3,70 (4H, t, J=4,7 Hz), 3,81-3,93 (2H, m), 4,18 (2H, s), 5,19-5,31 (1H, m), 5,23 (1H, t, J=5.3 Hz), 6.89 in (1H, DD, J=5,8, 2.7 Hz), 7,03 (1H, DD, J=5,8, 2.7 Hz), 7,94 (1H, s), 7,98 (1H, s), 8,91 (1H, s), 15,25 (1H, s).

MS (ESI): M+547.

Example 45

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: 0,98 (9H, s)2,03 (2H, TT, J=8,2, 7,2 Hz), the 2.46 (2H, t, J=8,2 Hz), with 3.79 (2H, t, J=7.2 Hz), was 4.02-4,16 (4H, m), of 4.05 (3H, s), 5,10 (1H, t, J=4,7 Hz), 5,14-by 5.18 (1H, m), 7,52 (1H, s), 7,60 (1H, DD, J=6,0, 2.6 Hz), 7,82 (1H, DD, J=6,4, and 2.6 Hz), 8,03 (1H, s), 8,78 (1H, s), 15,36 (1H, users).

MS (ESI): M+545.

Example 46

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: 0,98 (9H, s), 2,10 (2H, TT, J=8,0, 7,1 Hz)to 2.41 (2H, t, J=8.0 Hz), to 3.73 (2H, t, J=7,1 Hz), a 4.03 (3H, s), 4,05-4,11 (4H, m), 5,11 (1H, t, J=4.5 Hz), 5,13-5,17 (1H, m), 7,42 (1H, t, J=7,9 Hz), 7,51 (1H, s), 8,11 (1H, s), 8,79 (1H, s), 15,38 (1H, users).

MS (ESI): M+563.

Example 47

1H NMR (DMSO-d sub> 6, 400 MHz) (δ) ppm: 1,99-2,07 (2H, m), 2,09-of 2.26 (2H, m), 2,47 (2H, t, J=7,6 Hz), 3,14 (3H, s), 3,21-3,29 (1H, m), 3.33 and-to 3.41 (1H, m), with 3.79 (2H, t, J=7,6 Hz), 3,79-of 3.97 (2H, m), a 4.03 (3H, s), of 4.12 (2H, s), 5.17 to-of 5.26 (1H, m), a 5.25 (1H, t, J=5.3 Hz), 7,46 (1H, s), to 7.61 (1H, DD, J=6,2, 2.7 Hz), 7,81 (1H, DD, J=6,2, 2.7 Hz), 8,03 (1H, s), of 8.90 (1H, s), 15,42 (1H, s).

MS (ESI): M+547.

Example 48

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: of 1.18 (3H, d, J=6.5 Hz), 1,99-2,07 (2H, m), 2,48 (2H, t, J=7.9 Hz), 3,21 (3H, s), with 3.79 (2H, t, J=7,1 Hz), 3,84-3,91 (1H, m), 3,93-4,00 (2H, m), a 4.03 (3H, s), 4,11 (2H, s), 5,17-5,22 (1H, m,), to 5.21 (1H, t, J=5.3 Hz), 7,45 (1H, s), to 7.61 (1H, DD, J=6,2, 2,8 Hz), 7,81 (1H, DD, J=6,2, 2,8 Hz), 8,03 (1H, s), to 8.94 (1H, s)15,40 (1H, s)

MS (ESI): M+547.

Example 49

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: 0,98 (9H, s), 2.93 which are 2.98 (4H, m), 3,70-3,74 (4H, m), 4,00-4,14 (7H, m), 5,11 (1H, t, J=4,8 Hz), 5,13-5,19 (1H, m), 7,02-was 7.08 (1H, m), 7,52 (1H, s), 8,01 (1H, s), 8,78 (1H, s), shed 15.37 (1H, s).

MS (ESI): M+565.

Example 50

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: of 0.93 (3H, t, J=7,1 Hz)to 1.19 (3H, d, J=6.0 Hz), 3.04 from-3,10 (4H, m), 3,21-of 3.31 (1H, m), 3,50-3,60 (1H, m), 3,67-to 3.73 (4H, m), 3,84-4,10 (3H, m), Android 4.04 (5H, s), 5,14-a 5.25 (2H, m), 6,88-6,92 (1H, m), 6,98-7,02 (1H, m), 7,44 (1H, s), 7,95 (1H, s), 8,97 (1H, s)15,40 (1H, users).

MS (ESI): M+563.

Example 51

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.96 (9H, s), is 2.05 (2H, q, J=7.5 Hz), 2,45 is 2.55 (2H, m), 3,82 (2H, t, J=7,1 Hz), 4,00-4,12 (2H, m), 4.26 deaths (2H, s), 5,06-5,13 (2H, m), of 7.70 (1H, DD, J=6,1, 2.7 Hz), 7,83 (1H, DD, J=9,2, 2,2 Hz), 7,87 (1H, DD, J=6,4, 2.7 Hz), by 8.22 (1H, d, J=2.2 Hz), of 8.37 (1H, d, J=9,2 Hz), 8,82 (1H, s), 15,17 (1H, users).

MS (ESI): M+515.

Example 52

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: 0,97 (9H, s)of 1.24 (3H, t, J=7,50 Hz), 2,03 (2H, TT, J=7,5 7.5 Hz), 2,45 is 2.51 (2H, m), 2,88-2,95 (2H, m), of 3.78 (2H, t, J=7.5 Hz), a 4.03-4,11 (2H, m), 4.26 deaths (2H, s), 5,12 (1H, t, J=5.0 Hz), 5,16 with 5.22 (1H, m), EUR 7.57 (1H, DD, J=6,4, 2.7 Hz), 7,86 (1H, DD, J=6,4, 2.7 Hz), 7,95 (1H, ), 8,17 (1H, s), 8,80 (1H, s), 15,18 (1H, users).

MS (ESI): M+543.

Example 53

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.96 (9H, s), 3,07-of 3.12 (4H, m), 3,69-3,74 (4H, m), 4,00-4,12 (2H, m), 4,18 (2H, s), of 5.05-5,13 (2H, m), 6,97 (1H, DD, J=5,8, 3.0 Hz), was 7.08 (1H, DD, J=5,7, 3.0 Hz), 7,88 (1H, DD, J=9,2, 2,1 Hz), 8,23 (1H, d, J=2.1 Hz), at 8.36 (1H, d, J=9,2 Hz), 8,82 (1H, s), 15,18 (1H, users).

MS (ESI): M+517.

Example 54

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.96 (9H, s), 2,12 (2H, TT, J=7,9, and 6.9 Hz), 2,43 (2H, t, J=7.9 Hz in), 3.75 (2H, t, J=6.9 Hz), 4,00-4,11 (2H, m), 4,24 (2H, s), 5,07-5,12 (2H, m), a 7.62 (1H, t, J=7.9 Hz), 7,82 (1H, DD, J=9,1, 2.0 Hz), compared to 8.26 (1H, d, J=2.0 Hz), of 8.37 (1H, d, J=9.1 Hz), 8,82 (1H, s), 15,16 (1H, users).

MS (ESI): M+533.

Example 55

1H NMR (CHCl3, 400 MHz) (δ) ppm: of 1.06 (9H, s)of 1.30 (3H, t, J=7.5 Hz), 2,17 (2H, TT, J=7,5, 7.9 Hz), 2.49 USD (2H, t, J=7.9 Hz), 2.77-to 2,84 (2H, m in), 3.75 (2H, t, J=7.5 Hz), 4,14 (2H, DD, J=16.5, and 19.3 Hz), 4,28 is 4.35 (2H, m), 4,95 (1H, DD, J=9,0, 5,1 Hz)6,94 (1H, t, J=7.8 Hz), 7,68 (1H, s), of 8.25 (1H, s), 8,84 (1H, s), 15,14 (1H, s).

MS (ESI): M+561.

Example 56

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.96 (9H, s), 2,97-a 3.01 (4H, m), 3,71 is 3.76 (4H, m), 4,00-4,12 (2H, m), is 4.21 (2H, s), 5,06-5,13 (2H, m), 7,24 (1H, DD, J=7,7, 7,7 Hz), 7,83 (1H, DD, J=9,2, and 2.1 Hz), 8,24 (1H, d, J=1.9 Hz), at 8.36 (1H, d, J=9.3 Hz), 8,81 (1H, s), 15,19 (1H, users).

MS (ESI): M+535.

Example 57

1H NMR (DMSO-d6, 300 MHz) (δ) ppm: 0,73 (1H, d, J=6.4 Hz), 1,16 (1H, d, J=6.4 Hz), 2,30 is 2.46 (1H, m), 2,65 (3H, s), 3,74-of 3.85 (1H, m), 3,93-4,08 (4H, m), 4,22 (2H, s), 4,82-4,94 (1H, m), 5,19 (1H, t, J=,3 Hz), 7,47 (1H, s), 7,89 (1H, DD, J=6,4, and 2.3 Hz), 8,01 (1H, DD, J=6,8, and 2.3 Hz), 8,16 (1H, s)8,89 (1H, s), 15,41 (1H, s).

MS (ESI): M+530.

Example 58

1H NMR (DMSO-d6, 300 MHz) (δ) ppm: to 0.96 (9H, s), 3,70 (2H, t, J=4.9 Hz), 3,98 (2H, t, J=5.3 Hz), 4,01-4,11 (2H, m), 4,24 (4H, s), 5,06-of 5.15 (2H, m), 7,72 (1H, DD, J=7,9, 7.9 Hz), 7,83 (1H, d, J=9.4 Hz), of 8.27 (1H, s), 8.34 per (1H, d, J=9.4 Hz), 8,82 (1H, s), 15,19 (1H, users).

MS (ESI): M+549.

Example 59

1H NMR (DMSO-d6, 400 MHz) (δ) ppm: to 0.96 (9H, s), 2,96-to 3.02 (4H, m), 3,70 is 3.76 (4H, m), 4,00-4,12 (2H, m), is 4.21 (2H, s), 5,07-5,12 (2H, m), 7,22 (1H, DD, J=7,7, 7,7 Hz), 7,83 (1H, DD, J=9,0, 2.4 Hz), 8,24 (1H, d, J=2.0 Hz), at 8.36 (1H, d, J=9.0 Hz), 8,82 (1H, s), 15,18 (1H, users).

MS (ESI): M+535.

Experimental example 1

Here are the ways to assess the integrase inhibiting HIV activity of the compounds of the present invention.

(i) Construction of the expression system, recombinant integrase gene

Full integrase gene of HIV (J. Virol., 67, 425-437 (1993)), in which the phenylalanine at codon 185 replaced with histidine, was inserted between the sites of the restriction enzyme NdeI and XhoI plasmid peT21a(+) (Novagen), which was constructed in the expression vector integrase pET21a-IN-F185H.

(ii) Production and purification of the protein integrase

Recombinant Escherichia coli BL21 (DE3), transformed with the plasmid pET21a-IN-F185H obtained in (i), was cultured with shaking at 30°C in liquid medium containing ampicillin. When cultivation has reached the phase of logarithmic growth, to stimulate e is cpressey integrase gene was added isopropyl-β-D-thiogalactopyranoside. The cultivation was continued for 3 hours to stimulate the accumulation of protein integrase. Recombinant E. coli was collected as a precipitate in vitro separation in the centrifuge and kept at -80°C.

E. coli suspended in the buffer for lysis (20 mm HEPES (pH 7.5), 5 mm DTT, 10 mm CHAPS, 10% glycerol)containing 1 M sodium chloride, and subjected to repeated pressure and decreasing pressure to rupture the cells and separated by centrifugation at 4°C, 40000×g, 60 min for separation of water-soluble fraction (supernatant). The fraction was diluted 10-fold buffer for lysis without sodium chloride, mixed with SP-separate (GE healthcare Bioscience) and stirred at 4°C for 60 min, in order to carry out the adsorption of protein integrase on the resin. The resin was washed with buffer for lysis, containing 100 mm sodium chloride, and protein integrase was suirable buffer for lysis, containing 1 M sodium chloride.

The solution lirovannomu protein integrase was subjected to gel filtration through a column with superdex 75 (GE healthcare Bioscience). Protein was suirable buffer for lysis, containing 1 M sodium chloride.

The obtained fractions of the protein integrase was collected and kept at -80°C.

(iii) Obtaining DNA solution

Then DNA synthesized Greiner or FASMAC, was dissolved in buffer TE (10 mm Tris-hydrochloric acid (pH 8.0), 1 mm EDTA) and mixed with the DNA of the donor DNA target and each of the complementary C the drink (+and-chain) to 1 μm. The mixture was heated at 95°C for 5 min, at 80°C for 10 min, at 70°C for 10 min, at 60°C for 10 min, at 50°C for 10 min and at 40°C for 10 min and kept at 25°C to obtain double-stranded DNA, which was used for testing.

DNA donor (chain with Biotin attached to the 5'-end part).

+Chain donor: 5'-Biotin-ACC CTT TTA GTC AGT GTG GAA AAT CTC TAG CA-3' (SEQ ID NO:1).

-Chain donor: 5'-ACT GCT AGA GAT TTT CCA CAC TGA CTA AAA G-3' (SEQ ID NO:2).

DNA target (+, -chain, and both have digoxigenin attached at the 3'end).

+Chain target: 5'-TGA CCA AGG GCT AAT TCA CT-Dig-3' (SEQ ID NO:3).

Chain target: 5'-AGT GAA TTA GCC CTT GGT CA-Dig-3' (SEQ ID NO:4).

(iv) Determination of inhibitory enzyme (integrase HIV) activity

DNA donor was diluted with THE buffer to 10 nm or 5 nm), 50 μl of the product of the dilution was added to each well coated with streptavidin tiralongo microplate (Roche) and allowed to adsorb at 37°C for 60 minutes the Tablet were washed in phosphate buffer (PBS, Dulbecco, Sanko Junyaku Co., Ltd.), containing 0.1% tween-20, and phosphate buffer. Then the reaction mixture of the enzyme (70 μl), the test substance (10 μl)diluted reaction mixture of the enzyme, and 100 μg/ml (or 64 μg/ml (2 μm) protein integrase (10 ml) was added to each well and subjected to reaction at 37°C for 60 minutes

The composition of the reaction mixture of the enzyme: 30 mm MOPS (3-morpholino alsultanova acid), 5 mm magnesium chloride, 3 mm DTT (dithiotreitol), 0.1 mg/ml BSA (bovine serum albumin), 5% glycerol, 10% DMSO (dimethyl sulfoxide), 0.01% tween-20.

Then add 50 nm or 25 nm) DNA target (10 μl)was subjected to reaction at 37°C for 10 min and washed with phosphate buffer containing 0.1% tween-20, to stop the reaction.

Then was added 100 IU/ml of peroxidase labelled antibody solution against digoxigenin (Roche, 100 μl)and the mixture was subjected to reaction at 37°C for 60 min followed by washing with phosphate buffer containing 0.1% tween-20.

Added coloring solution for peroxidase (Bio Rad, 100 μl) and gave the opportunity for reaction at room temperature for 4 min (or 3 min). Color reaction was stopped by adding 1N. sulfuric acid (100 μl). The absorption was measured at 450 nm.

Inhibitory HIV integrase activity (IC50) compounds of the present invention was calculated from the degree of inhibition by the following formula:

The degree of inhibition (%) = [1-(target experience - blind experiment) / (control experience - blind experiment)] × 100

Target experience; the absorption of the wells in the presence of the test compound.

Supervisory experience; the absorption of the wells in the absence of the test compound.

Blind experience; the absorption of the wells in the absence of the test compound, in the absence of protein integrase.

The results are shown in tables 8 is 9, where each symbol means that the IC50is in the following range.

A: 1 µm≤IC50<10 microns

B: 0.1 ám≤IC50<1 μm

C: 0.01 µm≤IC50<0.1 ám

D: IC50<0.01 µm

Table 8
# exampleInhibiting the HIV integrase activity (IC50)# exampleInhibiting the HIV integrase activity (IC50)
1D16D
2D17D
3D18D
4D19D
5D20D
6D21D
7 D22D
8D23D
9D24C
10D25D
11D26D
12D27D
13D28D
14D29D
15D

56
Table 9
# exampleInhibiting the HIV integrase activity (IC50)# example32D46D
34D47C
35C48D
36D49D
37C50C
38D51D
39D52C
40C53D
41C54D
42D55C
43DD
44C57D
45D59C

Experimental example 2. Evaluation of antiviral activity

The effect of the combined use of the compounds of the present invention and the existing anti-HIV agents can be defined as follows.

For example, the effect of the combined application of two agents from existing inhibitors nucleoside-directed reverse transcriptase inhibitors (zidovudine, lamivudine, tenofovir), inhibitors nucleoside omnidirectional reverse transcriptase inhibitor (efavirenz) or protease inhibitors (indinavir, nelfinavir) and the test substance and the like are estimated with application of cells CEM-SS with HIV-1 IIIB by the XTT method.

In addition, assess the effect of the combined use of three agents of the test substance And, zidovudine and lamivudine or test substance And, tenofovir and lamivudine, and the like.

Before the test on the combined use of measured separately IC50and IC50each pharmaceutical agent. 5 concentrations of the pharmaceutical agent and 9 concentrations pharmacist the economic agent, defined on the basis of these results, combine for evaluating the effect of the combined use of the two agents. For the combined use of three agents, a high concentration of pharmaceutical agent and a pharmaceutical agent To combine with the concentration of the pharmaceutical agent A.

The test results of the test substance and the combination of it and only one drug combination or two drug combinations are analyzed on the basis of the program Prichard and Shipman MacSynergy II, version 2.01, and Deltagraph version 1.5d.

Three-dimensional graph is built from the data % inhibition at concentrations of each of the combined pharmaceutical agent, obtained from the conducted 3 times test with 95% (or 68%, 99%) confidence limits, and the effect of the combined application is evaluated on the basis computed from them numeric values µm2%. Evaluation criteria shown below.

Defining interaction
A strong synergistic effect
Weak synergistic effect
Additive effect
Weak antagonistic effect
Strong antagonistic action
μm2%
>100
+51 to+100
+50 to -50
-51 - -100
<-100

Experimental example 3. The test is metabolicheskuyu stability

Test metabolicheskoi stability in liver microsomes

Liposomes liver of a person or animal (rat or monkey) (Xenotech, LLC (Lenexa, KS, USA), 20 mg protein/ml, 2.5 ml) and a solution of coenzyme systems producing NADPH (β-nicotinamide adenine dinucleotide phosphate: 5.2 mm, D-glucose-6-phosphate: 13.2 mm, magnesium chloride: 13.2 mm, glucose-6-phosphatedehydrogenase: a 1.8 u/ml) (50 μl) suspended in a buffer of 100 mm potassium phosphate (pH 7.4, is 147.5 ml) and the suspension is mixed with the test substance (2 ál)dissolved in acetonitrile containing 0.5% DMSO. The mixture is incubated at 37°C for 0, 10 and 60 min, there was added acetonitrile containing formic acid (final concentration of 0.1%), and the mixture centrifuged. The test substance (unmodified compound) in the supernatant is measured by a combination of high performance liquid chromatography/mass spectrometry (LC/MS). Using the obtained measurement values of the residual ratio (%) is calculated by the following formula:

Residual ratio (%) = amount of test substance after incubation (0, 10 or 60 min)/number of the test substance at 0 min of incubation (100.

The compound of the present invention preferably detects the residual ratio after 60 minutes is not less than 40%, more preferably not less than 60%, even more preferably not less than 80%.

Below is an example of the preparation. This PR the measures is solely for the purpose of illustration and does not limit the invention.

Sample preparation

(a) compound of example 110 g
(b) lactose50 g
(c) corn starch10 g
(d) sodium salt of carboxymethylcellulose44 g
(e) magnesium stearate1 g

All quantities of components (a), (b) and (C) and 30 g (d) is kneaded with water, dried in vacuum and granularit. The obtained granules are mixed with 14 g (d) and 1 g (e) and turn them into tablets teletrauma machine, while receiving 1000 tablets, each contains 10 mg (a).

Industrial applicability

Compounds of the present invention reveal a high inhibitory activity against HIV integrase.

Therefore, these compounds can be pharmaceutical agents effective, for example, for prevention or treatment of AIDS, as integrase inhibitors, antiviral agents anti-HIV agents, and the like, possessing inhibiting the HIV integrase activity. In addition, combined use with other anti-HIV agents such as protease inhibitors, nucleoside reverse transcr PTZ and the like, they can be more effective anti-HIV agents. In addition, having a high inhibitory activity-specific integrase, they can be pharmaceutical agents that are safe for humans and possess a weaker side effects.

This application is based on patent applications No. 2006-174331, 2006-220082 and 2006-274143 registered in Japan, the contents of which are thus included as a reference.

The list of sequences

SEQ ID NO:1: + chain donor for determining the activity of HIV integrase.

SEQ ID NO:2: - chain donor for determining the activity of HIV integrase.

SEQ ID NO:3: + chain targets for determining the activity of HIV integrase.

SEQ ID NO:4: - chain targets for determining the activity of HIV integrase.

1. The compound represented by the following formula [I]or its pharmaceutically acceptable salt, or its MES:

where ring a is a monocyclic heterocyclic group, optionally substituted by 1-2 substituents selected from the following group a, where a monocyclic heterocyclic group selected from 1-pyrrolidinyl group, 2-oxopyrrolidin-1-ilen group, piperidino, 2-oxopiperidin-1-ilen group, 1-piperazinilnom group, morpholinopropan, 3-exmortis-4-ilen group, thiomorpholine, 1,1-d is oxoazetidin-2-ilen group, 2-oxoacridine-3-ilen group, 3-oxopyrrolidin-1-ilen group, 2-peredelnoj group, 2-thiazoline group and 1,2,4-oxadiazol-3-ilen group;
group a is a group consisting of a halogen atom, a C1-4alkyl group, -(CH2)n-ORa1and-CORa2where Ra1and Ra2are the same or different and each represents a hydrogen atom or a C1-4alkyl group and n is 0;
R1represents a C1-6alkyl group optionally substituted by 1 Deputy, selected from the following group;
group b represents the group consisting of-ORb1where Rb1represents a C1-4alkyl group;
R2represents a hydrogen atom, a C1-4alkyl group or-OR11where R11is an atom With1-4alkyl group;
R3and R4are the same or different and each represents a halogen atom;
R5represents a halogen atom;
m is 0 or 1; and
R6represents a hydrogen atom.

2. The compound according to claim 1 in which the ring a is a heterocyclic group selected from 1-pyrrolidinyl group, 2-oxopyrrolidin-1-ilen group, piperidino, 2-oxopiperidin-1-ilen group, 1-piperazinilnom group, morpholinopropan, thiomorpholine,3-exmortis-4-ilen group, 1,1-dioxothiazolidine-2-ilen group, 2-oxoacridine-3-ilen group and 3-oxopyrrolidin-1-ilen group, where the heterocyclic group is optionally substituted with 1-2 substituents selected from group a, or pharmaceutically acceptable salt, or MES.

3. The compound according to claim 1, where R2represents a C1-4alkyl group or-OR11where R11represents a C1-4alkyl group, or its pharmaceutically acceptable salt, or MES.

4. The compound according to claim 1, where R2represents a hydrogen atom, or its pharmaceutically acceptable salt, or MES.

5. The compound according to claim 1, where m is 1, or its pharmaceutically acceptable salt, or MES.

6. The compound according to claim 1, where m is 0, or its pharmaceutically acceptable salt, or MES.

7. The compound according to claim 1, selected from the group consisting of
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((R)-1-ethoxymethyl-2-hydroxyethyl)-7-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(pyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(2-oxoacridine-3-yl)benzyl]-1-((S)-1-hydroxymethyl-2-METI is propyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(piperidine-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(2-oxopiperidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-((R)-3-hydroxypyrrolidine-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-((S)-3-hydroxypyrrolidine-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(2-methyl-3-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[5-(4-acetylpiperidine-1-yl)-3-chloro-2-terbisil]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-5-(3,3-debtorprovidian-1-yl)-2-terbisil]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-((R)-3-ftorpirimidinu-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-((S)-3-ftorpirimidinu-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-IU is hydroxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((1R,2R)-1-hydroxymethyl-2-methoxypropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2,4-debtor-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((R)-1-ethoxymethyl-2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-[(R)-2-hydroxy-1-(methoxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-5-(1,1-dioxothiazolidine-2-yl)-2-terbisil]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-[(R)-2-hydroxy-1-(methoxymethyl)ethyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2,4-dif is the PR-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2,4-debtor-5-(2-oxopyrrolidin-1-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(thiomorpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((1R,2S)-1-hydroxymethyl-2-methoxypropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-3-methoxypropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(4-hydroxypiperidine-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-((1R,2R)-1-hydroxymethyl-2-methoxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-((1R,2S)-1-hydroxymethyl-2-methoxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(pyridin-2-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(thiazol-2-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-[(1R,2R)-2-ethoxy-1-(hydroxymethyl)propyl]-7-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-the top-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((R)-1-ethoxymethyl-2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-[(1R,2R)-2-ethoxy-1-(hydroxymethyl)propyl]-7-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-7-ethyl-1-((1R,2R)-1-hydroxymethyl-2-methoxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((R)-1-hydroxymethyl-2-methoxy-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-((R)-1-hydroxymethyl-2-methoxy-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-3-methoxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2,4-debtor-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-3-methoxypropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((1R,2R)-1-hydroxymethyl-2-methoxypropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2,4-debtor-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-7-methoxy-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-[(1R,2R)-2-ethoxy-1-(hydroxymethyl)propyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(2-oxopyrrolidin-1-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2,4-debtor-5-(2-oxopyrrolidin-1-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2,4-debtor-5-(2-oxopyrrolidin-1-yl)benzyl]-7-ethyl-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2,4-debtor-5-(morpholine-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2-fluoro-5-(5-methyl-1,2,4-oxadiazol-3-yl)benzyl]-1-((S)-1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid,
6-[3-chloro-2,4-debtor-5-(3-exmortis-4-yl)benzyl]-1-((S)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid and
6-[3-chloro-2,4-debtor-5-(morpholine-4-yl)benzyl]-1-((R)-1-hydroxymethyl-2,2-dimethylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
or is th pharmaceutically acceptable salt, or MES.

8. The compound represented by the formula:

or its pharmaceutically acceptable salt, or MES.

9. The compound represented by the formula:

or its pharmaceutically acceptable salt, or MES.

10. The compound represented by the formula:

or its pharmaceutically acceptable salt, or MES.

11. The compound represented by the formula:

or its pharmaceutically acceptable salt, or MES.

12. The compound represented by the formula:

or its pharmaceutically acceptable salt, or MES.

13. The compound represented by the formula:

or its pharmaceutically acceptable salt, or MES.

14. The compound represented by the formula:

or its pharmaceutically acceptable salt, or MES.

15. The compound represented by the formula:

or its pharmaceutically acceptable salt, or MES.

16. The compound represented by the formula:

or its pharmaceutically acceptable salt, or MES.

17. Pharmaceutical composition having inhibitory activity p is otiv HIV integrase, containing the compound according to any one of claims 1 to 16 or its pharmaceutically acceptable salt, or its MES and a pharmaceutically acceptable carrier.

18. Anti-HIV agent containing the compound according to any one of claims 1 to 16 or its pharmaceutically acceptable salt, or MES as an active ingredient.

19. The HIV integrase inhibitor containing the compound according to any one of claims 1 to 16 or its pharmaceutically acceptable salt, or MES as an active ingredient.

20. Anti-HIV agent containing the compound according to any one of claims 1 to 16 or its pharmaceutically acceptable salt, or MES in combination with one or more other types of substances that are active against HIV.

21. The use of compounds according to any one of claims 1 to 16 or its pharmaceutically acceptable salt, or MES to obtain anti-HIV agent.

22. The use of compounds according to any one of claims 1 to 16 or its pharmaceutically acceptable salt, or MES to get approved HIV integrase inhibitor.

23. The method of prevention or treatment due to HIV infectious disease in a mammal, comprising an introduction to the specified mammal an effective amount of a compound according to any one of claims 1 to 16 or its pharmaceutically acceptable salt, or MES.

24. The method according to item 23, further comprising the administration to a mammal an effective amount of one renesola other types of substances, active against HIV.

25. Method of inhibiting HIV integrase in a mammal, comprising an introduction to the specified mammal an effective amount of a compound according to any one of claims 1 to 16 or its pharmaceutically acceptable salt, or MES.

26. Composition against HIV-containing compound according to any one of claims 1 to 16 or its pharmaceutically acceptable salt, or its MES and a pharmaceutically acceptable carrier.

27. Pharmaceutical composition for inhibiting HIV integrase containing the compound according to any one of claims 1 to 16 or its pharmaceutically acceptable salt, or its MES and a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I , where: R1, R2, R3 and R4 independently from each other mean hydrogen, F, CI, Br, I; R5 designates hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, or cycloalkyl with 3, 4, 5 or 6 C atoms; R6 designates hydrogen; R7 and R8 independently from each other mean hydrogen, W means CrH2r or CsH2S-2; and one or more CH2-groups in C2H2r and CsH2s-2 can be substituted with NR17, oxygen or S; R17 means hydrogen, alkyl with 1, 2, 3 or 4 C atoms; r means 1, 2, 3, 4, 5 or 6; s means 2, 3 or 4; X designates-with C(O)- or -S(O)2-; Z means -C(O)- or a bond; and also to their pharmaceutically acceptable salts and trifluoroacetates. The invention also concerns application of the compounds of formula I, and also to a pharmaceutical composition.

EFFECT: preparation of new biologically active compounds exhibiting NHE3 inhibiting activity.

16 cl, 64 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, and more specifically to novel ethyl 5-R1-7-R2-1'-benzyl-3,3-dimethyl-1,2' -dioxo-5'-phenyl- 1',2,2',3,4,10-hexahydro-1H-spiro[acridine-9,3'-pyrrol]-4'-carboxylates of formula , where R1=H, Me; R2=H, OMe; R3=H, Me, OMe, Br, and to a method for synthesis of the said compounds.

EFFECT: obtaining novel compounds which can be used as primary products for synthesis of novel heterocyclic systems and in pharmacology as compounds with analgesic activity.

5 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 1-thio-D-glucitol compounds of formula I or to pharmaceutically acceptable salts thereof or hydrates of the compound or salts: , [where R1, R2, R3 and R4 are identical or different, and each is a hydrogen atom, C1-C6-alkyl group), A is -(CH2)n-, -CONH(CH2)n-, -O- or -(CH2)nCH=CH- (where n is an integer from 0 to 3, Ar1 is an arylene group, heteroarylene group, which is an unsaturated 5-9-member mono- or bicyclic group, containing 1-2 heteroatoms, selected from S and N, Ar2 is an aryl group or heteroaryl group which is an unsaturated 5-9-member mono- or bicyclic group containing 1-2 heteroatoms selected from O, S and N, and R5, R6, R7, R8, R9 and R10 are identical or different, and each is (i) a hydrogen atom, (ii) a halogen atom, (iii) a hydroxyl group, (iv) C1-8-alkyl group, optionally substituted with hydroxyl group(s), (v) -(CH2)m-Q {where m is an integer from 0 to 4, and Q is -CO2H, -ORc1, -CO2Ra3, -SRe1, -NHRa6 or -NRa7Ra7 (where each of Ra3, Ra6 and Ra7 is a C1-6-alkyl group, Rc1 is a C1-6-alkyl group, and Rc1 is a C1-6-alkyl group)}, (vi) -O-(CH2)m'-Q' {where m' is an integer from 1 to 4, and Q' is a hydroxyl group,-CO2H, -CO2Ra8, -CONRa10Ra10, -NRa12Ra12 (where each of Ra8, Ra10 and Ra12 is a C1-6-alkyl group)}, (vii) -ORf {where Rf is C3-7-cycloalkyl group or tetrahydropyranyl group)}, (viii) morpholine group, (ix) phenyl group, (x) pyridyl group]. The invention also relates to 1-thio-D-glucitol compounds of formulae IA, II, III, IV, to a pharmaceutical agent, to methods of obtaining 1-thio-D-glucitol compounds, as well as to compounds of formulae XIII, XIV.

EFFECT: obtaining novel biologically active compounds which are inhibitors of sodium-dependent co-transporter-2-glucose.

25 cl, 140 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: in formula (1), R1 is di-C1-6alkoxyphenyl group; A is one of the following groups (i)-(vi); (i) -CO-B-, where B is C1-6alkylene group; (ii) -CO-Ba-, where Ba is C2-6alkenylene group; (iii) -CH(OH)-B-; (iv) -COCH((C)OOR3)-Bb-, where R3 is C1-6alkyl group and Bb is C1-6alkylene group. Values of the other radicals are specified in the patent claim. Invention also concerns the pharmaceutical composition exhibiting properties of a phosphodiesterase PDE4 inhibitor containing the compound under the invention; the phosphodiesterase 4 inhibitor containing as an active component the compound of the invention; preventive or therapeutic preparation for atopic dermatitis containing as an active component the compound of the invention.

EFFECT: higher effectiveness of application of the compound.

8 cl, 24 tbl, 262 ex

FIELD: pharmacology.

SUBSTANCE: invention deals with formula I compounds and their sals pharmaceutically relevant in the capacity of phosphatidylinositol 3-kinase inhibitors, their preparation method as well as their application for production of a pharmaceutical preparation, a pharmaceutical compounds based thereon and a therapy method envisaging their application. In a formula compound R1 is represented by aminocarbonyl, non-obligatorily displaced with nitrile, or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with hydroxi, carboxi, C1-C8-alcoxicarbonyl, nitrile, phenyl, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkyl aminocarbonyl alkylcarbonyl that is non-obligatorily displaced with halogen, hydroxi, C1-C8-alkylanimo, di(C1-C8-alkyl)amino, carboxi, C1-C8-alcoxicarbonyl, nitrile, C1-C8-halogenalkyl or C1-C8-alkyl, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, non-obligatorily displaced with C1-C8-cycloalkyl or R1 is represented by C1-C8-alkylcarbonyl or C1-C8-alkylaminocarbonyl, each of them non-obligatorily displaced with C1-C8-alcoxi, non-obligatorily displaced with hydroxi or R1 is represented by C1-C8-alkylaminocarbonyl, displaced with phenyl, additionally displaced with hydroxi or R1 is represented by C1-C8-alkylcarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-4 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with C1-C8-alkyl on condition that the 6-membered heterocyclic ring is no 1-piperidyl or R1 is represented by C1-C8-alkylaminocarbonyl that is non-obligatorily displaced with a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring is non-obligatorily displaced with C1-C8-alkyl or R1 is represented by -(C=O)-(NH)a-Het, where a stands to denote 0 or 1 and Het stands to denote a 4-, 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) where the ring is non-obligatorily displaced with hydroxi, C1-C8-alkyl, C1-C8-alcoxi or a 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 0 or 1 and T stands to denote C3-C8-cycloalkyl that is non-obligatorily displaced with hydroxi or C1-C8-alkyl displaced with hydroxi or R1 is represented by -(C=O)-(NH)b-T, where b stands to denote 1 and T stands to denote phenyl that is non-obligatorily displaced with C1-C8-alkyl or C1-C8-alkyl displaced with hydroxi, R2 is represented by C1-C3-alkyl; one of R3 and R4 is represented by R6 while the other is represented by R7; R5 is represented by hydrogen or a halogen; R6 is represented by hydrogen, hydroxi, amino, -SOR8, -SO2R8, -SO2NH2, -SO2NR9R10, -COR8, -CONHR8, -NHSO2R8, nitrile, carboxi, -OR8 or C1-C8-halogenalkyl; R7 is represented by hydrogen, R11, -OR11, halogen, -SO2R8, ciano or C1-C8-halogenalkyl or, when R4 is represented by R7, R7 may equally be represented by -NR12R13; R8 and R11 are independently represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, nitrile, amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino; any R9 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with hydroxi, C1-C8-alcoxi, nitrile, amino, C1-C8-akrylamino, di(C1-C8-alkyl)amino or 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatom(s) selected from among the group consisting of oxygen and nitrogen where the ring where the ring is non-obligatorily displaced with C1-C8-alkyl, and R10 is represented by hydrogen or C1-C8-alkyl or R9 and R10 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl; any R12 is represented by C1-C8-alkyl or C3-C8-cycloalkyl, non-obligatorily displaced with amino, C1-C8-alkylamino or di(C1-C8-alkyl)amino and R13 is represented by halogen or C1-C8-alkyl or R12 and R13 together with the nitrogen atom they are connected to form a 5- or 6-membered heterocyclic ring that has 1-2 cyclic nitrogen heteroatoms where the ring is non-obligatorily displaced with C1-C8-alkyl.

EFFECT: proposed compounds are to be utilised for treatment of diseases mediated by phosphatidilinozitol 3-kinase such as allergy, psoriasis, diabetes, atherosclerosis, diabetes, cancer.

19 cl, 3 tbl, 181 ex

FIELD: pharmacology.

SUBSTANCE: invention concerns novel compounds of formula (1a), formula (1b), formula (1c) and formula (1d), as well as pharmaceutical composition based on them and their application in medicine obtainment. R1-R4, G, W, X, X1, U, V, a, b are defined in the invention claim.

EFFECT: compound with antagonistic effect on vasopressin V1A receptor.

73 cl, 133 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: invention claims compounds of the formula (I) with radicals as described in the claim, and medicine with inhibition effect on glycine absorption, based on compound of the formula (I) .

EFFECT: medicine for diseases treatment where glycine absorption inhibition can be effective.

21 cl, 1 tbl, 173 ex

FIELD: chemistry.

SUBSTANCE: there are disclosed 1-(2-aminobenzol)piperazine derivatives of formula (I) and pharmaceutically acceptable acid-additive salts with radical values specified in patent claim. The compounds are characterised with inhibiting effect on glycine I carrier. There is also disclosed medical product based on the compounds of formula (I).

EFFECT: compound can be used for treatment of the diseases associated with glycine uptake inhibition.

12 cl, 5 tbl, 396 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1 represents azido, -OR4, -NHR4 wherein R4 represents hydrogen atom or unsubstituted groups chosen from acyl, thioacyl, (C1-C6)-alkoxycarbonyl, (C3-C6)-cycloalkoxythiocarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy, -C(C=S)-S-(C1-C6)-alkyl, -(C=S)-NH2, -(C=S)-NH-(C1-C6)-alkyl, -C(=S)-N-((C1-C6)-alkyl)2, -C(=S)-NH-(C2-C6)-alkenyl, -C(C=S)-(C=O)-(C1-C6)-alkoxy, thiomorpholinylthiocarbonyl; R2 and R3 can be similar or different and represent independently hydrogen atom, halogen atom, (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl; heterocyclic moiety represents 5-membered heterocycle wherein Z represents sulfur (S), oxygen (O) atom or -NRb wherein Rb represents hydrogen atom or unsubstituted (C1-C6)-alkyl, (C3-C6)-cycloalkyl, aryl or aryl-(C1-C6)-alkyl; Y1 represents group =O or =S ; Y2 and Y3 represent independently hydrogen atom, and if Y2 and Y3 present in common on adjacent carbon atoms then they form 6-membered aromatic cyclic structure substituted if necessary with (C1-C6)-alkyl, or to its pharmaceutically acceptable salt. Also invention relates to a pharmaceutical composition possessing antibacterial activity and containing as an active compound the compound of the formula (I) taken in the effective dose and a pharmaceutically acceptable carrier, diluting agent, excipient. Also, invention relates to method for synthesis of compound of the formula (I). Method for synthesis of compound of the formula (I) wherein R1 represents group -NHR4 wherein R4 means acyl, (C1-C6)-alkoxycarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy and -(C=S)-S-(C1-C6)-alkyl involves acetylation of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 represents hydrogen atom and all symbols are given above and using halide. Method for synthesis of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 means thioacyl, (C3-C6)-cycloalkoxythiocarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl involves the following steps: (i) conversion of compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents hydrogen atom, and all symbols are given above to compound of the formula (I) wherein R1 represents isothiocyanate group by reaction with thiophosgene, and (ii) conversion of compound of the formula (I) wherein R1 represents isothiocyanate group to compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents -C(=S)-OR4d wherein R4d represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C2-C6)-alkenyl, and all symbols are given above, in reaction with alcohol. Compounds of the formula (I) are used in treatment of bacterial infection that involves administration of compound of the formula (I) in a patient needing in this treatment. Invention provides synthesis of oxazolidinone compounds possessing antibacterial activity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

7 cl, 1 tbl, 144 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to a morpholine type cinnamide derivative with general formula I or its pharmacologically acceptable salt, where (a) R1, R2 , R3 and R4 are identical or different and each represents a hydrogen atom or C1-6alkyl group; X1 represents a C1-6alkylene group, where the C1-6alkylene group can be substituted with 1-3 hydroxyl groups or C1-6alkyl groups, or a C3-8cycloalkyl group formed by two C1-6alkyl groups all bonded to the same carbon atom of the C1-6alkylene group; Xa represents a methoxy group or a fluorine atom; Xb represents an oxygen atom or a methylene group, under the condition that Xb represents only an oxygen atom when Xa represents a methoxy group; and Ar1 is an aryl group, pyridinyl group which can be substituted with 1-3 substitutes selected from A1 group of substitutes; (b) Ar1-X1- represents a C5-7cycloalkyl group condensed with a benzene ring, where one methylene group in the C5-7cycloalkyl group can be substituted with an oxygen atom, the C5-7cycloalkyl group can be substituted with 1-3 hydroxyl groups and/or C1-6alkyl groups, and R1, R2, R3, R4, Xa and Xb assume values given in (a); (d) Ar1-X1- and R4 together with the nitrogen atom bonded to the Ar1-X1- group and the carbon atom bonded to the R4 group form a 5-7-member nitrogen-containing heterocyclic group which is substituted with an aryl group or a pyridinyl group, where one methylene group in the 5-7-member nitrogen-containing heterocyclic group can be substituted with an oxygen atom, and the aryl or pyridinyl group can be substituted with 1-3 substitutes selected from A1 group of substitutes, Xb is an oxygen atom, and R1, R2, R3 and Xa assume values given in (a) and (b); group A1 of substitutes: (1) halogen atom. The invention also relates to a pharmaceutical composition containing a formula I compound, which is useful in treating Alzheimer's disease, senile dementia, Down syndrome or amyloidosis.

EFFECT: obtaining novel morpholine type cinnamide derivatives with inhibitory effect on amyloid-β production.

17 cl, 9 tbl, 113 ex

FIELD: chemistry.

SUBSTANCE: invention proposes 5-member heterocyclic inhibitors of kinase p38, including kinase p38α and kinase p38β, based on pyrazoles and imidazoles, with the general formula given below , in which ring B is phenyl, and C is a pyrazole or imidazole ring, and the rest of the symbols assume values given in paragraph 1 of the formula of invention.

EFFECT: there are described pharmaceutical compositions containing said compounds, as well as methods of using the compounds and compositions, including a method of treating, preventing or suppressing one or more symptoms of diseases and conditions mediated by kinase p38 which include, but not limited to, inflammatory diseases and conditions.

31 cl, 6 tbl, 175 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I), compounds, , their pharmacologically acceptable salt, solvate and hydrate, where A is an alkylene group, alkenyl group, alkynyl group, heteroalkylene group, cycloalkylene group, heterocylcoalkylene group, arylene group or heteroarylene group, where each of the said groups can be substituted, Q is CR4, X is CR7 or N, Y is CR6 or N, n equals 1, 2 or 3, m equals 1, 2 or 3, R1 is H, F, Cl, Br, I, OH, NH2, alkyl group or heteroalkyl group, R is H, F or Cl, R3 is H, alkyl group, alkenyl group, alkynyl group, heteroalkyl group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, alkylaryl group or heteroarylalkyl group, where each of the said groups can be substituted with one, two or more halogen atoms or amino groups, R4 is hydroxy, a group with formula OPO3R92 or OSO3R10 or a heteroalkyl group, containing at least one OH, NH2, SO3R10, PO3R92 or COOH group or ester group of natural amino acid or its derivative, where R9 groups independently represent H, alkyl, cycloalkyl, aryl or aralkyl, and R10 is H, alkyl, cycloalkyl, aryl or aralkyl, and further values of R5, R6, R7 and R8 are given in the formula of invention. The invention also relates to pharmaceutical compositions with antibacterial activity, containing compounds described above, as well as to use of formula (I) compounds and a pharmaceutical composition for treating bacterial infection.

EFFECT: new compounds are obtained and described, which can be used as antibacterial agents and which are effective against multi-drug resistant bacteria.

18 cl, 32 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula (I-a), where R1 and R2, each independently, represent -COORA (where RA is hydrogen or C1-8 alkyl), -CONRBSO2RC (where RB is hydrogen or C1-8 alkyl, RC is C1-8 hydrocarbon), -D-R1 is -CO-(CH2)2-R1, -CO-(CH2)3-R1, -CO-(CH2)4-R1 or C1-4alkylene-R1; E is a bond or C1-4alkylene; ring formula represents a 3,4-dihydro-2H-1,4-benzoxazine or 1H-indole ring; V is , where R110 is hydrogen or C1-8 alkyl, and the arrow shows that it is bonded to ring A; the group with formula is a phenyl group, which can contain a group with formula , where ring 2 is a C5-10 mono- or bicyclic aromatic carbocyclic ring, which can be partially or completely saturated, spirobicyclic carbocyclic ring, or a carbocyclic ring bonded by a bridge bond; where W is -O-CH2-, -O-(CH2)2, -O-(CH2)3, -O-(CH2)4, -O-(CH2)5, -CH2-O, -(CH2)2-O-, -(CH2)3-O-, -(CH2)4-O-, -(CH2)5-O-, -O-(CH2)3-O-, -O-(CH2)4-O-, -O-(CH2)5-O-, C1-6 alkylene, its N-oxide, its salt or its solvate. The invention also relates to a pharmaceutical composition based on formula I-a compound and its use.

EFFECT: obtaining new derivatives of benzoxazine and indole, with antagonistic effect on cysLT2 and which are useful for preventing and/or curing respiratory diseases, such as bronchial asthma, chronic obstructive lung diseases.

8 cl, 57 tbl, 261 ex

FIELD: chemistry.

SUBSTANCE: invention relates to formula (I) compounds and to their use in treating diseases related to lipid storage disorders, such as atherosclerosis and diabetes. In R1 represents hydrogen, alkyl, halogen, formyl, hydroxyalkyl or trifluoromethyl, R2 represents hydrogen, alkyl or halogen, R3 represents hydrogen or alkyl, R4 represents hydrogen, alkyl, hydroxy or alkoxy, R5 and R6 are chosen from hydrogen, alkyl, phenylalkyl, hydroxyalkyl, alkoxycarbonyl and phenyl, A represents aryl or heterocyclyl, m equals 0-3, n equals 0-1, p equals 0-3, sum of m, n and p equals 1-4, the bond between carbon atoms Ca and Cb is a single or double carbon-carbon bond.

EFFECT: obtaining new biologically active compounds.

27 cl, 147 ex

Cynnamide compound // 2361872

FIELD: chemistry.

SUBSTANCE: invention relates to a compound with formula (I) , where Ar1 is an imidazolyl group, which can be substituted with 1-3 substitutes; Ar2 is a pyridinyl group, pyrimidinyl group or phenyl group, which can be substituted with 1-2 substitutes; X1 is (1) -C≡C- or (2) double bond etc., which can be substituted, R1 and R2 are, for example, C1-6-alkyl group or C3-8-cycloalkyl group, which can be substituted; or to a pharmacologically acceptable salt of the said compound and pharmaceutical drugs for lowering production of Aβ42, containing formula (I) compound as an active ingredient.

EFFECT: wider field of use of the compounds.

26 cl, 1119 ex, 31 tbl

FIELD: chemistry.

SUBSTANCE: present invention pertains to new compounds with formula (I): where R1 and R2 each independently represents a hydrogen atom, C1-8 alkyl or a halogen atom; R3 represents C1-8 alkyl, which can be substituted with 1-3 halogen atom(s) or phenyl; R4 represents a hydrogen atom or C1-8 alkyl; R5 and R6 each independently represents a hydrogen atom; X represents a sulphur atom or oxygen atom; ring A is 4-(trifluoromethyl)piperidin-1-yl, 2,2-difluoro-1,3- benzodioxol-5-yl or 3,4-dihydro-1H-isoquinolin-2-yl. The invention also relates to salts or solvates of this derivative, as well as medicinal preparation, pharmaceutical composition, method of preventing and/or treating diseases, caused by PPAR, and use of this derivative.

EFFECT: obtaining new biologically active compounds, which can be used for preventing and/or treating diseases caused by PPARδ.

8 cl, 39 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. Claimed compounds have antibacterial effect. In formula (I) , X is ; R1 is i) hydrogen, ii) (CH2)nNR5R6, iv) NRCO2R, v) (C1-6alkyl)CN, CN, (CH2)pOH; Y is NR*, O or S(O)p; is phenyl or 5-6-member heteroaryl with N or S as heteroatoms; R3 is NR(C=X2)R12, NR*R12, or -(O)n-5-6-member heteroaryl with 1-3 heteroatoms selected out of N, O, which can be linked over either carbon atom or heteroatom; the indicated 5-6-member heteroaryl can be optionally substituted by 1-3 groups of R7; R4, R4a, R4b and R4c are independently i) hydrogen, ii) halogen; other radicals are defined in the claim.

EFFECT: pharmaceutical composition containing effective volume of the claimed compound.

13 cl, 1 dwg, 194 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound of the formula (I): wherein R1 represents azido, -OR4, -NHR4 wherein R4 represents hydrogen atom or unsubstituted groups chosen from acyl, thioacyl, (C1-C6)-alkoxycarbonyl, (C3-C6)-cycloalkoxythiocarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy, -C(C=S)-S-(C1-C6)-alkyl, -(C=S)-NH2, -(C=S)-NH-(C1-C6)-alkyl, -C(=S)-N-((C1-C6)-alkyl)2, -C(=S)-NH-(C2-C6)-alkenyl, -C(C=S)-(C=O)-(C1-C6)-alkoxy, thiomorpholinylthiocarbonyl; R2 and R3 can be similar or different and represent independently hydrogen atom, halogen atom, (C1-C6)-alkyl group, halogen-(C1-C6)-alkyl; heterocyclic moiety represents 5-membered heterocycle wherein Z represents sulfur (S), oxygen (O) atom or -NRb wherein Rb represents hydrogen atom or unsubstituted (C1-C6)-alkyl, (C3-C6)-cycloalkyl, aryl or aryl-(C1-C6)-alkyl; Y1 represents group =O or =S ; Y2 and Y3 represent independently hydrogen atom, and if Y2 and Y3 present in common on adjacent carbon atoms then they form 6-membered aromatic cyclic structure substituted if necessary with (C1-C6)-alkyl, or to its pharmaceutically acceptable salt. Also invention relates to a pharmaceutical composition possessing antibacterial activity and containing as an active compound the compound of the formula (I) taken in the effective dose and a pharmaceutically acceptable carrier, diluting agent, excipient. Also, invention relates to method for synthesis of compound of the formula (I). Method for synthesis of compound of the formula (I) wherein R1 represents group -NHR4 wherein R4 means acyl, (C1-C6)-alkoxycarbonyl, (C2-C6)-alkenyloxycarbonyl, (C2-C6)-alkenylcarbonyl, -C(=O)-C(=O)-(C1-C6)-alkoxy and -(C=S)-S-(C1-C6)-alkyl involves acetylation of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 represents hydrogen atom and all symbols are given above and using halide. Method for synthesis of compound of the formula (I) wherein R1 represents -NHR4 group wherein R4 means thioacyl, (C3-C6)-cycloalkoxythiocarbonyl, (C1-C6)-alkoxythiocarbonyl, (C2-C6)-alkenyloxythiocarbonyl involves the following steps: (i) conversion of compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents hydrogen atom, and all symbols are given above to compound of the formula (I) wherein R1 represents isothiocyanate group by reaction with thiophosgene, and (ii) conversion of compound of the formula (I) wherein R1 represents isothiocyanate group to compound of the formula (I) wherein R1 represents -NHR4 wherein R4 represents -C(=S)-OR4d wherein R4d represents (C1-C6)-alkyl, (C3-C6)-cycloalkyl, (C2-C6)-alkenyl, and all symbols are given above, in reaction with alcohol. Compounds of the formula (I) are used in treatment of bacterial infection that involves administration of compound of the formula (I) in a patient needing in this treatment. Invention provides synthesis of oxazolidinone compounds possessing antibacterial activity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of synthesis.

7 cl, 1 tbl, 144 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel pyrrolidine-2-ones of the formula (I): , wherein R1 means group chosen from the following formulae:

wherein each of them comprises optionally additional nitrogen (N) atom as a heteroatom; Z means optional substitute halogen atom, -CH2NH2, -NRaRb or -CN; Z' means optional substitute halogen atom, -CH2NH2 or -CN; alk means alkylene or alkenylene; T means sulfur atom (S), oxygen atom (O); R2 means hydrogen atom (H), -(C1-C3)-alkyl-CONRaRb, -(C1-C3)-alkyl-CO2-(C1-C4)-alkyl, -(C1-C3)-alkylmorpholino-group, -CO2-(C1-C4)-alkyl or -(C1-C3)-alkyl-CO2H; X means phenyl or 5- or 6-membered aromatic or nonaromatic heterocyclic group comprising one or two heteroatoms chosen from O, N or S wherein each of them is substituted optionally with 0-2 groups chosen from halogen atom, -CN, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -CF3, -NRaRb, -NO2, -N-(C1-C4)-alkyl-(CHO), -NHCO-(C1-C4)-alkyl, -NHSO2Rc, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc and -S(O)2NRaRb; Y means: (i) a substitute chosen from H, halogen atom, -CN, -(C1-C4)-alkyl, -(C2-C4)-alkenyl, -CF3, -NRaRb, -NO2, -N-(C1-C4)-alkyl-(CHO), -NHCO-(C1-C4)-alkyl, -NHSO2Rc, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc and -S(O)2NRaRb, or (ii) phenyl or 5- or 6-membered aromatic or nonaromatic heterocyclic group comprising one or two heteroatoms, chosen from O, N or S and wherein each of them is substituted optionally with 0-2 groups chosen from halogen atom, -CN, -(C1-C4)-alkyl, -(CH2)nNRaRb, -(CH2)nN+RaRbCH2CONH2, -(C0-C4)-alkyl-ORd, -C(O)Rc, -C(O)NRaRb, -S(O)nRc, -S(O)2NRaRb, =O, oxide at N atom in cycle, -CHO, -NO2 and -N-(Ra)(SO2Rc) wherein Ra and Rb mean independently H, -(C1-C6)-alkyl; Rc means -(C1-C6)-alkyl; Rd means H, -(C1-C6)-alkyl; n means 0-2, and to their pharmaceutically acceptable salts or solvates. Compounds inhibit Xa factor that allows their using as components of pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

10 cl, 144 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I , where: R1, R2, R3 and R4 independently from each other mean hydrogen, F, CI, Br, I; R5 designates hydrogen, alkyl with 1, 2, 3, 4, 5 or 6 C atoms, or cycloalkyl with 3, 4, 5 or 6 C atoms; R6 designates hydrogen; R7 and R8 independently from each other mean hydrogen, W means CrH2r or CsH2S-2; and one or more CH2-groups in C2H2r and CsH2s-2 can be substituted with NR17, oxygen or S; R17 means hydrogen, alkyl with 1, 2, 3 or 4 C atoms; r means 1, 2, 3, 4, 5 or 6; s means 2, 3 or 4; X designates-with C(O)- or -S(O)2-; Z means -C(O)- or a bond; and also to their pharmaceutically acceptable salts and trifluoroacetates. The invention also concerns application of the compounds of formula I, and also to a pharmaceutical composition.

EFFECT: preparation of new biologically active compounds exhibiting NHE3 inhibiting activity.

16 cl, 64 ex, 1 tbl

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