4-oxoquinoline compound and its using as hiv integrase inhibitor

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention relates to a new biologically active compound of 4-oxoquinoline that is useful as an anti-HIV agent and to its pharmaceutically acceptable salt. Invention describes an anti-HIV agent comprising compound of 4-oxoquinoline represented by the following formula [I] or its pharmaceutically acceptable salt as an active component wherein ring Cy represents phenyl group, naphthyl group or pyridyl group and each this group is substituted optionally with 1-5 substituted chosen from the following group A wherein A represents the group consisting of cyano-group, phenyl group, nitro-group, halogen atom, (C1-C4)-alkyl group, halogen-(C1-C4)-alkyl group, halogen-(C1-C4)-alkoxy-group, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3 and -COORa1 wherein Ra1 and Ra2 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or benzyl group, and Ra3 represents (C1-C4)-alkyl group; R1 represent a substitute chosen from the following group B, or (C1-C10)-alkyl group optionally substituted with 1-3 substitutes chosen from halogen atom and the following group B wherein the group B represents the group consisting of phenyl group optionally substituted with phenyl group or 1-5 halogen atoms; (C3-C6)-cycloalkyl group, imidazolyl group, benzothiophenyl group, thiazolyl group optionally substituted with 1-3 (C1-C6)-alkyl groups, morpholinyl group, pyridyl group, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4 and -NRa5COORa6 wherein Ra4 and Ra5 are similar or different and each represents hydrogen atom, (C1-C4)-alkyl group or phenyl group; Ra6 represents (C1-C4)-alkyl group; R2 represents hydrogen atom or (C1-C4)-alkyl group; R31 represents hydrogen atom, cyano-group, hydroxy-group, halogen atom or (C1-C4)-alkoxy-group; X represents -C-R32, and Y represents -C-R33 or nitrogen atom wherein R32 and R33 are similar or different and each represents hydrogen atom, cyano-group, halogen atom, pyrrolidinyl group, (C1-C10)-alkyl group optionally substituted with 1-3 halogen atoms, -ORa7, -SRa7, -NRa7Ra8, -NRa7CORa9, -COORa10 or -N=CH-NRa10Ra11 wherein Ra7 and Ra8 are similar or different and each represents hydrogen atom, phenyl group or (C1-C10)-alkyl group optionally substituted with (C3-C6)-cycloalkyl group or hydroxy-group; Ra9 represents (C1-C4)-alkyl group and Ra10 and Ra11 are similar or different and each represents hydrogen atom or (C1-C4)-alkyl group. Also, invention describes compound of the formula (III) given in the invention description, integrase inhibitor, antiviral agent, ant-HIV composition, anti-HIV agent, using compound of 4-oxoqionoline, method for inhibition of integrase activity, method for prophylaxis or treatment of viral infectious disease, pharmaceutical composition used for inhibition of integrase activity, antiviral composition and commercial package (variants). Invention provides the development of a pharmaceutical agent possessing inhibitory effect on activity of integrase.

EFFECT: valuable medicinal properties of compound, agent and composition.

40 cl, 7 tbl, 250 ex

 

The SCOPE of the INVENTION

The present invention relates to a new compound 4-oxacilin, useful as an anti-HIV agent, and to its pharmaceutically acceptable salt.The present invention relates also to a new application of some of the compounds 4-oxacilin and their pharmaceutically acceptable salts as anti-HIV agents.More specifically, the present invention relates to an anti-HIV agent containing the compound 4-oxacilin, which, in particular, shows anti-HIV activity, based on the integrase inhibitory activity, or its pharmaceutically acceptable salt.

BACKGROUND of the INVENTION

HIV (the human immunodeficiency virus (type 1))that belongs to the retrovirus is a virus that causes AIDS (acquired immunodeficiency syndrome).

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

Accordingly, a pharmaceutical agent that destroys HIV in the body or inhibits its growth, is effective for the treatment or prevention of AIDS.

HIV contains bimolecular RNA gene in the protein core, which is covered with a shell protein. RNA encodes several enzymes (protease, reverse transcriptase, integrase), characteristic of VIR is sa and the like, and contains translated reverse transcriptase and integrase in the nucleus, as well as protease inside the core and outside it.

HIV attaches to the cell host and enters into it, causing the destruction of the shell, and highlights the complex of RNA and integrase, etc. in the cytoplasm. From RNA through reverse transcriptase transcribed DNA, and forms a double-stranded DNA full length.DNA enters the nucleus of the host cell and integrated by integrase DNA of the host cell. The integrated DNA is transformed into mRNA under the action of a polymerase of the host cell, and from this mRNA under the action of HIV protease, etc. are synthesized various proteins needed for the formation of the virus, resulting eventually formed viral particles, which then undergo maturation and stand out.

Believe that such virus-specific enzymes essential for the growth of HIV. These enzymes have attracted interest as targets for the design of antiviral agents, and some anti-HIV agents has already been created.

For example, zidovudine, didanosine, lamivudine, etc. are already on sale as reverse transcriptase inhibitors and indinavir, nelfinavir, etc. as protease inhibitors.

Was also used combination therapy with multiple drugs at the same time using these pharmaceutical agents. the example has been clinically tested joint use of two reverse transcriptase inhibitors (zidovudine and didanosine), and the combined use of three agents reverse transcriptase inhibitors (zidovudine and lamivudine) and protease inhibitor (nelfinavir), etc. Such combination therapy with multiple drugs is becoming a major area of therapy AIDS (see, for example, Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adlescent. August 13, 2001).

However, it is known that some of these pharmaceutical agents cause side effects such as liver dysfunction, disorders of the Central nervous system (e.g., dizziness), etc. in Addition, problems arise due to the acquisition of resistance to pharmaceutical agents. Worse still, become aware of the emergence of HIV, which shows resistance to many drugs in combination therapy with several drugs.

Given these circumstances, would be further desirable to develop a new pharmaceutical agent, in particular the development of anti-HIV agent based on a new mechanism of action, and expected the establishment of an anti-HIV agent having the integrase inhibitory activity, as well as characterizing retrovirus integrase is an essential enzyme for growth of HIV.

However, an effective inhibitor of integrases is still not been found.

Known compounds are relatively similar with the anti-HIV agent of the present invention are disclosed in the following activities.

WO02/0704865 discloses the following compounds [A], [B], etc. as anti-HIV agents with the integrase inhibitory activity (see WO02/0704865, S. 118, the example I-62, S. 203, example I-152).

In addition, W2/36734 discloses the following compound [C], etc. as anti-HIV agents with the integrase inhibitory activity (see WO02/36734, S. 106, PR).

In addition, WO02/55079 discloses the following compound [D], etc. as anti-HIV agents with the integrase inhibitory activity (see WO02/055079, S. 79, app.1).

Connection [D]

However, these publications do not include connection 4-oxacilin, disclosed in the description of the present invention, and there is no description suggesting its existence.

Connections are relatively similar with the compound of the present invention are disclosed in the following activities.

In U.S. patent 3472859 revealed the following connections [E], etc. as antibacterial agents or antimicrobial agents (see U.S. patent 3472859, column 11, line 10).

Connection [E]

In addition, JP-A-48-26772 discloses the following compound [F], etc. in which the quality of the connections, possess antibacterial activity (see, for example, JP-A-48-26772, S. 6, example 9; KYUSHU KYORITSU UNIVERSITY, Memoirs of the Department of Engineering, No. 14, SS. 21-32, March 1990; Memoirs Kyushu Inst. Tech. (Eng.) No.14,SS. 13-16, 1984).

In addition, was conducted pharmacological evaluation of the following compounds [G], etc. as inhibitors dehydrogenase (see Journal of Medicinal Chemistry, table 1, vol. 15, No. 3, SS. 235-237, 1972).

In addition, JP-A-2002-534416 (family of patents: WO00/40561, U.S. patent 6248739, EP1140850) discloses the following compound [H], etc. as synthetic intermediates for compounds with antiviral activity (see JP-A-2002-534416, C. 141, the connection 60).

JP-A-2002-534417 (family of patents: WO00/40563, U.S. patent 6248736, EP1140851) discloses the following compound [J], etc. as synthetic intermediates for compounds with antiviral activity (see JP-A-2002-534417, S. 34, compound 18).

Connection [J]

In addition, WO01/98275 (family patents: U.S. 2001/103220) discloses the following compound [K], etc. as a synthetic intermediate for compounds with antiviral activity (see WO01/98275, S. 39, line 29).

Moreover, JP-A-4-360872 (family patents: U.S. 5985894, EP49871B1) discloses the following compound [L], etc. as the compounds having antagonistic activity against receptors of anti-angiotensin II (see JP-A-4-360872, p.64, Table 1).

The INVENTION

On the basis of pharmacological studies and obtained clinical results, etc. it was found that the anti-HIV agent is effective for preventing the onset of AIDS and its treatment, and more specifically, the compounds having the integrase inhibiting effect, can provide an effective anti-HIV agent.

Therefore, the aim of the present invention is to provide a pharmaceutical agent having anti-HIV activity, more specifically the pharmaceutical agent with the integrase inhibiting action.

The authors of the present invention made intensive studies in an attempt to detect the compounds having anti-HIV activity, more specifically the compounds having the integrase inhibiting activity, and completed the present invention.

Accordingly, the present invention is presented in the following paragraphs(1)-(41).

(1) Anti-HIV agent containing the compound 4-oxacilin, represented by the following formula [I]or its pharmaceutically acceptable salt as an active ingredient:

where

the ring Cyrepresents C3-10of plastics technology : turning & is the initial ring, optionally substituted by 1-5 substituents selected from the following group A or heterocyclic group, optionally substituted by 1-5 substituents selected from the following group A,

where the heterocyclic group is a saturated or unsaturated ring containing, besides atom(atoms) of carbon, at least one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom, group a represents a group consisting of cyanopropyl, phenyl group, nitro group, halogen atom, a C1-4alkyl group, Halogens1-4alkyl group, Halogens1-4alkyloxy, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -CORa3, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3, -COORa1and-NRa2COORa3,

where Ra1and Ra2the same or different, and each represents a hydrogen atom, a C1-4alkyl group or benzyl group, and Ra3represents C1-4alkyl group;

R1represented by the Deputy, selected from the following group B, or C1-10alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and the following group B,

where the group B represents the group consisting of C3-10the carbon ring, optionally substituted by 1-5 batch is italiani, selected from the above-mentioned group a, heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4and-NRa5COORa6,

where Ra4and Ra5the same or different, and each represents a hydrogen atom, a C1-4alkyl group, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a, and Ra6represents C1-4alkyl group, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the above group;

R2represents a hydrogen atom or a C1-4alkyl group;

R31represents a hydrogen atom, a cyano, a hydroxy-group, an amino group, a nitro-group, a halogen atom, a C1-4alkyl group, a C1-4alkoxygroup, C1-4alkylsulfonyl group, a halo is Jens 1-4alkyl group or Halogens1-4alkyloxy;

Xrepresents C-R32or a nitrogen atom; and

Yrepresents C-R33or nitrogen atom,

where R32and R33the same or different, and each represents a hydrogen atom, a cyano, a nitro-group, a halogen atom, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a, heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a or C1-10alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and the above-mentioned group B, -ORa7, -SRa7, -NRa7Ra8, -NRa7CORa9, -COORa10or-N=CH-NRa10Ra11,

where Ra7and Ra8the same or different, and each represents a hydrogen atom, group B or C1-10alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and the above-mentioned group B, Ra9represents C1-4alkyl group, and Ra10and Ra11the same or different, and each represents a hydrogen atom or a C1-4alkyl group.

(2) Anti-HIV agent according to the above p.(1), where X represents C-R32and Y represents C-R33.

(3) Anti-HIV agent according to the above p.(1), g the ring Cy is

where

R4and R6the same or different, and each represents a Deputy selected from the following group a,

where group a is the group consisting of cyanopropyl, phenyl group, nitro group, halogen atom, a C1-4alkyl group, Halogens1-4alkyl group, Halogens1-4alkyloxy, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -CORa3, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3, -COORa1and-NRa2COORa3,

where Ra1and Ra2the same or different, and each represents a hydrogen atom, a C1-4alkylene group or benzyl group, and Ra3represents C1-4alkyl group;

R5is Deputy selected from a hydrogen atom and group, and R4and R5may form a condensed ring together with a benzene ring, the substituents of which they are; and

m is 0 or an integer from 1 to 3, and when m is 2 or 3, then R6for each m may be the same or different.

(4) Anti-HIV agent according to the above p.(1), where R2represents a hydrogen atom.

(5) Compound 4-oxacilin, represented by the following formula [II] or its pharmaceutically acceptable salt:/p>

where

R4and R6the same or different, and each represents a Deputy selected from the following group a,

where group a is the group consisting of cyanopropyl, phenyl group, nitro group, halogen atom, a C1-4alkyl group, Halogens1-4alkyl group, Halogens1-4alkyloxy, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -CORa3, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3, -COORa1and-NRa2COORa3,

where Ra1and Ra2the same or different, and each represents a hydrogen atom, a C1-4alkyl group or benzyl group, and Ra3represents C1-4alkyl group;

R5is Deputy selected from a hydrogen atom and the above-mentioned group a, and R4and R5may form a condensed ring together with a benzene ring, the substituents of which they are;

m is 0 or an integer from 1 to 3, and when m is 2 or 3, then R6each m may be the same or different;

R1represented by the Deputy, selected from the following group B or C1-10alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and the following g is uppy B,

where the group B represents the group consisting of C3-10carbon rings,optionally substituted by 1-5 substituents selected from the above-mentioned group a, heterocyclic group (where the heterocyclic group is a saturated or unsaturated ring containing, besides atom(atoms) of carbon, at least one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom, as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4and-NRa5COORa6,

where Ra4and Ra5the same or different, and each represents a hydrogen atom, a C1-4alkyl group, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a, and Ra6represents C1-4alkyl group, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group (as defined above), not necessarily Thames is authorized 1-5 substituents, selected from the above group;

R31represents a hydrogen atom, a cyano, a hydroxy-group, an amino group, a nitro-group, a halogen atom, a C1-4alkyl group, a C1-4alkoxygroup, C1-4alkylsulfanyl group, Halogens1-4alkyl group or Halogens1-4alkyloxy; and

R32and R33the same or different, and each represents a hydrogen atom,a cyano, a nitro-group, a halogen atom, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a, heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a, C1-10alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and the above group B, ORa7,-Ra7, -NRa7Ra8, -NRa7CORa9, -COORa10or-N=CH-NRa10Ra11,

where Ra7and Ra8the same or different, and each represents a hydrogen atom, group B or C1-10alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and the above-mentioned group B, Ra9represents C1-4alkyl group, and Ra10and Ra11the same or different, and each represents a hydrogen atom or a C1-4alkyl is the RUPE.

(6) the Compound 4-oxacilin above p.(5), where R31represents a hydrogen atom,a cyano, a hydroxy-group or C1-4alkoxygroup, or its pharmaceutically acceptable salt.

(7) the Compound 4-oxacilin above p.(6), where R31represents a hydrogen atom, or its pharmaceutically acceptable salt.

(8)Connection 4-oxacilin above p.(5), where

R32and R33,the same or different, and each represents a hydrogen atom, cyano, halogen atom, heterocyclic group, optionally substituted by 1-5 substituents selected from the following group A,

where the heterocyclic group is a saturated or unsaturated ring containing, besides atom(atoms) of carbon, at least one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom, and the group a represents a group containing a cyano, a phenyl group, a nitrogroup, the atoms of halogen, C1-4alkyl group, Halogens1-4alkyl group, Halogens1-4alkyloxy, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -CORa3, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3, -COORa1and-NRa2COORa3,

where Ra1and Ra2the same or different, and each p is ecstasy a hydrogen atom, C1-4alkyl group or benzyl group, and Ra3represents C1-4alkyl group, a C1-10alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and the following group B,

where the group B represents the group consisting of C3-10the carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a, heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4and-NRa5COORa6,

where Ra4and Ra5the same or different, and each represents a hydrogen atom, a C1-4alkyl group, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a, and Ra6represents C1-4alkyl group, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group (as defined above), neobythites is but substituted by 1-5 substituents, selected from the above-mentioned group a, -ORa7, -SRa7, -NRa7Ra8, -NRa7CORa9, -COORa10or-N=CH-NRa10Ra11,

where Ra7and Ra8the same or different, and each represents a hydrogen atom, group B or C1-10alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and the above-mentioned group B, Ra9represents C1-4alkyl group, and Ra10and Ra11the same or different, and each represents a hydrogen atom or a C1-4alkyl group,

or its pharmaceutically acceptable salt.

(9) the Compound 4-oxacilin above p.(5), where R32represents a hydrogen atom, a cyano, a halogen atom, a C1-10alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and the following group B,

where the group B represents the group consisting of C3-10the carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a, heterocyclic group (where the heterocyclic group is a saturated or unsaturated ring containing, besides atom(atoms) of carbon, at least one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom), optionally substituted by 1-5 substituents selected from the above d is uppy And, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4and-NRa5COORa6,

where Ra4and Ra5the same or different, and each represents a hydrogen atom, a C1-4alkyl group, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a, and Ra6represents C1-4alkyl group, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a, -ORa7, -SRa7, -NRa7Ra8, -NRa7CORa9or-COORa10,

where Ra7and Ra8the same or different, and each represents a hydrogen atom, group B or C1-10alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and the above-mentioned group B, Ra9represents C1-4alkyl group, and Ra10represents a hydrogen atom or a C1-4alkyl group,

or farm citiesi acceptable salt.

(10) the Compound 4-oxacilin above p.(9)where R32represents a hydrogen atom, -ORa7or-NRa7Ra8where Ra7and Ra8the same or different, and each represents a hydrogen atom, group B or C1-10alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and the above group B, or its pharmaceutically acceptable salt.

(11) the Compound 4-oxacilin above p.(8), where

R33represents a hydrogen atom, a C1-10alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and the following group B,

where the group B represents the group consisting of C3-10carbon ringsoptionally substituted by 1-5 substituents selected from the above-mentioned group a, heterocyclic group (where the heterocyclic group is a saturated or unsaturated ring containing, besides atom(atoms) of carbon, at least one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom), optionally substituted by 1-5 substituents selected from the aforementioned group a, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4and-NRa5COORa6 ,

where Ra4and Ra5the same or different, and each represents a hydrogen atom, a C1-4alkyl group, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a, and Ra6represents C1-4alkyl group, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a, -ORa7or-NRa7Ra8,

where Ra7and Ra8the same or different, and each represents a hydrogen atom, group B or C1-10alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and the above-mentioned group B,

or its pharmaceutically acceptable salt.

(12) the Compound 4-oxacilin above p.(11)where R33represents a hydrogen atom, -ORa7or-NRa7Ra8,

where Ra7and Ra8the same or different, and each represents a hydrogen atom, group B or C1-10alkyl group, optionally substituted by 1-3 substituents selected from the atom haloge the a and the above-mentioned group B,

or its pharmaceutically acceptable salt.

(13) the Compound 4-oxacilin any of the above paragraphs.(8)-(12), where

Ra7and Ra8,the same or different, and each represents C1-10alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and the following group B, group B represents the group consisting of C3-10the carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a, heterocyclic group (where the heterocyclic group is a saturated or unsaturated ring containing, besides atom(atoms) of carbon, at least one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom), optionally substituted by 1-5 substituents selected from the aforementioned group a, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4and-NRa5COORa6,

where Ra4and Ra5the same or different, and each represents a hydrogen atom, a C1-4alkyl group, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group (as defined above)optionally substituted by 1-5 what zamestitelyami, selected from the above group a, and Ra6represents C1-4alkyl group, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a,

or its pharmaceutically acceptable salt.

(14) the Compound 4-oxacilin above p.(5), where

R4and R5the same or different, and each represents a Deputy selected from cyanopropyl, phenyl group, nitro group, halogen atom, a C1-4alkyl group, Halogens1-4alkyl group, Halogens1-4alkyloxy, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -NRa1CORa3, -SO2Ra3, -NRa2COORa3and-COORa1,

where Ra1and Ra2the same or different, and each represents a hydrogen atom, a C1-4alkyl group or benzyl group, and Ra3represents C1-4alkyl group,

or its pharmaceutically acceptable salt.

(15) the Compound 4-oxacilin above p.(14), where

R4represents a phenyl group, a halogen atom, a C1-4alkyl group, Halogens1-4alkyloxy, -ORa1, -NRa1Ra2 , -CONRa1Ra2, -SO2NRa1Ra2, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3or-COORa1,

where Ra1and Ra2the same or different, and each represents a hydrogen atom, a C1-4alkyl group or benzyl group, and Ra3represents C1-4alkyl group,

or its pharmaceutically acceptable salt.

(16) the Compound 4-oxacilin above p.(15)where R4represents a halogen atom,

or its pharmaceutically acceptable salt.

(17) the Compound 4-oxacilin above p.(5), where R5represents a hydrogen atom, a cyano, a phenyl group, a nitrogroup, a halogen atom, a C1-4alkyl group, Halogens1-4alkyl group, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2or-NRa1CORa3,

where Ra1and Ra2the same or different, and each represents a hydrogen atom, a C1-4alkyl group or benzyl group, and Ra3represents C1-4alkyl group,

or its pharmaceutically acceptable salt.

(18) the Compound 4-oxacilin above p.(5), where R6represents a halogen atom,

or its pharmaceutically acceptable salt.

(19) the Compound 4-oxacilin above p.(5), where m is 0 and is 1,

or its pharmaceutically acceptable salt.

(20) the Compound 4-oxacilin above p.(5), where R1represents C3-10carbon ring, optionally substituted by 1-5 substituents selected from the following group A,

where group a is the group consisting of cyanopropyl, phenyl group, nitro group, halogen atom, a C1-4alkalaygroup, Halogens1-4alkyl group, Halogens1-4alkyloxy, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -CORa3, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3, -COORa1and-NRa2COORa3,

where Ra1and Ra2the same or different, and each represents a hydrogen atom, a C1-4alkyl group or benzyl group, and Ra3represents C1-4alkyl group, Deputy selected from-NRa4Ra5, -NRa4CORa6, -NRa4SO2Ra6and-NRa5COORa6,

where Ra4and Ra5the same or different, and each represents a hydrogen atom, a C1-4alkyl group, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group (where the heterocyclic group is a saturated or unsaturated ring, steriade is, in addition to the atom(atoms) of carbon, at least one heteroatom selected from a nitrogen atom, oxygen atom and sulfur atom), optionally substituted by 1-5 substituents selected from the aforementioned group a, and Ra6represents C1-4alkyl group, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a, or

C1-10alkyl group, optionally substituted by 1-3 substituents selected from halogen atom and group B,

where the group B represents the group consisting of C3-10the carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a, heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4and-NRa5COORa6(where Ra4, Ra5, Ra6and the groupAnd have the above values),

or its pharmaceutically acceptable salt.

(21) the Compound 4-oxacilin above p.(20), where

R1 represents C1-10alkyl group, optionally substituted by 1-3 substituents selected from halogen atom and group B,

where the group B represents the group consisting of C3-10the carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a, heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4and-NRa5COORa6,

where Ra4and Ra5the same or different, and each represents a hydrogen atom, a C1-4alkyl group, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a, and Ra6represents C1-4alkyl group, a C3-10carbon ring, optionally substituted by 1-5 substituents selected from the above-mentioned group a or heterocyclic group (as defined above)optionally substituted by 1-5 substituents selected from the aforementioned group a,

or pharmaceuticas is acceptable salt.

(22) the Compound 4-oxacilin above p.(5), which is chosen from the group comprising the following compounds:

6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-1),

6-(2,3-dichlorobenzyl)-8-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-2),

6-(2,3-Chlorobenzyl)-1-(2-methanesulfonylaminoethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-3),

6-(2,3-dichlorobenzyl)-1-(2-imidazol-1-retil)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-4),

6-(2,3-dichlorobenzyl)-1-dimethylcarbamoyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-5),

6-(2,3-dichlorobenzyl)-1-methylcarbamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-6),

1-carbamoylmethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-7),

6-(2,3-dichlorobenzyl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-8),

6-(2,3-dichlorobenzyl)-4-oxo-1-sulfamoyl-1,4-dihydroquinoline-3-carboxylic acid (example 1-9),

1-(2-carboxyethyl)-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-10),

1-(2-hydroxyethyl)-6-naphthalene-1-ylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-11),

methyl ester of 6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-12),

1-(2-carbamoylethyl)-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-13),

6-(2,3-dichlorobenzyl)-4-oxo-1-(2-oxopropyl)-1,4-dihydroquinoline-3-carboxylic acid (example 1-14),

1-benzyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-15),

6-(2,3-dichlorobenzyl)-4-oxo-1-phenethyl-1,4-dihydroquinoline-3-carboxylic acid (example 1-16),

6-(2,3-dichlorobenzyl)-1-(3-phenylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-17),

6-(2,3-dichlorobenzyl)-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-18),

6-(2,3-dichlorobenzyl)-1-(4-phenylbutyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-19),

1-biphenyl-2-ylmethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-20),

6-(2,3-dichlorobenzyl)-1-(4-hydroxybutyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-21),

1-benzo[b]thiophene-2-ylmethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-22),

6-(2,3-dichlorobenzyl)-1-(3,4-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-23),

6-(2,3-dichlorobenzyl)-1-(2-dimethylaminoethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-24),

6-(2,3-dichlorobenzyl)-1-(3-hydroxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-25),

6-(2,3-dichlorobenzyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid is (example 1-26),

6-(2,3-dichlorobenzyl)-1-(2,2,2-triptorelin)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-27),

1-carboxymethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-28),

6-(2,3-dichlorobenzyl)-1-[2-(4-methylthiazole-5-ILTER]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-29),

6-(2,3-dichlorobenzyl)-1-(2-hydroxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-30),

6-(2,3-dichlorobenzyl)-1-(2-methylsulfonylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-32),

6-(2-chloro-6-terbisil)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-33),

6-(2,3-dichlorobenzyl)-1-(5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-34),

6-(2,3-dichlorobenzyl)-1-(2-morpholine-4-retil)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-35),

6-(2,3-dichlorobenzyl)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-36),

6-(2,3-dichlorobenzyl)-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-37),

6-(2,3-dichlorobenzyl)-4-oxo-1-propyl-1,4-dihydroquinoline-3-carboxylic acid (example 1-38),

1-butyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-39),

1-cyclopentylmethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-40),

6-(2,3-dichlorobenzyl)-1-(2-methanesulfonyl)-4-oxo-1,4-dihydroquinoline-3-carbonatite (example 1-41),

1-cyclohexylmethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-42),

6-(2,3-dichlorobenzyl)-1-(2-hydroxy-2-phenylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-43),

6-(2,3-dichlorobenzyl)-1-(2-foradil)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-44),

6-(2,3-dichlorobenzyl)-4-oxo-1-(2-pyridin-2-retil)-1,4-dihydroquinoline-3-carboxylic acid (example 1-45),

1-(2-amino-ethyl)-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-46),

6-(2,3-dichlorobenzyl)-1-(2-hydroxy-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-47),

1-(2-acetylamino)-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-48),

6-(2,3-dichlorobenzyl)-1-(2-ethoxycarbonylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-49),

6-(2,3-diferensial)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-50),

6-(2-chloro-4-terbisil)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-51),

6-(2-Chlorobenzyl)-4-oxo-1-phenethyl-1,4-dihydroquinoline-3-carboxylic acid (example 1-65),

6-(2-chloro-3-terbisil)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-66),

6-(2,3-dichlorobenzyl)-1-methylsulfonylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-68),

6-(2,3-dichlorobenzyl)-1-methanesulfonyl the Il-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-69),

1-tert-butylsulfonyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-70),

6-(2,3-dichlorobenzyl)-1-methylcarbamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-71),

6-(2,3-dichlorobenzyl)-1-dimethylsulphamoyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-72),

6-(2-chloro-3,6-diferensial)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-73),

6-(2,3-dichlorobenzyl)-1-(2,3-dihydroxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-74),

6-(2-chloro-6-terbisil)-1-sulfamoyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-75),

6-(2-chloro-6-terbisil)-1-methylcarbamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-76),

6-(2-chloro-6-terbisil)-1-dimethylsulphamoyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-77),

6-(2-chloro-3-methylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-79),

6-(2-bromobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-80),

6-(2-chloro-3-methoxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-82),

1-(2-hydroxyethyl)-6-(2-methanesulfonylaminoethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-85),

6-biphenyl-2-ylmethyl-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (when the er 1-86),

6-(2-Chlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-87),

6-(2-chloro-5-methylsulfonylbenzoyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-92),

1-(2-hydroxyethyl)-4-oxo-6-(2-triftormetilfullerenov)-1,4-dihydroquinoline-3-carboxylic acid (example 1-93),

6-(2-chloro-5-methylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-97),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-99),

6-(3-chloro-2,6-diferensial)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-100),

6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-101),

1-cyclopropyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-102),

1-amino-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2-1),

6-(2,3-dichlorobenzyl)-1-methoxycarbonylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2-2),

1-acetylamino-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2-3),

6-(2,3-dichlorobenzyl)-1-methanesulfonamido-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2-4),

6-(2,3-dichlorobenzyl)-1-(N-methanesulfonyl-N-methylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2-5),

6-(2,3-dichloran who yl)-1-dimethylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2-6),

6-(2,3-dichlorobenzyl)-1-methylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2-7),

6-(2,3-dichlorobenzyl)-1-ethylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2-8),

6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-1),

6-(3-chloro-2-methylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-2),

6-(3-chloro-2-methoxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-3),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-4),

6-(2,3-dichlorobenzyl)-5-hydroxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-5),

6-(2,3-dichlorobenzyl)-7-hydroxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-6),

1-(2-hydroxyethyl)-6-(2-methylaminomethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-7),

6-(2-dimethylaminoethyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-8),

6-(2,3-dichlorobenzyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid (example 3-9),

6-(2,3-dichlorobenzyl)-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-10),

1-cyclobutyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-12),

1-cyclopentyl-6-(2,3-shall chlorbenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-13),

6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-14),

6-(2-dimethylaminovinyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-16),

6-(3-chloro-2,4-diferensial)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-17),

6-(2-carboxybenzoyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-18),

1-(2-hydroxyethyl)-6-(2-methylsulfonylbenzoyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-19),

6-(2,3-dichlorobenzyl)-7-ethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-20),

7-chloro-6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-21),

6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-7-trifluoromethyl-1,4-dihydroquinoline-3-carboxylic acid (example 3-22),

(S)-6-(3-chloro-2-terbisil)-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-23),

(R)-6-(3-chloro-2-terbisil)-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-24),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-8-trifluoromethyl-1,4-dihydroquinoline-3-carboxylic acid (example 3-25),

6-(3-chloro-2-terbisil)-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-26),

7-cyano-6-(2,3-dichlorobenzyl)-1-(2-hydroc ITIL)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-27),

6-(2-ethylmethylamino)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-28),

6-[2-(N-methyl-N-propylamino)benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-29),

6-[2-(N-benzyl-N-methylamino)benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-30),

6-[2-(N-methanesulfonyl-N-methylamino)benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-31),

6-[2-(N-isopropyl-N-methylamino)benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-32),

1-tert-butyl-6-(3-chloro-2-terbisil)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-33),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-34),

8-amino-6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-35),

7-carboxy-6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-36),

6-(3-chloro-2,6-diferensial)-1-(2-hydroxyethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-37),

6-(3-chloro-2-terbisil)-8-dimethylamino-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-38),

8-acetylamino-6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-39),

5-cyano-6(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-40),

6-[2-(N-acetyl-N-methylamino)benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-41),

6-(2-diethylaminoethyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-42),

6-(3-chloro-2-terbisil)-1-(1,1-dimethyl-2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-43),

6-(3-chloro-2-terbisil)-7-ethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-44),

6-(3-chloro-2-terbisil)-7,8-dimethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-45),

6-(3-chloro-2-terbisil)-8-ethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-47),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-8-methylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-48),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-7-propyloxy-1,4-dihydroquinoline-3-carboxylic acid (example 3-49),

6-(3-chloro-2-terbisil)-7-(dimethylaminomethylene)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-50),

methyl ester of 6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-51),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-8-phenoxy-1,4-dihydroquinoline-3-carboxylic acid (example 3-52),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carbon is Aya acid (example 3-53),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-8-propylamino-1,4-dihydroquinoline-3-carboxylic acid (example 3-54),

6-(3-chloro-2-terbisil)-8-ethylamino-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-55),

(S)-6-(3-chloro-2-terbisil)-1-(2-hydroxy-1-methylethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-56),

(S)-6-(3-chloro-2,6-diferensial)-1-(2-hydroxy-1-methylethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-57),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-8-propyloxy-1,4-dihydroquinoline-3-carboxylic acid (358 for example),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-59),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-60),

(S)-6-(3-chloro-2-terbisil)-7-ethoxy-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-61),

6-(3-chloro-2-terbisil)-7-dimethylamino-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-62),

6-(3-chloro-2-terbisil)-7-cyclohexylmethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-63),

6-(3-chloro-2-terbisil)-8-diethylamino-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-64),

6-(3-chloro-2-terbisil)-7-methylamino-1-(2-hydroxyethyl)-4-ox who -1,4-dihydroquinoline-3-carboxylic acid (example 3-65),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-7-pyrrolidin-1-yl-1,4-dihydroquinoline-3-carboxylic acid (example 3-66),

(S)-6-(3-chloro-2-terbisil)-8-ethoxy-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-67),

(S)-6-(3-chloro-2-terbisil)-7-ethoxy-1-[1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-68),

6-(3-chloro-2-terbisil)-8-cyclohexylmethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-69),

(S)-6-(3-chloro-2-terbisil)-1-(1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-70),

(S)-6-(3-chloro-2-terbisil)-1-(1-hydroxymethyl-3-methylbutyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-71),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)propyl]-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-72),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)propyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-73),

(S)-6-(3-chloro-2-terbisil)-1-(2-hydroxy-1-methylethyl)-7-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-74),

(S)-6-(3-chloro-2-terbisil)-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-75),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-7-(2-hydroxyethyloxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-76),

6-(3-chloro-2-tormentil)-1-(2-hydroxyethyl)-7-(3-hydroxypropoxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-77),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-8-(2-hydroxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-78),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)propyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-79),

(S)-6-(3-chloro-2-terbisil)-8-dimethylamino-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-80),

(S)-6-(3-chloro-2-terbisil)-1-(2-hydroxy-1-phenylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-81),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)butyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-82),

6-(3-chloro-2-terbisil)-1-((1S,2S)-1-hydroxymethyl-2-methylbutyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-83),

(S)-6-(3-chloro-2-terbisil)-1-(2-hydroxy-1-methylethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-84),

(S)-6-(3-chloro-2-terbisil)-1-(1-benzyl-2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-85),

6-(2-chloro-5-methanesulfonylaminoethyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-1),

6-(2-active compounds)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-4),

6-(2-chloro-5-methylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-5),

6-(2-chloro-5-terbisil)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (primer-6),

6-(5-bromo-2-Chlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-7),

6-(2,3-dichlorobenzyl)-7-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-9),

6-(2-chloro-5-hydroxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-11),

6-(2,3-dichlorobenzyl)-5-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-12),

6-(2-ethoxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-13),

6-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-14),

6-(2,3-dichlorobenzyl)-7-methyl-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-15),

(S)-6-(3-chloro-2-terbisil)-1-(2-hydroxy-1-methylethyl)-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-16),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)propyl]-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-17),

(S)-6-(3-chloro-2-terbisil)-1-(1-cyclohexyl-2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-18),

(S)-6-(3-chloro-2-terbisil)-1-(1-hydroxymethyl-2-methylpropyl)-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-19),

(S)-6-(3-chloro-2-terbisil)-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic sour is a (example 4-20),

(S)-6-(3-chloro-2-terbisil)-8-ethoxy-1-[1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-21),

(S)-6-(3-chloro-2-terbisil)-1-[2-cyclohexyl-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-22),

(S)-6-(3-chloro-2-terbisil)-1-(1-hydroxymethyl-3-methylbutyl)-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-23),

(S)-6-(3-chloro-2-terbisil)-1-(1-hydroxymethyl-2-methylpropyl)-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-24),

(S)-6-(3-chloro-2-terbisil)-1-(1-hydroxymethyl-3-methylbutyl)-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-25),

(S)-6-(3-chloro-2-terbisil)-[2,2-dimethyl-1-(hydroxymethyl)propyl]-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-26),

6-(3-chloro-2-terbisil)-1-((1S,2S)-1-hydroxymethyl-2-methylbutyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-27),

6-(3-chloro-2-terbisil)-7-ethoxy-1-((1S,2S)-1-hydroxymethyl-2-methylbutyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-28),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)propyl]-7-methylsulfanyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-29),

(S)-6-(3-chloro-2-terbisil)-7-ethoxy-1-(1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-30),

(S)-6-(3-chloro-2-terbisil)-7-ethoxy-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-31),

(S)-6-(3-chloro-2-terbisil)-1-(1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-32),

(S)-6-(3-chloro-2-terbisil)-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-33),

(S)-6-(3-chloro-2-terbisil)-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-34),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)butyl]-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-35),

(S)-6-(3-chloro-2-terbisil)-7-ethoxy-1-[1-(hydroxymethyl)butyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-36),

(S)-6-(3-chloro-2-terbisil)-8-ethoxy-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-37),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)butyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-38),

6-(3-chloro-2-terbisil)-1-((1S,2S)-1-hydroxymethyl-2-methylbutyl)-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-39),

(S)-6-(3-chloro-2-terbisil)-1-(1-cyclohexyl-2-hydroxyethyl)-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-40),

(S)-6-(3-chloro-2-terbisil)-1-(1-cyclohexyl-2-hydroxyethyl)-8-ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-41),

(S)-6-(3-chloro-2-terbisil)-1-(1-cyclohexyl-2-hydroxyethyl)-7-m the toxi-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-42),

(S)-6-(3-chloro-2-terbisil)-1-(1-cyclohexyl-2-hydroxyethyl)-7-ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-43),

(S)-6-(3-chloro-2-terbisil)-1-(1-cyclohexyl-2-hydroxyethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-44),

(S)-6-(3-chloro-2-terbisil)-8-ethoxy-1-(1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-45),

(S)-6-(3-chloro-2-terbisil)-1-(1-hydroxymethyl-2-methylpropyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-46),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)butyl]-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example about 4-47),

(S)-6-(3-chloro-2-terbisil)-8-ethoxy-1-[1-(hydroxymethyl)butyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-48),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)butyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-49),

(S)-6-(3-chloro-2-terbisil)-1-(1-cyclohexyl-2-hydroxyethyl)-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-50) and

(S)-6-(3-chloro-2-terbisil)-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-52),

or its pharmaceutically acceptable salt.

(23) a Pharmaceutical composition comprising the compound 4-oxacilin any of the above paragraphs.(5)to(22) or its pharmaceutically acceptable salt and a pharmaceutical is viable media.

(24) the integrase Inhibitor containing the compound 4-oxacilin any of the above paragraphs.(1)to(22) or its pharmaceutically acceptable salt as an active ingredient.

(25)Antiviral agent containing the compound 4-oxacilin any of the above paragraphs.(5)to(22) or its pharmaceutically acceptable salt as an active ingredient.

(26) Anti-HIV agent containing the compound 4-oxacilin any of the above paragraphs.(5)to(22) or its pharmaceutically acceptable salt, as an active ingredient.

(27) Anti-HIV composition comprising the compound 4-oxacilin any of the above paragraphs.(1)to(22) or its pharmaceutically acceptable salt and one or more types of anti-HIV active substances as the active ingredient.

(28) Anti-HIV agent containing the compound 4-oxacilin forany of the above paragraphs.(1)to(22) or its pharmaceutically acceptable salt as an active ingredient for the treatment of multiple drugs, including other (other) anti-HIV agent(agents).

(29) Use of the compound 4-oxacilin any of the above paragraphs.(5)to(22) or its pharmaceutically acceptable salt to obtain an anti-HIV agent.

(30) the Use of the compounds 4-oxacilin any of the above paragraphs.(5)to(22) or its pharmaceutically acceptable salt to obtain inhibi the ora integrase.

(31) Use of the compound 4-oxacilin any of the above paragraphs.(5)to(22) or its pharmaceutically acceptable salt to obtain an antiviral agent.

(32) a Method of preventing or treating HIV infectious disease, which comprises administration to a mammal an effective amount of the compound 4-oxacilin any of the above paragraphs.(5)to(22) or its pharmaceutically acceptable salt.

(33) a Method for preventing or treating HIV infectious diseases at the above p.(32), which includes the further introduction to the specified mammal an effective amount of at least one other anti-HIV active substances.

(34) a Method of inhibiting integrase, which includes an introduction to the mammal an effective amount of the compound 4-oxacilin any of the above paragraphs.(5)to(22) or its pharmaceutically acceptable salt.

(35) a Method for prevention or treatment of viral infectious diseases, which includes an introduction to the mammal an effective amount of the compound 4-oxacilin any of the above paragraphs.(5)to(22) or its pharmaceutically acceptable salt.

(36) Anti-HIV composition comprising the compound 4-oxacilin any of the above paragraphs.(5)to(22) or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

(37) the Pharmaceutical companies who stand for inhibiting integrase, which contains the compound 4-oxacilin any of the above paragraphs.(5)-(22) or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

(38) Antiviral composition comprising the compound 4-oxacilin any of the above paragraphs.(5)to(22) or its pharmaceutically acceptable salt, and a pharmaceutically acceptable carrier.

(39) a Commercial package comprising the composition according to the above p.(36) and accompanying written instructions and written instructions indicated that the composition can or should be used for preventing or treating HIV infectious diseases.

(40) a Commercial package comprising the composition according to the above p.(37) and accompanying written instructions and written instructions indicated that the composition can or should be used for inhibiting integrase.

(41) a Commercial package comprising the composition according to the above p.(38) and accompanying written instructions and written instructions indicated that the composition can or should be used for prevention or treatment of viral infectious diseases.

Definitions of each of the substituents and each of the fragments used in this description have the following meanings.

Term is h "halogen atom" means a fluorine atom, the chlorine atom, bromine atom or iodine atom, preferably a fluorine atom, a chlorine atom or a bromine atom.

As R32, R33, R4, R5, R6, R6', R6", R6"'and groups And is particularly preferred fluorine atom and a chlorine atom, as R32and R5more preferable, a chlorine atom, and R31, R33, R4, R6', R6"'and halogen atom "C1-10alkyl group, optionally substituted by 1-3 substituents selected from halogen atom and group B", the preferred fluorine atom.

The term "C1-4alkyl group" means an alkyl group with unbranched or branched chain containing 1-4 carbon atoms, which is specifically represents methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, sec-boutelou group or tert-boutelou group.

As R2, R31and Ra6the preferred methyl group and ethyl group, as R4, R5, R6, R6', R6", R6"'and group preferred a methyl group, ethyl group and isopropyl group, and more preferred methyl group as Ra1and Ra2the preferred methyl group, ethyl group, through the group and isopropyl group, and b is more preferred methyl group, as Ra3, Ra9, Ra10, Ra11and group preferred a methyl group, and Ra4and Ra5the preferred methyl group, ethyl group and tert-bucilina group.

The term "Halogens1-4alkyl group" means "C1-4alkyl group, as defined above, which is substituted by an1-9, preferably 1-3, "halogen atoms", as defined above.

Its specific examples include 2-foretelling group, 2-chloraniline group, 2-bromatology group, 3-forproperty group, 3-chloropropylene group, 4-terbutaline group, 4-chlorobutanol group, triptorelin group, 2,2,2-triptorelin group, 3,3,3-triptorelin group, 4,4,4-triptorelin group, panafcortelone group, 2,2,2-Cryptor-1-triftormyetil group, etc.

As R31, R4, R5, R6, R6', R6", R6"'and groups And preferred triptorelin group.

The term "C1-4alkoxygroup" means alkyloxy, in which the alkyl fragment is "C1-4alkyl group, as defined above, and its specific examples include a methoxy group, ethoxypropan, propoxylate, isopropylacetate, butoxypropyl, isobutylacetate, tert-butylacrylate etc.

For R31preferred methoxy group.

The term "C1-4alkylsulfonyl group" means alkylsulfanyl group, where the alkyl fragment is "C1-4alkyl group, as defined above. Its specific examples include methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylphenyl group, butylsulfonyl group, isobutylamino group, tert-butylsulfonyl group, etc.

For R31preferred methylsulfanyl group.

The term "Halogens1-4alkyloxy" means Halogens1-4alkyloxy, where it allogeneically fragment means "Halogens1-4alkyl group, as defined above.

Its specific examples include 2-foratractorru, 2-chlorethoxyfos, 2-promediacorp, 3-ferroelectic, 3-chloropropoxy, 4-terbutylazine, 4-chlorotyrosine, cryptometrics, 2,2,2-tripterocarpa, 3,3,3-cryptocomplexity, 4,4,4-cryptosporiosis, panafcortelone, 2,2,2-Cryptor-1-triftormetilfullerenov etc.

For R31, R4, R5, R6, R6', R6", R6"'and groups And preferred cryptometrics.

The term "C3-10carbon ring" means a saturated or unsaturated cyclic hydrocarbon group containing 3 to 10 carbon atoms, examples of which include an aryl group, cycloalkyl group, the cycle is alkenylphenol group, or condensed ring.

Specific examples of the "aryl group" include phenyl group, naftalina group, pentylaniline group, azulinebloo group and the like, preferably phenyl group and naftalina group, particularly preferably phenyl group.

Specific examples of "cycloalkyl group" include 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" includes, at least, preferably 1 or 2 double bonds, and its specific examples include cyclopropyl group, cyclobutyl group, cyclopentadienyl group, cyclopentadienyls group, cyclohexenyl group, cyclohexadienyl group (2,4-cyclohexadiene-1-ilen group, 2,5-cyclohexadiene-1-ilen group and the like), cycloheptenyl group and cyclooctyl group, etc.

Specific examples of the condensed rings of these "aryl group", "cycloalkyl group" and "cycloalkenyl group" include 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-those whom rehydro-2-naftalina group and the like), perhydroanthracene group, etc.Preferably, it was a condensed ring consisting of a phenyl group and another ring, examples of which can be angenlina group, indayla group, 1,4-dihydronaphthalene group, 1,2,3,4-tetrahydronaphthalene group and the like, and particularly preferred indayla group.

The term "C3-10carbon ring, optionally substituted by 1-5 substituents selected from group a"means "C3-10carbon ring, as defined above, which is optionally substituted by 1-5, preferably 1-3 substituents selected from the following group A, and includes unsubstituted C3-10carbon ring".

The term "group" refers to a group consisting of cyanopropyl, phenyl group, nitro group, halogen atom"defined above, "C1-4alkyl group, as defined above, Halogens1-4alkyl group, as defined above, Halogens1-4alkyloxy", as defined above, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -CORa3, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3, -COORa1and-NRa2COORa3where Ra1and Ra2the same or different and each represents a hydrogen atom, "C1-4alkyl group, as defined above, or benzyl the second group, and Ra3is "C1-4alkyl group, as defined above.

Specific examples of "-ORa1include the hydroxy-group, a methoxy group, ethoxypropan, propoxylate, isopropylamino, tert-butoxypropan etc.

Specific examples of "-SRa1" include mercaptopropyl, methylsulfanyl group, ethylsulfonyl group, propylsulfonyl group, isopropylphenyl group, tert-butylsulfonyl group, etc.

Specific examples of "-NRa1Ra2" include an amino group, methylaminopropyl, ethylamino, propylamino, isopropylamino, tert-butylamino, dimethylaminopropyl, diethylaminopropyl, N-ethyl-N-methylaminopropyl, N-methyl-N-propylamino, N-isopropyl-N-methylaminopropyl, N-benzyl-N-methylaminopropyl etc.

Specific examples of "-CONRa1Ra2include karbamoilnuyu group, methylaminomethyl group, ethylaminomethyl group, propylaminoethyl group, isopropylaminocarbonyl group, tert-butylaminoethyl group, dimethylaminocarbonylmethyl group, diethylaminocarbonylmethyl group, N-methyl-N-ethylaminomethyl group, etc.

Specific examples of "-SO2NRa1Ra2include sulfamoyl group, methylaminomethyl group, ethylaminomethyl group, propylaminosulfonyl group is, isopropylaminocarbonyl group, tert-butylaminoethyl group, dimethylaminomethyl group, diethylaminomethyl group, N-methyl-N-ethylaminomethyl group, etc.

Specific examples of "-CORa3" include acetyl group, propionyl group, butyryloxy group, isobutyryloxy group, pivaloyloxy group, etc.

Specific examples of "-NRa1CORa3" include acetylamino, propionamido, bucillamine, isobutylamino, evaluieringsrapport, N-acetyl-N-methylaminopropyl etc.

Specific examples of "-SO2Ra3include methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylphenyl group, tert-butylsulfonyl group, etc.

Specific examples of "-NRa1SO2Ra3" include methylsulfonylamino, ethylsulfonylimidazo, propylsulfonyl, isopropylbenzylamine, tert-butylsulfonyl, N-methyl-N-(methylsulphonyl)amino group, etc.

Specific examples of "-COORa1include a carboxyl group, methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, tert-butoxycarbonyl group, etc.

And specific examples of "-NRa2COORa3" include methoxycarbonyl is infogruppu, ethoxycarbonylmethoxy, propoxycarbonyl, isopropoxycarbonyl, tert-butoxycarbonylamino etc.

As A preferred cyano, phenyl group, a nitrogroup, a fluorine atom, chlorine atom, bromine atom, methyl group, ethyl group, isopropyl group, triptorelin group, cryptometrics, the hydroxy-group, methoxy group, ethoxypropan, propoxylate, methylsulfanyl group, amino group, methylaminopropyl, atramentaria, isopropylamino, dimethylaminopropyl, diethylaminopropyl, N-ethyl-N-methylaminopropane, N-methyl-N-propylamino, N-isopropyl-N-methylaminopropane, N-benzyl-N-methylaminopropyl, carnemolla group, methylaminomethyl group, dimethylaminocarbonylmethyl group, alfamarine group, methylaminomethyl group, dimethylaminomethylene group, acetyl group, acetylamino, N-acetyl-N-methylaminopropyl, methylsulfonyl group, methylsulfonylamino, N-methyl-N-(methylsulphonyl)amino group, carboxyl group, methoxycarbonyl group, carboxyhaemoglobin and methoxycarbonylamino.

As A particularly preferred cyano, phenyl group, a nitrogroup, a fluorine atom, a chlorine atom, a bromine atom, a methyl group, triptorelin group, cryptometrics the group, the hydroxy-group, methoxy group, ethoxypropan, methylsulfanyl group, amino group, methylaminopropyl, dimethylaminopropyl, diethylaminopropyl, N-ethyl-N-methylaminopropane, N-methyl-N-propylamino, N-isopropyl-N-methylaminopropane, N-benzyl-N-methylaminopropyl, dimethylaminocarbonylmethyl group, methylaminomethyl group, dimethylaminomethylene group, acetylamino, N-acetyl-N-methylaminopropyl, methylsulfonyl group, N-methyl-N-(methylsulphonyl)amino group and carboxyl group, and more preferred fluorine atom and chlorine atom.

The number of substituents is preferably 1 to 3, and if "C3-10carbon ring" represents a phenyl group, ring Cy is preferably monosubstituted at position 2, monosubstituted at position 3, disubstituted in positions 2,3, disubstituted in positions 2,4, disubstituted in positions of 2.5 disubstituted at positions 2,6, trisemester in positions 2,3,4, trisemester in clauses 2,3,5, trisemester in the provisions 2,3,6, particularly preferably is disubstituted in positions 2,3.

Concrete examples of C3-10the carbon ring, optionally substituted by 1-5 substituents selected from group" include a phenyl group, naftalina group, 2-florfenicol group,

2-chloraniline group, 2-bromperidol group,

3-florfenicol group, 3-CHL is fanilow group,

3-bromperidol group, 4-florfenicol group,

2-nitrophenyl group, 3-nitrophenyl group,

2-cyanophenyl group, 3-cyanophenyl group,

2-methylphenyl group, 3-methylphenyl group,

4-methylphenyl group, 2-ethylphenyl group,

3-ethylphenyl group, 2-isopropylphenyl group,

3-isopropylphenyl group, 2-triftormetilfullerenov group,

3-triftormetilfullerenov 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-(trifluoromethyl)phenyl group,

3-(trifluoromethyl)phenyl group,

2-(cryptomelane)phenyl group,

3-(cryptomelane)phenyl group,

2-methylsulfinylphenyl group,

3-methylsulfinylphenyl group, 2-AMINOPHENYL group,

3-AMINOPHENYL group, 2-(methylamino)phenyl group,

3-(methylamino)phenyl group,

2-(dimethylamino)phenyl group,

3-(dimethylamino)phenyl group,

2-(acetylamino)phenyl group,

3-(acetylamino)phenyl group, 2-biphenylene group,

3-biphenylene group, 2-(methylsulphonyl)phenyl group,

3-(methylsulphonyl)phenyl group is at,

2-sulfamoylbenzoyl group, 3-sulfamoylbenzoyl group,

2-(methylaminomethyl)phenyl group,

3-(methylaminomethyl)phenyl group,

2-(dimethylaminomethyl)phenyl group,

3-(dimethylaminomethyl)phenyl group,

2-(dimethylsulphamoyl)phenyl group,

2-(methylsulfonylamino)phenyl group,

3-(methylsulfonylamino)phenyl group,

2-carbamoylethyl group, 3-carbamoylphenoxy 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,

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-5-nitrophenyl group, 2-chloro-3-methylphenylene group,

2-chloro-5-methylphenylene group,

2-chloro-3-(trifluoromethyl)phenyl group,

2-chloro-5-(trifluoromethyl)phenyl group,

2-chloro-3-hydroxyphenyl group,

2-chloro-5-hydroxyphenyl group,

2-chloro-3-meth is xianling group,

2-chloro-5-metoksifenilny group,

2-chloro-3-methylsulfinylphenyl group,

2-chloro-5-methylsulfinylphenyl 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-chloro-3-(acetylamino)phenyl group,

2-chloro-5-(acetylamino)phenyl group,

2-chloro-3-(methylsulphonyl)phenyl group,

2-chloro-5-(methylsulphonyl)phenyl group,

2-chloro-3-(methylsulfonylamino)phenyl group,

2-chloro-5-(methylsulfonylamino)phenyl group,

2,3,4-triptorelin group,

2-chloro-3,4-differenly group,

2-chloro-3,5-differenly 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,

3-chloro-2-fluoro-5-triftormetilfullerenov 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,

p is hohenloe group, cyclopropyl group,

cyclobutyl group, cyclopentyl group,

tsiklogeksilnogo group, 2-hydroxyisopropyl group,

3-hydroxyisobutyryl group,

3-hydroxycyclopent group,

2-hydroxycyclohexyl group,

3-hydroxycyclohexyl group,

4-hydroxycyclohexyl group, 4-indenolol group and 1H-inden-4-ilen group.

The ring Cy is preferably phenyl group,

naftalina group, 2-chloraniline group,

3-chloraniline group, 2-bromperidol group,

3-bromperidol group, 2-ethylphenyl group,

3-ethylphenyl group, 2-hydroxyphenyl group,

2-ethoxyphenyl group, 3-(cryptomelane)phenyl group,

3-(methylsulphonyl)phenyl group, 2,3-differenly group,

2,3-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-bromo-2-chloraniline group, 2-chloro-5-methylphenylene group,

2-chloro-5-hydroxyphenyl group,

2-chloro-5-(methylsulphonyl)phenyl group,

2-chloro-3,6-differenly group,

3-chloro-2,4-differenly group,

3-chloro-2,6-differenly group,

2-chloro-3-methylphenyl group, 3-chloro-2-methylphenylene group,

2-chloro-3-label iverilog group,

3-chloro-2-metoksifenilny group, 3-nitrophenyl group,

3-cyanophenyl group, 4-methylphenyl group,

3-triftormetilfullerenov group,

2-(cryptomelane)phenyl group,

3-hydroxyphenyl group, 3-ethoxyphenyl group,

3-AMINOPHENYL group, 2-(methylamino)phenyl group,

2-(dimethylamino)phenyl group,

2-(diethylamino)phenyl group,

2-(N-ethyl-N-methylamino)phenyl group,

2-(N-isopropyl-N-methylamino)phenyl group,

2-(N-benzyl-N-methylamino)phenyl group,

2-(N-acetyl-N-methylamino)phenyl group,

2-(N-methyl-N-methylsulfonylamino)phenyl group,

3-(methylamino)phenyl group, 2-carboxyphenyl group,

3-(dimethylaminoethyl)-phenyl group,

3-(acetylamino)phenyl group, 2-biphenylene group,

2-(methylsulphonyl)phenyl group,

2-chloro-5-methylsulfinylphenyl group,

2-chloro-5-methylphenylene group,

2-(methylaminomethyl)phenyl group,

2-(dimethylaminomethyl)phenyl group, or

3-(dimethylaminomethyl)phenyl group,

especially preferably 2-chloraniline group,

2-bromperidol group, 2-ethylphenyl group,

2-hydroxyphenyl group,

2-ethoxyphenyl group, 2,3-differenly group,

2,3-dichloraniline group, 2-chloro-3-florfenicol group,

3-the ENT-2-florfenicol group, 2-chloro-4-florfenicol group,

2-chloro-5-florfenicol group, 2-chloro-6-florfenicol group,

5-bromo-2-chloraniline group,

2-chloro-5-hydroxyphenyl group,

2-chloro-5-(methylsulphonyl)phenyl group,

2-chloro-3,6-differenly group,

3-chloro-2,6-differenly group,

2-chloro-3-methylphenylene group,

2-chloro-3-metoksifenilny group,

2-triftormetilfullerenov group,

2-(methylsulphonyl)phenyl group,

2-chloro-5-methylsulfinylphenyl group,

2-chloro-5-methylphenylene group or

2-(dimethylaminomethyl)phenyl group, and

even more preferably 2,3-dichloraniline group,

2,3-differenly group, 2-chloro-3-florfenicol group or

3-chloro-2-florfenicol group.

R1and group B preferably represent a phenyl group, 3,4-dichloraniline group, 2-biphenylene group,

cyclopropyl group, 2-hydroxyisopropyl group,

cyclobutyl group, 2-hydroxyisobutyrate group,

3-hydroxyisobutyrate group, cyclopentenone group,

2-hydroxycyclopent group,

3-hydroxycyclopent group, tsiklogeksilnogo group,

2-hydroxycyclohexyl group,

3-hydroxycyclohexyl group and

4-hydroxycyclohexyl group,

particularly preferably phenyl group,

3,4-dichlor nilina group, 2-biphenylene group,

cyclopropyl group, cyclobutyl group,

cyclopentolate group and tsiklogeksilnogo group.

As R32, R33, R1and group B preferred phenyl group and tsiklogeksilnogo group.

The term "heterocyclic group" means a saturated or unsaturated (including partially unsaturated and completely unsaturated) monocyclic 5 - or 6-membered heterocycle containing, besides carbon atom, at least one, preferably 1-4 heteroatoms selected from a nitrogen atom, oxygen atom and sulfur atom, and a condensed ring of these compounds or condensed ringC3-10carbon ring or heterocycle, where the carbon ring selected from benzene, cyclopentane and cyclohexane.

Examples of the "saturated monocyclic heterocyclic group" include pyrrolidinyl group, tetrahydrofuryl group, tetrahydrocannibinol group, imidazolidinyl group, pyrazolidine group, 1,3-DIOXOLANYL group, 1,3-oxathiolanes group, oxazolidinyl group, diazolidinyl group, piperidinyl group, piperazinilnom group, tetrahydropyranyloxy group, tetrahydropyranyloxy group, dioxinlike group, morpholinyl group, thiomorpholine group, 2-oxopyrrolidin group, 2-okopipi denilou group, 4-oxopiperidine group, 2,6-dioxopiperidin group, etc.Preferred pyrrolidinyl group, piperidinyl group or morpholinyl group.

Examples of the unsaturated monocyclic heterocyclic group" include pyrrolidinyl group, follow group, thienyl group, imidazolidinyl group, 1,2-dihydro-2-Oxymetazoline group, pyrazolidine group, diazolidinyl group, oxazolidinyl group, isoxazolyl group, thiazolidine group, isothiazolinone group, 1,2,4-triazolyl 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, pyrimidinyl 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 and 1,1-dioxo-1H-isothiazolinone group.Preferred examples include pyrrolidinyl group, follow group, tienluugu, imidazolidinyl group, pyrazolidine group, oxazolidinyl group, isooxazolyl group, thiazolidine group, isothiazolinone group, pyridyloxy group, 2-oxo-2,5-dihydropyrrolo group and 1,1-dioxo-1H-isothiazolinone group.

As the "heterocyclic group which is a condensed ring, you can specify indolenine group (for example, 4-indolering group, 7-indolering group and the like), isoindolyl group, 1,3-dihydro-1,3-dioxopiperidin group, benzofuranyl group (for example, 4-benzofuranyl group, 7-benzofuranyl group and the like), indazolinone group, isobenzofuranyl group, benzothiophene group (for example, 4-benzothiophene group, 7-benzothiophene group and the like), benzoxazolyl group (for example, 4-benzoxazolyl group, 7-benzoxazolyl group and the like ), benzimidazolyl group (for example, 4-benzimidazolyl group, 7-benzimidazolyl group and the like), benzothiazolyl group (for example, 4-benzothiazolyl group, 7-benzothiazolyl group and the like), indolizinyl group, pinolillo group, izohinolinove group, 1,2-dihydro-2-oxopyridine group, chinazolinei group, khinoksalinona group, indolinyl group, talinolol group, hyalinella group, perilou group, pteridinyl group, indolinyl the ing group, isoindolyl group, 5,6,7,8-tetrahydroquinoline group, 1,2,3,4-tetrahydroquinoline group, 2-oxo-1,2,3,4-tetrahydroquinoline group, benzo[1,3]dioxolo group, 3,4-methylenedioxyphenyl group, 4,5-ethylenediaminetetramethylene group, romanello group, romanello group, isopropanolol group, etc.

Preferably, the condensed ring consisted of a monocyclic 5 - or 6-membered heterocycle and a benzene ring.Specific examples include indolenine group, benzofuranyl group, benzothiophene group, benzimidazolyl group, benzoxazolyl group, benzothiazolyl group and a benzo[1,3]dioxolo group, etc.

The term "heterocyclic group optionally substituted by 1-5 substituents selected from group a" means "heterocyclic group"as defined above, which is optionally substituted by 1-5, preferably 1-3, substituents selected from group a"defined above, and includes unsubstituted "heterocyclic group".

"Heterocyclic group"preferably a is a monocyclic heterocycle containing 1 or 2 heteroatom, or a heterocycle, which represents a heterocycle condensed with a benzene ring.

Specific examples of"heterocyclic group optionally substituted by 1-5 for what estately, selected from group a", include pyrrolidinyloxy group, piperidinyl group, morpholinopropan, 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, imidazolidinyl group, 2-imidazolidinyl group, 3-imidazolidinyl group, 4-imidazolidinyl group, pyrazolidine group, 2-oxazolidinyl group, 3-isoxazolyl group, 2-thiazolidine group, 3-isothiazolinone group, 3-herperidin-2-ilen group, 3-chloropyridin-2-ilen group, 3-chloro-4-herperidin-2-ilen group, 3,5-dichloropyridine-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-dif is herperidin-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-benzothiophene group,

4-benzothiophene group, 7-benzothiophene 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, etc.

As the ring Cy preferred 2-Peregrina group and 4-Peregrina group,

as R1and group B preferred imidazolidine group, 2-Peregrina group, 2-benzothiophene group, morpholinopropan and 4-methylthiazole-5-ilen group, and

as R32and R33preferred pyrrolidinyl group.

The term "C1-10alkyl group, optionally substituted by 1-3 substituents selected from halogen atom and group B" means C1-10alkyl group optionally substituted by a group of substituents, selected from the "halogen atom", as defined above, and "group B", as defined on the Lee, and may represent unsubstituted alkyl group. Alkyl fragment is an alkyl group with unbranched or branched chain containing 1-10 carbon atoms. Specific examples include 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, 1,1-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, 1-ethyl-1-methylpropyloxy group, heptylene group, isoheptyl group, 1-methylhexanoic group, 1,1-dimethylpentyl group, 1,2-dimethylpentyl group, 1,3-dimethylpentyl group, 1,4-dimethylpentyl group, 1,1,2-trimethylethylene group, 1,1,3-trimethylethylene group, 1,2,2-trimethylethylene group, 1,2,3-trimethylethylene group, 1,3 .3m-trimethylethylene group, 1-ethylpentane group, 1-ethyl-2-methylbutyl group, 1-ethyl-3-methylbutyl GRU is PU, 2-ethyl-1-methylbutyl group, 1-propylethylene group, 1-ethyl-2,2-dimethylpropylene group, 1-isopropyl-2-methylpropyl group, 1-isopropyl-1-methylpropyl group, 1,1-diethylpropion group, 1,1,2,2-tetramethylpiperidine group, 1-isopropylamino group, 1-ethyl-1-methylbutyl group, octillo group, nonalloy group, deganello group and the like, preferably alkyl groups with unbranched or branched chain, containing 1 to 6 carbon atoms, especially preferred branched alkyl groups containing 1-6 atoms carbon.

The term "group B" represents the group consisting of C3-10the carbon ring, optionally substituted by 1-5 substituents selected from group a"defined above, "heterocyclic group optionally substituted by 1-5 substituents selected from group a"defined above, -ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4and-NRa5COORa6.

In the sense used in this description, Ra4and Ra5the same or different and each represents a hydrogen atom, "C1-4alkyl group"defined above, "C3-10carbon ring, optionally substituted by 1-5 substituent and, selected from group a"defined above or "heterocyclic group optionally substituted by 1-5 substituents selected from group a"defined above, and Ra6is "C1-4alkyl group"defined above, "C3-10carbon ring, optionally substituted by 1-5 substituents selected from group a"defined above or "heterocyclic group optionally substituted by 1-5 substituents selected from group a"defined above.

Specific examples of-ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4and-NRa5COORa6include the substituents listed in the definition "-ORa1", "-SRa1", "-NRa1Ra2", "-CONRa1Ra2", "SO2NRa1Ra2", "-CORa3", "-NRa1CORa3", "SO2Ra3", "-NRa1SO2Ra3", "-COORa1" and-NRa2COORa3" for "group a", respectively, and so on

Concrete examples of C1-10alkyl group, optionally substituted by 1-3 substituents selected from halogen atom and group B" include methyl group, ethyl group,

through the group, isopropyl group, boutelou group,

isobutylene group, sec-boutelou group, tert-is waste

group, pentelow group, isopentyl group,

1-methylbutyl group, 1-ethylpropyl group,

2-ethylpropyl group, 1,1-dimethylpropylene 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-methylpropyloxy group,

1-ethyl-2-methylpropyloxy group,

1,1,2-trimethylpropyl group,

1,2,2-trimethylpropyl group,

1-ethyl-1-methylpropyloxy group, heptylene group,

isoheptyl group, 1-methylhexanoic group,

1,1-dimethylpentyl group, 1,2-dimethylpentyl group,

1,3-dimethylpentyl group, 1,4-dimethylpentyl group,

1,1,2-trimethylethylene group, 1,1,3-trimethylethylene group,

1,2,2-trimethylethylene group, 1,2,3-trimethylethylene group,

1,3 .3m-trimethylethylene group, 1-ethylpentane group,

1-ethyl-2-methylbutyl group, 1-ethyl-3-methylbutyl group,

2-ethyl-1-methylbutyl group, 1-propylethylene group,

1-ethyl-2,2-dimethylpropylene group,

1-isopropyl-2-methylpropyloxy group,

1-isopropyl-1-methylpropyloxy group,

1,1-diethylpropion group,

1,1,2,2-tetramethylpiperidine group,

1-isopropylate is inuu group, 1-ethyl-1-methylbutyl group,

pharmacylow group, triptorelin group,

chlorethylene group, 2-foretelling group,

2-chloraniline group, 3-forproperty group,

2-chloropropylene group, 2,2,2-triptorelin group,

2-hydroxyethylene 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-methylpropyloxy 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,

3-methyl-1-(hydroxymethyl)boutelou group,

2-ethyl-1-(hydroxymethyl)boutelou group,

3-hydroxy-1-methylpropyloxy group,

1,1-dimethyl-3-hydroxypropyl group,

1,2-dimethyl-3-hydroxypropyl group,

1-isopropyl-3-hydroxypropyl group,

2,2-dimethyl-1-(2-what hydroxyethyl)through the group,

1-ethyl-3-hydroxypropyl group,

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,

2-ethyl-1-(hydroxymethyl)-2-methylbutyl group,

3,3-dimethyl-1-(hydroxymethyl)boutelou group,

1-(hydroxymethyl)pentelow group,

4-methyl-1-(hydroxymethyl)pentelow group,

methoxymethyl group, 2-methoxyaniline group,

methylsulfonylamino group,

2-(methylsulfanyl)ethyl group, 2-aminoethyl group,

2-(dimethylamino)ethyl group, carboxymethyl group,

2-carboxyaniline group, 2-carboxypropyl group,

3-carboxypropyl group, carbamoylmethyl group,

2-carbamoylethyl group, methylenecholesterol group,

dimethylaminocarbonylmethyl group,

2-(phenylenecarbonyl)ethyl group, 2-oxopropyl group,

methylsulfonylamino group,

2-(methylsulphonyl)ethyl group, sulfamoylbenzoyl group,

methylenecholesterol group,

dimethylaminocarbonylmethyl group,

tert-butylaminoethyl group,

2-(acetylamino)ethyl group,

2-(methylsulfonylamino)e the ilen group,

2-(ethoxycarbonyl)ethyl group, benzyl group,

fenetylline group, 3-phenylpropyl group,

4-phenylbutyl group, 2-biphenylmethanol group,

3,4-dichloraniline group, 2-hydroxy-2-phenylethylene group,

cyclopentylmethyl group, cyclohexylmethyl group,

2-cyclohexylamino group,

1-cyclohexyl-2-hydroxyethylene group,

1-cyclohexylmethyl-2-hydroxyethylene group,

phenylenecarbonyl group,

2-pyridine-2-ratelow group, 2-imidazol-1-ratelow group,

2-benzothiophen-2-ratelow group, 2-morpholinoethyl group,

2-(4-methylthiazole-5-yl)ethyl group,

1-carboxyaniline group, 1-carbamoylethyl group,

1-carboxy-2-methylpropyloxy group,

1-carbarnoyl-2-methylpropyloxy group,

2-hydroxy-1-(hydroxymethyl)through the group,

1-(hydroxymethyl)-2-mercaptoethyl group,

1-(hydroxymethyl)-3-(methylsulfanyl)through the 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)through the group,

5-amino-1-(hydroxymethyl)pentelow group, etc.

R1 preferably represents a methyl group, ethyl group, through the group, isopropyl group, boutelou group, isobutylene group, tert-boutelou group,

2-foretelling group, 2,2,2-triptorelin group,

2-hydroxyethylene group, 2-hydroxypropyl group,

3-hydroxypropyl group, 4-hydroxybutyl group,

5-hydroxypentanal group, 2,3-dihydroxypropyl group,

2-hydroxy-1-methylamino group,

2-hydroxy-1,1-dimethylethylene group,

2-hydroxy-1-(hydroxymethyl)ethyl group,

1-(hydroxymethyl)through the group,

2-hydroxy-2-methylpropyloxy group,

1-(hydroxymethyl)boutelou group,

1-(hydroxymethyl)-2-methylpropyloxy group,

1-(hydroxymethyl)-2,2-dimethylpropyl group,

1-(hydroxymethyl)-2-methylbutyl group,

1-(hydroxymethyl)-3-methylbutyl group,

2-hydroxy-1-phenylethylene group,

2-hydroxy-2-phenylethylene group,

1-(hydroxymethyl)-2-phenylethylene group,

2-methoxyamino group, methylsulfonylamino group,

2-(methylsulfanyl)ethyl group, 2-aminoethyl group,

2-(dimethylamino)ethyl group, carboxymethyl group,

2-carboxyaniline group, 3-carboxypropyl group,

carbamoylmethyl group, 2-carbamoylethyl group,

methylenecholesterol group,

dimethylaminocarbonylmethyl GRU is PU,

2-(phenylenecarbonyl)ethyl group, 2-oxopropyl group,

methylsulfonylamino group,

2-(methylsulphonyl)ethyl group, sulfamoylbenzoyl group,

methylenecholesterol group,

dimethylaminocarbonylmethyl group,

tert-butylaminoethyl group,

2-(acetylamino)ethyl group,

2-(methylsulfonylamino)ethyl group,

2-(ethoxycarbonyl)ethyl group, benzyl group,

fenetylline group, 3-phenylpropyl group,

4-phenylbutyl group, 2-biphenylmethanol group,

3,4-dichloraniline group, cyclopentylmethyl group,

cyclohexylmethyl group,

1-cyclohexyl-2-hydroxyethylene group,

1-cyclohexylmethyl-2-hydroxyethylene group,

2-pyridine-2-ratelow group, 2-imidazol-1-ratelow group,

2-morpholinoethyl group,

2-(4-methylthiazole-5-yl)ethyl group, or

benzothiophen-2-ylmethylene group,

particularly preferably alkyl group, a branched in position 1,and/or alkyl group substituted by a hydroxy-group. Specific examples include 2-hydroxy-1-methylamino group, 1-(hydroxymethyl)-2-methylpropyl group, 1-(hydroxymethyl)-2,2-dimethylpropyl group, 1-(hydroxymethyl)-2-methylbutyl group, 2-hydroxy-1-(hydroxymethyl)ethyl group and 2-phenyl-1-(g is proximity)ethyl group. If these particularly preferred substituents exist in optically active form, then S most preferred form.

R32and R33preferably represent methyl group, ethyl group and triptorelin group, and Ra7and Ra8preferably represent methyl group, ethyl group, through the group, isopropyl group, 2-hydroxyethyloxy group, 3-hydroxypropyl group and cyclohexylmethyl group, more preferably methyl group, ethyl group and isopropyl group, and particularly preferably a methyl group.

The ring Cy in the formula [I] is preferably "C3-10carbon ring, optionally substituted by 1-5 substituents selected from group a"defined above, more preferably

where R4, R5, R6and m have the above values.The preferred option is the same as that for the compound 4-oxacilin,represented by the formula [II], where m is preferably 0 or 1, more preferably 0.

Group And ring Cy is preferably a cyano, a phenyl group, a nitrogroup, "halogen atom"defined above, "C1-4alkyl group, as defined above, Halogens1-4alkyl group", as the definition is of higher "Halogens1-4alkyloxy", as defined above, "-ORa1", as defined above, "-SRa1", as defined above, "-NRa1Ra2", as defined above, "-CONRa1Ra2", as defined above, "-SO2NRa1Ra2", as defined above, "-NRa1CORa3", as defined above, "-SO2Ra3", as defined above, or-NRa1SO2Ra3", as defined above, more preferably a cyano, a phenyl group, a nitrogroup, "halogen atom", "C1-4alkyl group", "Halogens1-4alkyl group", "Halogens1-4alkyloxy", "-ORa1", "-SRa1", "-NRa1Ra2", "SO2Ra3", "SO2NRa1Ra2or-NRa1CORa3"and especially preferably "halogen atom", as defined above.

The ring Cy is more preferably represents

where R6', R6"and R6"'represent substituents selected from a hydrogen atom and "group"as defined above, and R4and R5have the above values.

R4preferably represents a phenyl group, "halogen atom"defined above, "C1-4alkyl group, as defined above, Halogens1-4alkyloxy", as defined above, "-ORa1", as defined above, "-NRa1Ra2", as defined above, "-S 2NRa1Ra2", as defined above, "-NRa1CORa3", as defined above, "-SO2Ra3", as defined above, "-COORa1"as defined above or-NRa1SO2Ra3", as defined above,

more preferably "halogen atom", "C1-4alkyl group", "Halogens1-4alkyloxy", "-ORa1or-NRa1Ra2"and especially preferably "halogen atom", as defined above,

R5represents preferably a hydrogen atom, a cyano, a nitro-group, "halogen atom"defined above, "C1-4alkyl group, as defined above, Halogens1-4alkyl group"defined above, "-ORa1", as defined above, "-SRa1", as defined above, "-NRa1Ra2", as defined above, "-CONRa1Ra2", as defined above, "-SO2NRa1Ra2", as defined above, or-NRa1CORa3", as defined above,

more preferably a hydrogen atom, halogen atom" or "C1-4alkyl group, and particularly preferably "halogen atom".

R6is preferably "halogen atom", "C1-4alkyl group"defined above, "-SO2Ra3", as defined above, "-ORa1"defined above or "-SRa1", as defined above, more preferably "halogen atom".

R6'and R6"' preferably the same or different and each represents a hydrogen atom or halogen atom", as defined above, R6"represents preferably a hydrogen atom, halogen atom"defined above, "C1-4alkyl group"defined above, "-SO2Ra3", as defined above, "-ORa1", as defined above, or-SRa1", as defined above, more preferably a hydrogen atom, halogen atom", "C1-4alkyl group, as defined above, or-SRa1", as defined above, and more preferably a hydrogen atom.

R1is preferably "C3-10carbon ring, optionally substituted by 1-5 substituents selected from group a"defined above, "heterocyclic group optionally substituted by 1-5 substituents selected from group a"defined above, "-ORa4"defined above (here especially preferred methoxy group), "-NRa4Ra5"defined above (here, specifically, the preferred amino group, methylaminopropyl, atramentaria or dimethylaminopropan), "-NRa4CORa6"defined above (here especially preferred acetylamino), "-NRa4SO2Ra6"defined above (here especially preferred methylsulfonylamino or N-methyl-N-(methyls Lionel)amino group), "-NRa5COORa6"defined above (here especially preferred methoxycarbonylamino) or "C1-10alkyl group, optionally substituted by 1-3 substituents selected from halogen atom and group B", as defined above, more preferably, "C3-10carbon ring, optionally substituted by 1-5 substituents selected from group a"defined above or "C1-10alkyl group, optionally substituted by 1-3 substituents selected from halogen atom and group B", more preferably "C1-10alkyl group, optionally substituted by 1-3 substituents selected from halogen atom and group B"as defined above.

R2represents preferably a hydrogen atom.

R31represents preferably a hydrogen atom, a cyano, a "halogen atom", as defined above, hydroxy-group or "C1-4alkoxygroup", as defined above, more preferably a hydrogen atom, a cyano, a "halogen atom"defined above or "C1-4alkoxygroup", as defined above, more preferably a hydrogen atom, cyano or C1-4alkoxygroup", as defined above, particularly preferably a hydrogen atom.

R32represents preferably a hydrogen atom, a cyano, a "halogen atom"defined above, "heterocyclic group optionally substituted by 1-5 substituents, selected from group a"defined above, "C1-10alkyl group, optionally substituted by 1-3 substituents selected from halogen atom and group B"defined above, "-ORa7", as defined above, "-SRa7", as defined above, "-NRa7Ra8", as defined above, "-COORa10", as defined above, or-N=CH-NRa10Ra11", as defined above, more preferably a hydrogen atom, "-ORa7", as defined above, "-SRa7", as defined above, or-NRa7Ra8", as defined above, more preferably a hydrogen atom or-ORa7", as defined above, particularly preferably "-ORa7".

R33represents preferably a hydrogen atom, "C1-10alkyl group, optionally substituted by 1-3 substituents selected from halogen atom and group B"defined above, "-ORa7", as defined above, or-NRa7Ra8", as defined above, more preferably a hydrogen atom, "-ORa7", as defined above, or-NRa7Ra8", as defined above, more preferably a hydrogen atom or-ORa7", as defined above, particularly preferably a hydrogen atom.

Preferably, one of R32and R33represented a hydrogen atom, and the other was "-ORa7"as defined above.

Preferably, R31represent wlel a hydrogen atom, and R32or R33different from the hydrogen atom.

The term "its pharmaceutically acceptable salt" means a salt which can be any, unless it is non-toxic salt of the compound of the above formula [I] or [II].For example, it can be obtained by reaction with inorganic acids such as chloride-hydrogen acid, sulfuric acid, phosphoric acid, Hydrobromic acid and the like; organic acids such as oxalic acid, malonic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, triperoxonane acid, gluconic acid, ascorbic acid, methylsulfonate acid, benzylmalonate acid and the like; inorganic bases such as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, the ammonium hydroxide and the like; organic bases such as methylamine, diethylamine, triethylamine, triethanolamine, Ethylenediamine, Tris(hydroxymethyl)methylamine, guanidine, choline, cinnolin and the like; or with amino acids such as lysine, arginine, alanine and the likeThe present invention encompasses a water-containing products, hydrate and solvate of each of the compounds.

In addition, the compounds represented by the above formula and [I] and [II], have different isomers.For example, E-form and Z-form are present in the form of geometric isomers, and if there is asymmetric carbon atom, enantiomers and diastereoisomers present as stereoisomers based on it, and there may be tautomers. Accordingly, the present invention includes all such isomers and mixtures thereof. The compound of the present invention is preferably isolated and purified from various isomers, by-products, metabolites and prodrugs, preferably compounds with purity of 90% or higher, or more preferred, with a degree of purity higher than 95%.

The present invention also includes prodrugs and metabolites of each of the compounds.

The term "prodrug" means a derivative compound of the present invention, which contains a chemically or metabolically degradable group, and which, when introduced into the body, turns into the original connection, demonstrating its inherent efficiency, including complex and a salt that does not contain covalent bonds.

The prodrug is used, for example, to improve absorption by oral administration or for delivery to the desired location.

As areas that you can modify, you can specify a highly reactive functional group of the compounds of the present invention, such as a hydroxyl group, carboxyl group, amino group, thiol group, etc.

Examples of the hydroxyl-modifying groups include acetyl group, propionyl group, isobutyryl group, pivaloyl group, benzoyloxy group, 4-methylbenzoyl group, dimethylcarbamoyl group, alphagroup etc. Examples carboxyl-modifying 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, etc.

Examples of amino-modifying 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, etc.

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

If the connection of the present inventionused in the form of pharmaceutical compositions, it is mixed with pharmaceutically acceptable carriers, excipients, diluents, which increases the amount of agents, desintegra what ora, stabilizers, preservatives, buffers, emulsifiers, flavoring agents, coloring agents, sweeteners, thickeners, corrective agents, agents that promote dissolution, and other additives, which are usually well-knownper sesuch as water, vegetable oil, alcohol (e.g. ethanol or benzyl alcohol, etc.), polyethylene glycol, glyceryltrinitrate, gelatin, carbohydrates (e.g. lactose, starch, etc.), magnesium stearate, talc, lanolin, petrolatum and the like, is formed in the form of tablets, pills, powders, granules, suppositories, injections, eye drops, liquids, capsules, tablets, aerosols, elixirs, suspensions, emulsions, syrups, etc.conventional methods and is administered systemically or topically, and orally or parenteral.

Although the dose varies depending on age, body weight, symptoms, treatment, method of administration and the like, it is usually from 0.01 mg to 1 g per introduction for adults, and it is administered one or more times a day orally, or in a unit dosage form for injection,such as a form for intravenous injection, etc.

For anti-HIV agent is usually required to extend over a long period of time, so that it was effective not only for short-term suppression of growth of the virus, but also to prevent new growth of the virus. This means the AET, what you need for a long introduction, and that inevitably frequent introduction of high single doses to maintain the effect over a longer period of time during the night. Such long-term administration of high doses increases the risk of side effects.

In light of this, one of the preferred types of compounds 4-oxacilin of the present invention is a compound which provides a high degree of absorption by oral administration, and such a connection, which is able to maintain the concentration of the introduced compound in the blood over a longer period of time.

The term "prevention of AIDS" mean, for example, the introduction of a pharmaceutical agent to an individual, the results of the HIV test which is positive, but has not yet developed a painful condition AIDS, the introduction of a pharmaceutical agent to an individual who demonstrates the improvement of the painful state AIDS after treatment, but which is still a carrier of HIV, which must be removed, and the patient is concerned about the possibility of relapse, and the introduction of a pharmaceutical agent to HIV without fear of infection.

Examples of "other anti-HIV agents" and "other anti-HIV active substances, which are used for combination therapy with carried alkemi drugs include anti-HIV antibodies,HIV vaccines, Immunostimulants, such as interferon and the like, HIV ribosome,HIV antisense drugs, nucleoside reverse transcriptase inhibitor, a protease inhibitor, an inhibitor of the formation of ties between receptor relationships (CD4, CXCR4, CCR5, and so on) of the host cell, recognizable by a virus, and virus, etc.

Specific examples of inhibitors of HIV reverse transcriptase inhibitors include Retrovir(R) (zidovudine), Epivir(R) (lamivudine), Zerit(R) (canlogin), Videx(R) (DDI), Hivid(R) (zalcitabine), Ziagen(R) (abovesurface), Viramune(R) (nevirapine), Stocrin(R) (efavirenz), Rescriptor(R) (delavirdine), Combivir(R) (zidovudine+lamivudine), Trizivir(R) (abovesurface+lamivudine+zidovudine), Coactinon(R) (emivirine), Phosphonovir(R), Coviracil(R), alovudine (3'-fluoro-3'-deoxythymidine), Thiovir (thiophosphoramidate acid), Capravirin (5-[(3,5-dichlorophenyl)thio]-4-isopropyl-1-(4-pyridylmethyl)imidazol-2-metanarrative acid), tenofovirdisproxil (fumarate bis(isopropoxycarbonyloxymethyl) ether (R)-[[2-(6-amino-9H-purine-9-yl)-1 methylethoxy]methyl]phosphonic acid), DPC-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, Phosphazid, UC-781, BCH-10618,DPC-083, Etravirine, BCH-13520, MIV-210, abovesurface/lamivudine, GS-7340 tel, GW-5634, GW-695634 etc. where (R) indicates registered trademark (hereinafter the same) and the names of other pharmaceutical agents are common names.

Specific examples of inhibitors of the HIV protease include Crixivan(R) (indinavirwhat ethanolate), saquinavir, Invirase(R) (saquinavir), Norvir(R) (ritonavir), Viracept(R) (nelfinavir mesilate), lopinavir, Prozei(R) (APV), Kaletra(R) (ritonavir+lopinavir), rosenwinkel ([4R-(4α,5α,6β)]-1,3―bis[(3-AMINOPHENYL)methyl]hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-andmeasurement), 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-carboxamid), GW-433908, TMC-126, DPC-681, buckminsterfullerene, MK-944A (MK944 (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)+indinavirwhat), JE-2147 ([2(S)-oxo-4-phenylmethyl-3(S)-[(2-methyl-3-oxy)phenylcarbonylamino]-1-oxobutyl]-4-[(2-were)methylamino]carb is Neal 4(R)-5,5-dimethyl-1,3-thiazole), BMS-232632 (dimethyl (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 acid), 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, fosamprenavir, darunavir, GW-0385, R-944, RO-033-4649, AG-1859, etc.

Examples of inhibitors of the HIV integrase presents S-1360, L-870810, and the like, examples of inhibitors of DNA polymerase or inhibitors of DNA synthesis presents Foscavir(R), ACH-126443 (L-2',3'-didehydrothymidine-5-fluorocytidine), entecavir ((1S,3S,4S)-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecycloartanol]guanine), calanolide A ([10R-(10α,11β,12α)]-11,12-dihydro-12-hydroxy-6,6,10,11-tetramethyl-4-propyl-2H,6H,10H-benzo[1,2-b:3,4-b':5,6-b"]Tripura-2-one), calanolide B, NSC-674447 (1,1'-azobisformamide), Iscador (extract of viscum alubm), Rubutecan etc., HIV antisense drug presents HGTV-43, GEM-92, etc., anti-HIV antibody or other antibodies presented NM-01, PRO-367, KD-247, Cytolin(R), TNX-355 (CD4 antibody), AGT-1, PRO-140 (CCR5 antibody), anti-CTLA-4 MAb and the like, examples of HIV vaccines or other vaccines presents ALVAC(R), AIDSVAX(R), Remune(R), HIV gp41 vaccine, HIV gp120 vaccine, HIV gp140 vaccine, HIV gp160 vaccine, HIV p17 vaccine, HIV p24 vaccine, HIV p55 vaccine, AlphaVax vector system, canarypox gp160 vaccine, AntiTat, MVA-F6 Nef vaccine, HIV rev HAC is different, C4-V3 peptide, p2249f, VIR-201, HGP-30W, TBC-3B, PARTICLE-3B, etc., antivenom (vaccine interferon-α), etc., interferon or interferon agonists presents Sumiferon(R), MultiFeron(R), interferon-τ, Reticulose, interferon-alpha of human leukocytes, etc., CCR5 antagonists presents SCH-351125 and the like, the pharmaceutical agent acting on HIV p24 presented GPG-NH2 (glycyl-shed-glycinamide) and the like, inhibitor of HIV fusion presentsFP-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 construction No3, penthousecom, FP-21399, PRO-542, enfuvirtide etc., agonists or antagonists of IL-2 presents interleukin-2, Imunace(R), Proleukin(R), Multikine(R), Ontak(R), etc., antagonists of TNF-α, Thalomid(R) (thalidomide), Remicade(R) (infliximab), burglaralarm (curdlan), etc., inhibitors α-glucosidase presents Bucast(R), etc., inhibitor polynucleotides represented by palmesino (peldesine)(2-amino-4-oxo-3H,5H-7-[(3-pyridyl)methyl]pyrrolo[3,2-d]pyrimidine), etc., agonists or inhibitors of apoptosis presents Arkin Z(R), Panavir(R), and Coenzyme Q10 (2-DECA(3-methyl-2-butylen)-5,6-dimethoxy-3-methyl-p-benzoquinone), etc. inhibitor of cholinesterase presents Cognex(R), etc. and immunomodulators presents Imunox(R), Prokine(R), Met-enkephaline (6-de-L-arginine-7-de-L-arginine-8-de-L-valinamide-adrenalina), WF-10 (10-Crat is a dilute solution of tetrachlorodecaoxide), Perthon, PRO-542, SCH-D, UK-427857, AMD-070, AK-602, etc.

In addition, examples are Neurotropin(R), Lidakol(R), Ancer 20(R), Ampligen(R), Anticort(R), Inactivin(R), etc., PRO-2000, gene Rev M10, HIV-specific cytotoxic T cells (CTL immunotherapy, ACTG Protocol 080 therapy, CD4-ζ gene therapy), SCA-binding protein, RBC-CD4 complex, Motexafin gadolinium, GEM-92, CNI-1493, (±)-FTC, Ushercell, D2S, BufferGel(R), VivaGel(R), Glyminox vaginal gel, nutriceuticals, 2F5, 2F5/2G12, VRX-496, Ad5gag2, BG-777, IGIV-C, BILR-255 etc.

As for the "other anti-HIV agents" and "other anti-HIV active substances"that can be used in combination therapy with compounds of the present invention and of several drugs, the preferred nucleoside reverse transcriptase inhibitor and a protease inhibitor. In combination, you can use two or three, or even more pharmaceutical agents, and one of the most preferred options is a combination of pharmaceutical agents with different mechanisms of action. In addition, it is preferable to choose pharmaceutical agents that do not lead to a doubling of the side effects.

The specific combination of pharmaceutical agents include combinations of groups, including Efavirenz, Tenofovir, Emtricitabine, Indinavir, Nelfinavir, Atanazavir, Ritonavir+Indinavir, Ritonavir+Lopinavir, Ritonavir+Saquinavir, Stavudine+Lamy is one, Zidovudine+Didanosine, Stavudine+Didanosine, Zidovudine+Lamivudine, Stavudine+Lamivudine and Emtriva and connection 4-oxacilin [I] of the present invention(Guidelines for the Use of Antiretroviral Agents in HIV-Infected Adults and Adolescents. August 13, 2001).Especially preferred therapy with two drugs, the combination with Efavirenz, Indinavir, Nelfinavir, Tenofovir, Emtricitabine, Zidovudine and Lamivudine, and therapy three lekarstvi by combining pairs 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+Efavirenz, Nelfinavir+Indinavir, Efavirenz+Lamivudine, Efavirenz+Zidovudine and Efavirenz+Indinavir.

Some examples of ways to produce compounds that are used to describe variants of the present invention, are presented below. However, the method of obtaining the compounds of the present invention is not limited to these examples.

Even without a description of the methods of obtaining, efficient access can be achieved, if necessary, by introducing protective groups at the functional groups and their subsequent removal in the next hundred is s, using the connection with the functional group as its predecessor at each stage, and turning this group into the desired functional group at an appropriate stage, changing the order of the corresponding production processes and stages, or using another method.

Connection processing on each of the stages can be performed in the usual way, where the isolation and purification carried out by selecting or combining, if necessary, conventional methods such as crystallization, recrystallization, distillation, separation, chromatography on silica gel, preparative HPLC and the like,

The method of obtaining 1-1

whereHal represents a halogen atom such as chlorine atom, bromine atom and the like; Hal1represents a halogen atom such as bromine atom, iodine atom and the like; R1Ais "C1-10alkyl group, optionally substituted by 1-3 substituents selected from halogen atom and group B"as defined above; R2Ais "C1-4alkyl group, as defined above, preferably methyl group or ethyl group; in connection [6], each of R2Amay differ from each other, but preferably they were the same; (R3)nis the Deputy of any of R31, R32and R33that can be the same and or different; n is an integer from 1 to 3; where the substituent R3is not at the same time Deputy in both * the provisions, and other symbols have the above values.

Stage 1

In a stream of argon or nitrogen interact powder zinc and 1,2-dibromethane in the solvent by heating, and the reaction add trimethylsilane. Then to the reaction solution was added a solution of compound [1], resulting in a receive connection [2].

The preferred solvents are the ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF) and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; and so on

Stage 2

The compound [2] is subjected to interaction with the compound [3] in a solvent in the presence of a catalyst and, if necessary,ligand, such as triphenylphosphine, three(2-furyl)phosphine and the like, in a stream of argon or nitrogen, under cooling or under heating, receiving the connection [4].

As catalysts 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 is a new catalyst, etc.

The preferred solvents are the ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran (THF) and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene, etc.

Stage 3

Connection [4] restore in the usual way, such as the recovery of zinc, or iron in a neutral or alkaline conditions; iron and acid; tin or tin chloride(II) and concentrated chloride-hydrogen acid; alkali and sulfide; alkaline hydrosulfite etc., catalytic recovery in the atmosphere of hydrogen and the like, receiving the connection [5].

For example, the compound [4] add acetic acid and powdered zinc under cooling and the mixture is subjected to interaction at room temperature, receiving the connection [5]. Alternatively, to a solution of compound [4] add palladium-on-coal in a mixed solvent consisting of THF and methanol, and the mixture is subjected to interaction in the atmosphere of hydrogen at room temperature, receiving the connection [5].

Stage 4

The compound [5] is subjected to interaction with the compound [6] in a solvent under heating.

As preferred solvents, you can specify alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and the like; hydrocarbon solvents, such is as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like, and mixtures of these solvents.

Then, after removal of solvent carry out the reaction of the residue in a solvent such as diphenyl ether or a mixture of diphenyl ether and diphenyl, such as Dowtherm A (brand, Fluka) and the like, resulting in heat gain connection [7].

Stage 5

The compound [7] is subjected to interaction with the compound [8] in a solvent in the presence of a base, receiving the compound [I-1].

As a basis you can specify potassium carbonate, sodium carbonate, lithium hydride, sodium hydride, potassium hydride and the like, preferably potassium carbonate.

As solvents it is possible to specify hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile and the like and mixtures of these solvents.

Stage 6

The compound [I-1] hydrolyzing in the solvent at room temperature or by heating under alkaline conditions, and the uses sodium hydroxide, the potassium hydroxide, lithium hydroxide and the like, or in acidic conditions, using chloride-hydrogen acid, sulfuric acid and the like, receiving the compound [I-2].

As solvents it is possible to specify, alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, carbon tetrachloride, 1,2-dichloroethane and the like; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile and the like; water and mixtures of these solvents.

Carrying out reaction according to a similar method to the method of obtaining 1-1 using the connection [20]represented by the formula

instead of compound [3]can be obtained compound [I].

The method of obtaining 1-2

An example of a method of obtaining using connection [9], which impose hydroxylamino group

where r is an integer from 1 to 6, RP1is hydroxylamino group, and other symbols have the above values.

Stage 1

Interact compounds [7], obtained by a similar method the method is obtaining 1-1, and connections [9] on a similar to the technique of the method of obtaining 1-1, at stage 5, when receiving the connection [10].

Stage 2

The protective group of compound [10] is removed in the usual way, getting the compound [I-3].

As hydroxylamine groups you can specify acetyl group, methoxycarbonyl group, methoxymethyl group, methoxyethoxymethyl group, trimethylsilyl group, tert-butyldimethylsilyl group, tert-butyldiphenylsilyl group, etc.

For example, if RP1represents acetyl group or methyloxycarbonyl group, in the reaction under heating in the presence of a base such as sodium hydroxide, potassium hydroxide and the like, is the removal of protective groups. You can use processing, including the addition of concentrated chloride-hydrogen acid and heating, heating in concentrated ammonia, etc.

For example, if RP1represents tert-butyldimethylsilyloxy group, removing the protective group can be carried out using the processing tetrabutylammonium in THF at room temperature, the processing in the presence of sodium hydroxide in THF by heating, treatment with a mixture of acetic acid-water-THF at room temperature or under heating, etc. At this stage, the removal of the protective groups in RP1and hydrolysis of R2AWMS is about to be implemented in two stages.

The method of obtaining 2-1

where Hal2represents a halogen atom and preferably a fluorine atom or a chlorine atom, RC3and RC4the same or different, and each represents a lower alkyl group such as methyl group, ethyl group and the like, R1Bis "C1-10alkyl group, optionally substituted by 1-3 substituents selected from halogen atom and group B"defined above, "C3-10carbon ring, optionally substituted by 1-5 substituents selected from group a"defined above, "heterocyclic group optionally substituted by 1-5 substituents selected from group a"defined above or "-ORa4", as defined above, and other symbols have the above values, and the substituent R3is not a substituent in position *.

Stage 1

Here Hal1is preferably bromine or iodine, and the compound [12] can be obtained in the usual halogenoalkanes.

For example, the compound [11] is subjected to interaction with a halogenation agent such as N-bromosuccinimide, N-jodatime, etc. in a solvent such as triftormetilfullerenov acid, acetic acid, sulfuric acid, DMF and the like, at room temperature or when heated, receiving the connection [12].

With the adiya 2

Galoyanized receive the usual way, for example, interacting compounds [12] when heated with a halogenation agent such as oxalicacid, thionyl chloride and the like, in a solvent such as a hydrocarbon solvent (e.g. toluene, xylene, etc.); halogenated solvent (such as dichloromethane, carbon tetrachloride, 1,2-dichloroethane, etc.); ethyl acetate, etc.

For example, if the halogenation agent using thionyl chloride, can be added catalytic amount of DMF.

Then add the connection [13]to carry out the reaction in a solvent in the presence of a base, such as triethylamine, diisopropylethylamine, potassium carbonate, pyridine and the like, at room temperature or by heating, after which the compound obtained is subjected to interaction with the compound [14] at room temperature or when heated, receiving the connection [15].

As solvents it is possible to specify hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, carbon tetrachloride, 1,2-dichloroethane and the like; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents such as acetonitrile and the like, ethyl acetate and mixtures of these solution is used.

Stage 3

Carry out the reaction of the compound [15] 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, receiving the connection [16].

As one of the preferred methods of preparation, it is possible to carry out the reaction of the compound [15] in the presence of 1,8-vasallo[5.4.0]-7-undecene, in a solvent, at room temperature or when heated, receiving the connection [16].

As solvents it is possible to specify hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, carbon tetrachloride, 1,2-dichloroethane and the like; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile and the like and mixtures of these solvents.

Stage 4

Connection [16] is subjected to interaction with the compound [2] is similar to the technique of the method of obtaining 1-1, in stage 2, receiving the compound [I-4].

Stage 5

The compound [I-4] hydrolyzing similar to the technique of the method of obtaining 1-1, at stage 6, when receiving the compound [I-5].

The method of obtaining 2-2

An example of the production method, which on the denotes the insertion and removal of hydroxylamino group.

where each symbol has the above values.

Stage 1

Connection [12], obtained according to a similar method of method of obtaining 2-1, in stage 1, is subjected to the interaction with the compound [13] and the compound [17] similar to the technique of the method of obtaining 2-1, in stage 2, when receiving the connection [18].

Stage 2

The protective group is introduced into the hydroxyl group of compound [18] the normal way and then carry out the cyclization of compounds similar to the technique of the method of obtaining 2-1, at stage 3, when receiving the connection [19].

Alternatively, carry out the cyclization of compounds [18] on a similar to the technique of the method of obtaining 2-1, at stage 3, and then the protective group is introduced into a hydroxyl group in the usual way, getting the connection [19].

For example, if RP1represents tert-butyldimethylsilyloxy group, compound [18] can be subjected to interaction with the imidazole and tert-butyldimethylsilyloxy in a solvent such as DMF and toluene at room temperature.

If RP1is methoxycarbonyl group, compound [18] can be subjected to interaction with pyridine and methylcarbonate in a solvent such as chloroform, under cooling or at room temperature.

A similar way of getting you can use for NH2-RA where R1Arepresents C1-10alkyl group, optionally substituted by at least one hydroxyl group instead of compound [17].

Stage 3

Connection [19] is subjected to interaction with the compound [2] is similar to the technique of the method of obtaining 1-1, in stage 2, receiving the compound [I-6].

Stage 4

The compound [I-6] hydrolyzing the usual way, similar to the technique of the method of obtaining 1-2, in stage 2, receiving the compound [I-7]. At this stage, the removal of the protective group RP1and hydrolysis of R2Acan be done in two stages.

The method of obtaining 3

where Ra7'represents C1-10alkyl group, optionally substituted by 1-3 substituents selected from halogen atom and group B, and other symbols have the above values.

The fluorine atom at the 4-oxacilin can be turned in-ORa7, -SRa7or-NRa7Ra8through interaction with nucleophilic agent in the usual way. Then they can be turned into-NRa7CORa9or-N=CH-NRa10Ra11the usual way.

This method of getting suitable for introduction of the substituent in position 7 4-octohedron.

The method of obtaining 3-1

Alkoxygroup injected into the connection [21] in the usual way, getting the compound [I-8].

For example, compound [I-8] m who should get interacting with the alkoxide of the metal when heated in an alcohol solvent such as methanol, ethanol, propanol, butanol and the like, with subsequent implementation of hydrolysis.

The solvent and the metal alkoxide must be selected in accordance with the desired alkoxygroup. If metoxygroup carry out the reaction with sodium methoxide or potassium methoxide in methanol, and in the case of ethoxypropan carry out the reaction with ethoxide sodium or ethoxide potassium in ethanol.

The method of obtaining 3-2

Exercise amination of compounds [21] in the usual way, getting the compound [I-9].

For example, compound [I-9] can be obtained by carrying out the reaction with the amine in an inactive organic solvent such as THF, dioxane, chloroform, dichloromethane, methanol, ethanol, pyridine and the like when heated.

In addition, compound [I-9] can also be obtained through interaction with the amine under irradiation with microwaves in DMF.

The method of obtaining 4

Examples of ways to obtain intermediate compound [12] is presented below.

where each symbol has the above values.

Stage 1

The protective group is introduced into the carboxyl group of compound [22] in the usual way, getting the connection [23].

If, for example, the esterification of the compound [23] can receive the th interacting with an alkylating agent such as methyliodide, etc. in a solvent such as DMF, THF, toluene and the like, in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, etc.

Stage 2

Connection [23] restores the normal way, similar to the technique of the method of obtaining 1-1, at stage 3, when receiving the connection [24].

Stage 3

Connection [24] halogenous in the usual way, similar to the technique of the method of obtaining 2-1, in stage 1, when receiving the connection [25].

Stage 4

Carry out the diazotization of the compound [25], using sodium nitrite and chloride-hydrogen acid or sulfuric acid in water or in an inactive organic solvent such as THF, dioxane, ethyl acetate, chloroform, dichloromethane, methanol, ethanol, pyridine and the like, under cooling or at room temperature, and then carry out halogenoalkane using a copper halide such as copper chloride and the like, and a concentrated chloride-hydrogen acid under cooling or under heating, receiving the connection [26]. In this case, preferably, Hal2represented the chlorine atom.

Stage 5

The protective group of the hydroxyl group of compound [26] is removed in the usual way, getting the connection [27].

For example, if RP1represents a methyl group is at, connection [27] can be obtained in the reaction with tribromide boron in dichloromethane under refrigeration.

Stage 6

Connection [27] is subjected to interaction with the compound [8] in the presence of a base in a solvent, receiving the connection [28].

As the compound [8] can be selected, for example, alkylating agents such as ethyliodide etc.

As a basis you can specify, potassium carbonate, sodium carbonate, lithium hydride, sodium hydride, potassium hydride and the like, preferably potassium carbonate.

As a solvent it is possible to specify, alcohol solvents such as methanol, ethanol, n-propanol, isopropanol and the like; hydrocarbon solvents such as benzene, toluene, hexane, xylene and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride, 1,2-dichloroethane and the like; ether solvents such as 1,4-dioxane, diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran and the like; polar solvents such as dimethylformamide, dimethylsulfoxide, acetonitrile and the like; water and mixtures of these solvents.

Stage 7

Connection [28] hydrolyzing the usual way, similar to the technique of the method of obtaining 1-1, at stage 6, when receiving the connection [12'].

Stage 8

If RP1in the compound [26] represents the target Deputy, the connection [12'] floor is arranged according to a similar method stage 7.

The method of obtaining 5

where each symbol has the above values.

Stage 1

Exercise halogenoalkane compounds [29] in the usual way, similar to the technique of the method of obtaining 2-1, in stage 1, when receiving the connection [30].

Stage 2

Connection [30] is subjected to interaction with the compound [13] and the compound [17] similar to the technique of the method of obtaining 2-1, in stage 2, when receiving the connection [31].

Stage 3

Connection [31] is subjected to interaction, similar to the technique of the method of obtaining 2-1, at stage 3, when receiving the connection [32].

Stage 4

Connection [32] is subjected to interaction, similar to the technique of the method of obtaining 2-2, in stage 2, when receiving the connection [33].

Stage 5

Connection [33] is subjected to interaction with the compound [2] is similar to the technique of the method of obtaining 1-1, in stage 2, receiving the compound [I-10].

Stage 6

The compound [I-10] hydrolyzing similar to the technique of the method of obtaining 1-2, in stage 2, receiving the compound [I-11].

Stage 7

The compound [I-12] can be obtained by introducing alkoxygroup in compound [I-11] in the usual way, similar to the technique of the method of obtaining 3-1.

Connection 4-oxacilin represented by the formula [I] of the present invention, its pharmaceutically acceptable with the ü and the method of obtaining explained in more detail with reference to examples, which should not be construed as limiting the invention.

Comparative example 1

Getting chloride solution of 2,3-dichloroaniline in THF

In a stream of argon to a suspension of powdered zinc (55,1 g, 843 mmol) in tetrahydrofuran (THF; 56 ml) is added 1,2-dibromoethane (2,9 ml, 33.8 mmol) and the mixture heated to boiling under reflux for 5 minutes Then add trimethylsilane (8.6 ml of 67.5 mmol) at 0°C and the mixture was stirred at 0°C for 5 min, then added dropwise while cooling with ice add a solution of 2,3-dichlorobenzaldehyde (82,4 g, 421,7 mmol) in THF (330 ml). After completion of adding dropwise, the mixture is heated to room temperature and stirred for 1 hour, receiving saline (2,3-dichloroaniline in THF.

Example 1-1Getting 6-(2,3-dichlorobenzyl)-1,4-dihydro-1-(2-hydroxyethyl)-4-oxo-3-quinoline-carboxylic acid

Stage 1Obtaining 1,2-dichloro-3-(4-nitrobenzyl)benzene

In a stream of argon bis(dibenzylideneacetone)palladium (0) (3.2 g, 5.6 mmol) and three(2-furyl)phosphine (2.6 g, and 11.2 mmol) dissolved in THF (310 ml). To this solution dropwise via cannula, while cooling with ice add a solution of chloride 2,3-dichloroaniline (421,7 mmol) in THF obtained in comparative example 1, and then added dropwise a solution of iodomethane (70,0, 281 mmol) in THF (700 ml). After stirring at room temperature for 2 hours to the reaction solution was added saturated aqueous solution of ameriglide and the mixture filtered through celite. The filtrate is concentrated under reduced pressure. To the residue water is added and the mixture extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the solid product resulting concentrate is collected by filtration. The filtrate is again concentrated under reduced pressure, and the solid product precipitated in the sludge in the concentrate is collected by filtration. The solid products formed as a result of filtering, unite, washed with n-hexane and dried in vacuum, obtaining the target product (60,2 g, yield 76%) as a pale brown solid.

1H NMR (CDCl3400 MHz) (δ) ppm: 4,24 (2H, s), to 7.09 (1H, d, J=7,7 Hz), 7,18 (1H, DD, J=7,8 Hz, 7.9 Hz), 7,32 (2H, d, J=8,9 Hz), 7,40 (1H, d, J=8.0 Hz), 8,15 (2H, d, J=8.7 Hz).

MS(ESI): M - 280

Stage 2Getting 4-(2,3-dichlorobenzyl)phenylamine

1,2-dichloro-3-(4-nitrobenzyl)benzene (25,0 g and 88.6 mmol)obtained in stage 1, is dissolved in acetic acid (400 ml) and portions add the powdered zinc (70 g, 1.1 mol) at 0°C. With the ect was stirred at room temperature for 1 h The reaction mixture was filtered through celite and washed with ethanol. The filtrate is concentrated under reduced pressure and precipitated in the concentration of the solid precipitate collected by filtration. The solid is obtained by filtration, washed with diethyl ether and dissolved in ethyl acetate (500 ml) and water (500 ml). Add 4 N. aqueous sodium hydroxide solution to neutralize the aqueous layer. The organic layer is separated and the aqueous layer was then extracted with ethyl acetate. The organic layers are combined, washed with water and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and precipitated in the concentration of the solid precipitate collected by filtration. The solid is obtained by filtration, washed with n-hexane and dried in vacuum, obtaining the target product (18,1 g, yield 81%) as a pale brown solid.

1H NMR (CDCl3400 MHz) (δ) ppm: to 3.52 (2H, users), to 4.01 (2H, s), 6,63 (2H, d, J=8,2 Hz), 6,97 (2H, d, J=8.1 Hz), 7,02 (1H, d, J=7,6 Hz), to 7.09 (1H, DD, J=7.8 Hz, 7.8 Hz), 7,31 (1H, d, J=7,8 Hz).

MS(ESI): M+ 252

Stage 3Obtain ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-4-oxo-3-chinainternational

4-(2,3-dichlorobenzyl)phenylamine (10.0 g, and 39.7 mmol), obtained in stage 2, is dissolved in toluene (100 ml) and add Aut diethylethylenediamine (8,8 ml, for 43.7 mmol). The mixture is heated at the boil under reflux for 3 hours the Reaction solution was concentrated under reduced pressure, and to dissolve the residue, add diphenyl ether (100 ml). The mixture is stirred under heating at 250°C within 3 hours After the mixture is allowed to cool, the reaction solution was added n-hexane and the precipitate is collected by filtration, washed with chloroform and dried in vacuum, obtaining the target product (10.1 g, yield 68%) as a pale yellow solid.

1H NMR (DMSO-d6400 MHz) (δ) ppm: of 1.27 (3H, t, J=7,1 Hz), 4,20 (2H, square, J=7,1 Hz), 4,27 (2H, s), 7,34-7,41 (2H, m), 7,55-EUR 7.57 (3H, m), of 7.90 (1H, s), 8,49 (1H, d, J=6.6 Hz), of 12.26 (1H, users).

MS(ESI): M+ 376

Stage 4Obtain ethyl 1-(2-acetoxyethyl)-6-(2,3-dichlorobenzyl)-1,4-dihydro-4-oxo-3-chinainternational

Ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-4-oxo-3-chinainternational, obtained in stage 3 (400 mg, 1.1 mmol), suspended in dimethylformamide (DMF); 8 ml) and add 2-Bromeliaceae (152 μl, 1.4 mmol) and potassium carbonate (440 mg, 3.2 mmol). The mixture is stirred under heating at 80°C. while stirring twice add 2-Bromeliaceae (152 μl, 1.4 mmol) and the mixture is stirred under heating at 80°C all within 1.5 hours After the mixture is allowed to cool, the reaction solution was added saturated aqueous ammoniacal and is adok collected by filtration, washed with water and dried in vacuum, obtaining the target product (468 mg, yield 95%) as a white solid.

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 1.25 (3H, t, J=9,3 Hz), a 1.88 (3H, s), 4,20 (2H, square, J=9,3 Hz), 4,27 (2H, s), 4,33-to 4.41 (2H, m), 4,59-to 4.62 (2H, m), 7,32-7,41 (3H, m), 7,54 (1H, DD, J=2,9 Hz, 10,2 Hz), to 7.64 (1H, DD, J=2,4 Hz, 11.2 Hz), 7,81 (1H, d, J=11.7 Hz), 7,88 (1H, d, J=2.4 Hz), to 8.57 (1H, s).

Stage 5

Getting 6-(2,3-dichlorobenzyl)-1,4-dihydro-1-(2-hydroxyethyl)-4-oxo-3-quinoline-carboxylic acid

Ethyl 1-(2-acetoxyethyl)-6-(2,3-dichlorobenzyl)-1,4-dihydro-4-oxo-3-chinainternational obtained in stage 4 (6.0 g, 13,0 mmol), suspended in ethanol (480 ml) and add 4 N. aqueous solution of sodium hydroxide (84 ml, 21 mmol). The mixture is heated at the boil under reflux for 30 minutes After the mixture is allowed to cool, the reaction solution was partially concentrated under reduced pressure. Add chloride-hydrogen acid, the precipitate is collected by filtration, washed with water and ethanol and dried in vacuum, obtaining the target product (4.5 g, yield 85%) as a white solid.

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,75 (2H, t, J=4,7 Hz), 4,36 (2H, s), 4,60 (2H, t, J=4,8 Hz), to 4.98 (1H, users), 7,37-7,39 (1H, m), 7,45 (1H, DD, J=1,4, and 7.6 Hz), EUR 7.57 (1H, DD, J=1.5 and 8.0 Hz), 7,81 (1H, DD, J=2.1 a, a 8.9 Hz), 8,02 (1H, d, J=8,8 Hz), 8,15 (1H, d, J=1,8 Hz), 8,86 (1H, s), 15,18 (1H, users).

MS (ESI): M+ 392

So melting point: 247-249°C

WHEN IS EP 1-2

Getting 6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinoline-carboxylic acid

Stage 1

Obtain 2,3-debtor-5-identies acid

2,3-differentyou acid (5.0 g, of 31.6 mmol) dissolved in triftormetilfullerenov acid (25 ml) and add N-jodatime (8,55 g, 38,0 mmol) by portions at 0°C in a stream of argon. The mixture is stirred at room temperature for 3 hours, and the reaction solution was poured into sodium sulfite in the icy water. The mixture is stirred, the precipitate is collected by filtration, washed with water and dried in vacuum, obtaining the target product (7.5 g, yield 84%) as a pale pink solid.

1H NMR (CDCl3300 MHz) (δ) ppm: 7,74 (1H, m), 8,11 (1H, m).

MS(ESI): M - 283

Stage 2

Obtain ethyl 2-(2,3-debtor-5-Ioganson)-3-(2-hydroxyethylamino)acrylate

2,3-debtor-5-identify acid (3.0 g, 10.6 mmol), obtained in stage 1, is dissolved in toluene and added dropwise thionyl chloride (3.0 ml, 41,1 mmol) and DMF (catalytic amount). The mixture is heated at the boil under reflux for 3 hours the Reaction solution was concentrated under reduced pressure and add THF (15 ml)to dissolve the residue. The resulting solution is added dropwise to a solution of 3-diethylaminoacetate (1.66 g, 11.6 mmol who) and triethylamine (1.77 ml, 12.7 mmol) in THF (10 ml) and the mixture is stirred under heating at 50°C for 2.5 hours After mixture is allowed to cool, the reaction mixture is filtered and washed with THF (10 ml). To the filtrate add aminoethanol (of 0.77 ml, 12.7 mmol), and the mixture is stirred under heating at 40°C within 1 h After the mixture is allowed to cool, the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer is washed with water 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 (ethyl acetate:hexane=2:1)to give the desired product (3.8 g, yield 85%) as a mixture of E form and Z form of a yellow solid.

1H NMR (CDCl3400 MHz) (δ) ppm: 0,91-of 1.09 (3H, m), 1,80-1,89 (1H, m), 3,52-3,63 (2H, m), 3,83-3,91 (2H, m), 3,98-4.09 to (2H, m), of 7.36-7,52 (2H, m), 8,15 (1H, d, J=14.4 Hz), and 9.6 (0,22H, users), 11,0 (0,78H, users).

MS(ESI): M+ 426

Stage 3

Obtain ethyl 2-(2,3-debtor-5-Ioganson)-3-[2-(tert-butyldimethylsilyloxy)ethylamino]acrylate

Ethyl 2-(2,3-debtor-5-Ioganson)-3-(2-hydroxyethylamino)acrylate (2.0 g, 4.7 mmol), obtained in stage 2, was dissolved in DMF (10 ml), add imidazole (705 mg, 10.4 mmol) and tert-butyldimethylsilyl (1,49 g, 9.9 mmol) and stirred at room temperature for 4 hours To implement the traditional solution was added water and the mixture extracted with ethyl acetate. The organic layer is washed with water 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 (ethyl acetate:hexane=1:4)to give the desired product (2.3 g, yield 91%) as a white solid.

1H NMR (CDCl3300 MHz) (δ) ppm: of 0.07 (6H, s)of 0.90 (9H, s)of 1.07 (3H, t, J=7,1 Hz), 3,45-3,55 (2H, m), 3,70-of 3.80 (2H, m), Android 4.04 (2H, square, J=7,1 Hz), 7,30 is 7.50 (2H, m)to 8.14 (1H, d, J=14.1 Hz), 10,80-11,10 (1H, m).

MS(ESI): M+ 540

Stage 4

Getting ethyl 1,4-dihydro-8-fluoro-6-iodine-1-[2-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-3-chinainternational

Ethyl 2-(2,3-debtor-5-Ioganson)-3-[2-(tert-butyldimethylsilyloxy)ethylamino]acrylate (2.3 g, 4.3 mmol), obtained in stage 3, was dissolved in THF (25 ml) and add sodium hydride (256 mg, 6.4 mmol) under cooling with ice. The mixture was stirred at 0°C for 1 hour. In order to neutralize the reaction solution was added 1 N. chloride-hydrogen acid (6.4 ml, 6.4 mmol). Then water is added and the mixture extracted with ethyl acetate. The organic layer is washed with water 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 (ethyl acetate:hexane=1:2 to ethyl acetate:Huck is an=2:1), receiving target product (2.0 g, yield 92%) as a white solid.

1H NMR (CDCl3300 MHz) (δ) ppm: -0,12 (6H, s)of 0.79 (9H, s)to 1.38 (3H, t, J=7,1 Hz), 3,90-4,00 (2H, m), 4,37 (2H, square, J=7,1 Hz), 4,40-4,50 (2H, m), of 7.69 (1H, DD, J=2.0 Hz, of 13.7 Hz), 8,40 (1H, s), 8,69 (1H, d, J=2.0 Hz).

MS(ESI): M+ 520

Stage 5

Obtain ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-[2-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-3-chinainternational

In a stream of argon is 1 M solution (2.9 ml, 2.9 mmol) chloride 2,3-dichloroaniline in THF, obtained the same way as the comparative example 1, is added to THF (20 ml) and then added bis(dibenzylideneacetone)palladium(0) (22 mg, 0,039 mmol), three(2-furyl)phosphine (18 mg, 0,077 mmol) and ethyl 1,4-dihydro-8-fluoro-6-iodine-1-[2-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-3-chinainternational (1.0 g, 1.9 mmol)obtained in stage 4. The mixture is stirred at room temperature for 17 h and then add a solution (1.0 ml, 1.0 mmol) chloride 2,3-dichloroaniline in THF. The mixture is heated at the boil under reflux for 1 h After the mixture is allowed to cool, the reaction solution was added saturated aqueous solution of ameriglide and insoluble materials are filtered off using celite. The filtrate is extracted with ethyl acetate and the organic layer washed with water and saturated salt solution and dried over sulfate on the model. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (ethyl acetate:hexane=1:1), and then using LC with programming temperature (ethyl acetate:chloroform=1:2), obtain the target product (562 mg, yield 53%) as a pale yellow oil.

1H NMR (CDCl3300 MHz) (δ) ppm: -0,13 (6H, s)of 0.79 (9H, s)to 1.38 (3H, t, J=7,1 Hz), 3,90-4,00 (2H, m)to 4.23 (2H, s), 4,37 (2H, square, J=7,1 Hz), 4,40-4,50 (2H, m), 7,10-to 7.50 (4H, m), 8,20-8,30 (1H, m), 8,39 (1H, s).

MS(ESI): M+ 552

Stage 6

Obtain ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-chinainternational

Ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-[2-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-3-chinainternational (350 mg, to 0.63 mmol)obtained in stage 5, was dissolved in THF (25 ml) and add tetrabutylammonium (1 M solution in THF; 1.9 ml, 1.9 mmol). The mixture is stirred at room temperature for 1 hour. To the reaction solution was added water, and the precipitate is collected by filtration, washed with water and dried in vacuum, obtaining the target product (279 mg, yield quantitative) as a pale yellow solid.

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 1.27 (3H, t, J=7,1 Hz), 3,65-of 3.80 (2H, m), is 4.21 (2H, square, J=7,1 Hz), 4,40-4,50 (2H, m), 4,99 (1H, m), 7,30-of 7.90 (5H, m), of 8.47 (1H, s).

MS(ESI): M+ 438

Stage 7

Getting 6-(2,3-dichlor nil)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-quinoline-carboxylic acid

Ethyl 6-(2,3-dichlorobenzyl)-1,4-dihydro-8-fluoro-1-(2-hydroxyethyl)-4-oxo-3-chinainternational (80 mg, 0.18 mmol)obtained in stage 6, dissolved in a mixture of ethanol (2 ml) and THF (1 ml) and add 1 N. aqueous sodium hydroxide solution (1 ml, 1.0 mmol). The mixture is stirred under heating at 60°C for 1 hour. After the mixture is allowed to cool, the reaction solution was added 10% aqueous citric acid solution. The precipitate is collected by filtration, washed with 30% aqueous ethanol and dried in vacuum, obtaining the target product (70 mg, yield 93%) as a white solid.

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 3.78 (2H, m), 4,35 (2H, s), with 4.64 (2H, m)5,00 (1H, m), 7,39 (2H, m), 7,47 (1H, m), 7,58 (1H, m), 8,00 (1H, m), 8,81 (1H, s), 14,80 (1H, s).

MS (ESI): M+409

EXAMPLE 3-38

Stage 1

2-chloro-3-nitrobenzoic acid (6,00 g, 29,77 mmol) dissolved in triftormetilfullerenov acid (40 ml) and added in several portions of N-iodosuccinimide (7,37 g, 32.76ˆ mmol) at 0°C. the Mixture was stirred at 40°C for 4 h, and the reaction solution is added to ice water. After stirring the precipitate is collected by filtration, washed with water and dried in vacuum. The obtained solid substance was dissolved in methanol (50 ml), add concentrated sulfuric acid (catalytic amount), and the mixture is heated at the boiling fix refrigerator for 5.5 hours The reaction solution is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (ethyl acetate:hexane=1:4)to give the target product (5.35 g, yield 53%) as a pale yellow solid.

1H NMR (CDCl3300 MHz) (δ) ppm: 3,98 (3H, s), 8,11 (1H, d, J=2.1 Hz), 8,24 (1H, d, J=2.1 Hz).

Stage 2

The compound (5.35 g, 15,67 mmol)obtained in stage 1, was dissolved in methanol (25 ml) and add 4 N. aqueous sodium hydroxide solution (10,00 ml, 4.00 mmol). The mixture is heated at the boil under reflux for 30 minutes After the mixture is allowed to cool, the reaction solution was added 1 N. chloride-hydrogen acid, the solid precipitate is collected by filtration and dried in vacuum, obtaining the target product (4,99 g, yield 97%) as a white solid.

1H NMR (CDCl3300 MHz) (δ) ppm: 8,14 (1H, d, J=2.0 Hz), 8,39 (1H, d, J=2.1 Hz).

Stage 3

Connection (4,99 g, 15,24 mmol), obtained in stage 2, is dissolved in toluene (50 ml) and added dropwise thionyl chloride (5,00 ml, 68,54 mmol) and dimethylformamide (catalytic amount). The mixture is heated at the boil under reflux for 1 hour. The reaction solution is concentrated under reduced pressure and add tetrahydrofuran (80 ml)to dissolve the residue. Obtained the solution is added dropwise to a solution of ethyl 3,3-diethylaminoacetate (to 2.29 g, 16,00 mmol) and triethylamine (2.55 ml, 18,30 mmol) in tetrahydrofuran (50 ml), and the mixture is stirred under heating at 50°C for 10 hours After mixture is allowed to cool, to the reaction mixture add aminoethanol (1,10 ml, 18,23 mmol) and the mixture is stirred under heating at 40°C for 1.5 hours. After the mixture is allowed to cool, to the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer is washed successively with water 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 (ethyl acetate:hexane=2:1), obtaining the target product (5.35 g, 75%yield) as a mixture of E-form and Z-form of a yellow solid.

1H NMR (CDCl3300 MHz) (δ) ppm: 0,82-a 1.01 (3H, m), 3,63 (2H, usher.), 3,85-4,06 (4H, m), 7,65-to 7.68 (1H, m), 8,02-of 8.06 (1H, m), 8,21-at 8.36 (1H, m), 9,78 (0,16H, usher.), of 11.15 (0,84H, usher.).

Stage 4

The compound (5.35 g, 11,42 mmol), obtained in stage 3, was dissolved in dimethylformamide (50 ml) and added imidazole (1,71 g, 25,12 mmol) and tert-butyldimethylsilyl chloride (3.62 in) to 24.02 mmol). The mixture is stirred at room temperature for 30 minutes To the reaction mixture, water is added and the mixture extracted with ethyl acetate. The organic layer is washed successively with water and feast upon the authorized salt solution and dried over sodium sulfate. After filtration and concentration under reduced pressure to get crude product (7,10 g) as a pale yellow solid.

Stage 5

The crude product (7,10 g)obtained in stage 4, was dissolved in tetrahydrofuran (70 ml) and cooled with ice add sodium hydride (731 mg, 18,27 mmol). The mixture was stirred at 0°C for 45 minutes To the reaction solution was added 1 N. chloride-hydrogen acid (18.3 ml) and water and stirred, the mixture is then extracted with ethyl acetate. The organic layer is washed successively with water and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and purified by chromatography on silica gel (ethyl acetate:hexane=1:4 to 1:2)to give the target product (5,58 g, yield 84%) as a yellow solid.

1H NMR (CDCl3300 MHz) (δ) ppm: -0,14 (6H, s)to 0.73 (9H, s)of 1.39 (3H, t, J=7,1 Hz), 3,74 (2H, t, J=4.6 Hz), was 4.02 (2H, t, J=4.6 Hz), 4,39 (2H, square, J=7,1 Hz), 8,13 (1H, d, J=2.2 Hz), and 8.50 (1H, s), of 9.02 (1H, d, J=2,2 Hz).

Stage 6

Connection (5,00 g, to 9.15 mmol)obtained in stage 5, was dissolved in tetrahydrofuran (100 ml) and in a stream of argon added bis(dibenzylideneacetone)palladium(0) (105 mg, 0.18 mmol) and three(2-furyl)phosphine (85 mg, of 0.37 mmol). Dropwise at 60°C, add a solution bromide-chloro-2-tormentilla (11,90 mmol) in tetrahydrofuran, obtained by the method of example 4-32 on stage 4. After complete addition, the mixture is heated at the boil under reflux for 4 hours After mixture is allowed to cool, the reaction solution was added saturated aqueous solution of ameriglide and insoluble substance is filtered off using celite. The filtrate is extracted with ethyl acetate, the organic layer washed successively with water 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 (ethyl acetate:hexane=1:2 to 1:1), obtaining the target product (2.67 g, yield 52%) as a brown oil.

1H NMR (CDCl3300 MHz) (δ) ppm: -0,19 (6H, s)0,70 (9H, s)of 1.39 (3H, t, J=7,1 Hz), to 3.73 (2H, t, J=4.6 Hz), a 4.03 (2H, t, J=4.6 Hz), 4,14 (2H, s), to 4.38 (2H, square, J=7,1 Hz), 7,02-7,14 (2H, m), 7,29-to 7.35 (1H, m), 7,73 (1H, d, J=2.2 Hz), and 8.50 (1H, s), 8,59 (1H, s).

Stage 7

Connection (1,00 g, to 1.79 mmol)obtained in stage 6, is dissolved in acetic acid (20 ml) and add the powdered zinc (1,16 g, 17,76 mmol). The mixture is stirred at room temperature for 4 h, the Reaction mixture was filtered through celite and to the filtrate add saturated aqueous sodium bicarbonate solution. The mixture is extracted with ethyl acetate. The organic layer is washed sequentially with saturated in denim solution of sodium bicarbonate, water 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 (ethyl acetate). To the obtained residue is added ethyl ether and the mixture is treated with ultrasound. After filtration of the mixture is dried in vacuum, obtaining the target product (730 mg, yield 77%) as a pale orange solid.

1H NMR (CDCl3300 MHz) (δ) ppm: -0,06 (6H, s)of 0.77 (9H, s)of 1.41 (3H, t, J=7,1 Hz)to 4.01 (2H, s)4,08 (2H, t, J=4,7 Hz), 4,39 (2H, square, J=7,1 Hz), 4,50 (2H, users), and 4.75 (2H, t, J=4,7 Hz), for 6.81 (1H, s), 6,94-was 7.08 (2H, m), 7,20-7,26 (1H, m), to $ 7.91 (1H, s), a 8.34 (1H, s).

Stage 8

The compound (100 mg, 0,19 mmol)obtained in stage 7, is dissolved in dimethylformamide (2 ml) and add methyliodide (0,029 ml, 0.47 mmol) and sodium hydride (23 mg, 0,56 mmol). The mixture is stirred at room temperature for 2 hours To the reaction mixture is added 10% aqueous citric acid solution, the mixture is stirred and extracted with ethyl acetate. The organic layer is washed successively with water and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and treated by chromatography on silica gel (ethyl acetate:hexane=2:1), receiving roughly purified product (45 mg) as a solid pale is Krasnogo color.

1H NMR (CDCl3300 MHz) (δ) ppm: -0,33 - -0,29 (6H, m), of 0.64 to 0.69 (9H, m), 1,23-of 1.41 (3H, m), 2,66-2,70 (6H, m), 3,55-3,59 (2H, m), 4,36-4,4,2 (4H, m), 4,82-4,96 (2H, m), of 6.96-7,11 (2H, m), 7.23 percent-7,30 (2H, m), 8,16-of 8.15 (1H, m), 8,40-8,66 (1H, m).

Stage 9

Crudely purified product (45 mg)obtained in stage 8, was dissolved in tetrahydrofuran (1 ml) and was added 1 M solution of tetrabutylammonium (of 1.00 ml, 1.00 mmol) in THF. The mixture is stirred at room temperature for 5 minutes To the reaction solution was added ethanol (1 ml) and 1 N. aqueous sodium hydroxide solution (1 ml, 1.00 mmol)and the mixture heated to boiling under reflux for 2 hours After mixture is allowed to cool, the reaction solution was added 10% aqueous citric acid solution. The mixture is stirred and extracted twice with chloroform. The organic layer was washed with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and subjected to chromatography on silica gel (chloroform:methanol:acetic acid=10:1:0.1), receiving roughly purified product. To crudely purified product type aqueous ethanol, and the mixture is treated with ultrasound. After filtration, the filtrate is dried in vacuum, obtaining the target product (22 mg, yield 27%) as a beige solid.

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 2.67 (6H, what), 3,39 (2H, m), is 4.21 (2H, s), 4.72 in (1H, t), equal to 4.97 (2H, t), 7,20-7,22 (1H, m), 7,40-to 7.50 (2H, m), the 7.65 (1H, s), to 7.84 (1H, s), 15,10 (1H, s).

MS(ESI): M+ 419

EXAMPLE 3-62

Stage 1

2,4-debtor-5-identify acid (3.00 g, or 10.60 mmol)obtained in example 4-33, in stage 1, was dissolved in toluene (10 ml) and added dropwise thionyl chloride (3,00 ml, 41,10 mmol) and dimethylformamide (catalytic amount). The mixture is heated at the boil under reflux for 1.5 hours, the Reaction solution is concentrated under reduced pressure and add tetrahydrofuran (15 ml)to dissolve the residue. The resulting solution is added dropwise to a solution of ethyl 3,3-diethylaminoacetate (1.66 g, 11,60 mmol) and triethylamine (1.77 ml, 12,70 mmol) in tetrahydrofuran (10 ml), and the mixture is stirred under heating at 50°C for 2.5 hours After mixture is allowed to cool, the reaction mixture is filtered and washed with tetrahydrofuran (10 ml). To the filtrate add aminoethanol (0,77 ml of 12.76 mmol), and the mixture is stirred under heating at 40°C for 1 hour. After the mixture is allowed to cool, the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer is washed successively with water and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified XP is matography on silica gel (ethyl acetate:hexane=2:1), getting crudely purified product (3.00 g, yield 67%) as a mixture of E-form and Z-form of a yellow solid.

Stage 2

The compound (3.00 g, 7,06 mmol)obtained in stage 1, was dissolved in dimethylformamide (15 ml) and added imidazole (1.06 g, 15,52 mmol) and tert-butyldimethylsilyl (2,23 g, 14,82 mmol). The mixture is stirred at room temperature for 14 hours To the reaction mixture, water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water 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 (ethyl acetate:hexane=1:4)to give the target product (3,22 g, yield 85%) as a white solid.

1H NMR (CDCl3300 MHz) (δ) ppm: 0,06 (6H, s)of 0.90 (9H, s)a 1.08 (3H, t, J=7,1 Hz), 3,51 (2H, usher.), with 3.79 (2H, t, J=4.9 Hz), of 4.05 (2H, square, J=7,1 Hz), 6,78 (1H, DD, J=7,9, and 9.4 Hz), 7,71 (1H, DD, J=7,3, 7,3 Hz), 8,11 (1H, d, J=14,0 Hz), 10,91 (1H, usher.).

Stage 3

Connection (3,22 g, 5,97 mmol), obtained in stage 2, was dissolved in tetrahydrofuran (35 ml) and cooled with ice add sodium hydride (358 mg, of 8.95 mmol). The mixture was stirred at 0°C for 2.5 hours To the reaction mixture add 1 N. chloride-hydrogen acid (8,90 ml of 8.90 mmol who) and water (35 ml), and the mixture is stirred. The precipitate is collected by filtration and purified by chromatography on silica gel (ethyl acetate:hexane=1:2 to 2:1), obtaining the target product (2,52 g, yield 81%) as a pale yellow solid.

1H NMR (CDCl3300 MHz) (δ) ppm: -0,11 (6H, s)of 0.79 (9H, s)of 1.39 (3H, t, J=7,1 Hz), of 3.96 (2H, t, J=4,8 Hz)to 4.23 (2H, t, J=4,8 Hz), to 4.38 (2H, square, J=7,1 Hz), 7,14 (1H, d, J=9.3 Hz), of 8.47 (1H, s), 8,93 (1H, d, J=7,2 Hz).

Stage 4

Connection (1,00 g of 1.93 mmol), obtained in stage 3, was dissolved in tetrahydrofuran (20 ml). In a stream of argon added bis(dibenzylideneacetone)palladium(0) (22 mg, 0,039 mmol) and three(2-furyl)phosphine (18 mg, 0,077 mmol). To this mixture is added dropwise at 60°C, add a solution of bromide 3-chloro-2-tormentilla (2.89 mmol) in tetrahydrofuran obtained as described above. After complete addition, the mixture is heated at the boil under reflux for 1 h After the mixture is allowed to cool, the reaction solution was added saturated aqueous solution of ameriglide. The insoluble substance is filtered off using celite. The filtrate is extracted with ethyl acetate, the organic layer washed successively with water 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 (utilized the t:hexane=2:1), receiving target product (573 mg, yield 55%) as a pale yellow solid.

1H NMR (CDCl3300 MHz) (δ) ppm: -0,12 (6H, s)to 0.78 (9H, s)to 1.38 (3H, t, J=7,1 Hz)to 3.99 (2H, t), of 4.13 (2H, s)to 4.23 (2H, t), 4,37 (2H, square, J=7,1 Hz), of 6.96-7,13 (3H, m), 7,25-7,31 (1H, m), 8,39 (1H, d), 8,46 (1H, ).

Stage 5

The compound (170 mg, 0.32 mmol), obtained in stage 4, was dissolved in tetrahydrofuran (1 ml) and add 2 N. aqueous sodium hydroxide solution (4,00 ml, 2.00 mmol). The mixture is heated at the boil under reflux for 3.5 hours After mixture is allowed to cool, the reaction solution was added 10% aqueous citric acid solution and the precipitate is collected by filtration, washed with 50% aqueous ethanol and dried in vacuum, obtaining the target product (117 mg, yield 94%) as a white solid.

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 3.73 (2H, usher.), of 4.25 (2H, s), 4,58 (2H, usher.), 4,96 (1H, usher.), 7,19-7,22 (1H, m), 7,30 and 7.36 (1H, m), 7,49-rate of 7.54 (1H, m), 8,03 (1H, d), 8,30 (1H, d), 8,88 (1H, s), 15,42 (1H, users).

Stage 6

Compound (65 mg, 0,17 mmol)obtained in stage 5, was dissolved in dimethyl sulfoxide (2.5 ml) and irradiated with microwave radiation at 50 watts and 120°C or below within 20 minutes After the mixture is allowed to cool, the reaction mixture is added 10% aqueous citric acid solution and the precipitate is collected by filtration, washed with water and dried in vacuum, receiving target product (66 mg, yield 96%) as a white solid.

1H NMR (DMSO-d6300 MHz) (δ) ppm: 2,88 (6H, s), 3,70-of 3.80 (2H, m), 4,22 (2H, s), 4,60-4,70 (2H, m), of 5.05 (1H, t), 7,20-7,31 (3H, m), 7,50-of 7.60 (1H, m), 7,80 (1H, s), 8,78 (1H, s), 15,30-15,40 (1H, users).

MS(ESI): M+ 419

EXAMPLE 3-73

Stage 1

2,4-debtor-5-identify acid (5,00 g, 17,60 mol) is dissolved in toluene (25 ml) and add oxalicacid (2.00 ml, 22,93 mmol) and dimethylformamide (catalytic amount). The mixture is stirred at room temperature for 12 hours After filtering the reaction solution, the filtrate is concentrated under reduced pressure and add toluene (20 ml). The insoluble substance is filtered off using celite. The filtrate is concentrated under reduced pressure and add tetrahydrofuran (20 ml)to dissolve the obtained residue. The resulting solution is added dropwise to a solution of ethyl 3,3-diethylaminoacetate (3.28 g, 22,91 mmol) and triethylamine (3,70 ml, 26,55 mmol) in tetrahydrofuran (20 ml). The mixture is heated at the boil under reflux for 1 h After the mixture is allowed to cool, to the reaction mixture are added water and ethyl acetate (50 ml). The mixture is stirred and separated. The organic layer is washed successively 1 N. chloride-hydrogen acid (20 ml) and water (200 ml), and dried over sodium sulfate. After f is mitrofania the filtrate is concentrated under reduced pressure, receiving the crude product (7,24 g) as a brown oil.

Stage 2

The crude product (7,24 g)obtained in stage 1, was dissolved in tetrahydrofuran (20 ml) and added dropwise (S)-2-amino-1-butanol (1.89 g, 21,24 mmol). The mixture is stirred under heating at 60°C within 1.5 hours After the mixture is allowed to cool, the reaction solution is concentrated under reduced pressure and the resulting residue is dissolved in dimethylformamide (20 ml). Add potassium carbonate (7,33 g, 53,02 mmol), and the mixture is stirred under heating at 70°C within 1 h After the mixture is allowed to cool, the reaction mixture was concentrated under reduced pressure. To the residue is added water (150 ml)and the mixture was stirred at room temperature for 30 minutes the Precipitate is collected by filtration. The obtained solid is washed with water (50 ml), then with a mixture (50 ml) hexane:diethyl ether=7:3, and dried in vacuum, obtaining the target product (4,69 g, yield 61%) as a white solid.

1H NMR (CDCl3300 MHz) (δ) ppm: to 0.97 (3H, t, J=7.4 Hz), of 1.40 (3H, t, J=7,1 Hz), 1,95-2,05 (1H, m), 2,11-of 2.21 (1H, m), of 4.05 (1H, usher.), 4,34-4,39 (5H, m), 5,59 (1H, usher.), 7,30 (1H, d, J=10.0 Hz), of 8.04 (1H, d, J=7,1 Hz), 8,58 (1H, s).

Stage 3

Connection (4,69 g, was 10.82 mmol), obtained in stage 2, was dissolved in dimethylformamide (20 ml) and added imidazole (950 mg, 3.95 mmol) and tert-butyldimethylsilyl (1,95 g, 12,96 mmol). The mixture is stirred at room temperature for a period of 14.5 hours To the reaction mixture, water is added, and the mixture is extracted with ethyl acetate (50 ml). The organic layer is washed three times with water and then 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 (ethyl acetate:hexane=3:7)to give the target product (of 5.06 g, yield 86%) as a yellow oil.

1H NMR (CDCl3300 MHz) (δ) ppm: -0,08 (3H, s), to-0.05 (3H, s)of 0.77 (9H, s), and 0.98 (3H, t, J=7.5 Hz), of 1.40 (3H, t, J=7.2 Hz), 1,94 is 2.10 (2H, m), 3,90 (2H, usher.), 4,35-4,43 (3H, m), 7,26 (1H, d, J=9.9 Hz), 8,59 (1H, s), of 8.95 (1H, d, J=7,2 Hz).

Stage 4

Connection of 5.06 g, 9,24 mmol), obtained in stage 3, was dissolved in tetrahydrofuran (20 ml) and in a stream of argon added bis(dibenzylideneacetone)palladium(0) (266 mg, 0.46 mmol) and three(2-furyl)phosphine (215 mg, of 0.92 mmol). Added dropwise a solution of bromide 3-chloro-2-tormentilla (18,50 mmol) in tetrahydrofuran obtained as described above. After complete addition, the mixture is stirred under heating at 60°C for 1 hour. After the mixture is allowed to cool, the reaction solution was added water and ethyl acetate, and the mixture is stirred and separated. The organic layer is washed successively 1 N. chloride-hydrogen acid, water,saturated aqueous sodium bicarbonate and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the residue purified by chromatography on silica gel (ethyl acetate:hexane=1:1 to 2:1), obtaining the target product (3,86 g, yield 74%) as a brown oil.

1H NMR (CDCl3300 MHz) (δ) ppm: -0,10 (3H, s)-0,06 (3H, s), 0,752 (9H, s), and 0.98 (3H, t, J=7.4 Hz), 1,4 (3H, t, J=7,1 Hz), 1,90-2,12 (2H, m)to 3.89 (2H, usher.), of 4.12 (2H, s), 4,35-4,49 (3H, m), 6,97-was 7.08 (2H, m), 7,22-7,29 (2H, m), 8,40 (1H, d, J=8.7 Hz), 8,58 (1H, s).

Stage 5

To the compound (3,86 g, 6,85 mmol)obtained in stage 4, added 28% sodium methoxide in methanol (40,00 ml, 0.20 mol), and water (2.00 ml, 0.11 mol) and the mixture heated to boiling under reflux for 5.5 hours. After the mixture is allowed to cool, the reaction solution is concentrated under reduced pressure and the obtained residue add 6 N. chloride-hydrogen acid. The mixture is stirred and extracted twice with ethyl acetate. The organic layer is washed successively with water and saturated salt solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue is recrystallized from ethanol (200 ml)to give the target product (2,03 g, yield 68%) as a white solid.

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 0.87 (3H, t, J=7,3 Hz), 1,80-2,10 (2H, m), 3,70-are 3.90 (2H, m), was 4.02 (3H, s), 4,11 (2H, s), 5,00-5,19 (2H, m), 7,16-7,24 (2H, m), 7,44-of 7.48 (2H, m), of 8.04 (1H, s), 878 (1H, C)15,44 (1H, s).

MS(ESI): M+ 434

EXAMPLE 3-75

Stage 1

2-fluoro-5-identify acid (6.60 g, 24,81 mmol) dissolved in chloroform (70 ml) and add oxalicacid (4,30 ml, 49,29 mmol) and dimethylformamide (catalytic amount). The mixture is stirred at room temperature for 3 hours the Reaction solution was concentrated under reduced pressure and add chloroform (35 ml)to dissolve the residue. The resulting solution is added dropwise to a solution of ethyl 3,3-diethylaminoacetate (4.26 deaths / g, 29,75 mmol) and triethylamine (5,19 ml, 37,24 mmol) in chloroform (35 ml) and the mixture is stirred at room temperature for 15 hours To separate the reaction solution is added water, 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 (ethyl acetate:hexane=1:2 to 1:1), obtaining the target product (6,40 g, yield 66%) as a mixture of E-form and Z-form in a solid orange color.

1H NMR (CDCl3400 MHz) (δ) ppm: to 0.94 (3H, t, J=7.2 Hz), is 2.88 (3H, users), and 3.31 (3H, users), of 3.97 (2H, square), is 6.78 (1H, DD, J=8,4, 10,0 Hz), 7,65-to 7.67 (1H, m), 7,78 (1H, s), a 7.85 (1H, users).

MS(ESI): M+ 392

Stage 2

The compound (300 mg, 0.77 mmol)obtained is as stage 1, dissolved in tetrahydrofuran (1.5 ml) and added dropwise (S)-(+)-tert-leucinol (0,12 ml of 0.92 mmol). The mixture is stirred under heating at 60°C for 1 hour. The reaction solution is concentrated under reduced pressure and the resulting residue is dissolved in dimethylformamide (1.2 ml). Add potassium carbonate (318 mg, 2,30 mmol), and the mixture is stirred under heating at 70°C for 5.5 h After cooling, to the reaction mixture add 1 N. chloride-hydrogen acid (5 ml) and the mixture is stirred under ice cooling for 30 minutes the Precipitate is collected by filtration, the obtained solid is washed with 30% aqueous ethanol (6 ml), then with a mixture (5 ml) hexane:diethyl ether=2:1 and dried in vacuum, obtaining the target product (276 mg, yield 81%) in the form of a pale yellow solid.

1H NMR (CDCl3300 MHz) (δ) ppm: 0,98 (9H, s)of 1.41 (3H, t, J=7.0 Hz), 4,25-to 4.41 (4H, m), with 4.64-4,70 (1H, m), 5,14 (1H, usher.), 7,46 (1H, d, J=9.0 Hz), 7,89 (1H, DD, J=2,2, 9.1 Hz), of 8.06 (1H, d, J=2.1 Hz), 8,69 (1H, s).

Stage 3

The compound (276 mg, of 0.62 mmol)obtained in stage 2, was dissolved in dimethylformamide (1 ml) and added imidazole (51 mg, 0.75 mmol) and tert-butyldimethylsilyl (122 mg, 0.81 mmol). The mixture is stirred at room temperature for 30 minutes To the reaction mixture, water is added, the mixture extracted twice with ethyl acetate, the organic layer washed twice is water, then 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 (ethyl acetate:hexane=3:5), obtaining the target product (314 mg, yield 91%) as a white amorphous substance.

1H NMR (CDCl3300 MHz) (δ) ppm: -0,09 (3H, s)-0,01 (3H, s)0,66 (9H, s), was 1.04 (9H, s)of 1.41 (3H, t, J=7.2 Hz), 4,10-to 4.14 (2H, m), and 4.40 (2H, square, J=7,0 Hz), 4,58-4,63 (1H, m), 7,39 (1H, d, J=9.3 Hz), 7,89 (1H, DD, J=2,2, 8,8 Hz), 8,67 (1H, s), 8,87 (1H, d, J=2.1 Hz).

Stage 4

The compound (314 mg, 0,56 mmol), obtained in stage 3, was dissolved in tetrahydrofuran (1.2 ml) and in a stream of argon added bis(dibenzylideneacetone)palladium(0) (16 mg, 0,028 mmol) and three(2-furyl)phosphine (13 mg, 0,056 mmol). Added dropwise a solution of bromide 3-chloro-2-tormentilla (1.13 mmol) in tetrahydrofuran obtained as described above. After complete addition, the mixture is stirred under heating at 50°C for 1.5 hours. After the mixture is allowed to cool, the reaction solution was added water and ethyl acetate and the mixture is stirred. The insoluble substance is filtered off using celite. The filtrate is separated, the organic layer washed successively with water and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and p the obtained residue is purified by chromatography on silica gel (ethyl acetate:hexane=1:1), receiving target product (283 mg, yield 87%) as a brown amorphous substance.

1H NMR (CDCl3400 MHz) (δ) ppm: -0,11 (3H, s)-0,01 (3H, s)0,63 (9H, s)of 1.06 (9H, s)of 1.41 (3H, t, J=7.0 Hz), 4,08-4,16 (4H, m), to 4.38 (2H, square, J=7,0 Hz), br4.61-of 4.67 (1H, m), 6,95-was 7.08 (2H, m), 7.23 percent-7,27 (1H, m), 7,47-7,49 (1H, m), 7,53-of 7.55 (1H, m), to 8.41 (1H, d, J=2.0 Hz), 8,68 (1H, s).

Stage 5

The compound (283 mg, 0.49 mmol)obtained in stage 4, is dissolved in ethanol (2 ml) and add 1 N. aqueous sodium hydroxide solution (of 1.00 ml, 1.00 mmol). The mixture is heated at the boil under reflux for 1 hour. After the mixture is allowed to cool, the reaction solution was added acetic acid (0.35 ml) and the mixture is stirred. The precipitate is collected by filtration, and the solid part is suspended in diethyl ether (10 ml). After filtration of the mixture is dried in vacuum, obtaining the target product (157 mg, yield 74%) as a white solid.

1H NMR (DMSO-d6400 MHz) (δ) ppm: 1.00 and (9H, s), 4,07-4,12 (2H, m), 4,30 (2H, s), 5,12-5,14 (2H, m), 7,20-of 7.25 (1H, m), 7,40 was 7.45 (1H, m), 7,51-7,53 (1H, m), 7,87 (1H, d), of 8.25 (1H, s), to 8.41 (1H, d, J=9,2 Hz), cent to 8.85 (1H, C), 15,20-15,21 (1H, usher.).

MS(ESI): M+ 432

EXAMPLE 4-20

Stage 1

2-chloro-4-hydroxybenzoic acid (5,18 g, 30,02 mmol) dissolved in triftormetilfullerenov acid (25 g) and portions add N-jodatime (6.75 g, 30,00 mmol) at 0°C. the Mixture premesis the Ute at room temperature for 15 h and then add triftormetilfullerenov acid (25 g). N-jodatime (2,02 g, 8.98 mmol) is added by portions at 0°C. the Mixture is stirred at room temperature for 13.5 hours, and the reaction mixture was added to ice water (300 ml). The mixture is stirred for 2 hours the Precipitate is collected by filtration, washed with water and dried in vacuum, obtaining the target product in the form of a mixture of 2-chloro-4-hydroxy-5-identies acid and 2-chloro-3,5-dead-4-hydroxybenzoic acid (8:2) (USD 5.76 g).

Stage 2

The mixture (to 3.89 g), obtained in stage 1, was dissolved in dimethylformamide (20 ml) and add potassium carbonate (8,97 g, 64,90 mmol) and isopropylated (6,50 ml, 65,15 mmol). The mixture is stirred under heating at 80°C for 2.5 hours. The reaction mixture was added to 1 N. chloride-hydrogen acid (100 ml), and then add toluene (100 ml). The mixture is stirred, and the insoluble substance is filtered off using celite. The filtrate is separated, the organic layer washed three times with water and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (ethyl acetate:hexane=1:9)to give the target product as a mixture (4,08 g).

Stage 3

A mixture of (4,08 g)obtained in stage 2, was dissolved in ethanol (20 ml) and add 1 N. aqueous sodium hydroxide solution (20,0 ml, 20.00 mmol). The mixture is heated at the boil under reflux for 24 hours After mixture is allowed to cool, the reaction solution was added 1 N. chloride-hydrogen acid (30 ml), and the mixture is stirred. The mixture is extracted three times with ethyl acetate. The organic layer is washed successively with water and saturated salt solution and dried over sodium sulfate. After filtration and concentration under reduced pressure to obtain the target product as a mixture (3,40 g).

Stage 4

A mixture of (3,40 g), obtained in stage 3, is dissolved in toluene (35 ml) and added dropwise thionyl chloride (3,40 ml, 46,61 mmol) and dimethylformamide (catalytic amount). The mixture is heated at the boil under reflux for 1.5 hours, the Reaction solution is concentrated under reduced pressure and add tetrahydrofuran (25 ml)to dissolve the residue. The resulting solution is added dropwise to a solution of ethyl 3,3-diethylaminoacetate (4,29 g, 30,00 mmol) and triethylamine (4,17 ml, 30,00 mmol) in tetrahydrofuran (10 ml)and the mixture heated to boiling under reflux for 14 hours After mixture is allowed to cool, to the reaction mixture are added water and ethyl acetate, the mixture is stirred and separated. The organic layer is washed successively with water and saturated salt solution and dried over sulfate n is sodium. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (ethyl acetate:hexane=1:1.5 to 1.5:1)to give the target product as a mixture (2,71 g).

Stage 5

The compound (300 mg)obtained in stage 4, was dissolved in tetrahydrofuran (2 ml) and add (S)-(+)-tert-leucinol (0.10 ml, 0.77 mmol). The mixture is heated at the boil under reflux for 20 minutes After the mixture is allowed to cool, the reaction solution is concentrated under reduced pressure and the resulting residue is dissolved in dimethylformamide (4 ml). Add imidazole (110 mg, of 1.61 mmol) and tert-butyldimethylsilyl (214 mg, of 1.42 mmol)and the mixture was stirred at room temperature for 20 minutes To the reaction solution was added water and the mixture extracted with ethyl acetate. The organic layer is washed successively with water 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 (ethyl acetate:hexane=1:4)to give the target product as a mixture (391 mg).

Stage 6

Compound (391 mg)obtained in stage 5, is dissolved in toluene (5 ml) and cooled with ice add sodium hydride (29 mg, 0.73 mmol). mesh stirred at room temperature for 30 min, to the reaction mixture are added dimethylformamide (3 ml), potassium carbonate (100 mg, to 0.72 mmol) and ethyliodide (0,058 ml, 0.73 mmol). The mixture is stirred under heating at 60°C within 30 minutes After mixture is allowed to cool, the reaction mixture was added to ice water. To neutralize add 1 N. chloride-hydrogen acid and the mixture extracted with ethyl acetate. The organic layer is washed successively with water 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 (ethyl acetate:hexane=4:5 to 2:1), obtaining the target product (258 mg, yield 19%) as a pale Belozerova solids.

1H NMR (CDCl3300 MHz) (δ) ppm: -0,09 (3H, s)0,00 (3H, s)to 0.67 (9H, s)of 1.05 (9H, s)of 1.40 (3H, t, J=7,1 Hz)of 1.46 (6H, d, J=6.0 Hz), 4.09 to-4,20 (2H, m), 4,39 (2H, square, J=7,1 Hz), 4,43-of 4.49 (1H, m), br4.61-4,69 (1H, m,), 6,87 (1H, s), at 8.60 (1H, s), to 8.94 (1H, s).

Stage 7

Ethyl 1,4-dihydro-1-{2,2-dimethyl-1-[(tert-butyldimethylsilyloxy)methyl]propyl}-6-iodine-7-isopropoxy-4-oxo-3-chinainternational (258 mg, 0.42 mmol)obtained in stage 6, is dissolved in tetrahydrofuran (5 ml). In a stream of argon added bis(dibenzylideneacetone)palladium(0) (9.7 mg, of 0.017 mmol) and dropwise at 60°C add three(2-furyl)phosphine (7.8 mg, 0,034 mmol) and a solution of bromide 3-chloro-2-Forbes linka (0,63 mmol) in tetrahydrofuran, received as described above. After complete addition, the mixture is heated at the boil under reflux for 1 h After the mixture is allowed to cool, the reaction solution was added saturated aqueous solution of ameriglide, the mixture is stirred and filtered through celite. To the filtrate water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, and the obtained residue roughly purified by chromatography on silica gel (ethyl acetate:hexane=1:1 to 2:1), receiving roughly purified product (216 mg) as a pale yellow oil.

Stage 8

Crudely purified product (216 mg)obtained in stage 7, dissolved in a mixture of ethanol (2 ml) and tetrahydrofuran (1 ml) and add 1 N. aqueous sodium hydroxide solution (2.00 ml, 2.00 mmol). The mixture is heated at the boil under reflux for 1 h After the mixture is allowed to cool, the reaction solution was added 10% aqueous citric acid solution and the mixture is stirred. The mixture is extracted with ethyl acetate. The organic layer is washed successively with water and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated at ponie nom pressure. The residue is treated with a mixture of diethyl ether and hexane. After filtration of the solid portion is dried in vacuum, obtaining the target product (140 mg, yield 68%)as a white solid.

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,97 (9H, s)of 1.18 (3H, d, J=5,9 Hz), of 1.26 (3H, d, J=6.0 Hz), Android 4.04-4.09 to (4H, m), 5,09-5,13 (3H, m), 7,12-7,21 (2H, m), 7,43-7,51 (2H, m), 8,19 (1H, s), 8,78 (1H, s), 15,46 (1H, s).

MS(ESI): M+ 490

EXAMPLE 4-32

Stage 1

2,4-debtor-5-identify acid (650,57 g to 2.29 mol) is dissolved in toluene (1300 ml) and added dropwise thionyl chloride (184 ml, 2,52 mol) and dimethylformamide (catalytic amount). The mixture was stirred at 90°C within 2 hours After mixture is allowed to cool, the reaction solution is concentrated under reduced pressure. The residue is dissolved in toluene (330 ml), then concentrated under reduced pressure and repeat all this again. The residue is dissolved in toluene (690 ml), the resulting solution is added dropwise to a solution of ethyl 3,3-diethylaminoacetate (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 within 3 hours After the mixture is allowed to cool, to the reaction mixture (S)-(+)-valinol (260,00 g, 2,52 mol) and the mixture is stirred at room temperature for 1 h To the reaction mixture add water (2600 ml), and the mixture is separated. The aqueous layer was EXT Airout toluene (680 ml). The organic layers are combined washed twice with water (2000 ml) and dried over sodium sulfate. After filtration and concentration under reduced pressure to get crude product (1180 g) as a brown oil.

Stage 2

The crude product (1180 g)obtained in stage 1, was dissolved in dimethylformamide (2500 ml) and add finely ground potassium carbonate (292,00 g, 1.06 mol). The mixture is stirred at room temperature for 22 hours, the Reaction mixture was added to ice water (approximately 10 l), and the mixture is stirred for 30 minutes the Precipitate is collected by filtration and washed with water (2000 ml). The obtained solid is dried in vacuo and suspended in ethyl acetate (5000 ml). In the filtration and drying under vacuum to obtain the target product (774,63 g, yield 82%) as a white-yellow solid.

1H NMR (DMSO-d6300 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, usher.), of 3.77 (1H, usher.), 3,86 (1H, usher.), to 4.23 (2H, square, J=7,0 Hz), 4,56 (1H, usher.), 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).

MS(ESI): M+ 448

Stage 3

Connection (626,15 g to 1.40 mol), obtained in stage 2, was dissolved in chloroform (1250 ml) and added dropwise pyridine (433 ml, the ceiling of 5.60 mol) and 4-(dimethylamino)pyridine (17,10 g, 0.14 mol). The solution methylcarbamate (529,30 g, 560 mol) in chloroform (1250 ml) is added dropwise at 10° C or below. After complete addition, the mixture is stirred at the same temperature for 30 minutes, the Reaction mixture was washed successively with water (1250 ml), 2 N. chloride-hydrogen acid (1250 ml), water (630 ml) and saturated aqueous sodium bicarbonate (630 ml) and dried over sodium sulfate. After filtration the residue is concentrated under reduced pressure to give crude desired compound (834,02 g) as a brown oil.

Stage 4

(Getting tertrahydrofuran ring solution of bromide 3-chloro-2-tormentilla)

In a stream of argon powder zinc (113,02 g of 1.73 mol) is suspended in tetrahydrofuran (350 ml) and added dropwise at 60°C 1,2-dibromethane (1,207 ml, 14,00 mmol) and trimethylsilane (8,88 ml 70,00 mmol). The mixture is stirred under heating for 30 minutes dropwise at 60°C, add a solution of 3-chloro-2-ftorangidridy (406,73 g, 1.82 mol) in tetrahydrofuran (700 ml). The mixture is stirred under heating for 1 hour, obtaining a solution of bromide 3-chloro-2-forbindelsen.

(Main stage)

The crude product (834,02 g), obtained in stage 3, is dissolved in tetrahydrofurane (1060 ml) and add dichlorobis(triphenylphosphine)palladium(II) (19,65 g 28,00 mmol) in a stream of argon, and added dropwise at 60°C, add a solution of bromide 3-chloro-2-tormentilla (1.82 mol). After complete addition, the mixture is agreat boiling under reflux for 1.5 hours. After the mixture is allowed to cool, the reaction solution was added toluene (2120 ml) and 20% aqueous solution of ammoniaand (1410 ml), the mixture is stirred and separated. The organic layer is washed twice with 20% aqueous solution of ammoniaand (710 ml), twice with saturated aqueous sodium bicarbonate solution (710 ml) and dried over magnesium sulfate. After filtration the filtrate is concentrated under reduced pressure, obtaining the crude product (849,34 g) as a brown oil.

Stage 5

The crude product (849,34 g)obtained in stage 4, is dissolved in isopropanol (1100 ml) and add 4 N. aqueous sodium hydroxide solution (1050 ml, 4.20 mmol). The mixture is stirred under heating at 50°C for 1.5 hours To the reaction solution was added activated charcoal (37 g), and the mixture is stirred at room temperature for 30 minutes the Mixture is filtered through celite and to the filtrate add 6 N. chloride-hydrogen acid (740 ml) and ethyl acetate (3650 ml). The mixture is stirred and separated. The organic layer is concentrated under reduced pressure, and the residue is suspended in isopropanol (1070 ml). The mixture was stirred at 60°C for 1 hour. After the mixture is allowed to cool, the solid part is collected by filtration. The obtained solid is washed with isopropanol (740 ml) and dried in vacuum, obtaining the target is not already installed (446,51 g, yield 73%) as a pale yellow solid.

1H NMR (DMSO-d6400 MHz) (δ) ppm: of 0.71 (3H, d, J=6.5 Hz), of 1.13 (3H, d, J=6.5 Hz), a 2.36 (1H, usher.), of 3.77 (1H, usher.), of 3.94 (1H, usher.), of 4.25 (2H, s), of 4.77 (1H, usher.), 5,16 (1H, t, J=2.4 Hz), 7,19-of 7.23 (1H, m), 7,32-to 7.35 (1H, m), of 7.48-7,52 (1H, m), 8,24-of 8.28 (2H, m), of 9.00 (1H, s), 15,00 (1H, s).

MS(ESI): M+ 436

Stage 6

Connection (443,59 g of 1.02 mol), obtained in stage 5, is dissolved in methanol (2400 ml) and added 28% sodium methoxide in methanol (2077 ml, 10,17 mol) and water (44,30 ml of 2.46 mol). The mixture is heated at the boil under reflux for 17,5 hours To the reaction solution was added activated charcoal (22 g) and the mixture is stirred at room temperature for 1 hour. The mixture is filtered through celite, and the filtrate concentrated under reduced pressure. To the residue water is added (1770 ml), and the mixture is stirred under ice cooling for 1 hour Then add another 6 N. chloride-hydrogen acid (1790 ml), and the mixture is stirred at room temperature for 2 hours To the mixture are added ethyl acetate (1770 ml)and the mixture is separated. The organic layer is washed twice with 10% salt solution (890 ml) and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the portion of the residue is recrystallized several times (the ultimate solvent for recrystallization was a mixture of methanol in the (a), receiving target product (28,60 g, yield 67%) as a white solid.

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 0.72 (3H, d, J=6.5 Hz), of 1.16 (3H, d, J=6.5 Hz), 2,30-of 2.50 (1H, m), 3,70-are 3.90 (1H, m), 3,90-4,00 (1H, m), a 4.03 (3H, s), of 4.12 (2H, s), 4.80 to the 4.90 (1H, m), 5,19 (1H, t, J=5,2 Hz), 7,19-7,25 (2H, m), 7,46-7,51 (2H, m), of 8.04 (1H, s), 8,88 (1H, s), 15,44 (1H, s).

MS (ESI): M+ 448

EXAMPLE 4-33

Stage 1

2,4-differentyou acid (600,00 g of 3.80 mol) is dissolved in concentrated sulfuric acid (2400 ml) and portions at 5°C or below add N-jodatime (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 (approximately 10 l) and add 10% aqueous solution of sodium sulfite (40 ml). The mixture is stirred for 30 minutes the Precipitate is collected by filtration. The suspension in water (approximately 3 l) and filtered again up until the pH of the filtrate becomes not less than 3. The obtained wet solid product (1677) is recrystallized from 50% aqueous ethanol (3000 ml)to give the target product (824,70 g, yield 76%) as a white solid.

1H NMR (CDCl3300 MHz) (δ) ppm: 6,94 (1H, DD, J=10,3, 10,3 Hz), 8,46 (1H, d, J=7.5 Hz).

Stage 2

Connection (150,00 g of 0.53 mol), obtained in stage 1, dissolved in ethyl acetate (750 ml) and add the ACS is Lillard (51,0 ml, 0,581 mol) and dimethylformamide (catalytic amount). The mixture is stirred at room temperature for 3.5 hours After filtering the reaction solution, the filtrate is concentrated under reduced pressure. Then the residue is dissolved in toluene (150 ml), the mixture is concentrated under reduced pressure and the process is repeated again. Tetrahydrofuran (300 ml) added to dissolve the residue, and the resulting solution is added dropwise to a solution of ethyl 3,3-diethylaminoacetate (83,2 g, 0,581 mol) and triethylamine (96 ml, China 0,686 mol) in tetrahydrofuran (450 ml). The mixture is heated at the boil under reflux for 15 hours After mixture is allowed to cool, the reaction mixture is filtered, and the filtrate concentrated under reduced pressure. Add ethyl acetate (750 ml)to dissolve the residue. The mixture is washed successively water ammoniacloridegas (400 ml), saturated aqueous sodium bicarbonate (200 ml) and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure to give crude desired compound (206,50 g) as a brown oil.

Stage 3

The crude product (206,50 g)obtained in stage 2, was dissolved in tetrahydrofuran (800 ml) and add hydrochloride (S)-(+)-tert-leucinol (81,10 g of 0.53 mol) and triethylamine (74 ml of 0.53 mol). CME is ü stirred at room temperature for 50 minutes After filtration of the reaction mixture, the filtrate is concentrated under reduced pressure and the resulting residue is dissolved in dimethylformamide (1000 ml). Add potassium carbonate (146,0 g, 1.06 mol), and the mixture is stirred under heating at 90°C for 3 hours Under ice cooling to the reaction mixture are added water (700 ml) and the precipitate collected by filtration and washed with water. Collected by filtration the solid part is suspended in 30% aqueous ethanol (1000 ml) and collected by filtration. This operation is repeated, using a mixture of hexane:diethyl ether=1:1. After filtration, the filtrate is dried in vacuum, obtaining the target product (184,74 g, yield 76%) as a white solid.

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,968 (9H, s)of 1.27 (3H, t), 3,96-3,98 (2H, m), 4,18-4,27 (2H, m), 4,80 (1H, t, J=7.0 Hz), of 5.05 (1H, usher.), by 8.22 (1H, d, J=11.2 Hz), at 8.60 (1H, s), 8,61 (1H, d, J=7,2 Hz).

Stage 4

Connection (150,00 g, 0.33 mol) obtained in stage 3, was dissolved in dimethylformamide (600 ml) and added imidazole (28,80 g, 0.42 mol) and tert-butyldimethylsilyl (28,80 g, 0.42 mol). The mixture is stirred at room temperature for 6 hours To the reaction mixture are added water (1200 ml) and the mixture extracted with ethyl acetate (800 ml). The organic layer is washed three times with water, then with saturated salt solution and dried over sodium sulfate. After filtration the filtrate con is intronaut under reduced pressure, and the resulting residue purified by chromatography on silica gel (ethyl acetate:hexane=1:3 to 1:2)to give the target product (164,30 g, yield 88%) as an amorphous substance of white color.

1H NMR (CDCl3300 MHz) (δ) ppm: -0,08 (3H, s)0,00 (3H, s)to 0.67 (9H, s)of 1.06 (9H, s)of 1.41 (3H, t, J=7,1 Hz), 4,05-4,18 (2H, m), 4,36-4,43 (3H, m), 7,32 (1H, d, J=10.3 Hz), 8,65 (1H, s), of 8.95 (1H, d, J=7,4 Hz).

Stage 5

Connection (75,0 g, 0.13 mol) obtained in stage 4, was dissolved in tetrahydrofuran (580 ml). In a stream of argon added bis(dibenzylideneacetone)palladium(0) (2,99 g, 5,20 mmol) and three(2-furyl)phosphine (2,41 g, 10,38 mmol)and dropwise at 60°add a solution of bromide 3-chloro-2-tormentilla (to 0.17 mol) in tetrahydrofuran. After complete addition, the mixture is heated at the boil under reflux for 2 hours After mixture is allowed to cool, the reaction solution was added ethyl acetate (75 ml) and saturated aqueous solution of ammoniaand (38 ml). The mixture is stirred at room temperature for 30 min and separated. The organic layer is washed twice with water (75 ml) and then with saturated salt solution (200 ml) and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue purified by chromatography on silica gel (ethyl acetate:hexane=1:2 to 1:1), obtaining the target product (66,80 g, yield 73%) as brown, the CSOs amorphous substance.

1H NMR (CDCl3300 MHz) (δ) ppm: -0,10 (3H, s)-0,01 (3H, s), 0,64 (9H, s)of 1.06 (9H, s)of 1.40 (3H, t, J=7,1 Hz), 4.04 the-4,15 (4H, m), 4,35-to 4.46 (3H, m), 6,95-7,03 (2H, m), 7.24 to 7,31 (2H, m), scored 8.38 (1H, d, J=8,8 Hz), 8,66 (1H, s).

Stage 6

Connection (2,41 g, 4.07 mmol), obtained in stage 5, is dissolved in methanol (20 ml) and added 28% sodium methoxide in methanol (8,4 ml, 40,70 mmol) and water (0.15 ml, 8,14 mmol). The mixture is heated at the boil under reflux for 18 hours To the reaction solution was added water (1.4 ml), the mixture is stirred at room temperature for 1.5 h and filtered using celite. The filtrate is concentrated under reduced pressure and to the residue is added water (25 ml) and 2 N. chloride-hydrogen acid (20 ml). The mixture is stirred for 5 min and extracted with ethyl acetate. The organic layer is washed with water and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure. The residue is treated with ultrasound in hexane (20 ml), and after maturation hexane is removed by decantation. This procedure was repeated three times. To the residue is added diethyl ether (30 ml)and the mixture is treated with ultrasound. The hard part is collected by filtration, and the obtained solid substance was dissolved by heating in ethyl acetate (15 ml). Add hexane (15 ml), and precrystallization target product (1,21 g, yield 64%) as a white solid.

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,99 (9H, s), 3,99-4,11 (7H, m), 5,11-5,20 (2H, m), 7,19-of 7.25 (2H, m), 7,49-7,52 (2H, m), 8,03 (1H, s), 8,78 (1H, s), 15,39 (1H, s).

MS(ESI): M+ 462

EXAMPLE 4-37

Stage 1

3-Methoxy-2-nitrobenzoic acid (20,00 g, 0.10 mol) is dissolved in dimethylformamide (100 ml) and add potassium carbonate (28,10 g, 0.20 mol) and methyliodide (7,60 ml, 0.12 mol). The mixture is stirred at room temperature for 1 h, the Reaction mixture was added to water (300 ml) and the mixture is stirred. The precipitate is collected by filtration, washed with water (200 ml) and dried in vacuum to give crude desired compound (23,90 g) as a white solid.

Stage 2

The crude product (23,90 g)obtained in stage 1, are suspended in a mixture of tetrahydrofuran (150 ml) and methanol (50 ml) and add 5% palladium-on-coal (wet) (2.30 g). The mixture is stirred in hydrogen atmosphere at room temperature for a period of 19.5 hours To the reaction mixture are added ethyl acetate (200 ml)and the mixture was filtered using celite. The filtrate is concentrated under reduced pressure, water is removed by azeotropic distillation with toluene, obtaining the crude product (18,80 g) as a brown oil.

Stage 3

The crude product (18,80 g), the floor is built in stage 2, dissolved in dimethylformamide (200 ml) and portions, at 5°add N-bromosuccinimide (17,98 g, 0.10 mol). After complete addition, the mixture was stirred at the same temperature for 30 minutes, the Reaction mixture was poured into water (500 ml) and extracted twice with ethyl acetate (300 ml). The organic layer is washed successively with water (300 ml), saturated aqueous sodium bicarbonate 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 (chloroform)to give the target product (25,11 g, yield 95%) as a yellow oil.

1H NMR (CDCl3300 MHz) (δ) ppm: 3,86 (6H, s), of 6.02 (2H, users), of 6.90 (1H, s), 7,60 (1H, s).

Stage 4

Connection (25,11 g, 96,54 mmol), obtained in stage 3, is suspended in water (50 ml) and add concentrated chloride-hydrogen acid (25 ml). Dropwise, at 5°C added an aqueous solution (100 ml) of sodium nitrite (7,33 g, 106,22 mmol). After complete addition, the mixture was stirred at the same temperature for 5 minutes the Reaction solution is added dropwise to a solution of copper chloride(I) (of 9.55 g, 96,47 mmol) in concentrated chloride-hydrogen acid (75 ml) at room temperature. After complete addition, the mixture is stirred pikantnoi temperature for 13 hours To the reaction solution was added water (200 ml)and the mixture extracted with ethyl acetate (400 ml). The organic layer is washed successively with water (400 ml) and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, obtaining the target product (15,18 g, yield 56%) of orange solid.

1H NMR (CDCl3300 MHz) (δ) ppm: to 3.92 (3H, s), 3,93 (3H, s), 7,16 (1H, d, J=2.1 Hz), 7,49 (1H, d, J=2.2 Hz).

Stage 5

Connection (74,80 g, 0.27 mol), obtained in stage 4, was dissolved in dichloromethane (300 ml) and added dropwise at 10°C or below was added 1 M solution trichromate boron in dichloromethane (700 ml, 0.70 mol). After complete addition, the mixture is stirred at room temperature for 1.5 hours the Reaction mixture was added to ice water (1500 ml)and the solid precipitate collected by filtration. The filtrate is separated and the aqueous layer was extracted with ethyl acetate (200 ml). The organic layers are combined and concentrated under reduced pressure. The hard part is collected by filtration, the residue is dissolved in diethyl ether (1000 ml) and extraction to add 1 N. aqueous sodium hydroxide solution (1000 ml). To the aqueous layer add 2 N. chloride-hydrogen acid (500 ml). The mixture is stirred and extracted with ethyl acetate (800 ml). The mixture was separated, the organic layer is washed successively with water and saturated salt solution, dried over sodium sulfate, filtered and concentrated under reduced pressure, obtaining the target product (63,83 g, yield 95%) as a beige solid.

1H NMR (DMSO-d6300 MHz) (δ) ppm: 7.23 percent (1H, d, J=2.4 Hz), 7,28 (1H, d, J=2.4 Hz), 10,99 (1H, s), 13,55 (1H, users).

Stage 6

Connection (63,83 g, 0.25 mol), obtained in stage 5, is dissolved in dimethylformamide (400 ml) and add potassium carbonate (87,70 g, 0.64 mol) and ethyliodide (81,20 ml of 1.02 mol). The mixture is stirred under heating at 50°C for 3 h, and the reaction mixture is added saturated aqueous solution of ammoniaand (600 ml) and ethyl acetate (400 ml). The mixture is separated, and the aqueous layer was extracted with ethyl acetate (400 ml). The organic layers are combined, washed successively with a solution of salt (three times) and saturated salt solution, dried over sodium sulfate, filtered and concentrated under reduced pressure, obtaining the target product (76,38 g, yield 98%) as a brown solid.

1H NMR (CDCl3400 MHz) (δ) ppm: of 1.39 (3H, t, J=7.2 Hz), to 1.48 (3H, t), 4,11 (2H, square), to 4.38 (2H, square, J=7,2 Hz), 7,12 (1H, d, J=2.0 Hz), 7,42 (1H, d, J=2.0 Hz).

Stage 7

Connection (76,38 g, 0.25 mol), obtained in stage 6, is dissolved in ethanol (250 ml) and add 8 N. aqueous sodium hydroxide solution (62,00 ml, 0.50 mol). The mixture was stirred at heat is assured at 50° C for 30 minutes To the reaction solution while cooling with ice add 2 N. chloride-hydrogen acid (250 ml), the mixture is stirred and extracted twice with ethyl acetate (350 ml). The organic layer is washed successively with water and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure, obtaining the target product (68,79 g, yield 99%) as a pale brown solid.

1H NMR (CDCl3400 MHz) (δ) ppm: 1.50 in (3H, t, J=6.8 Hz), of 4.12 (2H, square, J=6,8 Hz), 7,19 (1H, d, J=2.4 Hz), the 7.65 (1H, d, J=2,4 Hz).

Stage 8

Connection (85,17 g, 0.31 mol), obtained in stage 7, is dissolved in toluene (450 ml) and added dropwise thionyl chloride (44,40 ml, 0.61 mol) and dimethylformamide (catalytic amount). The mixture was stirred at 90°C for 1 hour. After the mixture is allowed to cool, the reaction solution is concentrated under reduced pressure. Then the residue is dissolved in toluene, the mixture is concentrated under reduced pressure. This procedure is repeated twice or more times. The residue is dissolved in tetrahydrofuran (250 ml)and the resulting solution was added dropwise to a solution of ethyl 3,3-diethylaminoacetate (43,60 g, 0.31 mol) and triethylamine (50,90 ml of 0.37 mol) in tetrahydrofuran (200 ml). The mixture is heated at boiling under reflux in the course is e 15 o'clock After the mixture is allowed to cool, to the reaction mixture are added water (300 ml) and ethyl acetate (500 ml). The mixture is stirred and separated. The organic layer is washed successively with water (300 ml) and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure to give crude desired compound (124,80 g) as a brown oil.

Stage 9

The crude product (124,80 g)obtained in stage 8, was dissolved in tetrahydrofuran (500 ml) and add hydrochloride (S)-(+)-tert-leucinol (46,80 g, 0.31 mol) and triethylamine (42,50 ml, 0.31 mol). The mixture is stirred at room temperature for 40 minutes After filtration of the reaction mixture, the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in ethyl acetate (800 ml), washed twice with water, then with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure to give crude desired compound (131,30 g) as a brown oil.

Stage 10

The crude product (131,30 g)obtained in stage 9, is dissolved in dimethylformamide (400 ml) and added imidazole (27,00 g, 0.40 mol) and tert-butyldimethylsilyl (41,30 g, 0.27 mol). The mixture is stirred at room temperature is within 14 PM To the reaction solution was added water and the mixture extracted twice with ethyl acetate (500 ml). The organic layer is washed three times with water and then with saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure to give crude desired compound (159,80 g) as a brown oil.

Stage 11

The crude product (159,80 g)obtained in stage 10, is dissolved in toluene (1100 ml) and add sodium hydride (15,80 g, 0.40 mol). The mixture is stirred under heating at 100°C for 14 hours To the reaction solution was added with ice cooling 1 N. chloride-hydrogen acid (400 ml), the mixture is stirred and separated. The organic layer is washed successively with water and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and the resulting residue is dissolved in dimethylformamide (500 ml). Add potassium carbonate (42,10 g, 0.31 mol) and ethyliodide (24,40 ml, 0.31 mol), and the mixture is stirred under heating at 50°C for 1.5 hours To the reaction solution while cooling with ice, add saturated aqueous solution of ammoniaand (400 ml), the mixture is stirred and extracted twice with ethyl acetate. The organic layer is washed successively with water, twice with a solution of salt and saturated the 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 (ethyl acetate:hexane=1:3 to 2:3)to give the target product (76,50 g, yield 45%) as a brown oil.

1H NMR (CDCl3400 MHz) (δ) ppm: -0,05 (3H, s), of 0.01 (3H, s)to 0.73 (9H, s), and 0.98 (9H, s)of 1.40 (3H, t), 1,53-to 1.59 (3H, m), 4,10-4,24 (4H, m), 4,34-of 4.44 (2H, m), 6,10-6,14 (1H, m), 7,22 (1H, s), 8,32 (1H, t, J=2,4 Hz), to 8.70 (1H, s).

Stage 12

Connection (76,50 g, 0.14 mol), obtained in stage 11, is dissolved in tetrahydrofuran (500 ml) and in a stream of argon added bis(dibenzylideneacetone)palladium(0) (3,17 g, 5.51 mmol) and three(2-furyl)phosphine (2,56 g, 11,03 mmol). Dropwise at 60°add a solution of bromide 3-chloro-2-tormentilla (0.28 mol) in tetrahydrofuran. After complete addition, the mixture is heated at the boil under reflux for 2.5 hours After mixture is allowed to cool, the reaction solution was added saturated aqueous solution of ammoniaand (600 ml). The mixture is stirred at room temperature for 1 hour and filtered using celite. The mixture is then separated, the aqueous layer was extracted twice with ethyl acetate. On the other hand, the organic layer is concentrated under reduced pressure, and the residue is dissolved in ethyl acetate. All an ethyl acetate layers are combined and washed successively 1 N. chloride-water is one acid and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure. The resulting residue is dissolved in dimethylformamide (400 ml) and add potassium carbonate (19,00 g, 0.14 mol) and ethyliodide (11,00 ml, 0.14 mol). The mixture is stirred under heating at 50°C for 1.5 hours To the reaction mixture while cooling with ice, add saturated aqueous solution of ammoniaand (400 ml), the mixture is stirred and extracted with ethyl acetate (500 ml). The organic layer was washed with water, salt solution (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 (ethyl acetate:hexane=1:2 to 1:1), obtaining the target product (72,10 g, yield 85%) as a brown oil.

1H NMR (CDCl3400 MHz) (δ) ppm: -0,07 (3H, s)0,00 (3H, s), 0,70 (9H, s)of 1.24 (9H, s)of 1.39 (3H, t, J=7.2 Hz), 1,51-and 1.54 (3H, m), of 4.05 (2H, s), 4,07-4,19 (4H, m), 4,33 is 4.45 (2H, m), 6,12-x 6.15 (1H, m), 6,99-7,02 (2H, m),? 7.04 baby mortality-to 7.09 (1H, m), 7,19-of 7.25 (1H, m), of 8.06 (1H, d, J=2.4 Hz), 8,69 (1H, s).

Stage 13

Connection (65,80 g, 0.11 mol), obtained in stage 12, is dissolved in ethanol (200 ml) and add 1 N. aqueous sodium hydroxide solution (640 ml, 0.64 mol). The mixture is heated at the boil under reflux for 2 hours To the reaction solution while cooling with ice add 2 N. chloride-hydrogen acid (350 m is), the mixture is stirred and extracted twice with ethyl acetate. The organic layer is washed successively with water and saturated salt solution and dried over sodium sulfate. After filtration the filtrate is concentrated under reduced pressure and to the residue is added diethyl ether (500 ml). The mixture is treated with ultrasound, the obtained solid is collected by filtration. Collected solid is added to ethyl acetate (250 ml) and dissolved by heating. Add hexane (50 ml), and precipitated precipitated solid is collected by filtration and dried in vacuum, obtaining the target product (41,10 g, yield 81%) as a white solid.

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,93 (9H, s), for 1.49 (3H, t, J=6.9 Hz), of 4.00 (2H, t, J=6.4 Hz), 4,20 (2H, s), 4,22-to 4.33 (2H, m), 5,12 (1H, t), 6,36 (1H, t, J=6.8 Hz), 7,21 (1H, m), 7,39-of 7.48 (2H, m), 7,54 (1H, s), 7,79 (1H, s), 8,79 (1H, s), 15,04 (1H, s).

MS (ESI): M+ 476

Examples (1-3)-(1-102), (2-1)to(2-8), (3-1)to(3-86), (4-1)-(4-54)

By way of examples 1-1 and 1-2 and the above examples, get connection examples (1-3)-(1-102), (2-1)to(2-8), (3-1)to(3-86) and (4-1)to(4-54). Their chemical structures are presented in tables 1, 2, 3 and 4.

Experimental examples

The article below explains the methodology for assessing the activity of the compounds of the present invention in relation to the inhibition of HIV integrase.

(i) Construction of expression system, recombinant integrase gene

185th vanilla is in full length gene of HIV integrase (J. Virol., 67, 425-437 (1993)) is replaced by histidine and embed in sites NdeI and XhoI restriction enzyme plasmid pET21a(+) (Novagen), resulting in a gain vector of the expression of the 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), cultivated with shaking at 30°C in liquid medium containing ampicillin. When the culture reaches the logarithmic phase of growth, add isopropyl-β-D-thiogalactopyranoside for promotion of the expression of the integrase gene. Cultivation continued for 3 h for promotion accumulation of protein integrase. Recombinant E. coli collected in a sediment separation using centrifugation and stored at -80°C.

E. coli suspended in Lisina buffer (20 mm HEPES (pH 7.5), 5 mm DTT, 10 mm CHAPS, 10% glycerol)containing 1 M sodium chloride, is subjected to cyclical effects of high/low pressure to divide, and divide by centrifugation at 4°C, 40000×g, 60 min for separation of water-soluble fraction (supernatant). It is diluted tenfold Lisinym buffer that does not contain sodium chloride, mixed with SP-Sepharose (Pharmacia Corporation) and stirred at 4°C for 60 min to ensure the adsorption of protein integrase on the resin. The resin is washed Lisinym buffer containing 100 mm chloride is the atrium, and protein integrase elute Lisinym buffer containing 1 M sodium chloride.

The solution lirovannomu protein integrase enter in column Superdex 75 (Pharmacia Corporation) to perform gel filtration. Protein elute Lisinym buffer containing 1 M sodium chloride.

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

(iii) Obtaining DNA solution

Following DNA synthesized according to the method Greiner, dissolved in TE buffer (10 mm Tris-chloride-hydrogen acid (pH 8.0), 1 mm EDTA) and mixed with donor DNA, micheneau DNA, each complementary chain (+ and - chain) to 1 μm. The mixture is heated at 95°C for 5 min, 80°C for 10 min, 70°C for 10 min, 60°C for 10 min, 50°C for 10 min and 40°C for 10 min and stored at 25°C, getting double-stranded DNA, which is used for testing.

Donor DNA (-chain containing the Biotin attached to the 5'-end)

Donor+chain: 5'-Biotin-ACC CTT TTA GTC AGT GTG GAA AAT CTC TAG CA-3' (sequence ID NO:1)

Donor-chain: 5'-ACT GCT AGA GAT TTT CCA CAC TGA CTA AAA G-3' (sequence ID NO:2)

Misheneva DNA (+,-chain, and both contain digoxigenin attached to the 3'-end)

Target+chain: 5'-TGA CCA AGG GCT AAT TCA CT-Dig-3' (sequence ID NO:3)

Target-chain: 5'-AGT GAA TTA GCC CTT GGT CA-Dig-3' (sequence ID NO:4)

(iv) Determining induruwa activity of the enzyme (HIV integrase)

The donor DNA is diluted TE buffer to 10 nm, of which 50 μl added to each microtiter wells tablet (Roche), coated with streptavidin, and allowed to adsorb at 37°C for 60 min the DNA was washed with phosphate buffer (Dulbecco PBS, Sanko Junyaku Co., Ltd.), containing 0.1% Tween 20 and phosphate buffer. Then the reaction mixture (70 µl) of the following composition, diluted reaction mixture of the test substance (10 μl) and 100 μg/ml protein integrase (10 μl) is added to each of the wells and allowed to react at 37°C for 60 minutes

Then add 50 nm mistaway DNA (10 ál), left to react at 37°C for 10 min and washed with phosphate buffer containing 0.1% Tween 20 for stopping the reaction.

Then add a solution of 100 Miu/ml of peroxidase labelled anti-digoxigenin antibody (Roche, 100 μl)and the mixture is left to react at 37°C for 60 min followed by rinsing with phosphate buffer containing 0.1% Tween 20.

Add colored solution of peroxidase (Bio Rad, 100 μl)and left to react at room temperature for 4 minutes Color reaction is stopped by adding 1 N. sulfuric acid (100 μl). Measure the absorbance at 450 nm.

The activity of inhibiting HIV integrase compound of the present invention (IR50) calculated on the basis of the degree of inhibition is calculated according to the following formula the Results are presented in tables 5, 6 and 7.

The degree of inhibition(%)=[1-(object-negative control)/(control-negative control)]×100

Object; the absorption of the wells in the presence of test compounds

Control; the absorption of the wells in the absence of the test compound

The negative control; the absorption of the wells in the absence of the test compound, in the absence of protein integrase

Evaluation of antiviral activity

The effect of the combined use of the compounds of the present invention in conjunction with known anti-HIV agents can be defined as follows.

For example, the effect arising from the application of two drugs, nucleoside reverse transcriptase inhibitors (zidovudine, lamivudine, tenofovir), non-nucleoside reverse transcriptase inhibitor (efavirenz) or protease inhibitor (indinavir, nelfinavir) and A test substance, and the like, appreciate in astrointestinal system using HIV-1 IIIB-infected CEM-SS cells by way Templ.

In addition, evaluate the effect of three drugs when applying A test substance, zidovudine and lamivudine, or A test substance, tenofovir and lamivudine, etc.

Before the test the combined application define IR50and CC50each pharmaceutical agent separately. The effect of two drugs is evaluated on the basis Combi the purpose of the five concentrations of the pharmaceutical agent and nine concentrations of the pharmaceutical agent, that have been defined on the basis of the above results. For the case of three drugs a high concentration of pharmaceutical agent and a pharmaceutical agent are mixed and the obtained concentrations combined with the concentration of the pharmaceutical agent for A valuation.

The experimental results for the test substance and a pharmaceutical agent that combine in the case of separate application and combined application, analyze, using programs Prichard and Shipman MacSynergy II version 2.01 and Delta graph version 1.5d. Three-dimensional graph built for 95% (or 68%, 99%) confidence level, using the percentage of inhibition at a concentration of each of the combined pharmaceutical agents, which are obtained from experiments in three repetitions, and the effect of the combined application assessed on the basis of the calculated from its numerical values µm2%. The evaluation criteria is presented below.

Defining interactionμm2%
A high degree of synergy>100
The low degree of synergy+51 to +100
Additivity+50 to -50
The low degree of antagonism-51 to -100
High is the degree of antagonism <-100

Table 1

Table 2

Table 3

Table 4

4-534-54

Table 5

approx. No.Activity by inhibition of the enzyme(HIV integrase), IR50(µm)approx. No.Activity by inhibition of the enzyme(HIV online is Graz), IR50(µm)
1-10,0291-20,033
1-30,361-40,24
1-60,141-70,067
1-80,0461-90,017
1-100,0721-110,18
1-120,711-130,14
1-140,0751-150,23
1-16to 0.0321-170,084
1-180,121-19of 0.081
1-200,691-210,074
1-220,111-230,19
1-240,291-250,16
1-260,181-270,076
1-280,0591-290,24
1-300,141-310,17
1-320,0681-330,14
1-340,351-360,18
1-370,111-380,17
1-390,181-400,11
1-410,211-420,13
1-430,0241-440,051
1-450,211-460,42
1-470,0981-480,38
1-490,0531-500,11
1-510,181-630,02
1-640,0561-650,12
1-660,0491-670,79
1-680,0491-690,074
1-700,0821-710,013
1-720,0251-730,031
1-740,0981-750,016
1-760,0281-770,063
1-780,591-790,077
1-800,351-860,15
1-870,141-880,45
1-920,281-930,37
-96 0,231-970,13
2-10,172-20,18
2-30,112-40,018
2-50,302-60,092
2-70,0792-80,085

Table 6

approx. No.Activity by inhibition of the enzyme(HIV integrase), IR50(µm)approx. No.Activity by inhibition of the enzyme(HIV integrase), IR50(µm)
3-10,473-20,2
3-30,193-40,011
3-50,0243-60,011
3-80,343-90,084
3-100,0183-120,016
3-130,0293-140,014
3-170,0133-200,01
3-210,033-220,79
3-230,00723-240,039
3-250,0693-2 0,011
3-270,0753-330,0087
3-340,0113-350,011
3-360,0513-370,011
3-380,0153-390,049
3-420,723-430,018
3-440,00963-450,015
3-470,00863-480,021
3-490,00793-500,018
3-520,0123-530,0079
3-540,00643-550,0087
3-560,0123-570,015
358 for0,0083-590,008
3-600,00553-610,0076
3-620,0273-630,017
3-640,0183-650,015
3-660,0483-670,0064
3-690,00433-720,0038
3-730,00333-7 0,0049
3-760,00853-770,0089
3-780,0163-790,0067
3-800,00883-860,14

Table 7

approx. No.Activity by inhibition of the enzyme(HIV integrase), IR50(µm)approx. No.Activity by inhibition of the enzyme(HIV integrase), IR50(μm) )
4-10,864-40,55
4-50,134-60,46
4-70,134-80,033
4-90,0214-110,22
4-120,0654-130,30
4-150,0314-160,0071
4-170,00314-180,0020
4-190,00294-200,0017
4-210,00454-220,0029
4-230,00384-240,0025
4-250,00194-260,015
4-270,00294-280,0027
4-290,00454-300,0029
4-310,00214-320,0029
4-330,00204-340,0039
4-350,00434-360,0037
4-370,00194-380,0033
4-390,00414-400,0043
4-410,00234-420,0023
4-430,00284-440,0024
4-450,00344-460,0050
About 4-470,00234-480,0030
4-490,00574-500,0031

Below are the results of NMR and mass spectra of examples of the compounds shown in tables 1-4:

Example 1-1

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,75 (2H, t, J=4,7 Hz), 4,36 (2H, s), 4,60 (2H, t, J=4,8 Hz), to 4.98 (1H, users), 7,37-7,39 (1H, m), 7,45 (1H, DD, J=1,4, and 7.6 Hz), EUR 7.57 (1H, DD, J=1.5 and 8.0 Hz), 7,81 (1H, DD, J=2.1 a, a 8.9 Hz), 8,02 (1H, d, J=8,8 Hz), 8,15 (1H, d, J=1,8 Hz), 8,86 (1H, s), 15,18 (1H, users).

MS (ESI): M+ 392

Example 1-2

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 3.78 (2H, m), 4,35 (2H, s), with 4.64 (2H, m)5,00 (1H, m), 7,39 (2H, m), 7,47 (1H, m), 7,58 (1H, m), 8,00 (1H, m), 8,81 (1H, s), 14,80 (1H, s).

MS (ESI): M+409

Example 1-3

1H NMR (DMSO-d6400 MHz) (δ) ppm: 2,85 (3H, s)to 3.41 (2H, m), 4,37 (2H, s), 4,63 (2H, t, J=5.6 Hz), 7,25-7,29 (1H, m), 7,39 (1H, DD, J=7,8, and 7.8 Hz), 7,47 (1H, DD, J=1.5 and 7.7 Hz), 7,58 (1H, DD, J=1.5 and 7.8 Hz), to 7.84 (1H, DD, J=2,0, a 8.9 Hz), 8,00 (1H, d, J=8,9 Hz), 8,15 (1H, d, J=1,8 Hz), 8,91 (1H, s).

MS (ESI): M+ 469

Example 1-4

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 4.38 (2H, s), to 4.46 (2H, t, J=5,9 Hz), the 4.90 (2H, t, J=5,9 Hz), at 6.84 (1H, s), 7,14 (1H, s), 7,37-7,47 (3H, m), to 7.59 (1H, m), 7,82 (1H, m), 8,01 (1H, m), 8,15 (1H, s), 8,66 (1H, s), 14,99 (1H, s).

MS (ESI): M+441

Example 1-5

1H NMR (DMSO-d6300 MHz) (δ) ppm: 2,87 (3H, s), of 3.12 (3H, s), 4,35 (2H, s)5,59 (2H, s), 7,38 was 7.45 (2H, m), EUR 7.57 (1H, m), 7,71-7,76 (2H, m)to 8.12 (1H, s), to 8.94 (1H, s).

MS (ESI): M+432

Example 1-6

1H NMR (DMSO-d6300 MHz) (δ) ppm: 2,64 (3H, d, J=4,4), 4,35 (2H, s), of 5.24 (2H, s), 7,35-7,47 (2H, m), 7,56-the 7.65 (2H, m), 7,80 (1H, m), 8,13 (1H, s), 8,32 (1H, square, J=4.4 Hz), of 9.00 (1H, s).

MS (ESI): M+418

Example 1-7

1H NMR (DMSO-d6300 MHz) (δ) ppm: 4,36 (2H, s), 5,23 (2H, s), 7,35-7,45 (2H, m), 7,54-the 7.65 (3H, m), 7,83-7,88 (2H, m), 8,13 (1H, s), 9,01 (1H, s).

MS (ESI): M+404

Example 1-8

1H NMR (DMSO-d6300 MHz) (δ) ppm: 1.57 in (6H, d, J=6.5 Hz), 4,37 (2H, s), of 5.24 (1H, m), 7,38 (1H, DD, J=7,7, 7,7 Hz) 7,46 (1H, DD, J=1,6, 7,7 Hz), 7,58 (1H, DD, J=1,6, 7,7 Hz), the 7.85 (1H, DD, J=2.1 a, a 8.9 Hz), 8,15-8,18 (2H, m), 8,86 (1H, s).

MS (ESI): M+389

Example 1-9

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 4.35 (2H, s), 5,98 (2H, s), 7,37-7,44 (4H, m), EUR 7.57 (H, m), 7,83 (1H, m), 8,10-to 8.12 (2H, m), 8,99 (1H, s).

MS (ESI): M+440

Example 1-10

1H NMR (DMSO-d6300 MHz) (δ) ppm: 2,85 (2H, m), 4,36 (2H, s), 4,74 (2H, m), 7,38-7,46 (2H, m), 7,58 (1H, m), a 7.85 (1H, m), 8,00 (1H, m)to 8.14 (1H, s), of 9.00 (1H, s).

MS (ESI): M+419

Example 1-11

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,74 (2H, dt, J=4,8, and 5.6 Hz), 4,59 (2H, t, J=4.9 Hz), of 4.66 (2H, s), to 4.98 (1H, t, J=5.6 Hz), of 7.48-7,53 (4H, m), a 7.85-8,08 (5H, m), 8,18 (1H, m), 8,83 (1H, s)15,24 (1H, users).

MS (ESI): M+373

Example 1-12

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,70 (2H, m), and 3.72 (3H, s), 4,27 (2H, s), to 4.38 (2H, m), 4,96 (1H, usher.), 7,32-7,41 (2H, m), 7,54 (1H, DD, J=1,8, 7,3 Hz), to 7.61 (1H, DD, J=2,2, 8,8 Hz), 7,76 (1H, d, J=8,8 Hz), 8,00 (1H, d, J=2.2 Hz), 8,55 (1H, s).

MS (ESI): M+405

Example 1-13

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 2.67 (2H, m), 4,37 (2H, s), to 4.73 (2H, m), 6,97 (1H, usher.), 7,38-of 7.48 (3H, m), 7,58 (1H, m), 7,87 (1H, m), 8,01 (1H, m), 8,15 (1H, s), 8,93 (1H, s).

MS (ESI): M+418

Example 1-14

1H NMR (DMSO-d6400 MHz) (δ) ppm: 2,30 (3H, s), 4,34 (2H, s), 5,62 (2H, s), 7,37 (1H, m), 7,44 (1H, m), 7,55 (1H, m), 7,72 for 7.78 (2H, m), 8,10 (1H, s), of 8.90 (1H, s).

MS (ESI): M+403

Example 1-15

1H NMR (DMSO-d6300 MHz) (δ) ppm: or 4.31 (2H, s), of 5.84 (2H, s), 7,26-7,41 (7H, m), 7,55 (1H, m), 7,73 (1H, m), 7,83 (1H, m), 8,13 (1H, m), 9,23 (1H, s), 15,18 (1H, users).

MS (ESI): M+437

Example 1-16

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,12 (2H, t, J=7,3 Hz), to 4.38 (2H, s), 4,78 (2H, t, J=7,3 Hz), 7,20-7,28 (5H, m), 7,37-7,47 (3H, m), 7,58 (1H, m), a 7.85 (1H, m), of 8.09 (1H, m), 8,15 (1H, s), 8,79 (1H, s), 15,07 (1H, users).

MS (ESI): M+451

Example 1-17

1H NMR (DMSO-d6300 MHz) (δ) ppm: 2,13 (2H, TT, J=7,3, 7,6 Hz), 2,70 (1H, t, J=7,6 Hz), 4,36 (2H, s), 4,58 (2H, t, J=7,3 Hz), 7,15-of 7.24 (5H, m), 7,38-7,44 (3H, m), EUR 7.57 (1H, m), 7,82 (1H, m), of 7.96 (1H, m), 8,13 (1H, ), 8,98 (1H, s), 15,14 (1H, users).

MS (ESI): M+465

Example 1-18

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 0.89 (6H, d, J=6,7 Hz)of 2.16 (1H, TCEs., J=6,7, and 7.6 Hz), 4,37 (2H, s), 4,39 (2H, d, J=7,6 Hz), 7,38-7,47 (2H, m), 7,58 (1H, m), 7,83 (1H, DD, J=2,0, a 8.9 Hz), 8,02 (1H, d, J=8,9 Hz)to 8.14 (1H, d, J=2.0 Hz), 8,97 (1H, s), br15.15 (1H, users).

MS (ESI): M+403

Example 1-19

1H NMR (DMSO-d6400 MHz) (δ) ppm: 1,61-of 1.64 (2H, m), 1,76-of 1.84 (2H, m)2,60 (2H, t, J=7.5 Hz), 4,36 (2H, s), 4,56 (2H, t, J=7.2 Hz), 7,15-7,17 (3H, m), 7,22-7,24 (2H, m), 7,38-7,40 (1H, m), 7,44 (1H, m), 7,56-to 7.59 (1H, m)of 7.82 (1H, d, J=2 Hz), of 7.96 (1H, d, J=8,9 Hz)to 8.14 (1H, d, J=1,8 Hz), 9,01 (1H, s), br15.15 (1H, users).

MS (ESI): M+ 514

Example 1-20

1H NMR (DMSO-d6400 MHz) (δ) ppm: 4,28 (2H, s), 5,73 (2H, s), 7,02 (1H, d, J=7,6 Hz), 7,27-the 7.43 (11H, m), 7,55 (1H, d, J=7,6 Hz), 7,60 to 7.62 (1H, m), 8,08 (1H, d, J=1.6 Hz), of 8.92 (1H, s), 14,97 (1H, users).

MS (ESI): M+ 502

Example 1-21

1H NMR (DMSO-d6400 MHz) (δ) ppm: 1,45-1,49 (2H, m), 1,81-of 1.85 (2H, m), 3,42 (2H, t, J=6.3 Hz), 4,36 (2H, s), 4,56 (2H, t, J=7.4 Hz), 7,38 (1H, DD, J=7,7, 7,8 Hz), 7,44-7,46 (1H, m), EUR 7.57 (1H, DD, J=1,4, and 7.8 Hz), 7,83 (1H, DD, J=2.0 a, 8,8 Hz), and 8.0 (1H, d, J=8,9 Hz)to 8.14 (1H, d, J=1,8 Hz), 9,01 (1H, s), 15,18 (1H, users).

MS (ESI): M+ 420

Example 1-22

1H NMR (DMSO-d6300 MHz) (δ) ppm: 4,32 (2H, s), 6,16 (2H, s), 7,32-7,42 (4H, m), 7,51-of 7.55 (2H, m), to 7.77-7,89 (3H, m), 8,06-to 8.12 (2H, m), 9,31 (1H, s), 15,02 (1H, users).

MS (ESI): M+ 494

Example 1-23

sup> 1H NMR (DMSO-d6300 MHz) (δ) ppm: or 4.31 (2H, s), of 5.83 (2H, s), 7,19-7,21 (1H, m), 7,33-the 7.43 (2H, m), 7,54-to 7.59 (2H, m), 7.68 per-7,79 (3H, m)to 8.12 (1H, s), a 9.25 (1H, s), 15,05 (1H, users).

MS (ESI): M+ 508

Example 1-24

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 2.18 (6H, s)of 2.64 (2H, usher.), 4,36 (2H, s), 4,63 (2H, usher.), 7,38-7,40 (1H, m), 7,45 (1H, d, J=1.3 Hz), 7,56-7,58 (1H, m), to 7.84 (1H, m), of 8.00 (1H, d, J=8,9 Hz)to 8.14 (1H, d, J=1.7 Hz), of 8.90 (1H, s), br15.15 (1H, users).

MS (ESI): M+ 419

Example 1-25

1H NMR (DMSO-d6400 MHz) (δ) ppm: 1,93-to 1.98 (2H, m), of 3.45 (2H, t, J=5.6 Hz), 4,36 (2H, s), 4,59 (2H, t, J=7,0 Hz), and 4.68 (1H, usher.), 7,37 (1H, DD, J=7,7, 7,8 Hz), 7,44-7,468 (1H, m), EUR 7.57 (1H, d, J=7.8 Hz), 7,83-to 7.99 (1H, m), of 8.00 (1H, d, J=8,9 Hz)to 8.14 (1H, s), 8,96 (1H, s), 15,16 (1H, users).

MS (ESI): M+ 406

Example 1-26

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,21 (3H, s), 3,70 (2H, t, J=4,8 Hz), 4,36 (2H, s), and 4.75 (2H, t, J=4,8 Hz), 7,38 (1H, DD, J=7,7, 7,7 Hz), 7,44-7,47 (1H, m), 7,58 (1H, DD, J=1,6, 7,8 Hz), 7,83 (1H, DD, J=2.1 a, a 8.9 Hz), of 8.04 (1H, d, J=8,9 Hz)to 8.14 (1H, d, J=2.0 Hz), 8,89 (1H, s), 15,14 (1H, users).

MS (ESI): M+ 406

Example 1-27

1H NMR (DMSO-d6300 MHz) (δ) ppm: 4,36 (2H, s), of 5.68 (2H, square, J=8.7 Hz), 7,38 (1H, DD, J=7,7, 7,7 Hz), 7,46 (1H, DD, J=1,7, 7,7 Hz), 7,89 (1H, DD, J=2.1 a, a 8.9 Hz), 8,13-8,16 (2H, m), 9,11 (1H, s), 14,71 (1H, users).

MS (ESI): M+ 430

Example 1-28

1H NMR (DMSO-d6300 MHz) (δ) ppm: 4,34 (2H, s), 4,78 (2H, s), 7,34-7,44 (2H, m), 7,55-EUR 7.57 (1H, m), of 7.69 (1H, d, J=8.7 Hz), 7,76 (1H, d, J=9.0 Hz), of 8.09 (1H, s), cent to 8.85 (1H, s), shed 15.37 (1H, users).

MS (ESI): M+ 406

Example 1-29

1H NMR (DMSO-d6400 MHz) (δ) ppm: 2,04 (3H, s), 3.27 to to 3.38 (2H, is), 4,37 (2H, s), 4,78 (2H, t, J=6.8 Hz), 7,37-7,39 (1H, m), 7,45-7,47 (1H, m), 7,58-to 7.61 (1H, m), a 7.85-7,87 (1H, m), 8,03-with 8.05 (1H, m), 8,15 (1H, s), 8,73 (1H, s), 8,81 (1H, s).

MS (ESI): M+ 473

Example 1-30

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 1.20 (3H, d, J=6.2 Hz), of 3.96 (1H, usher.), 4,15-to 4.23 (1H, m), 4,36 (2H, s), 4,65-4,69 (1H, m), 5,02 (1H, usher.), 7,37 (1H, DD, J=7,7, 8.0 Hz), was 7.45 (1H, d, J=6.6 Hz), EUR 7.57 (1H, d, J=8.1 Hz), 7,81 (1H, d, J=8,8 Hz), 8,03 (1H, d, J=9.1 Hz), 8,13 (1H, s), 8,84 (1H, s).

MS (ESI): M+ 406

Example 1-31

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,75 (2H, m), 4,19 (2H, s), br4.61 (2H, m)5,00 (1H, usher.), 7,27-7,40 (4H, m), 7,86 (1H, m), 8,02 (1H, m), compared to 8.26 (1H, m), 8,86 (1H, s), 15,29 (1H, s).

MS (ESI): M+357

Example 1-32

1H NMR (DMSO-d6400 MHz) (δ) ppm: 2,10 (3H, s), 2,95 (2H, t, J=6.6 Hz), 4,37 (2H, s), was 4.76 (2H, t, J=6.6 Hz), 7,38 (1H, DD, J=7,7, 7,8 Hz), 7,45-7,47 (1H, m), 7,58 (1H, DD, J=1.5 and 7.9 Hz), of 7.90 (1H, DD, J=2,0, a 8.9 Hz), of 8.00 (1H, d, J=8,9 Hz), 8,15 (1H, d, J=1,8 Hz), of 9.02 (1H, s), 15,12 (1H, users).

MS (ESI): M+ 422

Example 1-33

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,75 (2H, s)to 4.33 (2H, s), 4,60 (2H, t, J=4,8 Hz), to 4.98 (1H, usher.), 7,30-7,33 (1H, m), 7,39-7,42 (2H, m), 7,80 (1H, DD, J=1,7, and 8.9 Hz), 8,02 (1H, d, J=8,9 Hz), of 8.09 (1H, s), cent to 8.85 (1H, s), 15,14 (1H, users).

MS (ESI): M+ 375

Example 1-34

1H NMR (DMSO-d6300 MHz) (δ) ppm: 1,33-1,44 (4H, m), 1,75-of 1.81 (2H, m), 3,36-to 3.38 (2H, m), of 4.54 (2H, t, J=7.2 Hz), 7,38 (1H, DD, J=7,7, 7,7 Hz), 7,46 (1H, d, J=6,1 Hz), EUR 7.57 (1H, d, J=7.8 Hz), 7,83 (1H, d, J=8.7 Hz), of 8.00 (1H, d, J=8,9 Hz)to 8.14 (1H, s), 9,01 (1H, s), 15,19 (1H, users).

MS (ESI): M+ 434

Example 1-35

1H NMR (DMSO-d6400 MHz) (δ) ppm: 2,33-of 2.45 (4H, usher.), 2,64 (2, t, J=6.2 Hz), 3,52 (2H, t, J=4.4 Hz), 4,27 (2H, s), and 4.40 (2H, usher.), 7,34-7,42 (2H, m), 7,55-of 7.60 (2H, m), 7,71 (1H, d, J=8.6 Hz), of 8.04 (1H, s), to 8.57 (1H, s).

MS (ESI): M+ 461

Example 1-36

1H NMR (DMSO-d6300 MHz) (δ) ppm: 4,08 (3H, s), 4,37 (2H, s), 7,37 (1H, DD, J=7,7, 7,7 Hz), 7,44-7,46 (1H, m), EUR 7.57 (1H, DD, J=1,7, and 7.8 Hz), 7,84-7,87 (1H, m), 7,92 (1H, d, J=8,8 Hz)to 8.12 (1H, s), 9,01 (1H, s), 15,20 (1H, users).

MS (ESI): M+ 362

Example 1-37

1H NMR (DMSO-d6400 MHz) (δ) ppm: of 1.41 (3H, t, J=7,1 Hz), 4,36 (2H, s), 4,58 (2H, square, J=7,1 Hz), 7,38 (1H, DD, J=7,8, 7,7 Hz), 7,44-7,46 (1H, m), EUR 7.57 (1H, DD, J=1.5 and 7.9 Hz), 7,83 (1H, DD, J=2,1, 8,8 Hz), 8,01 (1H, d, J=8,8 Hz)to 8.14 (1H, s), of 9.02 (1H, s), 15,18 (1H, users).

MS (ESI): M+ 376

Example 1-38

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 0.90 (3H, t, J=7,3 Hz), 1,77-of 1.85 (2H, m), 4,36 (2H, s), 4,51 (2H, t, J=7,3 Hz), 7,38 (1H, DD, J=7,8, and 7.6 Hz), 7,44-7,46 (1H, m), 7,58 (1H, DD, J=1,7, and 7.8 Hz), 7,83 (1H, DD, J=2,1, 8,8 Hz), 8,02 (1H, d, J=8,9 Hz)to 8.14 (1H, d, J=2.0 Hz), of 9.02 (1H, s), 15,18 (1H, users).

MS (ESI): M+ 390

Example 1-39

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 0.90 (3H, t, J=7,3 Hz), of 1.30 to 1.37 (2H, m), 1,74-to 1.79 (2H, m), 4,36 (2H, s), of 4.54 (2H, t, J=7,3 Hz), 7,38 (1H, DD, J=7,6, and 7.8 Hz), 7,46 (1H, DD, J=1,7 and 7.6 Hz), 7,58 (1H, DD, J=1,7, 7,8 Hz), 7,83 (1H, DD, J=2.1 a, a 8.9 Hz), 8,00 (1H, d, J=8,9 Hz)to 8.14 (1H, d, J=2.0 Hz), 9,01 (1H, s), 15,18 (1H, users).

MS (ESI): M+ 404

Example 1-40

1H NMR (DMSO-d6400 MHz) (δ) ppm: 1,27-of 1.29 (2H, m), 1,47 of 1.50 (2H, m), 1,59-of 1.66 (4H, m), 2,31-to 2.40 (1H, m), 4,36 (2H, s), 4,51 (2H, d, J=7,6 Hz), 7,38-7,47 (2H, m), EUR 7.57 (1H, DD, J=1.5 and 7.8 Hz), 7,82 (1H, DD, J=2.0 a, 8,8 Hz), with 8.05 (1H, d, J=8,9 Hz)to 8.14 (1H, d, J=1,8 Hz), 9,028 (1H, s), 15,16 (1H, users).

MS (ESI): M+ 430

Example 1-41

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,11 (3H, s), of 3.77 (2H, t), 4,37 (2H, s), 4,99 (2H, t), 7,35-7,41 (1H, m), 7,47 (1H, d), 7,58 (1H, d, J=7.8 Hz), 7,83-a 7.92 (2H, m), 8,16 (1H, s), 9,05 (1H, s).

MS (ESI): M+ 454

Example 1-42

1H NMR (DMSO-d6300 MHz) (δ) ppm: 1,10 (4H, usher.), 1,54-of 1.65 (4H, usher.), to 1.83 (1H, usher.), 4,36 (2H, s), and 4.40 (2H, d, J=7,4 Hz), 7,38 (1H, DD, J=7,7, 7,8 Hz), 7,45-of 7.48 (1H, m), 7,58 (1H, DD, J=1,6, 7,8 Hz), 7,81-to 7.84 (1H, m), 8,02 (1H, d, J=8,9 Hz), 8,13 (1H, s), 8,93 (1H, s), 15,17 (1H, users).

MS (ESI): M+ 444

Example 1-43

1H NMR (DMSO-d6300 MHz) (δ) ppm: 4,37 (2H, s), 4,49-4,56 (1H, m), 4,77-4,82 (1H, m), 4,91 is equal to 4.97 (1H, m), of 5.81 (1H, d, J=4,7 Hz), 7,30-760 (8H, m), 7,81 (1H, d, J=11,0 Hz), 8,08 (1H, d, J=8,9 Hz), 8,17 (1H, d), 8,93 (1H with), 15,19 (1H, users).

MS (ESI): M+ 468

Example 1-44

1H NMR (DMSO-d6300 MHz) (δ) ppm: 4,37 (2H, s), 4,72 was 4.76 (1H, m)to 4.92 (2H, t, J=4.6 Hz), 4,98-free 5.01 (1H, m), 7,38 (1H, DD, J=7,8 and 8.1 Hz), 7,44-7,46 (1H, m), 7,58 (1H, DD, J=1,6, 7.9 Hz), to 7.84 (1H, DD, J=2,1, 9.0 Hz), 8,03 (1H, d, J=9.3 Hz), 8,15 (1H, d, J=1,8 Hz), 8,78 (1H, s), 8,98 (1H, s).

MS (ESI): M+ 394

Example 1-45

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,21 (2H, usher.), 4,27 (2H, s)and 4.65 (2H, usher.), 7,20-7,28 (2H, m), 7,33-7,41 (2H, m), 7,54-of 7.70 (5H, m), to 7.77 (1H, d, J=8.7 Hz), with 8.05 (1H, s), and 8.50 (1H, s), charged 8.52 (1H, s).

MS (ESI): M+ 453

Example 1-46

1H NMR (DMSO-d6300 MHz) (δ) ppm: at 2.93 (2H, t), 4,35 (2H, s), 4,48 (2H, s), 7,38 (1H, DD, J=7,7, 7,7 Hz), was 7.45 (1H, d, J=6.2 Hz), EUR 7.57 (1H, d, J=7,7 Hz), 7,82 (1H, d), 8,02 (1H, d, J=9.1 Hz), 8,13 (1H, s)of 8.92 (1H, C).

MS (ESI): M+ 391

Example 1-47

1H NMR (DMSO-d6300 MHz) (δ)ppm: 1,13 (6H, C)of 4.35 (2H, s), 4,50 (2H, s), the 4.90 (1H, users), 7,35-7,46 (2H, m), EUR 7.57 (1H, d, J=7,7 Hz), 7,78 (1H, d, J=7,1 Hz), 8,10 (1H, s), 8,19 (1H, d, J=9.0 Hz), 8,88 (1H, s), 15,22 (1H, users).

MS (ESI): M+ 420

Example 1-48

1H NMR (DMSO-d6300 MHz) (δ) ppm: 1,68 (3H, s), of 3.46 (2H, usher.), 4,36 (2H, s), 4,56 (2H, usher.), 7,38-of 7.60 (3H, m), 7,81-8,13 (4H, m), 8,80 (1H, s).

MS (ESI): M+ 433

Example 1-49

1H NMR (DMSO-d6300 MHz) (δ) ppm: 1,00 (3H, t, J=7,0 Hz)to 3.41 (2H, usher.), is 3.82 (2H, square), 4,36 (2H, s), of 4.57 (2H, usher.), from 7.24 (1H, m), 7,38 (1H, m), 7,46 (1H, m), 7,58 (1H, m), 7,83 (1H, m), 8,03 (1H, m), 8,13 (1H, s), 8,82 (1H, s).

MS (ESI): M+ 463

Example 1-50

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,75 (2H, m), 4.26 deaths (2H, s), br4.61 (2H, t, J=4,8 Hz)to 5.00 (1H, usher.), 7,17 and 7.36 (3H, m), 7,83 (1H, DD, J=2.0 a, 8,8 Hz), 8,03 (1H, d, J=8,9 Hz), 8,21 (1H, s), 8,87 (1H, s), 15,22 (1H, users).

MS (ESI): M+ 360

Example 1-51

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,75 (2H, m), 4,28 (2H, s), br4.61 (2H, t, J=4,8 Hz)to 5.00 (1H, usher.), 7,24-7,28 (1H, m), 7,44-of 7.55 (2H, m), 7,80 (1H, DD, J=2,1, 8,8 Hz), 8,02 (1H, d, J=8,9 Hz), 8,13 (1H, d, J=1.9 Hz), 8,86 (1H, s), 15,22 (1H, s).

MS (ESI): M+ 376

Example 1-52

1H NMR (CDCl3300 MHz) (δ) ppm: to 1.42 (3H, t, J=7,1 Hz), of 4.05 (2H, s), and 4.40 (2H, square, J=7,1 Hz), to 5.35 (2H, s), 7,13-7,28 (8H, m), 7,33-to 7.35 (2H, m), to 8.41 (1H, d, J=2.0 Hz), 8,58 (1H, s).

MS (ESI): M+ 398

Example 1-53

1H NMR (CDCl3300 MHz) (δ) ppm: 4,10 (2H, s), of 5.48 (2H, s), 7,13-to 7.50 (12H, m), to 8.41 (1H, d, J=1.9 Hz), 8,87 (1H, s), 14,96 (1H, users).

MS (ESI): M+ 370

Example 1-54

1H NMR (DMSO-d6300 MHz) (δ) ppm: 4,16 (2H, s), 5,44 (2H, s), 7,19-7,34 (5H, m), and 7.4 (1H, d, J=8,8 Hz), 7,83 (1H, DD, J=2,0, a 8.9 Hz), by 8.22 (1H, d, J=1.9 Hz), the remaining 9.08 (1H, s), of 13.58 (1H, users), 15,13 (1H, users).

MS (ESI): M+ 338

Example 1-55

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 0.89 (3H, t, J=7,3 Hz), 1,25-1,35 (5H, m), of 1.66 to 1.76 (2H, m), 4.09 to (2H, s), is 4.21 (2H, square, J=7,1 Hz), 4,34 (2H, t, J=7.2 Hz), 7,20-7,33 (5H, m), 7,66 (1H, DD, J=2,1, to 8.7 Hz), 7,74 (1H, d, J=8.7 Hz), of 8.06 (1H, d, J=1.9 Hz), 8,64 (1H, s).

MS (ESI): M+ 364

Example 1-56

1H NMR (CDCl3300 MHz) (δ) ppm: 0,99 (3H, t, J=7,3 Hz), USD 1.43 (2H, m), 1,84-of 1.94 (2H, m), is 4.15 (2H, s), 4,28 (2H, t, J=7.4 Hz), 7,20-7,34 (5H, m), 7,52 (1H, d, J=8,8 Hz), the 7.65 (1H, DD, J=2,1, 8,8 Hz), 8,42 (1H, d, J=1.9 Hz), 8,72 (1H, s), 15,04 (1H, users).

MS (ESI): M+ 336

Example 1-57

1H NMR (CDCl3300 MHz) (δ) ppm: of 1.41 (3H, t, J=7.2 Hz), 3,85 (3H, s), 4,11 (2H, s), 4,39 (2H, square, J=7,2 Hz), 7,17-to 7.35 (6H, m), 7,51 (1H, DD, J=2,4, and 8.4 Hz), 8,42 (1H, d, J=1,8 Hz), to 8.45 (1H, s).

MS (ESI): M+ 322

Example 1-58

1H NMR (CDCl3300 MHz) (δ) ppm: 3,99 (3H, s)to 4.16 (2H, s), 7,19-7,33 (5H, m), 7,52 (1H, d, J=8.7 Hz), to 7.68 (1H, DD, J=2.0 a, 8,7 Hz), to 8.41 (1H, s), 8,72 (1H, s).

MS (ESI): M+ 294

Example 1-59

1H NMR (DMSO-d6400 MHz) (δ) ppm: 2,08-of 2.15 (2H, m), 2,69 (2H, t, J=7.8 Hz), 4,16 (2H, s), of 4.57 (2H, t, J=7,3 Hz), 7,15-7,31 (10H, m), 7,81 (1H, DD, J=2.0 a, 8,8 Hz), 7,92 (1H, d, J=8,8 Hz), to 8.20 (1H, d, J=1.9 Hz), 8,96 (1H, s), 15,21 (1H, users).

MS (ESI): M+ 398

Example 1-60

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,11 (2H, t, J=7,3 Hz), 4,18 (2H, s), of 4.77 (2H, t, J=7.4 Hz), 7,19-to 7.35 (10H, m), 7,86 (1H, d, J=8.7 Hz), of 8.06 (1H, d, J=8,8 Hz), by 8.22 (1H, s), 8,76 (1H, s), 15,14 (1H, users).

MS (ESI): M+ 384

Example 1-61

1H NMR (VHI is-d 6300 MHz) (δ) ppm: 1,99-2,03 (2H, m), is 2.37 (2H, t, J=7,1 Hz), 4,17 (2H, s), of 4.54 (2H, t, J=7,3 Hz), 7,21-7,34 (5H, m), 7,87 (1H, DD, J=2.0 a, 8,8 Hz), with 8.05 (1H, d, J=8,8 Hz), 8,21 (1H, d, J=1.9 Hz), 8,98 (1H, s), 12,01 (1H, users), 15,28 (1H, users).

MS (ESI): M+ 366

Example 1-62

1H NMR (DMSO-d6300 MHz) (δ) ppm: 4,15 (2H, s), of 5.48 (2H, s), 7,06-7,10 (1H, m), 7,20-7,22 (1H, m), 7,28-7,34 (6H, m), 7,56-7,58 (2H, m), 7,74 (1H, d, J=8,8 Hz), to 7.84 (1H, d, and 8.9 Hz), 8,23 (1H, s), 9,10 (1H, s), 10,63 (1H, users), 15,18 (1H, users).

MS (ESI): M+ 413

Example 1-63

1H NMR (DMSO-d6300 MHz) (δ) ppm: and 3.72 (2H, m), 4.26 deaths (2H, s), 4,35 (2H, m), 5,23 (1H, usher.), 7,32-7,41 (2H, m), 7,53-7,58 (2H, m), 7,72 (1H, m), with 8.05 (1H, s), 8,63 (1H, s).

MS (ESI): M+391

Example 1-64

1H NMR (DMSO-d6300 MHz) (δ) ppm: and 3.72 (2H, m)to 4.23 (2H, s), 4,35 (2H, m), 5,24 (1H, usher.), 7,25-7,40 (3H, m), EUR 7.57 (1H, m), 7,72 (1H, m), 8,03 (1H, s), 8,63 (1H, s).

MS (ESI): M+375

Example 1-65

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,12 (2H, t, J=7,3 Hz), or 4.31 (2H, s), 4,78 (2H, t, J=7,3 Hz), 7,20 was 7.36 (7H, m), 7,46-of 7.48 (2H, m), 7,86 (1H, m), of 8.09 (1H, m), 8,15 (1H, s), 8,78 (1H, s), 15,08 (1H, users).

MS (ESI): M+417

Example 1-66

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,79 (2H, m), 4,39 (2H, s)and 4.65 (2H, m), 5,04 (1H, m), 7,31-7,47 (3H, m), 7,88 (1H, m), 8,07 (1H, m), 8,19 (1H, m), of 8.90 (1H, s), 15,25 (1H, s).

MS (ESI): M+375

Example 1-67

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,74 (2H, m), 4,35 (2H, s), to 4.62 (2H, m)5,00 (1H, usher.), a 7.62 (1H, m), 7,81 (1H, m), of 7.90 (1H, m), 8,02-8,13 (2H, m), 8,23 (1H, m), 8,32 (1H, m), 8,87 (1H, s).

MS (ESI): M+368

Example 1-68

1H NMR (DMSO-d6300 M is t) (δ ) ppm: 2,09 (3H, s), 4,35 (2H, s), of 5.75 (2H, s), 7,37 (1H, m), 7,44 (1H, m), 7,55 (1H, m), 7,83 (1H, m), 8,01 (1H, m)to 8.12 (1H, m), 9,10 (1H, s).

MS (ESI): M+407

Example 1-69

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,20 (3H, s), 4,36 (2H, s), from 6.22 (2H, s), of 7.36-7,47 (2H, m), 7,58 (1H, m), 7,86 (1H, m), 8,12-of 8.15 (2H, m), 9,04 (1H, s).

MS (ESI): M+439

Example 1-70

1H NMR (DMSO-d6300 MHz) (δ) ppm: 1,22 (9H, s), 4,36 (2H, s), of 5.99 (2H, s), 7,35-7,46 (3H, m), 7,58 (1H, m), to 7.84 (1H, m), 8,08-8,11 (2H, m), of 8.95 (1H, s), 14,75 (1H, usher.).

MS (ESI): M+496

Example 1-71

1H NMR (DMSO-d6300 MHz) (δ) ppm: 2,62 (3H, d, J=4,7 Hz), 4,36 (2H, s), 6,11 (2H, s), of 7.36-7,47 (2H, m), 7,54-of 7.60 (2H, m), to 7.84 (1H, m), 8,10-8,13 (2H, m), 8,98 (1H, s), 14,79 (1H, usher.).

MS (ESI): M+454

Example 1-72

1H NMR (DMSO-d6300 MHz) (δ) ppm: 2,77 (6H, s), 4,37 (2H, s), of 6.20 (2H, s), 7,39 (1H, DD, J=7,8, and 7.8 Hz), 7,47 (1H, DD, J=1,7, and 7.8 Hz), to 7.59 (1H, DD, J=1,7, and 7.8 Hz), 7,89 (1H, m), 8,11-to 8.14 (2H, m), 9,04 (1H, s), 14,69 (1H user.).

MS (ESI): M+468

Example 1-73

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,75 (2H, usher.), 4,36 (2H, s), 4,60 (2H, m)5,00 (1H, usher.), 7,39-7,49 (2H, m), 7,82 (1H, m), of 8.04 (1H, m), 8,11 (1H, s), 8,87 (1H, s), 15,14 (1H, users).

MS (ESI): M+393

Example 1-74

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 3.41 (1H, m), 3,51 (1H, m), 3,82 (1H, m), 4.26 deaths (1H, m), 4,36 (2H, s), 4,79 (1H, m), is 4.93 (1H, m), 5,19 (1H, m), 7,38 (1H, m), 7,46 (1H, m), 7,58 (1H, m), to 7.84 (1H, m), of 7.97 (1H, m,), 8,15 (1H, m), 8,84 (1H, s).

MS (ESI): M+421

Example 1-75

1H NMR (DMSO-d6300 MHz) (δ) ppm: 4,32 (2H, s), 5,98 (2H, s), 7,31-the 7.43 (5H, m), 7,80 (1H, m), of 8.06 (1H, m)to 8.12 (1H, m), 8,99 (1H, m), is 1.81 (1H, users).

MS (ESI): M+424

Example 1-76

1H NMR (DMSO-d6300 MHz) (δ) ppm: 2,62 (3H, d, J=4.4 Hz), 4,32 (2H, s), 6,11 (2H, s), 7,30-the 7.43 (3H, m), 7,53 (1H, square, J=4.4 Hz), to 7.84 (1H, m), of 8.06 (1H, s)to 8.12 (1H, m), 8,98 (1H, m), 14,74 (1H, s).

MS (ESI): M+438

Example 1-77

1H NMR (DMSO-d6300 MHz) (δ) ppm: 2,77 (6H, s)to 4.33 (2H, s), to 6.19 (2H, s), 7,27-7,44 (3H, m), 7,89 (1H, m), 8,06-to 8.14 (2H, m), 9,03 (1H, s), 14,64 (1H, s).

MS (ESI): M+452

Example 1-78

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,74 (2H, dt, J=4,8, and 5.6 Hz), 4,17 (2H, s), 4,60 (2H, t, J=4,8 Hz), 4,99 (1H, t, J=5.6 Hz), 7,20-to 7.32 (5H, m), 7,82 (1H, m), to 7.99 (1H, m), 8,21 (1H, m), 8,84 (1H, s), 15,27 (1H, s).

MS (ESI): M+323

Example 1-79

1H NMR (DMSO-d6300 MHz) (δ) ppm: 2,34 (3H, in), 3.75 (2H, usher.), 4,30 (2H, s), br4.61 (2H, t, J=4,7 Hz)to 5.00 (1H, usher.), 7,21-7,31 (3H, m), 7,81 (1H, DD, J=2,0, a 8.9 Hz), 8,01 (1H, d, J=8,9 Hz), 8,15 (1H, d, J=2.0 Hz), 8,86 (1H, s), 15,23 (1H, s).

MS (ESI): M+371

Example 1-80

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,76 (2H, m), or 4.31 (2H, s), br4.61 (2H, m), free 5.01 (1H, m), 7.23 percent (1H, m), of 7.36-7,47 (2H, m), the 7.65 (1H, m), 7,81 (1H, m), 8,02 (1H, m), 8,14 (1H, m), 8,86 (1H, s).

MS (ESI): M+401

Example 1-81

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 2.26 (3H, in), 3.75 (2H, m), of 4.12 (2H, s), 4,60 (2H, m), 4,99 (1H, m), 7,10-to 7.18 (4H, m), 7,80 (1H, m), to 7.99 (1H, m), to 8.20 (1H, m), cent to 8.85 (1H, s), 15,29 (1H, s).

MS (ESI): M+337

Example 1-82

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 3.73 (2H, dt, J=4,8, 5,2 Hz), of 3.84 (3H, s), 4,28 (2H, s), 4,60 (2H, t, J=4,8 Hz), 5,00 (1H, t, J=5,2 Hz),? 7.04 baby mortality-7,07 (2H, m), 7,30 (1H, m), 7,79 (1H, m), 8,00 (1H, m), 8,11 (1H, m), 8,84 (1H, s), 15,22 (1H, s).

MS (ESI): +387

Example 1-83

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,75 (2H, m), 4,50 (2H, s), to 4.62 (2H, m), 7,60-8,15 (5H, m), 8,35 (1H, s), 8,68 (1H, m), 8,87 (1H, s), 15,25 (1H, usher.).

MS (ESI): M+324

Example 1-84

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,75 (2H, m)to 4.33 (2H, s), to 4.62 (2H, m), EUR 7.57 (2H, d, J=6.3 Hz), 7,89 (1H, DD, J=2,1, to 8.7 Hz), 8,07 (1H, d, J=8.7 Hz), 8,32 (1H, d, J=2.1 Hz), to 8.62 (1H, d, J=6.3 Hz), 8,88 (2H, s).

MS (ESI): M+324

Example 1-85

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,21 (3H, s), of 3.77 (2H, m), br4.61 (2H, m), of 4.66 (2H, s), 5,02 (1H, m), 7,38 (1H, m), 7,55 (1H, m), 7,68 (1H, m), 7,81 (1H, m), 8,00-with 8.05 (2H, m), 8,19 (1H, m), 8,87 (1H, s).

MS (ESI): M+401

Example 1-86

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 3.73 (2H, m), is 4.15 (2H, s), 4,58 (2H, m)5,00 (1H, m), 7.23 percent is 7.50 (10H, m), 7,88-a 7.92 (2H, m), 8,83 (1H, s).

MS (ESI): M+399

Example 1-87

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,75 (2H, m), 4,30 (2H, s), br4.61 (2H, m)5,00 (1H, usher.), 7,26-7,38 (2H, m), 7,43-7,49 (2H, m), 7,82 (1H, m), 8,02 (1H, m), 8,14 (1H, m), 8,86 (1H, s), 15,32 (1H, s).

MS (ESI): M+357

Example 1-88

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,74 (2H, m), 4,25 (2H, s), 4,60 (2H, m), to 4.98 (1H, usher.), 7,25-7,53 (6H, m), to 7.59-7,66 (3H, m), 7,87 (1H, m), 8,10 (1H, m), 8,29 (1H, m), cent to 8.85 (1H, s), 15,30 (1H, s).

MS (ESI): M+399

Example 1-89

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,79 (2H, m)to 4.33 (2H, s), with 4.64 (2H, m), of 5.03 (1H, m), EUR 7.57-the 7.65 (3H, m), 7,76 (1H, m), to $ 7.91 (1H, m), of 8.06 (1H, m), 8,32 (1H, m), of 8.90 (1H, s), 15,31 (1H, s).

MS (ESI): M+391

Example 1-90

1H NMR (DMSO-d6400 MHz) (δ) ppm: of 1.30 (3H, t, J=6.8 Hz), 3,74 (2H, m), 3,98 (2H, square, J=6,8gts), of 4.12 (2H, s), 4,60 (2H, m), free 5.01 (1H, m), 6,76 (1H, m), 6,82-6,84 (2H, m), 7,20 (1H, m), 7,82 (1H, m), to 7.99 (1H, m), by 8.22 (1H, m), cent to 8.85 (1H, s).

MS (ESI): M+367

Example 1-91

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,75 (2H, m), 4,25 (2H, s), br4.61 (2H, m), 7,53 (1H, m), 7,66-7,71 (2H, m), 7,83-7,89 (2H, m), 8,02 (1H, m), of 8.28 (1H, m), 8,87 (1H, s).

MS (ESI): M+348

Example 1-92

1H NMR (DMSO-d6400 MHz) (δ) ppm: 2,48 (3H, m), 3,74 (2H, m), 4.26 deaths (2H, s), br4.61 (2H, m), 5,09 (1H, usher.), 7,19 (1H, m), 7,39 (2H, m), 7,82 (1H, m), of 8.04 (1H, m), 8,13 (1H, s), cent to 8.85 (1H, s), 15,22 (1H, s).

MS (ESI): M+403

Example 1-93

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,75 (2H, m), 4,24 (2H, s), br4.61 (2H, m), 5,02 (1H, usher.), 7,38-7,47 (4H, m), 7,80 (1H, m), 8,03 (1H, m), 8,16 (1H, m), 8,86 (1H, s), 15,23 (1H, s).

MS (ESI): M+407

Example 1-94

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,76 (2H, m)to 3.99 (2H, s), br4.61 (2H, m), 5,01 (3H, m), 6,41 (3H, m), 6,93 (1H, m), 7,78 (1H, m), 8,00 (1H, m), to 8.20 (1H, m), 8,86 (1H, s).

MS (ESI): M+338

Example 1-95

1H NMR (DMSO-d6300 MHz) (δ) ppm: 1,00 (3H, s), 3,76 (2H, m), of 4.13 (2H, s), br4.61 (2H, m), free 5.01 (1H, m), 6,98 (1H, m), 7.23 percent (1H, m), the 7.43 (2H, m), 7,81 (1H, m), 8,01 (1H, m), 8,21 (1H, m), 8,86 (1H, s), 9,87 (1H, ).

MS (ESI): M+380

Example 1-96

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 3.73 (2H, m), 4,18 (2H, s), 4,59 (2H, m), to 4.98 (1H, usher.), 7,26 (1H, s), 7,29 (1H, m), 7,39 (1H, m), 7,53 (1H, m), to 7.99 (1H, s), 8,24 (1H, m), cent to 8.85 (1H, s), 15,25 (1H, s).

MS (ESI): M+401

Example 1-97

1H NMR (DMSO-d6300 MHz) (δ) ppm: 2,28 (3H, in), 3.75 (2H, m), 4,25 (2H, s), br4.61 (2H, m), 5,04 (1H, usher.), 7,13 (1H, s), 7.29 trend was 7.36 (2H, m), 7,81 (1H, m), 8,03 (1H, m), 8,13 (1H, s), 8,86 (1H, is), 15,24 (1H, s).

MS (ESI): M+371

Example 1-98

1H NMR (DMSO-d6400 MHz) (δ) ppm: 2,59 (6H, in), 3.75 (2H, m)to 4.33 (2H, s), br4.61 (2H, m)5,00 (1H, m), to 7.59-to 7.64 (3H, m), 7,73 (1H, m), 7,87 (1H, m), 8,03 (1H, m), of 8.27 (1H, s), 8,86 (1H, s), 15,27 (1H, s).

MS (ESI): M+430

Example 1-99

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,75 (2H, m), 4.26 deaths (2H, s), br4.61 (2H, m)5,00 (1H, usher.), 7,21 (1H, m), 7,38-7,51 (2H, m), 7,83 (1H, m), 8,03 (1H, m), by 8.22 (1H, s), 8,87 (1H, s).

MS (ESI): M+375

Example 1-100

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,76 (2H, m), 4.26 deaths (2H, s), br4.61 (2H, m), 4,99 (1H, m), 7,25 (1H, m), to 7.61 (1H, m), 7,81 (1H, m), of 8.04 (1H, m), 8,16 (1H, m), 8,87 (1H, s), 15,16 (1H, s).

MS (ESI): M+393

Example 1-101

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,79 (2H, m)to 4.01 (3H, s), 4,19 (2H, s), with 4.64 with 4.65 (2H, m), 5,02 (1H, t, J=5.5 Hz), 7,25 (1H, d, J=1.6 Hz), 7,31-to 7.35 (2H, m), 7,56-7,58 (1H, m), 7,82 (1H, s), 8,78 (1H, s), 15,38 (1H, users).

MS (ESI): M+ 422

Example 1-102

1H NMR (DMSO-d6400 MHz) (δ) ppm: 1,19 (2H, m)of 1.30 (2H, m), 3,83 (1H, m), 4,37 (2H, s), 7,38 (1H, m), 7,46 (1H, m), EUR 7.57 (1H, m), 7,89 (1H, m)to 8.12 (1H, m), 8,24 (1H, m), 8,73 (1H, s), 15,05 (1H, s).

MS (ESI): M+387

Example 2-1

1H NMR (DMSO-d6300 MHz) (δ) ppm: 4,37 (2H, s), to 6.88 (2H, users), 7,35-7,47 (2H, m), 7,58 (1H, m), 7,87 (1H, DD, J=2.1 a, a 8.9 Hz), 8,08 (1H, d, J=2.1 Hz), 8,16 (1H, d, J=8,9 Hz), 8,86 (1H, s)15,24 (1H, users).

MS (ESI): M+362

Example 2-2

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,75 (3H, users), 4,36 (2H, s), 7,35 (1H, m), 7,42 (1H, m), 7,54 (1H, m), 7,72 (1H, m), a 7.85 (1H, m), 8,10 (1H, s), 9,03 (1H, s), of 11.61 (1H, users).

MS (ESI): M+420

Example 2-3/p>

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 2.16 (3H, s), 4,36 (2H, s), 7,35-7,45 (2H, m), 7,58 (1H, DD, J=1,8, 7,8 Hz), 7,76-a 7.85 (2H, m), 8,10 (1H, s), 8,96 (1H, s), 12,02 (1H, users), 14,77 (1H, users).

MS (ESI): M+ 405

Example 2-4

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 3.32 (3H, s), 4,37 (2H, s), 7,38 (1H, m), 7,46 (1H, m), 7,58 (1H, m), 7,86 (1H, m), 8,06-8,10 (2H, m), 8,82 (1H, s), 14,60 (1H, usher.).

MS (ESI): M+440

Example 2-5

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 3.46 (3H, s), 3,53 (3H, s), 4,37 (2H, s), 7,38 (1H, DD, J=7,8, and 7.8 Hz), 7,47 (1H, DD, J=2,1, 7,8 Hz), 7,58 (1H, DD, J=2,1, 7,8 Hz), 7,88 (1H, DD, J=1,8, and 8.7 Hz), of 7.97 (1H, d, J=8.7 Hz), to 8.12 (1H, d, J=1,8 Hz), 9,11 (1H, s), 15,54 (1H, users).

MS (ESI): M+454

Example 2-6

1H NMR (DMSO-d6300 MHz) (δ) ppm: 2,96 (6H, s), 4,36 (2H, s), 7,38 (1H, DD, J=7,8, and 7.8 Hz), 7,46 (1H, DD, J=2.0 a, 7,8 Hz), EUR 7.57 (1H, DD, J=2.0 a, 7,8 Hz), 7,86 (1H, DD, J=2,2, 8,8 Hz)to 8.12 (1H, d, J=2.2 Hz), of 8.25 (1H, d, J=8,8 Hz), the 9.25 (1H, s), 15,14 (1H, users).

MS (ESI): M+390

Example 2-7

1H NMR (DMSO-d6400 MHz) (δ) ppm: 2,84 (3H, d), 4,35 (2H, s), 7,19 (1H, square), 7,38 (1H, m), 7,45 (1H, m), 7,55 (1H, m), a 7.85 (1H, m), 8,09-8,11 (2H, m), 8,99 (1H, m).

MS (ESI): M+376

Example 2-8

1H NMR (DMSO-d6300 MHz) (δ) ppm: 1,09 (3H, t, J=7,1 Hz), 3,13 (2H, DQC., J=6,1, 7,1 Hz), 4,36 (2H, s), 7,19 (1H, t, J=6,1 Hz), 7,38 (1H, DD, J=7,7, 7,7 Hz), 7,46 (1H, DD, J=1,7, 7,7 Hz), 7,58 (1H, DD, J=1,7, and 7.8 Hz), the 7.85 (1H, DD, J=2,1, 8,8 Hz), 8,10 (1H, d, J=2.1 Hz), 8,15 (1H, d, J=8,8 Hz), 8,99 (1H, s), 15,14 (1H, users).

MS (ESI): M+390

Example 3-1

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,75 (2H, m), with 3.79 (3H, s), 4,28 (2H, s), of 4.57 (2H, m), 5,02 (1H, m), 7,17 (H, m), 7,32 (1H, m), EUR 7.57 (2H, m), 7,76 (1H, m), 8,83 (1H, m), of 15.75 (1H, s).

MS (ESI): M+421

Example 3-2

1H NMR (DMSO-d6400 MHz) (δ) ppm: 2,24 (3H, s), of 3.77 (2H, DD, J=5,2, 5.6 Hz), 4,27 (2H, s), br4.61 (2H, t, J=5,2 Hz), of 5.05 (1H, t, J=5.6 Hz), 7.23 percent (2H, m), 7,34 (1H, m), 7,76 (1H, m), 8,03 (1H, m), 8,08 (1H, m), 8,86 (1H, s), 15,23 (1H, s).

MS (ESI): M+371

Example 3-3

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 3.73 (5H, s), is 4.21 (2H, s), br4.61 (2H, t, J=4,8 Hz), free 5.01 (1H, t, J=5,2 Hz), 5,02 (1H, m), 7,12 (1H, m), 7,25 (1H, m), 7,37 (1H, m), 7,81 (1H, m), 8,01 (1H, m), 8,19 (1H, m), 8,86 (1H, s), 15,26 (1H, s).

MS (ESI): M+387

Example 3-4

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 3.80 (2H, m)to 4.01 (3H, s), of 4.12 (2H, s)and 4.65 (2H, m), 5,02 (1H, m), 7,17-to 7.50 (4H, m), 8,03 (1H, s), 8,81 (1H, s), 15,45 (1H, s).

MS (ESI): M+405

Example 3-5

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,74 (2H, t), 4,17 (2H, s), 4,56 (2H, t), 5,02 (1H, usher.), then 7.20 (1H, m),7,31 (1H, m), 7,38 (1H, m), 7,52-7,56 (2H, m), 8,86 (1H, s), 13,63 (1H, s).

MS (ESI): M+407

Example 3-6

1H NMR (DMSO-d6400 MHz) (δ) ppm: of 3.78 (2H, t), 4,18 (2H, s), of 4.44 figure-4.49 (2H, m), to 5.08 (1H, t), 7,20-of 7.25 (2H, m), 7,34-7,40 (1H, m), 7,56 (1H, d), of 7.82 (1H, s), 8,77 (1H, s), 11,10-11,30 (1H, usher.), 15,49 (1H, s).

MS (ESI): M+ 408

Example 3-7

1H NMR (DMSO-d6400 MHz) (δ) ppm: 2,68 (3H, d, J=4.4 Hz), 3,74 (2H, t, J=4,8 Hz), Android 4.04 (2H, s), 4,60 (2H, t, J=4,8 Hz), free 5.01 (1H, t), at 5.27 (1H, square, J=5,2 Hz), 6,51-6,56 (2H, m), to 6.95 (1H, d), 7,07-to 7.09 (1H, m), 7,78 (1H, d, J=9,2 Hz), 7,98 (1H, d, J=8,8 Hz), 8,21 (1H, s), 8,84 (1H, s), 15,33 (1H, s).

MS (ESI): M+ 353

Example 3-8

1H NMR (DMSO-d6400 MHz) (δ) ppm: 2,62 (6H, s), 3,74 (2H, t), are 4.24 (2H, s) 4,60 (2H, t, J=4,8 Hz), free 5.01 (1H, t), 6,97-7,05 (2H, m), 7,21 (2H, m), to 7.77 (1H, d, J=11.2 Hz), of 7.97 (1H, d), 8,16 (1H, s), cent to 8.85 (1H, s), 15,29 (1H, s).

MS (ESI): M+ 367

Example 3-9

1H NMR (DMSO-d6400 MHz) (δ) ppm: of 4.35 (2H, s), 7,11 (1H, d, J=8,8 Hz), 7,37-7,40 (1H, m), 7,44 (1H, d), 7,56 (1H, d), 7,69-7,74 (6H, m), 8,19 (1H, s), 8,68 (1H, s), 14,99 (1H, s).

MS (ESI): M+ 424

Example 3-10

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,84-of 3.95 (4H, m), 4,36 (2H, s), 5,11-5,19 (3H, m), 7,38 (1H, m), 7,45 (1H, d), EUR 7.57 (1H, d), of 7.82 (1H, d, J=9,2 Hz), 8,15 (1H, d, J=8,8 Hz), of 8.90 (1H, s), 15,21 (1H, s).

MS (ESI): M+ 422

Example 3-11

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,76 (2H, t), of 4.05 (2H, s), 4,59 (2H, t)5,00 (1H, t), is 6.61 (1H, d), only 6.64 (1H, s)6,70 (1H, d, J=8.0 Hz), 7,09-7,11 (1H, m), 7,81 (1H, d, J=8,8 Hz), 8,00 (1H, d, J=8,8 Hz), 8,21 (1H, s), 8,86 (1H, s), of 9.30 (1H, s), 15,30 (1H, s).

MS (ESI): M+ 340

Example 3-12

1H NMR (DMSO-d6400 MHz) (δ) ppm: 1,80-1,90 (2H, m), 2,45-of 2.50 (2H, m), 2,60-2,70 (2H, m), 4,36 (2H, s), 5,11-5,16 (1H, m), 7,38-7,40 (1H, m), 7,45 (1H, d), EUR 7.57 (1H, d), 7,81 (1H, d, J=8,8 Hz), to 7.93 (1H, d), 8,14 (1H, C)8,68 (1H, s), 15,16 (1H, s).

MS (ESI): M+ 402

Example 3-13

1H NMR (DMSO-d6400 MHz) (δ) ppm: 1,70-1,90 (4H, m), 1.91 a is 2.00 (2H, m), 2,20-of 2.30 (2H, m), 4,37 (2H, s), 5,20-and 5.30 (1H, m), 7,38-7,40 (1H, m), 7,45 (1H, d), EUR 7.57 (1H, d), 7,86 (1H, d), 8,16 (1H, d), 8,19 (1H, s), 8,75 (1H, s), 15,16 (1H, s).

MS (ESI): M+ 416

Example 3-14

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,70-of 3.80 (2H, m), of 3.96 (3H, s), 4,32 (2H, s), to 4.81 (2H, t), of 4.90 (1H, t), 7,35-the 7.43 (2H, m), 7,54-to 7.59 (2H, m), 7,69 (1H, s), 8,69 (1H, s), 15,16 (1H, s).

MS (ESI): M+ 422

Example 3-15

1H NMR (DMSO-d6300 MHz) δ ) ppm: 2,88 (3H, s), 2,95 (3H, s), 3,70-of 3.80 (2H, m), is 4.21 (2H, s), br4.61 (2H, t), at 4.99 (1H, t), 7,20-of 7.23 (1H, m), 7,33 (1H, s), 7,37-7,38 (2H, DH), 7,86 (1H, d), 8,02 (1H, d, J=8,8 Hz), compared to 8.26 (1H, s), 8,86 (1H, s), 15,30 (1H, s).

MS (ESI): M+ 395

Example 3-16

1H NMR (DMSO-d6400 MHz) (δ) ppm: a 2.71 (6H, s), 3,70 is 3.76 (2H, m), 4,58 (2H, s), 4,60 (2H, t, J=5,2 Hz), 5,02 (1H, t), 7,42 (1H, d), 7,51 (1H, m), of 7.64 (1H, m), 7,80 (1H, d), to 7.84 (1H, d), 8,01 (1H, d, J=8,8 Hz), 8,11 (1H, s), 8,86 (1H, s), 15,25 (1H, s).

MS (ESI): M+ 431

Example 3-17

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 3.73 of 3.75 (2H, m), 4,24 (2H, s), br4.61 (2H, t)5,00 (1H, t, J=5.6 Hz), 7,31 (1H, m), of 7.48-7,51 (1H, m), to 7.84 (1H, d), 8,02 (1H, d), 8,21 (1H, s), 8,87 (1H, s), 15,22 (1H, s).

MS (ESI): M+ 394

Example 3-18

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,70-of 3.80 (2H, m), 4,56 (2H, s), 4,60 (2H, t)5,00 (1H, t), 7,38-the 7.43 (2H, m), 7,52-rate of 7.54 (1H, m), 7,78 (1H, d), 7,87 (1H, d, J=7.8 Hz), 7,98 (1H, d, J=8,9 Hz), 8,11 (1H, s), 8,84 (1H with), 12,60-13,00 (1H, usher.), 15,29 (1H, s).

MS (ESI): M+ 368

Example 3-19

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,74-of 3.77 (2H, m), 4,58 (2H, s), br4.61 (2H, t), 5,02 (1H, t, J=5.6 Hz), 7,29 (1H, d), 7,46 (1H, m), 7,56 (1H, m), of 7.70 (1H, m), 7,81 (1H, d), 7,87 (1H, d), 8,01 (1H, s), 8,18 (1H, ), 8,86 (1H, s), 15,27 (1H, s).

MS (ESI): M+ 417

Example 3-20

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 1.37 (3H, t, J=6.9 Hz), 3,70-of 3.80 (2H, m), 4,22 (2H, s), 4,28 (2H, square, J=6,9 Hz)and 4.65 (2H, t)5,00 (1H, t), 7,30-7,34 (3H, m), 7,60 (1H, d), 7,92 (1H, s), 8,80 (1H, s), 15,44 (1H, ).

MS (ESI): M+ 436

Example 3-21

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,76 (2H, m), and 4.40 (2H, s), 4,63 (2H, t, J=5,1 Hz), 5,02 (1H, t, J=5.6 Hz), 7,20 (1H, d, J=6.3 Hz), 7,35-7,39 (1H, m), a 7.62 (1H, is, J=6.3 Hz), 8,00 (1H, s), 8,32 (1H, s)8,89 (1H, s), a trend of 15.87 (1H, s).

MS (ESI): M+ 426

Example 3-22

1H NMR (DMSO-d6400 MHz) (δ) ppm: of 3.80 (2H, t, J=5.3 Hz), 4,48 (2H, s), and 4.75 (2H, t, J=4.6 Hz), is 5.06 (1H, t, J=5.6 Hz), 7,24 (1H, d, J=6.3 Hz), 7,39-7,42 (1H, m), the 7.65 (1H, d, J=6,7 Hz), 7,95 (1H, s), 8,40 (1H, s), of 9.00 (1H, s), 14,62 (1H, s).

MS (ESI): M+ 460

Example 3-23

1H NMR (DMSO-d6400 MHz) (δ) ppm: 1,53 (3H, d, J=6.4 Hz), 3,76-a 3.83 (2H, m), 4.26 deaths (2H, s), 5,19-5,23 (2H, m), 7,20-7,22 (1H, m), 7,41-7,49 (2H, m), 7,86 (1H, d), 8,17 (1H, d, J=8,8 Hz), 8,24 (1H, s), 8,88 (1H, s).

MS (ESI): M+ 390

Example 3-24

1H NMR (DMSO-d6400 MHz) (δ) ppm: 1,53 (3H, d, J=6.8 Hz), 3,76-3,82 (2H, m), 4.26 deaths (2H, s), 5,19-5,23 (2H, m), 7,22-7,24 (1H, m), 7,41-7,49 (2H, m), 7,86 (1H, d), 8,17 (1H, d, J=9,2 Hz), 8,24 (1H, s), 8,88 (1H, s).

MS (ESI): M+ 390

Example 3-25

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,40-3,50 (2H, m), 4,34 (2H, s), of 4.57 (2H, t), 4,89 (1H, t), 7.24 to 7,27 (1H, m), 7,45-7,51 (2H, m), 8,35 (1H, s), to 8.45 (1H, s), of 9.00 (1H, s), 14,30-14,40 (1H, usher.).

MS (ESI): M+ 444

Example 3-26

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,84-of 3.96 (4H, m), 4.26 deaths (2H, s), 5,13-5,18 (3H, m), 7,19-7,21 (1H, m), 7,40-of 7.48 (2H, m), to 7.84 (1H, d, J=9,2 Hz), 8,15 (1H, d, J=8,8 Hz), 8,23 (1H, s), of 8.90 (1H, s)15,24 (1H, s).

MS (ESI): M+ 406

Example 3-27

1H NMR (DMSO-d6400 MHz) (δ) ppm: of 3.77 (2H, t, J=5,2 Hz), a 4.53 (2H, s), and 4.68 (2H, t, J=4,8 Hz), free 5.01 (1H, t, J=5.6 Hz), 7,32 (1H, d, J=6.0 Hz), 7,39-the 7.43 (1H, m), of 7.64 (1H, d, J=6.4 Hz), 8,07 (1H, s), 8,79 (1H, s), 8,96 (1H, s), 14,61 (1H, s).

MS (ESI): M+ 417

Example 3-28

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 0.97 (3H, t, J=7.2 Hz), 2,58 (3H, s)2,84 (2H, the century, J=7,2 Hz), of 3.77 (2H, t), is 4.21 (2H, s), 4,60 (2H, t)5,00 (1H, t), 7,00-7,02 (1H, m), 7,12 (1H, d), 7,20-7,24 (2H, m), 7,78 (1H, d, J=8,8 Hz), 7,98 (1H, d, J=8,8 Hz), 8,17 (1H, s), 8,84 (1H, s), 15,31 (1H with).

MS (ESI): M+381

Example 3-29

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,78 (3H, t, J=7.2 Hz), of 1.42 (2H, m), of 2.56 (3H, s), was 2.76 (2H, t, J=6.8 Hz), 3,74 (2H, t)to 4.23 (2H, s), 4,60 (2H, t, J=4,8 Hz), 5,02 (1H, t, J=5.6 Hz), 7,00-7,03 (1H, m), to 7.09 (1H, d), 7,20-7,21 (2H, m), to 7.77 (1H, d, J=9,2 Hz), to 7.99 (1H, d, J=8,8 Hz), 8,15 (1H, s), cent to 8.85 (1H, s), 15,30 (1H, s).

MS (ESI): M+395

Example 3-30

1H NMR (DMSO-d6400 MHz) (δ) ppm: 2,52 (3H, s), of 3.77 (2H, t, J=4,8 Hz)to 4.01 (2H, s), 4,30 (2H, s), br4.61 (2H, t), 4,90-5,10 (1H, usher.), 7,03-to 7.09 (2H, m), 7,20-7,26 (7H, m), 7,76 (1H, d), 7,98 (1H, d), 8,17 (1H, s), cent to 8.85 (1H, s), 15,30 (1H, s).

MS (ESI): M+443

Example 3-31

1H NMR (DMSO-d6400 MHz) (δ) ppm: 2,94 (3H, s)to 3.09 (3H, in), 3.75 (2H, m), 4,13-4,18 (1H, m), of 4.44-4,48 (1H, m), br4.61 (2H, t), 5,02 (1H, t, J=5.6 Hz), 7,33-7,37 (3H, m), 7,52 (1H, d, J=9,2 Hz), 7,81 (1H, d), 8,01 (1H, d, J=8,8 Hz), 8,15 (1H, s), 8,86 (1H, s), 15,27 (1H, s).

MS (ESI): M+431

Example 3-32

1H NMR (DMSO-d6400 MHz) (δ) ppm: a 1.01 (6H, d), 2,52 (3H, s), 3,12-3,19 (1H, m), of 3.73 of 3.75 (2H, m), 4,20 (2H, s), 4,60 (2H, t), 5,02 (1H, t), 7,00-7,02 (1H, m), 7,11 (1H, d), 7,19-7,22 (2H, m), to 7.77 (1H, d, J=8,8 Hz), 7,98 (1H, d, J=9,2 Hz), 8,18 (1H, s), 8,84 (1H, s), 15,31 (1H, s).

MS (ESI): M+395

Example 3-33

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 1.86 (9H, s), 4.26 deaths (2H, s), 7,22-7,24 (1H, m), 7,42-7,49 (2H, m), 7,79 (1H, d, J=9,2 Hz), of 8.28 (1H, s), 8,39 (1H, d, J=8,8 Hz), 8,98 (1H, s), 15,16 (1H, s).

MS (ESI): M+388

Example 3-34

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,71 (2H, m), of 3.96 (3H), is 4.21 (2H, s), to 4.81 (2H, t), 4,89 (1H, t), 7,19-7,24 (1H, m), 7,40-7,52 (3H, m), to 7.77 (1H, s), 8,68 (1H, s), 15,17 (1H, s).

MS (ESI): M+406

Example 3-35

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,75 (2H, m), 4.09 to (2H, s), a 4.83 (2H, t), 5,33 (1H, t), of 5.81 (2H, s), to 7.15 (1H, s), 7,15-7,24 (1H, m), of 7.36 (1H, m), of 7.48 (1H, m), EUR 7.57 (1H, s), 8,77 (1H, s), shed 15.37 (1H, s).

MS (ESI): M+391

Example 3-36

1H NMR (DMSO-d6400 MHz) (δ) ppm: with 3.79 (2H, t), 4,60 (2H, s), and 4.68 (2H, t), of 5.05 (1H, t), 7,11 (1H, d, J=6.0 Hz), 7,30-7,34 (1H, m), EUR 7.57 (1H, d, J=6.8 Hz), 8,02 (1H, s), scored 8.38 (1H, s), of 8.95 (1H, s), 13,60-14,00 (1H, user.), 14,88 (1H, s).

MS (ESI): M+436

Example 3-37

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,70-and 3.72 (2H, m), 4,98 (3H, s)to 4.23 (2H, s), to 4.81 (2H, t), 4,89 (1H, t), 7,20-7,26 (1H, m)to 7.50 (1H, s), 7,62-to 7.67 (2H, m), 8,68 (1H, s), 15,10 (1H, s).

MS (ESI): M+424

Example 3-38

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 2.67 (6H, s), 3,39 (2H, m), is 4.21 (2H, s), 4.72 in (1H, t), equal to 4.97 (2H, t), 7,20-7,22 (1H, m), 7,40-to 7.50 (2H, m), the 7.65 (1H, s), to 7.84 (1H, s), 15,10 (1H, s).

MS (ESI): M+419

Example 3-39

1H NMR (DMSO-d6300 MHz) (δ) ppm: 2,10 (3H, s), 4,50-4,60 (2H, m)to 4.23 (2H, s)and 4.65 (2H, t)5,00 (1H, t), 7,20-7,30 (1H, m), 7,40-to 7.50 (2H, m), the 7.65 (1H, s), to 8.20 (1H, s), 8,83 (1H, s), and 10.20 (1H, s), 15,00 (1H, s).

MS (ESI): M+433

Example 3-40

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,74 of 3.75 (2H, m), 4,55 (2H, s)and 4.65 (2H, t)5,00 (1H, t), 7,17 (1H, d, J=6.3 Hz), 7,34-7,39 (1H, m), a 7.62 (1H, d, J=6.6 Hz), 7,73 (1H, d, J=9.3 Hz), a 8.34 (1H, d, J=9.3 Hz), 8,97 (1H, s), 14,62 (1H, s).

MS (ESI): M+417

Example 3-41

1H NMR (DMSO-d6400 MHz) (δ) ppm: 1,45 (3H, s), of 2.97 (3H, s), 3,74 is 3.76 (2H, m), of 4.12 (2H, s), and 4.6 (2H, m)of 5.03 (1H, t, J=5.6 Hz), 7.24 to 7,30 (1H, m), 7,30-7,39 (3H, m), 7,76 (1H, d), 8,01 (1H, d, J=8,8 Hz), 8,13 (1H, s), 8,87 (1H, s), 15,23 (1H, s).

MS (ESI): M+ 395

Example 3-42

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 0.88 (6H, t, J=7.2 Hz), 2.91 in (4H, square, J=6,8 Hz in), 3.75 (2H, m)to 4.23 (2H, s), 4,60 (2H, t), 5,02 (1H, t, J=5.6 Hz), 7,00-7,06 (1H, m), 7,14-of 7.25 (3H, m), to 7.77 (1H, d), 7,98 (1H, d, J=8,8 Hz), 8,16 (1H, s), 8,84 (1H, s), 15,32 (1H, s).

MS (ESI): M+ 395

Example 3-43

1H NMR (DMSO-d6400 MHz) (δ) ppm: 1,78 (6H, s)to 3.99 (2H, s), 4,25 (2H, s)to 4.23 (2H, s)5,52 (1H, usher.), 7,20-7,22 (1H, m), 7,42-7,49 (2H, m), 7,76 (1H, d, J=9,2 Hz), of 8.27 (1H, s), a 8.34 (1H, d, J=9,2 Hz), 9,05 (1H, s).

MS (ESI): M+ 404

Example 3-44

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 1.36 (3H, t, J=6.9 Hz), 3,70-of 3.80 (2H, m), of 4.12 (2H, s), 4,24 (2H, square, J=7,0 Hz), to 4.62 (2H, t)5,00 (1H, t), 7,16-7,27 (3H, m), 7,40-7,50 (1H, m)to 8.12 (1H, s), 8,80 (1H, s), 15,50 (1H with).

MS (ESI): M+ 420

Example 3-45

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,70-of 3.80 (2H, m), of 3.84 (3H, s), 3,85 (3H, s), 4,19 (2H, s), and 4.75 (2H, t)to 4.92 (1H, t, J=5.6 Hz), 7,21-7,28 (2H, m), 7,45 is 7.50 (1H, m), 7,95 (1H, s), is 8.75 (1H, s), 15,09 (1H, s).

MS (ESI): M+ 436

Example 3-46

1H NMR (DMSO-d6300 MHz) (δ) ppm: 2,62 (3H, s), 3,74 (2H, m), was 4.02 (2H, s), br4.61 (2H, t), free 5.01 (1H, t), 5,50-the ceiling of 5.60 (1H, m), 6.30-in-to 6.43 (3H, m), 6,95-7,01 (1H, m), 7,82 (1H, d), to 7.99 (1H, d, J=8,8 Hz), 8,21 (1H, s), cent to 8.85 (1H, s), 15,33 (1H, s).

MS (ESI): M+ 353

Example 3-47

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 1.42 (3H, t, J=6.8 Hz), 3,70-of 3.80 (2H, m), 4,20-to 4.23 (4H, m), 4,84-5,00 (3H, m), 7,20-7,30 (1H, m), 7,40-7,49 (3H, m), to 7.77 (1H, s), 8,67 (1H, s).

MS (ESI): M+ 420

Example 3-48

1H NMR (D IS CO-d 6300 MHz) (δ) ppm: 2,78 (3H, s), 3,60-3,70 (2H, m)to 4.16 (2H, s), 4.75 V-4,79 (2H, m), 5,38 (1H, t), 6,20-6,27 (1H, m), 7,07 (1H, s), 7,20-of 7.23 (1H, m), 7,39-7,49 (3H, m), 8,80 (1H, s), 15,32 (1H, s).

MS (ESI): M+ 405

Example 3-49

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 0.94 (3H, t, J=7.2 Hz), 1,72-of 1.78 (2H, m), of 3.77 (2H, m), 4,13-to 4.14 (4H, m), to 4.62 (2H, t)to 5.00 (1H, usher.), 7,12-to 7.18 (2H, m), 7,26 (1H, s), 7,44-7,46 (1H, m), 8,13 (1H, s), 8,79 (1H, s), 15,49 (1H, s).

MS (ESI): M+ 434

Example 3-50

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,00 (3H, s), is 3.08 (3H, s), 3.75 to of 3.77 (2H, m)to 4.16 (2H, s), of 4.57 (2H, t)5,00 (1H, t, J=5.6 Hz), 7,09-to 7.18 (2H, m), 7,24 (1H, s), 7,40-7,41 (1H, m), a 7.85 (1H, s), 8,01 (1H, s), 8,72 (1H, s), 15,67 (1H, s).

MS (ESI): M+ 446

Example 3-51

1H NMR (DMSO-d6300 MHz) (δ) ppm: and 3.72 (3H, s), 3.72 points-of 3.80 (2H, m), of 3.95 (3H, s)4,06 (2H, s), 4,40-4,50 (2H, m)5,00 (1H, t), 7,12 (1H, s), 7,15-7,19 (2H, m), 7,40 was 7.45 (1H, m), 7,88 (1H, s), 8,51 (1H, s).

MS (ESI): M+ 420

Example 3-52

1H NMR (DMSO-d6400 MHz) (δ) ppm: of 3.77 (2H, m), 4,17 (2H, s), 4.72 in (2H, t, J=4,8 Hz), equal to 4.97 (1H, t, J=5.6 Hz), was 7.08 (2H, d, J=7,6 Hz), 7,09-of 7.25 (2H, m), 7,31 and 7.36 (2H, m), 7,43-7,49 (3H, m), of 8.04 (1H, s), 7,76 (1H, ), 15,02 (1H, s).

MS (ESI): M+ 468

Example 3-53

1H NMR (DMSO-d6400 MHz) (δ) ppm: 1,24 (6H, d, J=7,2 Hz in), 3.75 (2H, t)4,08 (2H, s), br4.61 (2H, t), 4,99-5,04 (2H, m), 7,11-7,20 (2H, m), 7,28 (1H, s), 7,43 was 7.45 (1H, m), 8,17 (1H, s), 8,79 (1H, s), 15,52 (1H, s).

MS (ESI): M+ 434

Example 3-54

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,99 (3H, t, J=7,3 Hz), 1,60-1,70 (2H, m), 3.00 and-3,10 (2H, m), 3,70-of 3.80 (2H, m), is 4.15 (2H, s), 4,82 (2H, t), of 5.50 (1H, t), of 6.20 (1H, t), was 7.08 (1H, s), 7,10-7,20 (1H, m), 7,40-7,51 (3H, m), 8,78 (1H, s), 15,30-15,40 (H, user.).

MS (ESI): M+ 433

Example 3-55

1H NMR (DMSO-d6300 MHz) (δ) ppm: 1,24 (3H, t, J=6.9 Hz), is 3.08 (2H, m), 3,71-of 3.80 (2H, m), is 4.15 (2H, s), a 4.83 (2H, t), 5,43 (1H, t), 6,21 (1H, t), 7,10 (1H, s), 7,17-of 7.23 (1H, m), of 7.36-7,52 (3H, m), 8,78 (1H, s).

MS (ESI): M+ 419

Example 3-56

1H NMR (DMSO-d6300 MHz) (δ) ppm: 1,53 (3H, d, J=6,8 Hz), and 3.72 (2H, m)to 3.99 (3H, s), is 4.21 (2H, s), 5,12 (1H, t), 5,70-5,90 (1H, m), 7,20-7,21 (1H, m), 7,40-of 7.55 (3H, m), 7,76 (1H, s), cent to 8.85 (1H, s), 15,00-15,20 (1H, user.).

MS (ESI): M+ 420

Example 3-57

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 1.52 (3H, d, J=6.8 Hz), 3,71 (2H, t), of 4.00 (3H, s)to 4.23 (2H, s), 5,10 (1H, t), 5,80-5,90 (1H, m), 7,20-7,30 (1H, m), 7,51 (1H, s), 7,60-to 7.67 (2H, m), cent to 8.85 (1H, s), the 14.90-15,10 (1H, user.).

MS (ESI): M+ 438

Example 358 for

1H NMR (DMSO-d6400 MHz) (δ) ppm: of 1.03 (3H, d, J=8,4 Hz), 1,78-to 1.87 (2H, m), of 3.73 of 3.75 (2H, m), of 4.12 (2H, t), 4,20 (2H, s), is 4.85 (2H, t)to 4.92 (1H, t), 7,20 (1H, m), 7,39-7,51 (3H, m), 7,76 (1H, s), 8,68 (1H, s), 15,17 (1H, s).

MS (ESI): M+ 434

Example 3-59

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 1.35 (6H, s), 3.72 points of 3.75 (2H, m), 4,20 (2H, s), a 4.83-4,91 (4H, m), 7,20 (1H, m), 7,39-7,49 (3H, m), 7,74 (1H, s), 8,66 (1H, s), 15,18 (1H, s).

MS (ESI): M+ 434

Example 3-60

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,86 (3H, t, J=7,3 Hz), 1,80-2,10 (2H, m), 3,70-are 3.90 (2H, m), 4.26 deaths (2H, s), 5,00-5,10 (1H, m)to 5.17 (1H, t, J=5.4 Hz), 7,19-7,24 (1H, m), 7,39-7,51 (2H, m), to 7.84 (1H, d, J=8,8 Hz), 8,20 (1H, d, J=8,8 Hz), 8,23 (1H, s), 8,86 (1H, s)15,24 (1H, s).

MS (ESI): M+ 404

Example 3-61

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 1.36 (3H, t, J=6.9 Hz), of 1.52 (3H, d, J=6.6 Hz), 3,78-of 3.80 (2H, m), of 4.12 (2H, s), 4.26 deaths (2H, square, =7,0 Hz), to 5.21-and 5.30 (2H, m), 7,16-7,24 (2H, m), 7,40-7,46 (2H, m)to 8.14 (1H, s), 8,81 (1H, s), 15,40-15,60 (1H, usher.).

MS (ESI): M+ 434

Example 3-62

1H NMR (DMSO-d6300 MHz) (δ) ppm: 2,88 (6H, s), 3,70-of 3.80 (2H, m), 4,22 (2H, s), 4,60-4,70 (2H, m), of 5.05 (1H, t), 7,20-7,31 (3H, m), 7,50-of 7.60 (1H, m), 7,80 (1H, s), 8,78 (1H, s), 15,30-15,40 (1H, usher.).

MS (ESI): M+ 419

Example 3-63

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,90-of 1.29 (5H, m), 1,62 and 1.80 (6H, m), 3.75 to of 3.78 (2H, m), of 3.96 (2H, d, J=10,8 Hz), 4,13 (2H, s), 4,60-to 4.62 (2H, m), 5,02 (1H, t), 7,06-7,24 (2H, m), 7,14 (1H, s), 7,42-7,44 (1H, m), 8,16 (1H, s), 8,79 (1H, s).

MS (ESI): M+ 488

Example 3-64

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,85-to 0.89 (6H, m), 2,96-of 3.00 (2H, m), of 3.10-3.20 (2H, m), 3.33 and is 3.40 (2H, m), 4,22 (2H, s), 4,74 (1H, t), 5,09-5,10 (2H, m), 7,20 (1H, m), 7,38-7,47 (2H, m), to 7.59 (1H, s), 7,89 (1H, s), 8,72 (1H, s), 15,08 (1H, s).

MS (ESI): M+ 447

Example 3-65

1H NMR (DMSO-d6300 MHz) (δ) ppm: only 2.91 (3H, d, J=4,7 Hz), 3.75 to-3,81 (2H, m)to 4.01 (2H, s), 4,50-4,55 (2H, m), 5,04 (1H, t, J=5.5 Hz), 6,59 (1H, s), 6,60 of 6.68 (1H, m), 7,15-7,24 (2H, m), 7,51-of 7.55 (1H, m), 7,63 (1H, s), 8,65 (1H, s), 15,90 (1H, s).

MS (ESI): M+ 405

Example 3-66

1H NMR (DMSO-d6300 MHz) (δ) ppm: 1,91 is 2.00 (4H, m), 3,40-to 3.50 (4H, m), 3,70-3,81, (2H, m), 4,30 (2H, s), 4,50-4,55 (2H, m), of 5.05 (1H, t), 6.87 in (1H, s), 7,10 for 7.12 (1H, m), 7.18 in-7,21 (1H, m), 7,49-7,52 (1H, m), 7,72 (1H, C)8,69 (1H, s), 15,65 (1H, s).

MS (ESI): M+ 445

Example 3-67

1H NMR (DMSO-d6400 MHz) (δ) ppm: the 1.44 (3H, t), of 1.55 (3H, d), 3,70-of 3.77, (2H, m), 4,19 (2H, s), 4,28 (2H, square, J=8,8 Hz), 5,14 (1H, t), of 5.83-5,90 (1H, m), 7,20 (1H, m), 7,39-7,40 (1H, m), of 7.48-to 7.50 (2H, m), of 7.75 (1H, ), 8,86 (1H, s), 15,13 (1H, s).

MS (ESI): M+ 434

Example 3-8

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,86 (3H, t, J=7,3 Hz)to 1.37 (3H, t, J=6.9 Hz), 1,80-2,00, (2H, m), 3,70-are 3.90 (2H, m), of 4.12 (2H, s), 4,20-to 4.28 (2H, m), 5,00-5,17 (2H, m), 7,14-7,30 (2H, m), 7,42-7,49 (2H, m), 8,14 (1H with), 8,78 (1H, s), 15,50 (1H, s).

MS (ESI): M+ 448

Example 3-69

1H NMR (DMSO-d6400 MHz) (δ) ppm: 1,09-of 1.27 (5H, m), 1,68-to 1.82 (6H, m), 3,71-to 3.73 (2H, m), 3,99 (2H, d, J=5.6 Hz), 4,20 (2H, s), 4.80 to around 4.85 (2H, m)to 4.92 (1H, t, J=5.6 Hz), 7,20 (1H, m), 7,38-7,40 (1H, m), 7,40-7,53 (2H, m), of 7.75 (1H, s), 8,68 (1H, s), 15,16 (1H, s).

MS (ESI): M+ 488

Example 3-70

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,70 (3H, d, J=6.4 Hz), of 1.12 (3H, d, J=6.4 Hz), 2,30-to 2.40 (1H, m), 3.75 to of 3.78 (1H, m), 3.95 to 4.00 points (1H, m), 4,25 (2H, s), 4.80 to around 4.85 (1H, m), is 5.18 (1H, t), 7,20-7,21 (1H, m), 7,41-of 7.48 (2H, m), to 7.84 (1H, d), 8,21 (1H, s), of 8.25 (1H, d, J=9,2 Hz), of 8.92 (1H, s), 15,21 (1H, s).

MS (ESI): M+ 418

Example 3-71

1H NMR (DMSO-d6400 MHz) (δ) ppm: of 0.85 (3H, d), of 0.90 (3H, d), of 1.40-1.50 (1H, m), 1,80 is 1.91 (2H, m), 3,71-of 3.80 (2H, m), 4,25 (2H, s), 5,15-5,20 (2H, m), 7,20-7,21 (1H, m), 7,41-of 7.48 (2H, m), to 7.84 (1H, d, J=8,8 Hz), by 8.22 (1H, s), 8,24 (1H, d, J=8,8 Hz), 8,83 (1H, s), 15,20 (1H, s).

MS (ESI): M+ 432

Example 3-72

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,86 (3H, t, J=7,3 Hz)of 1.23 (6H, m), 1,80-2,00 (2H, m), 3,70-are 3.90 (2H, m), 4.09 to (2H, s), 5,00-5,18 (3H, m), 7,12-7,21 (2H, m), 7,44-7,47 (2H, m), to 8.20 (1H, s), 8,79 (1H, s), 15,54 (1H, C).

MS (ESI): M+ 462

Example 3-73

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 0.87 (3H, t, J=7,3 Hz), 1,80-2,10 (2H, m), 3,70-are 3.90 (2H, m), was 4.02 (3H, s), 4,11 (2H, s), 5,00-5,19 (2H, m), 7,16-7,24 (2H, m), 7,44-of 7.48 (2H, m), of 8.04 (1H, s), 8,78 (1H, s), 15,44 (1H, C).

MS (ESI): M+ 434

Example 3-74

1H NMR (DMSO-d6 300 MHz) (δ) ppm: of 1.23 (6H, DH)and 1.51 (3H, d, J=6.6 Hz), of 3.77 (2H, t), 4.09 to (2H, s), 4,90-5,10 (1H, m), 5,19-and 5.30 (2H, m), 7,12-7,21 (2H, m), 7,41-7,47 (2H, m), to 8.20 (1H, s), 8,81 (1H, s), 15,55 (1H, s).

MS (ESI): M+ 448

Example 3-75

1H NMR (DMSO-d6400 MHz) (δ) ppm: 1.00 and (9H, s), 4,07-4,12 (2H, m), 4,30 (2H, s), 5,12-5,14 (2H, m), 7,20-of 7.25 (1H, m), 7,40 was 7.45 (1H, m), 7,51-7,53 (1H, m), 7,87 (1H, d), of 8.25 (1H, s), to 8.41 (1H, d, J=9,2 Hz), cent to 8.85 (1H, C), 15,20-15,21 (1H, usher.).

MS (ESI): M+ 432

Example 3-76

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,70-3,81 (4H, m), is 4.15 (2H, s), 4,24 (2H, t, J=5.0 Hz), 4,60-to 4.62 (2H, m), 5,00-5,02 (2H, m), 7,15-7,20 (1H, m), 7,32-7,34 (2H, m), 7,44-7,49 (1H, m), of 8.06 (1H, s), 8,79 (1H, s), 15,48 (1H, s).

MS (ESI): M+ 436

Example 3-77

1H NMR (DMSO-d6300 MHz) (δ) ppm: 1,90-of 1.92 (2H, m), 3,53-of 3.54 (2H, m), 3,70-of 3.80 (2H, m), of 4.12 (2H, s), 4,20-4,30 (2H, m), 4,60-4,70 (3H, m), 5,02 (1H, t), 7,16-7,22 (2H, m), 7,30 (1H, s), 7,40-7,50 (1H, m), 8,11 (1H, ), 8,80 (1H, s).

MS (ESI): M+ 450

Example 3-78

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 3.10-3.20 (2H, m), 3,60-of 3.80 (4H, m), is 4.15 (2H, s), 4,78-4,85 (3H, m), and 5.30-of 5.40 (1H, m), 6,10-of 6.20 (1H, m), 7,15-7,20 (2H, m), 7,30-7,52 (3H, m), 8,77 (1H, s), 15,33 (1H, s).

MS (ESI): M+ 435

Example 3-79

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 0.89 (3H, t, J=7.4 Hz), 1,90-2,00 (2H, m), 3,70-of 3.80 (2H, m)to 3.99 (3H, s), 4,22 (2H, s), of 5.15 (1H, t, J=5.4 Hz), 5,70-5,80 (1H, m), 7,19-7,24 (1H, m), 7,38-7,52 (2H, m), 7,55 (1H, s), to 7.77 (1H, s), 8,86 (1H, s), 15,12 (1H, s).

MS (ESI): M+ 434

Example 3-80

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 1.59 (3H, d, J=7,2 Hz), 2,61 (3H, s), 2,80 (3H, s), 4,20 (2H, s), 4,96 (1H, t, J=5.6 Hz), 6,50-6,60 (1H, m), 7,19-of 7.23 (1H, m), 7,40-7,49 (2H, m), 7,60 (1H, s), 7,80 (1H,s), 8,81 (1H, s), 15,06 (1H, s).

MS (ESI): M+ 433

Example 3-81

1H NMR (DMSO-d6300 MHz) (δ) ppm: 4,10-and 4.40 (4H, m), 5,50-the ceiling of 5.60 (1H, m), 6,20-6,30 (1H, m), 7,19-7,22 (1H, m), 7,30-7,40 (6H, m), 7,40-7,50 (1H, m), to 7.77 (1H, d), of 8.00 (1H, d), 8,21 (1H, s), 9,03 (1H, s), 15,11 (1H, s).

MS (ESI): M+ 452

Example 3-82

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,86 (3H, t), of 1.18 to 1.34 (2H, m), 1,87-to 1.98 (2H, m), of 3.73-a-3.84 (2H, m), 4,25 (2H, s), 5,13-5,17 (2H, m), 7,21 (1H, m), 7,41-of 7.48 (2H, m), 7,83 (1H, d, J=8.0 Hz), 8,19 (1H, d), by 8.22 (1H, C), cent to 8.85 (1H, s), 15,22 (1H, s).

MS (ESI): M+ 418

Example 3-83

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 0.72 (3H, t, J=7,3 Hz), 0,90-1,20 (5H, m), 2,10-of 2.30 (1H, m), 3,70-of 3.80 (1H, m), 3,90-4,10 (1H, m), 4.26 deaths (2H, s), 4,90-5,00 (1H, m), 5,10-5,20 (1H, m), 7,20-of 7.25 (1H, m), 7,40-7,52 (2H, m,), to 7.84 (1H, d, J=7.8 Hz), 8,23 (1H, s), compared to 8.26 (1H, d), of 8.92 (1H, s), 15,22 (1H, s).

MS (ESI): M+ 432

Example 3-84

1H NMR (DMSO-d6300 MHz) (δ) ppm: and 1.54 (3H, d, J=6.6 Hz), 3,81-3,82 (2H, m), was 4.02 (3H, s), of 4.12 (2H, s), with 5.22 (1H, t, J=5.4 Hz), 5,23-of 5.40 (1H, m), 7,15-7,26 (2H, m), 7,44 is 7.50 (2H, m), with 8.05 (1H, s), 8,82 (1H, s), 15,46 (1H, s).

MS (ESI): M - 418

Example 3-85

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,25-to 3.38 (2H, m), 3,82-to 3.89 (2H, m), is 4.21 (2H, s), 5,27 (1H, t), 5.40 to-5,50 (1H, m), 7,10-7,21 (6H, m), 7,30-7,40 (1H, m), 7,40-7,50 (1H, m), to 7.77 (1H, d), 8,14 (1H, d), 8,14 (1H, s), 8,96 (1H, s), br15.15 (1H, s).

MS (ESI): M+ 466

Example 3-86

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,70-of 3.80 (2H, m), 4,42 (2H, s), 4,69 (2H, t), of 4.95 (1H, t), 7,37-7,42 (1H, m), 7,51 (1H, d, J=6.2 Hz), to 7.59 (1H, d, J=7.9 Hz), 8,48 (1H, s), 8,99 (1H, s), 9,04 (1H, s), 14,68 (1H, ).

MS (ESI): M+ 393

Example 4-1

1H NMR (DMSO-d6 400 MHz) (δ) ppm: 3,26 (3H, s), 3,74 (2H, m), 4,42 (2H, s), br4.61 (2H, m), 5,09 (1H, usher.), for 7.78 (1H, m), to 7.84 (2H, m), 8,04-8,07 (2H, m), 8,18 (1H, m), 8,86 (1H, s), 15,19 (1H, s).

MS (ESI): M+435

Example 4-2

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 3.73 (2H, m)to 4.23 (2H, s), 4,59 (2H, m), 4,99 (1H, usher.), then 7.20 (1H, m), 7,31-7,34 (2H, m), 7,44 (1H, m), a 7.85 (1H, m), 8,01 (1H, s), compared to 8.26 (1H, m), cent to 8.85 (1H, s), 15,27 (1H, s).

MS (ESI): M+407

Example 4-3

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 1.15 (3H, t, J=7,6 Hz), to 2.57 (2H, square, J=7,6 Hz), to 3.73 (2H, m), of 4.13 (2H, s), 4,59 (2H, m), 4,99 (1H, m), 7,05 (2H, m), 7,13 (1H, m), 7,20 (1H, m), 7,81 (1H, m), 7,98 (1H, m), 8,21 (1H, s), 8,84 (1H, s), 15,28 (1H, s).

MS (ESI): M+351

Example 4-4

1H NMR (DMSO-d6300 MHz) (δ) ppm with 1.07 (3H, t, J=7,53 Hz), 2,58 (2H, square, J=7,53 Hz), 3,76 (2H, m), 4,22 (2H, s), br4.61 (2H, m), 5,02 (1H, m), 7,19-of 7.23 (4H, m), 7,76 (1H, m), 8,01 (1H, m), of 8.09 (1H, s), 8,86 (1H, s), 15,26 (1H, s).

MS (ESI): M+351

Example 4-5

1H NMR (DMSO-d6300 MHz) (δ) ppm: 2,28 (3H, in), 3.75 (2H, m), 4,24 (2H, s), br4.61 (2H, m), 5,04 (1H, usher.), 7,13 (1H, d, J=8.1 Hz), 7,28 and 7.36 (2H, m), 7,81 (1H, d, J=6,7 Hz), 8,03 (1H, d, J=8,9 Hz), 8,13 (1H, s), 8,86 (1H, s)15,24 (1H, users).

MS (ESI): M+ 372

Example 4-6

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,75 (2H, m), the 4.29 (2H, s), to 4.62 (2H, m), 5,07 (1H, m), 7,19 (1H, m), 7,40 (1H, m), 7,52 (1H, m), to 7.84 (1H, m), with 8.05 (1H, m), 8,19 (1H, s), 8,87 (1H, s), 15,20 (1H, s).

MS (ESI): M+375

Example 4-7

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,75 (2H, m), the 4.29 (2H, s), br4.61 (2H, t, J=5.0 Hz), free 5.01 (2H, t, J=5.4 Hz), was 7.45 (1H, d), 7,51 (1H, d, J=11.2 Hz), 7,74 (1H, d), to 7.84 (1H, DD), 8,01 (1H, d), of 8.15 (1H, s), 8,86 (1H, C), 15,21 (1H, users).

MS (ESI): M+ 436

Example 4-8

Example 4-9

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,76 (2H, m), 4,34 (2H, s), 4,59 (2H, m), free 5.01 (1H, m), 7,37 (2H, m), a 7.62 (1H, m), 8,07 (2H, m), 8,88 (1H, s), 14,99 (1H, s).

MS (ESI): M+409

Example 4-10

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,20 (3H, s), 3,74 (2H, m), or 4.31 (2H, s), br4.61 (2H, t)5,00 (1H, t), 7,55-7,66 (2H, m), 7,78 (1H, d), 7,84-7,89 (2H, m), 8,03 (1H, d, J=8,9 Hz), 8,30 (1H, s), 8,86 (1H, s), 15,27 (1H, users).

MS (ESI): M+ 402

Example 4-11

1H NMR (DMSO-d6400 MHz) (δ) ppm: 3,75 (2H, m), 4,18 (2H, s), br4.61 (2H, m), 5,02 (1H, m), 6,69 (1H, m), 6,77 (1H, m), 7.23 percent (1H, m), 7,80 (1H, m), 8,02 (1H, m), 8,15 (1H, s), 8,86 (1H, s), to 9.66 (1H, s)15,24 (1H, ).

MS (ESI): M+373

Example 4-12

1H NMR (DMSO-d6300 MHz) (δ) ppm: 3,75 (2H, m), the 4.29 (2H, s), 4,58 (2H, m)5,00 (1H, s), 7,31 (1H, m), 7,35 (1H, m), 7,58 (1H, m), 7,71 (1H, m), 7,82 (1H, m), 8,86 (1H, s).

MS (ESI): M+409

Example 4-13

1H NMR (DMSO-d6400 MHz) (δ) ppm: of 1.34 (3H, t, J=6.8 Hz), to 3.73 (2H, m)4,00 (2H, square, J=6,8 Hz), 4.09 to (2H, s), 4,59 (2H, m)5,00 (1H, m), 6.89 in (1H, m), to 6.95 (1H, m), 7,19 (1H, m), 7,27 (1H, m), 7,83 (1H, m), 7,97 (1H, m), 8,24 (1H, s), 8,84 (1H, s), 15,33 (1H, s).

MS (ESI): M+367

Example 4-14

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 3.73 (2H, m)4,06 (2H, s), 4,60 (2H, m), of 5.05 (1H, m), 6,74 (1H, m), 6,85 (1H, m), 7,05 (1H, m), 7,14 (1H, m), 7,82 (1H, m), to 7.99 (1H, m), 8,19 (1H, s), 8,84 (1H, s), of 9.55 (1H, ), 15,34 (1H, s).

MS (ESI): M+339

Example 4-15

1H NMR (DMSO-d6400 MHz) (δ) ppm: 2.49 USD (3H, s), of 3.77 (2H, m), 4,27 (2H, s), 4,60 (2H, m), 5,01 (1H, s), 7,17 (1H, m), 7,35 (1H, m), to 7.59 (1H, m), 7,78 (1H, s), 7,95 (1H, s), 8,81 (1H, s), 15,22 (1H, s).

MS ESI): M+406

Example 4-16

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 1.35 (3H, d), of 1.40 (3H, d), and 1.54 (3H, d, J=6,8 Hz), and 3.72 (2H, m), 4,20 (2H, s), 4,86 to 4.92 (1H, m), 5,12 (1H, t, J=5,2 Hz), 5,80-5,90 (1H, m), 7,20 (1H, m), 7,39-7,52 (3H, m), 7,74 (1H with), 8,84 (1H, s), 15,13 (1H, s).

MS (ESI): M+ 448

Example 4-17

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 0.89 (3H, t, J=7.2 Hz), of 1.35 to 1.37 (6H, d), 1,88 e 2.06 (2H, m), of 3.73-with 3.79 (2H, m), 4,20 (2H, s), 4.80 to 5,00 (1H, m), 5,16 (1H, t), 5,81 of 5.84 (1H, m), 7,20 (1H, m), 7,40-7,53 (3H, m), 7,75 (1H, s), 8,83 (1H, s), 15,09 (1H, s).

MS (ESI): M+ 462

Example 4-18

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,80-1,40 (6H, m), 1,40-1,60 (2H, m), 1,70-1,80 (1H, m), 1,80-2,10 (2H, m), 3,70-of 3.80 (1H, m), 3,90-4,00 (1H, m), 4.26 deaths (2H, s), 4.80 to 5,00 (1H, m), 5,19 (1H, t), 7,22-of 7.25 (1H, m), 7,42-7,49 (2H, m), a 7.85 (1H, d), by 8.22 (1H, s), compared to 8.26 (1H, d, J=9.1 Hz), of 8.95 (1H, s).

MS (ESI): M+ 458

Example 4-19

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,70 (3H, d, J=6.6 Hz), to 1.14 (3H, d, J=6.4 Hz), 1,21-of 1.24 (6H, m), 2,20-2,40 (1H, m), 3,70-of 3.80 (1H, m), 3,90-4,00 (1H, m), 4.09 to (2H, s), 4.80 to the 4.90 (1H, m), 5,00-5,20 (2H, m), 7,12-7,22 (2H, m), 7,43-7,47 (2H, m), 8,19 (1H, s), 8,87 (1H, s), 15,51 (1H, s).

MS (ESI): M+ 476

Example 4-20

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,97 (9H, s)of 1.18 (3H, d, J=5,9 Hz), of 1.26 (3H, d, J=6.0 Hz), Android 4.04-4.09 to (4H, m), 5,09-5,13 (3H, m), 7,12-7,21 (2H, m), 7,43-7,51 (2H, m), 8,19 (1H, s), 8,78 (1H, s), 15,46 (1H, s).

MS (ESI): M+ 490

Example 4-21

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 0.89 (3H, t, J=7,6 Hz)of 1.44 (3H, t), 1,92 e 2.06 (2H, m), of 3.78 (2H, m), 4,19 (2H, s), 4,25 (2H, square), to 5.17 (1H, t, 5.6 Hz), 5,78-of 5.83 (1H, m), 7,20 (1H, m), 7,39-7,51 (3H, m), 7,76 (1H, ), cent to 8.85 (1H, s), 15,11 (1H, s).

MS (ESI): M+ 448

Example 4-22

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,80-1,30 (6H, m), 1,50-1,80 (5H, m), 1,80-1,90 (2H, m), 3,60-of 3.80 (2H, m), 4.26 deaths (2H, s), 5,10-5,20 (2H, m), 7,22 (1H, m), 7,30 is 7.50 (2H, m), a 7.85 (1H, d), 8,23 (1H, d), 8,23 (1H, s), 8,84 (1H, s), 15,20 (1H, s).

MS (ESI): M+ 472

Example 4-23

1H NMR (DMSO-d6400 MHz) (δ) ppm: of 0.85 (3H, d), of 0.91 (3H, d), 1,24-of 1.27 (6H, m), 1,35 was 1.43 (1H, m), 1,70-1,80 (1H, m), 1,91-of 1.95 (1H, m), 3.75 to of 3.80 (2H, m), 4,08 (2H, s), 5,00-5,10 (1H, m), 5,16-5,19 (2H, m), 7,14-7,21 (2H,, m), 7,43-7,44 (2H, m), 8,18 (1H, s), 8,79 (1H, s).

MS (ESI): M+ 490

Example 4-24

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 0.72 (3H, d), of 1.09 (3H, d), 1,37-of 1.40 (6H, m), 2,35-of 2.38 (1H, m), of 3.77-with 3.79 (1H, m), 3,91-of 3.94 (1H, m), 4,20 (2H, s), 4.92 in-4,96 (1H, m), 5,23 (1H, t), 5,74-USD 5.76 (1H, m), 7,21 (1H, m), 7,40-7,53 (3H, m), of 7.75 (1H, s), 8,88 (1H, s), 15,08 (1H, s).

MS (ESI): M+ 476

Example 4-25

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,84 (3H, d, J=6,8 Hz)of 0.87 (3H, d, J=6,4 Hz)to 1.37 (3H, d, J=11.2 Hz), of 1.42 (3H, d, J=10,8 Hz), 1,83-to 1.87 (2H, m), 3,79-of 3.80 (2H, m), 4,20 (2H, s), 4,90-4,96 (1H, m), 5,20 (1H, t), between 6.08-6,10 (1H, m), 7,21 (1H, m), 7,39-of 7.55 (3H, m), of 7.75 (1H, s), 8,78 (1H, s), 15,08 (1H, s).

MS (ESI): M+ 490

Example 4-26

1H NMR (DMSO-d6400 MHz) (δ) ppm: of 0.91 (9H, s)of 1.35 (3H, d), the 1.44 (3H, d), as 4.02-a 4.03 (2H, m), 4,20 (2H, s), 4,92-of 4.95 (1H, m), of 5.15 (1H, t), to 6.43 (1H, t), 7,19-7,21 (1H, m), 7,39-of 7.48 (2H, m), 7,55 (1H, s), 7,79 (1H, C)8,80 (1H, s), 15,05 (1H, s).

MS (ESI): M+ 490

Example 4-27

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,76 (3H, t), 0,97-1,03 (2H, m)of 1.12 (3H, d), 2,10-of 2.20 (1H, m), 3.75 to of 3.80 (1H, m), 3,98-was 4.02 (1H, m), was 4.02 (3H, s), 4,11 (2H, s), 4,92-of 4.95 (1H, m), 5,19 (1H, t), 7,16-of 7.25 (2H, m), 7,44 is 7.50 (2H, m), 8,02 (1H, s), 8,87 (1H, s)15,40 (1H, s).

MS (ESI): M+ 462

the example 4-28

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,74 (3H, t, J=7,6 Hz), 0,99-of 1.03 (2H, m), is 1.11 (3H, d), of 1.37 (3H, t, J=6.8 Hz), 2,10-of 2.20 (1H, m), 3,70-of 3.80 (1H, m), 3.96 points-of 4.00 (1H, m), 4,11 (2H, s), 4.26 deaths (2H, square, J=7,2 Hz), 4.92 in-5,00 (1H, m), is 5.18 (1H, t), 7,14-to 7.18 (1H, m), 7.24 to to 7.25 (1H, m),7,40 (1H, s), 7,44-7,46 (1H, m)to 8.12 (1H, s), 8,86 (1H, s), 15,46 (1H, s).

MS (ESI): M+ 476

Example 4-29

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 0.89 (3H, t, J=7,3 Hz), 1,98 is 2.01 (2H, m), 2,70 (3H, s), 3,80-are 3.90 (2H, m), is 4.21 (2H, s), 5,10-to 5.21 (2H, m), 7,15-7,22 (2H, m), 7,49-7,51 (1H, m), the 7.65 (1H, s), of 8.04 (1H, s), 8,84 (1H, C)15,25 (1H, s).

MS (ESI): M+ 450

Example 4-30

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,70 (3H, d, J=6.5 Hz)and 1.15 (3H, d, J=6.5 Hz), of 1.37 (3H, t, J=6.9 Hz), 2,30-to 2.40 (1H, m), 3,70-of 3.80 (1H, m), 3,90-4,00 (1H, m), 4,11 (2H, s), 4,20-4,30 (2H, m), 4.80 to the 4.90 (1H, m), 5,18 (1H, t), 7,14-7,20 (1H, m), 7.24 to 7,26 (1H, m), 7,43-7,49 (2H, m), 8,13 (1H, s), 8,87 (1H, s), 15,49 (1H, s).

MS (ESI): M+ 462

Example 4-31

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,97 (9H, s)to 1.37 (3H, t, J=6.9 Hz), was 4.02-4,11 (4H, m), 4,25-or 4.31 (2H, m), 5,10-5,20 (2H, m), 7,14-7,26 (2H, m), 7,44-7,49 (2H, m)to 8.12 (1H, s), 8,78 (1H, s), 15,43 (1H, s).

MS (ESI): M+ 476

Example 4-32

1H NMR (DMSO-d6300 MHz) (δ) ppm: to 0.72 (3H, d, J=6.5 Hz), of 1.16 (3H, d, J=6.5 Hz), 2,30-of 2.50 (1H, m), 3,70-are 3.90 (1H, m), 3,90-4,00 (1H, m), a 4.03 (3H, s), of 4.12 (2H, s), 4.80 to the 4.90 (1H, m), 5,19 (1H, t), 7,19-of 7.25 (2H, m), 7,46-7,51 (2H, m), of 8.04 (1H, s), 8,88 (1H, s), 15,44 (1H, s).

MS (ESI): M+ 448

Example 4-33

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,99 (9H, s), 3,99-4,11 (7H, m), 5,11-5,20 (2H, m), 7,19-of 7.25 (2H, m), 7,49-7,52 (2H, m), 8,03 (1H, s), 8,78 (1H, s), 15,39 (1H, s).

MS (ESI): M+ 462

Example 4-34

1 6300 MHz) (δ) ppm: 0,93 (9H, s), 3,90-a 4.03 (5H, m), 4,22 (2H, s), 5,10 (1H, t), of 6.20 (1H, t), 7,20-7,30 (1H, m), 7,40-EUR 7.57 (2H, m), 7,60 (1H, s), 7,79 (1H, s), 8,78 (1H, s), 15,05 (1H, s).

MS (ESI): M+ 462

Example 4-35

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,86 (3H, t, J=7.2 Hz), 1,19-of 1.29 (8H, m), 1,90-of 1.93 (2H, m), 3.72 points-of 3.80 (2H, m), 4,08 (2H, s), 5,02-5,04 (1H, m), 5,10-5,20 (2H, m), 7,11-7,22 (2H, m), 7,43-7,46 (2H, m), 8,18 (1H, s), 8,78 (1H, s), 15,51 (1H, s).

MS (ESI): M+ 476

Example 4-36

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 0.88 (3H, t, J=7.2 Hz), 1,20-of 1.35 (2H, m)of 1.36 (3H, t, J=6.8 Hz), 1,80-2,00 (2H, m), 3,70-of 3.80 (2H, m), 4,11 (2H, s), 4,25 (2H, square, J=7,2 Hz), to 5.17 (1H, t, J=5.6 Hz), 7,14-to 7.18 (1H, m,), 7,24-7,26 (1H, m), 7,41 (1H, s), 7,41 was 7.45 (1H, m), 8,13 (1H, s), 8,78 (1H, s), 15,48 (1H, s).

MS (ESI): M+ 462

Example 4-37

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,93 (9H, s), for 1.49 (3H, t), of 4.00 (2H, t, J=6.4 Hz), 4,20 (2H, s), 4,22-to 4.33 (2H, m), 5,12 (1H, t), 6,36 (1H, t, J=6.8 Hz), 7,21 (1H, m), 7,39-of 7.48 (2H, m), 7,54 (1H, s), 7,79 (1H, ), 8,79 (1H, s), 15,04 (1H, s).

MS (ESI): M+ 476

Example 4-38

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 0.89 (3H, t, J=8.0 Hz), 1,23-of 1.40 (2H, m), 1,80-2,00 (2H, m), 3.75 to 3,90 (2H, m), was 4.02 (3H, s), 4,11 (2H, s), 5,10-to 5.21 (2H, m), 7,16-7,24 (2H, m), 7,44-7,49 (2H, m), 8,03 (1H, s), 8,80 (1H, s), 15,44 (1H, usher.).

MS (ESI): M+ 448

Example 4-39

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,74 (3H, t, J=7,1 Hz), 0,84-1,24 (11H, m), 2,10-of 2.30 (1H, m), 3,70-of 3.80 (1H, m), 3,90-4,00 (1H, m), 4.09 to (2H, s), 4.80 to to 5.17 (3H, m), 7,15-7,22 (2H, m), 7,40-to 7.50 (2H, m), 8,19 (1H, s), 8,87 (1H, s), 15,51 (1H, s).

MS (ESI): M+ 490

Example 4-40

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,80-0,89 (1H, m), 1.04 million-1,30 (11H, m), 1,50-1,60 (2H,m), 1,70-1,80 (1H, m), 1.93 and is 2.01 (2H, m), of 3.73 is 3.76 (1H, m), 3.96 points-of 4.00 (1H, m), 4,07 (2H, s), 4.80 to 4,89 (1H, m), 5,00-5,17 (2H, m), 7,12-7,21 (2H, m), 7,40-7,42 (2H, m), 8,17 (1H, s), 8,87 (1H, s).

MS (ESI): M+ 516

Example 4-41

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,80-1,30 (6H, m)of 1.46 (3H, t, J=6.9 Hz), 1,50-1,70 (2H, m), 1,70-1,80 (1H, m), 1,90-2,10 (2H, m), 3,70-3,81 (1H, m), 3,92-4,00 (1H, m), 4,20 (3H, s)to 4.23 (2H, square, J=6.6 Hz), 5,20 (1H, t, J=4,8 Hz), 5,70-of 5.81 (1H, m), 7,19-7,24 (1H, m), 7,38-7,51 (3H, m), to 7.77 (1H, s), 8,91 (1H, s), 15,11 (1H, s).

MS (ESI): M+ 502

Example 4-42

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,84-of 1.30 (6H, m), 1,50-1,70 (2H, m), 1,70-1,90 (1H, m), 1,94 is 2.10 (2H, m), 3,70-with 3.79 (1H, m), 3,90-4,00 (1H, m), a 4.03 (3H, s), 4,10 (2H, s), 4.80 to 5,00 (1H, m), 5,19 (1H, m), 7,19-7,30 (2H,, m), 7,43-of 7.48 (2H, m), 8,02 (1H, s), 8,87 (1H, s), 15,45 (1H, s).

MS (ESI): M+ 488

Example 4-43

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,80-1,00 (1H, m), 1,14 of 1.28 (5H, m)to 1.37 (3H, t, J=6.9 Hz), 1,50-1,70 (2H, m), 1,70-1,80 (1H, m), 1,90-2,10 (2H, m), 3,70-of 3.80 (1H, m), 3,90-4,00 (1H, m), 4,11 (2H, s), 4,25 (2H, square), 4,80-5,00 (1H, m), is 5.18 (1H, m), 7,17-7,26 (2H, m), 7,41-7,47 (2H, m), 8,13 (1H, s)8,89 (1H, s).

MS (ESI): M+ 502

Example 4-44

1H NMR (DMSO-d6300 MHz) (δ) ppm: 0,80-1,00 (1H, m), 1,00-1,40 (5H, m), 1,50-1,70 (2H, m), 1,70-1,80 (1H, m), 1,90-2,10 (2H, m), 3,70-of 3.80 (1H, m), 3,90-4,00 (1H, m), 3,98 (3H, s), is 4.21 (2H, s), 5,20 (1H, m), the ceiling of 5.60-5,70 (1H, m), 7,19-of 7.25 (1H, m), 7,39-rate of 7.54 (3H, m), to 7.77 (1H, s)of 8.92 (1H, s).

MS (ESI): M+ 488

Example 4-45

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,74 (3H, d, J=4.0 Hz), a 1.08 (3H, d, J=8.0 Hz), a 1.45 (3H, t, J=8.0 Hz), a 2.36-2.40 a (2H, m), 3,70-of 3.80 (1H, m), 3,89-3,93 (1H, m), 4,19 (2H, s), 4.26 deaths (2H, square, J=8.0 Hz), 5,20 (1H, t, J=8.0 Hz), 5,69-5,73 (1H, m), 7,17-7,20 (1H, m), 7,39 (1H, m), 48-7,51 (2H, m), 7,76 (1H, s)8,89 (1H, s).

MS (ESI): M+ 462

Example 4-46

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 0.73 (3H, d, J=6.8 Hz), a 1.08 (3H, d, J=6.8 Hz), 2,20-2,40 (2H, m), 3,81-3,91 (1H, m), 3,91-to 3.99 (1H, m)to 3.99 (3H, s), 4,22 (2H, s), 5,20 (1H, m), 5,55-to 5.58 (1H, m), 7,10-7,22 (1H, m), 7,41-of 7.55 (3H, m), to 7.77 (1H, s), 8,91 (1H, s), 15,09 (1H, s).

MS (ESI): M+ 448

The example about 4-47

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 0.85 (3H, d, J=7,3 Hz), 1,10-of 1.34 (2H, m)of 1.33 (6H, d, J=6.0 Hz), 1.70 to a 2.00 (2H, m in), 3.75 (2H, m), 4,17 (2H, s), 4.80 to the 4.90 (1H, m), 5,14 (1H, m), 5,80-6,00 (1H, m), 7,10-7,20 (1H, m), 7,30 is 7.50 (3H, m), 7,72 (1H, s), 8,80 (1H, s).

MS (ESI): M+ 476

Example 4-48

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 0.89 (3H, t), 1,20-1,40 (2H, m)of 1.44 (3H, t), 1,80-2,00 (2H, m), of 3.78 (2H, m), 4,20 (2H, s)to 4.23 (2H, square, J=6,8 Hz), 5,16 (1H, t, J=5.6 Hz), 5,90-of 5.92 (1H, m), 7,15-7,21 (1H, m), 7,39-7,52 (3H, m), 7,76 (1H, s), 8,84 (1H, s), 15,10 (1H, s).

MS (ESI): M+ 462

Example 4-49

1H NMR (DMSO-d6400 MHz) (δ) ppm: to 0.89 (3H, t), of 1.23 and 1.35 (2H, m), 1,87 is 1.96 (2H, m), 3.72 points-with 3.79 (2H, m), 3,98 (3H, s), is 4.21 (2H, s), of 5.15 (1H, t, J=5,2 Hz), 5,85-5,88 (1H, m), 7,15-7,21 (1H, m), 7,39-of 7.48 (2H, m), 7,54 (1H, s), 7,76 (1H, s), cent to 8.85 (1H, s), 15,10 (1H, s).

MS (ESI): M+ 448

Example 4-50

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,80-1,00 (1H, m), 1,11-1,20 (4H, m), 1,20-1,30 (1H, m)of 1.35 (3H, d), of 1.40 (3H, d), 1,55-1,70 (2H, m), 1,72 and 1.80 (1H, m), 1,95 is 2.10 (2H, m), of 3.77-with 3.79 (1H, m), 3.95 to 3,98 (1H, m), 4,20 (2H,with), 4,91-4,94 (1H, m), of 5.24 (1H, t), 5,81-of 5.83 (1H, m), 7,15-7,21 (1H, m), 7,39-to 7.50 (2H, m), 7,53 (1H, s), 7,74 (1H, s)8,89 (1H, s), 15,09 (1H, s).

MS (ESI): M+ 516

Example 4-51

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 0.91 (9H, s)to 1.48 (3H, t, J=6.9 Hz), 3,90-4,00 (2H, m), 4,1 (2H, C), 4,22 (2H, square, J=7,0 Hz), 4,90-5,00 (1H, m), 6,10-of 6.20 (1H, m), 7,17-7,22 (1H, m), 7,34 and 7.36 (2H, m), 7,45 is 7.50 (1H, m), to 7.77 (1H, s), is 8.75 (1H, s).

MS (ESI): M+ 476

Example 4-52

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,93 (9H, s), 3,90-was 4.02 (2H, m), is 4.15 (2H, s), 4.80 to to 4.81 (1H, m), of 5.05 (1H, m), 7,19-7,21 (1H, m), 7,35-7,40 (1H, m), 7,43 was 7.45 (1H, m), EUR 7.57 (1H, d), 8,01-8,03 (1H, d, J=8,8 Hz), 8,12 (1H, s), 8,76 (1H, s).

MS (ESI): M+ 432

Example 4-53

1H NMR (DMSO-d6400 MHz) (δ) ppm: 0,81 (3H, d), of 1.20 (3H, d), 2,28-to 2.41 (1H, m), 3,98 (3H, s), 4,00-of 4.05 (2H, m), 4,08 (2H, s), 4,51-4,60 (1H, m), 7,02-was 7.08 (2H, m), 7,19 (1H, s), 7,28-7,30 (1H, m), 8,15 (1H, s), 8,60 (1H, s).

MS (ESI): M+ 448

Example 4-54

1H NMR (DMSO-d6300 MHz) (δ) ppm: of 0.95 (9H, s), of 3.96 (3H, s), 3.96 points-a 4.03 (4H, m), a 4.83 (1H, m)to 5.17 (1H, m), 7,13-of 7.23 (2H, m), 7,28 (1H, s), 7,42-7,47 (1H, m), 7,80 (1H, s), 8,73 (1H, s).

MS (ESI): M+ 462

The list of sequences

sequence ID NO:1: donor+circuit for determining the activity of HIV integrase

sequence ID NO:2: donor - circuit for determining the activity of HIV integrase

sequence ID NO:3: target+circuit for determining the activity of HIV integrase

sequence ID NO:4: targeting the circuit for determining the activity of HIV integrase

Industrial applicability

As is evident from the above results, the compounds of the present invention possess high inhibitory activity against HIV integrase.

Therefore, compounds of the present invention are useful as pharmacist the economic agents for the prevention or treatment of AIDS, as anti-HIV agents with activity against inhibition of HIV integrase. In addition, when combined with other anti-HIV agents such as protease inhibitors, reverse transcriptase inhibitors and the like, these connections can become more effective anti-HIV agents. Since the compounds of the present invention possess high inhibitory ability, specific against the integrases, they can provide a safe pharmaceutical agents with minimal side effects for the person.

1. Antovic agent containing the compound 4-oxacilin, represented by the following formula [I]or its pharmaceutically acceptable salt as an active ingredient:

where

ring su represents a phenyl group, naftalina group or pyridyloxy group, each of which is optionally substituted by 1-5 substituents selected from the following group a,

where group a is the group consisting of cyanopropyl, phenyl group, nitro group, halogen atom, With1-4alkyl group, Halogens1-4alkyl group, halogenaryloxy, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -NRa1CORa3, -SO2Ra3, -N a1SO2Ra3and-COORa1,

where Raland Ra2the same or different, and each represents a hydrogen atom, a C1-4alkyl group or benzyl group, and Ra3is1-4alkyl group;

R1represented by the Deputy, selected from the following group b, or C1-10alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and the following group b, where group b represents the group consisting of phenyl groups, optionally substituted phenyl group or 1 to 5 halogen atoms; C3-6cycloalkyl group, imidazolidine group, benzothiophene group, thiazolidine group, optionally substituted by 1-3 C1-6alkyl groups, morpholinyl group, peredelnoj group, ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4and-NRa5COORa6,

where Ra4and Ra5the same or different, and each represents a hydrogen atom, a C1-4alkyl group or phenyl group, Ra6is1-4alkyl group;

R2represents a hydrogen atom or a C1-4alkyl group;

R31represents the atom bodoro is a, a cyano, a hydroxy-group, halogen atom or With1-4alkoxygroup;

X represents C-R32; and

Y represents C-R33or nitrogen atom,

where R32and R33the same or different, and each represents a hydrogen atom, a cyano, a halogen atom, pyrrolidinyloxy group, C1-10alkyl group, optionally substituted by 1-3 halogen atoms, -ORa7, -SRa7, -NRa7Ra8, -NRa7CORa9, -COORa10or-N=CH-NRa10Ra11,

where Ra7and Ra8the same or different, and each represents a hydrogen atom, phenyl group or1-10alkyl group, optionally substituted C3-6cycloalkyl group or a hydroxy-group, Ra9is1-4alkyl group, and Ra10and Ra11the same or different, and each represents a hydrogen atom or a C1-4alkyl group.

2. Antovic agent according to claim 1, where Y represents C-R33.

3. Antovic agent according to claim 1, where the ring su is

where

R4and R6the same or different, and each represents a Deputy selected from the group A (which has the values specified in claim 1);

R5is Deputy selected from a hydrogen atom and the group (which has a value the tion, specified in claim 1); and

m is 0 or an integer from 1 to 3, and when m is 2 or 3, then R6for each m may be the same or different.

4. Antovic agent according to claim 1, where R2represents a hydrogen atom.

5. Connection 4-oxacilin, represented by the following formula [II]or its pharmaceutically acceptable salt:

where

R4and R6the same or different, and each represents a Deputy selected from the following group a,

where group a is the group consisting of cyanopropyl, phenyl group, nitro group, halogen atom, With1-4alkyl group, Halogens1-4alkyl group, Halogens1-4alkyloxy, -ORa1, -SRa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3and-COORa1,

where Ra1and Ra2the same or different, and each represents a hydrogen atom, a C1-4alkyl group or benzyl group, and Ra3is1-4alkyl group;

R5represented by the Deputy chosen from a hydrogen atom and the above-mentioned group A;

m is 0 or an integer from 1 to 3, and when m is 2 or 3, then R6for each of m can be Odin is new or different;

R1represented by the Deputy, selected from the following group b or C1-10alkyl group, optionally substituted by 1-3 substituents selected from a halogen atom and the following group b,

where group is the group consisting of phenyl groups, optionally substituted phenyl group or 1 to 5 halogen atoms;

With3-6cycloalkyl group, imidazolidine group, benzothiophene group, thiazolidine group, optionally substituted by 1-3 C1-6alkyl groups, morpholinyl group, peredelnoj group ORa4, -SRa4, -NRa4Ra5, -CONRa4Ra5, -SO2NRa4Ra5, -CORa6, -NRa4CORa6, -SO2Ra6, -NRa4SO2Ra6, -COORa4and-NRa5COORa6,

where Ra4and Ra5the same or different, and each represents a hydrogen atom, a C1-4alkyl group or phenyl group, and Ra6is1-4alkyl group;

R31represents a hydrogen atom, a cyano, a hydroxy-group, halogen atom or With1-4alkoxygroup; and

R32and R33the same or different, and each represents a hydrogen atom, a cyano, a halogen atom, pyrrolidinyloxy group1-10alkyl group, optionally substituted with 1-3 halo atoms is s, ORa7,-SRa7, -NRa7Ra8, -NRa7CORa9, -COORa10or-N=CH-NRa10Ra11,

where Ra7and Ra8the same or different, and each represents a hydrogen atom, phenyl group or1-10alkyl group, optionally substituted C3-6cycloalkyl group or a hydroxy-group, Ra9is1-4alkyl group, and Ra10and Ra11the same or different, and each represents a hydrogen atom or a C1-4alkyl group.

6. Connection 4-oxacilin according to claim 5, where R31represents a hydrogen atom, a cyano, a hydroxy-group or1-4alkoxygroup, or its pharmaceutically acceptable salt.

7. Connection 4-oxacilin according to claim 6, where R31represents a hydrogen atom, or its pharmaceutically acceptable salt.

8. Connection 4-oxacilin according to claim 5, where

R32and R33the same or different, and each represents a hydrogen atom, a cyano, a halogen atom, pyrrolidinyloxy group1-10alkyl group, optionally substituted by 1-3 halogen atoms, ORa7, -SRa7, -NRa7Ra8, -NRa7CORa9, -COORa10or-N=CH-NRa10Ra11,

where Ra7and Ra8the same or different, and each represents a hydrogen atom, phenyl group or1-10alkyl groups is, optionally substituted C3-6cycloalkyl group or a hydroxy-group, Ra9is1-4alkyl group, and Ra10and Ra11the same or different, and each represents a hydrogen atom or a C1-4alkyl group, or its pharmaceutically acceptable salt.

9. Connection 4-oxacilin according to claim 5, where

R32represents a hydrogen atom, a cyano, a halogen atom, pyrrolidinyloxy group1-10alkyl group, optionally substituted by 1-3 halogen atoms, ORa7, -SRa7, -NRa7Ra8, -COORa10or-N=CH-NRa10Ra11,

where Ra7and Ra8the same or different, and each represents a hydrogen atom or a C1-10alkyl group, optionally substituted C3-6cycloalkyl group or a hydroxy-group, and Ra10and Ra11the same or different, and each represents a hydrogen atom or a C1-4alkyl group, or its pharmaceutically acceptable salt.

10. Connection 4-oxacilin according to claim 9, where R32represents a hydrogen atom, -ORa7or-NRa7Ra8where Ra7and Ra8the same or different, and each represents a hydrogen atom or a C1-10alkyl group, optionally substituted C3-6cycloalkyl group or a hydroxy-group,

or farmatsevticheskaia salt.

11. Connection 4-oxacilin of claim 8, where

R33represents a hydrogen atom, a C1-10alkyl group, optionally substituted by 1-3 halogen atoms, -ORa7, -NRa7Ra8or-NRa7CORa9,

where Ra7and Ra8the same or different, and each represents a hydrogen atom, phenyl group or1-10alkyl group, optionally substituted C3-6cycloalkyl group or a hydroxy-group, and Ra9is1-4alkyl group,

or its pharmaceutically acceptable salt.

12. Connection 4-oxacilin according to claim 11, where

R33represents a hydrogen atom, -ORa7or-NRa7Ra8,

where Ra7and Ra8the same or different, and each represents a hydrogen atom, a phenyl group or a C1-10alkyl group, optionally substituted C3-6cycloalkyl group or a hydroxy-group, or its pharmaceutically acceptable salt.

13. Connection 4-oxacilin on any of PP-12, where Ra7and Ra8the same or different, and each represents C1-10alkyl group, optionally substituted C3-6cycloalkyl group or a hydroxy-group, or its pharmaceutically acceptable salt.

14. Connection 4-oxacilin according to claim 5, where

R4and R5the same elerslie, and each represents a Deputy selected from cyanopropyl, phenyl group, nitro group, halogen atom, a C1-4alkyl group, Halogens1-4alkyl group, Halogens1-4alkyloxy, -ORa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -NRa1CORa3, -SO2Ra3, -NRa1SO2Ra3and-COORa1,

where Ra1and Ra2the same or different, and each represents a hydrogen atom, a C1-4alkyl group or benzyl group, and Ra3is1-4alkyl group, or its pharmaceutically acceptable salt.

15. Connection 4-oxacilin at 14, where

R4represents a phenyl group, a halogen atom, a C1-4alkyl group, Halogens1-4alkyloxy, -ORa1, -NRa1Ra2, -SO2NRa1Ra2, -NRa1CORa3, -SO2Ra3, -HRa1SO2Ra3or-COORa1,

where Ra1and Ra2the same or different, and each represents a hydrogen atom, a C1-4alkyl group or benzyl group, and Ra3is1-4alkyl group, or its pharmaceutically acceptable salt.

16. Connection 4-oxacilin indicated in paragraph 15, where R4represents a halogen atom, or its pharmaceutically acceptable salt.

17. Connection 4-ACS the quinoline according to claim 5, where

R5represents a hydrogen atom, a cyano, a phenyl group, a nitrogroup, a halogen atom, a C1-4alkyl group, Halogens1-4alkyl group, Halogens1-4alkyloxy, -ORa1, -NRa1Ra2, -CONRa1Ra2, -SO2NRa1Ra2, -NRa1CORa3or-SO2Ra3,

where Ra1and Ra2the same or different, and each represents a hydrogen atom or a C1-4alkyl group, and Ra3is1-4alkyl group, or its pharmaceutically acceptable salt.

18. Connection 4-oxacilin according to claim 5, where R6represents a halogen atom, or its pharmaceutically acceptable salt.

19. Connection 4-oxacilin according to claim 5, where m is 0 or 1, or its pharmaceutically acceptable salt.

20. Connection 4-oxacilin according to claim 5, where R1is:

phenyl group optionally substituted phenyl group or 1 to 5 halogen atoms, C3-6cycloalkyl group, -NRa4Ra5, -NRa4CORa6, -NRa4SO2Ra6and NRa5COORa6,

where Ra4and Ra5the same or different, and each represents a hydrogen atom, a C1-4alkyl group or phenyl group, and Ra6is1-4alkyl group,

or

With1-10alkyl groups is, optionally substituted by 1-3 substituents selected from halogen atom and group b (which has the values listed in item 5),

or its pharmaceutically acceptable salt.

21. Connection 4-oxacilin according to claim 20, where

R1represents C1-10alkyl group, optionally substituted by 1-3 substituents selected from halogen atom and group b (which has the values listed in item 5),

or its pharmaceutically acceptable salt.

22. Connection 4-oxacilin according to claim 5, which is chosen from the group which includes the following connections:

6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-1),

6-(2,3-dichlorobenzyl)-8-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-2),

6-(2,3-dichlorobenzyl)-1-(2-methanesulfonylaminoethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-3),

6-(2,3-dichlorobenzyl)-1-(2-imidazol-1-retil)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-4),

6-(2,3-dichlorobenzyl)-1-dimethylcarbamoyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-5),

6-(2,3-dichlorobenzyl)-1-methylcarbamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-6),

1-carbamoylmethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-7),

6-(2,3-dichlorobenzyl)-1-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-8),

6-(2,3-dichlorobenzyl)-4-oxo-1-sulfamoyl-1,4-dihydroquinoline-3-carboxylic acid (example 1-9),

1-(2-carboxyethyl)-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-10),

1-(2-hydroxyethyl)-6-naphthalene-1-ylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-11),

methyl ester of 6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-12),

1-(2-carbamoylethyl)-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-13),

6-(2,3-dichlorobenzyl)-4-oxo-1-(2-oxopropyl)-1,4-dihydroquinoline-3-carboxylic acid (example 1-14),

1-benzyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-15),

6-(2,3-dichlorobenzyl)-4-oxo-1-phenethyl-1,4-dihydroquinoline-3-carboxylic acid (example 1-16),

6-(2,3-dichlorobenzyl)-1-(3-phenylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-17),

6-(2,3-dichlorobenzyl)-1-isobutyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-18),

6-(2,3-dichlorobenzyl)-1-(4-phenylbutyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-19),

1-biphenyl-2-ylmethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-20),

6-(2,3-shall chlorbenzyl)-1-(4-hydroxybutyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-21),

1-benzo[b]thiophene-2-ylmethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-22),

6-(2,3-dichlorobenzyl)-1-(3,4-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-23),

6-(2,3-dichlorobenzyl)-1-(2-dimethylaminoethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-24),

6-(2,3-dichlorobenzyl)-1-(3-hydroxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-25),

6-(2,3-dichlorobenzyl)-1-(2-methoxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-26),

6-(2,3-dichlorobenzyl)-1-(2,2,2-triptorelin)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-27),

1-carboxymethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-28),

6-(2,3-dichlorobenzyl)-1-[2-(4-methylthiazole-5-yl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-29),

6-(2,3-dichlorobenzyl)-1-(2-hydroxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-30),

6-(2,3-dichlorobenzyl)-1-(2-methylsulfonylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-32),

6-(2-chloro-6-terbisil)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-33),

6-(2,3-dichlorobenzyl)-1-(5-hydroxyphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-34),

6-(2,3-dichlorobenzyl)-1-(2-morpholine-4-retil)-4-oxo-1,-dihydroquinoline-3-carboxylic acid (example 1-35),

6-(2,3-dichlorobenzyl)-1-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-36),

6-(2,3-dichlorobenzyl)-1-ethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-37),

6-(2,3-dichlorobenzyl)-4-oxo-1-propyl-1,4-dihydroquinoline-3-carboxylic acid (example 1-38),

1-butyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-39),

1-cyclopentylmethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-40),

6-(2,3-dichlorobenzyl)-1-(2-methanesulfonyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-41),

1-cyclohexylmethyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-42),

6-(2,3-dichlorobenzyl)-1-(2-hydroxy-2-phenylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-43),

6-(2,3-dichlorobenzyl)-1-(2-foradil)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-44),

6-(2,3-dichlorobenzyl)-4-oxo-1-(2-pyridin-2-retil)-1,4-dihydroquinoline-3-carboxylic acid (example 1-45),

1-(2-amino-ethyl)-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-Z-carboxylic acid (example 1-46),

6-(2,3-dichlorobenzyl)-1-(2-hydroxy-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-47),

1-(2-acetylamino)-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-48),

6-(2,3-dichlorobenzyl)-1-(2-ethoxycarbonylmethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-49),

6-(2,3-diferensial)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-50),

6-(2-chloro-4-terbisil)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-51),

6-(2-Chlorobenzyl)-4-oxo-1-phenethyl-1,4-dihydroquinoline-3-carboxylic acid (example 1-65),

6-(2-chloro-3-terbisil)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-66),

6-(2,3-dichlorobenzyl)-1-methylsulfonylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-68),

6-(2,3-dichlorobenzyl)-1-methanesulfonyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-69),

1-tert-butylsulfonyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-70),

6-(2,3-dichlorobenzyl)-1-methylcarbamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-71),

6-(2,3-dichlorobenzyl)-1-dimethylsulphamoyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-72),

6-(2-chloro-3,6-diferensial)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-73),

6-(2,3-dichlorobenzyl)-1-(2,3-dihydroxypropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-74),

6-(2-chloro-6-terbisil)-1-sulfamoyl the l-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-75),

6-(2-chloro-6-terbisil)-1-methylcarbamoylmethyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-76),

6-(2-chloro-6-terbisil)-1-dimethylsulphamoyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-77),

6-(2-chloro-3-methylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-79),

6-(2-bromobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-80),

6-(2-chloro-3-methoxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-82),

1-(2-hydroxyethyl)-6-(2-methanesulfonylaminoethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-85),

6-biphenyl-2-ylmethyl-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-86),

6-(2-Chlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-87),

6-(2-chloro-5-methylsulfonylbenzoyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-92),

1-(2-hydroxyethyl)-4-oxo-6-(2-triftormetilfullerenov)-1,4-dihydroquinoline-3-carboxylic acid (example 1-93),

6-(2-chloro-5-methylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-97),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-99),

6-(3-chloro-2,6-debtorrent the l)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-100),

6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-101),

1-cyclopropyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 1-102),

1-amino-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2-1),

6-(2,3-dichlorobenzyl)-1-methoxycarbonylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2-2),

1-acetylamino-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2-3),

6-(2,3-dichlorobenzyl)-1-methanesulfonamido-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2-4),

6-(2,3-dichlorobenzyl)-1-(N-methanesulfonyl-N-methylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2-5),

6-(2,3-dichlorobenzyl)-1-dimethylamino-4-oxo-1,4-dihydroquinoline-Z-carboxylic acid (example 2-6),

6-(2,3-dichlorobenzyl)-1-methylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2-7),

6-(2,3-dichlorobenzyl)-1-ethylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 2-8),

6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-5-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-1),

6-(3-chloro-2-methylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-2),

6-(3-chloro-2-methoxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-Urbanova acid (example 3-3),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-4),

6-(2,3-dichlorobenzyl)-5-hydroxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-5),

6-(2,3-dichlorobenzyl)-7-hydroxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-6),

1-(2-hydroxyethyl)-6-(2-methylaminomethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-7),

6-(2-dimethylaminoethyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-8),

6-(2,3-dichlorobenzyl)-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid (example 3-9),

6-(2,3-dichlorobenzyl)-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-10),

1-cyclobutyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-12),

1-cyclopentyl-6-(2,3-dichlorobenzyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-13),

6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-14),

6-(2-dimethylaminovinyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-16),

6-(3-chloro-2,4-diferensial)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-17),

6-(2-carboxybenzoyl)--(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-18),

1-(2-hydroxyethyl)-6-(2-methylsulfonylbenzoyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-19),

6-(2,3-dichlorobenzyl)-7-ethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-20),

7-chloro-6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-21),

6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-7-trifluoromethyl-1,4-dihydroquinoline-3-carboxylic acid (example 3-22),

(S)-6-(3-chloro-2-terbisil)-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-23),

(R)-6-(3-chloro-2-terbisil)-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-24),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-8-trifluoromethyl-1,4-dihydroquinoline-3-carboxylic acid (example 3-25),

6-(3-chloro-2-terbisil)-1-[2-hydroxy-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-26),

7-cyano-6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-27),

6-(2-ethylmethylamino)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-28),

6-[2-(N-methyl-N-propylamino)benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-29),

6-[2-(N-benzyl-N-methylamino)benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-shall hydrochinon-3-carboxylic acid (example 3-30),

6-[2-(N-methanesulfonyl-N-methylamino)benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-31),

6-[2-(N-isopropyl-N-methylamino)benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-32),

1-tert-butyl-6-(3-chloro-2-terbisil)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-33),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-34),

8-amino-6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-35),

7-carboxy-6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-36),

6-(3-chloro-2,6-diferensial)-1-(2-hydroxyethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-37),

6-(3-chloro-2-terbisil)-8-dimethylamino-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-38),

8-acetylamino-6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-39),

5-cyano-6-(2,3-dichlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-40),

6-[2-(N-acetyl-N-methylamino)benzyl]-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-41),

6-(2-diethylaminoethyl)-1-(2-hydroxyethyl)-4-oxo-,4-dihydroquinoline-3-carboxylic acid (example 3-42),

6-(3-chloro-2-terbisil)-1-(1,1-dimethyl-2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-43),

6-(3-chloro-2-terbisil)-7-ethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-44),

6-(3-chloro-2-terbisil)-7,8-dimethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-45),

6-(3-chloro-2-terbisil)-8-ethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-47),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-8-methylamino-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-48),

6-(3-Chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-7-propyloxy-1,4-dihydroquinoline-3-carboxylic acid (example 3-49),

6-(3-chloro-2-terbisil)-7-(dimethylaminomethylene)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-50),

methyl ester of 6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-51),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-8-phenoxy-1,4-dihydroquinoline-3-carboxylic acid (example 3-52),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-53),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-8-propylamino-1,4-dihydroquinoline-3-carboxylic acid (example 3-54),

6-(3-chloro-2-terbisil)-8-ethylamino-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-55),

(S)-6-(3-chloro-2-terbisil)-1-(2-hydroxy-1-methylethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-56),

(S)-6-(3-chloro-2,6-diferensial)-1-(2-hydroxy-1-methylethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-57),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-8-propyloxy-1,4-dihydroquinoline-3-carboxylic acid (358 for example),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-59),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-60),

(S)-6-(3-chloro-2-terbisil)-7-ethoxy-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-61),

6-(3-chloro-2-terbisil)-7-dimethylamino-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-62),

6-(3-chloro-2-terbisil)-7-cyclohexylmethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-63),

6-(3-chloro-2-terbisil)-8-diethylamino-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-64),

6-(3-chloro-2-terbisil)-7-methylamino-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-65),

< num="2299"> 6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-4-oxo-7-pyrrolidin-1-yl-1,4-dihydroquinoline-3-carboxylic acid (example 3-66),

(S)-6-(3-chloro-2-terbisil)-8-ethoxy-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-67),

(S)-6-(3-chloro-2-terbisil)-7-ethoxy-1-[1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-68),

6-(3-chloro-2-terbisil)-8-cyclohexylmethoxy-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-69),

(S)-6-(3-chloro-2-terbisil)-1-(1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-70),

(S)-6-(3-chloro-2-terbisil)-1-(1-hydroxymethyl-3-methylbutyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-71),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)propyl]-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-72),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)propyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-73),

(S)-6-(3-chloro-2-terbisil)-1-(2-hydroxy-1-methylethyl)-7-isopropyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-74),

(S)-6-(3-chloro-2-terbisil)-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-75),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-7-(2-hydroxyethyloxy)-4-oxo-1,4-Digi rhinolin-3-carboxylic acid (example 3-76),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-7-(3-hydroxypropoxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-77),

6-(3-chloro-2-terbisil)-1-(2-hydroxyethyl)-8-(2-hydroxyethylamino)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-78),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)propyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-79),

(S)-6-(3-chloro-2-terbisil)-8-dimethylamino-1-(2-hydroxy-1-methylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-80),

(S)-6-(3-chloro-2-terbisil)-1-(2-hydroxy-1-phenylethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-81),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)butyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-82),

6-(3-chloro-2-terbisil)-1-((1S,2S)-1-hydroxymethyl-2-methylbutyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-83),

(S)-6-(3-chloro-2-terbisil)-1-(2-hydroxy-1-methylethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-84),

(S)-6-(3-chloro-2-terbisil)-1-(1-benzyl-2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 3-85),

6-(2-chloro-5-methanesulfonylaminoethyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-1),

6-(2-active compounds)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-Z-carboxylic acid (example 4-4),

6-(2-chloro-5-methylbenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-5),

6-(2-chloro-5-terbisil)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-6),

6-(5-bromo-2-Chlorobenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-7),

6-(2,3-dichlorobenzyl)-7-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-9),

6-(2-chloro-5-hydroxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-11),

6-(2,3-dichlorobenzyl)-5-fluoro-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-12),

6-(2-ethoxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-13),

6-(2-hydroxybenzyl)-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-14),

6-(2,3-dichlorobenzyl)-7-methyl-1-(2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-15),

(S)-6-(3-chloro-2-terbisil)-1-(2-hydroxy-1-methylethyl)-8-isopropoxy-4-oxo-1,4-dihydroquinoline-Z-carboxylic acid (example 4-16),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)propyl]- 8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-17),

(S)-6-(3-chloro-2-terbisil)-1-(1-cyclohexyl-2-hydroxyethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (PR which measures 4-18),

(S)-6-(3-chloro-2-terbisil)-1-(1-hydroxymethyl-2-methylpropyl)-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-19),

(S)-6-(3-chloro-2-terbisil)-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-20),

(S)-6-(3-chloro-2-terbisil)-8-ethoxy-1-[1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-21),

(S)-6-(3-chloro-2-terbisil)-1-[2-cyclohexyl-1-(hydroxymethyl)ethyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-22),

(S)-6-(3-chloro-2-terbisil)-1-(1-hydroxymethyl-3-methylbutyl)-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-23),

(S)-6-(3-chloro-2-terbisil)-1-(1-hydroxymethyl-2-methylpropyl)-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-24),

(S)-6-(3-chloro-2-terbisil)-1-(1-hydroxymethyl-3-methylbutyl)-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-25),

(S)-6-(3-chloro-2-terbisil)-[2,2-dimethyl-1-(hydroxymethyl)propyl]-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-26),

6-(3-chloro-2-terbisil)-1-((1S,2S)-1-hydroxymethyl-2-methylbutyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-27),

6-(3-chloro-2-terbisil)-7-ethoxy-1-((1S,2S)-1-hydroxymethyl-2-methylbutyl)-4-oxo-1,4-dihydroquinoline-3-ka is oil acid (example 4-28),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)propyl]-7-methylsulfanyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-29),

(S)-6-(3-chloro-2-terbisil)-7-ethoxy-1-(1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-30),

(S)-6-(3-chloro-2-terbisil)-7-ethoxy-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-31),

(S)-6-(3-chloro-2-terbisil)-1-(1-hydroxymethyl-2-methylpropyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-32),

(S)-6-(3-chloro-2-terbisil)-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-33),

(S)-6-(3-chloro-2-terbisil)-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-34),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)butyl]-7-isopropoxy-4-oxo-1,4-dihydroquinoline-Z-carboxylic acid (example 4-35),

(S)-6-(3-chloro-2-terbisil)-7-ethoxy-1-[1-(hydroxymethyl)butyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-36),

(S)-6-(3-chloro-2-terbisil)-8-ethoxy-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-37),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)butyl]-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-38),

6-(3-chloro-2-terbisil)-1-((1S,2S)-1-hydroxymethyl-2-methylbutyl)-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-39),

(S)-6-(3-chloro-2-terbisil)-1-(1-cyclohexyl-2-hydroxyethyl)-7-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-40),

(S)-6-(3-chloro-2-terbisil)-1-(1-cyclohexyl-2-hydroxyethyl)-8-ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-41),

(S)-6-(3-chloro-2-terbisil)-1-(1-cyclohexyl-2-hydroxyethyl)-7-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-42),

(S)-6-(3-chloro-2-terbisil)-1-(1-cyclohexyl-2-hydroxyethyl)-7-ethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-43),

(S)-6-(3-chloro-2-terbisil)-1-(1-cyclohexyl-2-hydroxyethyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-44),

(S)-6-(3-chloro-2-terbisil)-8-ethoxy-1-(1-hydroxymethyl-2-methylpropyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-45),

(S)-6-(3-chloro-2-terbisil)-1-(1-hydroxymethyl-2-methylpropyl)-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-46),

(S)-6-(3-chloro-2-terbisil)-1-[1-(hydroxymethyl)butyl]-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example about 4-47),

(S)-6-(3-chloro-2-terbisil)-8-ethoxy-1-[1-(hydroxymethyl)butyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-48),

(S)-6-(3-chlorine is-2-terbisil)-1-[1-(hydroxymethyl)butyl]-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-49),

(S)-6-(3-chloro-2-terbisil)-1-(1-cyclohexyl-2-hydroxyethyl)-8-isopropoxy-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-50) and

(S)-6-(3-chloro-2-terbisil)-1-[2,2-dimethyl-1-(hydroxymethyl)propyl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (example 4-52),

or its pharmaceutically acceptable salt.

23. The integrase inhibitor containing the compound 4-oxacilin according to any one of claims 1 to 22 or its pharmaceutically acceptable salt as an active ingredient.

24. Antiviral agent containing the compound 4-oxacilin on any of pp.5-22 or its pharmaceutically acceptable salt as an active ingredient.

25. Antiviral agent according to paragraph 24, which is antovic agent.

26. Antovic composition containing the compound 4-oxacilin according to any one of claims 1 to 22 or its pharmaceutically acceptable salt and one or more of the other types antovic active substances as the active ingredient.

27. Antovic agent containing the compound 4-oxacilin according to any one of claims 1 to 22, or its pharmaceutically acceptable salt as an active ingredient for the treatment of multiple drugs, including other (other) antovic agent(agents).

28. The use of compounds 4-oxacilin on any of pp.5-22 or its pharmaceutically acceptable salt to obtain integrase inhibitor.

29. Prima is giving compound 4-oxacilin on any of pp.5-22 or its pharmaceutically acceptable salt to obtain an antiviral agent.

30. The application of clause 29, where the antiviral agent is antovic agent.

31. Method of inhibiting integrase, which includes an introduction to the mammal an effective amount of the compound 4-oxacilin on any of pp.5-22 or its pharmaceutically acceptable salt.

32. The method of prevention or treatment of viral infectious diseases, which includes an introduction to the mammal an effective amount of the compound 4-oxacilin on any of pp.5-22 or its pharmaceutically acceptable salt.

33. The method according to p, where viral infectious disease is an HIV infectious disease.

34. The method according to p, which includes the further introduction to the specified mammal an effective amount of at least one other antovic active substances.

35. Pharmaceutical composition for inhibiting integrase, which contains the compound 4-oxacilin on any of pp.5-22 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

36. Antiviral composition comprising the compound 4-oxacilin on any of pp.5-22 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

37. The antiviral composition according p, which represents antovic composition.

38. Commercial package comprising the composition according p and Mgr is suggested to her written statement, moreover, in a written statement indicates that the composition can or should be used for inhibiting integrase.

39. Commercial package comprising the composition according p and accompanying written instructions and written instructions indicated that the composition can or should be used for prevention or treatment of viral infectious diseases.

40. Commercial packaging § 39, where the composition is a composition according to clause 37 and where written instructions as viral infectious diseases specified HIV infectious disease.

Priority from 20.11.2002 on paragraphs 1-21 and 23-40 for objects, where X represents C-R32; Y represents C-R33, R31represents a hydrogen atom, a cyano, a hydroxy-group, halogen atom or With1-4alkoxygroup; R32and R33the same or different, and each represents a hydrogen atom, a cyano, a halogen atom, Halogens1-4alkyl group; R1is Deputy selected from the group B, or C1-6alkyl group, optionally substituted by 1-3 substituents selected from halogen atom and group b, and Ra1and Ra2in group a, the same or different, and each represents a hydrogen atom or a C1-4alkyl group and 22 for the compounds of examples 1-1 to 1-102 and when the ' from 2-1 to 2-8.

Priority from 11.03.2003 on paragraphs 1-21 and 23-40 for objects, where the radicals are other than the above, values and paragraph 22 for the compounds of examples 3-1 to 3-86.

The priority of 16.05.2003 on paragraph 22 for the compounds of examples 4-1 to 4-54.



 

Same patents:

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing heterocyclic compounds describing by the general formula (I): . Invention describes a method for preparing compounds of the formula (I) wherein R1 represents hydrogen atom or alkyl group; A represents ethylene group that can be substituted with alkyl or trimethylene group that can be substituted with alkyl; D represents nitro- or cyano-group; X represents oxygen or sulfur atom, or the group of the formula: or wherein R3 represents hydrogen atom or alkyl group; Z represents 2-chloropyrid-5-yl. Method involves interaction of compound of the formula (II): wherein A, D and X abovementioned values with a base in the presence of diluting agent followed by interaction of the reaction mixture with a mixture consisting of 2-chloro-5-chloromethylpyridine/2-chloro-5-methylpyridine with corresponding hydrochlorides.

EFFECT: simplified technology, enhanced yield of end product.

4 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to water-soluble azole compounds that can be used in biology and medicine. Invention describes a water-soluble azole compound of the formula (I):

or its pharmaceutically acceptable salt wherein each R and R1 means independently hydrogen atom or (C1-C6)-alkyl; A means group of the formula:

wherein R3 represents phenyl group with one or more halide atoms as substitutes; R4 represents hydrogen atom or -CH3; R5 represents hydrogen atom or in common with R4 it can represent =CH2; R6 represents 5- or 6-membered nitrogen-containing cycle that can comprise if necessary as substituted one or more groups taken among halogen atom, =O group, phenyl substituted with one or more groups taken among -CN, -(C6H4)-OCH2-CF2-CHF2 and -CH=CH-(C6H4)-OCH2-CF2-CHF2 or phenyl substituted with one or more groups taken among halogen atom and methylpyrazolyl group. Also, invention describes a method for preparing a water-soluble azole compound. Invention provides preparing new compounds that can be useful in medicine.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a prophylactic or therapeutic agent used against hyperlipidemia and comprising as an active component the heterocyclic compound of the formula [1]:

or its pharmaceutically acceptable salt wherein R1 represents aryl optionally substituted with similar or different one-three groups taken among alkyl, halogenalkyl, trihalogen alkyl, alkoxy-group and halogen atom; Het represents bivalent aromatic heterocyclic group of the formula [5]:

wherein X represents oxygen, sulfur atom or NR6 wherein R6 represents hydrogen atom or alkyl; R2 represents hydrogen atom, alkyl or trihalogenalkyl; D represents alkylene and alkenylene; E represents group of the formulae [3] or [4] wherein Y represents oxygen or sulfur atom; R3 and R4 are similar or different and each represents hydrogen atom or alkyl; p = 1; Z represents carboxy-group, alkoxycarbonyl, cyano-group or 1H-5-tetrazolyl. Also, invention relates to new compounds belonging to group of above enumerated heterocyclic compounds of the formula [1] that show effect reducing blood triglycerides level, low density lipoprotein cholesterol, glucose and insulin or effect enhancing high density lipoprotein cholesterol and effect reducing the atherogenic effect. Therefore, these compounds can be used in prophylaxis or treatment of hyperlipidemia, arteriosclerosis, heart ischemic disease, brain infarction, rheocclusion after percutaneous intraluminal coronary angioplasty, diabetes mellitus and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

29 cl, 1 tbl, 170 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to the improved method for preparing compound of the formula: . Method involves interaction of compound of the formula: with compound of the formula: wherein Q means chlorine or bromine atom in the presence of solvent or diluting agent, an interphase catalyst and a base wherein solvent or diluting agent represent carbonic acid esters, an interphase catalyst represents ammonium quaternary salt, and a base represents carbonate. Method provides inhibition of process in formation of undesirable isomers.

EFFECT: improved preparing method.

1 cl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indol-3-yl of the formula (I):

wherein each A and B represents independently of one another oxygen atom (O), NH, CONH, NHCO or a direct bond; X means (C1-C2)-alkylene or a direct bond; R1 means hydrogen atom (H); R2 means hydrogen atom (H); R3 means NHR6, -NR6-C(=NR6)-NHR6, -C(=NR6)-NHR6, -NR6-C(=NR9)-NHR6, -C(=NR9)-NHR6 or Het1; each R4 and R5 represents independently of one another hydrogen atom (H); R7 means -(CH2)o-Ar, Het, OR6; R6 means hydrogen atom (H); R7 means (C1-C10)-alkyl, (C3-C10)-cycloalkyl; R8 means Hal, NO2 (nitro-group), CN (cyano-group), Z, -(CH2)o-Ar, COOR1, OR1, CF3, OCF3, NHR1; R9 means CN or NO2; Z means (C1-C6)-alkyl; Ar means aryl that can represent unsubstituted, monosubstituted, or polysubstituted R8; Hal means F, Cl, Br, J; Het means saturated, partially or completely saturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members wherein 1 or 2 nitrogen atom (N) and/or 1 or two sulfur atom (S) present, and heterocyclic radical can be monosubstituted with phenyl; Het1 means saturated, partially or completely unsaturated monocyclic or bicyclic heterocyclic radical comprising from 5 to 10 ring members and from 1 to 4 nitrogen atoms (N) that can be unsubstituted or monosubstituted NHX, or oxo-group; n = 0, 1 or 2; m = 0, 1, 2, 3, 4, 5 or 6; o means 0, 1 or 2; and their physiologically acceptable salts and solvates. Compounds of the formula (I) elicit intergin-inhibitory effect that allows their using as components of pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

11 cl, 4 sch, 1 tbl, 34 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to epothilones with modified thiazole substituent, methods for production thereof and pharmaceutical composition capable of cell growth inhibiting containing the same. Claimed compounds have general formula I , wherein P-Q represents double carbon bond or epoxy; R represents H, C1-C6-alkyl; G represents ; R1 represents and ; G1 and G2 represent hydrogen; G3 represents O, S, and NZ1; G4 represents H, optionally substituted C1-C6-alkyl, OZ2, Z2C=O and Z4SO2; G5 represents halogen, N3, CN, NC, heteroaryl containing nitrogen or oxygen, and heterocycle; G6 represents H, C1-C6-alkyl, or OZ5, wherein Z5 represents H, C1-C6-alkyl; G9 represents oxygen; Z1 represents H, optionally substituted C1-C6-alkyl, optionally substituted acyl; Z2 represents optionally substituted C1-C6-alkyl or aryl; Z4 represents optionally substituted aryl.

EFFECT: new epothilones capable of cell growth inhibiting.

19 cl, 39 ex

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes derivative of 3,4-dihydroisoquinoline of the formula (I) or its nontoxic salt and a pharmaceutical agent comprising its as an active component (wherein all symbols have the same values as given in description). Compound of the formula (I) possesses agonistic effect on CB2-receptors and, therefore, it can be used for prophylaxis and/or treatment of different diseases, for example, asthma, nasal allergy, atopic dermatitis, autoimmune diseases, rheumatic arthritis, immune dysfunction, postoperative pain and carcinomatous pain.

EFFECT: valuable medicinal properties of derivatives.

14 cl, 33 tbl, 561 ex

Muscarinic agonists // 2269523

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of the general formula (I): wherein Z1 represents -CR1 or nitrogen atom (N); Z2 represents -CR2; Z3 represents -CR3 or N; Z4 represents -CR4; W1 represents oxygen (O), sulfur (S) atom or -NR5; one of W2 and W3 represents N or -CR6 and another among W2 and W3 represents CG; W1 represents NG; W2 represents -CR5 or N; W3 represents -CR6 or N; or W1 and W3 represent N and W2 represents NG; G represents compound of the formula (II): wherein Y represents oxygen atom (O), -C(O)- or absent; p = 1, 2, 3, 4 or 5; Z is absent; each t = 2. Also, invention describes a method for enhancing activity of the muscarinic cholinergic receptor and a method for treatment of morbid states when modification of cholinergic and, especially, muscarinic receptors m1, m4 or both m1 and m4 offers the favorable effect.

EFFECT: valuable medicinal properties of agonists.

14 cl, 2 tbl, 101 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: method relates to piperazinedione compounds of formula I wherein and are independently direct bond or double bond; F represents H or CH(RaRb), when is single bong, or C(RaRb), when is double bond; Z represents R3O-(Ar)-B, wherein B represents CH(Rc), when is single bond or C(Rc), when is double bond; Ar represents piridyl; and R3 represents alkyl, aryl, C(O)Rd, C(O)NRdRe or SO2Rd ; R1 and R2 are independently H, C(O)Rd. Compounds of formula I have antitumor activity. Methods for treatment of tumors and angiogenesis inhibition also are disclosed.

EFFECT: new compounds useful in treatment of tumors and angiogenesis inhibition.

42 cl, 23 ex

FIELD: biochemistry.

SUBSTANCE: invention relates to new compounds of formula wherein R1 represents linear or branched C1-C9-alkyl optionally substituted with C3-C8-cycloalkyl, C6-cycloalkyl, 2-furil; 3-furil, 2-thiazolyl, 2-thenyl, 3-thienyl, phenyl; X represents oxygen, NR4, wherein R4 is H, C1-C4-alkyl; Z represents H with the proviso, that when X and Y are oxygen, R1 is not methyl, ethyl, isopropyl, isobutyl or phenyl; and when X is oxygen, and Y is NR2, wherein R2 is hydrogen, methyl, isopropyl or tert-butyl R1 is not methyl. Compounds of present invention are useful as synthetic intermediates for bioactive substances.

EFFECT: new synthetic intermediates for bioactive substances.

8 cl, 28 dwg, 3 tbl, 38 ex

FIELD: organic chemistry, chemical technology, herbicides, agriculture.

SUBSTANCE: invention relates to new sulfonamides of the formula (I):

and their salt wherein A represents substituted or unsubstituted benzene ring or 5-membered, or 6-membered substituted or unsubstituted heteroaromatic ring taken among the group comprising thienyl, pyrazolyl, imidazolyl, pyridyl wherein optional substitutes are taken among the group consisting of halogen atom, substituted or unsubstituted (C1-C4)-alkyl, unsubstituted or substituted (C1-C4)-alkoxy-group, nitro-group, phenyl, phenoxy-group, benzoyl and (C1-C4)-alkylcarboxylate when any alkyl fragment in the latter indicated substituted is substituted with one or some halogen atoms, (C1-C4)-alkoxy-groups, cyano-group and phenyl; Q represents -O-, -S- or group of the formula: -CXX' wherein X and X' can be similar or different and each represents hydrogen atom, halogen atom, cyano-group, alkyl comprising 1-8 carbon atoms, or the group -ORa, -SRa; or one of X and X' represents hydroxy-group and another has values determine above; Ra means (C1-C8)-alkyl, phenyl; Rb means (C1-C8)-alkyl, phenyl; Y means nitrogen atom or the group CR9; R1 means unsubstituted (C1-C8)-alkyl or that substituted with halogen atom, cyano-group, phenyl or (C1-C4)-alkoxycarbonylamino-group, or it represents phenyl; R2 means hydrogen atom (H), (C1-C4)-alkyl; R3 and R4 can be similar or different and each represents (C1-C4)-alkyl, (C1-C4)-alkoxy-group, halogen atom; R9 means hydrogen atom (H) under condition that when Q represents oxygen atom (O) or -S- then ring A represents 5-membered substituted or unsubstituted heteroaromatic ring and determined above. Compounds of the formula (I) possess the herbicide activity that allows their using for eradication of weeds. Also, invention describes a method for preparing compounds of the formula (I).

EFFECT: improved preparing method, valuable properties of compounds.

9 cl, 5 tbl, 18 ex

Chalcone coumarins // 2266291

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): or their pharmaceutically acceptable salts or solvates wherein Ar represents a substituted or unsubstituted (preferably aromatic one) carbocyclic or heterocyclic group wherein abovementioned carbocyclic or heterocyclic group comprises 5 or 6 atoms in cyclic structure wherein a heteroatom is taken among the group consisting of nitrogen (N) and sulfur (S) atom and any substitutes at Ar group are taken independently of one another of the group consisting of Cl, Br, F atoms and OR10 wherein R10 represents saturated or unsaturated lower hydrocarbon (C1-C6)-radical of normal or branched structure; R represents OR10 wherein R10 corresponds to above given value; R1 represents lower hydrocarbon (C1-C6)-radical of normal or branched structure under condition that if R1 represents -CH3 and R means -OCH3 or -OH then Ar group can't represent 4-methoxyphenyl or 3,4-dimethoxyphenyl. Also, invention proposes a component of medicinal agent used in treatment or prophylaxis of neoplasms. Also, invention proposes a pharmaceutical composition possessing with an anti-proliferative activity and comprising the effective amount of one or some compounds of the formula (I) in combination with one or some pharmaceutically acceptable additives. Invention provides the development of chalcone coumarins possessing with the enhanced anti-proliferative effect with respect to sensitive tumor cells, cells with resistance to conventional chemotherapeutic agents, among them, to anti-tumor medicinal agents of the last generation represented by paclitaxel and docetaxel.

EFFECT: valuable medicinal properties of compounds and compositions.

1 tbl, 21 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of imidazole of the formula (I):

or its pharmaceutically acceptable salts wherein X represents -CH2-(CH2)p-, -O-; R1 represents phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl wherein indicated phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl are substituted optionally with 1-3 substitutes taken independently among halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group and OH-(C1-C6)-alkyl; R2 represents hydrogen atom (H) or (C1-C6)-alkyl; R3 represents H or (C1-C6)-alkyl; R4 represents H or (C1-C6)-alkyl; R5 represents H, or R5 and R7 form in common a bond; each R6 represents independently halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group or OH-(C1-C6)-alkyl; R7 represents H, or R7 and R5 form in common a bond; each R8 represents independently -OH, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl or (C1-C6)-alkoxy group; m = 0, 1, 2 or 3; n = 0 or 1; p = 0 or 1; r = 0 or 1; t = 0. Also, invention relates to a method for preparing compounds of the formula (I) and to a pharmaceutical composition showing affinity to alpha-2-adrenoceptors based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used in aims for treatment of neurological disturbances, psychiatric disorders or disturbances in cognitive ability, diabetes mellitus, lipolytic diseases, orthostatic hypotension or sexual dysfunction.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

25 cl, 1 tbl, 14 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to benzimidazole derivatives or their salts useful in medicine of the general formula (1): wherein R1 and R2 can comprise similar or different values and represent independently of one another hydrogen atom, halogen atom, cyano-group, hydroxyl group, alkyl group comprising 1-4 carbon atoms, alkoxy-group comprising 1-4 carbon atoms, trifluoromethyl group; A represents unsubstituted, linear alkylene group comprising 1-7 carbon atoms; E represents group -COOR3 comprising 1-6 carbon atoms; G represents unsubstituted, linear alkylene group comprising 1-6 carbon atoms; M represents a simple bond or -S(O)m- wherein m represents a whole number in the range 0, 1 or 2; J represents substituted or unsubstituted heterocyclic group comprising 4-10 carbon atoms and one heteroatom in ring taken among the group consisting of nitrogen atom or sulfur atom excluding unsubstituted pyridine ring; a substitute in indicated aromatic heterocyclic group is taken among halogen atom, cyano-group, linear alkyl group comprising 1-6 carbon atoms, linear alkoxy-group comprising 1-6 carbon atoms, trifluoromethyl group and trifluoromethoxy-group wherein one or more indicated substituted can be replaced by random positions in ring; X represents methane group (-CH=). Also, invention relates to a pharmaceutical composition used in inhibition of human chymase activity based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for prophylaxis and/or treatment of inflammatory disease, cardiovascular disease, allergic disease, respiratory disease or osseous either cartilaginous metabolic disease.

EFFECT: valuable medicinal properties of compounds and composition.

14 cl, 3 tbl, 20 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to new 5-aryl-1-phenyl-4-heteroyl-3-hydroxy-3-pyrroline-2-ones of the formula:

wherein (1) X means sulfur atom (S); R means (CH3)2CH; (2) X means sulfur atom (S); R means (CH3)3C; (3) X means oxygen atom (O); R means (CH3)3C. Compounds of the formula (I) are prepared by interaction of the corresponding heteroylpyruvic acid methyl ester with mixture of aniline and aromatic aldehyde in acetic acid medium at short-time heating. Compounds elicit an anti-bacterial activity with value MIC = 3.9-7.8 mcg/ml as compared with 62-1000 mcg/ml for analogue.

EFFECT: valuable properties of compounds.

1 tbl, 3 ex

The invention relates to organic chemistry and can find application in medicine

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes derivatives of substituted triazoldiamine of the formula (I): wherein R1 represents (C1-C4)-alkyl, phenyl possibly substituted with halogen atom, amino-group substituted with -SO2-(C1-C4)-alkyl, imidazolyl, 1,2,4-triazolyl, imidazolidinone, dioxidoisothiazolidinyl, (C1-C4)-alkylpiperazinyl, residue -SO2- substituted with amino-group, (C1-C4)-alkylamino-group, (C1-C4)-dialkylamino-group, pyridinylamino-group, piperidinyl, hydroxyl or (C1-C4)-dialkylamino-(C1-C3)-alkylamino-group; R2 represents hydrogen atom (H); or R1 represents H and R2 means phenyl possibly substituted with halogen atom or -SO2-NH2; X represents -C(O)-, -C(S)- or -SO2-;R3 represents phenyl optionally substituted with 1-3 substitutes comprising halogen atom and nitro-group or 1-2 substitutes comprising (C1-C4)-alkoxy-group, hydroxy-(C1-C4)-alkyl, amino-group or (C1-C4)-alkyl possibly substituted with 1-3 halogen atoms by terminal carbon atom; (C3-C7)-cycloalkyl possibly substituted with 1-2 groups of (C1-C4)-alkyl; thienyl possibly substituted with halogen atom, (C1-C4)-alkyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C2-C4)-alkenyl that is substituted possibly with -CO2-(C1-C4)-alkyl, (C1-C4)-alkoxy-group, pyrrolyl, pyridinyl or amino-group substituted with -C(O)-C1-C4)-alkyl; (C1-C4)-alkyl substituted with thienyl or phenyl substituted with halogen atom; (C2-C8)-alkynyl substituted with phenyl; amino-group substituted with halogen-substituted phenyl; furyl, isoxazolyl, pyridinyl, dehydrobenzothienyl, thiazolyl or thiadiazolyl wherein thiazolyl and thiadiazolyl are substituted possibly with (C1-C4)-alkyl; to their pharmaceutically acceptable salts, a pharmaceutical composition based on thereof and a method for its preparing. New compounds possess selective inhibitory effect on activity of cyclin-dependent kinases and can be used in treatment of tumor diseases.

EFFECT: improved preparing method, valuable medicinal and biochemical properties of compounds and composition.

16 cl, 3 tbl, 26 ex

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