Derivatives of thiophene

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of thiophene of the general formula (I): , wherein R1 is chosen from group consisting of hydrogen atom (H), -C(O)R7, -CO2R7, -C(O)NR7R8, -C(O)N(R7)OR8, -C(O)N(R7)-R2-OR8, -C(O)N(R7)-Ph, -C(O)N(R7)-R-Ph, -C(O)N(R7)S(O)2R8, -R2-OR7, -R2-O-C(O)R7, -C(S)R7, -C(S)NR7R8, -C(S)N(R7)-Ph, -C(S)N(R7)-R2-Ph, -R2-SR7, -CN, -OR7 and Het wherein Het represents tetrazolyl; Q1 represent group of the formula: -(R2)a-(Y1)b-(R2)c-R3 wherein a, b and a are similar or different and each means independently 0 or 1, and at least one among a or b means 1; n means 0, 1, 2, 3 or 4; Q2 represents group of the formula: -(R2)aa-(Y2)bb-(R2)cc-R4, or two adjacent Q2 groups represent -OR7 and in common with carbon atoms to which they are bound form 5-7-membered heterocycle comprising 1 or 2 heteroatoms chosen from oxygen atom (O); R5 is chosen from group consisting of H, alkyl and -NR7R8, or their pharmaceutically acceptable salts and solvates. Compounds can be used in treatment of states mediated by Polo-like kinase and sensitive neoplasm. Also, invention describes a method for synthesis of these compounds and preparing pharmaceutical compositions based on thereof.

EFFECT: valuable medicinal properties of compounds and pharmaceutical compositions.

27 cl, 1 tbl, 199 ex

 

The present invention relates to new compounds, to pharmaceutical preparations containing these compounds and to the use of these compounds in therapy. More specifically, the present invention relates to new compounds and methods of treating conditions mediated by Polo-like kinase, sensitive tumors and other conditions.

Polo-like kinase ("PLK) are evolutionarily conservative serine/threonine kinase, which plays a critical role in the regulation of processes of the cell cycle. PLK plays a role in the entry into mitosis and exit from mitosis in various organisms from yeast cells to mammalian cells. PLK includes PLK1, PLK2 and PLK3.

It is known that Polo-like kinase required for mitosis in yeast, Drosophila and Xenopus. For example, mutations in the homologous PLK genes in these organisms lead to razuporyadochyeniye mitotic spindle, and mutations in Drosophila can be lethal to embryos. Experiments on RNA interference in Drosophila polo showed that extirpation polo in S2 cells leads to the stop of the G2/M and apoptosis. PLK1 is a human homolog of the Drosophila polo. I believe that she is involved in the process of entry into mitosis by activating cdk1 phosphorylation and activation of the phosphatase cdc25C, which, in turn, removes inhibiting phosphate with cdk1. This starts the activation loop on what I cdk1, that leads to entry into mitosis. PLK1 also phosphorylates cyclin B1, cyclenbuy partner cdk1, resulting in nuclear localization. It is shown that during mitosis, PLK1 is involved in the maturation of centrosomes and dynamics of microtubules involved in the formation of the mitotic spindle. PLK1 is also involved in the process of exit of cells from mitosis through phosphorylation and activation subunit of anaphase stimulating complex (cdc16 and cdc27). PLK1 also phosphorylates proteins cohesin holding sister chromatids together, exposing the cleavage sites separate and making possible the separation of sister chromatid during anafazy. PLK1 also may be involved in cytokinesis through phosphorylation of the kinesin-like motor protein MLKP1. Thus, inhibition of PLK1 gives you the ability to inhibit several stages of mitosis. Expression and activity of PLK protein increases during the cell cycle, reaching its peak during mitosis, when he also maximally phosphorylated. PLK1 mRNA is strongly expressed in cells with a high mitotic index. PLK2 (induced by serum kinase, SNK) and PLK3 (kinase related to proliferation, PRK induced by fibroblast growth factor kinase, FNK) were originally identified as immediate early genes. PLK2 is not well characterized, and PLK3 in all probability, including both the on in regulation of cell cycle progression through M phase, but does not function as PLK1. Recently published work confirms that PLK3 plays an important role in the regulation of the dynamics of microtubules and function of centrosomes during mitosis.

Overexpression of PLK1 in all probability significantly associated with tumor cells (including cancer). Published studies have shown high levels of expression of RNA PLK1 in >80% of tumors of the lung and breast cancer with little expression or lack of expression in adjacent normal tissues. Several studies have shown a correlation between the expression of PLK, histological evaluation and prognosis in several cancer types. Significant correlations were found between the percentage of PLK-positive cells and histological assessment of ovarian cancer and endometrial cancer (P<0,001). In these studies noted that PLK is strongly expressed in cells growing carcinoma of the endometrium, and that this may be a reflection of the degree of malignancy and proliferation of endometrial carcinoma. Using analysis of RT-PCR (reverse transcriptase, polymerase chain reaction) overexpression of PLK was detected in 97% of carcinomas of the esophagus and 73% of gastric carcinomas compared to normal tissues. Moreover, patients with high levels of overexpression of PLK in carcinoma of the esophagus before toulali a much more unsatisfactory from the point of view of the forecast group, than patients with low levels of overexpression of PLK. In cancer of head and neck cancer increased expression of PLK1 mRNA was observed in most tumors. Analysis of Kaplan-Meier (Kaplan-Meier) showed that patients with moderate levels of expression of PLK1 live longer than patients with high levels of expression of PLK1. Examination of patients with non-small cell lung cancer gave similar results regarding the expression of PLK1.

A promising approach in cancer chemotherapy has been the interruption of mitosis antimicrotubule drugs. Taxanes and Vinca alkaloids have been used effectively in the clinic, but they have undesirable side effects. Moreover, it seems that many tumors have weakened checkpoint G2/M cell cycle; in response to the interruption of mitosis, these tumors are trying to ignore mitosis, which leads to mitotic catastrophe and cell death. The results of several studies suggest that interruption of mitosis by purposeful influence on PLK can be a real approach to selective destruction of tumor cells. The need for new approaches to the treatment of tumors is stored in this field.

A BRIEF DESCRIPTION of the INVENTION

According to the first aspect of the invention proposed compound of formula (I):

where R1selected from the group consisting of H, alkyl, alkenyl, quinil, -C(O)R7, -CO2R7, -C(O)NR7R8, -C(O)N(R7OR8, -C(O)N(R7)-R2-OR8, -C(O)N(R7)-Ph, -C(O)N(R7)-R2-Ph, -C(O)N(R7)C(O)R8, -C(O)N(R7)CO2R8, -C(O)N(R7)C(O)NR7R8, -C(O)N(R7)S(O)2R8, -R2-OR7, -R2-O-C(O)R7, -C(S)R7, -C(S)NR7R8, -C(S)N(R7)-Ph, -C(S)N(R7)-R2-Ph, -R2-SR7, -C(=NR7)NR7NR8, -C(=NR7)N(R8)-Ph, -C(=NR7)N(R8)-R2-Ph, -R2-NR7R8, -CN, -OR7, -S(O)fR7, -S(O)2NR7R8, -S(O)2N(R7)-Ph, -S(O)2N(R7)-R2-Ph, -NR7R8, -N(R7)-Ph, -N(R7)-R2-Ph, -N(R7)-SO2R8and Het;

Ph represents a phenyl, possibly substituted from 1 to 3 times a Deputy selected from the group consisting of halogen, alkyl, -OH, -R2-OH, -O-alkyl, -R2-O-alkyl, -NH2, -N(H)alkyl, -N(alkyl)2, -CN and-N3;

Het is a 5-7-membered heterocycle having 1, 2, 3 or 4 heteroatoms selected from N, O and S, or 5-6-membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O and S, each possibly substituted 1 to 2 times a Deputy selected from the group consisting of halogeno, alkyl, oxo, -OH, -R2-OH-O-alkyl, -R2-O-alkyl, -NH2, -N(H)alkyl, -N(alkyl)2, -CN and-N3;

Q1represents a group of formula: -(R2)a(Y1)b-(R2)c-R3where

a, b and C are identical or different and each independently denotes 0 or 1, and at least one of a or b is 1;

n means 0,1,2, 3, or 4;

Q2represents a group of formula: -(R2)aa(Y2)bb-(R2)cc-R4,

or two adjacent groups Q2selected from the group consisting of alkyl, alkenyl, -OR7, -S(O)fR7and-NR7R8and together with the carbon atoms to which they are linked, they form With5-6cycloalkyl,5-6cycloalkenyl, phenyl, 5-7-membered heterocycle having 1 or 2 heteroatoms selected from N, O and S, or 5-6-membered heteroaryl having 1 or 2 heteroatoms selected from N, O and S;

AA, bb and cc are the same or different and each independently denotes 0 or 1;

Y1and Y2the same or different and each is independently selected from the group consisting of-O-, -S(O)f-, -N(R7)-, -C(O)-, -OC(O)-, -CO2-, -C(O)N(R7)-, -C(O)N(R7)S(O)2-, -OC(O)N(R7)-, -OS(O)2-, -S(O)2N(R7)-, -S(O)2N(R7)C(O)-, -N(R7)S(O)2-, -N(R7)C(O)-, -N(R7)CO2- , and-N(R7)C(O)N(R7)-;

R2the same or different and each is independently selected from the group consisting of alkylene, Alcanena and akinlana;

R3and R4the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, alkenyl, quinil, -C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, -C(S)NR7R8, -C(=NR7R8, -C(=NR7)NR7R8, -CR7=N-OR7, -OR7, -S(O)fR7, -S(O)2NR7R8, -NR7R8, -N(R7)C(O)R8, -N(R7)S(O)2R8, -NO2, -CN, -N3and groups of the formula (II):

where ring a is selected from the group consisting of C5-10cycloalkyl,5-10cycloalkenyl, aryl, 5-10-membered heterocycle having 1, 2 or 3 heteroatoms selected from N, O and S and 5-10-membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S;

each d is 0 or 1;

E. means 0, 1, 2, 3 or 4;

R6the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, Ph, Het, -CH(OH)-R2-OH, -C(O)R7, -CO2R7, -CO2-R2-Ph, -CO2-R2-Het, -C(O)NR7R8, -C(O)N(R7)C(O)R7, -C(O)N(R7)CO2R7, -C(O)N(R7)C(O)NR7R8, -C(O)N(R7)S(O)2R7, -C(S)R7, -C(S)NR7R8, -C(=NR7R8, -C(=NR7)NR7R8, -CR7 =N-OR8,=O, -OR7, -OC(O)R7, -OC(O)Ph, -OC(O)Het, -OC(O)NR7R8, -O-R2-S(O)2R7, -S(O)fR7, -S(O)2NR7R8, -S(O)2Ph, -S(O)2Het, -NR7R8, -N(R7)C(O)R8, -N(R7)-CO2R8, -N(R7)-R2-CO2R8, -N(R7)C(O)NR7R8, -N(R7)-R2-C(O)NR7R8, -N(R7)C(O)Ph, -N(R7)C(O)Het, -N(R7)Ph, -N(R7)Het, -N(R7)C(O)NR7-R2-NR7R8, -N(R7)C(O)N(R7)Ph,-N(R7)C(O)N(R7)Het, -N(R7)C(O)N(R7)-R2-Het, -N(R7)S(O)2R8, -N(R7)-R2-S(O)2R8, -NO2, -CN and-N3;

moreover, when in the definition of Q1b mean 1 and mean 0, then R3not is halogen, -C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, -C(S)NR7R8, -C(=NR7R8, -C(=NR7)NR7R8, -CR7=N-OR7, -OR7, -S(O)fR7, -S(O)2NR7R8, -NR7R8, -N(R7)C(O)R8, -N(R7)S(O)2R8, -NO2, -CN, or-N3;

moreover, when in the definition of Q2bb is 1 and cc is 0, then R4not is halogen, -C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, -C(S)NR7R8, -C(=NR7R8, -C(=NR7)NR7R8, -CR7=N-OR7 , -OR7, -S(O)fR7, -S(O)2NR7R8, -NR7R8, -N(R7)C(O)R8, -N(R7)S(O)2R8, -NO2, -CN, or-N3;

R5selected from the group consisting of N, halogeno, alkyl, cycloalkyl, -OR7, -S(O)fR7, -NR7R8, -NHC(O)R7, -NHC(O)NR7R8and-NHS(O)2R7;

f denotes 0, 1 or 2; and

each R7and each R8the same or different and each is independently selected from the group consisting of H, alkyl, alkenyl, quinil, cycloalkyl and cycloalkenyl;

moreover, when R1represents-CO2CH3and n means 0, Q1is not HE; or its pharmaceutically acceptable salt, MES or physiologically functional derivative.

In another aspect of the invention proposed pharmaceutical composition comprising a compound of formula (I). In one embodiment the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, diluent or excipient.

In the third aspect of the invention, a method of treatment of a condition mediated by PLK, the animal. The method includes the introduction of the animal a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative.

In the fourth the second aspect of the invention, a method of treating susceptible neoplasms in animals. The method includes the introduction of the animal a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative. Sensitive tumor may be selected from the group consisting of breast cancer, colon cancer, lung cancer, prostate cancer, lymphoma, leukemia, endometrial cancer, melanoma, pancreatic cancer, ovarian cancer, squamous cell carcinoma, carcinoma of the head and neck and esophageal cancer.

In the fifth aspect of the invention, a method for treating a condition characterized by inappropriate cellular proliferation. The method includes bringing the cells into contact with a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative.

In the sixth aspect of the present invention, a method for inhibiting cell proliferation. The method includes bringing the cells into contact with a sufficient for inhibition of cell proliferation by the amount of the compounds of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative.

In another aspect of the present invention, a method for inhibiting mitosis in a cell. The method includes centuries the decline in cell number of the compounds of formula (I) or its pharmaceutically acceptable salt, the MES or physiologically functional derivative, sufficient for inhibiting mitosis in a cell.

In another aspect of the present invention, a method for obtaining compounds of formula (I), including the interaction of the compounds of formula (III):

with the compound of the formula (IV):

where R10selected from the group consisting of alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl and suitable protective group of carboxylic acid.

In another aspect of the present invention proposed radiolabelled compound of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative. In one embodiment of the present invention proposed trithiolane compound of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative. In another aspect of the present invention proposed biotinylated compound of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative.

In another aspect of the present invention proposed a compound of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative for use in therapy.

In e is e one other aspect of the present invention proposed a compound of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative for use in the treatment of condition mediated by PLK, the animal.

In still another aspect of the present invention proposed a compound of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative for use in the treatment of susceptible neoplasms in animals.

In another aspect of the present invention proposed a compound of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative for use in the treatment of a condition characterized by inappropriate cellular proliferation.

In another aspect of the present invention proposed a compound of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative for use in the inhibition of cell proliferation.

In another aspect of the present invention proposed a compound of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative for use in the inhibition of mitosis in the cell.

In another aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative is about to prepare medications for the treatment condition, mediated by PLK, the animal.

In another aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative for the preparation of drugs for the treatment of susceptible neoplasms in animals.

In another aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative for the preparation of drugs for the treatment of a condition characterized by inappropriate cellular proliferation.

In another aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative for the preparation of medicaments for the inhibition of cell proliferation.

In another aspect of the present invention proposed the use of the compounds of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative for the preparation of medicaments for inhibiting mitosis in a cell.

In another aspect of the present invention proposed a pharmaceutical composition comprising a compound of formula (I), for use in the treatment of sensitive is voobrazovaniya the animal.

DETAILED description of the INVENTION

Used herein, the term "compound of the invention" or "compound of formula (I)" refers to the compound of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative. Similarly, in relation to allocated intermediate compounds, such as, for example, the compounds of formula (III) and formula (VIII), the phrase "a compound of formula (number)" means a compound having that formula and pharmaceutically acceptable salt, solvate or physiologically functional derivatives.

Used herein, the terms "alkyl" and "alkylene" refers to a straight or branched hydrocarbon chains containing from 1 to 8 carbon atoms. Examples of "alkyl" here include methyl, ethyl, n-propyl, n-butyl, n-pentyl, isobutyl, isopropyl and tert-butyl, but not limited to. Examples of "alkylene" here include methylene, ethylene, propylene, butylene, and isobutylene, but not limited to. The term "alkyl" also includes substituted alkyl. Alkyl groups may be substituted one or more times by halogen. Thus, "alkyl" among other halogenated Akilov include trifluoromethyl and triptorelin.

Used herein, the term "alkenyl" refers to a straight or branched hydrocarbon chains containing from 2 to 8 atoms of carbon is a (if not otherwise specified the number of atoms) and at least one and up to three carbon-carbon double bonds. Examples of "alkenyl" here include ethynyl and propanil, but not limited to. "Alkenyl" also includes substituted alkenyl. Alkeneamine groups may be substituted one or more times by halogen.

Used herein, the term "quinil" refers to a straight or branched hydrocarbon chains containing from 2 to 8 carbon atoms (unless otherwise specified, the number of atoms) and at least one and up to three carbon-carbon triple bonds. Examples of "quinil" here include ethinyl and PROPYNYL, but not limited to. "Quinil" also includes substituted quinil. Alkyline groups may be substituted one or more times by halogen.

Used herein, the term "cycloalkyl" refers to non-aromatic monocyclic carbocyclic ring having from 3 to 8 carbon atoms (unless otherwise specified, the number of atoms and a single carbon-carbon double bond. "Cycloalkyl include as an example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. "Cycloalkyl" also includes substituted cycloalkyl. Cycloalkyl may possibly be substituted on any available carbon with one or more substituents selected from the group consisting of halogeno,1-3of alkyl (including halogenated, for example, perfluoroalkyl), -OH, -O-C1-3alkyl is, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -CN and-N3. Preferred cycloalkyl groups include3-6cycloalkyl and replaced With3-6cycloalkyl.

Used herein, the term "cycloalkenyl" refers to non-aromatic monocyclic carbocyclic ring having from 3 to 8 carbon atoms (unless otherwise specified, the number of atoms) and up to three carbon-carbon double bonds. "Cycloalkenyl" includes, as an example cyclobutenyl, cyclopentenyl and cyclohexenyl. "Cycloalkenyl" also includes substituted cycloalkenyl. Cycloalkenyl may possibly be substituted on any available carbon with one or more substituents selected from the group consisting of halogeno,1-3of alkyl (including halogenated, for example, perfluoroalkyl), -OH, -O-C1-3of alkyl, -NH2, -NH(C1-3alkyl), -N(C1-3alkyl)2, -CN and-N3.

The term "halogen" or "halogen" refers to fluorine, chlorine, bromine and iodine.

Used herein, the term "oxo" refers to a group =O, directly attached to the carbon atom hydrocarbon ring (i.e cycloalkenyl, aryl, heterocyclic or heteroaryl rings), and to N-oxides, sulfones and sulfoxidov, where N or S atoms are heterocyclic or heteroaryl ring.

The term "aryl" relates the I monocyclic carbocyclic groups and condensed bicyclic carbocyclic groups, having from 6 to 13 carbon atoms (unless otherwise specified, the number of atoms) and having at least one aromatic ring. Examples of specific aryl groups include phenyl and naphthyl, but not limited to. One particular aryl group according to the invention is phenyl.

The terms "heterocycle" and "heterocyclic" refer to monocyclic saturated or unsaturated non-aromatic groups and condensed bicyclic saturated or unsaturated non-aromatic groups having the specified number of members and containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, unless otherwise specified the number of heteroatoms). Examples of particular heterocyclic groups include tetrahydrofuran, dihydropyran, tetrahydropyran, Piran, tieton, 1,4-dioxane, 1,3-dioxane, 1,3-dioxolane, piperidine, piperazine, tetrahydropyrimidine, pyrrolidine, morpholine, thiomorpholine, thiazolidine, oxazolidine, tetrahydrothiopyran, tetrahydrothiophene and the like, but not limited to.

The term "heteroaryl" refers to aromatic monocyclic groups and condensed bicyclic groups in which at least one ring is aromatic, with a specific number of members and containing 1, 2, 3 or 4 heteroatoms selected from N, O and S, unless otherwise specified amount gateroad the MOU). Examples of particular heteroaryl groups include furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazol, oxadiazole, thiadiazole, isothiazol, pyridine, pyridazine, pyrazin, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophen indole and indazole, but not limited to.

The term "members" (and its variants, such as "member") in the context of heterocyclic and heteroaryl groups applies to all atoms, carbon atoms and heteroatoms of N, O and/or S, which form a ring. Thus, example 6-membered heterocyclic ring is piperidine, and example 6-membered heteroaryl ring is pyridine.

Used herein, the term "may" means that the following situation(s) can take place or not take place, and includes situations that occur, and situations that are not.

According to the present invention proposed the compounds of formula (I):

where

R1selected from the group consisting of H, alkyl, alkenyl, quinil, -C(O)R7, -CO2R7, -C(O)NR7R8, -C(O)N(R7OR8, -C(O)N(R7)-R2-OR8, -C(O)N(R7)-Ph, -C(O)N(R7)-R2-Ph, -C(O)N(R7)C(O)R8, -C(O)N(R7)CO2R8, -C(O)N(R7)C(O)NR7R8, -C(O)N(R7)S(O)2R8, -R2-OR7, -R2/sup> -O-C(O)R7, -C(S)R7, -C(S)NR7R8, -C(S)N(R7)-Ph, -C(S)N(R7)-R2-Ph, -R2-SR7, -C(=NR7)NR7R8, -C(=NR7)N(R8)-Ph, -C(=NR7)N(R8)-R2-Ph, -R2,-NR7R8, -CN, -OR7, -S(O)fR7, -S(O)2NR7R8, -S(O)2N(R7)-Ph, -S(O)2N(R7)-R2-Ph, -NR7R8, -N(R7)-Ph, -N(R7)-R2-Ph, -N(R7)-SO2R8and Het;

Ph represents a phenyl, possibly substituted from 1 to 3 times a Deputy selected from the group consisting of halogen, alkyl, -OH, -R2-OH, -O-alkyl, -R2-O-alkyl, -NH2, -N(H)alkyl, -N(alkyl)2, -CN and-N3;

Het is a 5-7-membered heterocycle having 1, 2, 3 or 4 heteroatoms selected from N, O and S, or 5-6-membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O and S, each possibly substituted 1 to 2 times a Deputy selected from the group consisting of halogeno, alkyl, oxo, -OH, -R2-OH, -O-alkyl, -R2-O-alkyl, -NH2, -N(H)alkyl, -N(alkyl)2, -CN and-N3;

Q1represents a group of formula: -(R2)a(Y1)b-(R2)c-R3where

a, b and C are identical or different and each independently denotes 0 or 1, at least one of a or b is 1;

n means 0, 1, 2, 3 or 4;

Q2is a group fo the formula: -(R 2)aa(Y2)bb-(R2)cc-R4,

or two adjacent groups Q2selected from the group consisting of alkyl, alkenyl, -OR7, -S(O)fR7and-NR7R8and together with the carbon atoms to which they are linked, they form With5-6cycloalkyl,5-6cycloalkenyl, phenyl, 5-7-membered heterocycle having 1 or 2 heteroatoms selected from N, O and S, or 5-6-membered heteroaryl having 1 or 2 heteroatoms selected from N, O and S;

aa, bb and cc are the same or different and each independently denotes 0 or 1;

Y1and Y2the same or different and each is independently selected from the group consisting of-O-, -S(O)r-, -N(R7)-, -C(O)-, -OC(O)-, -CO2-, -C(O)N(R7)-, -C(O)N(R7)S(O)2-, -OC(O)N(R7)-, -OS(O)2-, -S(O)2N(R7)-, -S(O)2N(R7)C(O)-, -N(R7)S(O)2-, -N(R7)C(O)-, -N(R7)CO2- , and-N(R7)C(O)N(R7)-;

R2the same or different and each is independently selected from the group consisting of alkylene, Alcanena and akinlana;

R3and R4the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, alkenyl, quinil, -C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, -C(S)NR7R8, -C(=NR7R8, -C(=NR7)NR7R8, -CR7=N-OR7, -OR7, -S(O)fR7, -S(O) 2NR7R8, -NR7R8, -N(R7)C(O)R8, -N(R7)S(O)2R8, -NO2, -CN, -N3and groups of the formula (II):

where

ring a is selected from the group consisting of C5-10cycloalkyl,5-10cycloalkenyl, aryl, 5-10-membered heterocycle having 1, 2 or 3 heteroatoms selected from N, O and S and 5-10-membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S;

each d is 0 or 1;

E. means 0,1,2, 3, or 4;

R6the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, Ph, Het, -CH(OH)-R2-OH, -C(O)R7, -CO2R7, -CO2-R7-Ph, -CO2-R2-Het, -C(O)NR7R8, -C(O)N(R7)C(O)R7, -C(O)N(R7)CO2R7, -C(O)N(R7)C(O)NR7R8, -C(O)N(R7)S(O)2R7, -C(S)R7, -C(S)NR7R8, -C(=NR7R8, -C(=NR7)NR7R8, -CR7=N-OR8, =O, -OR7, -OC(O)R7, -OC(O)Ph, -OC(O)Het, -OC(O)NR7R8, -O-R2-S(O)2R7, -S(O)fR7, -S(O)2NR7R8, -S(O)2Ph, -S(O)2Het, -NR7R8, -N(R7)C(O)R8, -N(R7)-CO2R8, -N(R7)-R2-CO2R8, -N(R7)C(O)NR7R8, -N(R7)-R2-C(O)NR7R8 , -N(R7)C(O)Ph, -N(R7)C(O)Het, -N(R7)Ph, -N(R7)Het, -N(R7)C(O)NR7-R2-NR7R8, -N(R7)C(O)N(R7)Ph, -N(R7)C(O)N(R7)Het, -N(R7)C(O)N(R7)-R2-Het, -N(R7)S(O)2R8, -N(R7)-R2-S(O)2R8, -NO2, -CN and-N3;

moreover, when in the definition of Q1b mean 1 and mean 0, then R3not is halogen, -C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, -C(S)NR7R8, -C(=NR7R8, -(=NR7)NR7R8, -CR7=N-OR7, -OR7, -S(O)fR7, -S(O)2NR7R8, -NR7R8, -N(R7)C(O)R8, -N(R7)S(O)2R8, -NO2, -CN, or-N3;

moreover, when in the definition of Q2bb is 1 and cc is 0, then R4not is halogen, -C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, -C(S)NR7R8, -C(=NR7R8, -C(=NR7)NR7R8, -CR7=N-OR7, -OR7, -S(O)fR7, -S(O)2NR7R8, -NR7R8, -N(R7)C(O)R8, -N(R7)S(O)2R8, -NO2, -CN, or-N3;

R5selected from the group consisting of N, halogeno, alkyl, cycloalkyl, -OR7, -S(O)fR7, -NR7R8, -NHC(O)R7, -NHC(O)NR7R8and-NHS(O)2R7;

f means , 1 or 2; and

each R7and each R8the same or different and each is independently selected from the group consisting of H, alkyl, alkenyl, quinil, cycloalkyl and cycloalkenyl;

moreover, when R1represents-CO2CH3and n means 0, Q1is not HE;

or its pharmaceutically acceptable salt, MES or physiologically functional derivative.

In one embodiment of compounds of formula (I) R1selected from the group consisting of alkyl, alkenyl, quinil, -C(O)R7, -CO2R7, -C(O)NR7R8, -C(O)N(R7)-R2-OR8, -R2-OR7, -C(S)NR7R8, -C(=NR7)NR7R8, -CN, -S(O)fR7, -S(O)2NR7R8and Het, or any shortened version of this group of values. In yet another embodiment of the compounds of formula (I) R1selected from the group consisting of-C(O)R7, -CO2R7, -C(S)NR7R8, Het and -- C(O)NR7R8or any shortened version of this group of values. In yet another embodiment of the compounds of formula (I) R1selected from the group consisting of-C(O)R7, -CO2R7and-C(O)NR7R8or any shortened version of this group of values. In the private embodiment R1selected from the group consisting of-CO2R7and-C(O)NR7R8or any abbreviated Varian is and this group of values. In one embodiment R1represents-CO2R7. In another embodiment R1represents-C(O)NR7R8.

Specific examples of the groups R1include-SLEEP-PINES3, -COOH, -COON3, -C(O)NH2, -CONH(alkyl), -CON(alkyl)(alkyl), -CONH(Et-OH), -CONH(benzyl), -CONH(phenyl), -S(O)2NH2and-S(O)2N(H)CH3, -CH2OH, -C(S)NH2, -CN and-tetrazol, or any shortened version of this group of values, but they are not limited. In the private embodiment R1selected from the group consisting of-CO2H and-C(O)NH2.

Q1defined as a group of the formula -(R2)a(Y1)b-(R2)c-R3.

In the above formula a, b and C are identical or different and each independently denotes 0 or 1.

In one embodiment in the definition of Q1and means 0. In the embodiment, in which a represents 1, and therefore, there is a group (R2)a, R2is usually alkylen or albaniles, more specifically alkylen. In one particular embodiment in the definition of Q1and means 1, and (R2)arepresents a C1-3alkylen.

In one embodiment of compounds of formula (I) in the definition of Q1b means 1; hence, there is Y1. In one such embodiment Y1selected from-O-, -S(O)f-, -N(R7)-, -C(O)-, -OC(O)-, -CO2-, -C(O)N(Rsup> 7)-, -C(O)N(R7)S(O)2-, -OC(O)N(R7)-, -OS(O)2-, -S(O)2N(R7)-, -S(O)2N(R7)C(O)-, -N(R7)S(O)2-, -N(R7)C(O)-, -N(R7)CO2- , and-N(R7)C(O)N(R7)-. In a particular embodiment Y1selected from-O-, -N(R7)-, -C(O)-, -OC(O)-, -C(O)N(R7)-, -OS(O)2-, -S(O)2N(R7)-, -N(R7)S(O)2- , and-N(R7)C(O)- or any shortened version of this group of values. In another private embodiment Y1selected from-O-, -N(R7)-, -C(O)-, -OS(O)2-, -N(R7)S(O)2- , and-N(R7)C(O)- or any shortened version of this group of values. In a particular embodiment b is 1, and Y1represents-O-, -N(R7)-, -C(O) -, or-OS(O)2-. In one particular embodiment b is 1, and Y1represents-O-. In another specific embodiment b is 1, Y1represents-N(R7)-, and R7represents H or alkyl, more specifically N. In another specific embodiment b is 1, and Y1represents-C(O)-. In another specific embodiment b is 1, and Y1is a-OS(O)2-.

The variable in the formula Q1may indicate 0 or 1. In one embodiment with means 1. In one such embodiment (R2)cis alkylene or albaniles, more specifically alkylen. In a particular embodiment in the definition of Q1the means 1, and (R2)crepresents a C1-3alkylen.

In one embodiment of the invention the compounds of formula (I) have a substituent in the position in which it is Q1so when a, b and C all mean 0, then R3does not represent N. In one particular embodiment in the definition of compounds of the present invention at least one of a or b is 1. In yet another specific embodiment in the definition of Q1b and C both mean 1. In yet another specific embodiment in the definition of Q1and means On, and b and C both mean 1.

In accordance with the definition of b, Y1and R3can be selected from the group consisting of N, halogeno, alkyl, alkenyl, quinil, -C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, -C(S)NR7R8, -C(=NR7R8, -C(=NR7)NR7R8, -CR7=N-OR7, -OR7, -S(O)fR7, -S(O)2NR7R8, -NR7R8, -N(R7)C(O)R8, -N(R7)S(O)2R8, -NO2, -CN, -N3and groups of the formula (II):

.

In one embodiment R3in the definition of Q1selected from the group consisting of H, alkyl, alkenyl, quinil and groups of the formula (II), or any shortened version of this group of values. In a particular embodiment, R3selected from the group consisting of H, is Lila, alkenyl and quinil, or any shortened version of this group of values. In one embodiment, when R3represents alkyl, then R3represents a C2-6alkyl.

In a particular embodiment, R3represents a group of formula (II).

in the formula (II) in this description is called a "ring". Ring a is selected from C5-10cycloalkyl,5-10cycloalkenyl, aryl, 5-10-membered heterocycle having 1, 2 or 3 heteroatoms selected from N, O and S and 5-10-membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S. In Q1ring And may be associated with R2, Y1(when with mean 0) or thiophene ring (when a and b with mean 0) via any suitable carbon atom or heteroatom. In one embodiment in the definition of Q1R3represents a group of formula (II)and ring a is selected from C5-10cycloalkyl,5-10cycloalkenyl, aryl, 5-10-membered heterocampa having 1, 2 or 3 heteroatoms selected from N, O and S and 5-10-membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S. In another embodiment in the definition of Q1R3represents a group of formula (II)and ring a is selected from aryl, 5-10-membered heterocycle having 1, 2 or 3 heteroatoms selected from N, O and S and 5-10-membered heteroaryl having 1, 2 or 3 heteroatom, selected from N, O and S. In a particular embodiment in the definition of Q1R3represents a group of formula (II)and ring a is selected from aryl and 5-10-membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S.

In one embodiment in the definition of Q1R3represents a group of formula (II)and ring a is selected from the group consisting of cycloalkyl, tetrahydropyran, tetrahydrofuran, research, piperidine, phenyl, naphthyl, thiophene, furan, pyrrole, pyrrolidine, pyrrolidinone, imidazole, benzofuran, benzimidazole, pyridyl,

,,,,

or any shortened version of this group of values. In one particular embodiment ring a is a phenyl. In yet another particular embodiment ring a is a pyridyl.

Private, more specific examples of groups defining Q1in the compounds of formula (I)selected from the group consisting of:

,,,,

,,

,,

and,

or any shortened version of this group of values.

One private group, which determines Q1represents a

.

In one more specific embodiment Q1represents a

.

In another more specific embodiment Q1represents a

.

In another more specific embodiment Q1represents a

.

In one embodiment in the definition of compounds of formula (I) R3represents a group of formula (II), and d is 0 or 1. In the private embodiment, in which R3represents a group of formula (II), and d is 1, R2represents a C1-3alkylen. In another embodiment d is 0.

In one embodiment, in which the definition of the compounds of formula (I) R3represents a group of formula (II), e is 0, 1, 2 or 3. In a particular embodiment e is 0 or 1. In another embodiment e is 1. In another embodiment e is 2.

In one embodiment, in which the definition of the compounds of formula (I) R3represents a group of formula (II), R6the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, alkenyl, quinil is, cycloalkyl, Ph, Het, -CH(OH)-R2-OH, -C(O)R7, -C(O)NR7R8,=O, -OR7, -S(O)fR7, -S(O)2NR7R8, -S(O)2Ph, -NR7R8, -N(R7)C(O)R8, -N(R7)-CO2R8, -N(R7)S(O)2R8, -NO2, -CN and-N3or any shortened version of this group of values. In a particular embodiment, R3represents a group of formula (II), a R6the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, alkenyl, quinil, cycloalkyl, -OR7, -S(O)fR7, -S(O)2NR7R8, -NR7R8, -N(R7)S(O)2R8, -NO2and-CN, or any shortened version of this group of values. In yet another private embodiment R3represents a group of formula (II), and R6the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, -OR7, -S(O)fR7, -S(O)2NR7R8and-NO2or any shortened version of this group of values.

More specifically, in one embodiment, in which R3represents a group of formula (II), R6the same or different and each is independently selected from the group consisting of H, F, Cl, Br, I, methyl, trifloromethyl, ethyl, propyl, isopropyl, cyclopropyl, isobutyl, tert-butyl, Attila, propenyl, ACE Elena, O-methyl, O-diformate, O-trifloromethyl, O-ethyl, O-propyl, O-isopropyl, O-cyclopropyl, -SO2-methyl, -SO2-NH2, -NH2, -NH(alkyl), -N(alkyl)alkyl, -NH(cyclopropyl), -NHSO2-methyl, -NO2and-CN, or any shortened version of this group of values.

In one embodiment Q1defined so that when b is 1 and means On, then the group R3not is halogen, -C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, -C(S)NR7R8, -C(=NR7R8, -C(=NR7)NR7R8, -CR7=N-OR7, -OR7, -S(O)fR7, -S(O)2NR7R8, -NR7R8, -N(R7)C(O)R8, -N(R7)S(O)2R8, -NO2, -CN, or-N3.

In one embodiment, when R1represents-CO2CH3and n means 0, then Q1is not a HE. In one embodiment Q1is not HE.

In one embodiment n is 0, 1 or 2 or any shortened version of this group of values. In one particular embodiment n is 0, and therefore, benzimidazole ring is not substituted at positions C-4, C-5, C-6 and C-7. In another embodiment n is 2, and Vice-Q2are in positions C-5 and C-6. In another specific embodiment n is 1. In another specific embodiment n is 2.

Q2PR is dstanley a group of the formula -(R 2)AA(Y2)bb-(R2)cc-R4. Q2can be located at any of positions C-4, C-5, C-6 and/or C-7 benzimidazole ring. In one embodiment n is 1 and Q2is in state S-5. In one embodiment n is 1, and Q2is in position C-6.

In the above formula AA, bb and cc are the same or different and each independently denotes 0 or 1.

In one embodiment of AA means 0, so (R2)aanot present. In the embodiment, in which AA is 1, (R2)aais usually alkylen or albaniles, more specifically alkylen. In a particular embodiment in the definition of Q2AA means 1, a (R2)aarepresents a C1-3alkylen.

In one embodiment in the definition of compounds of formula (I) bb means 0. In another embodiment of the compounds of formula (I) in the definition of Q2bb means 1, so Y2present. In one such embodiment Y2selected from-O-, -S(O)f-, -N(R7)-, -C(O)-, -OC(O)-, -CO2-, -C(O)N(R7)-, -C(O)N(R7)S(O)2-, -OC(O)N(R7)-, -OS(O)2-, -S(O)2N(R7)-, -S(O)2N(R7)CO-, -N(R7)S(O)2-, -N(R7)C(O)-, -N(R7)CO2- , and-N(R7)C(O)N(R7)-. In a particular embodiment of the bb is 1, and Y2selected from-O-, -S(O)f-, -N(R7)-, -C(O)-, -OC(O)-, -CO2-, -C(O)N(R7)- -OS(O) 2-, -N(R7)SO2-, -N(R7)C(O)-, -N(R7)CO2- , and-N(R7)C(O)N(R7)-or any of any shortened version of this group of values. In another private embodiment of the bb is 1, and Y2selected from-O-, -S(O)f-, -N(R7)-, -CO2-, -C(O)N(R7)-, -N(R7)S(O)2- , and-N(R7)C(O)-, -N(R7)CO2- , and-N(R7)C(O)N(R7)- or any shortened version of this group of values. In yet another private embodiment in the definition of Q2bb is 1, and Y2selected from-O-, -S(O)f-, -N(R7)-, -C(O)2and-C(O)N(R7)- or any shortened version of this group of values. In one particular embodiment in the definition of Q2bb is 1, and Y2represents-O-. In yet another specific embodiment in the definition of Q2bb is 1, and Y2selected from-S(O)f-where f means 2. In another specific embodiment of the bb means 1, Y2selected from-N(R7)-, and R7represents H or alkyl, more specifically N. In another specific embodiment of the bb is 1, and Y2represents-C(O)2-. In another specific embodiment of the bb is 1, and Y2represents-C(O)N(R7)-.

Variable SS in the formula Q2may indicate 0 or 1. In one embodiment of the cc means 1. In one such embodiment (R2)ccis alkylene or albaniles, more con is the specific alkylen. In a particular embodiment in the definition of Q2cc means 1, and (R2)ccrepresents a C1-3alkylen.

In accordance with the definition of bb, Y2and cc, R4can be selected from the group consisting of N, halogeno, alkyl, alkenyl, Akinola, -C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, -C(S)NR7R8, -C(=NR7R8, -C(=NR7)NR7R8, -CR7=N-OR7, -OR7, -S(O)fR7, -S(O)2NR7R8, -NR7R8, -N(R7)C(O)R8, -N(R7)S(O)2R8, -NO2, -CN, -N3and groups of the formula (II):

.

In one embodiment R4in the definition of Q2selected from the group consisting of N, halogeno, alkyl, alkenyl, quinil, -C(O)NR7R8, -OR7, -S(O)fR7, -S(O)2NR7R8, -NR7R8, -N(R7)C(O)R8, -N(R7)S(O)2R8, -NO2, -CN, -N3and groups of the formula (II), or any shortened version of this group of values. In a particular embodiment, R4selected from the group consisting of N, halogeno, alkyl, -OR7, -S(O)fR7, -S(O)2NR7R8, -NR7R8and groups of the formula (II), or any shortened version of this group of values. In another embodiment R4selected from N, halogeno, alkyl, -OR7 , -NR7R8and groups of the formula (II) or any shortened version of this group of values.

In a particular embodiment, R4represents a group of formula (II). In the embodiment, in which R4represents a group of formula (II), ring a is selected from C5-10cycloalkyl,5-10cycloalkenyl, aryl, 5-10-membered heterocampa having 1, 2 or 3 heteroatoms selected from N, O and S and 5-10-membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S. In another embodiment, in which R4represents a group of formula (II), ring a is selected from C5-6cycloalkyl,5-6cycloalkenyl, aryl, 5-10-membered heterocampa having 1, 2 or 3 heteroatoms selected from N, O and S and 5-10-membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S. In Q2ring And may be associated with R2, Y2(when SS is 0) or benzimidazole (where AA, bb and SS 0) via any suitable carbon atom or heteroatom. In one embodiment in the definition of Q2R4represents a group of formula (II)and ring a is selected from aryl, 5-10-membered heterocycle having 1, 2 or 3 heteroatoms selected from N, O and S and 5-10-membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S. In a particular embodiment in the definition of Q2R4is a group fo the formula (II), and ring a is selected from aryl and 5-10 membered heterocycle having 1, 2 or 3 heteroatoms selected from N, O and S.

In one embodiment in the definition of Q2R4represents a group of formula (II)and ring a is selected from the group consisting of cycloalkyl, oxetane, oxazole, thiazole, research, piperidine, piperazine, phenyl, naphthyl, thiophene, furan, pyrrolidine, pyrrolidinone, imidazole, triazole, imidazolidinone, benzofuran, benzodioxan, benzimidazole and pyridyl, or any shortened version of this group of values. In a more particular embodiment ring a is selected from the research, piperidine, piperazine, phenyl, pyrrolidinone, imidazolidinone and pyrrolidine or any shortened version of this group of values.

More specifically, in one embodiment R4the same or different and each is independently selected from the group consisting of H, F, Cl, Br, I, methyl, trifloromethyl, ethyl, propyl, isopropyl, cyclopropyl, isobutyl, tert-butyl, Attila, propenyl, acetylene, O-methyl, O-trifloromethyl, O-ethyl, O-propyl, O-isopropyl, O-cyclopropyl, -SO2-methyl, -SO2NH2, -NH2, -NH(alkyl), -N(alkyl)alkyl, -NH(cyclopropyl), -NHC(O)-methyl, -NHC(O)NH2, -NHSO2-methyl, morpholino and piperazinil, or any shortened version of this group of values.

Private, more specific, examples of groups, defined the actual operation Q 2in the compounds of formula (I)selected from the group consisting of:

H, halogeno, alkyl, alkenyl,,,,

,,,

,,,

,,,

,,

,,

and.

In one embodiment Q2represents-O-alkyl. In one particular embodiment Q2represents halogeno.

In one embodiment of compounds of formula (I) R4represents a group of formula (II), and d is 0 or 1. In the private embodiment, in which R4represents a group of formula (II) and d is 1, R2represents a C1-3alkylen. In one embodiment d is 0.

In one embodiment, in which in the compounds of formula (I) R4represents a group of formula (II), e is 0, 1, 2 or 3. In a particular embodiment e is 0 or 1. In one embodiment e is 0. In another embodiment e is 1. In another voplosheniya means 2.

In one embodiment, in which in the compounds of formula (I) R4represents a group of formula (II), R6the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, alkenyl, quinil, Het, -C(O)R7, -CO2R7, -C(O)NR7R8,=O, -OR7, -S(O)fR7, -S(O)2NR7R8, -NR7R8and-N(R7)S(O)2R8or any shortened version of this group of values. In a particular embodiment, R6the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, =O, -OR7, -S(O)fR7, -S(O)2NR7R8and-NR7R8or any shortened version of this group of values.

More specifically, in one embodiment R6the same or different and each is independently selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, Attila, propenyl, cyclopropyl, pyrimidyl, -C(O)-alkyl, -CO2-alkyl, -C(O)NH2, acetylene, oxo, O-methyl, O-ethyl, O-propyl, O-isopropyl, O-cyclopropyl, -SO2-methyl, -SO2NH2, -NH2, -NH(alkyl), -N(alkyl)alkyl, -NH(cyclopropyl) and-NHSO2-bromide, or any shortened version of this group of values.

In another embodiment of the present invention two adjacent groups Q2selected from the group SOS is oasa from alkyl, alkenyl, -OR7, -S(O)fR7and-NR7R8and together with the carbon atoms to which they are linked, they form With5-6cycloalkyl,5-6cycloalkenyl, phenyl, 5-7-membered heterocycle having 1 or 2 heteroatoms selected from N, O and S, or 5-6-membered heteroaryl having 1 or 2 heteroatoms selected from N, O and S. Under "two adjacent groups Q2" it is meant that two groups Q2associated with the neighboring carbon atoms (for example C-4 and C-5). For example, in one embodiment two adjacent groups Q2represent-OR7and together with atoms to which they are linked, they form a heterocyclic group, such as:

or

In another embodiment two adjacent groups Q are alkyl and together with atoms to which they are linked, they form cycloalkyl group, such as:

.

In another embodiment two adjacent groups Q2defined as-OR7and-NR7R8respectively and, together with the atoms to which they are linked, they form a heterocyclic group, such as:

Based on these examples specialists in the art can easily identify additional embodiment. Preferably, in compounds of formula (I), g is e n means 2, two adjacent groups Q2together with the atoms to which they are linked, form5-6cycloalkyl,5-6cycloalkenyl, phenyl, 5-7-membered heterocycle having 1 or 2 heteroatoms selected from N, O and S, or 5-6-membered heteroaryl having 1 or 2 heteroatoms selected from N, O and S.

In one embodiment Q2defined so that when bb is 1 and cc is 0, then R4not is halogen, -C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, -C(S)NR7R8, -C(=NR7R8, -C(=NR7)NR7R8, -CR7=N-OR7, -OR7, -S(O)fR7, -S(O)2NR7R8, -NR7R8, -N(R7)C(O)R8, -N(R7)S(O)2R8, -NO2, -CN, or-N3.

In one embodiment R5selected from the group consisting of N, halogeno, alkyl, -NR7R8and-S(O)fR7or any shortened version of this group of values. In another embodiment R5selected from the group consisting of N, halogeno, alkyl, and-NR7R8or any shortened version of this group of values. In one particular embodiment, R5represents N. In another specific embodiment R5represents-NH2.

More specifically, in one embodiment R5selected from the group consisting of H, F, Cl, Br, I, methyl, trifloromethyl, ethyl, propyl, what sapropel, -S-methyl, -SO2-bromide and-NH2or any shortened version of this group of values.

Compounds of the present invention also include compounds of formula (Ia):

where all the variables such as defined above, and their pharmaceutically acceptable salt, solvate, and physiologically functional derivatives.

According to the present invention also suggested that the compounds of formula (Ib):

where R9the same or different and each is selected from H, halogen and alkyl and all other variables such as defined above, and their pharmaceutically acceptable salt, solvate, and physiologically functional derivatives.

It should be clear that the present invention covers all combinations and short versions of specific groups of values that are defined above.

Specific compounds of formula (I) include compounds described in the Examples section that follows below, but not limited to. Some specific compounds of formula (I) include:

5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxamide;

5-(5-(metiloksi)-6-{[2-(4-methyl-1-piperazinil)ethyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophencarboxylic;

3-[1-(2-chlorophenyl)ethoxy]-5-(5,6-dimethoxy-1H-gasoline idazole-1-yl)thiophene-2-carboxamide;

5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[1-(2-were)ethoxy]thiophene-2-carboxamide;

5-(5-amino-1H-benzimidazole-1-yl)-3-[1-(2-chlorophenyl)ethoxy]thiophene-2-carboxamide;

5-{6-[(4-piperidinylmethyl)oxy]-1H-benzimidazole-1-yl}-3-({[2-(trifluoromethyl)phenyl]-methyl}oxy)-2-thiophencarboxylic;

5-(6-(metiloksi)-5-{[3-(2-oxo-1-pyrrolidinyl)propyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophencarboxylic;

5-[6-{[3-(dimethylamino)propyl]oxy}-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophencarboxylic;

5-(5-(metiloksi)-6-([2-(4-morpholinyl)ethyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophencarboxylic;

5-[6-(2-morpholine-4-ylethoxy)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide;

5-[6-(2-pyrrolidin-1 ylethoxy)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide;

5-[5-fluoro-6-(2-morpholine-4-ylethoxy)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide;

5-[6-(methylsulphonyl)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide;

3-[(3-bromopyridin-4-yl)methoxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide;

5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(triptoreline)benzyl]oxy}thiophene-2-carboxamide;

3-{[2-(deformedarse)benzyl]oxy}-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-CA is backslid;

3-[(2-chloropyridin-3-yl)methoxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide;

5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(2-herperidin-3-yl)methoxy]thiophene-2-carboxamide;

3-[(2-aminopyridine-4-yl)methoxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide;

3-[(6-chloro-1,3-benzodioxol-5-yl)methoxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide;

5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(2-nitrobenzyl)oxy]thiophene-2-carboxamide;

3-[(3-aminobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide;

5-(6-bromo-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]-oxy}thiophene-2-carboxamide;

3-[(2,6-dichlorobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide;

3-[(2-bromobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide;

5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(2-formylmethyl)oxy]thiophene-2-carboxamide;

5-(1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide;

5-(1H-benzimidazole-1-yl)-3-[(2-nitrobenzyl)oxy]thiophene-2-carboxamide;

5-(6-methoxy-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide;

2-(aminocarbonyl)-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)Tien-3-yl-2-methylbenzenesulfonate;

and their pharmaceutically acceptable salt, solvate, and physiologically functional derivatives, but are not limited to.

For experts who s in this area is obvious that the compounds of the present invention can be used also in the form of their pharmaceutically acceptable salts or MES or physiologically functional derivative. Pharmaceutically acceptable salts of compounds of formula (I) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as Quaternary ammonium salts. More specific examples of suitable salts include salts of the following acids: hydrochloric, Hydrobromic, sulfuric, phosphoric, nitric, Perlina, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, Panova, malonic, hydroxymaleimide, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluensulfonate, methanesulfonate (mesilate), naphthalene-2-sulfonic, benzolsulfonat, hydroxynaphthalene, iodomethane, Apple, Sterol, tanning and the like. Other acids, such as oxalic acid, though, and are not pharmaceutically acceptable may be useful in obtaining salts, used as intermediates in obtaining the compounds according to the invention and their pharmaceutically acceptable salts. More specific examples of suitable salts with bases include sodium, lithium, potassium, MAG is eevie, aluminum, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, kalinovye, diethanolamine, Ethylenediamine, N-methylglucamine and procainamide salt.

The term "MES", as used here, refers to a complex of variable stoichiometry formed the dissolved substance (compound of formula (I)) and a solvent. For example, the solvents include water, methanol, ethanol or acetic acid.

The term "physiologically functional derivative"used herein refers to any pharmaceutically acceptable derivative of the compound of the present invention, for example, complex ether or amide compounds of formula (I), which with the introduction of the animal, particularly a mammal, such as man, able to give (directly or indirectly) a compound of the present invention or its active metabolite (see, for example, Burger''s Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: Principles And Practice).

Methods of obtaining pharmaceutically acceptable salt, solvate, and physiologically functional derivatives of the compounds of formula (I) are conventional in the art (see, for example, Burger''s Medicinal Chemistry And Drug Discovery, 5th Edition, Vol 1: Principles And Practice).

As it is obvious to experts in the art, the following methods for obtaining compounds of formula (I) some intermediate compounds which may exist in the form of pharmaceutically acceptable salts, the solvate or physiologically functional derivatives of the compounds. The terms that are applied to each intermediate compound used in the method of obtaining compounds of formula (I)have the same values as the values specified above in relation to compounds of formula (I). Methods of obtaining pharmaceutically acceptable salt, solvate, and physiologically functional derivatives such intermediate compounds are well known in the art and similar ways of getting pharmaceutically acceptable salt, solvate, and physiologically functional derivatives of the compounds of formula (I).

Some compounds of formula (I) can exist in stereoisomeric forms (e.g., they may contain one or more asymmetric carbon atoms or can exhibit CIS/TRANS-isomerism). Individual stereoisomers (enantiomers and diastereomers and their mixtures are included in the scope of the present invention. The present invention also covers the individual isomers of the compounds represented by formula (I), in the form of mixtures of their isomers in which one or more than one chiral centre inverted. Some compounds of formula (I) can be obtained as a mixture of regioisomers. The present invention comprises as a mixture of regioisomers and individual connections. It is also obvious that with the organisations of the formula (I) may exist in tautomeric forms, other than that which is shown by this formula, and they are also included in the scope of the present invention. In one particular embodiment of the present invention chiral compounds are in the R-conformation (i.e. the R-isomer of the compound).

Compounds of the present invention are typical inhibitors of PLK. Under the PLK inhibitor refers to a compound that demonstrates pIC50more than 4 in the analysis of inhibition of PLK described below in the Examples, or IC50less than 100 microns in the analysis of growth inhibition using methylene blue as described below in the Examples; more specifically PLK inhibitor is a compound that demonstrates pIC50more than 5 or IC50less than 10 microns using the methods described below in the Examples.

According to the present invention also provides compounds of formula (I) for use in drug therapy in an animal, e.g. a mammal such as man. In particular, according to the present invention proposed the compounds of formula (I) for use in the treatment of condition mediated by PLK. According to the present invention also suggested that the compounds of formula (I) for use in the treatment of susceptible neoplasms. According to the present invention proposed the compounds of formula (I) for use in treating a condition characterized by nasao the relevant cell proliferation. According to the present invention also suggested that the compounds of formula (I) for use in the inhibition of cell proliferation. According to the present invention also provides compounds of formula (I) for use in the inhibition of mitosis in the cell.

According to the present invention proposed ways to treat several conditions or diseases, all of which include the stage of introducing a therapeutically effective amount of the compounds of formula (I). Used herein, the term "treatment" refers to alleviating specific state, to eliminate or mitigate the symptoms of this condition, slowing or halting the progression of this condition and prevent or hinder the re-emergence of this condition in a previously afflicted subject.

Used herein, the term "therapeutically effective amount" means the amount of the compounds of formula (I)sufficient to cause the biological or therapeutic response, cell culture, tissue, system, animal (including human), the entity to which it is introduced, which is set for example by a researcher or Clinician. For example, a therapeutically effective amount of the compounds of formula (I) for the treatment of a condition mediated by PLK, is a quantity sufficient to treat the condition, incidental the data PLK, the subject has. Similarly, a therapeutically effective amount of the compounds of formula (I) for the treatment chuvstvitelnaja neoplasm is an amount sufficient for the treatment of susceptible neoplasms in the subject. In one embodiment of the present invention is a therapeutically effective amount of the compounds of formula (I) represents a quantity sufficient to inhibit cell mitosis. In yet another embodiment of the present invention is a therapeutically effective amount of the compounds of formula (I) represents a quantity sufficient for regulating, modulating, binding or inhibiting PLK.

The precise therapeutically effective amount of compounds of formula (I) will depend on a number of factors, including, without limitation, by age and mass subjected to the treatment of the patient, the precise disorder requiring treatment and its severity, the type of drug and route of administration, and, ultimately, will be determined by the attending physician or veterinarian. In a typical case, the compound of formula (I) should be introduced for treatment in the range from 0.1 to 200 mg/kg of body weight of the recipient (animal) per day and usually in the range from 1 to 100 mg/kg of body weight per day. Acceptable daily dosage might range from about 0.1 to about 2000 mg/day and preferably will bring the flax 0.1 to about 100 mg/day.

In one aspect of the present invention methods of regulating, modulating, binding or inhibiting PLK for treating conditions mediated by PLK. "Regulating, modulating, binding or inhibiting PLK" refer to the regulation, modulating, binding or inhibiting the activity of PLK, as well as regulating, modulating, binding or inhibiting overexpression of PLK. Such States include some neoplasms (including cancer and tumors)that are associated with PLK, and condition characterized by inappropriate cellular proliferation.

According to the present invention, a method of treatment of a condition mediated by PLK, an animal such as a mammal (e.g., human), comprising an introduction to the animal a therapeutically effective amount of the compounds of formula (I). Condition mediated by PLK, known in the art and include neoplasms and condition characterized by inappropriate cellular proliferation, but not limited to.

According to the present invention is also a method of treating susceptible neoplasms (cancer or tumor) in an animal such as a mammal (e.g., human), comprising an introduction to the animal a therapeutically effective amount of the compounds of formula (I). The term is susceptible neoplasm" here refers to neoplasms, are treatable inhibitor of PLK. Neoplasms that are associated with PLK and therefore treatable by PLK inhibitor known in the art and include both primary and metastatic tumors and cancers. For example, sensitive tumors within the scope of the present invention include breast cancer, colon cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), prostate cancer, lymphoma, leukemia, endometrial cancer, melanoma, ovarian cancer, pancreatic cancer, squamous cell carcinoma, carcinoma of the head and neck and esophageal cancer, but not limited to. The compounds of formula (I) can be used for the treatment of susceptible neoplasms alone or can be used together with some existing types of chemotherapy to provide additive or synergistic effects, and/or can be used to restore the viability of some existing types of chemotherapy and radiation.

According to the present invention a method of treating a condition characterized by inappropriate cellular proliferation. Under "inappropriate cell proliferation" refers to cell proliferation caused by inappropriate cell growth, CL is the exact proliferation, caused by excessive cell division, cell proliferation, due to the rapid cell division, cell proliferation, caused by the inappropriate survival of cells and/or cell proliferation in normal cells, occurring with normal speed, which, however, is undesirable. Condition characterized by inappropriate cellular proliferation include neoplasms, vascular proliferative disorders, fibrotic disorders, proliferative disorders mesangial cells and metabolic disorders, but not limited to. Vascular proliferative disorders include arthritis and restenosis. Fibrotic disorders include cirrhosis and atherosclerosis. Proliferative disorders mesangial cells include glomerulonephritis, malignant nephrosclerosis, thrombotic microangiopathic syndromes, rejection of organ transplants and glomerulopathy. Metabolic disorders include psoriasis, prolonged wound healing, inflammation and neurodegenerative diseases. Osteoarthritis and other dependent proliferation of osteoclasts diseases of excessive bone resorption are examples of conditions characterized by inappropriate cellular proliferation, in which cell proliferation takes place in the normal CL is located at normal speed but still undesirable.

According to the present invention a method of inhibiting cell proliferation, comprising bringing the cells into contact with a sufficient for inhibition of proliferation of this cell number of the compounds of formula (I). In one particular embodiment the cell is a tumor cell. In another specific embodiment the cell is an improper proliferative cell. The term "improper proliferative cell", as used here, refers to cells that grow improper (abnormal)cells, which are divided excessively or share rapidly, to cells that are dissimilar (abnormally) survive, and/or to normal cells, which proliferate at normal speed, but the proliferation of spam. Tumor cells (including cancer cells) are an example of improper proliferative cells, but are not only dissimilar, proliferative cells.

PLK of sadbhavna for cell mitosis, and, accordingly, the compounds of formula (I) are effective for the inhibition of mitosis. The term "inhibition of mitosis" refers to the inhibition of entry into M-phase of the cell cycle, inhibition of the normal passage of the M-phase of the cell cycle immediately after the entry into M-phase and inhibition of standards is a high exit from M-phase of the cell cycle. Thus, the compounds of the present invention can inhibit mitosis by inhibiting the entry of cells into mitosis, inhibition of passage of cells through mitosis or inhibition of the release of cells from mitosis. In one aspect of the present invention, a method for inhibiting mitosis in a cell, comprising introducing into the cell sufficient for the inhibition of mitosis amount of the compounds of formula (I). In one particular embodiment the cell is a tumor cell. In another specific embodiment the cell is an improper proliferative cell.

According to the present invention also proposed the use of the compounds of formula (I) for the preparation of drugs for the treatment of a condition mediated by PLK, an animal such as a mammal (e.g. human). According to the present invention also proposed the use of the compounds of formula (I) for the preparation of drugs for the treatment of susceptible neoplasms in animals. According to the present invention also proposed the use of the compounds of formula (I) for the preparation of drugs for the treatment of a condition characterized by inappropriate cellular proliferation. According to the present invention also proposed the use of the compounds of formula (I) for the preparation of drugs for Engibarov the tion of cell proliferation. According to the present invention also proposed the use of the compounds of formula (I) for the preparation of drugs for ingibirovaniya mitosis in the cell.

Despite the fact that, for use in the treatment there is the possibility of introducing the compounds of formula (I) in unprocessed chemicals, it is usually as an active ingredient is administered in a pharmaceutical composition or a pharmaceutical product.

Thus, according to the proposed invention is also a pharmaceutical composition comprising a compound of formula (I). The pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, diluents and/or excipients. The carrier(s), diluent(s) and/or excipient(s) must be acceptable in the sense of compatibility with other ingredients and is safe for the recipient. According to another aspect of the invention a method of preparing a pharmaceutical preparation comprising mixing the compounds of formula (I) with one or more pharmaceutically priemium carriers, diluents and/or excipients.

The pharmaceutical preparations can be in the form of a standard dose containing a given amount of active ingredient on the standard dose. Such a standard dose may contain Ter is piticescu effective dose of the compounds of formula (I) or a fraction of a therapeutically effective dose, such that at certain times you can enter multiple times the standard dosage forms to achieve the desired therapeutically effective dose. Preferred standard drugs are drugs containing a daily dose or poddaszu active ingredient, as described here above, or an appropriate proportion. In addition, these pharmaceutical preparations can be prepared by any of the methods well known in the pharmaceutical field.

The pharmaceutical preparations can be adapted for administration by any appropriate route, for example orally (including translocally or sublingual), rectal, nazalnam, local (including translocally, sublingual or transdermal), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such preparations can be prepared by any method known in the pharmaceutical field, for example by combining the active ingredient with the carrier(s) or excipient(s).

Pharmaceutical preparations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids suitable for food foams or creams; or fluid is x emulsions oil-in-water or liquid emulsions water-in-oil.

For example, for oral administration in the form of a tablet or capsule, the active drug component can be combined with oral non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders prepared by grinding connection to a suitable fineness and mixing with a similarly comminuted pharmaceutical carrier such as good food carbohydrate, such as, for example, starch or mannitol. Can also be corrigent, preservative, dispersing agent and a dye.

Capsules can be made by preparing a powder mixture as described above, and fill it molded gelatin shells. Before filling in the powder mixture can be added glidant and lubricants such as colloidal silicon dioxide, talc, magnesium stearate, calcium stearate or solid polyethylene glycol. To increase the availability of medicines if swallowed capsules can be added loosening or solubilizers agent, such as agar-agar, calcium carbonate or sodium carbonate.

Moreover, if desired or necessary, the mixture can also be introduced by suitable binding agents, lubricating agents, disintegrating agents and coloring agents. Suitable binders include starch, gelatin, genuine cowhide leather-makes the e sugar, such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums, such as Arabian gum, tragakant or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Used in these dosage forms lubricating agents include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrating agents include starch, methylcellulose, agar, bentonite, xanthan gum and the like, but not limited to. Tablets are made, for example, by preparing a powder mixture, granulating or aggregation, adding lubricants and baking powder and pressed into tablets. A powder mixture is prepared by mixing compound, comminuted in a suitable manner, with a diluent or base as described above, and possibly with a bonding agent, such as carboxymethylcellulose, alginate, gelatine or polyvinylpyrrolidone, moderator of dissolution such as paraffin, accelerator resorbtive, such as a Quaternary salt, and/or absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture may be subjected to granulation moisture binding agent, such as syrup, starch paste, sticky mass of Arabian gum or solutions of cellulose is s and polymeric materials, and push through a sieve. As an alternative to granulating the powder mixture can be filtered through a tablet machine to produce in the resulting imperfectly formed lumps, razdavlennyh to granules. These granules can be lubricated to prevent sticking to the tablet press-forms by adding stearic acid, stearate, talc or mineral oil. Mix with added lubricity agents then pressed into tablets. In addition, the compounds of the present invention can be combined with free flowing inert carrier and directly compressed into tablets without conducting stages of granulation or aggregation. Tablets can be coated with a transparent or opaque protective sheath consisting of an insulating layer Melaka, a layer of sugar or polymeric material and finish coats of wax. In order to distinguish different standard doses, these coatings can be added dyes.

Liquids for oral administration, such as solution, syrups and elixirs can be prepared in the form of a standard dose so that a given quantity contains a predetermined amount of the active ingredient. Syrups can be prepared by dissolving the compounds in an aqueous solution with a suitable taste, while elixirs are prepared with use is of a non-toxic alcohol filler. Suspensions can be prepared by dispersing the compound in a non-toxic filler. Solubilization and emulsifiers, such as ethoxylated isostearyl alcohols and ethers of polyoxyethylenesorbitan, preservatives, corrigentov, such as mint oil, or natural sweeteners or saccharin or other artificial sweeteners and the like can also be added.

If required, the standard drugs for oral administration can be microencapsulated. This drug can also be prepared for prolonged or extended release, for example by coating or embedding granular material in polymers, wax or the like.

The compounds of formula (I) can also be entered in the form of liposomal delivery systems, such as small single-layer vesicles, large single-layer and multi-layered vesicles vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholine.

The compounds of formula (I) can also be delivered using monoclonal antibodies as individual carriers to which is connected the molecules of these compounds. The connection can also be connected with soluble polymers, such as carriers capable of delivering Lekarstvo the e means to the target. Such polymers can include peptides, polyvinylpyrrolidone, peranovic copolymer, polyhydroxyethylmethacrylate, polyhydroxyethylmethacrylate or polyethylenepolyamine, substituted palmitoleate remains. In addition, the compounds can be combined with biodegradable polymers useful for achieving controlled release of drugs, such as polylactic acid, polietilen-caprolacton, polyhydroxyalkane acid, polyarteritis, Polyacetals, policyidreference, polycyanoacrylate and sewn or amphipatic block copolymers of hydrogels.

Pharmaceutical preparations adapted for transdermal administration, can be represented in the form of separate patches, designed to maintain close contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient may be delivered from the patch by iontophoresis as described in Pharmaceutical Research, 3 (6): 318 (1986).

Pharmaceutical preparations adapted for local injection, can be prepared in the form of ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, spree, aerosols or oils.

For treatment of the eye or other external tissues, for example mouth and skin, preparations are preferably applied in the form of ointment or cream for external use is about application. In the preparation of ointment active ingredient can be used with either paraffin or mixed with water ointment base. Alternatively, the active ingredient may be incorporated into the cream base oil-in-water or with a basis of water-in-oil.

Pharmaceutical preparations adapted for local injection into the eye include eye drops, in which the active ingredient is dissolved or suspended in a suitable carrier, in particular in aqueous solvent.

Pharmaceutical preparations adapted for local injection in the mouth include cakes, lozenges and gargling.

Pharmaceutical preparations adapted for rectal administration, can be represented in the form of suppositories or enemas.

Pharmaceutical preparations adapted for nasal administration, in which the carrier is a solid include a coarse powder having a particle size in the range, for example, from 20 to 500 microns which is administered by inhalation through the nose, that is, a rapid inhalation through the nasal passage of the powder from the container which is held close to the nose. Suitable drugs for administration as a nasal spray or nasal drops, in which the carrier is a liquid, include aqueous or oily solutions of the active ingredient.

Pharmaceutical preparations adapted on the I administration by inhalation, include fine dust or mists that may be generated by various types of dosing aerosols under pressure, nebulizers or insufflators.

Pharmaceutical preparations adapted for vaginal administration, can be presented as pessaries, tampons, creams, gels, pastes, foams or spree.

Pharmaceutical preparations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostatic tools and dissolved substances that make the drug isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions, which may contain suspendresume agents and thickening agents. These drugs can be presented in containers with a single dose or multiple doses, for example sealed ampoules and vials and may be stored in dried by freezing (liofilizirovannom) condition requiring only the addition of sterile liquid carrier, for example water for injections, immediately prior to use. Prepared for immediate injection solutions and suspensions can be obtained from sterile powders, granules and tablets.

It should be borne in mind that in addition to the ingredients particularly mention the output above, drugs may include other conventional in the art agents relating to this type is considered a drug, for example agents that are suitable for oral administration may include corrigentov.

In the above-described methods of treatment and applications of the compound of formula (I) can be used, in combination with one or more other compounds of formula (I) or in combination with other therapeutic agents. In particular, methods of treating conditions mediated by PLK, and methods of treating susceptible neoplasms provided by the combination with other chemotherapeutic, hormonal agents and/or agents on the basis of antibodies, as well as combined with surgical therapy and radiotherapy. The term "chemotherapy"as used here, refers to any chemical agent that has a therapeutic effect on the subject, which it is introduced. "Chemotherapeutic agents" include antineoplastic agents, analgesics and anti-emetics, but not limited to. Used here, "antineoplastic agents" include both cytostatic and cytotoxic agents. Thus, the combination therapy according to the present invention includes the introduction of at least one of the compounds of formula (I) and is using at least one other way of treating cancer. In one embodiment of the combination therapy according to the present invention includes the introduction of at least one of the compounds of formula (I) and at least one other chemotherapeutic agent. In one particular embodiment of the present invention includes the introduction of at least one of the compounds of formula (I) and at least one anticancer agent. In an additional aspect of the present invention the methods of treatment and use, as they are described above, including the introduction of the compounds of formula (I) together with at least one chemotherapeutic agent. In one particular embodiment the chemotherapeutic agent is an anticancer agent. In another embodiment of the present invention proposed a pharmaceutical composition, as described above, additionally containing at least one other chemotherapeutic agent, more specifically, a chemotherapeutic agent, which is an antitumor agent.

Usually any chemotherapeutic agent that has activity against sensitive tumors that are treated can be used in combination with compounds of the formula (I) provided that this particular agent is clinically compatible with the treatment using the compounds of formula (I). Typical protivoop the left agents, useful in the present invention include antimicrotubule agents such as diterpenoids and Vinca alkaloids; coordinating platinum complexes; alkylating agents such as nitrogen mustard analogues, oxazaphosphorine, alkyl sulphonates, nitrosoanatabine and triazine; antibiotic agents, such as anthracyclines, aktinomitinov and bleomycin; topoisomerase II inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and antifolate compounds; inhibitors of topoisomerase I, such as camptothecin; hormones and hormonal analogs; inhibitors of signal transduction pathways; inhibitors of angiogenesis preceptory tyrosine kinase; immunotherapy agents; proapoptotic agents; and the transfer inhibitors signals of the cell cycle, but not limited to.

Antimicrotubule or antimitoticescoe agents are phasespecific agents, active against microtubules tumor cells during M-phase or phase of the mitotic cell cycle. Examples antimicrotubule agents include diterpenoids and Vinca alkaloids, but not limited to. Examples of diterpenoids include paclitaxel and its analog docetaxel, but not limited to. Examples of Vinca alkaloids include vinblastine, vincristine and vinorelbine, but they are not limited to what are stated.

Coordination complexes of platinum are naphazoline antitumor agents that interact with DNA. The platinum complexes penetrate into tumor cells, hydratious and form intra - and megamachine-linking with DNA, causing adverse biological effect on the tumor. Examples of coordination complexes of platinum include cisplatin and carboplatin, but not limited to.

Alkylating agents are naphazoline antitumor agents and strong electrophiles. Usually alkylating agents by alkylation of a covalent bond with DNA via nucleophilic groups of the DNA molecule, such as phosphate, amino and hydroxyl groups. Such alkylation impairs the functioning of nucleic acids, leading to cell death. Examples of alkylating agents include nitrogen mustard analogues, such as cyclophosphamide, melphalan and chlorambucil; alkyl sulphonates such as busulfan; nitrosoanatabine, such as carmustine; and triazine, such as dacarbazine, but not limited to.

Antibiotic chemotherapeutic agents are naphazoline agents that bind to DNA or intercalibrate it. Typically, this action leads to stable DNA complexes or damage to circuits that disrupts the normal functioning of the licensing of nucleic acids, leading to cell death. Examples of antibiotic antineoplastic agents include aktinomitinov, such as dactinomycin, anthracycline, such as daunorubicin and doxorubicin; and bleomycin, but not limited to.

Inhibitors of topoisomerase II include epipodophyllotoxin, but not limited to. Epipodophyllotoxin are phasespecific antitumor agents isolated from plants Mandrake. Epipodophyllotoxin usually affects cells in the phases S and G2cell cycle through the formation of ternary complexes with topoisomerase II and DNA, which leads to breaks in the DNA strands. Chain breaks accumulate, it is necessary cell death. Examples of epipodophyllotoxins include etoposide and teniposide, but not limited to.

Uneasiest to tumors antimetabolites are phasespecific antitumor agents that are active in the S phase (DNA synthesis) of the cell cycle by inhibiting DNA synthesis or by inhibiting the synthesis of purine or pyrimidine bases, thereby limiting DNA synthesis. As a result, the phase S does not leak, and is followed by cell death. Examples related to neoplasms of antimetabolites include fluorouracil, methotrexate, cytarabine, mercaptopurine and tioguanin, but not limited to.

Camptothecine, including camptosar is n and the derivatives of camptothecin, available or are in development as inhibitors of topoisomerase I. Suppose that the cytotoxic activity of camptothecin related to their inhibitory activity against topoisomerase I. Examples of camptothecins include irinotecan, topotecan, and the various optical forms of 7-(4-methylpiperazine-methylene)-10,11-Ethylenedioxy-20-camptothecin, but not limited to.

Hormones and hormonal analogues are useful compounds for the treatment of cancers in which there is a relationship between the hormone(s) and the growth and/or lack of growth of the cancer. Examples of hormones and hormonal analogues, which are considered useful in the treatment of neoplasms include adrenocorticosteroids, such as prednisone and prednisolone, which are useful in the treatment of malignant lymphoma and acute leukemia in children; aminoglutetimid and other aromatase inhibitors such as anastrozole, letrazole, varsol and exemestane, are useful in the treatment of adrenocortical cancer and hormone-dependent breast cancer containing estrogen receptors; progestin, such as megestrol acetate, useful in the treatment of hormone-dependent breast cancer and endometrial cancer; estrogen, androgens and antiandrogens, such as flutamide, nilutamide, bikalutamid, ciproteron acetate and 5α-reductase, such as finasteride and dutasteride, is useful in the treatment of prostate cancer and benign prostatic hyperplasia; antiestrogens, such as tamoxifen, toremifene, raloxifene, droloxifene and idoxifene, useful in the treatment of hormone-dependent breast cancer; and gonadotropin-releasing hormone (GnRH) and its analogues, which stimulate the release of luteinizing hormone (LH) and/or follicle-stimulating hormone (FSH), for the treatment of prostate cancer, such as agonists and antagonists of LHRH, such as goserelin acetate and leuprolide, but not limited to.

Inhibitors of signal transduction pathways are those inhibitors that block or inhibit the chemical process that causes intracellular changes. This change represents a cell proliferation or differentiation. Inhibitors of signal transduction, useful in the present invention include inhibitors of the receptor tyrosinekinase, preceptory tyrosinekinase, blockers SH2/SH3 domains, serine/treoninove kinase, phosphatidyl-Inositol-3-kinase, myo-Inositol signalling pathway and the Ras-oncogene.

Some protein-tyrosine kinase catalyze the phosphorylation of specific tyrosine residues in various proteins involved in the regulation of cell growth. Such protein-tyrosine kinase can be broadly classified as receptor or preceptories kinase. Receptor tyrosine kinase are transmembrane proteins which, having an extracellular ligand-binding domain, a transmembrane domain and tyrosinekinase domain. Receptor tyrosine kinase involved in the regulation of cell growth, and they are sometimes called receptors of growth factors. It has been shown that inappropriate or uncontrolled activation of many of these kinases, i.e. aberrant kinase receptor activity against growth factors, for example, by overexpression or mutation leads to uncontrolled cell growth. Accordingly, aberrant activity of these kinases was associated with malignant tissue growth. Therefore, inhibitors of these kinases could provide treatments for cancer. The receptors of growth factors include, for example, the receptor for epidermal growth factor (EGFr, ErbB2 and rb4), the receptor for the secreted platelet-growth factor (Derived), receptor endothelial growth factor vascular (VEGFR), tyrosinekinase with domains homologous immunoglobulinemia and epidermal rostovomu factor (TIE-2)receptor, insulin growth factor-I (IGF-I), macrophage-colony stimulating factor (cfms), CPD, ckit, cmet, receptors of fibroblast growth factor (FGF), Trk receptors (TrkA, TrkB and TrkC), Afrin receptors (eph) and RET-proto-oncogene. Some inhibitors of receptors of growth factors are under development and include antagonists of the ligand is in, antibodies, inhibitors tyrosinekinase, antisense oligonucleotides and aptamers. The receptors of growth factors and agents that inhibit the functioning of the receptors of growth factors, which are described, for example, Kath, John C., Exp. Opin. Ther. Patents (2000) 10 (6): 803-818; Shawver et al DOT Vol 2, No.2 February 1997; and Lofts, F.J. et al, "Growth Factor Receptors as Targets," New Molecular Targets for Cancer Chemotherapy, Ed. Workman, Paul & Kerr, David, CRC Press 1994, London.

Tyrosine kinase, which are receptor kinases and growth factors, are called preceptories tyrosine kinases. Preceptory tyrosine kinase, useful in the present invention, which are targets or potential targets of anticancer drugs include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (focal adhesion kinase), Brutons-tyrosinekinase and Bcr-Abl. Such preceptory kinase and agents that inhibit the functioning of preceptory tyrosinekinase described in Sinh, S, and Corey, S.J., (1999) Journal of Hematotherapy and Stem Cell Research 8 (5): 465-80; and Bolen, J.B., Brugge, J.S., (1997) Annual Review of Immunology, 15: 371-404.

Blockers S2/S3 domains are agents that disrupt the binding of SH2 - or S3-domains of a number of enzymes or adapting proteins, including PI3-K R subunit, Src-kinase family, adaptorname molecules (Shc, Crk, Nck, Grb2 and Ras-GAP. S2/S3 domains as targets for anticancer drugs are discussed in Smithgall, I.E. (1995), Journal of Pharmacological and Toxicological Methods, 34 (3): 125-32.

Inhibitors of serine/treoninove kinases on the hunger blockers MAR-kinase cascade, including blockers Raf-kinases (Rafk), mitogen or extracellular regulated kinase (MEK) and extracellular regulated kinase (ERK); and blockers family of protein kinases, including blockers of RCC subtypes (alpha, beta, gamma, Epsilon, mu, lambda, iota, Zeta), IkB kinase family (IKKa, IKKb), kinases RKV-family, family members Akt-kinase and TGF-beta receptor kinases. These serine/threonine kinases and their inhibitors described in Yamamoto, T., Tawa, S., Kaibuchi, K., (1999), Journal of Biochemistry, 126 (5): 799-803; Brodt, P., Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60, 1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys, 27: 41-64; Philip, P.A, and Harris, A.L. (1995), Cancer Treatment and Research, 78: 3-27; Lackey, K. et al., Bioorganic and Medicinal Chemistry Letters, (10), 2000, 223-226; and Martinez-lacaci, L., et al., Int. J. Cancer (2000), 88 (1), 44-52.

Inhibitors of members of the phosphatidyl-Inositol-3-kinase family, including blockers R-kinase, ATM, DNA-RK and Ku, are also useful in combination with compounds of the present invention. Such kinases are discussed in Abraham, R.T. (1996), Current Opinion in Immunology, 8 (3), 412-8; Canman, C.E., Lim, D.S. (1998), Oncogene 17 (25), 3301-3308; Jackson, S.P. (1997), International Journal of Biochemistry and Cell Biology, 29 (7): 935-8; and Zhong, H. et al, Cancer Res, (2000), 60 (6), 1541-1545.

Also useful in combination with compounds of the present invention are inhibitors of myo-Inositol signalling pathway, such as inhibitors of phospholipase C and myoinositol counterparts. Such signaling inhibitors described in Powis, G., and Kozikowski, A., (1994), New Molecular Targets for Cancer Chemotherapy, ed, Paul Workman and David Kerr, CRC Press, 1994, London.

Another group of inhibitors of signal transduction pathways, useful in combination with the compound of the present invention are inhibitors of Ras oncogenes. Such inhibitors include inhibitors farnesyltransferase, geranyl-geranyl-transferase and SAAH-proteases, as well as antisense oligonucleotides, ribozymes and immunotherapy. It was shown that these inhibitors block the activation of Ras in cells containing mutant Ras wild-type, acting thus as antiproliferative agents. Inhibition of Ras-oncogene discussed in Scharovsky, O.G., Rozados, V.R., Gervasoni, S.I., Matar, P. (2000)Journal of Biomedical Science, 7 (4): 292-8; Ashby, M.N. (1998), Current Opinion in Lipidology, 9 (2): 99-102; and BioChim. Biophys. Acta, (1989), 1423 (3): 19-30.

As mentioned above, antibodies against the ligand-binding receptor kinase can also serve as inhibitors of signal transduction. This group of inhibitors of signal transduction pathways includes the use of humanized antibodies against the extracellular ligand-binding domain of the receptor tyrosine kinase. For example, Imclone C225 EGFR-specific antibody (see Green, M.C. et al, Monoclonal Antibody Therapy for Solid Tumors, Cancer Treat. Rev., (2000), 26 (4), 269-286); Herceptin® rb2-antibody (see Tyrosine Kinase Signaling in Breast Cancer: ErbB Family Receptor Tyrosine Kinase, Breast Cancer Res., 2000, 2 (3), 176-183); and SW VFR2-specific antibody (see Brekken, R.A. et. al, Selective Inhibition of VEGFR2 Activity by a Monoclonal Ati-VEGF Antibody Blocks Tumor Growth in Mice Cancer Res. (2000), 60, 5117-5124).

Inhibitors of angiogenesis receptor kinases can also find use in the present invention. Inhibitors of angiogenesis associated with VEGFR and TIE2 discussed above in relation to inhibitors of signal transduction (both receptors are receptor tyrosine kinases). Other inhibitors may be useful in combination with compounds of the present invention. For example, anti-VEGF antibodies, which do not recognize VEGFR (the receptor tyrosinekinase), however, are associated with ligand; small molecule inhibitors of integrin (v beta)that will inhibit angiogenesis; endostatin and angiostatin (non-RTK) may also demonstrate the usefulness in combination with inhibitors of PLK.

The agents used in immunotherapy regimens may also be useful in combination with compounds of the formula (I).

The agents used in proapoptotic treatment regimens (e.g. bcl-2 antisense oligonucleotides)can also be used in combination according to the present invention. Members of the Bcl-2-family proteins block apoptosis. Because positive regulation of bcl-2 was associated with resistance to chemical attack. Studies have shown that epidermal growth factor (EGF) stimulates anti-apoptotic members of the bcl-2 family (i.e. mcl-1). Therefore, strategies designed negative re is lirovaniya of bcl-2 expression in tumors, demonstrated beneficial effects in the clinic and are currently undergoing phase II/III trials, namely G3139 bcl-2-antisense oligonucleotide (Genta). Such proapoptotic strategy, using the methodology of application of antisense oligonucleotides to bcl-2, are discussed in the Waters JS, et al., J. Clin. Oncol. 18: 1812-1823 (2000); and Kitada S, et al., Antisense Res.Dev.4:71-79 (1994).

Inhibitors of signaling inhibit cell cycle molecules involved in controlling the cell cycle. Cyclin-dependent kinase (CDK) and their interaction with cyclename control the course of the cell cycle in eukaryotes from beginning to end. Coordination between activation and inactivation of various complexes of cyclin/CDK required for normal progress throughout the cell cycle. Several inhibitors of the signaling cell cycle are under development. For example, examples of the cyclin-dependent kinases, including CDK2, CDK4 and CDK6, and their inhibitors are described in Rosania, et al., Exp. Opin. Ther. Patents, 10 (2): 215-230 (2000).

In one embodiment of the methods of the present invention include the introduction of animal compounds of formula (I) in combination with an inhibitor of signal transduction pathways, in particular gefitinib (IRESSA®).

Methods and applications using these combinations may include the introduction of the compounds of formula (I) and other chemotherapeutic/antineoplastic agent is or sequentially in any order, or simultaneously in separate or combined pharmaceutical compositions. Obviously, when combined in the same two drug compounds must be stable and compatible with each other and other components of the drug and can be prepared in the form of a preparation for injection. When preparing individually, they can be provided in the form of any convenient preparation method, known for such connections in this field.

When the compound of formula (I) is used in combination with a chemotherapeutic agent, the dose of each compound may differ from the dose when the connection use one. Acceptable dose can can easily be determined by experts in the field of technology. In order to achieve the desired combined therapeutic effect must be selected acceptable dose of a compound(s) of formula (I) and the other therapeutically active agent(s) and the relative timings of administration, and this choice is the competence of the doctor.

The compounds of formula (I) can easily be obtained by the methods provided below in Scheme 1,

Scheme 1

where R1selected from the group consisting of H, alkyl, alkenyl, quinil, -C(O)R7, -CO2R7, -C(O)NR7R8, -C(O)N(R7OR8, -C(O)N(R7)-R2-OR 8, -C(O)N(R7)-Ph, -C(O)N(R7)-R2-Ph, -C(O)N(R7)C(O)R8, -C(O)N(R7)CO2R8, -C(O)N(R7)C(O)NR7R8, -C(O)N(R7)S(O)2R8, -R2-OR7, -R2-O-C(O)R7, -C(S)R7, -C(S)NR7R8, -C(S)N(R7)-Ph, -C(S)N(R7)-R2-Ph, -R2-SR7, -C(=NR7)NR7R8, -C(=NR7)N(R8)-Ph, -C(=NR7)N(R8)-R2-Ph, -R2-NR7R8, -CN, -OR7, -S(O)fR7, -S(O)2NR7R8, -S(O)2N(R7)-Ph, -S(O)2N(R7)-R2-Ph, -NR7R8, -N(R7)-Ph, -N(R7)-R7-Ph, -N(R7)-SO2R8and Het;

Ph represents a phenyl, possibly substituted from 1 to 3 times a Deputy selected from the group consisting of halogen, alkyl, -OH, -R2-OH, -O-alkyl, -R2-O-alkyl, -NH2, -N(H)alkyl, -N(alkyl)2, -CN and-N3;

Het is a 5-7-membered heterocycle having 1, 2, 3 or 4 heteroatoms selected from N, O and S, or 5-6-membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O and S, each possibly substituted 1 to 2 times a Deputy selected from the group consisting of halogeno, alkyl, oxo, -OH, -R2-OH, -O-alkyl, -R2-O-alkyl, -NH2, -N(H)alkyl, -N(alkyl)2, -CN and-N3;

Q1represents a group of formula -(R2)a(Y1)b-(R2) c-R3, a, b and C are identical or different and each independently denotes 0 or 1, and at least one of a or b is 1;

n means 0, 1, 2, 3 or 4;

Q2represents a group of formula -(R2)aa(Y2)bb-(R2)cc-R4,

or two adjacent groups Q2selected from the group consisting of alkyl, alkenyl, -OR7, -S(O)fR7and-NR7R8and together with the carbon atoms to which they are linked, they form With5-6cycloalkyl,5-6cycloalkenyl, phenyl, 5-7-membered heterocycle having 1 or 2 heteroatoms selected from N, O and S, or 5-6-membered heteroaryl having 1 or 2 heteroatoms selected from N, O and S;

AA, bb and cc are the same or different and each independently denotes 0 or 1;

Y1and Y2the same or different and each independent selected from the group consisting of-O-, -S(O)f-, -N(R7)-, -C(O)-, -OC(O)-, -CO2-, -C(O)N(R7)-, -C(O)N(R7)S(O)2-, -OC(O)N(R7)-, -OS(O)2-, -S(O)2N(R7)-, -S(O)2N(R7)C(O)-, -N(R7)S(O)2-, -N(R7)C(O)-, -N(R7)CO2- , and-N(R7)C(O)N(R7)-;

R2the same or different and each is independently selected from the group consisting of alkylene, Alcanena and akinlana;

R3and R4the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, alkenyl of quinil, -C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, -C(S)NR7R8, -C(=NR7R8, -C(=NR7)NR7R8, -CR7=N-OR7, -OR7, -S(O)fR7, -S(O)2NR7R8, -NR7R8, -N(R7)C(O)R8, -N(R7)S(O)2R8, -NO2, -CN, -N3and groups of the formula (II):

where ring a is selected from the group consisting of C5-10cycloalkyl,5-10cycloalkenyl, aryl, 5-10-membered heterocycle having 1, 2 or 3 heteroatoms selected from N, O and S and 5-10-membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S;

each d is 0 or 1;

E. means 0, 1, 2, 3 or 4;

R6the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, Ph, Het, -CH(OH)-R2-OH, -C(O)R7, -CO2R7, -CO2-R2-Ph, -CO2-R2-Het, -C(O)NR7R8, -C(O)N(R7)C(O)R7, -C(O)N(R7)CO2R7, -C(O)N(R7)C(O)NR7R8, -C(O)N(R7)S(O)2R7, -C(S)R7, -C(S)NR7R8, -C(=NR7R8, -C(=NR7)NR7R8, -CR7=N-OR8,=O, -OR7, -OC(O)R7, -OC(O)Ph, -OC(O)Het, -OC(O)NR7R8, -O-R2-S(O)2R7, -S(O)fR7, -S(O)2NR7R8-S(O)2Ph, S(O) 2Het, -NR7R8, -N(R7)C(O)R8, -N(R7)-CO2R8, -N(R7)-R2-CO2R8, -N(R7)C(O)NR7R8, -N(R7)-R2-C(O)NR7R8, -N(R7)C(O)Ph, -N(R7)C(O)Het, -N(R7)Ph, -N(R7)Het, -N(R7)C(O)NR7-R2-NR7R8, -N(R7)C(O)N(R7)Ph, -N(R7)C(O)N(R7)Het, -N(R7)C(O)N(R7)-R2-Het, -N(R7)S(O)2R8, -N(R7)-R2-S(O)2R8, -NO2, -CN and-N3;

moreover, when Q1defined in such a way that b means 1 and with means O then R3not is halogen, -C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, -C(S)NR7R8, -C(=NR7R8, -C(=NR7)NR7R8, -CR7=N-OR7, -OR7, -S(O)fR7, -S(O)2NR7R8, -NR7R8, -N(R7)C(O)R8, -N(R7)S(O)2R8, -NO2, -CN, or-N3;

moreover, when Q2defined in such a way that bb is 1 and cc stands for O, then R4not is halogen, -C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, -C(S)NR7R8, -C(=NR7R8, -C(=NR7)NR7R8, -CR7=N-OR7, -OR7, -S(O)fR7, -S(O)2NR7R8, -NR7R8, -N(R7)C(O)R8, -N(R7)S(O)2R8 , -NO2, -CN, or-N3;

R5selected from the group consisting of N, halogeno, alkyl, cycloalkyl, -OR7, -S(O)fR7, -NR7R8, -NHC(O)R7, -NHC(O)NR7R8and-NHS(O)2R7;

f denotes 0, 1 or 2; and

each R7and each R8the same or different and each is independently selected from the group consisting of H, alkyl, alkenyl, quinil, cycloalkyl and cycloalkenyl; and

R10selected from the group consisting of alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl and suitable protective group of carboxylic acid.

In General, the method of obtaining compounds of formula (I) (all formulas and all variables opredeloeny above in connection with Scheme 1) involves the following stages:

a) interaction of the compounds of formula (III) with the compound of the formula (IV) with a compound of formula (I);

b) the possible conversion of the compounds of formula (I) and its pharmaceutically acceptable salt, MES or physiologically functional derivative; and

C) possible conversion of the compounds of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative into another compound of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative.

More specifically, the compounds of formula (I) can be obtained by vzaimode istia the compounds of formula (IV) with the compound of the formula (III) with a compound of the formula (I-A):

where all the variables such as defined in connection with Scheme 1.

The compound of the formula (I-A) can be transformed into its pharmaceutically acceptable salt, MES or physiologically functional derivative or can be converted into another compound of formula (I-A) or its pharmaceutically acceptable salt, MES or physiologically functional derivative according to the methods described below, and by methods conventional in the art.

The interaction of the compounds of formula (III) with the compound of the formula (IV) is usually carried out in an inert solvent at room temperature. In a typical case, two molar equivalent of compound of formula (III) is combined with one molar equivalent of a compound of formula (IV). Examples of suitable inert solvents for this reaction include chloroform, dichloromethane, tetrahydrofuran, dioxane and toluene, but not limited to.

The compound of formula (IV) can be obtained by reacting the compounds of formula (V) with sulfurylchloride:

where all the variables such as defined in connection with Scheme 1.

The compounds of formula (V) are commercially available or can be obtained using ordinary knowledge in the art. In a typical case, the interaction of the compounds of formula (V) with sulfury the chloride at room temperature gives compound of formula (IV). Optionally, you can use the excess sulfurylchloride. Examples of suitable solvents include chloroform, dichloromethane and toluene, but not limited to. See Corral, C.; Lissavetzky, J, Synthesis, 847-850 (1984).

The compound of formula (III) can be obtained in several ways.

According to one method, the compound of formula (III) are obtained in accordance with the following Scheme 2:

Scheme 2

where all the variables such as defined in connection with Scheme 1.

In General, this method of obtaining the compounds of formula (III) (all formulas and all variables opredeloeny above in connection with Scheme 1) involves the following stages:

a) restoring the compounds of formula (VII) with a compound of formula (VIII); and

b) interaction of the compounds of formula (VIII) with collisuem reagent to obtain the compounds of formula (III).

The order of the above stages are not critical to the practical implementation of this invention, and in practice this method can be implemented by carrying out these stages in any suitable manner at the discretion of the person skilled in the technical field.

More specifically, the compound of formula (III) can be obtained by reacting the compounds of formula (VIII) with collisuem reagent. There are several cyclessa reagents that can be used with this is the stage of the way. In one embodiment the compound of formula (III-A) (i.e. a compound of formula (III), where R5represents H or alkyl) are obtained by reacting the compounds of formula (VIII) with collisuem reagent of formula (IX):

where R11represents H or alkyl, and all other variables such as defined in connection with Scheme 1.

This interaction can be carried out using standard techniques (see White, A., et al., J. Med. Chem. 43: 4084-4097 (2000); Jiang, J.-L, et al., Synthetic Comm. 28: 4137-4142 (1998); Tanaka, A., et al., Chem. Pharm. Bull. 42: 560-569 (1994); Tian, W, et al., Synthesis 12: 1283-1286 (1992); Buckle, D. R., et al., J. Med. Chem. 30: 2216-2221 (1987); and Raban, M., et al., J. Org. Chem. 50: 2205-2210 (1985)). The reaction can be carried out in the absence or in the presence of a suitable solvent. The reaction mixture can be heated to a temperature of from about 50 to about 230°C. the Reaction is usually carried out with an excess of the compounds of formula (IX). You can use the additional acid. Examples of suitable acids include hydrochloric acid, Hydrobromic acid, perchloro acid, sulfuric acid, paratoluenesulfonyl acid, methanesulfonate acid and triftormetilfullerenov acid, but not limited to. Examples of suitable solvents for this reaction include water, methanol, ethanol, isopropanol, tetrahydrofuran, dichloromethane, toluene, N,N-d is methylformamide, dimethyl sulfoxide and acetonitrile, but not limited to. The compounds of formula (IX) are commercially available.

The compound of formula (VIII) can be obtained by recovering the compounds of formula (VII):

where all the variables such as defined in connection with Scheme 1.

The recovery may be carried out using conventional methods and reducing agents (see Rangarajan, M., et al., Bioorg. Med. Chem. 8: 2591-2600 (2000); White, A.W., et al., J. Med. Chem. 43: 4084-4097 (2000); Silvestri, R., et al., Bioorg. Med. Chem. 8: 2305-2309 (2000); Nagaraja, D., et al., Tetrahedron Lett. 40: 7855-7856 (1999); Jung, F., et al., J. Med. Chem. 34: 1110-1116 (1991); Srivastava, R.P., et al., Pharmazie 45: 34-37 (1990); Hankovszky, H.O., et al., Can. J. Chem. 67: 1392-1400 (1989); Ladd, D.L, et al., J. Org. Chem. 53: 417-420 (1988); Mertens, A., et al., J. Med. Chem. 30: 1279-1287 (1987); and Sharma, for K.S., et al., Synthesis 4: 316-318 (1981)). Examples of suitable reducing agents for this reaction include palladium with hydrogen, palladium with ammonium formate, platinum oxide with hydrogen, Nickel-hydrogen chloride tin(II), iron with acetic acid, aluminum ammonium chloride, borane, dithionite sodium and hydrazine, but not limited to. The reaction mixture can be heated to a temperature of between about 50 and about 120°C. Suitable solvents for this reaction vary and include water, methanol, ethanol, ethyl acetate, tetrahydrofuran and dioxane, but not limited to.

The compound of formula (VII) can the be obtained in several ways. In one embodiment the compound of formula (VII) are obtained by reacting the compounds of formula (VI) with ammonia:

where all the variables such as defined in connection with Scheme 1.

This reaction can be carried out using conventional techniques (see Silvestri, R., et al., Bioorg. Med. Chem. 8: 2305-2309 (2000); Hankovszky, H.O, et al., Can. J. Chem. 67:1392-1400 (1989); Nasielski-Hinkens, R., et al., Heterocycles 26: 2433-2442 (1987); Chu, K.Y., et al., J. Chem. Soc. Perkm Trans. 1 10: 1194-1198 (1978)). The reaction is usually carried out with an excess of ammonia, and the reaction mixture can be heated to a temperature of from about 50 to about 100°C. Examples of suitable solvents for this reaction include water, methanol, ethanol, isopropanol, tetrahydrofuran, dioxane and 1,2-dimethoxyethan, but not limited to.

The compounds of formula (VI) are commercially available or can be obtained using standard methods and reagents.

In another embodiment the compound of formula (VII) can be obtained by reacting a protected compound of formula (X) in the conditions of nitration to obtain a protected compound of formula (VII) (i.e VII-A), and then removing the protective group from compounds of formula (VII-A):

where PG is a protecting group and all other variables such as defined in connection with Scheme 1.

Protection of anilines before the hat is the usual transformation, well known to the person skilled in the art (see Kocienski, P.J. Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994; Greene, T.W, Wuts, P. G. M. Protecting Groups in Organic Synthesis (2ndEdition), J. Wiley and Sons, 1991). Suitable protective groups for this purpose include acetyl, TRIFLUOROACETYL, benzyloxycarbonyl, allyloxycarbonyl, 2-(trimethylsilyl)etoxycarbonyl, phenylsulfonyl and paratoluenesulfonyl, but not limited to. Reagents and conditions vary according to the specific nature of the protective group. Typical reagents include acetic anhydride, triperoxonane anhydride, benzylchloride, allylchloroformate, 4-nitrophenyl 2-(trimethylsilyl)ethylcarbonate, phenylsulfonyl and paratoluenesulfonyl, but not limited to. In some cases, you need to add the base. Examples of suitable bases include potassium carbonate, sodium carbonate, trialkylamine, pyridine and tert-piperonyl potassium, but not limited to. Suitable solvents for this transformation include dichloromethane, chloroform, tetrahydrofuran, acetic acid, methanol, ethanol, water, toluene, and diethyl ether, but not limited to.

Nitration of anilines also well documented in the literature, and the above-mentioned reaction can be carried out using these standard techniques (see Wissner, A., et al., J. Med. Chem. 46: 49-63 (2003); Duggan, S.A, et al., J. Org. Chem. 66: 4419-4426 (201); Clews, J., et al., Tetrahedron Lett. 56: 8735-8746 (2000); and Kagechika H, J. Med. Chem. 31: 2182-2192 (1988)). The nitration can be carried out using different nitrious reagents, including 70%aqueous nitric acid, fuming nitric acid, ammonium nitrate triperoxonane anhydride and potassium nitrate with triftormetilfullerenov acid, but not limited to. The reaction is usually carried out at room temperature, but in some cases, the reaction mixture can be heated to a temperature of from about 40 to about 100°C. Suitable solvents include acetic acid, sulfuric acid, acetic anhydride, dichloromethane and chloroform, but not limited to.

Nitration gives compound of formula (VII-A) (i.e. protected compound of formula (VII)). Cleavage of the protective group of aniline to obtain the compounds of formula (VII) can be carried out in many different traditional ways (see Kocienski, P.J. Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994; Greene, T.W., Wuts, P. G. M. Protecting Groups in Organic Synthesis (2ndEdition), J.Wiley and Sons, 1991).

The compound of formula (X) can be obtained by introducing a protective group to the corresponding aniline. These anilines are commercially available or can be obtained using standard techniques.

The compound of the formula (III-A) can be converted into a compound of the formula (III-B). This transformation may shall be carried out by halogenation of compounds of formula (III-A) to obtain the compounds of formula (III-B):

where X1represents halogen (in particular Cl, Br or I), and all other variables such as defined in connection with Scheme 1.

This type of transformation is well described in the literature (see Taylor, E. C., et al., J. Org. Chem. 56: 6937-6939 (1991); Mistry, A. G et al., Tetrahedron Lett. 27:1051-1054 (1986); and Apen, P. G., et al., Heterocycles 29: 1325-1329 (1989)). Suitable halogenation agents include N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide, chlorine, bromine and iodine, but not limited to. Examples of suitable solvents include dichloromethane, chloroform, diethyl ether, tetrahydrofuran, and acetone, but not limited to.

The compound of the formula (III-B) can also be obtained directly from compounds of formula (VIII). This method includes stage 1) interaction of the compounds of formula (VIII) with phosgene or a phosgene equivalent to the connection with obtaining the compounds of formula (XII) and (2) the interaction of the compounds of formula (XII) with oxyhalogenation phosphorus obtaining the compounds of formula (III-B),

where R12the same or different and each is independently selected from the group consisting of Cl, methoxy, ethoxy, trichlormethane, amino and N-imidazolyl;

X1represents halogen (in particular Cl, Br or I, more particularly Cl or Br), and all other variables such as defined in connection with Scheme 1.

F is Shen or the equivalent of phosgene connection is collisuem reagent and is typically a compound of the formula (XI), shown above. The phosgene and phosgene equivalent to the compounds of formula (XI) are commercially available. Examples of suitable compounds of the formula (XI) include phosgene, dimethylcarbonate, diethylcarbamyl, 1,1'-carbonyldiimidazole, urea and triphosgene, but not limited to. The interaction of the compounds of formula (VIII) with phosgene or a phosgene equivalent to the connection can be carried out using conventional techniques (see Silvestri, R., et al., Bioorg. Med. Chem. 8: 2305-2309 (2000); Wright, J. L, et al., J. Med. Chem. 43: 3408-3419 (2000); Penieres, G. S., et al., Synthetic Comm. 30: 2191-2195 (2000); Von der Saal, W., et al, J. Med. Chem. 32: 1481-1491 (1989)). Typically, this reaction proceeds in an inert solvent or without him. The reaction mixture in some cases, can be heated to a temperature of from approximately 50 to approximately 250°C. it May be desirable possible adding to the reaction mixture a suitable base. Examples of such bases include trialkylamines, pyridine, 2,6-lutidine, potassium carbonate, sodium carbonate and sodium bicarbonate, but not limited to. Examples of suitable solvents for this reaction include dichloromethane, chloroform, N,N-dimethylformamide, tetrahydrofuran, toluene and acetone, but not limited to.

The interaction of the compounds of formula (XII) with oxyhalogenation phosphorus obtaining the compounds of formula (III-B) can be carried out using conventional methods is (see Blythin, D.J., et al., J. Med. Chem. 29: 1099-1113 (1986); and Crank, G., Aust. J. Chem. 35: 775-784 (1982)). Examples of suitable reagents include phosphorus oxychloride and oxybromide phosphorus, but not limited to. Suitable solvents include dichloromethane, chloroform, dichloroethane and toluene, but not limited to. You can use the possible heating in the range of from about 50 to about 150°C.

The compound of the formula (III-B), obtained by any method can be converted into a compound of the formula (III-C) by reacting with an amine of the formula HNR7R8:

where all the variables such as defined above.

The interaction of the halogen-substituted benzimidazole of the formula (III-B) with an amine to obtain the compounds of formula (III-C) can be carried out using conventional techniques (see Alcalde, E., et al., J. Org. Chem. 56: 4233-4238 (1991); Katsushima, T., et al., J. Med. Chem. 33: 1906-1910 (1990); Young, R. C., et al., J. Med. Chem. 33: 2073-2080 (1990); Iemura, R., et al., J. Med. Chem. 29: 1178-1183 (1986); and Benassi, R., et al., J. Chem. Soc. Perkin Trans. 2 10: 1513-1521 (1985)). At desire it is possible to use an acid catalyst. Examples of suitable acid catalysts include hydrochloric acid and paratoluenesulfonyl acid, but not limited to. The reaction mixture can be heated to a temperature of from about 50 to about 220°C. Suitable solvents for this reaction VK is ucaut water, ethanol, isopropanol, 1-methyl-2-pyrrolidone, N,N-dimethylformamide, dimethylsulfoxide, toluene, xylene and tetrahydrofuran, but not limited to.

In another embodiment the compound of formula (III-D) (i.e. the compound of formula (III), where R5represents H or alkyl) are obtained in accordance with the method shown below in Scheme 3:

Scheme 3

where R13represents H or alkyl, and all other variables such as defined in connection with Scheme 1.

In General, this method of obtaining the compounds of formula (III-D) (all formulas and all variables are defined above in connection with Scheme 1) involves the following stages:

a) interaction of the compounds of formula (XIII) with a suitable allermuir agent with obtaining the compounds of formula (XIV);

b) interaction of the compounds of formula (XIV) in the conditions of nitration with obtaining the compounds of formula (XV);

C) the restoration of the compounds of formula (XV) with a compound of formula (XVI); and

d) cyclization of the compounds of formula (XVI) with a compound of the formula (III-D).

The order of the above stages are not critical to the practical implementation of this invention, and this method can be implemented in practice with the implementation stages in any suitable manner at the discretion of the person skilled in the technical field.

More specifically, the connection is their formula (III-D) can be obtained by cyclization of compounds of formula (XVI):

where all the variables such as defined in connection with Schemes 1-3.

This type of cyclization reaction is well documented in the literature (see Brana, M. F., et al., J. Med. Chem. 45: 5813-5816 (2002); Fonseca, I., et al., Tetrahedron 57: 1793-1799 (2001); White, A.W., et al., J. Med. Chem. 43: 4084-4097 (2000); and Tamura, S.Y., et al., Biorg. Med. Chem. Lett. 7:1359-1364 (1997)). The reaction can be carried out in the absence or in the presence of a suitable solvent. The reaction mixture can be heated to a temperature of from about 50 to about 200°C. Typically use an excess of the appropriate acid. Examples of suitable acids include acetic acid, triperoxonane acid, hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonate acid, paratoluenesulfonyl acid and pyridinium paratoluenesulfonyl, but not limited to. Also can be used dehydrating reagent. Examples of suitable dehydrating reagents include magnesium sulfate, sodium sulfate, phosphorus pentoxide and molecular sieves, but not limited to. Examples of suitable solvents include dichloromethane, chloroform, toluene, xylenes, methanol, ethanol and water, but not limited to.

The compound of formula (XVI) can be obtained by recovering the compounds of formula (XV):

where all the variables that the s, as defined in connection with Schemes 1-3.

The recovery may be carried out using traditional methods and vosstanovitelya (see Rangarajan, M., et al., Bioorg. Med. Chem. 8: 2591-2600 (2000); White, A.W., et al., J. Med. Chem. 43: 4084-4097 (2000); Silvestri, R., et al., Bioorg. Med. Chem. 8: 2305-2309 (2000); Nagaraja, D., et al., Tetrahedron Lett. 40: 7855-7856 (1999); Jung, F., et al., J. Med. Chem. 34:1110-1116 (1991); Srivastava, R.P., et al., Pharmazie 45: 34-37 (1990); Hankovszky, H.O., et al., Can. J. Chem. 67: 1392-1400 (1989); Ladd, D.L, et al., J. Org. Chem. 53: 417-420 (1988); Mertens, A., et al., J. Med. Chem. 30: 1279-1287 (1987); and Sharma, for K.S., et al., Synthesis 4: 316-318 (1981)). Examples of suitable reducing agents for this reaction include palladium with hydrogen, palladium with ammonium formate, platinum oxide with hydrogen, Nickel-hydrogen chloride tin(II), iron with acetic acid, aluminum ammonium chloride, borane, dithionite sodium and hydrazine, but not limited to. The reaction mixture can be heated to a temperature of between about 50 and about 120°C. Suitable solvents for this reaction vary and include water, methanol, ethanol, ethyl acetate, tetrahydrofuran and dioxane, but not limited to.

The compound of formula (XV) can be obtained by reacting the compounds of formula (XIV) in the conditions of nitration:

where all the variables such as defined in connection with Schemes 1-3.

The interaction of the compounds of formula (XIV) in the conditions of nitration can be the ü conducted in the same way, as described above for the nitration of compounds of formula (X).

The compound of formula (XIV) can be obtained by acylation of compounds of formula (XIII):

where all the variables such as defined in connection with Schemes 1-3.

The acylation of anilines is a simple transformation, a well-known specialist in the art, and such standard methods of acylation can be used for carrying out the above reaction (see Larock, R.. Comprehensive Organic Transformations, VCH Publishers, Inc, New York, pp.972-976, 979, 981 (1989)). Usually, the acylation reaction is carried out with the use of alleluya agents, such as allalone, allanheld or carboxylic acid, in the presence of the reagent(s) combination. Examples of suitable combination of reagents include N,N-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, O-(7-sabastiano-1-yl)-N,N,N',N'-tetramethylurea hexaphosphate and N,N'-carbonyldiimidazole, but not limited to. Suitable solvents include N,N-dimethylformamide, tetrahydrofuran, dioxane, toluene, benzene, 1,2-dimethoxyethane and 1-methyl-2-pyrrolidone, but not limited to. Anilines of the formula (XIII) are commercially available or can be easily obtained from commercially available material using standard techniques.

For specialists in this about the Asti obviously, the compound of formula (I) can be converted into another compound of formula (I) using techniques well known in the art. For example, the compound of formula (I-A) can be converted into a compound of the formula (I-B) or (I-C) in the manner illustrated in figure 4:

Scheme 4

where Q3represents a group of formula -(R2)a(Y3)j-(R2)c-R3,

j is 0 or 1;

Y3selected from the group consisting of-S(O)f-, -N(R7)-, -C(O)-, -OC(O)-, -CO2-, -C(O)N(R7)-, -C(O)N(R7)S(O)2-, -OC(O)N(R7)-, -OS(O)2-, -S(O)2N(R7)-, -S(O)2N(R7)C(O)-, -N(R7)S(O)2-, -N(R7)C(O)-, -N(R7)CO2- , and-N(R7)C(O)N(R7)-;

LG represents a suitable leaving group; and

all other variables such as defined above in connection with Scheme 1.

In General, the method of obtaining the compounds of formula (I-B) comprises the following stages:

a) interaction of the compounds of formula (I-A) with a base and a compound of formula (XVIII) with a compound of the formula (I-B); or

b) interaction of the compounds of formula (I-A) with the compound of the formula (IXX) in Mitsunobu with obtaining the compounds of formula (I-B).

More specifically, the compound of formula (I-B) can be obtained by reacting compounds of the shape of the s (I-A) with the compound of the formula (XVIII). The compounds of formula (XVIII) are commercially available or can be obtained using ordinary knowledge in the art. This reaction can be carried out in an inert solvent, conveniently at room temperature in the presence of a suitable base. The compound of the formula (I-A) and the compound of formula (XVIII) may be present in equimolar amounts, however, you might want to use a slight excess of the compound of formula (XVIII). Examples of suitable bases for this reaction include potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride and potassium hydride, but not limited to. Examples of suitable inert solvents for this reaction include N,N-dimethylformamide, tetrahydrofuran, dioxane and 1,2-dimethoxyethan, but not limited to.

In another embodiment the compound of formula (I-B) can be obtained by reacting the compounds of formula (I-A) with the compound of the formula (IXX). The compounds of formula (IXX) are commercially available or can be obtained using ordinary knowledge in the art. This reaction is carried out in an inert solvent under standard conditions of Mitsunobu (see Hughes, D.L, Org. React. 42: 335-656 (1992); and Mitsunobu, O., Synthesis, 1-28 (1981)). Typically, the compound of formula (I-A), compound of formula (IXX), triarylphosphine and dialkyldithiocarbamate subjected to interaction at room temperaturepressure suitable triarylphosphines include triphenylphosphine, three-pair-tolylphosphino and trimethyltin, but not limited to. Examples of suitable dialkyldithiocarbamato include diethylazodicarboxylate, diisopropylsalicylic and di-tert-utilisationbased, but not limited to. Examples of suitable inert solvents for this reaction include tetrahydrofuran, dioxane, 1,2-dimethoxyethane, dichloromethane and toluene, but not limited to.

The compound of the formula (I-A) can also be converted into a compound of the formula (I-C) according to the following Scheme 5:

Scheme 5

where M represents-B(OH)2, -B(OR14)2-Sn(R14)2, Zn-halogeno, Zn-R14, Mg-halogeno, Cu-halogeno, Cu-R14where R14represents an alkyl or cycloalkyl, and all other variables such as defined above in relation to Schemes 1-4.

In General, the method of obtaining compounds of formula (I-C) includes the following stages:

a) interaction of the compounds of formula (I-A) with a suitable reagent, forming triplet (cryptomerlone), obtaining the compounds of formula (XX); and

b) the combination of the compounds of formula (XX) with a compound selected from the group consisting of the compounds of formula (XXI), (XXII) and (XXIII)using a catalyst based on palladium(0) to obtain the compounds of formula (I-C).

More specifically, the connection is their formula (I-C) can be obtained by reacting the compounds of formula (XX) with the compound, selected from the group consisting of the compounds of formula (XXI), (XXII) and (XXIII)using a catalyst based on palladium(0). The reaction can be carried out in an inert solvent in the presence of palladium(0). The reaction mixture can be heated to a temperature of from about 50 to about 150°C. typically the reaction is performed by reacting equimolar amount of the compound of formula (XX) with equimolar amounts of compounds selected from the group consisting of the compounds of formula (XXI), (XXII) and (XXIII). The catalyst based on palladium(0) is usually present in quantities of 1-10 molar percent based on the compound of formula (XX). Examples of suitable palladium catalysts include tetrakis(triphenylphosphine)palladium(0) and Tris(dibenzylideneacetone)palladium(0), but they are not limited. It is also possible formation of a catalyst based on palladium(0) in situ using sources of palladium(II). Examples of suitable sources of palladium(II) include palladium(II)acetate, palladium(II)chloride, triptorelin palladium(II), dichlorobis(triphenyl-phosphine)palladium(II) and bis(diphenylphosphinomethyl)-palladium(II) dichloride, but not limited to. Suitable solvents for this reaction include N,N-dimethylformamide, tetrahydrofuran, dioxane, toluene, benzene, 1,2-dimethoxyethane and 1-methyl-2-pyrrolidin, but they do not limit the expansions. If desirable, the reaction mixture can be added as additives to the base and phosphines. Examples of suitable bases include cesium carbonate, sodium carbonate and trialkylamine, but not limited to. Examples of suitable phosphine additives include triphenylphosphine, tributylphosphine, diphenylphosphinoethyl and 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl, but not limited to. The compounds of formula (XXI), (XXII) and (XXIII) can be purchased, or received in the form of individual compounds or formed in situ using well-known in the art knowledge (see Luker, T.J, et. al., Tetrahedron Lett. 41: 7731-7735 (2000); Yin, J., et. al., Org. Lett. 2: 1101-1104 (2000); Wolfe, J.P., et. al., Can. J. Cnem. 78: 957-962 (2000); Littke, A.F., et. al., J. Am. Cnem. Soc. 122: 4020-4028 (2000); Hundertmark, T., et. al., Org. Lett. 2: 1729-1731 (2000); Buchwald. S.L, ACE. Cnem. Res. 31: 805-818 (1998); Suzuki, A., J. were obtained Cnem. 576:147-168 (1999); Negishi, E., J. were obtained. Cnem. 576:179-194 (1999); Stanforth, S.P, Tetrahedron 54: 263-303 (1998); Littke, A.F., Angew. Cnem., Int. Ed. 37: 3387-3388 (1999); and Thorand, S., et. al., J. Org. Cnem. 63, 8551-8553 (1998)).

The compound of formula (XX) can be formed from compounds of formula (I-A) using a suitable reagent, forming triplet. This reaction is usually carried out in an inert solvent using a base and a reagent, created for the conversion of alcohols in triflate (i.e. reagent constituting triplet). Examples of suitable bases include sodium carbonate, trialkylamine, pyridine, hydride is the atrium and bis(trimethylsilyl)amide lithium but they are not limited. This reaction preferably proceeds at a temperature of from about 0 to about 25°C. Appropriate reagents, forming triplet, for this reaction include triftormetilfullerenov anhydride, triftormetilfullerenov and N-phenyltrichlorosilane, but not limited to. Suitable inert solvents for this reaction include tetrahydrofuran, dichloromethane, toluene, chloroform, diethyl ether and dioxane, but not limited to.

As another example, the methods of transformation of compounds of formula (I) into another compound of formula (I), the compound of formula (I-A), (I-B) or (I-S) (collectively called compound of the formula (I-D)), can be converted into another compound of formula (I):

where R1other than-CO2R10;

and all other variables such as defined in connection with Schemes 1-5.

Depending on the specific target compounds of formula (I) for the conversion of compounds of formula (I-D) into another compound of formula (I) can be used several ways using conventional techniques. For example, according to one method, a compound of the formula (I-D) can be converted into a compound of the formula (I-E) by removing the protective group of carboxylic acid:

where all per the time such as defined in connection with Schemes 1-5.

There are several options to implement this transformation. Examples of suitable conditions include basic hydrolysis, if R1represents-CO2Me, removing protection from a proton acid, if R1represents-CO2-tert-Bu, removing protection in conditions of catalysis based on palladium(0), if R1is a CO2CH2CH=CH2, removing protection tetrabutylammonium, if R1is a CO2CH2CH2Si(CH3)3and hydrogenolysis, if R1is a CO2CH2Ph, but do not stop there. Other suitable conditions for compounds with different values of R10should be obvious to experts in the given field of technology. The choice of protective groups and terms of remove protection should be obvious to a person skilled in the art, and detailed information on this issue is available in the literature (see Kocienski, P.J. Protecting Groups, Georg Thieme Veriag, Stuttgart, 1994; Greene, T.W., Wuts, P. G. M. Protecting Groups in Organic Synthesis (2ndEdition), J.Wiley and Sons, 1991).

The compound of the formula (I-E) can then be converted into a compound of the formula (I-F) by heating:

where all the variables such as defined above in connection with Schemes 1-5.

This reaction can be carried out in an inert process the. Usually the reaction mixture is heated to a temperature of from about 80 to about 120°C. Examples of suitable solvents for this reaction include acetic acid, propionic acid, N,N-dimethylformamide, dimethylsulfoxide, ethanol, dioxane and toluene, but not limited to.

The compound of the formula (I-E) can then be converted into a compound of the formula (I-G) standard reactions of amide combination with an amine of the formula HNR7R8,

where all the variables such as defined in connection with Schemes 1-5.

This reaction can be carried out in an inert solvent using a variety of commercially available reagents combinations. A suitable combination of reagents include N,N-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1,1'-carbonyldiimidazole and benzotriazol-1-yloxytris(dimethyl-amino)phosphonium hexaflurophosphate, but not limited to. Other suitable reagents combinations should be obvious to experts in the given field of technology. Carboxylic acid can be converted into the corresponding acid chloride, and then treated with the amine of the formula HNR7R8. Suitable reagents for the reaction of such anhydrides include oxalicacid, thionyl chloride and 1-chloro-N,N,2-trimethyl-1-propanolamine, but not limited to, In the reaction mixture for the keyboard may possibly be added to the base. This reaction may require heating to a temperature of from about 40 to about 100°C. Suitable bases include trialkylamines, pyridine and 4-(dimethylamino)pyridine, but not limited to. Examples of suitable solvents for this reaction include dichloromethane, chloroform, benzene, toluene, N,N-dimethylformamide and dichloromethane, but not limited to.

In an alternative embodiment the compound of formula (I-G') are obtained directly from the compounds of formula (I-D)

where all the variables such as defined in connection with Schemes 1-5.

This reaction is usually carried out in a sealed vessel with an excess of ammonia. Usually the reaction mixture is heated to a temperature of from about 50 to about 120°C. Suitable solvents for this reaction include methanol, ethanol, isopropanol, tetrahydrofuran and dioxane, but not limited to.

The dehydration of compounds of formula (I-G') can be used to obtain the compounds of formula (I-H)

where all the variables such as defined in connection with Schemes 1-5.

The dehydration reaction may be conducted using various reagents. Suitable dehydrating reagents include thionyl chloride, triperoxonane anhydride, phosphorus oxychloride, phosphorus pentoxide,N, N-dice logicalgroove, but they are not limited. The reaction mixture can be heated to a temperature of from about 50 to about 150°C. Suitable solvents for this reaction include dichloromethane, chloroform, benzene, toluene, N,N-dimethylformamide and dichloromethane, but not limited to.

The compound of the formula (I-J) can be obtained in two-stage method of transformation, including (a) the conversion of compounds of formula (I-E) in a compound of the formula (I-I) by combining with N,O-dimethylhydroxylamine and b) the interaction of the compounds of formula (I-I) with a nucleophile of the formula M1-R7,

where M1represents Li, Mg, halogen, Cu-halogeno or CE-halogeno, and all the variables such as defined in connection with Schemes 1-5.

The reaction mix with N,O-dimethylhydroxylamine can be performed in the same way as described above for the conversion of compounds of formula (I-E) in a compound of the formula (I-G). The addition of the nucleophile to the amide Weinrebe (Weinreb) (I-I) is usually carried out at a temperature in the range of from about -30 to about 5°C. Suitable solvents for this reaction include tetrahydrofuran, dioxane, diethyl ether, toluene, 1,2-dimethoxyethane and hexane, but not limited to, (see Weinreb, S.M., et. al., Tetrahedron Lett. 22: 3815-3818 (1981)). The nucleophiles of formula M1-R7are commercially available and which can be obtained, using the well-known in the art knowledge.

The compound of the formula (I-K) can be obtained from compounds of formula (I-D) by reduction with hydride,

where all the variables such as defined in connection with Schemes 1-5.

This reaction can be carried out in an inert solvent at a temperature in the range of from about -78 to about 25°C. Suitable reducing agents include diisobutylaluminum hydride, alumoweld lithium borohydride lithium, but not limited to. Suitable solvents vary greatly depending on the reducing agent. Appropriate choice of solvent for this reaction is obvious to experts in the art based on the choice of reducing agent. Examples of suitable solvents include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, dioxane, dichloromethane, toluene and hexane, but not limited to.

The compound of the formula (I-K) may be subjected to oxidation reaction to obtain compounds of formula (I-L),

where all the variables such as defined in connection with Schemes 1-5.

This reaction can be carried out using a large variety of traditional oxidants. Suitable oxidizing agents include manganese dioxide, dimethyl sulfoxide /oxalyl the reed/ triethylamine, pyridinium chlorproma, pyridinium dichromate and tetrapropylammonium perruthenate / 4-methylmorpholine N-oxide, but not limited to. Examples of suitable solvents for the oxidation reaction include dichloromethane, chloroform, diethyl ether, toluene and tetrahydrofuran, but not limited to.

The compound of the formula (I-L) can then be converted into a compound of the formula (I-M) by reacting with a nucleophile of the formula M1-R16,

where M1represents Li, Mg, halogen, Cu-halogeno or CE-halogeno;

R16represents H, alkyl, alkenyl or quinil; and all other variables such as defined in connection with Schemes 1-5.

The addition of the nucleophile M1-R16to the aldehyde of the formula (I-L) is usually carried out at a temperature in the range of from about -78 to about 5°C. Suitable solvents for this reaction include tetrahydrofuran, dioxane, diethyl ether, toluene, 1,2-dimethoxyethane and hexane, but not limited to.

Alternatively, the previously described method, the compound of formula (I-J) can also be obtained from compounds of formula (I-M). More specifically, the compound of formula (I-J) can be obtained by oxidation of compounds of formula (I-M)

where R16represents H, alkyl, alkene is l or quinil; and all other variables such as defined in connection with Schemes 1-5.

This reaction can be carried out using a large variety of traditional oxidants. Examples of suitable oxidizing agents include manganese dioxide, dimethyl sulfoxide /oxalicacid/ triethylamine, pyridinium chlorproma, pyridinium dichromate and tetrapropylammonium perruthenate / 4-methylmorpholine N-oxide, but not limited to. Suitable solvents for this reaction include dichloromethane, chloroform, diethyl ether, toluene and tetrahydrofuran, but not limited to.

Then the compound of formula (I-J) can be converted into a compound of the formula (I-M') by reacting with a nucleophile of the formula M1-R16,

where M1represents Li, Mg, halogen, Cu-halogeno or CE-halogeno;

R16represents H, alkyl, alkenyl or quinil; and

all other variables such as defined above in connection with Schemes 1-5.

The nucleophiles of formula M1-R16are commercially available or can be obtained using well-known in the art knowledge.

The addition of the nucleophile to the aldehyde of the formula (I-J) is usually carried out at a temperature in the range of from about -78 to about 5°C. Suitable solvents for this reaction include tetrahydrofuran, dioxane, diethyl ether, toluene, 1,2-dimethoxyethane and hexane, but not limited to.

The compound of the formula (I-M) can then be converted into a compound of the formula (I-N) by halogenation of compounds of formula (I-M)

where X2represents halogeno;

R16represents H, alkyl, alkenyl or quinil; and all other variables such as defined in connection with Schemes 1-5.

This reaction can be performed using any conventional halogenation reagent. Examples of suitable halogenation reagents include triphenylphosphine /iodine/ imidazole, triphenylphosphine / tetrabromide carbon, pentachloride phosphorus, thionyl chloride, tribromide phosphorus, hydrofluoric acid / potassium fluoride and dimethyl sulfide / N-bromosuccinimide, but not limited to. Suitable solvents for this reaction include tetrahydrofuran, dioxane, diethyl ether, dichloromethane, chloroform, acetonitrile, toluene, 1,2-dimethoxyethane and hexane, but not limited to.

The compound of the formula (I-N) can then be converted into a compound of the formula (I-O) recovery,

where X2represents halogeno;

R16represents H, alkyl, alkenyl or quinil; and

all other variables such as defined above in connection with Scheme is Oh 2.

This reaction can be carried out in an inert solvent in various conditions. Examples of suitable reducing agents for this reaction include lithium /ammonia, zinc/ acetic acid, triethylborohydride lithium hydride presence of TBT, alumoweld lithium and iodide samarium(II). Suitable solvents for this reaction vary greatly depending on the reducing agent. Examples of suitable solvents include tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, dioxane, toluene and hexane, but not limited to.

The compound of the formula (I-L) can then be converted into a compound of the formula (I-P) by reacting with the compound of the formula (XXV):

where all the variables such as defined above in connection with Schemes 1-5.

This reaction is carried out in an inert solvent, generally at room temperature. The synthesis and use of the compounds of formula (XXV) are similar to those described in Mueller, S., et al., Synlett 6: 521-522 (1996). Typically this reaction is carried out using methanol as solvent and a base such as potassium carbonate.

In another embodiment the compound of formula (I-Q) can be converted into a compound of the formula (I-R), which in turn can be converted into a compound of the formula (I-S), or the compound of formula (I-Q) can be directly converted into a compound of the formula (I-S):

where n' is 0, 1, 2 or 3;

LG is the same or different and each represents a suitable leaving group and all other variables such as defined above in connection with Schemes 1-5.

The compounds of formula (I-Q) can be obtained by any of the methods described above. The compound of the formula (I-Q) can then be converted into a compound of the formula (I-R) or the compound of formula (I-S).

The compound of the formula (I-R) can be obtained in either of two ways. According to the first method, the compound of formula (I-R) are obtained by reacting the compounds of formula (I-Q) with the compound of the formula LG-(R2)cc-LG (XXVII)where all variables are such as defined above. Specific examples of suitable leaving groups include-Cl, -Br, -I, -OSO2CH3and-OSO2-phenyl, but not limited to. Suitable compounds of formula (XXVII) are commercially available or can be obtained using standard techniques. The reaction can be carried out in an inert solvent, conveniently at room temperature in the presence of a suitable base. Examples of suitable bases for this reaction include potassium carbonate, sodium carbonate, cesium carbonate, sodium hydride and potassium hydride, but not limited to. Examples of suitable inert solvents for this reaction include N,N-dimethylformamide, tetrahydrofuran, dioxane and 1,2-dimethoxyethan is, but not limited to.

According to the second method, the compound of formula (I-R) are obtained by reacting the compounds of formula (I-Q) with the compound of the formula HO-(R2)cc-LG (XXVIII), where all variables such as defined above. Specific examples of suitable leaving groups include the groups mentioned above. The compounds of formula (XXVIII) are commercially available or can be obtained using standard techniques. The reaction is carried out in an inert solvent under standard conditions of Mitsunobu. See Hughes, D.L, Org. React. 42: 335-656 (1992); and Mitsunobu, O., Synthesis, 1-28 (1981). Typically, the compound of formula (I-Q) and the compound of formula (XXVIII) together are subjected to interaction with triarylphosphines and dialkyldithiocarbamato at room temperature. Examples of suitable triarylphosphines include triphenylphosphine, tri-para-tolylphosphino and trimethyltin, but not limited to. Examples of suitable dialkyldithiocarbamato include diethylazodicarboxylate, diisopropylsalicylic and di-tert-utilisationbased, but not limited to. Examples of suitable inert solvents for this reaction include tetrahydrofuran, dioxane, 1,2-dimethoxyethane, dichloromethane and toluene, but not limited to.

The compound of the formula (I-R) can be converted into a compound of the formula (I-S) by reacting with a suitable nucleophile for the introduction of groups which R 4. Examples of suitable nucleophiles include ammonia, primary and secondary amines, alkoxides of metals, dialkoxy metals, potassium cyanide, sodium azide, organolithium reagents, organoborate and Grignard reagents, but not limited to. The specific conditions for these substitutions vary, but the use of these types of nucleophiles to the introduction of the group R4is common in the art. Replacement of the leaving group in this nucleophile will lead either to the introduction of the functional group, R4or to obtain intermediate compound from which the functional group R4can be easily introduced in a conventional means an expert in this field.

Alternatively, the compound of formula (I-S) can be obtained directly from compounds of formula (I-Q) using procedures similar to those described above for the conversion of compounds of formula (I-Q) in the compound of the formula (I-R). More specifically, the compound of formula (I-S) can be obtained by reacting the compounds of formula (I-Q) with the compound of the formula LG-(R2)cc-R4(XXIX) under conditions similar to those described above for the interaction of the compounds of formula (I-Q) with the compound of the formula (XXVII). The compounds of formula (XXIX) are commercially available or can be obtained using traditional methods.

In another embodiment of the compounds is their formula (I-Q) is converted into a compound of the formula (I-S) by reacting with the compound of the formula HO-(R 2)cc-R4(XXX) in the conditions described above for the interaction of the compounds of formula (I-Q) with the compound of the formula (XXVIII). The compounds of formula (XXX) are commercially available or can be obtained using traditional methods.

As another example, the compound of formula (I-T) can be converted into a compound of the formula (I-U), which may possibly then be converted into a compound of the formula (I-V),

where R15represents alkyl or phenyl, and

all other variables such as defined above in connection with Schemes 1-5.

The compound of the formula (I-T) can be converted into a compound of the formula (I-U) by reacting with a suitable acid, such as triperoxonane acid (TFA). This reaction can be carried out in the absence or in the presence of an inert solvent at ambient temperature. Suitable solvents for this reaction include dichloromethane and chloroform, but not limited to.

The compound of the formula (I-U) can then be converted into a compound of the formula (I-V) by reacting with sulphonylchloride formula (XXXI). This reaction can be carried out in an inert solvent at ambient temperature using a number of grounds. Examples of suitable bases include triethylamine, N,N-diisopropylethylamine and pyridine, but is not limited to. Suitable solvents for this reaction include dichloromethane, chloroform, tetrahydrofuran, 1,2-dimethoxyethane, dioxane and N,N-dimethylformamide, but not limited to.

In another embodiment the compound of formula (I-W) can be converted into a compound of the formula (I-X). The compound of the formula (I-X) can then be converted into a compound of the formula (I-Y)

where R5aselected from the group consisting of-OR7and-NR7R8a

all other variables such as defined above in connection with Schemes 1-5.

The compound of the formula (I-W) can be oxidized to compounds of formula (I-X) using a conventional oxidizing agent such as, for example, 3-chloroperoxybenzoic acid. As a result of interaction of the compounds of formula (I-X) with a suitable nucleophile of the formula R5athe compound of the formula (I-X) is transformed into a compound of the formula (I-Y). Specific examples of suitable nucleophiles for this reaction include sodium hydroxide, sodium acetate, ammonia and mono - and di-substituted amines, but not limited to. The reaction with the nucleophile is usually carried out using equimolar amount or slight excess of the nucleophile in an inert solvent, such as THF (tetrahydrofuran), at ambient temperature or elevated temperature. In another embodiment the compound of formula (I-X)can be converted into a compound of the formula (I-Y) in a sealed tube at an elevated temperature between 80° With 120°using an excess of ammonia in an appropriate solvent, such as methanol, ethanol, isopropanol, tetrahydrofuran and dioxane.

Similarly, the compound of formula (I-AA) can also be converted into a compound of the formula (I-BB) by oxidation and the compound of formula (I-BB) can be converted into a compound of the formula (I-CC) by reacting with ammonia,

where all the variables such as defined above in connection with Schemes 1-5.

Phase transformation of compounds of formula (I-AA) in the compound of the formula (I-C) can be carried out by reacting the compounds of formula (I-AA) with a suitable oxidant, such as, for example, 3-chloroperoxybenzoic acid. The compound of the formula (I-BB) can be converted into a compound of the formula (I-SS) by reacting with an excess of ammonia in a sealed tube at an elevated temperature between 80 and 120°in a suitable solvent. Suitable solvents for this reaction include methanol, ethanol, isopropanol, tetrahydrofuran and dioxane, but not limited to.

The following is an example of how the transformation of compounds of formula (I) into another compound of formula (I) involves reacting a compound of the formula (I-DD) with tianyoude reagent to obtain the compounds of formula (I-EE),

where all variables such that Campidano above in connection with Schemes 1-5.

This reaction can be carried out in an inert solvent, and the reaction mixture can be heated to a temperature of from about 65°With up to approximately 100°C. Examples of suitable tianyoude reagents include pentasulfide phosphorus, 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphate-2,4-disulfide and the like, but not limited to. Suitable solvents for this reaction include xylene, dioxane and toluene, but not limited to.

Further, the compound of formula (I-FF) can be converted into a compound of formula I-GG) by communicating with a source of azide in an inert solvent,

where all the variables such as defined above in connection with Schemes 1-5.

Examples of suitable sources include azide attestation acid, sodium azide with ammonium chloride, sodium azide with aluminium chloride and sodium azide with zinc bromide(II), but not limited to. As an example, some preferred solvents include dimethylformamide, dimethylsulfoxide, N-methylpyrrolidinone, toluene and the like, but not limited to. The reaction mixture can be heated to a temperature of from about 23°With up to approximately 150°C.

In another embodiment the compound of formula (I-HH) can be converted into a compound of the formula (I-II) with use the of Protocol combinations,

where all the variables such as defined in any of the Schemes 1-5.

This reaction conversion can be carried out by reacting the compounds of formula (I-HH) with a suitable reagent combination in an inert solvent followed by the addition of a source of hydroxylamine and possible reasons. Suitable reagents combinations include 1,1-carbonyldiimidazole, oxalicacid, dicyclohexylcarbodiimide and 1-(N,N-diphenylcarbamate)pyridinium chloride, but not limited to. Preferably, the hydroxylamine is hydroxylamine hydrochloride. Suitable bases include triethylamine, sodium methoxide and diisopropylethylamine, but not limited to. The reaction mixture can be heated to a temperature of from about 0°With up to about 80°C. Examples of suitable solvents for this reaction include dimethylformamide, dichloromethane and tetrahydrofuran, but not limited to.

In yet another example of the transformation with the use of the combination of the compound of formula (I-KK) are obtained from the compounds of formula (I-JJ) as follows:

where n' is 0, 1, 2 or 3;

PG is a protective group, and all other variables such as defined above in any of the Schemes 1-5.

The protective group is generally protective the group of carboxylic acids, the removal of which leads to the production of acid. Cleavage of the protective group of carboxylic acid can be carried out in many different ways, conventional in the art (see Kocienski, P.J. Protecting Groups, Georg Thieme Veriag, Stuttgart, 1994; Greene, T.W., Wuts, P. G. M. Protecting Groups in Organic Synthesis (2ndEdition), J. Wiley and Sons, 1991).

After removal of the protective group of the obtained carboxylic acid is subjected to interaction with the use of the combination with obtaining the compounds of formula (I-KK). This reaction can be carried out by reacting the compounds of formula (I-JJ), from which the protective group is removed with a suitable reagent combination in an inert solvent followed by the addition of a primary or secondary amine and possible reasons. Suitable reagents combinations include 1,1-carbonyldiimidazole, oxalicacid, dicyclohexylcarbodiimide and O-(7-sabastiano-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate, but not limited to. Suitable bases include triethylamine, diisopropylethylamine and the like, but not limited to. The reaction mixture can be heated to a temperature of from about 0°With up to about 80°C. Examples of suitable solvents include dimethylformamide, dichloromethane and tetrahydrofuran, but not limited to.

In yet another example of the transformation to IP is by the use of Protocol combinations of a compound of the formula (I-MM) obtained from the compounds of formula (I-LL) as follows:

where n' is 0, 1, 2 or 3,

PG is a protective group, and

all other variables such as defined above in any of the Schemes 1-5.

The protective group is a protective group of amino group, the removal of which results in Amin. Cleavage of the protective group of the amino group can be carried out in many different ways, conventional in the art (see Kocienski, P.J. Protecting Groups, Georg Thieme Verlag, Stuttgart, 1994; Greene, T.W., Wuts, P. G. M. Protecting Groups in Organic Synthesis (2ndEdition), J.Wiley and Sons, 1991).

After removal of the protective group of the obtained amine is subjected to interaction with the use of the combination with obtaining the compounds of formula (I-MM). This reaction can be carried out by reacting the compounds of formula (I-LL), which removed the protective group, with a carboxylic acid in the presence of a suitable reagent combination in an inert solvent and possible reasons. Suitable reagents combinations include 1,1-carbonyldiimidazole, oxalicacid, dicyclohexylcarbodiimide and O-(7-sabastiano-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate, but not limited to. Suitable bases include triethylamine, diisopropylethylamine and the like, but not limited to. The reaction mixture may be heated to a temperature of from about 0 With up to about 80°C. Examples of suitable solvents include dimethylformamide, dichloromethane and tetrahydrofuran, but not limited to.

Based on this description, and the examples in it, a specialist in the art can easily convert the compound of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative into another compound of formula (I) or its pharmaceutically acceptable salt, MES or physiologically functional derivative.

According to the present invention also suggested radiolabelled compounds of formula (I) and biotinylated the compounds of formula (I), and variants on solid media. Radiolabelled compounds of formula (I) and biotinylated the compounds of formula (I) can be obtained using standard techniques. For example, radiolabelled compounds of formula (I) can be obtained by reacting the compounds of formula (I) with tritium gas in the presence of a suitable catalyst to obtain a radiolabelled compounds of formula (I).

In one embodiment of compounds of formula (I) trithiolane.

Radiolabelled compounds of formula (I) and biotinylated the compounds of formula (I) useful in the anal is : to identify compounds which inhibit PLK, for identification of compounds for treatment of a condition mediated by PLK, for the treatment of susceptible neoplasms, for the treatment of conditions characterized by inappropriate proliferation, inhibition of cell proliferation and inhibition of mitosis in the cell. Accordingly, according to the present invention, a method of analysis for the identification of such compounds, including stage-specific binding of radiolabelled compounds of formula (I) or biotinylated compounds of formula (I) with the protein target or cell homogenates. More specifically, appropriate methods of analysis include analysis of competitive binding. Radiolabelled compounds of formula (I) and biotinylated the compounds of formula (I), and their variants on solid media can be used in the analysis methods, traditional in this area.

The following examples are intended for illustration only and are in no way intended to limit the scope of the present invention, this invention is defined by the following claims.

The reagents are commercially available or they are obtained according to the methods described in the literature. In the above structures "Me" refers to the group-CH3.

Example 1: Methyl 2-chloro-3-oxo-2,3-di is Idro-2-thiophenecarboxylate

To a solution of methyl-3-hydroxy-2-thiophenecarboxylate (5,00 g; of 31.6 mmol) in chloroform (10 ml) dropwise over 2 minutes in an atmosphere of N2added 1M sulfurylchloride in dichloromethane (34,8 ml, 34.8 mmol). The mixture was stirred for 4 hours at room temperature and volatiles were removed under reduced pressure. A solid substance was recrystallized from hexane to obtain methyl 2-chloro-3-oxo-2,3-dihydro-2-thiophenecarboxylate (4,60 g; 76%) as white needle crystals.1H NMR (CDCl3): δ 8.38 (d, 1H), 6.23 (d, 1H), 3.84 (s, 3H); MS (mass spectrometry) m/z 193 (M+1).

Example 2A: Methyl-5-(1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate

To a solution of methyl 2-chloro-3-oxo-2,3-dihydro-2-thiophenecarboxylate (0,050 g; 0.26 mmol) in chloroform (1.0 ml) (and in a separate reaction in acetic acid (1.0 ml)) was added benzimidazole (0,061 g; 0.52 mmol) to each reaction mixture. The reaction mixture with chloroform was stirred for 22 hours at room temperature and then was diluted with chloroform (2.0 ml). The organic phase is washed with water (1.0 ml) and the phases were separated. The organic phase was analyzed by LC-MS (liquid chromatography-mass spectrometry), and then concentrated under reduced pressure before formation of the solid residue. The residue was washed with water (2 ml), Phi is trevali and dried. The reaction mixture with acetic acid was stirred at room temperature for 66 hours and analyzed by LC-MS. The reaction mixture was diluted with water (5 ml), then cooled in ice for 30 minutes and the solids were collected by filtration and dried at 50°under vacuum. The solids from both reaction mixtures (with chloroform and acetic acid) were analyzed by the method of1H-NMR. When both of the reaction mixture has reached a sufficient degree of purity, their contents were combined with obtaining methyl-5-(1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate (0,058 g; 41%) as a solid orange-brown color.1H NMR (DMSO-d6(DMSO-dimethyl sulfoxide)): δ 10.87 (br s, 1H), 8.69 (s, 1H), 7.80 (m, 2H), 7.39 (m, 2H), 7.14 (s, 1H), 3.79 (s, 3H). MS m/z 275 (M+1).

Example 2B: Methyl-5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate and 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic

To a mixture of methyl-5-(1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate (0,058 g; 0.21 mmol) and potassium carbonate (0,032 g; 0.23 mmol) in dimethylformamide (0,50 ml) was added α-bromo-ortho-xylene (31 μl; 0.23 mmol). The mixture was stirred for 6 hours at room temperature and then was diluted with water (1.0 ml). The mixture was extracted with ether (2×3 ml) and obyedinenny the ether extract was concentrated to dryness under reduced pressure. The residue was treated with 2M ammonia in methanol (3 ml) in a test tube made of glass Pyrex, sealed Teflon screw cap and the reaction mixture was heated up to 80°under stirring using a magnetic stirrer for 3 days. The reaction mixture was cooled, added fresh 2M ammonia in methanol (2 ml), the tube again tightly closed and heated at 80°for another 2 days. The reaction mixture was cooled and to it was added silica gel (0.5 g), and then evaporated volatiles under reduced pressure. The pre-adsorbed solids were loaded into the cartridge loading solids and subjected to gradient elution, starting with a mixture of ethyl acetate/hexane (25:75) and ending with ethyl acetate (100%) using ciliegiolo RediSep cartridge (4,2 g; ISCO). Methyl ester (higher Rf value) easily separated from carboxamides product and the appropriate fractions were combined and concentrated under reduced pressure to obtain methyl 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate (0,0092 g) in the form of not quite white solids (1H NMR (DMSO-d6): δ 8.72 (s, 1H), 7.86 (d, 1H), 7.81 (d, 1H), 7.76 (s, 1H), 7.55 (d, 1H), 7.42 (m, 1H), 7.38 (dd, 1H), 7.26 (m, 3H), 5.38 (s, 2H), 3.77 (s, 3H), 2.39 (s, 3H). MC m/z 379 (M+1)); and 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate (0,0136 g) in VI is e solid reddish-brown color ( 1H NMR (DMSO-d6): δ 8.65 (s, 1H), 7.80 (d, 1H), 7.68 (s+br s, 2H), 7.49 (d, 1H), 7.40 (m, 3H), 7.28 (m, 3H), 6.85 (br s, 1H), 5.43 (s, 2H), 2.39 (s, 3H). MC m/z 364 (M+1)).

Example 3: Methyl-5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate

To a mixture of methyl-5-(1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate (0,500 g; 1.82 mmol) and potassium carbonate (0,277 g; a 2.01 mmol) in dimethylformamide (5.0 ml) was added α-bromo-ortho-xylene (0,27 ml; a 2.01 mmol). The mixture was stirred for 18 hours at room temperature, then was diluted with water (20 ml) and was extracted with ether (2×50 ml). The organic layer was washed with water (10 ml), saturated brine (10 ml) and dried (MgSO4). Concentrating the organic phase under reduced pressure gave 0,395 g of crude methyl-5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate in a solid yellow color.1H NMR (DMSO-d6): δ 8.71 (s, 1H), 7.84 (d, 1H), 7.79 (d, 1H), 7.75 (s, 1H), 7.53 (d, 1H), 7.42 (dd, 1H), 7.38 (dd, 1H), 7.24 (m, 3H), 5.36 (s, 2H), 3.75 (s, 3H), 2.37 (s, 3H). MC m/z 379 (M+1).

Example 4: 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic

A mixture of methyl-5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate (0,114 g; 0,302 mmol) and 2M ammonia in methanol (5 ml) was heated at 80°C for 48 h in vitro glass Pyrex with tight-fitting navynews is the action scene Teflon cover. The reaction mixture was cooled, added fresh 2M ammonia in methanol (2 ml) and heated at 80°C for 72 h, the Reaction mixture was re-cooled, re-added fresh 2M ammonia in methanol (2 ml) and heated at 80°C for 48 hours the Reaction mixture was concentrated under reduced pressure and the solid residue was dissolved in a mixture of methanol/ethyl acetate (1:1). To the solution was added silica gel (0.5 g), volatile components were removed under reduced pressure. Pre-adsorbed substance was Packed in a cartridge for loading solids and suirable on a silica gel RediSep cartridge (4,2 g; ISCO) using ethyl acetate and collected fractions in 18 ml of the Appropriate fractions were combined and concentrated to dryness to obtain a solid residue. The solids triturated with a mixture of methanol/ether (1:2), collected by filtration, washed with ether (2 ml) and dried with getting 0,021 g of 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate in the form of a solid pale yellow color.1H NMR (DMSO-d6): δ 8.65 (s, 1H), 7.80 (d, 1H), 7.69 (s, 1H), 7.77 and 6.85 (2xbr s, 2H), 7.48 (d, 1H), 7.40 (m, 3H), 7.28 (m, 3H), 5.43 (s, 2H), 2.39 (s, 3H). MC m/z 364 (M+1).

Example 5: 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiencarbazone acid

To a solution of methyl-5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic the TA (0,393 g; 1.04 mmol) in dioxane (4.0 ml) was added 1M aqueous lithium hydroxide (4.0 ml). The mixture was stirred for 18 hours at room temperature. The reaction mixture was acidified to pH 1-2 1H. hydrochloric acid (4 ml), the solids were collected by filtration and dried to obtain 0,334 g of 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic acid in a solid yellow color.1H NMR (DMSO-d6): δ 12.8 (br s, 1H), 8.69 (s, 1H), 7.80 (2xd, 2H), 7.70 (s, 1H), 7.52 (d, 1H), 7.40 (m, 2H), 7.24 (m, 3H), 5.32 (s, 2H), 2.37 (s, 3H). MS m/z 365 (M+1).

Example 6: 5-(1H-benzimidazole-1-yl)-N-methyl-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic

To a mixture of 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic acid (0,050 g; 0.14 mmol) in dichloromethane (2 ml) was added 1-chloro-2,N,N-trimethylpsoralen (0,027 ml; 0.20 mmol) and this reaction mixture was stirred for 1 hour at room temperature. To the reaction mixture was added methylamine (8M) in ethanol (52 μl; 0.42 mmol) followed by the addition of diisopropylethylamine (49 μl, 0.28 mmol). The reaction was fully completed in 2 hours. After stirring for 66 hours the contents of the reaction mixture was distributed between dichloromethane (3 ml) and water (1 ml). A two-phase mixture was separated and the organic phase was dried over MgSO4. The organic phase was concentrated under reduced pressure and the residue races is Irali with ether. The solids were collected by filtration and dried to obtain 0,037 g of 5-(1H-benzimidazole-1-yl)-N-methyl-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate in a solid yellow color.1H NMR (DMSO-d6): δ 8.63 (s, 1H), 7.80 (d, 1H), 7.74 (d, 1H), 7.63 (s, 1H), 7.42 (m, 4H), 7.27 (m, 3H), 5.44 (s, 2H), 2.81 (d, 3H), 2.39 (s, 3H). MS m/z 378 (M+1).

Example 7: 5-(1H-benzimidazole-1-yl)-N,N-dimethyl-3-[(2-methylbenzyl)-oxy]-2-thiophencarboxylic

By analogy with Example 6 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic acid (0,050 g; 0.14 mmol) in dichloromethane (2 ml), 1-chloro-2,N,N-trimethylpsoralen (0,027 ml; 0.20 mmol), dimethylamine (2M) in tetrahydrofuran (210 μl; 0.42 mmol) and diisopropylethylamine (49 μl; 0.28 mmol) was obtained 5-(1H-benzimidazole-1-yl)-N,N-dimethyl-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic (0,032 g; 60%) as a solid yellow-korichneviye.1H NMR (DMSO-d6): δ 8.63 (s, 1H), 7.79 (2xd, 2H), 7.64 (s, 1H), 7.40 (m, 3H), 7.26 (m, 3H), 5.30 (s, 2H), 2.98 (s, 6N), 2.34 (s, 3H). MC m/z 392 (M+1).

Example 8: 5-(1H-benzimidazole-1-yl)-N-isopropyl-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic

By analogy with Example 6 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic acid (0,050 g; 0.14 mmol) in dichloromethane (2 ml), 1-chloro-2,N,N-trimethylpsoralen (0,027 ml; 0.20 mmol), Isopropylamine (36 μl; 0.42 mmol) and Diisopropylamine the ina (49 μl; 0.28 mmol) was obtained 5-(1H-benzimidazole-1-yl)-N-isopropyl-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic (0,033 g; 59%) as a solid yellow color.1H NMR (DMSO-d6): δ 8.66 (s, 1H), 7.81 (2xd, 2H), 7.73 (s, 1H), 7.52 (d, 1H), 7.44 (m, 1H), 7.38 (m, 1H), 7.30 (m, 3H), 7.14 (d, 1H), 5.44 (s, 2H), 3.99 (m, 1H), 2.41 (s, 3H), 1.06 (d, 6H). MC m/z 406 (M+1).

Example 9: 5-(1H-benzimidazole-1-yl)-N-(2-hydroxyethyl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic

By analogy with Example 6 5-(1H-benzimidazole-1-yl)-3-(2-methylbenzylamino)-2-thiophencarboxylic acid (0,050 g; 0.14 mmol) in dichloromethane (2 ml), 1-chloro-2,N,N-trimethylpsoralen (0,027 ml; 0.20 mmol), ethanolamine (25 μl; 0.42 mmol) and diisopropylethylamine (49 μl; 0.28 mmol) was obtained 5-(1H-benzimidazole-1-yl)-N-(2-hydroxyethyl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic (0.036 g; 64%) as a solid yellow color.1H NMR (DMSO-d6): δ 8.65 (s, 1H), 7.80 (2xd, 2H), 7.71 (s, 1H), 7.54 (m, 2H), 7.44 (m, 1H), 7.37 (m, 1H), 7.27 (m, 3H), 5.45 (s, 2H), 4.80 (t, 1H), 3.46 (m, 2H), 3.36 (m, 2H), 2.40 (s, 3H). MC m/z 408 (M+1).

Example 10: 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-N-phenyl-2-thiophencarboxylic

By analogy with Example 6 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic acid (0,050 g; 0.14 mmol) in dichloromethane (2 ml), 1-chloro-2,N,N-trimethylpsoralen (0,027 ml; 0.20 mmol), aniline (38 μl; 0.42 mmol) and diisopropylethylamine (49 μl; 0.28 mm is l) was obtained 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-N-phenyl-2-thiophencarboxylic (0,044 g; 73%) as a solid yellow color.1H NMR (DMSO-d6): δ 9.30 (s, 1H), 8.72 (s, 1H), 7.85 (m, 2H), 7.81 (s, 1H), 7.61 (d, 1H), 7.41 (m, 4H), 7.32 (m. 5H), 7.09 (m, 1H), 5.56 (s, 2H), 2.44 (s, 3H). MC m/z 440 (M+1).

Example 11: 5-(1H-benzimidazole-1-yl)-N-benzyl-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic

By analogy with Example 6 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic acid (0,050 g; 0.14 mmol) in dichloromethane (2 ml), 1-chloro-2,N,N-trimethylpsoralen (0,027 ml; 0.20 mmol), benzylamine (46 μl; 0.42 mmol) and diisopropylethylamine (49 μl; 0.28 mmol) was obtained 5-(1H-benzimidazole-1-yl)-N-benzyl-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic (0,038 g; 61%) as a solid yellow color.1H NMR (DMSO-d6): δ 8.65 (s, 1H), 7.81 (m, 3H), 7.69 (s, 1H), 7.42 (m, 3H), 7.27 (m, 8H), 5.43 (s, 2H), 4.49 (d, 2H), 2.29 (s, 3H). MS m/z 454 (M+1).

Example 12: 5-(1H-benzimidazole-1-yl)-3-benzyloxy-2-thiophencarboxylic

By analogy with Example 4 methyl-5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate (0,109 g; 0,299 mmol) and 2M ammonia in methanol (5 ml) was obtained 5-(1H-benzimidazole-1-yl)-3-benzyloxy-2-thiophencarboxylic (0,031 g; 30%) as a solid white color.1H NMR (DMSO-d6): δ 8.63 (s, 1H), 7.76 (dd, 2H), 7.70 and 7.01 (2xbr s, 2H), 7.64 (s, 1H), 7.55 (d, 2H), 7.44 (m, 5H), 5.42 (s, 2H). MS m/z 350 (M+1).

Example 13: 5-(1H-benzimidazole-1-yl)-3-[(3-methylbenzyl)oxy]-2-type carboxamid

By analogy with Example 4 methyl-5-(1H-benzimidazole-1-yl)-3-[(3-methylbenzyl)oxy]-2-thiophenecarboxylate (0,114 g; 0,301 mmol) and 2M ammonia in methanol (5 ml) was obtained 5-(1H-benzimidazole-1-yl)-3-[(3-methylbenzyl)oxy]-2-thiophencarboxylic (0,019 g; 17%) as a solid white color.1H NMR (DMSO-d6): δ 8,63 (s, 1H), 7.77 (dd, 2H), 7.70 and 7.00 (2xbr s, 2H), 7.63 (s, 1H), 7.36 (m, 5H), 7.19 (d, 1H), 5.37 (s, 2H), 2.33 (s, 3H). MS m/z 364 (M+1).

Example 14: 5-(1H-benzimidazole-1-yl)-3-[(3-methoxybenzyl)oxy]-2-thiophencarboxylic

By analogy with Example 4 methyl-5-(1H-benzimidazole-1-yl)-3-[(3-methoxybenzyl)oxy]-2-thiophenecarboxylate (amount of 0.118 g; 0,299 mmol) and 2M ammonia in methanol (5 ml) was obtained 5-(1H-benzimidazole-1-yl)-3-[(3-methoxybenzyl)oxy]-2-thiophencarboxylic (0,034 g; 30%) as not quite white solid.1H NMR (DMSO-d6): δ 8.63 (s, 1H), 7.77 (dd, 2H), 7.66 and 7.05 (2xbr s, 2H), 7.63 (s, 1H), 7.38 (m, 3H), 7.12 (m, 2H), 6.94 (d, 1H), 5.38 (s, 2H), 3.76 (s, 3H). MS m/z 380 (M+1).

Example 15: 5-(1H-benzimidazole-1-yl)-3-[(3-Chlorobenzyl)oxy]-2-thiophencarboxylic

By analogy with Example 4 methyl-5-(1H-benzimidazole-1-yl)-3-[(3-Chlorobenzyl)oxy]-2-thiophenecarboxylate (0,120 g; 0,301 mmol) and 2M ammonia in methanol (5 ml) was obtained 5-(1H-benzimidazole-1-yl)-3-[(3-Chlorobenzyl)oxy]-2-thiophencarboxylic (0,031 g; 27%) as a solid white color.1 H NMR (DMSO-d6): δ at 8.62 (s, 1H), 7.80 (d, 1H), 7.70 (m, 4H), 7.63 (s, 1H), 7.54 and 7.09 (2xbr s, 2H), 7.42 (m, 3H), 5.41 (s, 2H). MS m/z 384 (M+1).

Example 16: 5-(1H-benzimidazole-1-yl)-3-[(4-methylbenzyl)oxy]-2-thiophencarboxylic

By analogy with Example 4 methyl-5-(1H-benzimidazole-1-yl)-3-[(4-methylbenzyl)oxy]-2-thiophenecarboxylate (0,114 g; 0,301 mmol) and 2M ammonia in methanol (5 ml) was obtained 5-(1H-benzimidazole-1-yl)-3-[(4-methylbenzyl)oxy]-2-thiophencarboxylic (0,0069 g; 6%) in the form of not-quite-white solid.1H NMR (DMSO-d6): δ 8.63 (s, 1H), 7.78 (dd, 2H), 7.69 and 6.98 (2xbr s, 2H), 7.64 (s, 1H), 7.40 (m, 4H), 7.24 (d, 2H), 5.36 (s, 2H), 2.31 (s, 3H). MC m/z 364 (M+1).

Example 17: 5-(1H-benzimidazole-1-yl)-3-[(4-Chlorobenzyl)oxy]-2-thiophencarboxylic

By analogy with Example 4 methyl-5-(1H-benzimidazole-1-yl)-3-[(4-Chlorobenzyl)oxy]-2-thiophenecarboxylate (0,120 g; 0,301 mmol) and 2M ammonia in methanol (5 ml) was obtained 5-(1H-benzimidazole-1-yl)-3-[(4-Chlorobenzyl)oxy]-2-thiophencarboxylic (0.015 g; 13%) in the form of not-quite-white solid.1H NMR (DMSO-d6): δ at 8.62 (s, 1H), 7.78 (dd, 2H), 7.70 and 7.03 (2xbr s, 2H), 7.62 (s, 1H), 7.54 (AB q, 4H), 7.40 (m, 2H), 5.41 (s, 2H). MC m/z 384 (M+1).

Example 18A: methyl-3-hydroxy-5-(5-methyl-1H-benzimidazole-1-yl)-2-thiophenecarboxylate and methyl-3-hydroxy-5-(6-methyl-1H-benzimidazole-1-yl)-2-thiophenecarboxylate

On analogues of the Example 2A from methyl 2-chloro-3-oxo-2,3-dihydro-2-thiophenecarboxylate (0,050 g; 0.26 mmol) and 5-methyl-1H-benzimidazole (0,069 g; 0.52 mmol) in chloroform (1.0 ml), and in a separate reaction in acetic acid (1.0 ml)was obtained the mixture of isomers 1:1 methyl-3-hydroxy-5-(5-methyl-1H-benzimidazole-1-yl)-2-thiophenecarboxylate and methyl-3-hydroxy-5-(6-methyl-1H-benzimidazole-1-yl)-2-thiophenecarboxylate (0,063 g; 42%) as a solid pale yellow color.1H NMR (DMSO-d6): δ 10.84 (br s, 2H), 8.63, 8.59 (2xs, 2H), 7.65 (m, 4H), 7.22 (m, 2H), 7.12 (d, 2H), 3.79, 3.78 (2xs, 6H), 2.47, 2.44 (2xs, 6H). MC m/z 289 (M+1).

Example 18B: methyl-5-(5-methyl-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate/methyl-5-(6-methyl-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate and 5-(5-methyl-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic/5-(6-methyl-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic

By analogy with Example 2C from a mixture of isomers 1:1 methyl-3-hydroxy-5-(5-methyl-1H-benzimidazole-1-yl)-2-thiophenecarboxylate and methyl-3-hydroxy-5-(6-methyl-1H-benzimidazole-1-yl)-2-thiophenecarboxylate (to 0.055 g; 0,19 mmol), potassium carbonate (0,029 g; 0.21 mmol), α-bromo-ortho-xylene (28 μl; 0.21 mmol) and dimethylformamide (0,50 ml)and then 2M ammonia in methanol (3 ml), was obtained a mixture of isomers 1:1 methyl-5-(5-methyl-1H-benzimidazole-1-yl)-3-[(2-methyl-benzyl)is XI]-2-thiophenecarboxylate and methyl-5-(6-methyl-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate (0,017 g; 23%) in the form of oil of amber (1H NMR (DMSO-d6): δ 8.67 (s, 1H), at 8.62 (s, 1H), 7.74 (d, 1H), 7.73 (s, 2H), 7.67 (d, 1H), 7.60 (s, 2H), 7.54 (d, 2H), 7.26 (m, 8H), 5.37 (s, 4H), 4.09 (q, 2H), 3.77, 3.76 (2xs, 6N), 3.16 (d, 4H), 2.45, 2.39 (2xs, 6H). MS m/z 393 (M+1)) and isomeric mixture (1:1) 5-(5-methyl-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophene-carboxamide and 5-(6-methyl-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate (0,057 g; 79%) as a solid yellow-brown color (1H NMR (DMSO-d6): δ 8.59, 8.55 (2xs, 2H), 7.67 (m, 4H), 8.64 (s, 2H), 8.59, 8.53 (2xs, 2H), 7.50 and 6.87 (2 br s, 4H), 7.28 (m, 8H), 5.42 (s, 4H), 3.32, 3.31 (2xs, 6H), 2.45, 2.39 (2xs, 6H). MS m/z 365 (M+1)).

Example 19A: methyl-3-hydroxy-5-(5,6-dimethyl-1H-benzimidazole-1-yl)-2-thiophenecarboxylate

By analogy with Example 2A from methyl 2-chloro-3-oxo-2,3-dihydro-2-thiophenecarboxylate (0,050 g; 0.26 mmol) and 5,6-dimethyl-1H-benzimidazole (0,076 g; 0.52 mmol) in chloroform (1.0 ml), and in a separate reaction in acetic acid (1.0 ml)was obtained methyl-3-hydroxy-5-(5,6-dimethyl-1H-benzimidazole-1-yl)-2-thiophenecarboxylate (0,079 g; 50%) in the form solid pale yellow color.1H NMR (DMSO-d6): δ 10.81 (br s, 1H), 8.54 (s, 1H), 7.59 (s, 1H), 7.56 (s, 1H), 7.11 (s, 1H), 3.79 (s, 3H), 2.37 (s, 3H), 2.33 (s, 3H). MS m/z 303 (M+1).

Example 19C: methyl 5-(5,6-dimethyl-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate and 5-(5,6-dimethyl-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic

By analogy with Example 2 from methyl 3-hydroxy-5-(5,6-dimethyl-1H-benzimidazole-1-yl)-2-thiophenecarboxylate (0,074 g; 0.24 mmol), potassium carbonate (0.037 g; 0.27 mmol), α-bromo-ortho-xylene (36 μl; 0.27 mmol) and dimethylformamide (0,50 ml)and then 2M ammonia in methanol (3 ml) was obtained methyl 5-(5,6-dimethyl-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate (0,011 g; 11%) as a solid pale yellow color (1H NMR (DMSO-d6): δ 8.58 (s, 1H), 7.70 (s, 1H), 7.58 (m, 3H), 7.26 (m, 3H), 5.37 (s, 2H), 3.76 (s, 3H), 2.39 (s, 6H), 2.34 (s, 3H). MC m/z 407 (M+1)) and 5-(5,6-dimethyl-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic (0,0066 g; 7%) in the form of not quite white solids (1H NMR (DMSO-d6): δ 8.50 (s, 1H), 7.68, 6.85 (2xbr s, 2H), 7.62 (s, 1H), 7.54 (d, 2H), 7.50 (d. 1H), 7.28 (m, 3H), 5.42 (s, 2H), 2.39 (s, 3H), 2.37 (s, 3H), 2.34 (s, 3H). MC m/z 392 (M+1)).

Example 20A: methyl-5-(5-chloro-1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate and methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate

By analogy with Example 2A from methyl 2-chloro-3-oxo-2,3-dihydro-2-thiophenecarboxylate (0,050 g; 0.26 mmol) and 5-chloro-1H-benzimidazole (0,079 g; 0.52 mmol) in chloroform (1.0 ml), and in a separate reaction in acetic acid (1.0 ml)was obtained the mixture of isomers 1:1 methyl-5-(5-chloro-1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate and met the l-5-(6-chloro-1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate (0,103 g; 64%) as a solid pale yellow color.1H NMR (DMSO-d6): δ 10.91, at 10.89 (2xbr s, 2H), 8.76, 8.71 (2xs, 2H), 7.89 (s, 1H), 7.82 (d, 1H), 7.81 (s, 2H), 7.42 (m, 2H), 7.17, 7.15 (2xs, 2H), 3.79 (2xs, 6N). MC m/z 309 (M+1).

Example 20B: methyl-5-(5-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate/methyl-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate and 5-(5-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic/5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic

By analogy with Example 2C from a mixture of isomers 1:1 methyl-5-(5-chloro-1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate and methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate (0,095 g; 0.31 mmol), potassium carbonate (0,047 g; 0.34 mmol), α-bromo-ortho-xylene (46 μl; 0.34 mmol) and dimethylformamide (0,50 ml) followed by treatment was obtained a solid mixture. Treatment of residual solids 2M ammonia in methanol (3 ml) at elevated temperature and subsequent chromatography gave a mixture of methyl-5-(5-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate and methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate (0,016 g; 6%) as a solid pale yellow color (1 H NMR (DMSO-d6): δ 8.79 (s, 1H), 7.90 (d, 1H), 7.86 (d, 1H), 7.78 (s, 1H), 7.50 (m, 2H), 7.26 (m, 3H), 5.37 (s, 2H), 3.77 (s, 3H), 2.38 (s, 3H). MC m/z 413 (M+1)) and a mixture of 5-(5-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate and 5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate (0,021 g; 8.5 percent) in the form of a solid pale yellow color1H NMR (DMSO-d6): δ 8.72, 8.67 (2xs, 2H), 7.80 (m, 4H), 7.72 and 6.88 (2xbr s, 4H), 7.70 (s, 2H), 7.44 (m, 4H), 7.28 (m, 6H), 5.43, 5.42 (2xs, 4H), 2.39 (2xs, 6H). MC m/z 398 (M+1)).

Example 21: methyl-5-(1H-benzimidazole-1-yl)-3-isopropoxy-2-thiophenecarboxylate

To a mixture of methyl-5-(1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate (0,150 g; 0.55 mmol) and potassium carbonate (0.083 g; a 0.60 mmol) in dimethylformamide (5.0 ml) was added 2-jumprope (60 μl; of 0.60 mmol). The mixture was heated at 65°C for 3 hours and then the reaction mixture was additionally added 2-jumprope (164 μl). The mixture was heated at 80°C for 64 hours and then was diluted with water (2.0 ml) and was extracted with ether (2×5.0 ml). The organic layer was washed with saturated saline solution (2.0 ml) and dried (MgSO4). The organic layer was filtered and concentrated under reduced pressure to obtain residue, which was dissolved in EtOAc and was preadsorbed on silica gel (1.5 g). Elution of adsorbed on silica gel substance on RediSep column (4,2 g; ISCO) using gradient the th elution from a mixture of EtOAc/hexane (25:75) to EtOAc (100) gave 0,082 g methyl-5-(1H-benzimidazole-1-yl)-3-isopropoxy-2-thiophenecarboxylate in a solid yellow color. MC m/z 317 (M+1).

Example 22: 5-(1H-benzimidazole-1-yl)-3-isopropoxy-2-thiophencarboxylic

By analogy with Example 4 methyl-5-(1H-benzimidazole-1-yl)-3-isopropoxy-2-thiophenecarboxylate (0,080 g; 0.25 mmol) and 7M ammonia in methanol (3.0 ml) was obtained 5-(1H-benzimidazole-1-yl)-3-isopropoxy-2-thiophencarboxylic (0,045 g; 60%) as not quite white solid.1H NMR (DMSO-d6): δ 8.64 (s, 1H), 7.78 (2xd, 2H), 7.68 and 6.93 (2br s, 2H), 7.55 (s, 1H), 7.37 (2xt, 2H), 4.80 (m, 1H), 1.36 (d, 6N). MS m/z 302 (M+1).

Example 23: 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carbonitrile

5-(1H-Benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophencarboxylic (0,0285 g; 0,0784 mmol) was dissolved in 2 ml of pyridine and cooled to 0°C. Triperoxonane anhydride (0,017 ml; 0,120 mmol) was added dropwise with a syringe. The mixture was stirred for 15 minutes and warmed up to room temperature. After 1 hour, was added 2 ml of dichloromethane, then five drops triperoxonane anhydride to dissolve the insoluble components of the mixture. After 14 hours the reaction mixture was poured into dichloromethane and brine. The layers were separated and the aqueous layer was washed twice with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum. Purification with flash chromatography gave 0.0075 g (28%) 5-(1H-benzimidazole-1-the l)-3-[(2-methylbenzyl)oxy]thiophene-2-carbonitrile in the form of a solid pale yellow color. 1H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.83 (s+m, 3H), 7.49-7.25 (m, 6H), 5.44 (s, 2H), 2.40 (s, 3H). MS (m/z 346 (m+1).

Example 24: {5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]Tien-2-yl}methanol

Methyl-5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiophenecarboxylate (0,276 g; advanced 0.729 mmol) was dissolved in 7 ml of dichloromethane and cooled to -78°C. dropwise with a syringe was added diisobutylaluminum hydride (1.5 M in toluene; 2.0 ml; 3.0 mmol). After 1 hour, dropwise with a syringe was added an additional amount diisobutylaluminum hydride (1.5m in toluene; 1.0 ml; 1.5 mmol). The reaction mixture was left to mix for another 10 minutes. Dropwise with a pipette and added to methanol (1-2 ml) and the mixture was heated to room temperature. Carefully with a pipette and added dilute aqueous hydrochloric acid (5% HCl, wt./about). The mixture was poured into ethyl acetate and water, the layers were separated. The organic layers washed with brine and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum. Purification with flash chromatography resulted in 0,175 g (68%) of {5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]Tien-2-yl}methanol in the form of a solid reddish-brown color.1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.78 (d, J=7. Hz, 1H), 7.64 (d, J=7.4 Hz, 1H), 7.48 (s, 1H), 7.45-7.19 (m, 6H), 5.42 (br s, 1H), 5.16 (s, 2H), 2.37 (s, 3H). MS (m/z 351 (m+1).

Example 25: 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carbaldehyde

{5-(1H-Benzimidazole-1-yl)-3-1(2-methylbenzyl)oxy]Tien-2-yl}methanol (0,0535 g; 0,153 mmol) was dissolved in 5 ml of dichloromethane with stirring. One portion was added manganese dioxide (of 0.133 g; 1.53 mmol). The mixture was left to mix for 1 hour, and then filtered through a layer of celite, good washing with dichloromethane. The solvent was removed in vacuum and the solid was dried under high vacuum to obtain 0,0508 g (95%) 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carbaldehyde in the form of a solid reddish-brown color.1H NMR (300 MHz, DMSO-d6) δ 9.96 (s, 1H), 8.79 (s, 1H), 7.93 (d, J=7.9 Hz, 1H), 7.83 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.77-7.35 (m, 3H), 7.31-7.22 (m, 3H), 5.47 (s, 2H), 2.40 (s, 3H).

Example 26: (+/-)-1-{5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-Tien-2-yl}ethanol

Methylanisole (0,35 ml, 3.0m in diethyl ether; 1.05 mmol) was added to 3 ml of diethyl ether with stirring. The solution was cooled to 0°and dropwise with a syringe was added 5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carbaldehyde (0,0943 g; 0,271 mmol) in 3 ml dichloromethane. The reaction mixture was stirred for 30 minutes and extinguished the relax is by 5 ml of water. The mixture was heated to room temperature and was added 5%HCl solution in a quantity sufficient to dissolve the magnesium salts. The mixture was poured into ethyl acetate and the layers were separated. The organic layer is washed with brine and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum to obtain 0,0965 g(98%) (+/-)-1-{5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]Tien-2-yl}ethanol in a solid brown color.1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.77 (d, J=7.3 Hz, 1H), 7.64 (d, J=7.5 Hz, 1H), 7.48-7.22 (m, 7H), 5.61 (m, 1H), 5.15 (s, 2H), 5.08 (m, 1H), 2.38 (s, 3H), 1.39,1.36 (2xs, 3H).

Example 27: 1-{5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]Tien-2-yl}alanon

Using the procedure described in Example 25, allowed to obtain 1-{5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]Tien-2-yl}Etalon.1H NMR (300 MHz, DMSO-d6) δ 8.76 (s, 1H), 7.90 (d, J=7.9 Hz, 1H), 7.82 (d, J=7.6 Hz, 1H), 7.78 (s, 1H), 7.55-7.24 (m, 6H), 5.44 (s, 2H), 2.46 (s, 3H), 2.41 (s, 3H).

Example 28:1-{4-[(2-methylbenzyl)oxy]Tien-2-yl}-1H-benzimidazole

5-(1H-Benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-2-thiencarbazone acid (0,105 g; in 0.288 mmol) was dissolved in 4 ml acetic acid in a flask equipped with a reflux condenser. The flask was placed in an oil bath with a temperature of 80°Scheres 65 hours, the reaction mixture was cooled to room temperature and poured into ethyl acetate. The solution was washed with saturated NaHCO3(3X) and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuum. The crude product was filtered through a short column of silica gel, washing with a mixture of ethyl acetate/hexane (1:1). The filtrate was concentrated in vacuum to obtain 0,0850 g (92%) of 1-{4-[(2-methylbenzyl)oxy]Tien-2-yl}-1H-benzimidazole in the form of butter dark orange color, which later hardened when standing.1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.77 (d, J=7.3 Hz, 1H), 7.69 (d, J=7.5 Hz, 1H), 7.46-7.20 (m, 7H), 6.80 (d, J=1.9 Hz, 1H), 5.11 (s, 2H), 2.36 (s, 3H).

Example 29: {5-(1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]Tien-2-yl}acetate

{5-(1H-Benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]Tien-2-yl}methanol (0,0278 g; 0,0793 mmol) was dissolved with stirring in 4 ml of dichloromethane. 4-Dimethylamino-pyridine (0,0194 g; strength of 0.159 mmol) was added in one portion. Was added via syringe acetic anhydride (0.075 ml; 0,795 mmol). After two hours the reaction mixture was poured into ethyl acetate. The organic layer is washed with 5% HCl, saturated NaHCO3and a salt solution. The organic layer was dried over MgSO4, filtered and concentrated in vacuum. The residue was filtered through a short column of silica gel, washing with a mixture of ethyl acetate/hexane (1:1). The filtrate was concentrated in vacuum to obtain 0,0276 g (89%) of {5-(1H-BAA is imidazol-1-yl)-3-[(2-methylbenzyl)oxy]Tien-2-yl}methyl acetate in the form of a dark oil, which later hardened when standing.1H NMR (300 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.79 (d, J=7.4 Hz, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.59 (s, 1H), 7.46-7.19 (m, 6N), 5.23 (s, 2H), 5.14 (s, 2H), 2.36 (s, 3H), 2.03 (s, 3H).

Example 30: methyl-5-(1H-benzimidazole-1-yl)-3-{[(trifluoromethyl)-sulfonyl]oxy}-thiophene-2-carboxylate

Methyl-5-(1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate (0,275 g; 1.00 mmol) was dissolved with stirring in 7 ml of dichloromethane. Was added N,N-diisopropylamino-amine (0,230 ml; of 1.32 mmol) via syringe. Was added N-denitrifier-sulfonamide (0,429 g; 1.20 mmol) in one portion. After 18 hours the reaction mixture was poured into dichloromethane and brine. The layers were separated and the aqueous layer washed with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum. Purification with flash chromatography gave 0,406 g (100%) methyl-5-(1H-benzimidazole-1-yl)-3-{[(trifluoromethyl)-sulfonyl]oxy}-thiophene-2-carboxylate in the form of a solid white color.1H NMR (300 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.88 (s, 1H), 7.85 (d, J=8.4 Hz, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.49-7.38 (m, 2H), 3.91 (s, 3H).

Example 31: methyl-3-aniline-5-(1H-benzimidazole-1-yl)thiophene-2-carboxylate

Methyl-5-(1H-benzimidazole-1-yl)-3-{[(trifluoromethyl)sulfonyl]oxy}-thiophene-2-carboxylate (0,200 g; 0,492 mmol), cesium carbonate (0,224 g; 0,687 mmol), racemic ,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0,0306 g; 0,0490 mmol) and Tris(dibenzylidene-acetone)dipalladium(0) (0,0225 g; 0,0250 mmol) were combined in a flask equipped with a reflux condenser. Added 5 ml of toluene, and then aniline (0,0540 ml; 0,593 mmol). The mixture was heated to 110°C and kept at this temperature for 18 hours. The mixture was cooled to room temperature and was adsorbing on silica gel. Purification with flash chromatography gave was 0.138 g (80%) of methyl 3-aniline-5-(1H-benzimidazole-1-yl)thiophene-2-carboxylate in the form of not-quite-white solid.1H NMR (300 MHz, DMSO-d6) δ 9.01 (s, 1H), 8.77 (s, 1H), 7.84 (d, J=7.7 Hz, 1H), 7.79 (d, J=7.6 Hz, 1H), 7.51 (s, 1H), 7.45-7.33 (m, 6H), 7.08 (m, 1H), 3.84 (s, 3H).

Example 32: methyl-5-(1H-benzimidazole-1-yl)-3-(benzoylamine)thiophene-2-carboxylate

Methyl-5-(1H-benzimidazole-1-yl)-3-{[(trifluoromethyl)sulfonyl]oxy}-thiophene-2-carboxylate (0,350 g; 0,861 mmol), cesium carbonate (0,393 g; to 1.21 mmol), racemic 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0,0536 g; 0,0860 mmol) and Tris(dibenzylidene-acetone)dipalladium(0) (0,0394 g; 0,0430 mmol) were combined in a flask equipped with a reflux condenser. Added 12 ml of toluene, then benzamid (0.125 g; 1,03 mmol). The mixture was heated to 100°C and held at this temperature for 40 hours. The mixture was cooled to room temperature and was adsorbing on silica gel. Purification with flash chromatography gave 0,282 g (87%) of methyl 5-(1H-benzimidazole-1-yl)-3-(benzoylamine)t is open-2-carboxylate in the form of a solid white color. 1H NMR (300 MHz, DMSO-d6) δ 11.11 (s, 1H), 8.81 (s, 1H), 8.40 (s, 1H), 8.00 (m, 2H), 7.83 (m, 2H), 7.72-7.60 (m, 3H), 7.50-7.38 (m, 2H), 3.93 (s, 3H). MS (m/z 378 (m+1).

Example 33: 5-(1H-benzimidazole-1-yl)-3-(benzoylamine)thiophene-2-carboxylic acid

Methyl-5-(1H-benzimidazole-1-yl)-3-(benzoylamine)thiophene-2-carboxylate (0,275 g; advanced 0.729 mmol) was dissolved in 15 ml of dioxane with stirring. Added 15 ml of a 1M solution of LiOH and the mixture was stirred for 16 hours at room temperature. Slowly through the pipette was added 15 ml of 2M HCl solution, which led to the formation of solids. The mixture was filtered and the solid is washed with diethyl ether. The solid was collected and dried under high vacuum to obtain 0,0963 g (36%) of 5-(1H-benzimidazole-1-yl)-3-(benzoylamine)thiophene-2-carboxylic acid in the form of a solid reddish-brown color.1H NMR (300 MHz, DMSO-d6) δ 11.31 (s, 1H), 8.79 (s, 1H), 8.39 (s, 1H), 7.97 (m, 2H), 7.83 (m, 2H), 7.73-7.60 (m, 3H), 7.50-7.36 (m, 2H).

Example 34: 5-(5-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-thiophene-2-carboxylic acid

On similar to that described in Example 33 methodology of methyl-5-(5-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylate (0,323 g; 0,782 mmol) was obtained 0,253 g (81%) of 5-(5-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylic acid in the form of a solid which substances pale yellow color. 1H NMR (300 MHz, DMSO-d6) δ 12.81 (br s, 1H), 8.77 (s, 1H), 7.90 (d, J=1.9 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.72 (s, 1H), 7.54-7.44 (m, 2H), 7.28-7.20 (m, 3H), 5.33 (s, 2H), 2.38 (s, 3H).

Example 35: 5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-thiophene-2-carboxylic acid

On similar to that described in Example 33 methodology of methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylate (0,176 g; 0,426 mmol) was obtained 0,150 g (88%) of 5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylic acid in the form of a solid pale yellow color.1H NMR (300 MHz, DMSO-d6) δ 12.81 (s, 1H), 8.71 (s, 1H), 7.82 (m, 2H), 7.72 (s, 1H), 7.54 (m, 1H), 7.40 (dd, J=8.7, 1.8 Hz, 1H), 7.29-7.21 (m, 3H), 5.35 (s, 2H), 2.39 (s, 3H).

Example 36: 5-(5-chloro-1H-benzimidazole-1-yl)-N-methoxy-N-methyl-3-[(2-methylbenzyl)oxy]thiophene-2-carboxamide

5-(5-Chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylic acid (0,100 g; 0,251 mmol), N,O-dimethylhydroxylamine hydrochloride (0,0490 g; 0,502 mmol) and 4-dimethylaminopyridine (0,0062 g; 0,051 mmol) was dissolved in 5 ml dichloromethane. Was added triethylamine (0,077 ml; 0,550 mmol) with a syringe, and then was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0,0870 g; 0,454 mmol) in one portion. The reaction mixture was stirred for 65 hours and poured into ethyl acetate and water. The layers were separated and the organic layer about ivali saline. The combined aqueous layers were extracted with ethyl acetate and the combined organic layers were dried over MgSO4. Filtration, concentration in vacuo and purification with flash chromatography led to 0,0772 g (70%) of 5-(5-chloro-1H-benzimidazole-1-yl)-N-methoxy-N-methyl-3-[(2-methylbenzyl)oxy]thiophene-2-carboxamide in the form of oil, which hardened on standing.1H NMR (300 MHz, DMSO-d68.76 (s, 1H), 7.90 (d, J=2.0 Hz, 1H), 7.84 (d, J=8.8 Hz, 1H), 7.71 (s, 1H), 7.55 (d, J=7.4 Hz, 1H), 7.46 (dd, J=8.8 Hz, 2.0 Hz, 1H), 7.29-7.20 (m, 3H), 5.30 (s, 2H), 3.69 (s, 3H), 3.21 (s, 3H), 2.37 (s, 3H).

Example 37: 5-(6-chloro-1H-benzimidazole-1-yl)-N-methoxy-N-methyl-3-[(2-methylbenzyl)oxy]thiophene-2-carboxamide

On similar to that described in Example 36 the technique of 5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylic acid (0,0430 g; to 0.108 mmol) was obtained 0,0423 g (89%) of 5-(6-chloro-1H-benzimidazole-1-yl)-N-methoxy-N-methyl-3-[(2-methylbenzyl)oxy]thiophene-2-carboxamide in the form of oil, which was hardened when standing.1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.56 (d, J=7.3 Hz, 1H), 7.41 (dd, J=8.5, 2.1 Hz, 1H), 7.29-7.20 (m, 3H), 5.32 (s, 2H), 3.68 (s, 3H), 3.32 (s, 3H), 2.38 (s, 3H).

Example 38: 1-{5-(5-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-Tien-2-yl}alanon

5-(5-Chloro-1H-benzimidazole-1-yl)-N-methoxy-N-methyl-3-[(2-methylbenzyl)-oxy]thiophene-2-carboxamid (0,0750 g; 0,170 mmol was dissolved in 5 ml of tetrahydrofuran and cooled to -78° C. was Added methylmagnesium (0,170 ml, 3.0m in diethyl ether; 0,510 mmol) dropwise via syringe. After 5 minutes the reaction mixture was heated to 0°C and kept at this temperature for another 30 minutes. The reaction mixture was suppressed by adding dropwise 2 ml of 5% HCl. The mixture was poured into ethyl acetate and brine, the layers were separated. The aqueous layer was extracted with ethyl acetate and the combined organic layers were dried over MgSO4. Filtration, concentration in vacuo and purification with flash chromatography gave 0,0658 g (98%) 1-{5-(5-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]Tien-2-yl}ethanone in a solid bright yellow.1H NMR (300 MHz, DMSO-d6) δ 8.83 (s, 1H), 7.91 (m, 2H), 7.79 (s, 1H), 7.53 (m, 1H), 7.49 (dd, J=8.8, 2.1 Hz, 1H), 7.29 (s, 1H), 7.28 (m, 2H), 5.43 (s, 2H), 2.46 (s, 3H), 2.41 (s, 3H).

Example 39: 1-{5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-Tien-2-yl}alanon

On similar to that described in Example 38 method 5-(6-chloro-1H-benzimidazole-1-yl)-N-methoxy-N-methyl-3-[(2-methylbenzyl)-oxy]thiophene-2-carboxamide (0,0400 g; 0,0905 mmol) was obtained 0,0320 g (89%) of 1-{5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]Tien-2-yl}ethanone in a solid yellow color.1H NMR (300 MHz, DMSO-d6) δ 8.77 (s, 1H), 7.89 (d, J=1.7 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.78 (s, 1H), 7.55 (d, J=6.6 Hz, 1H), 7.43 (dd, J=8.6 Hz, 1.9 Hz, 1H), 7.33-7.25 (m, 3H), 5.45 (s, 2H), 2.46 (s, 3H), 2.41 (s, 3H).

When the EP 40: methyl-5-(5-fluoro-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate and methyl 5-(6-fluoro-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate

Methyl 2-chloro-3-oxo-2,3-dihydro-2-thiophenecarboxylate (0,250 g; of 1.30 mmol) was dissolved in 15 ml of chloroform with stirring. Added 5-fermentability (0,389 g; of 2.86 mmol) and the mixture was left to mix for 65 hours. The reaction mixture was poured into Polynesians NaCl and dichloromethane. The layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum. Purification with flash chromatography gave 0,267 g (70%) of a mixture of regioisomers 1:1 methyl-5-(5-fluoro-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate and methyl 5-(6-fluoro-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate in the form of a solid reddish-brown color.1H NMR (300 MHz, DMSO-d6) δ 10.90, 10.87 (2xs, 1H), 8.75, 8.68 (2xs, 1H), 7.84-7.79 (m, 1H), 7.66-7.59 (m, 1H), 7.32-7.20 (m, 1H), 7.15 (s, 1H), 3.79 (s, 3H).

Example 41: methyl-3-hydroxy-5-(5-methoxy-1H-benzimidazole-1-yl)-thiophene-2-carboxylate and methyl 3-hydroxy-5-(6-methoxy-1H-benzimidazole-1-yl)thiophene-2-carboxylate

On similar to that described in Example 40 technique using 5-methoxybenzimidazole (0,424 g; of 2.86 mmol) was received is 0.260 g (66%) of a mixture of regioisomers 1:1 methyl-5-(5-methoxy-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate and methyl 5(6-methoxy-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate in the form of a solid reddish-brown color. 1H NMR (300 MHz, DMSO-d6) δ 10.85 (s, 1H), 8.63, 8.52 (2xs, 1H), 7.70, 7.67 (2xd, J=8.0 Hz, 1H), 7.33, 7.23 (2xd, J=2.4 Hz, 1H), 7.14, 7.11 (2xs, 1H), 7.03, 6.97 (2xdd, J=9.0, 2.4 Hz, 1H), 3.84, 3.82, 3.79, 3.78 (4xs, 12H).

Example 42: methyl-5-(5-bromo-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate and methyl 5-(6-bromo-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate

On similar to that described in Example 40 technique using 5-bromobenzimidazole (2.20 g; and 11.2 mmol) was obtained of 1.03 g (53%) of a mixture of regioisomers 1:1 methyl-5-(5-bromo-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate and methyl 5-(6-bromo-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate in the form of a solid reddish-brown color.1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.74, 8.70 (2xs, 1H), 8.02, 7.93 (2xd, J=1.8 Hz, 1H), 7.77 (m, 1H), 7.54 (m, 1H), 7.17, 7.15 (2xs, 1H), 3.79 (s, 3H).

Example 43: methyl 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate

On similar to that described in Example 40 methodology using 5,6-dichlorobenzimidazole (2.15 g; 11.5 mmol) was obtained 0,359 g (18%) of methyl 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate in the form of a solid reddish-brown color.1H NMR (300 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.78 (s, 1H), 8.12 (s, 1H), 8.02 (s, 1H), 7.18 (s, 1H), 3.79 (s, 3H).

Example 44: methyl 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)--hydroxythiophene-2-carboxylate

On similar to that described in Example 40 methodology using 5,6-dimethoxy-benzimidazole (2.00 g; 11,22 mmol) was obtained 0,632 g (34%) of methyl 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate in the form of a solid reddish-brown color.1H NMR (300 MHz, DMSO-d6) δ 10.81 (s, 1H), 8.46 (s, 1H), 7.34 (s, 1H), 7.24 (s, 1H), 7.13 (s, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 3.79 (s, 3H).

Example 45: methyl 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylate

Methyl-5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate (0,0900 g; 0,262 mmol) was dissolved in 5 ml of N,N-dimethylformamide with stirring. Was added solid potassium carbonate (0,0430 g; 0,311 mmol) in one portion. Was added 2-methylbenzylamine (0,042 ml; 0.31 mmol) using a syringe. The reaction mixture was stirred for 65 hours and poured into ethyl acetate and water. The layers were separated and the organic layer was washed with salt solution. The combined aqueous layers were extracted with ethyl acetate and the combined organic layers were dried over MgSO4. The solution was filtered, concentrated in vacuo, and purified flash chromatography with getting 0,107 g (91%) of methyl 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylate in the form of not-quite-white solid.1H NMR (300 MHz, DMSO-d6) ; 8.80 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.79 (s, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.28-7.24 (m, 3H), 5.38 (s, 2H), 3.77 (s, 3H), 2.39 (s, 3H).

Example 46: methyl-5-(5-fluoro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)-oxititan-2-carboxylate and methyl 5-(6-fluoro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylate

On similar to that described in Example 45 method using a regioisomeric mixture of 1:1 methyl-5-(5-fluoro-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate and methyl 5-(6-fluoro-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate (0,262 g; 0,896 mmol) was obtained 0,291 g (82%) of the regioisomeric mixture of 1:1 methyl-5-(5-fluoro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)-oxy]thiophene-2-carboxylate and methyl 5-(6-fluoro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylate in the form of not-quite-white solid.1H NMR (300 MHz, DMSO-d6) δ 8.78, 8.71 (2xs, 1H), 7.95-7.50 (m, 5H), 7.35-7.22 (m, 3H), 5.39, 5.37 (2xs, 2H), 3.77 (s, 3H), 2.39 (s, 3H).

Example 47: methyl-5-(5-methoxy-1H-benzimidazole-1-yl)-3-[(2-methyl-benzyl)oxy]-thiophene-2-carboxylate and methyl 5-(6-methoxy-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylate

On similar to that described in Example 45 method using a regioisomeric mixture of 1:1 methyl-5-(5-methoxy-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate and methyl 5-(6-IU the hydroxy-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate (0,255 g; 0,838 mmol) was obtained 0,249 g (73%) of the regioisomeric mixture of 1:1 methyl-5-(5-methoxy-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-thiophene-2-carboxylate and methyl 5-(6-methoxy-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylate in the form of not-quite-white solid.1H NMR (300 MHz, DMSO-d6) δ 8.67, 8.55 (2xs, 1H), 7.95, 7.76-7.67, 7.56-7.53 (m, 3H), 7.34, 7.30-7.21, 7.07-6.97 (m, 5H), 5.38, 5.37 (2xs, 2H), 3.84, 3.83, 3.77, 3.76 (4xs, 12H), 2.39 (s, 3H).

Example 48: methyl-5-(5-bromo-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)-oxy]-thiophene-2-carboxylate and methyl 5-(6-bromo-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-thiophene-2-carboxylate

On similar to that described in Example 45 method using a regioisomeric mixture of 1:1 methyl-5-(5-bromo-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate and methyl 5-(6-bromo-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate (0,750 g; 2,12 mmol) was obtained 0,681 g (70%) of the regioisomeric mixture of 1:1 methyl-5-(5-bromo-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)-oxy]thiophene-2-carboxylate and methyl 5-(6-bromo-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylate in the form of not-quite-white solid.1H NMR (300 MHz, DMSO-d6) δ 8.77, 8.71 (2xs, 1H), 8.04, 7.95 (2xd, J=1.8 Hz, 1H), 7.83-7.75, 7.60-7.52, 7.27-7.11 (m, 7H), 5.38, 5.37 (2xs, 2H), 3.77 (s, 3H), 2.40, 2.39 (s, 3H).

Example 49: methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-chloro-4-fluoro-benzyl)oxy]thiophen-carboxylate

On similar to that described in Example 45 technique using methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate (0,100 g; 0,324 mmol) and 2-chloro-4-ftorangidridy (0,0869 g; 0,389 mmol) was obtained 0,131 g (90%) of methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-chloro-4-terbisil)oxy]-thiophene-2-carboxylate in the form of not-quite-white solid.1H NMR (300 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.89 (d, J=1.9 Hz, 1H), 7.84-7.78 (m, 2H), 7.78 (s, 1H), 7.56 (dd, J=8.8, 2.7 Hz, 1H), 7.42 (dd, J=8.6, 1.9 Hz, 1H), 7.35 (ddd, J=8.7, 8.7, 2.7 Hz, 1H), 5.42 (s, 2H), 3.78 (s, 3H).

Example 50: methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2,4-debtor-benzyl)oxy]-thiophene-2-carboxylate

On similar to that described in Example 45 technique using methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate (0,100 g; 0,324 mmol) and 2,4-diferenciada (0,054 ml; 0,39 mmol) was obtained 0,122 g (87%) of methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2,4-diferensial)oxy]thiophene-2-carboxylate in the form of not quite white solids.1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.89 (d, J=1.9 Hz, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.77-7.69 (m, 1H), 7.76 (s, 1H), 7.42 (dd, J=8.6, 1.9 Hz, 1H), 7.35 (m, 1H), 7.19 (m, 1H), 5.41 (s, 2H), 3.77 (s, 3H).

Example 51: methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-(pyridin-3-yl-methoxy)thiophene-2-carboxylate

On similar to that described in Example 45 methodology with IP is the use of methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate (0,100 g; 0,324 mmol), 3-(methyl bromide)pyridine hydrobromide (0,0980 g; 0,387 mmol) and potassium carbonate (0,107 g; 0,774 mmol) was obtained 0,0393 g (30%) methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-(pyridine-3-ylethoxy)thiophene-2-carboxylate in the form of a solid reddish-brown color.1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1H), 8.72 (m, 1H), 8.58 (dd, J=4.8, 1.5 Hz, 1H), 7.93 (m, 1H), 7.86 (d, J=1.9 Hz, 1H), 7.83 (d, J=8.7 Hz, 1H), 7.73 (s, 1H), 7.48 (m, 1H), 7.42 (dd, J=8.7, 1.9 Hz, 1H), 5.45 (s, 2H), 3.79 (s, 3H).

Example 52: methyl-5-(1H-benzimidazole-1-yl)-3-(prop-2-ynyloxy)thiophene-2-carboxylate

On similar to that described in Example 45 technique using methyl-5-(1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate (0,250 g; 0,911 mmol) and propargylamine (0,12 ml; 80% in toluene; at 1.08 mmol) was obtained 0,211 g (74%) of methyl-5-(1H-benzimidazole-1-yl)-3-(prop-2-ynyloxy)thiophene-2-carboxylate in the form of a solid reddish-brown color.1H NMR (300 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.88 (d, J=7.7 Hz, 1H), 7.81 (d, J=7.5 Hz, 1H), 7.61 (s, 1H), 7.49-7.36 (m, 2H), 5.07 (d, J=2.3 Hz, 2H), 3.78 (s, 3H), 3.73 (t, J=2.3 Hz, 1H). MS (m/z 313 (m+1).

Example 53: methyl-5-(5-bromo-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxylate and methyl 5-(6-bromo-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate

On similar to that described in Example 45 the methodology used is eat regioisomeric mixture of 1:1 methyl-5-(5-bromo-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate and methyl 5-(6-bromo-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate (0,200 g; 0,566 mmol) and 2-triftormetilfosfinov (0,163 g; 0,682 mmol) was obtained regioisomeric mixture of products 1:1. The mixture was separated with flash chromatography with getting 0,0952 g (33%) of methyl-5-(5-bromo-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxylate in the form of not quite white solids (1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.04 (d, J=1.8 Hz, 1H), 7.97 (d, J=7.6 Hz, 1H), 7.85-7.77 (m, 2H), 7.75 (s, 1H), 7.62 (m, 1H), 7.60 (d, J=1.9 Hz, 1H), 7.58 (d, J=1.8 Hz, 1H), 5.50 (s, 2H), 3.78 (s, 3H)) and g 0,0970 (34%) of methyl-5-(6-bromo-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)-benzyl]-oxy}thiophene-2-carboxylate in the form of not quite white solids (1H NMR (300 MHz, DMSO-d6) δ 8.73 (s, 1H), 7.99-7.94 (m, 2H), 7.85-7.71 (m, 4H), 7.62 (m, 1H), 7.53 (dd, J=8.6, 1.5 Hz, 1H), 5.52 (s, 2H), 3.78 (s, 3H)).

Example 54: methyl 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(2-trifluoromethyl-benzyl)oxy]thiophene-2-carboxylate

On similar to that described in Example 45 technique using methyl-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate (to 0.108 g; 0,323 mmol) and 2-triftormetilfosfinov (0,232 g; 0,971 mmol) was obtained 0,109 g (69%) of methyl 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(2-trifloromethyl)-oxy]thiophene-2-carboxylate in the form of a not quite white solid.1H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.84-7.76 (m, 2H), 7.66 (s, 1H), 7.61 (dd, J=7.7, 7.7 Hz, 1H), 7.35 (s, 1H), 7.26 (s, 1H), 5.53 (s, 2H), 3.84 (s, 3 is), 3.83 (s, 3H), 3.78 (s, 3H).

Example 55: methyl-3-[(2,6-dichlorobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxylate

On similar to that described in Example 45 technique using methyl-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate (0,100 g; 0,299 mmol) and 2,6-dichlorobenzamide (0,0869 g; 0,362 mmol) was obtained 0,117 g (79%) of methyl 3-[(2,6-dichlorobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxylate in the form of not-quite-white solid.1H NMR (300 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.78 (s, 1H), 7.62 (d, J=1.5 Hz, 1H), 7.59 (s, 1H), 7.51 (dd, J=9.3, 6.8 Hz, 1H), 7.35 (s, 1H), 7.31 (s, 1H), 5.52 (s, 2H), 3.87 (s, 3H), 3.83 (s, 3H), 3.71 (s, 3H).

Example 56: methyl-3-[(2-bromobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxylate

On similar to that described in Example 45 technique using methyl-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate (0,100 g; 0,299 mmol) and 2-bromobenzylamine (0,0905 g; 0,362 mmol) was obtained 0,114 g (76%) of methyl 3-[(2-bromobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxylate in the form of not-quite-white solid.1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.73 (ddd, J=7.6, 7.6, 1.0 Hz, 1H), 7.68 (m, 1H), 7.68 (s, 1H), 7.49 (ddd, J=7.6, 7.6, 1.2 Hz, 1H), 7.35 (s, 1H), 7.34 (ddd, J=7.6, 7.6, 1.6 Hz, 1H), 7.26 (s, 1H), 5.40 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 3.79 (s, 3H).

Example 57: methyl 5-(5,6-dichloro-1 is-benzimidazole-1-yl)-3-(3-FuelMAX)-thiophene-2-carboxylate

Methyl-5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate (0,0900 g; 0,262 mmol) and triphenylphosphine (0,0890 g; 0,339 mmol) was dissolved in 4 ml of tetrahydrofuran under stirring. The reaction mixture was cooled to 0°and added 3-furanmethanol (0,030 ml; 0.35 mmol) with a syringe. Added diethylazodicarboxylate (0,053 ml; 0.34 mmol) dropwise via syringe. The reaction mixture was heated to room temperature and was stirred for 3 hours. The mixture was adsorbing on silica gel and purified flash chromatography with getting 0,0725 g (65%) of methyl 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(3-FuelMAX)-thiophene-2-carboxylate in the form of a mixture with diacylhydrazine-1,2- - in primary forms, which could easily be removed by subsequent processing.1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.14 (s, 1H), 8.07 (s, 1H), 7.85 (dd, J=1.6, 0.9 Hz, 1H), 7.72 (s, 1H), 7.70 (dd, J=1.6, 1.6 Hz, 1H), 6.61 (dd, J=1.9, 0.8 Hz, 1H), 5.25 (s, 2H), 3.77 (s, 3H).

Example 58: methyl 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(2-furyl-methoxy)-thiophene-2-carboxylate

On similar to that described in Example 57 technique using methyl-5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate (0,0900 g; 0,262 mmol) and furfuryl alcohol (0,029 ml; 0.34 mmol) was obtained 0,0525 g (47%) of methyl 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(2-FuelMAX)-thiophene-2-carboxylate in the form of a mixture is diacylhydrazine-1,2- - in primary forms, which could easily be removed by subsequent processing.1H NMR (300 MHz, DMSO-d6) δ 8.79 (s, 1H), 8.14 (s, 1H), 8.09 (s, 1H), 7.76 (s, 1H), 7.75 (dd, J=1.9, 0.8 Hz, 1H), 6.71 (dd, J=3.2, 0.8 Hz, 1H), 6.51 (dd, J=3.2, 1.9 Hz, 1H), 5.36 (s, 2H), 3.75 (s, 3H).

Example 59: methyl 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(Tien-3-ylethoxy)-tamofen-2-carboxylate

On similar to that described in Example 57 technique using methyl-5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate (0,0900 g; 0,262 mmol) and 3-thiophenemethyl (to 0.032 ml, 0.34 mmol) was obtained 0,0745 g (65%) of methyl 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(Tien-3-ylethoxy)-thiophene-2-carboxylate in the form of a mixture with diacylhydrazine-1,2-in primary forms, which could easily be removed by subsequent processing.1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.14 (s, 1H), 8.04 (s, 1H), 7.71 (s, 1H), 7.66 (m, 1H), 7.60 (dd, J=5.0, 2.9 Hz, 1H), 7.22 (dd, J=5.0, 1.2 Hz, 1H), 5.38 (s, 2H), 3.78 (s, 3H).

Example 60: methyl 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(Tien-2-ylethoxy)-thiophene-2-carboxylate

On similar to that described in Example 57 technique using methyl-5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate (0,0775 g; 0,226 mmol) and 2-thiophenemethyl (0,028 ml; 0.30 mmol) was obtained 0,0599 g (60%) of methyl 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(Tien-2-ylethoxy)-thiophene-2-carboxylate in the form of a mixture with diacylhydrazine-1,2-in primary forms, of which the first could easily be removed by subsequent processing. 1H NMR (300 MHz, DMSO-d6) δ 8.78 (s, 1H), 8.14 (s, 1H), 8.05 (s, 1H), 7.75 (s, 1H), 7.61 (dd, J=5.0,1.2 Hz, 1H), 7.30 (dd, J=3.5, 1.2 Hz, 1H), 7.07 (dd, J=5.0, 3.5 Hz, 1H), 5.57 (s, 2H), 3.77 (s, 3H).

Example 61: 5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-thiophene-2-carboxamide

Methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylate (0.172 g; 0,417 mmol) were placed in a test tube. Was added ammonia in methanol (15.0 ml; 2.0m in Meon, 30 mmol) and the vessel was tightly closed. The tube was placed in an oil bath, preheated to 80°C and stirred at this temperature for 24 hours. The reaction mixture was cooled to room temperature and was added 15.0 ml of a solution of ammonia in methanol. The vessel is again hermetically closed and heating was continued for an additional 44 hours. The reaction mixture was cooled to room temperature and was adsorbing on silica gel. Purification with flash chromatography gave 0,0417 g (24%) of unreacted educt and 0,0820 g (49%) of 5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-thiophene-2-carboxamide in the form of a solid yellow color.1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 7.82 (d, J=8.8 Hz, 1H), 7.78 (d, J=2.1 Hz, 1H), 7.72 (br s, 1H), 7.70 (s, 1H), 7.51 (d, J=7.0 Hz, 1H), 7.40 (dd, J=8.6, 2.1 Hz, 1H), 7.34-7.21 (m, 3H), 6.88 (br s, 1H), 5.44 (s, 2H), 2.40 (s, 3H).

Example 62: 5-(6-bromo-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxamide

p>

On similar to that described in Example 61 method using methyl-5-(6-bromo-1H-benzimidazole-1-yl)-3-[[2-(trifluoromethyl)benzyl]oxy}-thiophene-2-carboxylate (0,0950 g; 0,186 mmol) was obtained 0,0557 g (60%) 5-(6-bromo-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]-oxy}thiophene-2-carboxamide in the form of not quite a white solid.1H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.91 (d, J=1.6 Hz, 1H), 7.89-7.71 (m, 5H), 7.68 (s, 1H), 7.67 (m, 1H), 7.52 (dd, J=8.6, 1.8 Hz, 1H), 6.81 (br s, 1H), 5.56 (s, 2H).

Example 63: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide

On similar to that described in Example 61 method using methyl-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(2-trifloromethyl)-oxy]thiophene-2-carboxylate was obtained 0,0351 g (34%) of 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxamide in the form of a solid light reddish-brown color.1H NMR (300 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.90-7.58 (m, 5H), 7.60 (s, 1H), 7.34 (s, 1H), 7.21 (s, 1 H), 6.82 (br s,1H), 5.56 (s, 2H).

Example 64: 3-[(2,6-dichlorobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide

On similar to that described in Example 61 method using methyl-3-[(2,6-dichlorobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxylate (0.15 g; 0,233 mmol) was obtained 0,0392 g (35%) 3-[(2,6-dichlorobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide in the form of not-quite-white solid.1H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.79 (s, 1H), 7.68 (br s, 1H), 7.63 (d, J=1.5 Hz, 1H), 7.60 (s, 1H), 7.52 (dd, J=9.1, 6.9 Hz, 1H), 7.35 (s, 1H), 7.30 (s, 1H), 6.63 (br s, 1H), 5.58 (s, 2H), 3.87 (s, 3H), 3.83 (s, 3H).

Example 65: 3-[(2-bromobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide

On similar to that described in Example 61 method using methyl-3-[(2-bromobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxylate (0,112 g; 0,222 mmol) was obtained 0,0296 g (27%) 3-[(2-bromobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide in the form of a solid yellow color.1H NMR (300 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.78-7.64 (m, 3H), 7.66 (s, 1H), 7.47 (m, 1H), 7.86 (m, 1H), 7.34 (s, 1H), 7.21 (s, 1H), 6.91 (br s, 1H), 5.46 (s, 2H).

Example 66: 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)-oxy]thiophene-2-carboxylic acid

On similar to that described in Example 33 method using methyl-5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylate (0,105 g; 0,235 mmol) was obtained 0,0695 g (68%) of 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylic acid in the form of a solid light reddish-brown color.1 H NMR (300 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.78 (s, 1H), 8.14 (s, 1H), 8.04 (s, 1H) 7.73 (s, 1H), 7.53 (m, 1H), 7.29-7.22 (m, 3H), 5.35 (s, 2H), 2.39 (s, 3H).

Example 67: 5-(5-fluoro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-thiophene-2-carboxylic acid and 5-(6-fluoro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-thiophene-2-carboxylic acid

On similar to that described in Example 33 methodology using a regioisomeric mixture of 1:1 methyl-5-(5-fluoro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)-oxy]thiophene-2-carboxylate and methyl 5-(6-fluoro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)-oxy]thiophene-2-carboxylate (0,285 g; 0,719 mmol) was obtained 0,215 g (78%) of the regioisomeric mixture 1:1 5-(5-fluoro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-thiophene-2-carboxylic acid and 5-(6-fluoro-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-thiophene-2-carboxylic acid in a solid yellow color.1H NMR (300 MHz, DMSO-d6) δ 12.81 (br s, 1H), 8.76, 8.69 (2xs, 1H), 7.84 (m, 1H), 7.72, 7.70 (2xs, 1H), 7.66 (m, 1H), 7.53 (d, J=6.3 Hz, 1H), 7.36-7.19 (m, 4H), 5.35, 5.34 (2xs, 2H), 2.38 (s, 3H).

Example 68: 5-(5-methoxy-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-thiophene-2-carboxylic acid and 5-{6-methoxy-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)-oxy]thiophene-2-carboxylic acid

On similar to that described in Example 33 methodology using a regioisomeric mixture of 1: methyl 5-(5-methoxy-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-thiophene-2-carboxylate and methyl 5-(6-methoxy-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylate (0,243 g; 0,595 mmol) was obtained 0,217 g (92%) of the regioisomeric mixture of 1:1 5-(5-methoxy-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylic acid and 5-(6-methoxy-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylic acid in the form of a solid pale yellow color.1H NMR (300 MHz, DMSO-d6) δ 8.93, 8.79 (2xs, 1H), 7.80-7.68 (m, 2H), 7.53 (d, J=6.6 Hz, 1H), 7.35, 7.31-7.17 (m, 4H), 7.10, 7.04 (2xdd, J=9.0, 2.4 Hz, J=8.9, 2.3 Hz, 1H), 5.34 (s, 2H), 2.38 (s, 3H).

Example 69: 5-(5-bromo-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-thiophene-2-carboxylic acid and 5-(6-bromo-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylic acid

On similar to that described in Example 33 methodology using a regioisomeric mixture of 1:1 methyl-5-(5-bromo-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)-oxy]thiophene-2-carboxylate and methyl 5-(6-bromo-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)-oxy]thiophene-2-carboxylate (0,100 g; 0,219 mmol) was obtained 0,0599 g (62%) of the regioisomeric mixture 1:1 5-(5-bromo-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-thiophene-2-carboxylic acid and 5-(6-bromo-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylic acid in a solid yellow color.1H NMR (300 MHz, DMSO-d6) δ 12.81 (br s, 1H), 8.75, 8.70 (s, 1H), 8.04, 7.93 (2xd, J=1.8 Hz, J=1.8 Hz, 1H), 7.81, 7.77 (2xd, J=8.8 Hz, J=8.7 Hz, 1H), 7.73, 7.72 (2xs, 1H), 7.61-7.50 (m, 2H), 7.31-7.20 (m, 3H), 5.35, 5.33 (2xs, 2H), 2.39, 2.38 (s, 3H).

Example 70: 5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-chloro-4-terbisil)-oxy]thiophene-2-carboxylic acid

On similar to that described in Example 33 method using methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-chloro-4-terbisil)oxy]thiophene-2-carboxylate (0,128 g; 0,284 mmol) was obtained 0,0805 g (65%) 5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2-chloro-4-terbisil)oxy]-thiophene-2-carboxylic acid in the form of solid white color.1H NMR (300 MHz, DMSO-d6) δ 12.88 (br s, 1H), 8.73 (s, 1H), 7.93-7.74 (m, 3H), 7.71 (s, 1H), 7.55 (dd, J=8.8, 2.5 Hz, 1H), 7.41 (dd, J=8.6, 1.9 Hz, 1H), 7.34 (ddd, J=9.7, 8.5, 2.5 Hz, 1H), 5.39 (s, 2H).

Example 71: 5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2,4-diferensial)oxy]-thiophene-2-carboxylic acid

On similar to that described in Example 33 method using methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2,4-diferensial)oxy]thiophene-2-carboxylate (0,119 g; 0,274 mmol) was obtained 0,0860 g (75%) of 5-(6-chloro-1H-benzimidazole-1-yl)-3-[(2,4-diferensial)oxy]-thiophene-2-carboxylic acid in the form of not-quite-white solid.1H NMR (300 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.87 (d, J=1.8 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.72 (m, 1H), 7.71 (s, 1H), 7.41 (dd, J=8.6, 2.0 Hz, 1H), 7.34 (m, 1H), 7.18 (m, 1H), 5.38 (s, 2H).

Example 72: 5-(6-chloro-1H-benzimidazole-1-yl)-3-(pyridine-3-ylethoxy)-thiophene-2-carboxylic acid

On similar to that described in Example 33 method using methyl-5-(6-chloro-1H-benzimidazole-1-yl)-3-(pyridine-3-ylethoxy)thiophene-2-carb is celata (0,0380 g; 0,0950 mmol) was obtained 0,010 g (27%) 5-(6-chloro-1H-benzimidazole-1-yl)-3-(pyridine-3-ylethoxy)thiophene-2-carboxylic acid in the form of a solid reddish-brown color.1H NMR (300 MHz, DMSO-d6) δ 8.88 (s, 1H), 8.77 (m, 1H), 8.72 (s, 1H), 8.32 (d, J=7.9 Hz, 1H), 7.87-7.79 (m, 3H), 7.69 (s, 1H), 7.42 (dd, J=8.6, 2.0 Hz, 1H), 5.52 (s, 2H).

Example 73: 5-(1H-benzimidazole-1-yl)-3-(prop-2-ynyloxy)thiophene-2-carboxylic acid

On similar to that described in Example 33 method using methyl-5-(1H-benzimidazole-1-yl)-3-(prop-2-ynyloxy)thiophene-2-carboxylate (0,183 g; 0,586 mmol) was obtained 0,175 g (100%) 5-(1H-benzimidazole-1-yl)-3-(prop-2-ynyloxy)thiophene-2-carboxylic acid in the form of a solid reddish-brown color.1H NMR (300 MHz, CD3OD) δ 9.83 (s, 1H), 7.98 (m, 2H), 7.77 (m, 2H), 7.71 (s, 1H), 5.02 (d, J=2.3 Hz, 2H), 3.17 (t, J=2.3 Hz, 1H). MS (m/z 299 (m+1).

Example 74: 5-(6-bromo-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxylic acid

On similar to that described in Example 33 method using methyl-5-(6-bromo-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}-thiophene-2-carboxylate (0,0155 g; 0,0303 mmol) was obtained 0,0080 g (53%) 5-(6-bromo-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxylic acid in the form of solid yellow color.1H NMR (300 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.98-7.93 (m, 2H, 7.84-7.74 (m, 3H), 7.68 (s, 1H), 7.62 (m, 1H), 7.53 (dd, J=8.6, 1.9 Hz, 1H), 5.50 (s, 2H).

Example 75: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylic acid

On similar to that described in Example 33 method using methyl-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(2-trifloromethyl)-oxy]thiophene-2-carboxylate (0,0691 g; 0,140 mmol) was obtained 0,0558 g (83%) of 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]-oxy}thiophene-2-carboxylic acid in a solid yellow color.1H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.95 (d, J=7.6 Hz, 1H), 7.84-7.74 (m, 2H), 7.65-7.56 (m, 2H), 7.34 (s, 1H), 7.25 (s, 1H), 5.50 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H).

Example 76: 3-[(2-bromobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxylic acid

On similar to that described in Example 33 method using methyl-3-[(2-bromobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxylate (0,0719 g; 0,143 mmol) was obtained 0,0597 g (85%) of 3-[(2-bromobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxylic acid in a solid yellow color.1H NMR (300 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.77-7.66 (m, 2H), 7.63 (s, 1H), 7.47 (m, 1H), 7.38-7.29 (m, 2H), 7.26 (s, 1H), 5.37 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H).

Example 77: 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(3-FuelMAX)-thiophene-2-carboxylic acid

On similar to that described in Example 33 method using methyl-5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(3-FuelMAX)-thiophene-2-carboxylate (0,0715 g; 0,169 mmol) was obtained 0,0476 g (69%) of 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(3-FuelMAX)thiophene-2-carboxylic acid in the form of reddish-brownish-orange color.1H NMR (300 MHz, DMSO-d6) δ at 12.82 (br s, 1H), 8.78 (s, 1H), 8.13 (s, 1H), 8.06 (s, 1H), 7.85 (s, 1H), 7.69 (m, 1H), 7.68 (s, 1H), 6.61 (m, 1H), 5.21 (s, 2H).

Example 78: 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(2-FuelMAX)-thiophene-2-carboxylic acid

On similar to that described in Example 33 method using methyl-5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(2-FuelMAX)-thiophene-2-carboxylate (0,0525 g; 0,124 mmol) was obtained 0,0289 g (57%) of 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(2-FuelMAX)thiophene-2-carboxylic acid in a solid yellow color.1H NMR (300 MHz, DMSO-d6) δ 12.85 (br s, 1H), 8.78 (s, 1H), 8.14 (s, 1H), 8.08 (s, 1H), 7.74 (dd, J=1.9, 0.7 Hz, 1H), 7.71 (s, 1H), 6.70 (d, J=3.2 Hz, 1H), 6.51 (dd, J=3.2,1.9 Hz, 1H), 5.32 (s, 2H).

Example 79: 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(Tien-3-ylethoxy)-thiophene-2-carboxylic acid

On similar to that described in Example 33 method using methyl-5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(Tien-3-ylethoxy)-thiophene-2-carboxylate (0,0730 g; 0,166 mmol) was obtained 0,0476 g (67%) of 5-(5,6-dichloro-1H-Benson Gasol-1-yl)-3-(Tien-3-ylethoxy)thiophene-2-carboxylic acid in a solid yellow color. 1H NMR (300 MHz, DMSO-d6) δ 12.84 (br s, 1H), 8.77 (s, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.67 (s, 1H), 7.66 (m, 1H), 7.59 (dd, J=5.0, 3.0 Hz, 1H), 7.22 (dd, J=5.0, 1.2 Hz, 1H), 5.35 (s, 2H).

Example 80: 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(Tien-2-ylethoxy)-thiophene-2-carboxylic acid

On similar to that described in Example 33 method using methyl-5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(Tien-2-ylethoxy)-thiophene-2-carboxylate (0,0580 g; 0,132 mmol) was obtained 0,0341 g (61%) of 5-(5,6-dichloro-1H-benzimidazole-1-yl)-3-(Tien-2-ylethoxy)thiophene-2-carboxylic acid in the form of a solid pale yellow color.1H NMR (300 MHz, DMSO-d6) δ 8.77 (s, 1H), 8.13 (s, 1H), 8.03 (s, 1H), 7.70 (s, 1H), 7.61 (dd, J=5.0, 1.1 Hz, 1H), 7.30 (dd, J=3.5, 1.1 Hz, 1H), 7.07 (dd, J=5.0, 3.5 Hz, 1H), 5.54 (s, 2H).

Example 81: methyl-3-[(2-chloro-4-terbisil)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophen-2-carboxylate

On similar to that described in Example 45 technique using methyl-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxylate (0,100 g; 0,299 mmol) and 2-chloro-4-ftorangidridy (0,0809 g; 0,362 mmol) was obtained 0,0963 g (68%) of methyl-3-[(2-chloro-4-terbisil)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-the carboxylate in the form of a solid yellow color.1H NMR (300 MHz, DMSO-d6) δ 8.50 (s, 1H), 7,80 (dd, J=8.6. 6.2 Hz, 1H), 7.70 (s, 1H), 7.55 (dd, J=8.8, 2.6 Hz, 1H), 7.39-7.31 (m, 1H), 7.35 (s, 1H), 7.27 (s, 1H), 5.41 (s, 2H), 3.85 (s, 3H), 383 (s, 3H), 3.78 (s, 3H).

Example 82 N-({5-(5-methoxy-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)-oxy]Tien-2-yl}carbonyl)methanesulfonamide and N-({5-(6-methoxy-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]Tien-2-yl}carbonyl)-methanesulfonamide

Regioisomeric mixture 1:1 5-(5-methoxy-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylic acid and 5-(6-methoxy-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylic acid (0,100 g; 0,254 mmol), 4-dimethylaminopyridine (0,0403 g; 0,330 mmol) and methanesulfonamide (0,0313 g; 0,329 mmol) was dissolved in 4 ml of dichloromethane with stirring. Was added triethylamine (0,046 ml; 0.33 mmol) via syringe followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0,0633 g; 0,330 mmol) in one portion. The mixture was stirred for 12 hours and then poured into 5%aqueous HCl solution and ethyl acetate. The layers were separated and the organic layer was washed with salt solution. The combined aqueous layers were extracted with ethyl acetate and the combined organic layers were dried over MgSO4. Filtration, concentration in vacuo and purification with flash chromatography gave 0,0826 g (69%) of the regioisomeric mixture of 1:1 N-({5-(5-methoxy-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]Tien-2-yl}carbonyl)-methanesulfonamide and N-({5-(6-methoxy-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]Tien-2-yl}to bonil)-methanesulfonamide in the form of a solid pale green color. 1H NMR (300 MHz. DMSO-d6) δ 9.97 (br s, 1H), 8.70. 8.58 (2xs, 1H), 7.83-7.68 (m, 2H), 7.55 (m, 1H), 7.37-7.21 (m, 4H), 7.07, 7.01 (2xdd, J=8.8, 2.3 Hz, 1H), 5.51 (s, 2H), 3.85, 3.83 (2xs, 3H), 3.37, 3.36 (2xs, 3H), 2.41 (s, 3H). MC (m/z 472 (m+1).

Examples 83-158

Unless otherwise indicated, the following compounds were obtained in a similar manner in accordance with the General methods described for Examples 2A, 33, 40, 45, 57 (or the Intermediate of example 21) and 61 (where instead of 2M NH3in the Meon used 7M NH3in the Meon).

Example 83: 5-(5-chloro-2-methyl-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylic acid and 5-(6-chloro-2-methyl-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]thiophene-2-carboxylic acid

1H NMR (400 MHz, CD3OD) δ 7.61-7.56 (m, 1H); 7.46 (d, J=7.2 Hz, 1H); 7.28-7.21 (m, 6N); 5.34 (s, 2H); 2.52 (s, 3H); 2.43 (s, 3H). MS (ERI-(electrospray ionization registration of negative ions), m/z 411 (m-1).

Example 84: 3-(benzyloxy)-5-(5-chloro-1H-benzimidazole-1-yl)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.88 (d, J=2.01 Hz, 1H), 7.78-7.70 (m, 2H), 7.65 (s, 1H). 7.56-7.52 (m, 2H), 7.46-7.35 (m, 4H), 7.01 (s, 1H), 5.40 (s, 2H). MS (ERI+ (electrospray ionization with the registration of a positive ion), m/z 383 (m+1).

Example 85: 5-(5-chloro-1H-benzimidazole-1-yl)-3-({2-[(phenylsulfonyl)-methyl]benzyl)oxy)thiophene-2-carboxylic acid and 5-(6-chloro-1H-b is Intimidator-1-yl)-3-({2-[(phenylsulfonyl)methyl]benzyl}oxy)thiophene-2-carboxylic acid

1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.70 (s, 1H), 7.91 (d, J=1.96 Hz, 1H), 7.84-7.58 (m, 17H), 7.47 (dd, J=1.96 Hz, 8.74 Hz, 1H), 7.43-7.26 (m, 5H), 7.12 (t, J=7.76 Hz, 2H), 5.38 (s, 4H), 4.93 (s, 4H). MS (ERI+, m/z 540 (m+1).

Example 86: 5-(5-chloro-1H-benzimidazole-1-yl)-3-{1-[3-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxylic acid and 5-(6-chloro-1H-benzimidazole-1-yl)-3-{1-[3-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxylic acid

1H NMR (400 MHz, DMSO-d6) δ 12.94 (br s, 2H), 8.70 (s, 1H), 8.65 (s, 1H), 7.94-7.63 (m, 13H), 7.58 (s, 2H), 7.41 (t, J=8.03, 2H), 5.88 (dd, J=6.06 Hz, 11.06 Hz, 2H), 1.64 (d, J=6.24 Hz, 6N). MS (ERI+, m/z 467 (m+1).

Example 87: 5-[6-(2,2,2-triptoreline)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy]thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.86-7.63 (m, 7H), 7.38 (d, J=2.38 Hz, 1H), 7.10 (dd, J=2.29 Hz, 8.88 Hz, 1H), 6.82 (br s, 1H), 5.56 (s, 2H), 4.86 (q, J=8.85 Hz, 2H). MS (ERI+, m/z 516 (m+1).

Example 88: 5-(2,2-debtor-5H-[1,3]dioxolo[4,5-f]benzimidazole-5-yl)-3-{[2-(trifluoromethyl)benzyl]oxy)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.92 (s, 1H), 7.88 (s, 1H), 7.87-7.64 (m, 6H), 6.79 (br s, 1H), 5.56 (s, 2H). MS (ERI+, m/z 498 (m+1).

Example 89: 5-(7,8-dihydro-1H,6N-[1,4]dioxano[2,3-f]benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.85 (s, 1H), 7.83 (s, 1H), 7.77 (t, J=7.60 Hz, 1H), 7.69 (br s, 1H), 7.64 (t, J=7.60 Hz, 1H), 7.60 (s, 1H), 7.36 (s, 2H), 6.76 (br s, 1H), 5.54 (s, 2H), 4.15-4.06 (m, 4H), 2.11 (t, J=4.94 Hz, 2H). MS (ERI+, m/z 490 (m+1).

Example 90: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[3-(dimethylamino)benzyl]oxy}thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.73 (br s, 1H), 7.60 (s, 1H), 7.33 (s, 1H), 7.20 (t, J=7.87 Hz, 1H), 7.15 (s, 1H), 7.07 (br s, 1H), 6.88 (s, H), 6.79 (d, J=7.51 Hz, 1H), 6.70 (dd, J=2.29 Hz 8.33 Hz, 1H), 5.34 (s, 2H,), 3.82 (s, 6H), 2.89 (s, 6H).

Example 91: 3-[(6-chloro-1,3-benzodioxol-5-yl)methoxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.73 (br s, 1H), 7.67 (s, 1H), 7.35 (s, 1H), 7.33 (s, 1H), 6.90 (br s, 1H), 6.11 (s, 2H), 5.36 (s, 2H), 3.86 (s, 3H), 3.83 (s, 3H). MS (ERI+, m/z 488 (m+1).

Example 92: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(2-nitrobenzyl)oxy]thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.19 (d, J=8.1 Hz, 1H), 7.84 (t, J=7.6 Hz, 1H), 7.78-7.76 (m, 2H), 7.65 (m, 1H), 7.57 (s, 1H), 7.32 (s, 1H), 7.09 (br s, 1H), 7.07 (s, 1H), 5.79 (s, 2H), 3.81 (s, 3H), 3.76 (s, 3H). MS (ERI+, m/z 455 (m+1).

Example 93: 3-(1,1'-biphenyl-2-ylethoxy)-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.72 (m, 1H), 7.61 (br s, 1H), 7.52-7.48 (m, 2H), 7.46-7.33 (m, 8H), 7.15 (s, 1H), 6.62 (br s, 1H), 5.34 (s, 2H),3.83 (s, 3H), 3.82 (s, 3H). MS (ERI+, m/z 486 (m+1).

Example 94: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(3-jobensis)-oxy]thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.96 (m, 1H), 7.73 (d, J=7.3 Hz, 1H), 7.59-7.57 (m, 3H), 7.34 (s, 1H), 7.15 (s, 1H), 7.10 (br s, 1H), 5.38 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H). MS (ERI+, m/z 536 (m+1).

Example 95: 3-[(2-cyanobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.98 (d, J=7.3 Hz, 1H), 7.85-7.77 (m, 3H), 7.70 (s, 1H), 7.62 (m, 1H), 7.35 (s, 1H), 7.22 (s, 1H), 6.92 (br s, 1H), 5.60 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H). MS (ERI+, m/z 435 (m+1).

Example 96: 3-[(3-aminobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl]thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.73 (br s, 1H), 7.53 (s, 1H), 7.34 (s, 1H), 7.16 (s, 1H), 7.04 (t, J=7.7 Hz, 1H), 7.00 (br s, 1H), 6.67-6.63 (m, 2H), 6.64 (d, J=7.8 Hz, 1H), 5.27 (s, 2H), 5.18 (d, J=7.8 Hz, 2H), 3.83 (m, 6H). MS (ERI+, m/z 425 (m+1).

Example 97: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(methylthio)benzyl]-oxy}thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.70 (br s, 1H), 7.66 (s, 1H), 7.55 (d, J=7.5 Hz, 1H), 7.41 (m, 2H), 7.33 (s, 1H), 7.21 (s, 2H), 6.87 (br s, 1H), 5.40 (s, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 2.50 (s, 3H). MS (ERI+, m/z 456 (m+1).

Example 98: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(methylsulfinyl)benzyl]oxy}thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.99 (d, J=7.7 Hz, 1H), 7.73-7.68 (m, 3H), 7.65-7.62 (m, 2H), 7.34 (s, 1H), 7.21 (s, 2H), 6.92 (br s, 1H), 5.50 (m, 2H), 3.84 (s, 3H), 3.83 (s, 3H), 2.77 (s, 3H). MS (ERI+, m/z 472 (m+1).

Example 99: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(methylsulphonyl)benzyl]oxy}thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 8.03 (d, J=7.8 Hz, 1H), 7.86-7.79 (m, 2H), 7.70-7.67 (m, 2H), 7.59 (s, 1H), 7.33 (s, 1H), 7.19 (s, 1H), 7.11 (br s, 1H), 5.79 (s, 2H), 3.82 (m, 6H), 3.34 (s, 3H). MS (ERI+, m/z 488 (m+1).

Example 100: 3-[(2-aminopyridine-4-yl)methoxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.91 (d, J=5.1 Hz, 1H), 7.76 (br s, 1H), 7.46 (s, 1H), 7.33 (s, 1H), 7.12 (s, 1H), 7.07 (br s, 1H), 6.56 (d, J=5.2 Hz, 1H), 6.49 (s, 1H) 6.03 (s, 2H), 5.31 (s, 2H), 3.82 (s, 3H), 3.81 (s, 3H). MS (ERI+, m/z 426 (m+1).

Example 101: 3-[(2-chloropyridin-3-yl)methoxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.45 (dd, J=4.8, 1.9 Hz, 1H), 8.43 (s, 1H), 8.11 (dd, J=7.7, 1.8 Hz, 1H), 7.75 (s, 1H), 7.66 (s, 1H), 7.53 (dd, J=7.4, 4.8 Hz, 1H), 7.34 (s, 1H), 7.21 (s, 1H), 7.00 (br s, 1H), 5.49 (s, 2H), 3.84 (s,, 3H), 3.83 (s, 3H). MS (ERI+, m/z 445 (m+1).

Example 102: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(2-herperidin-3-yl)methoxy]thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.28 (d, J=4.5 Hz, 1H), 8.19 (m, 1H), 7.87 (m, 1H), 7.67 (s, 1H), 7.45 (m, 1H),7.34 (s, 1H), 7.21 (s, 1H), 6.97 (br s, 1H), 5.49 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H). MS (ERI+, m/z 429 (m+1).

Example 103: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(2-vinylbenzyl)-oxy]thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.73-7.70 (m, 2H), 7.61 (m, 1H), 7.48-7.36 (m, 2H), 7.26 (s, 1H), 7.24-7.14 (m, 3H). 6.82 (br s, 1H), 5.87 (d, J=16.6 Hz, 1H), 5.54 (d, J=11.8 Hz, 1H), 5.54 (s, 2H), 3.88 (s, 3H), 3.86 (s, 3H). MS (ERI+, m/z 436 (m+1).

Example 104: 3-[{4-(aminocarbonyl)benzyl]oxy}-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.01 (br s, 1H), 7.93 (d, J=8.2 Hz, 2H), 7.76 (br s, 1H), 7.65 (d, J=8.2 Hz, 2H), 7.61 (s, 1H), 7.43 (br s, 1H), 7.36 (s, 1H), 7.16 (s, 1H), 7.12 (br s, 1H), 5.51 (s, 2H), 3.85 (m, 6H). MC (ERI+, m/z 453 (m+1).

Example 105: 3-[(2-acetylphenyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 8.05 (d, J=7.8 Hz, 1H), 7.72-7.64 (m, 2H), 7.59-7.55 (m, 2H), 7.35 (s, 1H), 7.17 (s, 1H), 7.17 (m, 2H), 5.66 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 2.65 (s, 3H). MC (ERI+, m/z 452 (m+1).

Example 106: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(2-ethynylphenyl)oxy]thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.72 (br s, 1H), 7.66-7.51 (m, 3H), 7.49-7.41 (m, 2H), 7.34 (s, 1H), 7.20 (s, 1H), 6.94 (br s, 1H), 5.50 (s, 2H), 4.54 (s, 1H), 3.85 (s, 3H), 3.83 (s, 3H). MC (ERI+, m/z 434 (m+1).

Example 107: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(triptoreline)benzyl]oxy}is iophen-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.76 (m, 2H), 7.65 (s, 1H), 7.56 (m, 1H), 7.50-7.46 (m, 2H), 7.34 (s, 1H), 7.22 (s, 1H), 6.86 (br s, 1H). 5.48 (s, 2H), 3.84 (s, 3H), 3.83 (s, 3H). MS (ERI+, m/z 494 (m+1).

Example 108: 3-{[2-(deformedarse)benzyl]oxy}-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.72 (br s, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.64,(s, 1H), 7.51-7.47 (m, 2H), 7.34 (s, 1H), 7.32-7.28 (m, 2H), 7.21 (s, 1H), 6.91 (br s, 1H), 5.43 (s, 2H), 3.84 (s, 3H). 3.83 (s, 3H). MS (ERI+, m/z 476 (m+1).

Example 109: 3-{[2-(1,2-dihydroxyethyl)benzyl]oxy}-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 1H), 7.64 (br s, 1H), 7.59 (s, 1H), 7.52 (d, J=7.5 Hz, 1H), 7.46 (d, J=7.3 Hz, 1H), 7.37 (m, 1H), 7.32-7.28 (m, 2H). 7.17 (s, 1H), 6.92 (br s, 1H), 5.49 (m, 2H), 5.35 (d, J=4.0 Hz, 1H), 4.87 (m, 1H), 4.81 (t, J=5.8 Hz, 1H), 3.98 (m, 1H), 3.80 (s, 6H), 3.53 (m, 1H). MS (ERI+, m/z 470 (m+1).

Example 110: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(2-formylmethyl)oxy]thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.41 (s, 1H), 8.02 (m, 1H), 7.73-7.64 (m, 4H), 7.58 (s, 1H), 7.34 (s, 1H), 7.15 (s, 1H), 7.02 (m, 1H), 5.81 (s, 2H), 3.82 (s, 3H), 3.81 (s, 3H), 2.65 (s, 3H). MS (ERI+, m/z 438 (m+1).

Example 111: 3-(cyclohexylmethoxy)-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.43 (s, 1H), 7.73 (br s, 1H), 755 (s, 1H), 7.34 (s, 1H), 7.25 (s, 1H), 6.89 (s, 1H), 4.13 (d, J=6.3 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 1.88-1.64 (m, 6H), 1.31-1.01 (m, 5H). MS (ERI+, m/z 416 (m+1).

Example 112: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-(tetrahydro-2H-Piran-2-ylethoxy)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.72 (br s, 1H), 7.53 (s, 1H), 7.33 (s, 1H), 7.25 (s, 1H), 7.09 (br s, 1H), 4.30 (dd, J=10.8, 3.2 Hz, 1H), 4.20 (dd, J=10.6, 6.9 Hz, 1H), 3.92 (d, J=11.1 Hz, 1H), 3.86 (s, 3H), 3.83 (s, 3H), 3.72 (m, 1H), 1.83 (m, 1H), 1.64 (d, J=13.1 Hz, 1H), 1.54-1.47 (m, 4H), 1.38 (m, 1H). MS (ERI+, m/z 418 (m+1).

Example 113: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-(2-morpholine-4-ylethoxy)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.41 (s, 1H), 7.75 (br s, 1H), 7.56 (s, 1H), 7.52 (br s, 1H), 7.34 (s, 1H), 7.25 (s, 1H), 4.38 (t, J=4.6 Hz, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.59 (m, 4H), 2.72 (t, J=6.7 Hz, 2H), 2.47 (m, 4H). MS (ERI+, m/z 433 (m+1).

Example 114: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-(2-phenylethane)-thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.64 (br s, 1H), 7.56 (s, 1H), 7.37-7.31 (m, 5H), 7.26-7.23 (m, 2H), 6.75 (br s, 1H), 4.53 (t, J=6.8 Hz, 2H), 3.85 (s, 3H), 3.82 (s, 3H), 3.15 (t, J=6.7 Hz, 2H). MS (ERI+, m/z 424 (m+1).

Example 115: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-(3-phenylpropoxy)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.70 (br s, 1H), 7.52 (s, 1H), 7.34 (s, 1H), 7.31-7.24 (m, 5H), 7.19 (m, 1H), 6.97 (br s, 1H), 4.31 (t, J=6.8 Hz, 2H), 3.83 (s, 3H), 3.83 (s, 3H), 2.76 (t, J=6.7 Hz, 2H), 2.13 (m, 2H). MS ERIE+, m/z 438 (m+1).

Example 116: 5-(1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]-oxy}thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.87-7.85 (m, 2H), 7.82-7.77 (m, 3H), 7.72-7.64 (m, 3H), 7.45-7.36 (m, 2H), 6.79 (br s, 1H), 5.56 (s, 2H). MS (ERI+, m/z 418 (m+1).

Example 117: 5-(1H-benzimidazole-1-yl)-3-[(2-nitrobenzyl)oxy]thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.19 (d, J=7.6 Hz, 1H), 7.84-7.62 (m, 7H), 7.41-7.35 (m, 2H), 7.05 (br s, 1H), 5.78 (s, 2H). MS (ERI+, m/z 395 (m+1).

Example 118: 5-(6-methoxy-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.87-7.61 (m, 7H), 7.21 (d, J=2.4 Hz, 1H), 6.98 (dd, J=8.9, 2.4 Hz, 1H), 6.81 (br s, 1H), 5.56 (s, 2H), 3.83 (s, 3H).

Example 119: 3-[(2-bromobenzyl)oxy]-5-[6-(trifluoromethyl)-1H-benzimidazole-1-yl]thiophene-2-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 8.86 (s, 1H), 8.05-7.99 (m, 2H), 7.83-7.67 (m, 5H), 7.47 (ddd, J=8.8, 7.5, 1.3 Hz, 1H), 7.37 (ddd, J=9.4, 7.6, 1.8 Hz, 1H), 6.95 (br s,1H), 5.46 (s, 2H).

Example 120: 3-[(3-bromopyridin-4-yl)methoxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 1H), 8.63 (d, J=5.0 Hz, 1H), 8.42 (s, 1H), 7.77 (br s, 1H), 7.62 (d, J=5.0 Hz, 1H), 7.59 (s, 1H). 7.33 (s, 1H), 7.19 (s, 1H), 7.08 (br s, 1H), 5.49 (s, 2H), 3.824 (s, 3H), 3.818 (s, 3H). MS (ERI+, m/z) 489, 491 (m+1).

Por the measures 121: 5-[6-(methylsulphonyl)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}-thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.93 (s, 1H), 8.24 (d, J=1.7 Hz, 1H), 8.05 (d, J=8.60 Hz, 1H), 7.92 (dd, J=8.4, 1.7 Hz, 1H), 7.89-7.77 (m, 5H), 7.65 (m, 1H), 6.84 (br s, 1H), 5.54 (s, 2H), 3.29 (s, 3H). MS (ERI+, m/z 496 (m+1).

Example 122: 5-{6-[(methylsulphonyl)amino]-1H-benzimidazole-1-yl}-3-{[2-(trifluoromethyl)benzyl]-oxy}thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 9.85 (s. 1H), 8.64 (s, 1H), 7.86 (d, J=7.9 Hz, 1H), 7.82-7.71 (m, 6H), 7.66 (m, 1H), 7.25 (dd, J=8.8, 2.0 Hz, 1H), 6.79 (br s, 1H), 5.52 (s, 2H), 2.98 (s, 3H).

Example 123: 5-(6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]-oxy}thiophene-2-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.87-7.74 (m, 3H), 7.70-7.61 (m, 2H), 7.60 (s, 1H), 7.25 (s, 1H), 7.24 (s, 1H), 6.76 (br s, 1H), 5.55 (s, 2H), 4.29 (m, 4H). MS (ERI+, m/z 476 (m+1).

Example 124: 5-(6,7-dihydro-1H-[1,4]like[2,3-f]benzimidazole-1-yl)-3-{[1-(methylsulphonyl)-piperidine-4-yl]methoxy}thiophene-2-carboxamide

1H NMR (300 MHz, DMSO-d6) δ 8.48 (s, 1H), 7.71 (br s, 1H), 7.51 (s, 1H), 7.27 (s, 1H), 7.23 (s, 1H), 6.87 (br s, 1H), 4.29 (br s, 4H), 4.21 (m, 2H), 3.60 (m, 2H), 2.85 (s, 3H), 2.74 (m, 2H), 2.08-1.81 (m, 3H), 1.36 (m, 2H). MS (ERI+, m/z 493 (m+1).

Example 125: 1-[5-(aminocarbonyl)-4-({[2-(trifluoromethyl)phenyl]methyl}-oxy)-2-thienyl]-1H-benzimidazole-5-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.36 (d, J=0.9 Hz, 1H), 8.10 (br s, 1H), 7.99 (dd, J8.6, the 1.4 Hz, 1H), 7.88-7.62 (m, 7H), 7.41 (br s, 1H), 6.80 (br s, 1H), 5.56 (s, 2H). MC (ERI+, m/z 461 (m+1).

Example 126: 3-[1-(2-chlorophenyl)ethoxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.83 (br s, 1H), 7.68 (dd, J=7.7, 2.0 Hz, 1H), 7.48 (dd, J=7.8, 1.2 Hz, 1H), 7.43 (ddd, J=7.5, 7.4, 1.2 Hz, 1H), 7.35 (ddd, J=7.8, 7.6, 1.8 Hz, 1H), 7.32 (s, 1H), 7.14 (br s, 1H), 7.13 (s, 1H), 7.02 (s, 1H), 6.01 (q, J=6.4 Hz, 1H), 3.81 (s, 3H), 3.79 (s, 3H), 1.72 (d, J=6.4 Hz, 3H). MC (ERI+, m/z 458 (m+1).

Example 127: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[1-(2-were)ethoxy]thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 7.96-7.92 (m, 1H), 7.84 (br s, 1H), 7.81-7.73 (m, 2H), 7.58-7.52 (m, 1H), 7.31 (s, 1H), 7.15 (br s, 1H), 7.05 (s, 1H), 7.01 (s, 1H), 6.01-5.96 (m, 1H), 3.81 (s, 3H), 3.78 (s, 3H), 1.75 (d, J=6.0 Hz, 3H). MC (ERI+, m/z 492 (m+1).

Example 128: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-([4-methoxybenzyl)oxy]thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.68 (br s, 1H), 7.60 (s, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.32 (s, 1H), 7.15 (s, 1H), 6.99 (br s, 1H), 6.95 (d, J=8.8 Hz, 2H), 5.32 (s, 2H), 3.83 (s, 3H), 3.81 (s, 3H), 3.74 (s, 3H). MS (ERI+, m/z 440 (m+1).

Intermediate example 1: methyl 5-(1H-benzimidazole-1-yl)-3-(phenylethynyl)-2-thiophenecarboxylate

Methyl-5-(1H-benzimidazole-1-yl)-3-{[(trifluoromethyl)sulfonyl]oxy}-2-thiophenecarboxylate (0,300 g; 0,738 mmol) was dissolved in 7 ml of N,N-dimethylformamide with stirring. EXT is ulali the triethylamine (0.21 in ml; 1.5 mmol) with a syringe. Added copper iodide(I) (0,0141 g; 0,0740 mmol), TRANS-dichlorobis(triphenylphosphine)palladium(II) (0,0258 g; 0,0368 mmol). Added phenylacetylene (0,12 ml; 1.1 mmol) via syringe and the mixture was heated up to 80°C for 16 hours. The mixture was cooled to room temperature and poured into ethyl acetate and water. The layers were separated and the organic layer was washed with salt solution. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum. Clean flash chromatographia gave 0,212 g (80%) of methyl-5-(1H-benzimidazole-1-yl)-3-(phenylethynyl)-2-thiophenecarboxylate.1H NMR (300 MHz, DMSO-d6) δ 8.76 (s, 1H), 7.85 (m, 2H), 7.80 (s, 1H), 7.64-7.58 (m, 2H), 7.52-7.35 (m, 5H), 3.92 (s, 3H). MS (ERI+, m/z 359 (m+1).

Example 129: 5-(1H-benzimidazole-1-yl)-3-(phenylethynyl)thiophene-2-caboxylic

5-(1H-Benzimidazole-1-yl)-3-(phenylethynyl)thiophene-2-carboxamide was obtained from methyl-5-(1H-benzimidazole-1-yl)-3-(phenylethynyl)-2-thiophenecarboxylate by the method similar to the method described in Example 61, except that used 7M NH3in the Meon instead 2M NH3in the Meon.1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.09 (br s, 1H), 7.85-7.80 (m, 2H), 7.72 (s, 1H), 7.67-7.63 (m, 2H), 7.53-7.36 (m, 6N). MS (ERI+, m/z 344 (m+1).

Intermediate example 2: methyl 5-(1H-benzimidazole-1-yl)-3-(2-phenylethyl)-2-Tiefeng rboxylic

Methyl-5-(1H-benzimidazole-1-yl)-3-(phenylethynyl)-2-thiophenecarboxylate (0,110 g; 0,307 mmol) was dissolved in 10 ml of ethyl acetate under stirring. Was added 10%palladium on coal (0,0327 g; 0,0307 mmol) and the reaction mixture was placed in an atmosphere of hydrogen at a pressure of 1 atmosphere (98 kPa) for 16 hours. The mixture was filtered through celite, washing with ethyl acetate. The filtrate was concentrated, allowing 0,109 g (98%) of methyl-5-(1H-benzimidazole-1-yl)-3-(2-phenylethyl)-2-thiophenecarboxylate.1H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 7.80 (d, J=7.5 Hz, 1H), 7.72 (d, J=7.2 Hz, 1H), 7.49 (s, 1H), 7.46-7.17 (m, 7H), 3.84 (s, 3H), 3.32 (m, 2H), 2.95 (m, 2H). MS (ERI+, m/z 363 (m+1).

Example 130: 5-(1H-benzimidazole-1-yl)-3-(2-phenylethyl)thiophene-2-carboxamide

5-(1H-Benzimidazole-1-yl)-3-(2-phenylethyl)thiophene-2-carboxamide was obtained from methyl-5-(1H-benzimidazole-1-yl)-3-(2-phenylethyl)-2-thiophenecarboxylate by the method similar to the method described in Example 61, except that used 7M NH3in the Meon instead 2M NH3in the Meon.1H NMR (300 MHz, DMSO-d6) δ 8.58 (s, 1H), 7.79 (d, J=7.3 Hz, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.56 (br s, 2H), 7.44-7.17 (m, 8H), 3.22 (m, 2H), 2.95 (m, 2H). MS (ERI+, m/z 348 (m+1).

Example 131: 5-(1H-benzimidazole-1-yl)-3-[methyl(phenyl)amino]thiophene-2-carboxamide

The compound was obtained according to the methods similar to the methods op the toboggan in Examples 31 and 61. 1H NMR (300 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.83-7.67 (m, 3H), 7.46-7.23 (m, 6H), 6.91-6.84 (m, 3H), 3.28 (s, 3H). MS (ERI+, m/z 349 (m+1).

Example 132: 5-(1H-benzimidazole-1-yl)-3-[(phenylsulfonyl)amino]-thiophene-2-carboxamide

The compound was obtained according to procedures similar to the procedures described in Example 32, except that used the sulfonamide instead of benzamide, and in Example 61.1H NMR (300 MHz, DMSO-d6) δ 11.40 (s, 1H), 8.75 (s, 1H), 7.95-7.90 (m, 3H), 7.88 (br s, 1H), 7.82 (m, 1H), 7.71 (m, 1H), 7.65-7.58 (m, 3H), 7.51 (s, 1H), 7.45 (m, 1H), 7.40 (m, 1H). MS (ERI+, m/z 399 (m+1).

Intermediate example 3: methyl-5-(1H-benzimidazole-1-yl)-3-({[(phenylmethyl)oxy]carbonyl}amino)-2-thiophenecarboxylate

Methyl-5-(1H-benzimidazole-1-yl)-3-{[(trifluoromethyl)sulfonyl]oxy}-2-thiophenecarboxylate (1,11 g; 2,73 mmol), cesium carbonate (1.25 g; of 3.84 mmol), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (0,0850 g; 0,137 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (0.0625 g; 0,0683 mmol) were combined in a reaction flask with 30 ml of toluene under stirring. Added benzylcarbamoyl (0,495 g; of 3.27 mmol) and the reaction mixture was heated to 100°C for 40 hours. The reaction mixture was cooled to room temperature, was directly adsorbing on silica gel and purified flash chromatography with getting 0,604 g (54%) of methyl-5-(1H-benzimidazole-1-yl)-3-({[(phenylmethyl)oxy]carbonyl}amino)-2-thiophenecarboxylate. 1H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 1H), 8.76 (s, 1H), 8.03 (s, 1H), 7.84-7.77 (m, 2H), 7.49-7.28 (m, 7H), 5.26 (s, 2H), 3.86 (s, 3H). MS (ERI+. m/z 408 (m+1).

Intermediate example 4: methyl 5-(1H-benzimidazole-1-yl)-3-({[(phenylmethyl)oxy]carbonyl}{[2-(trifluoromethyl)phenyl]methyl}amino)-2-thiophenecarboxylate

Methyl-5-(1H-benzimidazole-1-yl)-3-({[(phenylmethyl)oxy]carbonyl}-amino)-2-thiophenecarboxylate (0.400 g; 0,982 mmol) and cesium carbonate (1,02 g; 3,13 mmol) were placed with stirring in a flask with 12 ml of N,N-dimethylformamide. Was added 2-(trifluoromethyl)benzylbromide (0,704 g; 2,95 mmol) and the reaction mixture was stirred for 16 hours. The mixture was poured into water and ethyl acetate and the layers were separated. The organic layer is washed with brine and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum. Flash chromatography gave slightly polluted methyl-5-(1H-benzimidazole-1-yl)-3-({[(phenylmethyl)oxy]-carbonyl}{[2-(trifluoromethyl)phenyl]methyl}amino)-2-thiophenecarboxylate, which was directly transferred to the next stage. MS (ERI+, m/z 567 (m+1).

Intermediate example 5: 5-(1H-benzimidazole-1-yl)-3-({[(phenylmethyl)oxy]carbonyl}-{[2-(trifluoromethyl)phenyl]methyl}amino)-2-thiencarbazone acid

Methyl-5-(1H-benzimidazole-1-yl)-3-({[(phenylmethyl)oxy]carbonyl}{[2-(reformer)phenyl]methyl}amino)-2-thiophenecarboxylate (0,555 g; 0,982 mmol) was dissolved with stirring in 10 ml of tetrahydrofuran. Added 10 ml of 1 n LiOH solution and the mixture was left to mix for 16 hours. The mixture was poured into diethyl ether and water and the layers were separated. The organic layer was washed with water and a layer of diethyl ether was then discarded. The combined aqueous layers were acidified to pH about 2 with concentrated HCl and was extracted three times with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum to obtain 0,528 g (97%) of 5-(1H-benzimidazole-1-yl)-3-({[(phenylmethyl)oxy]carbonyl}{[2-(trifluoromethyl)phenyl]methyl}amino)-2-thiophencarboxylic acid in the form of not-quite-white solid.1H NMR (400 MHz, DMSO-d6) δ 13.60 (br s, 1H), 8.58 (s, 1H), 7.85 (d, J=7.7 Hz, 1H), 7.76 (d, J=7.0 Hz, 1H), 7.70 (d, J=7.7 Hz, 1H), 7.65 (dd, J=7.7, 7.7 Hz, 1H), 7.54-7.43 (m, 4H), 7.41-7.24 (m, 6H), 5.14 (s, 2H), 5.14 (s, 2H,). MS (ERI+, m/z 552 (m+1).

Intermediate example 6: benzyl-2-(aminocarbonyl)-5-(1H-benzimidazole-1-yl)Tien-3-yl-[2-(trifluoromethyl)-benzyl]carbamate

5-(1H-Benzimidazole-1-yl)-3-({[(phenylmethyl)oxy]carbonyl}{[2-(trifluoromethyl)phenyl]methyl}amino)-2-thiencarbazone acid (0,200 g; 0,363 mmol) and ammonium chloride (0,0388 g; 0,725 mmol) was added under stirring in a flask with 5 ml of N,N-dimethylformamide. Was added N-methylmorpholine (0,080 ml, 0.73 mmol) via syringe. Was added 1-hydroxybenzene the evils (0,0981 g; 0,726 mmol)and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0,0974 g, 0.508 mmol). The mixture was stirred for 16 hours and poured into ethyl acetate and 1N. HCl. The layers were separated and the organic layer was washed with salt solution. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum. Purification with flash chromatography gave 0,171 g (86%) of benzyl-2-(aminocarbonyl)-5-(1H-benzimidazole-1-yl)Tien-3-yl-[2-(trifluoromethyl)-benzyl]carbamate in the form of not-quite-white solid.1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 7.85-7.75 (m, 2H), 7.75-7.69 (m, 3H), 7.66 (dd, J=7.4, 7.4 Hz, 1H), 7.50 (dd, J=7.5, 7.5 Hz, 1H), 7.47-7.27 (m, 9H), 5.16 (s, 2H), 5.11 (br s, 2H). MS (ERI+, m/z 551 (m+1).

Example 133: 5-(1H-benzimidazole-1-yl)-3-[[2-(trifluoromethyl)benzyl]-amino}-thiophene-2-carboxamide

Phenylmethyl-[2-(aminocarbonyl)-5-(1H-benzimidazole-1-yl)-3-thienyl]{[2-(trifluoromethyl)phenyl]methyl}carbamate (of) 0.157 g; 0,285 mmol) was dissolved with stirring in 10 ml of ethyl acetate. Was added 10%palladium on coal (0,0606 g; 0,0570 mmol) and the solution was placed in an atmosphere of hydrogen at a pressure of 1 atmosphere (98 kPa). The reaction mixture was stirred for 48 hours and was convinced that the reaction was not complete. The reaction mixture was filtered through a layer of celite and washed with ethyl acetate. The filtrate was concentrated in vacuum and purified flash chromatography with getting 0,0257 g (22%) of pure product and 0,112 mg of a mixture of educt and product. 1H NMR (400 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.16 (dd, J=6.6, 6.6 Hz, 1H), 7.81-7.74 (m, 2H), 7.73-7.67 (m, 2H), 7.64 (d, J=7.7 Hz, 1H), 7.50 (dd, J=7.5, 7.5 Hz, 1H), 7.43-7.33 (m, 2H), 7.19 (s, 1H), 7.14 (br s, 2H), 4.71 (d, J=6.2 Hz, 2H). MS (ERI+, m/z 417 (m+1).

Intermediate example 7: 2-(metiloksi)-5-nitrophenyl 2,2-dimethylpropanoate

Commercially available 2-methoxy-5-NITROPHENOL (10.0 g; 59,1 mmol) was dissolved in 150 ml of dichloromethane with 4-dimethylaminopyridine (0,722 g; 5,91 mmol). Was added triethylamine (9,88 ml; for 70.9 mmol) via syringe. Slowly with a syringe was added pivaloate (8,01 ml; 65,0 mmol). The reaction mixture was stirred for ten minutes and was poured into 1 N. HCl. The layers were separated and the aqueous layer washed with dichloromethane. The combined organic layers were washed with saturated NaHCO3and a salt solution. The organic layers were dried over MgSO4, filtered and concentrated in vacuum. The selected solid is triturated with hexane, was filtered, washed with hexane and 2-methylbutane. The solid was air-dried and collected with the receipt of 13.0 g (87%) of 2-(metiloksi)-5-nitrophenyl 2,2-dimethylpropanoate.1H NMR (400 MHz, CDCl3) δ 8.16 (dd, J=9.2, 2.8 Hz, 1H), 7.95 (d, J=2.8 Hz, 1H), 7.01 (d, J=9.2 Hz, 1H), 3.92 (s, 3H), 1.38 (s, 9H).

Intermediate example 8: 5-amino-2-(metiloksi)phenyl,2-dimethylpropanoate

2-(Metiloksi)-5-nitrophenyl,2-DIMETHYLPROPANE the (13,0 g; 51,4 mmol) was dissolved with stirring in 150 ml of ethyl acetate. Was added 10%palladium on coal (1.64 g; 1.54 mmol) and the solution was stirred in hydrogen atmosphere at a pressure of 1 atmosphere (98 kPa) for 16 hours. The reaction mixture was filtered through celite and well washed with ethyl acetate. The filtrate was concentrated in vacuum to obtain 11.3 g (98%) of 5-amino-2-(metiloksi)phenyl,2-dimethylpropanoate in a solid pink color.1H NMR (400 MHz, CDCl3) δ 6.80 (d, J=8.6 Hz, 1H), 6.55 (dd, J=8.6, 2.8 Hz, 1H), 6.45 (d, J=2.8 Hz, 1H), 3.73 (s, 3H), 1.35 (s, 9H).

Intermediate example 9: 2-(metiloksi)-4-nitro-5-[(TRIFLUOROACETYL)amino]phenyl,2-dimethylpropanoate

5-Amino-2-(metiloksi)phenyl,2-dimethylpropanoate (10,53 g; 47,1 mmol) was dissolved with stirring in 200 ml of chloroform. One portion was added ammonium nitrate (6,79 g; 84,8 mmol). The mixture was cooled to 0°and dropwise via the dropping funnel over 1 hour was added triperoxonane anhydride (36 ml, 260 mmol). The reaction mixture was heated to room temperature and was stirred for another six hours. The reaction mixture was suppressed by careful addition of 100 ml saturated NaHCO3and was stirred for 15 minutes. The mixture was poured into a separating funnel and the layers were separated. The aqueous layer was washed with dichloromethane. The combined organic layers were dried over MgSO4Phil is trevali and concentrated in vacuum to obtain 16.5 g (96%) of 2-(metiloksi)-4-nitro-5-[(TRIFLUOROACETYL)amino]phenyl,2-dimethylpropanoate in a solid yellow color. 1H NMR (400 MHz, CDCl3) δ 11.36 (br s, 1H), 8.49 (s, 1H), 7.84 (s, 1H), 3.91 (s, 3H), 1.38 (s, 9H).

Intermediate example 10: 5-amino-2-(metiloksi)-4-NITROPHENOL

2-(Metiloksi)-4-nitro-5-[(TRIFLUOROACETYL)amino]phenyl,2-dimethylpropanoate (16.5 g; 45,2 mmol) was dissolved with stirring in 200 ml of methanol and 200 ml of water. Was added potassium carbonate (31,2 g, 226 mmol) and the solution was stirred for sixteen hours at room temperature. At this point convinced that the reaction was not until the end, and the reaction mixture was heated to the temperature of reflux distilled for two hours. The mixture was cooled to room temperature and most of the methanol was removed in vacuum. Added ethyl acetate and the pH of the solution was brought to about 7 using concentrated HCl. The layers were separated and the organic layer was washed with salt solution. The combined aqueous layers were saturated with NaCl, then extracted with ethyl acetate (2x) and 20% isopropanol in ethyl acetate (4x). The combined organic extracts were dried over MgSO4, filtered and concentrated in vacuum. The selected solid is triturated with diethyl ether, filtered and washed with diethyl ether and 2-methylbutane. Solid orange color was air-dried and collected with getting to 7.15 g (86%) of 5-amino-2-(metiloksi)-4-NITROPHENOL.1H NMR (400 MHz, CDCl3) δ 10.66 (b s, 1H), 7.36 (br s, 2H), 7.32 (s, 1H), 6.36 (s, 1H), 3.73 (s, 3H). MS (ERI+, m/z 185 (m+1).

Intermediate example 11: 5-{[(1,1-dimethylethyl)(diphenyl)-silyl]oxy}-4-(metiloksi)-2-nitroaniline

5-Amino-2-(metiloksi)-4-NITROPHENOL (6,90 g; 37.5 mmol) was dissolved with stirring in 100 ml of acetonitrile. Was added triethylamine (6.30 ml; 45,2 mmol) via syringe. Slowly with a syringe was added tert-butylchloroformate (9.75 ml; 37.5 mmol). The reaction mixture was stirred for 2 hours and was convinced that the reaction was not complete. With a syringe was added an additional amount of triethylamine (of 1.57 ml, 11.3 mmol) and tert-butylchloroformate (2,94 ml, 11.3 mmol). The reaction mixture was additionally stirred for 15 minutes and poured into ethyl acetate and 1 N. NaOH. The layers were separated and the organic layer was washed with salt solution. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum. The selected substance was passed through a layer of silica gel and the fractions containing the product were concentrated. Dedicated viscous oil was a mixture of unidentified silyl products and 5-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4-(metiloksi)-2-nitroaniline. The output is not determined and the crude substance is transferred to the next stage. MS (IS RI+, m/z 423 (m+1).

Intermediate example 12: [5-{[(1,1-dimethylethyl)(diphenyl)-silyl]oxy}-4-(metiloksi)-2-nitrophenyl]formamide

Acetic anhydride (17,7 ml, 188 mmol) slowly with stirring was added to formic acid (14.1 ml; 374 mmol). The mixture was placed in an oil bath at 50°With one hour. After cooling to room temperature the crude substance containing 5-([(1,1-dimethylethyl)(diphenyl)-silyl]oxy}-4-(metiloksi)-2-nitroaniline was dissolved in 100 ml of dichloromethane and was added to the reaction mixture. The reaction mixture was left to mix for 14 hours and extinguished, carefully adding 100 ml of water. The reaction mixture was slowly poured into saturated NaHCO3and dichloromethane. The layers were separated and the aqueous layer washed with dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to obtain the crude substance containing [5-{[(1,1-dimethylethyl)(diphenyl)-silyl]oxy}-4-(metiloksi)-2-nitrophenyl]formamide. The output is not determined and the crude substance is transferred to the next stage. MS (ERI+, m/z 451 (m+1).

Intermediate example 13: [2-amino-5-{[(1,1-dimethylethyl)-(diphenyl)silyl]oxy}-(metiloksi)phenyl]-formamide

The crude substance containing [5-{[(1,1-dimethylethyl)(diphenyl)-silyl]oxy}-4-(metiloksi)-2-nitrophenyl]formamide, dissolved the under stirring in 200 ml of ethyl acetate. Was added 10%palladium on coal (1.20 g; 1.13 mmol) and the mixture was placed in an atmosphere of hydrogen at a pressure of 1 Atmosfera (98 kPa) for 24 hours. The reaction mixture was filtered through celite, washing with ethyl acetate and chloroform. The filtrate was concentrated in vacuo to obtain the crude substance containing [2-amino-5-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-4-(metiloksi)phenyl]-formamide. The output is not determined and the crude substance is transferred to the next stage. MS (ERI+, m/z 421 (m+1).

Intermediate example 14: 5-{[(1,1-dimethylethyl)(diphenyl)-silyl]oxy}-6-(metiloksi)-1H-benzimidazole

The crude substance containing [2-amino-5-{[(1,1-dimethylethyl)-(diphenyl)-silyl]oxy}-4-(metiloksi)phenyl]-formamide, was dissolved with stirring in 200 ml of chloroform. Added magnesium sulfate (13,54 g, 112 mmol) in one portion. Added pyridinium paratoluenesulfonyl (11.3 g; 45,0 mmol) and the reaction mixture was left to mix for 16 hours. Making sure that the reaction was not until the end, the mixture was additionally heated to a temperature of 40-50°C for 8 hours. The reaction mixture was cooled to room temperature and was added solid NaHCO3(10 g). The mixture was stirred for 30 minutes and filtered to remove all solids. The filtrate was concentrated to a final volume of approximately 100-200 ml, and at this point about what went formation of significant quantities of solids. Was added 200 ml of diethyl ether and hexanol (1:1) and this mixture was filtered. The solid is washed with hexane and 2-methylbutane. The solid was air-dried, collected and determined that it is tonilou salt (toilet) of the target product. This solid was placed in a separating funnel with 1 N. NaOH and was extracted twice with isopropanol in dichloromethane (1:4). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum to obtain 7,80 g (52% over 4 steps) of 5-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-6-(metiloksi)-1H-benzimidazole.1H NMR (400 MHz, DMSO-d6) δ 12.00 (br s, 1H), 7.93 (s, 1H), 7.72-7.67 (m, 4H), 7.49-7.39 (m, 6H), 7.07 (s, 1H), 6.78 (s, 1H), 3.65 (s, 3H), 1.07 (s, 9H). MS (ERI+, m/z 403 (m+1).

Intermediate example 15: methyl-5-[6-{[(1,1-dimethylethyl)-(diphenyl)silyl]oxy}-5-(metiloksi)-1H-benzimidazole-1-yl]-3-hydroxy-2-thiophenecarboxylate and methyl-5-[5-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-6-(metiloksi)-1H-benzimidazole-1-yl-3-hydroxy-2-thiophenecarboxylate

and

5-{[(1,1-Dimethylethyl)(diphenyl)silyl]oxy}-6-(metiloksi)-1H-benzimidazole (4.12 g; 10.2 mmol) was dissolved with stirring in 50 ml of chloroform. Was added methyl 2-chloro-3-oxo-2,3-dihydro-2-thiophenecarboxylate (0,982 g; 5,10 mmol) in one portion. The reaction mixture was left to mix for 5 days. Added 50 ml of the odes and the pH was brought to about 6-7, using saturated NaHCO3. The layers were separated and the aqueous layer was extracted with dichloromethane (1x) and ethyl acetate (1x). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum. The residue was purified flash chromatography with receipt of 2.40 g (84%) of the regioisomeric mixture of 1,2-1,4:1 methyl-5-[6-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-5-(metiloksi)-1H-benzimidazole-1-yl]-3-hydroxy-2-thiophenecarboxylate and methyl-5-[5-{[(1,1-dimethylethyl)(diphenyl)-silyl]oxy}-6-(metiloksi)-1H-benzimidazole-1-yl]-3-hydroxy-2-thiophenecarboxylate.1H NMR (300 MHz, DMSO-d6) δ 10.84, 10.74 (br s, 1H), 8.50, 8.42 (s, 1H), 7.76-7.69 (m, 4H), 7.54-7.41 (m, 6H), 7.36, 7.23 (s, 1H), 7.13, 7.00 (s, 1H), 6.93, 6.91 (s, 1H), 3.86, 3.82 (s, 3H), 3.744, 3.737 (s, 3H), 1.12, 1.11 (s, 9H). MC (3PM+, m/z 403 (m+1).

Intermediate example 16: methyl-5-[6-{(1,1-dimethylethyl)-(diphenyl)silyl]oxy}-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate and methyl-5-[5-{[(1,1-dimethylethyl](diphenyl)silyl]oxy}-6-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate

and

Regioisomeric mixture of methyl 5-[6-{[(1,1-dimethylethyl)(diphenyl)silyl]-oxy}-5-(metiloksi)-1H-benzimidazole-1-yl]-3-hydroxy-2-thiophenecarboxylate and methyl-5-[5-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-6-(metiloksi)-1H-benzimidazole-1-yl]-3-hydroxy-2-thiophenecarboxylate (of 3.97 g; 7,11 mmol was dissolved in stirring in 40 ml of N,N-dimethylformamide. Was added potassium carbonate (1.18 g; 8,54 mmol) in one portion. Was added 2-(trifluoromethyl)benzylbromide (2,04 g; 8,53 mmol) in one portion. The reaction mixture was left to mix for 16 hours and was poured into water and ethyl acetate. The layers were separated and the organic layer was washed with salt solution. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum. Purification with flash chromatography gave 2.65 g (52%) of methyl-5-[5-{[(1,1-dimethylethyl)(diphenyl)-silyl]oxy}-6-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]-methyl}oxy)-2-thiophenecarboxylate and 2.13 g (42%) of methyl 5-[6-{[(1,1-dimethylethyl)(diphenyl)-silyl]oxy}-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]-methyl}oxy)-2-thiophenecarboxylate. Data for (5-OTBDPS, 6-OMe):1H NMR (300 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.98 (d, J=7.4 Hz, 1H), 7.88-7.60 (m, 8H), 7.55-7.42 (m, 6H), 7.25 (s, 1H), 6.94 (s, 1H), 5.54 (s, 2H), 3.81 (s, 3H), 3.73 (s, 3H), 1.11 (s, 9H). MS (ERI+, m/z 717 (m+1). Data for (5-OMe, 6-OTBDPS):1H NMR (300 MHz, DMSO-d6) δ 8.57 (s, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.88-7.79 (m, 2H), 7.76-7.61 (m, 5H), 7.56 (s, 1H), 7.51-7.41 (m, 6H), 7.37 (s, 1H), 7.05 (s, 1H), 5.43 (s, 2H), 3.84 (s, 3H), 3.74 (s, 3H), 1.12 (s, 9H). MS (ERI+, m/z 717 (m+1).

Intermediate example 17: methyl-5-[5-hydroxy-6-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-tipinterracial

Methyl-5-[5-{[(1,1-dimethylethyl)(di is enyl)-silyl]oxy}-6-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]-methyl}oxy)-2-thiophenecarboxylate (1.54 g; of 2.15 mmol) was dissolved in 20 ml of tetrahydrofuran under stirring. The solution was cooled to 0°and slowly with a syringe was added tetrabutylammonium (3,20 ml; 1.0m in THF (tetrahydrofuran); 3,20 mmol). The reaction mixture was stirred for ten minutes and extinguished by adding 50 ml of 0.5 n HCl. The mixture was poured into ethyl acetate and the layers were separated. The organic layer is washed with brine and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum. Purification with flash chromatography gave 0,761 g (74%) of methyl-5-[5-hydroxy-6-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]-methyl}oxy)-2-thiophenecarboxylate as not quite white solid.1H NMR (400 MHz, DMSO-d6) δ 9.07 (s, 1H), 8.47 (s, 1H), 7.96 (d, J=7.9 Hz, 1H), 7.84-7.76 (m, 2H), 7.65 (s, 1H), 7.62 (dd, J=7.9. 7.7 Hz. 1H), 7.24 (s, 1H), 7.13 (s, 1H), 5.53 (s, 2H), 3.86 (s, 3H), 3.78 (s, 3H).

The intermediate case 18: methyl-5-[6-hydroxy-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate

This compound was obtained in a manner analogous to the method described previously for the synthesis of methyl-5-[5-hydroxy-6-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]-methyl}oxy)-2-thiophenecarboxylate. The interaction of methyl-5-[6-{[(1,1-dimethylethyl)-(diphenyl)silyl]oxy}-5-(METI is hydroxy)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate (3,22 g; of 4.49 mmol) tetrabutylammonium (6,74 ml; 1.0m in THF; 6,74 mmol) resulted in the receipt of 1.76 g (82%) of methyl 5-[6-hydroxy-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)-phenyl]methyl}oxy)-2-thiophenecarboxylate in the form of a solid pale yellow color.1H NMR (400 MHz, DMSO-d6) δ 8.72 (s, 1H), 7.98 (d, J=7.7 Hz, 1H), 7.85-7.77 (m, 2H), 7.72 (s, 1H), 7.62 (dd, J=7.9, 7.7 Hz, 1H), 7.32 (s, 1H), 7.30 (s, 1H), 5.50 (s, 2H), 3.86 (s, 3H), 3.78 (s, 3H).

Intermediate example 19: 5-{[(1,1-dimethylethyl)(diphenyl)-silyl]oxy}-1H-benzimidazole

This compound was obtained in four steps from commercially available 4-amino-3-NITROPHENOL by method similar to the procedure described for the synthesis of 5-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-6-(metiloksi)-1H-benzimidazole.1H NMR (400 MHz, DMSO-d6) δ 12.15 (br s, 1H), 8.03 (s, 1H), 7.74-7.67 (m, 4H), 7.51-7.39 (m, 6H), 7.37 (d, J=8.6 Hz, 1H), 6.81 (d, J=2.2 Hz, 1H), 6.75 (dd, J=8.6, 2.2 Hz, 1H), 1.05 (s, 9H). MS (ERI+, m/z 373 (m+1).

Intermediate example 20: methyl-5-(6-{[(1,1-dimethylethyl)-(diphenyl)silyl]oxy}-1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate and methyl-5-(5-{[(1,1-dimethylethyl]diphenyl)silyl]oxy)-1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate

and

5-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-6-(metiloksi)-1H-benzimidazole (9,43 g; to 25.3 mmol) was dissolved in 125 ml of chloroform with stirring. Was added methyl-2 the PRS-3-oxo-2,3-dihydro-2-thiophenecarboxylate (2,44 g; 12.7 mmol) in one portion. The reaction mixture was left to mix for 10 days. Added 100 ml of water and the pH was brought to about 6-7 using saturated NaHCO3. The layers were separated and the aqueous layer was extracted with dichloromethane (1X) and ethyl acetate (1x). The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum. The residue was purified flash chromatography with receipt of 5.48 g (82%) of the regioisomeric mixture of (1,0-1,1:1) methyl-5-(6-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate and methyl-5-(5-{[(1,1-dimethylethyl)-(diphenyl)silyl]oxy}-1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate.1H NMR (300 MHz, DMSO-d6) δ 10.85, 10.78 (br s, 1H), 8.59, 8.54 (s, 1H), 7.78-7.70 (m, 4H), 7.64, 7.60 (dd, J=8.8, 0.6 Hz and d, J=8.8 Hz, 1H), 7.56-7.43 (m, 6H), 7.10, 6.96 (s, 1H), 7.05-6.88 (m, 2H), 3.85, 3.81 (s, 3H), 1.11, 1.09 (s, 9H). MS (ERI+, m/z 529 (m+1).

Intermediate example 21: methyl-5-(6-{[(1,1-dimethylethyl)-(diphenyl)silyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]-methyl}oxy)-2-thiophenecarboxylate and methyl-5-(5-{[((1,1-dimethylethyl)(diphenyl)-silyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate

and

Polystyrene-triphenylphosphine (9,84 g; 1,58 mmol/gram; a 15.5 mmol) was stirred in 100 ml of dichloromethane within ten minutes. Added a regioisomeric mixture of methyl-5-6-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate and methyl-5-(5-{[(1,1-dimethylethyl)-(diphenyl)silyl]oxy}-1H-benzimidazole-1-yl)-3-hydroxy-2-thiophenecarboxylate (5,48 g; 10.4 mmol) in one portion. Was added 2-(trifluoromethyl)benzyl alcohol (1,68 ml; 12.6 mmol) via syringe and the solution was cooled to 0°C. Di-tert-butyl-azodicarboxylate (3.58 g; a 15.5 mmol) was dissolved in 20 ml dichloromethane and added dropwise via addition funnel. The reaction mixture was heated to room temperature and was stirred for 1.5 hours. The mixture was filtered through filter paper and the solid is washed with dichloromethane and methanol. The filtrate was concentrated and purified flash chromatography with getting 2,89 g (41%) of methyl-5-(5-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate and 2,69 g (38%) of methyl-5-(6-{[(1,1-dimethylethyl)(diphenyl)silyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate. Data for 5-OTBDPS of regioisomer:1H NMR (300 MHz, DMSO-d6) δ 8.66 (s, 1H), 7.98 (d, J=7.6 Hz, 1H), 7.86-7.60 (m, 9H), 7.56-7.44 (m, 6N), 7.01 (s, 1H), 6.99 (dd, J=6.7, 2.4 Hz, 1H), 5.51 (s, 2H), 3.79 (s, 3H), 1.10 (s, 9H). MS (ERI+, m/z 687 (m+1). Data for 6-OTBDPS of regioisomer:1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.99 (d, J=7.6 Hz, 1H), 7.87-7.57 (m, 9H), 7.54-7.42 (m, 6H), 7.07 (d, J=2.0 Hz, 1H), 6.92 (dd, J=8.8, 2.3 Hz, 1H), 5.46 (s, 2H), 3.84 (s, 3H), 1.11 (s, 9H). MS (ERI+, m/z 687 (m+1).

Intermediate example 22: methyl-5-(6-hydroxy-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)-phenyl]methyl}oxy)-2-thiophenecarboxylate

This connection is Addendum was received by way similar to the method described previously for the synthesis of methyl-5-[5-hydroxy-6-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]-methyl}oxy)-2-thiophenecarboxylate. The interaction of methyl-5-(6-{[(1,1-dimethylethyl)-(diphenyl)silyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)-phenyl]-methyl}oxy)-2-thiophenecarboxylate (2,69 g; to 3.92 mmol) tetrabutylammonium (5,9 ml; 1.0m in THF; 5.9 mmol) resulted in the receipt of 1.42 g (81%) of methyl-5-(6-hydroxy-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)-phenyl]methyl}-oxy)-2-thiophenecarboxylate as not quite white solid.1H NMR (300 MHz, DMSO-d6) δ 9.72 (s, 1H), 8.60 (s, 1H), 8.01 (d, J=7.7 Hz, 1H), 7.89-7.79 (m, 2H), 7.75 (s, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 7.27 (d, J=1.8 Hz, 1H), 6.87 (dd, J=8.7, 2.2 Hz, 1H), 5.53 (s, 2H), 3.81 (s, 3H).

Intermediate example 23: methyl-5-(5-hydroxy-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)-phenyl]methyl}oxy)-2-thiophenecarboxylate

This compound was obtained in a manner analogous to the method described previously for the synthesis of methyl-5-[5-hydroxy-6-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]-methyl}oxy)-2-thiophenecarboxylate. The interaction of methyl-5-(5-{[(1,1-dimethylethyl)-(diphenyl)silyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)-phenyl]-methyl}oxy)-2-thiophenecarboxylate (2,89 g; is 4.21 mmol) tetrabutylammonium (6.3 ml; 1.0m in THF; 6.3 mmol) resulted in the receipt of 1.56 g (83%) of methyl-5-(5-hydroxy-H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)-phenyl]methyl}-oxy)-2-thiophenecarboxylate as not quite white solid. 1H NMR (400 MHz, DMSO-d6) δ 9.46 (s, 1H), 8.64 (s, 1H), 7.97 (d, J=7.0 Hz, 1H), 7.86-7.76 (m, 2H), 7.72-7.59 (m, 3H), 7.09 (s, 1H), 6.92 (d, J=8.1 Hz, 1H), 5.51 (s, 2H), 3.77 (s, 3H).

Intermediate example 24: methyl-5-(6-(metiloksi)-5-{[3-(2-oxo-1-pyrrolidinyl)propyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate

Polystyrene-triphenylphosphine (0,397 g; 1,58 mmol/g; 0,627 mmol) were placed in a flask with 6 ml dichloromethane and stirred for 5 minutes. Was added 5-[5-hydroxy-6-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate (0,150 g; 0,314 mmol) in one portion. Was added 1-(3-hydroxypropyl)pyrrolidine (0,059 ml; 0,412 mmol) via syringe and the mixture was cooled to 0°C. Di-tert-butyl-azodicarboxylate (0,144 g; of 0.625 mmol) was dissolved in 1 ml dichloromethane and added dropwise with a syringe. The reaction mixture was heated to room temperature and was stirred for 1.5 hours. The reaction mixture was filtered through filter paper and washed with dichloromethane and methanol. The filtrate was concentrated in vacuo, and purified flash chromatography with getting 0.152 g (80%) of methyl-5-(6-(metiloksi)-5-{[3-(2-oxo-1-pyrrolidinyl)propyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate.1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.97 (d, J=7.9 Hz, 1H), 7.84-7.77 (m, 2H), 7.68 (s, 1H), 7.62(dd, J=7.3, 7.3 Hz, 1H), 7.34 (s, 1H), 7.28 (s, 1H), 5.54 (s, 2H), 4.02 (t, J=6.3 Hz, 2H), 3.86 (s, 3H), 3.79 (s, 3H), 3.41-3.29 (m, 4H), 2.21 (t, J=8.1 Hz, 2H), 1.99-1.88 (m, 4H). MS (ERI+, m/z 604 (m+1).

Example 134: 5-(6-(metiloksi)-5-{[3-(2-oxo-1-pyrrolidinyl)propyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophencarboxylic

5-(6-(Metiloksi)-5-{[3-(2-oxo-1-pyrrolidinyl)propyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophencarboxylic was obtained from methyl 5-(6-(metiloksi)-5-{[3-(2-oxo-1-pyrrolidinyl)propyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)-phenyl]methyl}oxy)-2-thiophenecarboxylate by the method similar to the method described in Example 61, except that used 7M NH3in the Meon instead 2M NH3in the Meon.1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.86-7.60 (m, 5H), 7.59 (s, 1H), 7.30 (s, 1H), 7.20 (s, 1H), 6.80 (br s, 1H), 5.54 (s, 2H), 3.99 (t, J=6.2 Hz, 2H), 3.82 (s, 3H), 3.39-3.28 (m, 4H), 2.18 (t, J=8.1 Hz, 2H), 1.97-1.85 (m, 4H). MS (ERI+, m/z 549 (m+1).

Intermediate example 25: methyl-5-[6-{[3-(dimethylamino)propyl}oxy-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate

Methyl-5-[6-hydroxy-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)-phenyl]methyl}oxy)-2-thiophenecarboxylate (0,150 g; 0,313 mmol) and triphenylphosphine (0,361 g; 1.38 mmol) was stirred in 6 ml of dichloromethane. Added 3-dimethylamino-1-propanol (0,13 ml; 1 mmol) via syringe and the solution was cooled to 0° C. dropwise with a syringe was added diethyl-azodicarboxylate (0,12 ml; from 0.76 mmol)and the solution was heated to room temperature. After 3 hours the reaction mixture was suppressed by adding 2-3 ml of methanol. The reaction mixture was absorbed directly onto silica gel and purification with flash chromatography gave 0,112 g (63%) of methyl 5-[6-{[3-(dimethylamino)propyl]oxy}-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate.1H NMR (400 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.97 (d, J=7.7 Hz, 1H), 7.84-7.77 (m, 2H), 7.67 (s, 1H), 7.62 (dd, J=7.5, 7.5 Hz, 1H), 7.35 (s, 1H), 7.29 (s, 1H), 5.53 (s, 2H), 4.06 (t, J=6.4 Hz, 2H), 3.84 (s, 3H), 3.79 (s, 3H), 2.47 (t, J=7.0 Hz, 2H), 2.21 (s, 6N), 1.91 (m, 2H). MS (ERI+, m/z 564 (m+1).

Example 135: 5-[6-{[3-(dimethylamino)propyl]oxy}-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophencarboxylic

5-[6-{[3-(Dimethylamino)propyl]oxy}-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophencarboxylic was obtained from methyl 5-[6-{[3-(dimethylamino)propyl]oxy}-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate by the method similar to the method described in Example 61, except that used 7M NH3in the Meon instead 2M NH3in the Meon.1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.88-7.60 (m, 5H), 7.59 (s, 1H), 7.32 (s, 1H), 7.20 (s, 1H), 6.8 (br s, 1H), 5.53 (s, 2H), 4.02 (t, J=6.3 Hz, 2H), .81 (s, 3H), 2.35 (t, J=7.0 Hz, 2H), 2.11 (s, 6H), 1.86 (m, 2H). MS (ERI+, m/z 549 (m+1).

Intermediate example 26: methyl-5-[6-[(2-chloroethyl)oxy]-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate

This compound was obtained in a manner analogous to the method described previously for the synthesis of methyl-5-[6-{[3-(dimethylamino)propyl]oxy}-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate. The interaction of methyl-5-[6-hydroxy-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)-phenyl]methyl}oxy)-2-thiophenecarboxylate (0,150 g; 0,313 mmol), triphenylphosphine (0,740 g; 2.82 mmol), 2-chloroethanol (0,13 ml, 1.9 mmol) and diethyl-azodicarboxylate (0.25 ml; 1.6 mmol) led to 0,117 g (69%) of methyl 5-[6-[(2-chloroethyl)oxy]-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]-methyl}oxy)-2-thiophenecarboxylate.1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.95 (d, J=7.7 Hz, 1H), 7.83-7.75 (m, 2H), 7.67 (s, 1H), 7.60 (dd, J=7.9, 7.7 Hz, 1H), 7.37 (s, 1H), 7.31 (s, 1H), 5.51 (s, 2H), 4.30 (t, J=5.1 Hz, 2H), 3.97 (t, J=5.1 Hz, 2H), 3.84 (s, 3H), 3.77 (s, 3H). MS (ERI+, m/z 541 (m+1).

Intermediate example 27: 5-[6-[(2-chloroethyl)oxy]-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiencarbazone acid

Methyl-5-[6-[(2-chloroethyl)oxy]-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]-methyl}oxy)-2-thiopental is kilat (0,115 g; 0,213 mmol) was dissolved in 10 ml of methanol under stirring. Added a 1.0m solution of lithium hydroxide (10 ml; 10 mmol) and the mixture was stirred for 24 hours. Having determined that the reaction was not until the end, the reaction mixture was additionally heated to 40°C for 24 hours. The reaction mixture was cooled to room temperature and was poured into 0.5 n NaOH and diethyl ether. The layers were separated and the aqueous layer washed with diethyl ether. Diethylamine layers were discarded and the aqueous layer was acidified with concentrated HCl. The aqueous layer was extracted with ethyl acetate (2X) and dichloromethane. The combined organic layers were dried over MgSO4, filtered and concentrated to obtain 0,0800 g (71%) of 5-[6-[(2-chloroethyl)oxy]-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)-phenyl]methyl}oxy)-2-thiophencarboxylic acid in a solid white color.1H NMR (400 MHz, DMSO-d6) δ 12.85 (br s, 1H), 8.52 (s, 1H), 7.96 (d, J=7.5 Hz, 1H), 7.84-7.75 (m, 2H), 7.64-7.58 (m, 2H), 7.38 (s, 1H), 7.31 (s, 1H), 5.50 (s, 2H), 4.31 (t, J=5.1 Hz, 2H), 3.98 (t, J=5.1 Hz, 2H), 3.85 (s, 3H)). MS (ERI+, m/z 527 (m+1).

Intermediate example 28: 5-[6-[(2-chloroethyl)oxy]-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophencarboxylic

5-[6-[(2-Chloroethyl)oxy]-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifter-methyl)phenyl]methyl}oxy)-2-thiencarbazone acid (0,0790 g; 0,150 mmol) and chloride Ammon is I (0,0160 g; 0,299 mmol) were placed in the flask. Added 5 ml of N,N-dimethylformamide and the mixture was stirred. Was added N-methylmorpholine (to 0.032 ml, 0.29 mmol) with a syringe. Was added 1-hydroxybenzotriazole (0,0405 g; 0,300 mmol) in one portion. Was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0,0403 g; 0,210 mmol) and the mixture was stirred for 64 hours. The reaction mixture was poured into ethyl acetate and 1 N. HCl and the layers were separated. The organic layer is washed with brine and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated. Purification with flash chromatography gave 0,0760 g (96%) of 5-[6-[(2-chloroethyl)oxy]-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate as not quite white solid.1H NMR (300 MHz, DMSO-d6) δ 8.49 (s, 1H), 7.91-7.64 (m, 5H), 7.65 (s, 1H), 7.41 (s, 1H), 7.31 (s, 1H), 6.84 (br s, 1H), 5.59 (s, 2H), 4.34 (t, J=5.0 Hz, 2H), 4.02 (t, J=5.0 Hz, 2H), 3.88 (s, 3H).

Example 136: 5-(5-(metiloksi)-6-{[2-(4-methyl-1-piperazinil)ethyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophencarboxylic

5-[6-[(2-Chloroethyl)oxy]-5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)-phenyl]methyl}oxy)-2-thiophencarboxylic (0,0750 g; 0,143 mmol) was dissolved in 3 ml of 1-methylpiperazine and was heated to 90°C in an oil bath. After 3 hours of OHL who was waiting to room temperature and was adsorbing a mixture of NaHCO 3and silica gel (1:5). The sample was purified flash chromatography and concentrated in vacuum. The residue was dissolved in approximately 5 ml of methanol was added 1 ml of 1 N. HCl in diethyl ether with stirring. Added an excess of diethyl ether to cause precipitation of solid white. The mixture was filtered and the solid is washed with diethyl ether. The solid was air-dried and collected with getting 0,0496 g (52%) of 5-(5-(metiloksi)-6-{[2-(4-methyl-1-piperazinil)ethyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]-methyl}oxy)-2-thiophencarboxylic in the form of its di-HCl salt. For the NMR analysis in a test tube for NMR was added solid Na2CO3that the sample is translated in the free base in situ.1H NMR (400 MHz, DMSO-d6) δ 8.42 (s, 1H), 7.88-7.58 (m, 5H), 7.59 (s, 1H), 7.32 (s, 1H), 7.24 (s, 1H), 6.80 (br s, 1H), 5.54 (s, 2H), 4.10 (t, J=5.7 Hz, 2H), 3.81 (s, 3H), 2.69 (t, J=5.8 Hz, 2H), 2.48-2.15 (m, 8H), 2.10 (s, 3H). MS (ERI+, m/z 590 (m+1).

Unless otherwise indicated, the following compounds were obtained in accordance with the General methods described in Examples 134, 135 and 136 using the appropriate intermediates.

Example 137: 5-(5-(metiloksi)-6-{[2-(4-morpholinyl)ethyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophencarboxylic

1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.87-7.63 (m, 5H), 7.62 (s, 1H, 7.34 (s, 1H), 7.27 (s, 1H), 6.82 (br s, 1H), 5.56 (s, 2H), 4.13 (t, J=5.9 Hz, 2H), 3.83 (s, 3H), 3.59-3.54 (m, 4H), 2.73 (t, J=5.9 Hz, 2H). MS (ERI+, m/z 577 (m+1).

Example 138: 5-[6-(2-morpholine-4-ylethoxy)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.86 (d, J=8.06 Hz, 2H), 7.79 (t, J=7.6 Hz, 1H), 7.73 (br s, 1H), 7.68 (s, 1H), 7.65 (d, J=6.41 Hz, 2H). 7.23 (d, J=1.65 Hz, 1H), 6.99 (dd, J=2.01 Hz, J=8.79 Hz, 1H), 6.82 (br s, 1H), 5.56 (s, 1H), 4.15 (t, J=5.58 Hz, 2H), 3.58 (t, J=4.39 Hz, 4H), 2.73 (t, J=5.58 Hz, 2H). MS (ERI+, m/z 547 (m+1).

Example 139: 5-[6-(2-pyrrolidin-1 ylethoxy)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.50 (s, 1H), 7.86 (s, 1H), 7.84 (s, 1H), 7.79 (t, J=7.60 Hz, 1H), 7.73 (br s, 1H), 7.68-7.64 (m, 3H), 7.23 (d, J=1.83 Hz, 1H), 6.99 (dd, J=2.11 Hz, 8.70 Hz, 1H), 6.82 (br s, 1H), 5.56 (s, 2H), 4.14 (t, J=5.58 Hz, 2H), 2.85 (br s, 2H), 2.57 (br s, 4H), 1.70 (br s, 4H). MC (ERI+, m/z 531 (m+1).

Example 140: 5-[5-fluoro-6-(2-morpholine-4-ylethoxy)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide

1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1H), 7.85-7.63 (m, 7H), 7.43 (d, J=7.48 Hz, 1H), 6.83 (br s, 1H), 5.55 (s, 2H), 4.23 (t, J=5.64 Hz, 2H), 3.57 (t, J=4.43 Hz, 4H), 2.75 (t, J=5.64 Hz, 2H). MC (ERI+, m/z 565 (M+1).

Example 141: 5-(5-hydroxy-1H-benzimidazole-1-yl)-3-[(2-methylbenzyl)oxy]-thiophene-2-carboxylic acid

1H NMR (400 MHz, CD3OD) δ 9.64 (s, 1H); 7.69-7.63 (m, 2H); 7.49 (d, J=7.4 Hz, 1H); 7.24-7.18 (m, 5H); 5.37 (s, 2H); 2.43 (s, 3H). MC (ERI+, m/z 380 (M+).

Example 142: 5-[5-(2-methoxyethoxy)-1H-benzimidazole-1-yl]-3-[(2-methylbenzyl)oxy]thiophene-2-carboxamide

1H NMR (400 MHz, CD3OD) δ 8.45 (s, 1H); 7.83-7.78 (m, 2H); 7.73 (t, J=7.1 Hz, 1H); 7.65-7.59 (m, 2H); 7.43 (s, 1H); 7.29 (d, J=2.2 Hz, 1H); 7.10 (dd, J=2.2, 4.7 Hz, 1H); to 5.58 (s, 2H); 4.20-4.18 (m, 2H); 3.80-3.78 (m, 2H); 3.44 (s, 3H). MS (ERI+, m/z 491 (M+).

Intermediate example 29: 1,1-dimethylethyl 4-[({1-[5-[(metiloksi)carbonyl]-4-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thienyl]-1H-benzimidazole-6-yl}oxy)methyl]-1-piperidinecarboxylate

Methyl-5-(6-hydroxy-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)-phenyl]methyl}-oxy)-2-thiophenecarboxylate (0,150 g; 0,335 mmol) and 1,1-dimethylethyl 4-({[(4-were)sulfonyl]oxy}methyl)-1-piperidine-carboxylate (0,161 g; 0,436 mmol] was dissolved in 5 ml of N,N-dimethylformamide with stirring. Added cesium carbonate (0,164 g; 0,503 mmol) in one portion and the reaction mixture was heated to 60°C in an oil bath. The reaction mixture was stirred at this temperature for seven hours and cooled to room temperature. The mixture was poured into water and ethyl acetate and the layers were separated. The organic layer is washed with brine and the combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over MgSO4that was filtered and koncentrira is whether in vacuum. The residue was purified flash chromatography with getting 0,186 g (86%) of 1,1-dimethylethyl 4-[({1-[5-[(metiloksi)carbonyl]-4-({[2-(trifluoromethyl)phenyl]-methyl}oxy)-2-thienyl]-1H-benzimidazole-6-yl}oxy)methyl]-1-piperidinecarboxylate.1H NMR (400 MHz, DMSO-d6) δ 8.59 (s, 1H), 8.00 (d, J=8.0 Hz, 1H), 7.87-7.79 (m, 2H), 7.74-7.60 (m, 3H), 7.28 (d, J=2.1 Hz, 1H), 7.03 (dd, J=8.8, 2.2 Hz, 1H), 5.56 (s, 2H), 4.02 (m, 2H), 3.95 (d, J=6.5 Hz, 1H), 3.82 (s, 3H), 2.78 (br s, 1H), 2.00 (br s, 1H), 1.87-1.76 (m, 2H), 1.43 (s, 9H), 1.84-1.12 (m, 2H). MS (ERI+, m/2) 646 (m+1).

Example 143: 5-{6-[(4-piperidinylmethyl)oxy]-1H-benzimidazole-1-yl}-3-({[2-(trifluoromethyl)phenyl]-methyl}oxy)-2-thiophencarboxylic

1,1-Dimethylethyl-4-[({1-[5-(aminocarbonyl)-4-({[2-(trifluoromethyl)phenyl]-methyl}-oxy)-2-thienyl]-1H-benzimidazole-6-yl}oxy)methyl]-1-piperidinecarboxylate was dissolved in 7 ml of methanol under stirring. Added 4 ml of concentrated HCl and the solution was heated to 45°C for 1 hour. The solution was cooled to room temperature and concentrated in vacuum to obtain 0,0866 g (87%) 5-{6-[(4-piperidinylmethyl)oxy]-1H-benzimidazole-1-yl}-3-({[2-(trifluoromethyl)phenyl]-methyl}oxy)-2-thiophencarboxylic in the form of its salt with HCl. For1H NMR analysis in a test tube for NMR was added solid Na2CO3to in situ translate the sample in free base.1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 7.85-7.81 (m, 2H), 7.80-7.71 (m, 2H), 7.67-7.60 (m, 3H), 7.16 (d, J=2.2 Hz, 1H), 6.96 (dd, J=8.8, 2.2 Hz, 1H), 6.81 (br s, 1H), .54 (s, 2H), 4.09 (m, 2H), 3.89-3.81 (m, 2H), 2.93 (d, J=10.6 Hz, 1H), 1.83 (br s, 1H), 1.73-1.62 (m, 2H), 1.27-1.05 (m, 2H). MC (ERI+, m/z 531 (m+1).

Example 144: 5-(1H-benzimidazole-1-yl)-3-(benzyloxy)-N-hydroxythiophene-2-carboxamide

To a cooled (0° (C) to a solution of 5-(1H-benzimidazole-1-yl)-3-(benzyloxy)thiophene-2-carboxylic acid (100 mg; 0.28 mmol) in dichloromethane (2.0 ml) was added dimethylformamide (22 μl; 0.28 mmol), then 2.0m solution oxalicacid in dichloromethane (310 μl; and 0.62 mmol). The reaction mixture was stirred at 0°C for 40 minutes, then was added to a solution of hydroxylamine hydrochloride (78 mg; 1.12 mmol) and triethylamine (233 μl; 1,67 mmol) in a mixture of 85:15 tetrahydrofuran/N2O (1 ml). The reaction mixture was stirred at room temperature for 45 minutes, then poured into 1M aqueous HCl and was extracted with dichloromethane. The organic extracts were washed with saline and dried over Na2SO4. Filtration and concentration followed by reversed-phase preparative HPLC (high performance liquid chromatography (30-70% acetonitrile/H2O with 0.1%formic acid) gave 5-(1H-benzimidazole-1-yl)-3-(benzyloxy)-N-hydroxythiophene-2-carboxamide (10 mg; 10%) as not quite white solid.1H NMR (400 MHz, CDCl3) δ 9.51 (s, 1H), 8.08 (s, 1H), 8.89-8.84 (m, 1H), 7.60-7.56 (m, 1H), 7.47-7.37 (m, 8H), 6.95 (s, 1H), 5.30 (s, 2H). MS (ERI+, m/z 365 (m+1).

Example 145: 5-(5,dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carbothioamide

To a solution of 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide (50 mg, 0.10 mmol) in 1,4-dioxane (1.5 ml) was added a reagent Lawesson (32 mg, 0.08 mmol). The reaction mixture was heated to 80°C for 3 hours, cooled to room temperature and was additionally added to the reagent Lawesson (32 mg, 0.08 mmol). The reaction mixture was heated to 80°C for 2 hours, then cooled to room temperature. The reaction mixture was poured into 1M aqueous HCl and was extracted with dichloromethane. The organic extracts were dried over Na2SO4. Filtration and concentration followed by reversed-phase preparative HPLC (30-70% acetonitrile/H2O with 0.1% formic acid) gave 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carbothioamide (25 mg; 48%) as a solid pale yellow color.1H NMR (400 MHz, DMSO-d6) δ 9.63 (s, 1H), 8.35 (m, 2H), 7.76-7.65 (m, 3H), 7.56-7.51 (m, 1H), 7.47 (s, 1H), 7.23 (s, 1H), 7.11 (s, 1H), 5.49 (s, 2H), 3.72 (s, 3H), 3.71 (s, 3H). MS (ERI+, m/z 493 (m+1).

Example 146: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy]thiophene-2-carbonitrile

To a solution of 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide (150 mg, 0.31 mmol) in dichloromethane (2 ml) was added 2-chloro-1,3-dimeth imidazolidinone (120 mg; 0.71 mmol) and triperoxonane acid (50 μl; of 0.65 mmol). To this solution was added triethylamine (200 μl; 1.44 mmol). The mixture was stirred 18 hours, then was additionally added 2-chloro-1,3-dimethylimidazolidine (120 mg; 0.71 mmol) and triperoxonane acid (50 μl; of 0.65 mmol), then triethylamine (200 μl; 1.44 mmol). The mixture was stirred for 4 hours, then poured in H2O and was extracted with dichloromethane. The organic extracts washed with aqueous 5% HCl, water (saturated), NaHCO3, brine and dried over Na2SO4. Filtration and concentration followed by chromatography on silica gel (elution gradient 40-95% EtOAc/hexane) gave 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carbonitrile (66 mg; 46%) as a solid yellow color.1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.80-7.72 (m, 2H), 7.66 (t, J=7.60 Hz, 1H), 7.51 (t, J=7.51 Hz, 1H), 7.31 (s, 1H), 6.99 (s, 1H), 6.82 (s, 1H), 5.55 (s, 2H), 3.96 (s, 3H), 3.92 (s, 3H). MS (ERI+, m/z 459 (m+1).

Example 147: 5,6-dimethoxy-1-(5-(1H-tetrazol-5-yl)-4-{[2-(trifluoromethyl)-benzyl]oxy]Tien-2-yl)-1H-benzimidazole

In the reaction vessel microwave apparatus Smithcreator Microwave was added 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}-thiophene-2-carbonitrile (53 mg; 0.11 mmol), sodium azide (20 mg; 0.31 mmol), ammonium chloride (16 mg; 0.31 mmol) and dimethylformamide (2.0 ml). Reactio the hydrated vessel was tightly closed and heated at 120° C for 20 minutes in the microwave apparatus Smithcreator Microwave. The reaction vessel was cooled to room temperature, opened, and additionally was added sodium azide (20 mg; 0.31 mmol) and ammonium chloride (16 mg; 0.31 mmol). The vessel was tightly closed and heated at 120°C for 10 minutes in the microwave apparatus was then cooled to room temperature and opened. The mixture was poured into water (saturated) NaHCO3and washed with diethyl ether. The aqueous layer was then acidified to a pH of 1.0 by adding concentrated HCl, then was extracted with ethyl acetate. The organic extract was washed with saline and dried over Na2SO4. Filtration and concentration followed by reversed-phase preparative HPLC (30-70% acetonitrile/H2O with 0.1% formic acid) gave 5,6-dimethoxy-1-(5-(1H-tetrazol-5-yl)-4-{[2-(trifluoromethyl)benzyl]oxy}-Tien-2-yl)-1H-benzimidazole (25 mg; 43%) as a solid white color.1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.81 (d, J=7.87 Hz, 1H), 7.69-7.56 (m, 3H), 7.32 (s, 1H), 7.08 (s, 1H), 6.99 (s, 1H), 5.57 (s, 2H), 3.95 (s, 3H), 3.93 (s, 3H). MS (ERI+, m/z 502 (m+1).

Intermediate example 30: methyl-3-hydroxy-5-[2-(methylthio)-1H-benzimidazole-1-yl]thiophene-2-carboxylate

A mixture of 2-(methylthio)-1H-benzimidazole (5.0 g; 25,9 mmol) and methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate (8.53 g; 51,9 mmol) was dissolved in chloroform (100 ml) and ice vinegar is th acid (12 ml). Was stirred at room temperature for 72 hours. The reaction mixture was poured into a separating funnel containing dichloromethane (150 ml), washed with distilled water (2×100 ml). The combined aqueous layers were extracted with dichloromethane (2×50 ml). The combined organic layers were washed with distilled water (3×100 ml). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was dissolved in dichloromethane and methanol and was added silica gel (35 g). Then evaporated volatile components under reduced pressure, the pre-adsorbed solids were loaded into the cartridge loading solids and subjected to the isocratic elution dichloromethane (100%)using a RediSep silica gel cartridge (330 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to obtain methyl 3-hydroxy-5-[2-(methylthio)-1H-benzimidazole-1-yl]thiophene-2-carboxylate (4,75 g) in the form of not-quite-white solid.1H NMR (400 MHz, CDCl3): δ 9.77 (s, 1H), 7.71-7.68 (m, 1H), 7.36-7.34 (m, 1H), 7.30-7.26 (m, 1H), 7.24-7.20 (m, 1H), 6.87 (s, 1H), 3.93 (s, 3H), 2.78 (s, 3H). MS (ERI+, m/z 321 (M+1).

Intermediate example 31: methyl-5-[2-(methylthio)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy]thiophene-2-carboxylate

By analogy with Example 54, vzaimodejstvie-hydroxy-5-[2-(methylthio)-1H-benzimidazole-1-yl]thiophene-2-carboxylate (4.5 g; 14.0 mmol) and 1-(methyl bromide)-2-(trifluoromethyl)benzene (3,36 g; 14.0 mmol) resulted in the receipt of methyl-5-[2-(methylthio)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxylate (of 5.99 g) as a solid reddish-brown color.1H NMR (400 MHz, CDCl3): δ 7.93 (d, J=7.7 Hz, 1H), 7.8-7.76 (m, 2H), 7.65-7.58 (m, 3H), 7.37-7.34 (m, 1H), 7.29-7.21 (m, 2H), 5.46 (s, 2H), 3.77 (s, 3H), 2.71 (s, 3H). MS (ERI+, m/z 479 (M+1).

Intermediate example 32: methyl-5-[2-(methylsulphonyl)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate

To a solution of methyl-5-[2-(methylthio)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (150 mg, 0.31 mmol) in dichloromethane (5 ml) under nitrogen atmosphere was added 3-chloroperoxybenzoic acid (77%) (178 mg; 0,79 mmol) and stirred at room temperature for 24 hours. Concentrated under reduced pressure to obtain a solid substance whitish color. Was dissolved in chloroform (100 ml) and the reaction mixture was poured into a separating funnel. Washed with saturated aqueous NaHCO3(2×50 ml) and brine (2×50 ml). The organic layer was dried (MgSO4), filtered and concentrated under reduced pressure to get a Golden oil. Was dissolved in dichloromethane (25 ml) was added silica gel (500 mg), and then evaporated volatile components when pony is hinnon pressure. Pre adsorbirovanny solids were loaded into the cartridge loading solids and subjected to gradient elution using a mixture of ethyl acetate/hexane (20:80) to ethyl acetate/hexane (50:50)using a RediSep silica gel cartridge (12 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to obtain methyl 5-[2-(methylsulphonyl)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxylate (130 mg) as a solid white color.1H NMR (400 MHz, CDCl3): δ 7.97 (d, J=7.8 Hz, 1H), 7.89-7.86 (m, 1H), 7.69-7.62 (m, 2H), 7.49-7.39 (m, 4H), 7.16 (s, 1H), 5.46 (s, 2H), 3.91 (3, 3H), 3.50 (s, 3H). MS (ERI+, m/z 511 (M+1).

Intermediate example 33: 5-[2-(methylthio)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy]thiophene-2-carboxamide

By analogy with Example 61, the interaction of methyl-5-[2-(methylthio)-1H-benzimidazole-1-yl]-3-([2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (160 mg; 0,343 mmol) and 7 N. NH3in methanol (10 ml; 70,0 mmol) yielded 5-[2-(methylthio)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxamide (136 mg) as a solid white color.1H NMR (400 MHz, DMSO-d6): δ 7.84-7.75 (m, 4H), 7.65-7.62 (m, 2H), 7.56 (s, 1H), 7.32-7.30 (m, 1H), 7.28-7.20 (m, 2H), 6.87 (bs, 1H), 5.50 (s, 2H), 2.70 (s, 3H). MS (ERI+, m/z 464 (M+1).

Intermediate example 34: 5-[2-(methylsulphonyl)-1H-benzimidazo the-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide

To a solution of 5-[2-(methylthio)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxamide (1,25 g; 2,69 mmol) in dichloromethane (50 ml) under nitrogen atmosphere was added 3-chloroperoxybenzoic acid (77%) (1.86 g; 8,29 mmol) and stirred at room temperature for 24 hours. Concentrated under reduced pressure to get not quite a white solid. Was dissolved in dichloromethane and methanol, was added silica gel (10.0 g), then evaporated volatile components under reduced pressure. The pre-adsorbed solids were loaded into the cartridge loading solids and subjected to gradient elution using a mixture of ethyl acetate/hexane (15:85) to ethyl acetate/hexane (60:40)using a RediSep silica gel cartridge (40 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to obtain 5-[2-(methylsulphonyl)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide (869 mg) in the form of not-quite-white solid.1H NMR (400 MHz, CDCl3): δ 7.89-7.87 (m, 1H), 7.76-7.74 (m, 1H), 7.66-7.61 (m, 2H), 7.54-7.44 (m, 4H), 7.25 (s, 1H), 7.02 (bs, 1H), 5.69 (bs, 1H), 5.44 (s, 2H), 3.51 (s, 3H). MS (ERI+, m/z 496 (M+1).

Example 148: 5-(2-amino-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}Tioman-2-carboxamide

Method a: In GE is metecno a sealed tube was heated up to 80° C for 24 hours a mixture of 5-[2-(methylsulphonyl)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide (410 mg; 0,827 mmol) in 7 BC, NH3in methanol (20 ml, 140 mmol). Cooled the reaction mixture to room temperature and the precipitate was filtered through a ceramic funnel. The filtrate was concentrated under reduced pressure to obtain solid residue (180 mg)which was dissolved in methanol and dichloromethane. Was added silica gel (250 mg), and then evaporated volatile components under reduced pressure. The pre-adsorbed solids were loaded into the cartridge loading solids and subjected to gradient elution using a mixture of dichloromethane/methanol (100:0) to dichloromethane/methanol (85:15)using a RediSep silica gel cartridge (4 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to obtain 5-(2-amino-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide (25 mg) as a solid reddish-brown color.1H NMR (400 MHz, DMSO-d6): δ 8.83 (s, 2H), 7.90-7.75 (m, 4H), 7.65-7.62 (m, 2H), 7.42 (d, J=7.9 Hz, 1H), 7.34-7.23 (m, 2H), 7.17 (d, J=8.6 Hz, 1H), 6.93 (bs, 1H), 5.47 (s, 2H). MS (ERI+, m/z 433 (M+1).

Method: In a tightly closed tube methyl-5-[2-(methylsulphonyl)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}-thiophene-2-carboxylate was subjected to were is deystviy 7 N. NH3in methanol to obtain 5-(2-amino-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]-oxy}thiophene-2-carboxamide.

Example 149: methyl 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-nitrophenyl)sulfonyl]oxy}thiophene-2-carboxylate

To a solution of 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxamide (170 mg; 0.50 mmol) and N,N-diisopropylethylamine (of 0.12 ml, 0.70 mmol) in dichloromethane (5 ml) was added 2-nitrobenzenesulfonamide (130 mg; a 0.60 mmol). The solution was stirred 1 h and during this time was added silica gel (5 g). Volatile components are evaporated under reduced pressure and the pre-adsorbed solids were loaded into the cartridge loading solids and subjected to gradient elution using a mixture of hexane/ethyl acetate (80:20) to hexane/ethyl acetate (0:100)using a RediSep silica gel cartridge (4 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to obtain methyl 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[(2-nitrophenyl)sulfonyloxy}thiophene-2-carboxylate (240 mg) as a solid white color.1H NMR (400 MHz, CDCl3) δ 8.31 (dd, J=8.0, 1.5 Hz, 1H), 7.96 (s, 1H), 7.91-7.81 (m, 3H), 7.32 (s, 1H), 7.19 (s, 1H), 7.15 (s, 1H), 3.98 (s, 3H), 3.97 (s, 3H), 3.76 (s, 3H). MS (ERI+, m/z 520 (m+1).

Example 150: methyl 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[(trifluoromethyl)Sul who were radioactive]oxy}thiophene-2-carboxylate

The compound was obtained in accordance with the General method described in Example 30.1H NMR (400 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.84 (s, 1H), 7.35 (s, 1H), 7.26 (m, 3H), 3.89 (s, 3H), 3.84 (s, 3H), 3.81 (s, 3H). MS (ERI+, m/z 467 (m+1).

Example 151: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[(2-were)sulfonyl]oxy}thiophene-2-carboxylic acid

To a solution of methyl 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-([(2-were)sulfonyl]oxy}thiophene-2-carboxylate (100 mg; 0.20 mmol) in tetrahydrofuran (2 ml) was added 0.1 G. of NaOH (2 ml; 0.20 mmol). The solution was stirred 1 h, during which time the solution was neutralized by adding 0.1 G. of HCl (2 ml, 0.20 mmol), and the precipitate precipitated solid white. Filtration under vacuum gave 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[(2-were)sulfonyl]oxy}thiophene-2-carboxylic acid (7 mg) as a solid white color.1H NMR (400 MHz, CDCl3) δ 9.50 (s, 1H), 7.88 (d, J=8.0 Hz, 1H), 7.54 (dd, J=8.3, 7.1 Hz, 1H), 7.49 (s, 1H), 7.42 (d, J=9.3 Hz, 1H), 7.32-7.27 (m, 1H), 7.19 (s, 1H), 7.15 (s, 1H), 4.03 (s, 3H), 4.02 (s, 3H), 2.81 (s, 3H). MS (ERI+, m/z 475 (m+1).

Example 152: 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxamide triptorelin

The solid 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(4-methoxybenzyl)oxy]thiophene-2-carboxamide (400 mg; of 0.91 mmol) was added triperoxonane to the slot (2 ml). A bright red solution was stirred for 10 minutes, during this time was added ether (20 ml)and the precipitate precipitated solid pink color. Filtration under vacuum gave 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxamide triptorelin (300 mg) in a solid pink color.1H NMR (400 MHz, DMSO-d6) δ 8.70 (s, 1H), 7.33 (s, 1H), 7.23 (s, 1H), 7.10 (s, 1H), 7.05 (br s, 1H), 3.83 (s, 3H), 3.82 (s, 3H). MS (ERI+, m/z 320 (m+1).

Example 153: 2-(aminocarbonyl)-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)Tien-3-yl-2-nitrobenzenesulfonate

To a solution of 5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-hydroxythiophene-2-carboxamide of triptoreline (44 mg, 0.10 mmol) and N,N-diisopropylethylamine (0,058 ml; 0.33 mmol) in dichloromethane (2 ml) was added 2-nitrobenzenesulfonamide (24 mg; 0.11 mmol). The solution was stirred 3 h and during this time was added silica gel (2 g). Volatile components are evaporated under reduced pressure and the pre-adsorbed solids were loaded into the cartridge loading solids and subjected to elution with a gradient from ethyl acetate (100%) to a mixture of ethyl acetate/methanol (80:20)using a RediSep silica gel cartridge (4 g; ISCO). The appropriate fractions were combined and concentrated under reduced pressure to obtain methyl 2-(aminocarbonyl)-5-(5,6-dimethoxy-1H-benzimidazole-1-the l)Tien-3-yl-2-nitrobenzenesulfonate (37 mg) as a solid white color. 1H NMR (400 MHz, DMSO-d6) δ 8.38 (s, 1H), 8.22-7.93 (m, 4H), 7.80 (br s, 1H), 7.40 (s, 1H), 7.34 (br s, 1H), 7.33 (s, 1H), 7.15 (s, 1H), 3.82 (s, 3H), 3.81 (s, 3H). MS (ERI+, m/z 505 (m+1).

Example 154: 2-(aminocarbonyl)-5-(5,6-dimethoxy-1H-benzimidazole-1-yl]Tien-3-yl-2-methylbenzenesulfonic

2-(Aminocarbonyl)-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)Tien-3-yl-2-methylbenzenesulfonate was obtained by the method similar to the method described above to obtain 2-(aminocarbonyl)-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)Tien-3-yl-2-nitrobenzenesulfonate, except that used 2-methylsulfonylamino instead of 2-nitrobenzenesulfonamide.1H NMR (400 MHz, DMSO-d6) δ 8.35 (s, 1H), 7.91 (dd, J=8.0, 1.2 Hz, 1H), 7.79 (br s, 1H), 7.72 (add, J=7.7, 7.4, 1.3 Hz, 1H), 7.56 (a, J=7.4 Hz, 1H), 7.45 (dd, J=7.7, 7.7 Hz, 1H), 7.34 (br s, 1H), 7.32 (s, 1H), 7.15 (s, 1H), 7.05 (s, 1H), 3.80 (s, 3H), 3.80 (s, 3H), 2.68 (s, 3H). MS (ERI+, m/z 474 (m+1).

Intermediate example 35: 1-(5-(methoxycarbonyl)-4-{[2-(trifluoromethyl)benzyl]oxy}Tien-2-yl)-1H-benzimidazole-5-carboxylic acid

To a solution of vinyl-1-(5-(methoxycarbonyl)-4-{[2-(trifluoromethyl)benzyl]-oxy}Tien-2-yl)-1H-benzimidazole-5-carboxylate (500 mg; 0.97 mmol) in tetrahydrofuran (3.0 ml) was added morpholine (178 μl; 2.04 mmol)and then tetrakis(triphenylphosphine)-palladium(0) (56 mg; 0.05 mmol). The reaction mixture was stirred at room temperature for 1 hour, then poured in 05M aqueous HCl and ethyl acetate. The organic layer was washed with water, brine and dried over Na2SO4. Filtration and concentration gave 1-(5-(methoxycarbonyl)-4-{[2-(trifluoromethyl)benzyl]-oxy}Tien-2-yl)-1H-benzimidazole-5-carboxylic acid (455 mg; 98%) as a solid reddish-brown color.1H NMR (400 MHz, DMSO-d6) δ 13.02 (b, 1H), 8.87 (s, 1H), 8.33 (s, 1H), 8.03 (dd, J=8.60 and 1.46 Hz, 1H), 7.92-7.98 (m, 2H), 7.77-7.83 (m, 3H), 7.59-7.64 (m, 1H), 5.51 (s, 2H), 3.78 (s, 3H). MS (ERI+, m/z 476 (m+1).

Example 155: 1-(5-(aminocarbonyl)-4-{[2-(trifluoromethyl)benzyl]oxy}Tien-2-yl)-N - [2-(methylsulphonyl)ethyl]-1H-benzimidazole-5-carboxamide

To a solution of 1-(5-(methoxycarbonyl)-4-{[2-(trifluoromethyl)benzyl]oxy}-Tien-2-yl)-1H-benzimidazole-5-carboxylic acid (35 mg; 0,073 mmol), 2-(methylsulphonyl)ethanamine (14 mg, 0.11 mmol) and diisopropylethylamine (35 μl; 0.20 mmol) in dimethylformamide (1.0 ml) was added O-(7-sabastiano-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate] (35 mg; mmol 0,092). The reaction mixture was stirred for 12 hours, then poured into aqueous saturated NaHCO3and were extracted with ethyl acetate. The combined extracts were washed with water, brine and dried over Na2SO4. Filtration and concentration gave crude methyl-5-[5-({[2-(methylsulphonyl)ethyl]amino}carbonyl)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxylate (40 mg, 95%)as a light brown oil. The oil was stirred in a solution of 7M ammonia in methanol (10 ml; 70 mmol) at 80°in a sealed, thick-walled glass tube high pressure for 16 hours. The reaction mixture was cooled to room temperature, concentrated and purified by reversed-phase preparative HPLC (gradient of 10-90% acetonitrile/H2O with 0.1% formic acid) to give 1-(5-(aminocarbonyl)-4-{[2-(trifluoromethyl)benzyl]oxy}Tien-2-yl)-N-[2-(methylsulphonyl)ethyl]-1H-benzimidazole-5-carboxamide (23 mg, 55%) as a solid white color.1H NMR (400 MHz, DMSO-d6) δ 8.84 (t, J=5.58 Hz, 1H), 8.76 (s, 1H), 8.30 (s, 1H), 7.94 (dd, J=8.60 and 1.28 Hz, 1H), 7.70-7.89 (m, 6N), 7.65 (t, J=7.60 Hz, 1H), 6.79 (b, 1H), 5.55 (s, 2H), 3.71 (q, J=6.41 Hz, 2H), 3.41 (t, J=6.87 Hz, 2H), 3.04 (s, 3H). MS (ERI+, m/z 566 (m+1).

Example 156: 1-(5-(aminocarbonyl)-4-{[2-(trifluoromethyl)benzyl]oxy}Tien-2-yl)-N-[2-(2-Oxymetazoline-1-yl)ethyl]-1H-benzimidazole-5-carboxamide

To a solution of 1-(5-(methoxycarbonyl)-4-[[2-(trifluoromethyl)benzyl]oxy}-Tien-2-yl)-1H-benzimidazole-5-carboxylic acid (112 mg; 0.23 mmol), 1-(2-amino-ethyl)imidazolidin-2-she (85 mg; 0.35 mmol) and diisopropylethylamine (110 μl; and 0.62 mmol) in dimethylformamide (2.0 ml) was added O-(7-sabastiano-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate] (115 mg; 0.30 mmol). The reaction mixture was stirred for 2 hours, then poured into ethyl acetate and washed with 5%-n is aqueous HCl, aqueous saturated NaHCO3, water, brine and dried over Na2SO4. Filtration and concentration gave crude methyl-5-[5-({[2-(2-Oxymetazoline-1-yl)ethyl]amino}carbonyl)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)-benzyl]-oxy}thiophene-2-carboxylate (128 mg; 95%) as a solid reddish-brown color. This solid was stirred in a solution of 7M ammonia in methanol (10 ml; 70 mmol) at 80°in a sealed, thick-walled glass tube high pressure for 16 hours. The reaction mixture was cooled to -10°and added chilled diethyl ether. The obtained suspension was filtered, washing the solids cooled diethyl ether. The solids were then dried under vacuum to obtain 1-(5-(aminocarbonyl)-4-{[2-(trifluoromethyl)benzyl]-oxy}Tien-2-yl)-N-[2-(2-Oxymetazoline-1-yl)ethyl]-1H-benzimidazole-5-carboxamide (53 mg; 44%) as a solid white color.1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.64 (t, J=5.49 Hz. 1H), 8.28 (s, 1H), 7.70-7.94 (m, 7H), 7.65 (t, J=7.60 Hz, 1H), 6.79 (b, 1H), 6.28 (s, 1H), 5.55 (s, 2H), 3.36-3.44 (m, 4H), 3.18-3.27 (m, 4H). MS (ERI+, m/z 572 (m+1).

Intermediate example 36: methyl-5-{6-[(tert-butoxycarbonyl)amino]-1H-benzimidazole-1-yl}-3-hydroxythiophene-2-carboxylate and methyl 5-{5-[(tert-butoxycarbonyl]amino]-1H-benzimidazole-1-yl}-3-hydroxythiophene-2-carboxylate

and

These compounds were obtained by the method similar to the method described in Example 2A. MS (ERI-, m/z) 388 (m-1).

Intermediate example 37: methyl-5-{6-[(tert-butoxycarbonyl)amino]-1H-benzimidazole-1-yl}-3-[1-(2-chlorophenyl)ethoxy]-thiophene-2-carboxylate and methyl 5-{5-[(tert-butoxycarbonyl)amino]-1H-benzimidazole-1-yl}-3-[1-(2-chlorophenyl)ethoxy]thiophene-2-carboxylate

and

These compounds were obtained by the method similar to the method described in Example 57 or Intermediate example 21. MS (ERI+, m/z 428 (m+1).

Intermediate example 38: methyl-5-(6-amino-1H-benzimidazole-1-yl)-3-[1-(2-chlorophenyl)ethoxy]thiophene-2-carboxylate and methyl 5-(5-amino-1H-benzimidazole-1-yl)-3-[1-(2-chlorophenyl)ethoxy]thiophene-2-carboxylate

and

Regioisomeric mixture of methyl 5-{6-[(tert-butoxycarbonyl)amino]-1H-benzimidazole-1-yl}-3-[1-(2-chlorophenyl)ethoxy]thiophene-2-carboxylate and methyl 5-{5-[(tert-butoxycarbonyl)amino]-1H-benzimidazole-1-yl}-3-[1-(2-chlorophenyl)ethoxy]thiophene-2-carboxylate (0,610 g; 1.57 mmol) was dissolved in 20 ml dichloromethane at the mixing. Added triperoxonane acid (6 ml) with a syringe. The reaction mixture was left to mix for 2 hours at room temperature, and then the reaction see what camping was diluted with ethyl acetate and neutralized by bicarbonate. The layers were separated and the organic layer was washed with salt solution. The combined aqueous layers were extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuum. Purification with flash chromatography gave 0,1915 g (39%) of methyl-5-(6-amino-1H-benzimidazole-1-yl)-3-[1-(2-chlorophenyl)ethoxy]thiophene-2-carboxylate and 0,1182 g (24%) of methyl-5-(5-amino-1H-benzimidazole-1-yl)-3-[1-(2-chlorophenyl)ethoxy]thiophene-2-carboxylate. Data for (6-NH2):1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.75 (dd, J=7.8, 1.6 Hz, 1H), 7.50-7.30 (m, 6H), 6.92 (d, J=1.8 Hz, 1H), 6.62 (dd, J=8.6, 2.0 Hz, 1H), 5.93 (q, J=6.2 Hz, 1H), 5.30 (bs, 2H). 3.80 (s, 3H), 1.61 (d, J=6.2 Hz, 3H). MS (ERI+, m/z 428 (m+1). Data for (5-NH2):1H NMR (400 MHz, DMSO-d6) δ 8.44 (s, 1H), 7.72 (dd, J=7.7, 1.7 Hz, 1H), 7.49-7.39 (m, 2H), 7.38-7.31 (m, 2H), 7.30 (s, 1H), 6.84 (d, J=2.2 Hz, 1H), 6.69 (dd, J=8.7, 2.1 Hz, 1H), 5.96 (q, J=6.4 Hz, 1H), 5.05 (bs, 2H), 3.80 (s, 3H), 1.61 (d, J=6.4 Hz, 3H). MS (ERI+, m/z 428 (m+1).

Example 157: 5-(5-amino-1H-benzimidazole-1-yl)-3-[1-(2-chlorophenyl)-ethoxy]thiophene-2-carboxamide

5-(5-Amino-1H-benzimidazole-1-yl)-3-[1-(2-chlorophenyl)ethoxy]thiophene-2-carboxamide was obtained from methyl 5-(5-amino-1H-benzimidazole-1-yl)-3-[1-(2-chlorophenyl)ethoxy]thiophene-2-carboxylate according to the method similar to the method described in Example 61, except that used 7M NH3in the Meon instead 2M NH3in the Meon.1H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 7.77 (bs, 1H, 7.67 (dd, J=7.7, 1.7 Hz, 1H), 7.50 (dd, J=8.0, 1.4 Hz, 1H), 7.48-7.33 (m, 2H), 7.23 (d, J=8.8 Hz, 1H), 7.09 (bs, 1H), 7.07 (s, 1H), 6.85 (d, J=1.8 Hz, 1H), 6.68 (dd, J=8.6, 2.0 Hz, 1H), 5.98 (q, J=6.4 Hz, 1H), 5.06 (bs, 2H), 1.72 (d, J=6.4 Hz, 3H). MS (ERI+, m/z 413 (m+1).

Intermediate example 39: methyl-3-[1-(2-chlorophenyl)-ethoxy]-5-(6-{[(1-methylpiperidin-3-yl)carbonyl]amino}-1H-benzimidazole-1-yl)thiophene-2-carboxylate

A solution of 1-methylpiperidin-3-carboxylic acid hydrochloride (63 mg; 0.35 mmol), HATU (2-(7-Aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexaflurophosphate) (133 mg, 0.35 mmol) and diisopropylethylamine (of 0.12 ml, 0.70 mmol) in DMF (dimethylformamide) (3 ml) was added to a stirred solution of methyl 5-(6-amino-1H-benzimidazole-1-yl)-3-[1-(2-chlorophenyl)ethoxy]-thiophene-2-carboxylate (149 mg; 0.35 mmol) in DMF (3 ml). The resulting solution was allowed to mix at room temperature for 2 hours the Reaction mixture was then diluted with EtOAc and washed several times with water. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified column flash chromatography to obtain methyl 3-[1-(2-chlorophenyl)ethoxy]-5-(6-{[(1-methylpiperidin-3-yl)carbonyl]amino}-1H-benzimidazole-1-yl)thiophene-2-carboxylate (123 mg; 64%). Data:1H NMR (400 MHz, CDCl3) δ 8.39 (bs, 1H), 7.91 (s, 1H), 7.73-7.66 (m, 2H), 7.35-7.27 (m, 2H), 7.25-7.19 (m, 1H), 7.15 (bs, 1H), 6.72 (s, 1H), 5.83 (q, J=6.4 Hz, 1H), 3.90 (s, 3H), 3.03 (bs, 2H), 2.86 (bs, 2H), 2.52 (bs, 3H), 1.90 (bs, 4H), 1.73 (d, J=6.4 Hz, 3H). MS (IS RI+, m/z 553 (m+1).

Intermediate example 40: methyl-3-[1-(2-chlorophenyl)ethoxy]-5-(5-{[(1-methylpiperidin-3-yl)carbonyl]amino}-1H-benzimidazole-1-yl)thiophene-2-carboxylate

The specified connection was obtained by the method similar to the method described in Intermediate example 39.1H NMR (400 MHz, CDCl3) δ 7.97 (bs, 2H), 7.69-7.62 (m, 2H), 7.41-7.29 (m, 3H), 7.27-7.22 (m, 1H), 6.69 (s, 1H), 5.82 (q, J=6.3 Hz, 1H), 3.91 (s, 3H), 3.04 (bs, 2H), 2.85 (bs, 2H), 2.48 (bs, 3H), 1.99 (bs, 2H), 1.86 (bs, 2H), 1.74 (d, J=6.3 Hz, 3H). MS (ERI-, m/z 551 (m-1).

Example 158: 3-[1-(2-chlorophenyl)ethoxy]-5-(6-{[1-methylpiperidin-3-yl)carbonyl]amino}-1H-benzimidazole-1-yl)thiophene-2-carboxamide

The specified connection was obtained by the method similar to the method described in Intermediate example 61, except that used 7M NH3in the Meon instead 2M NH3in the Meon.1H NMR (400 MHz, DMSO-d6) δ 10.19 (s, 1H), 8.50 (s, 1H), 8.38 (s, 1H), 7.84 (bs, 1H), 7.73-7.66 (m, 2H), 7.51-7.32 (m, 4H), 7.30 (s, 1H), 7.11 (bs, 1H), 5.94 (q, J=6.4 Hz, 1H), 2.90-2.86 (m, 1H), 2.75-2.71 (m, 1H), 2.63-2.57 (m, 1H), 2.20 (s, 3H), 2.10-2.01 (m, 1H), 1.93-1.79 (m, 2H), 1.74 (d, J=6.4 Hz, 3H), 1.72-1.67 (m, 1H), 1.53-1.38 (m, 2H). MS (ERI+, m/z 538 (m+1).

Example 159. Biological examples

I. Analysis of the inhibition of PLK1

A. Obtaining 6x N-terminal His-tagged PLK kinase domain

6x N-terminal His-tagged PLK kinase domain (amino acids 21-346 preceded by MKKGHHHHHHD) SEQ ID: No. 1 received from INFI is new baculovirus So ni cells under control of the polyhedrin promoter. All procedures were performed at 4°C. the Cells were literally in 50 mm HEPES, 200 mm NaCl, 50 mm imidazole, 5% glycerol; pH 7.5. The homogenate was centrifuged at 14000 rpm in a SLA-1500 rotor for 1 h and the supernatant was filtered through a 1.2 micron filter. The supernatant was loaded on a column with Nickel-chelate separate (Amersham Pharmacia) and washed lytic buffer. Protein was suirable using stepwise 20%, 30% and 100% buffer B, which represents 50 mm HEPES, 200 mm NaCl, 300 mm imidazole, 5% glycerol; pH 7.5. The fractions containing PLK, were identified by means of SDS-PAGE (polyacrylamide gel electrophoresis). The fractions containing PLK, five were diluted with 50 mm HEPES, 1 mm DTT (dithiothreitol), 5%glycerol, pH 7.5, and then were applied to a column of SP-separate (Amersham Pharmacia). After washing the column with 50 mm HEPES, 1 mm DTT, 5%glycerol, pH 7.5, PLK was suirable stages 50 mm HEPES, 1 mm DTT, 500 mm NaCl; 5%glycerol; pH 7.5. PLK was concentrated using a membrane, cut-off molecular weight of 10 kDa, and then was applied to a column for gel filtration Superdex 200 (Amersham Pharmacia), equilibrated 25 mm HEPES, 1 mm DTT, 500 mm NaCl, 5% glycerol; pH 7.5. The fractions containing PLK, were identified by means of SDS-PAGE. PLK were pooled, divided into aliquots and stored at -80°C. the quality Control samples was carried out using mass spectrometry, N-terminal sequencing and amino acid the analysis.

C. the enzyme Activity +/- inhibitors was determined as follows.

Compounds were added to the tablet (1 μl in 100% DMSO). As controls were used DMSO (final concentration 2%) and EDTA (ethylenediaminetetraacetate) (final concentration of 55.5 mm). The reaction mixture And cook in 4°as follows:

The reaction mixture (substrate mixture):

25 mm HEPES, pH 7,2

15 mm MgCl2

2 μm ATP (adenosine triphosphate)

33R-γATP (10 CI/mmol) of 0.1 µci/well

2 μm peptide substrate (Biotin-Ahx-SFNDTLDFD) SEQ ID: No. 2. The reaction mixture is prepared at 4°as follows:

The reaction mixture (enzyme mix):

25 mm HEPES, pH 7,2

15 mm MgCl2

0.15 mg/ml BSA (bovine serum albumin)

2 mm DTT

2-10 nm PLK1 kinase domain

The reaction mixture (20 μl) is added to the wells. The reaction mixture (20 μl) is added to the wells. Incubated for 1.5 h at room temperature. The enzymatic reaction is stopped by adding 175 μl of the mixture of granules SPA/EDTA (29 mm EDTA, 2.5 mg/ml streptavidin coated SPA-granules in standard PBS (phosphate buffered saline) Dulbecco (without Mg2+and CA2+), 60 μm ATP). Tablets centrifuged in the closed position (after 1 h incubation at room temperature) at 1000×g for 7 min or left to stand for sedimentation during the night, then tablets MF is primarily in Packard TopCount for 30 seconds per well.

C. Results

The obtained data are given below in Table 1. In Table 1: +=plC50<5; ++=plC505-7;+++=plC50>7.

II. Analysis of the inhibition of growth using methylene blue

Normal foreskin fibroblasts human (HFF) and cell lines tumor human colon (HCT 116, RKO), lung (N), prostate (RS) and breast cancer (MCF7) were cultured in DMEM (modified by Dulbecco environment Needle) (Life Technologies) with high glucose containing 10%fetal calf serum (FBS), at 37°C in a humid incubator in an atmosphere of 10% CO290% of air. Cells were harvested using trypsin/EDTA, counted using hemocytometer and were sown in 96-well plate for tissue culture (Falcon 3075) in 100 μl of the appropriate medium at the following densities: HFF 5000 cells per well, NST 3000 cells per well, RKO 2500 cells per well, N 2000 cells per well, RS 8000 cells per well, MCF7 4000 cells per well. The next day, compounds were diluted in DMEM containing 100 μg/ml gentamicin, double the final desired concentration of 10 mm concentrated solutions in DMSO. 100 μl per well of these dilution was added to 100 µl of the environment on the cell plates. In the control wells were added to the medium containing 0.6% DMSO. Compounds diluted in DMEM, was added to all cell lines, the Final concentration of DMSO in all wells was 0.3%. Cells were incubated at 37°With a 10% CO2within 3 days. The medium was removed by suction. Cell biomass was assessed by staining cells with methylene blue (Sigma M9140, 0.5% in a mixture of ethanol/water 50:50), 90 μl per well, and incubation at room temperature for at least 30 minutes. The dye was removed, the tablets were washed gently running water and air-dried. To release the dye from the cells was added 100 μl of a solution to solubilize (1% N-lauroyl-sarcosine, sodium salt, Sigma L5125, in PBS), and the tablet was carefully shaken for approximately 30 minutes. The optical density at 620 nm was measured on a microplate reader. The percentage of inhibition of cell growth was calculated relative to control wells treated by the media. The concentration of compound that inhibits 50% of cell growth (IC50was interpolable using nonlinear regression (Levenberg-Marquardt) and the equation y=Vmax*(1-(x/(K+x)))+Y2, where K equals the IC50. The obtained data are given below in Table 1. In the Table: +=10->30 μm; ++=1-10 μm; +++=<1 micron.

Table 1
ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
4/td> +++
13+++
14+++
15+++
34+++N+
ST+
HFF+
MCF7+
RS+
RKO+
35+++N+
ST+
HFF+
MCF7+
RS+
RKO+
39++N+
ST+
HFF+
MCF7+
RS+
RKO+
61+++N++
ST++
HFF+
MCF7++
RS +
RKO++

ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
62+++N+++
ST+++
HFF++
MCF7+++
RS+
RKO+++
63+++N+++
ST+++
HFF++
MCF7+++
RS++
RKO+++
64+++N+++
ST++
HFF+
MCF7++
RS+
RKO++
65+++N+++
ST+++
HFF+
MCF7+++
RS+
RKO+++
66+++N+
ST+
HFF+
MCF7+
RS+
RKO+

ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
67+++N+
ST+
HFF+
MCF7+
RS+
RKO+
68+++N+
ST+
HFF+
MCF7+
RS+
RKO+
69+++N+
ST+
HFF+
MCF7+
RS+
RK +
70+++N+
ST+
HFF+
MCF7+
RS+
RKO+
71+++N+
ST+
HFF+
MCF7+
RS+
RKO+

tr>
ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
72+++N+
ST+
HFF+
MCF7+
RS+
RKO+
74+++N++
ST+
HFF+
MCF7+
RS+
RKO+
75+++N+
ST++
HFF+
MCF7+
RS+
RKO+
76+++N+
ST+
HFF+
MCF7+
RS+
RKO+
77+++N+
ST+
HFF+
MCF7+
RS+
RKO+

ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
78+++N+
ST+
HFF+
MCF7+
RS+
RKO+
7 +++N+
ST+
HFF+
MCF7+
RS+
RKO+
80+++N+
ST+
HFF+
MCF7+
RS+
RKO+
83++
84+++
85++N+
ST+
HFF+
MCF7+
RS+
RKO+
86+++
87+++N++
ST++
HFF+

Mew cell line
ExampleThe average pIC50inhibition of the enzyme PLKIC50(µm)
MCF7++
RS+
RKO++
88++N+
ST+
HFF+
MCF7++
RS+
RKO+
89+++N++
ST++
HFF+
MCF7++
RS+
RKO++
90+++N++
ST++
HFF+
MCF7++
RS+
RKO++
91+++A+++
N+++
ST+++
HFF+
MCF7+++
RS++
RKO+++
92+++N+++
ST+++

ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
HFF++
MCF7+++
RS++
RKO+++
93++N+
ST+
HFF+
MCF7+
RS+
RKO+
94+++N++
ST++
HFF++
MCF7++
RS++
RKO++
95+++N++
ST++
HFF+
MCF7++
RS+
RKO++
96+++N++
ST++
HFF+
MCF7++
RS+
RKO++
97+++N++
ST++

ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
HFF++
MCF7++
RS++
RKO++
98+++N++
ST++
HFF+
MCF7++
RS++
RKO++
99+++N++
ST++
HFF+
MCF7++
RS+
RKO++
100+++N+
ST+
HFF+
MCF7+
RS+
RKO+
101+++A++
N++
ST++
HFF+
MCF7++
RS++
RKO+++

ExampleThe average pIC50inhibition of the enzyme PLKMeB cell lineIC50(µm)
102+++A++
N++
ST++
HFF+
MCF7++
RS+
RKO+++
103+++N++
ST++
HFF+
MCF7++
RS+
RKO++
104+++N++
ST++
HFF+
MCF7++
RS+
RKO++
105+++N++
ST++
HFF+
MCF7++
RS+
RKO++
106+++N++
ST++
HFF+
MCF7++
RS+

ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
RKO++
107+++A +++
N+++
ST++
HFF++
MCF7++
RS++
RKO+++
108+++A+++
N+++
ST+++
HFF+
MCF7+++
RS+
RKO+++
109++N+
ST+
HFF+
MCF7+
RS+
RKO+
110+++N++
ST+++
HFF+
MCF7++
RS++
RKO+++
111+++N++
ST++
HFF+

ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
MCF7++
RS++
RKO++
112++N++
ST+
HFF+
MCF7+
RS+
RKO++
113++N+
ST+
HFF+
MCF7+
RS+
RKO+
114++N+
ST+
HFF+
MCF7+
RS+
RKO+
115+++N++
ST++
HFF+
MCF7 ++
RS+
RKO++
116+++N+++
ST++
HFF++

+
ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
MCF7+++
RS+
RKO+++
117+++N+++
ST+++
HFF+
MCF7+++
RS++
RKO+++
118+++N+++
ST++
HFF++
MCF7+++
RS+
RKO+++
119+++N++
ST++
HFF
MCF7++
RS+
RKO++
120+++A++
N++
ST++
HFF+
MCF7++
RS+
RKO+++
121+++A++
N++

ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
ST++
HFF+
MCF7++
RS+
RKO++
122+++N++
ST++
HFF+
MCF7++
RS+
RKO++
123 +++N++
ST++
HFF++
MCF7++
RS+
RKO++
124+++N+
ST+
HFF+
MCF7+
RS+
RKO+
125+++N++
ST++
HFF+
MCF7++
RS+
RKO++

ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
126+++A+++
N+++
ST+++
HFF+++
MCF7++
RS++
RKO+++
127+++A+++
N+++
ST+++
HFF++
MCF7+++
RS++
RKO+++
128++N++
ST+
HFF+
MCF7++
RS+
RKO++
129++N+
ST+
HFF+
MCF7+
RS+
RKO+
130++N+
ST++
HFF+
MCF7++

ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
RC/td> +
RKO++
131++N++
ST++
HFF+
MCF7++
RS+
RKO++
132+++N+
ST+
HFF+
MCF7+
RS+
RKO+
133++N+
ST++
HFF+
MCF7+
RS+
RKO++
134+++A++
N++
ST++
HFF+
MCF7++
RS+
RKO++

ExampleThe average pIC50ingibirovany the enzyme PLK MeB cell lineIC50(µm)
135+++N+++
ST+++
HFF++
MCF7+++
RS++
RKO+++
136+++N+++
ST+++
HFF++
MCF7+++
RS++
RKO+++
137+++N++
ST+++
HFF+
MCF7++
RS++
RKO++
138+++N+++
ST++
HFF++
MCF7++
RS+
RKO+++
139+++N++
ST++
HFF +
MCF7++
RS++
RKO+++

ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
140+++N++
ST++
HFF+
MCF7++
RS++
RKO+++
141+++
142+++N++
ST++
HFF+
MCF7++
RS+
RKO++
143+++A++
N++
ST+++
HFF++
MCF7+++
RS++
RKO+++
144++
145+++N+
ST+
HFF+
MCF7+
RS+
RKO+
146++
147+++N+
ST+

ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
HFF+
MCF7+
RS+
RKO+
148++N++
ST++
HFF+
MCF7++
RS+
RKO++
149+++N++
ST++
HF +
MCF7+
RS+
RKO+
150++N+
ST+
HFF+
MCF7+
RS+
RKO+
151+++N+
ST+
HFF+
MCF7+
RS+
RKO+

ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
152++N+
ST+
HFF+
MCF7+
RS+
RKO+
153+++N+
ST+
HFF+
MCF7+
RS+
RKO+
154+++A+++
N+++
ST++
HFF+
MCF7+++
RS+
RKO+++
155+++N+
ST+
HFF+
MCF7+
RS+
RKO+
156+++N+
ST+
HFF+
MCF7+
RS+

ExampleThe average pIC50inhibition of the enzyme PLKMew cell lineIC50(µm)
RKO+
157+++N+++
ST +++
HFF+
MCF7+++
RS+++
RKO+++

The example of the pharmaceutical composition

The pharmaceutical preparation of the compound of example 143 used as initial solution for subsequent dilution for infusion of 5%dextrose in water (D5W)containing acetic acid (10 mm), contains a compound at a concentration of 4 mg/ml in 0.1m acetate (pH 5.0).

Preparation of the starting solution of the compound (4 mg/ml): 20 ml vial is weighed 40 mg connections, add 10 ml of 0.1 m acetate buffer solution and treated with ultrasound for 25 minutes.

The preparation of a pharmaceutical preparation, diluted for infusion (0.1 mg/ml solution of compound of 4 mg/ml): 100 ml volumetric flask quantitatively transfer 2.5 ml of the original solution and diluted to the volume with a mixture of 10 mm acetic acid / 90% D5W.

1. Derivatives of thiophene of the General formula (I)

where R1selected from the group consisting of H, -C(O)R7, -CO2R7, -C(O)NR7R8, -C(O)N(R7OR8, -C(O)N(R7)-R2-OR8, -C(O)N(R7)-Ph, -C(O)N(R7)-R2-Ph, -C(O)N(R7)S(O)2R8, -R2-OR7, -R2-O-C(O)R7, -C(S)R7, -C(S)NR7Rsup> 8, -C(S)N(R7)-Ph, -C(S)N(R7)-R2-Ph, -R2-SR7, -CN, -OR7and Het;

Ph represents phenyl;

Het represents tetrazolyl;

Q1represents a group of formula -(R2)a(Y1)b-(R2)c-R3where

a, b and C are identical or different and each independently denotes 0 or 1 and at least one of a or b is 1;

n means 0, 1, 2, 3 or 4;

Q2represents a group of formula -(R2)aa(Y2)bb(R2)cc-R4

or two adjacent groups Q2represent-OR7and together with the carbon atoms to which they are linked, form a 5-7-membered heterocycle having 1 or 2 heteroatoms selected from O;

AA, bb and cc are the same or different and each independently denotes 0 or 1;

Y1and Y2the same or different and each is independently selected from the group consisting of-O-, -S(O)f, -N(R7)-, -C(O)-, -C(O)N(R7)-, -OS(O)2-, -N(R7)S(O)2- , and-N(R7)C(O)-;

R2the same or different and each is independently selected from the group consisting of alkylene, Alcanena and akinlana;

R3and R4the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, alkenyl, quinil, C(O)R7, -C(O)NR7 R8, -CO2R7, -C(S)R7, -OR7, -S(O)fR7, -NR7R8, -N(R7)S(O)2R8, -CN and a group of the formula (II)

where ring a is selected from the group consisting of C5-10cycloalkyl, aryl, 5-10-membered heterocycle having 1, 2 or 3 heteroatoms selected from N, O and S and 5-10-membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S; R2is alkylene;

each d is 0 or 1;

E. means 0, 1, 2, 3 or 4;

R6the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, Ph, -CH(OH)-R2HE, -C(O)R7, -C(O)NR7R8, -C(S)R7=O,

-OR7, -S(O)fR7, -S(O)2Ph, -NR7R8, -NO2and-CN;

and when in the definition of Q1b mean 1 and mean 0, then R3not is halogen, -C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, -OR7, -S(O)fR7, -NR7R8, -N(R7)S(O)2R8or-CN;

and when in the definition of Q2bb is 1 and cc is 0, then R4not is halogen, -C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, -OR7, -S(O)fR7,-NR 7R8, -N(R7)S(O)2R8or-CN;

R5selected from the group consisting of H, alkyl, and-NR7R8;

f denotes 0, 1 or 2; and

each R7and each R8the same or different and each is independently selected from the group consisting of H, alkyl;

moreover, when R1represents-CO2CH3and n means 0, Q1is not HE,

or its pharmaceutically acceptable salt or MES.

2. The compound according to claim 1, where R1selected from the group consisting of-C(O)R7, -CO2R7and-C(O)NR7R8.

3. The compound according to claim 1, where R1selected from the group consisting of-CO2R7and-C(O)NR7R8.

4. The compound according to any one of claims 1 to 3, where b means 1.

5. The compound according to claim 1, where in the definition of Q1b means 1 and Y1selected from-O-, -N(R7)-, -OS(O)2-, -N(R7)SO2- , and-N(R7)C(O)-.

6. The compound according to claim 1, with means 1.

7. The compound according to claim 1, where R3selected from the group consisting of H, alkyl, alkenyl, quinil and groups of the formula (II)

8. The compound according to claim 1, where R3represents a group of formula (II) and ring a is selected from aryl, 5-10-membered heterocycle having 1, 2 or 3 heteroatoms selected from N, O and S and 5-10-membered heteroaryl having 1, 2 or 3, g is teratoma, selected from N, O and S.

9. The compound according to claim 1, where R3represents a group of formula (II) and ring a is selected from the group consisting of cycloalkyl, tetrahydropyran, research, piperidine, phenyl, thiophene, furan, pyridyl and

10. The compound according to claim 1, where Q1selected from the group consisting of the following:

and

11. The compound according to claim 1, where R3represents a group of formula (II) and e is 0, 1, 2, or 3.

12. The compound according to claim 1, where R3represents a group of formula (II) and d is 0.

13. The compound according to claim 1, where R3represents a group of formula (II) and R6the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, alkenyl, quinil, cycloalkyl, -OR7, -S(O)fR7, -NR7R8, -NO2and-CN.

14. The compound according to claim 1, where n means 0, 1 or 2.

15. The compound according to claim 1, where in the definition of Q2bb is 1 and Y2represents-O-, -S(O)f, -N(R7 )-, -C(O)-, -C(O)N(R7)-, -N(R7)S(O)2- , and-N(R7)C(O)-.

16. The compound according to claim 1, where cc stands for 1.

17. The compound according to claim 1, where R4the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, alkenyl, -OR7, -S(O)fR7, -NR7R8, -N(R7)S(O)2R8and groups of the formula (II)

.

18. The compound according to claim 1, where R5represents H, alkyl or-NR7R8.

19. A compound selected from the group consisting of

5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)-benzyl]oxy}thiophene-2-carboxamide;

5-(5-(metiloksi)-6-{[2-(4-methyl-1-piperazinil)ethyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate;

3-[1-(2-chlorophenyl)ethoxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide;

5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[1-(2-were)ethoxy]thiophene-2-carboxamide;

5-(5-amino-1H-benzimidazole-1-yl)-3-[1-(2-chlorophenyl)ethoxy]thiophene-2-carboxamide;

5-{6-[(4-piperidinylmethyl)oxy]-1H-benzimidazole-1-yl}-3-({[2-(trifluoromethyl)phenyl]-methyl}oxy)-2-thiophenecarboxylate;

5-(6-(metiloksi)-5-{[3-(2-oxo-1-pyrrolidinyl)propyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate;

5-[6-{[3-(dimethylamino)propyl]oxy}5-(metiloksi)-1H-benzimidazole-1-yl]-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate;

5-(5-(metiloksi)-6-{[2-(4-morpholinyl)ethyl]oxy}-1H-benzimidazole-1-yl)-3-({[2-(trifluoromethyl)phenyl]methyl}oxy)-2-thiophenecarboxylate;

5-[6-(2-morpholine-4-ylethoxy)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide;

5-[6-(2-pyrrolidin-1 ylethoxy)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide;

5-[5-fluoro-6-(2-morpholine-4-ylethoxy)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide;

5-[6-(methylsulphonyl)-1H-benzimidazole-1-yl]-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide;

3-[(3-bromopyridin-4-yl)methoxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide;

5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-{[2-(triptoreline)benzyl]oxy}thiophene-2-carboxamide;

3-{[2-(deformedarse)benzyl]oxy}-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide;

3-[(2-chloropyridin-3-yl)methoxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide;

5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(2-herperidin-3-yl)methoxy]thiophene-2-carboxamide;

3-[(2-aminopyridine-4-yl)methoxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide;

3-[(6-chloro-1,3-benzodioxol-5-yl)methoxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide;

5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(2-nitrobenzyl)oxy]TIF is n-2-carboxamide;

3-[(3-aminobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide;

5-(6-bromo-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]-oxy}thiophene-2-carboxamide;

3-[(2,6-dichlorobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide;

3-[(2-bromobenzyl)oxy]-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)thiophene-2-carboxamide;

5-(5,6-dimethoxy-1H-benzimidazole-1-yl)-3-[(2-formylmethyl)oxy]thiophene-2-carboxamide;

5-(1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide;

5-(1H-benzimidazole-1-yl)-3-[(2-nitrobenzyl)oxy]thiophene-2-carboxamide;

5-(6-methoxy-1H-benzimidazole-1-yl)-3-{[2-(trifluoromethyl)benzyl]oxy}thiophene-2-carboxamide;

2-(aminocarbonyl)-5-(5,6-dimethoxy-1H-benzimidazole-1-yl)Tien-3-yl-2-methylbenzenesulfonate;

and their pharmaceutically acceptable salts, solvate.

20. The pharmaceutical composition inhibiting PLK (Polo-like kinase), which contains the compound according to any one of claims 1 to 19.

21. The pharmaceutical composition according to claim 20, further containing a pharmaceutically acceptable carrier, diluent or excipient.

22. The pharmaceutical composition according to claim 20, further containing chemotherapeutic agent.

23. A method of obtaining a compound according to any one of claims 1 to 19, including the interaction of the compounds of formula (III)

with the compound of the formula (IV)

where R10selected from the group consisting of alkyl and suitable protective group of carboxylic acid, Q2and R5have the meanings indicated in claim 1.

24. The method according to item 23, further comprising a stage of transformation of compounds of formula (I) and its pharmaceutically acceptable salt or MES.

25. The method according to any of PP and 24 additionally includes the stage of transformation of compounds of formula (I) or its pharmaceutically acceptable salt or MES into another compound of formula (1) or its pharmaceutically acceptable salt or MES.

26. A pharmaceutical composition comprising a compound according to any one of claims 1 to 19, intended for use in the treatment of susceptible neoplasms in animals.

27. The compound of formula (Ib)

where R1selected from the group consisting of H, -C(O)R7, -CO2R7, __-C(O)NR7R8, -C(O)N(R7OR8, -C(O)N(R7)-R2-OR8, -C(O)N(R7)-Ph, -C(O)N(R7)-R2-Ph, -C(O)N(R7)S(O)2R8, -R2OR7, -R2-O-C(O)R7, -C(S)R7, -C(S)NR7R8, -C(S)N(R7)-Ph, -C(S)N(R7)-R2-Ph, -R2-SR7, -CN, -OR7and Het;

Ph represents phenyl;

p num="1291"> Het represents tetrazolyl;

n means 0, 1, 2, 3 or 4;

Q2represents a group of formula -(R2)aa(Y2)bb-(R2)cc-R4

or two adjacent groups Q2represent-OR7and together with the carbon atoms to which they are linked, form a 5-7-membered heterocycle having 1 or 2 heteroatoms selected About;

AA, bb and CC are the same or different and each independently denotes 0 or 1;

Y2the same or different and each is independently selected from the group consisting of-O-, -S(O)f, -N(R7)-, -C(O)-, -C(O)N(R7)-, -OS(O)2-, -N(R7)S(O)2- , and-N(R7)C(O)-;

R2is alkylene;

R4the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, alkenyl, quinil, C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, -OR7, -S(O)fR7, -NR7R8, -N(R7)S(O)2R8, -CN and a group of the formula (II)

where ring a is selected from the group consisting of C5-10cycloalkyl, aryl, 5-10-membered heterocycle having 1, 2 or 3 heteroatoms selected from N, O and S;

R2is alkylene;

each d is 0 or 1;

E. means 0, 1, 2, 3 or 4;

R6the same or different and each is independently selected from the group consisting of N, halogeno, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, Ph, -CH(OH)-R2-OH, -C(O)R7, -C(O)NR7R8, -C(S)R7,

=O, -OR7, -S(O)fR7, -S(O)2Ph, -NR7R8, -NO2and-CN;

and when in the definition of Q2bb is 1 and cc is 0, then R4not is halogen, -C(O)R7, -C(O)NR7R8, -CO2R7, -C(S)R7, OR7, -S(O)fR7, -NR7R8, -N(R7)S(O)2R8or-CN;

R5selected from the group consisting of H, alkyl, and-NR7R8;

f denotes 0, 1 or 2 and

each R7and each R8the same or different and each is independently selected from the group consisting of H, alkyl; and

R9the same or different and each is selected from H and alkyl,

or its pharmaceutically acceptable salt or MES.

28. R-isomer of the compound according to item 27.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compound represented by the structural formula: or its pharmaceutically acceptable salt wherein Z represents -(CH2)n-; double dotted line represents a double bond; n = 0-2; R1 and R2 are chosen independently from the group comprising hydrogen atom (H), alkyl with 1-6 carbon atoms; R3 means H, hydroxy-, alkoxy-group with 1-6 carbon atoms, -C(O)OR17 or alkyl with 1-6 carbon atoms; Het means monocyclic heteroaromatic group consisting of 6 atoms and comprising 5 carbon atoms and one heteroatom chosen from nitrogen atom (N) and wherein Het is bound through ring carbon atom and wherein Het-group has one substitute W chosen independently from the group comprising bromine atom (Br), heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N; heterocycloalkyl representing group consisting of 4 carbon atoms and one heteroatom chosen from N substituted with OH-substituted alkyl with 1-6 carbon atoms or =O; R21 -aryl-NH-; -C(=NOR17)R18; R21-aryl; R41-heteroaryl representing group consisting of 5-6 atoms comprising 3-5 carbon atoms and 1-4 heteroatoms chosen independently from the group: N, S and O; R8 and R10 are chosen independently from group comprising R1; R9 means H; R11 is chosen from group comprising R1 and -CH2OBn wherein Bn means benzyl; B means -(CH2)n4CR12=CR12a(CH2)n5; n4 and n5 mean independently 0; R12 and R12a are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; X means -O-; Y means =O; R15 is absent as far as double dotted line mean a simple bond; R16 means lower alkyl with 1-6 carbon atoms; R17 and R18 are chosen independently from group comprising H, alkyl with 1-6 carbon atoms; R21 means 1-3 substituted chosen independently from group comprising hydrogen atom, -CN, -CF3, halogen atom, alkyl with 1-6 carbon atoms and so on; R22 is chosen independently from group comprising hydrogen atom; R24-alkyl with 1-10 carbon atoms; R25-aryl and so on; R23 is chosen independently from group comprising hydrogen atom, R24-alkyl with 1-10 carbon atoms, R25-aryl and -CH2OBn; R24 means 1-3 substitutes chosen independently from group comprising hydrogen atom, halogen atom, -OH, alkoxy-group with 1-6 carbon atoms; R25 means hydrogen atom; R41 means 1-4 substitutes chosen independently from group comprising hydrogen atom, alkyl with 1-6 carbon atoms and so on. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to receptors activated by protease and comprising the effective dose of derivative of nor-seco-chimbacine of the formula (I) and a pharmaceutically acceptable excipient. Also, invention relates to methods for inhibition of thrombin and cannabinoid receptors comprising administration in mammal derivative of nor-seco-chimbacine of the formula (I) in the effective dose as active substance. Invention provides derivatives of nor-seco-chimbacine as antagonists of thrombin receptors.

EFFECT: valuable medicinal and biological properties of compounds and pharmaceutical composition.

8 cl, 1 tbl, 18 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

FIELD: organic chemistry, chemical technology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of heteroaryl-substituted aminocyclohexane of the formula (I) and their pharmaceutically acceptable salts possessing the inhibitory effect on activity of 2,3-oxydosqualene-lanosterolcyclase (OSC). In the formula (I) V means a simple bond, oxygen atom (O), -CH=CH-CH2- or -C≡C-; m and n = 0-7 independently of one another and m+n = 0-7 under condition that m is not 0 if V means O; o = 0-2; A1 means hydrogen atom, lower alkyl, hydroxy-lower alkyl or lower alkenyl; A2 means lower alkyl, or A1 and A2 are bound and form 5-6-membered cycle, and -A1-A2- means (C4-C5)-alkylene; A3 and A4 mean hydrogen atom independently of one another; A5 means hydrogen atom, lower alkyl; A6 means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally substituted with one substitute chosen independently from the group including halogen atom, lower alkyl, lower alkoxy-group and 5-6-membered heteroaryl comprising nitrogen or sulfur atom as a heteroatom, Also, invention relates to a pharmaceutical composition and using proposed compound for preparing medicinal agents. Proposed compounds can be used in treatment of such diseases as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycosis, parasitic infections, cholelithiasis, tumors and/or hyperproliferative disorders, and/or in disordered tolerance to glucose and diabetes mellitus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

24 cl, 7 sch, 28 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

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

11 cl, 2 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes new derivatives of triazole of the general formula (I): wherein X represents group of the general formula (II): wherein R' means halogen atom; R4 means (C1-C6)-alkyl; L means group of the formula: -La-Lb wherein La means a simple bond, oxygen atom, phenyl group that can be optionally substituted with halogen atom, cyano-group, (C1-C6)-alkyl, (C1-C6)-alkoxy-group or (C1-C6)-alkyl substituted with a single group -O-P(=O)(OH)2, naphthyl group, 5-membered heteroaryl group comprising as a heteroatom oxygen (O) or sulfur (S) atom, or (C3-C7)-cycloalkyl group that is substituted with carboxyl group; and Lb means (C1-C5)-alkylene group that can be optionally substituted with (C1-C6)-alkyl, carboxyl group or di-[(C1-C6)-alkyl]-amino-(C1-C6)-alkyl group; R means hydrogen atom, (C1-C6)-alkanoyl that can be optionally substituted with group: -Q-NR2'R3' wherein Q means a simple bond or carbonyl group, and R2' and R3' in common with nitrogen atom with that they are bound form piperazinyl ring substituted with (C1-C6)-alkyl and/or carboxyl group, or group: -O-P(=O)(OH)2; or their pharmacologically acceptable salts, pharmaceutical composition based on thereof, and a method for treatment of fungal infections.

EFFECT: valuable medicinal properties of compounds and composition, improved method for treatment of infections.

24 cl, 14 tbl, 1 dwg, 45 ex

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, medicine, pharmacy.

SUBSTANCE: invention relates to novel biologically active compounds that act as agonists of arginine-vasopressin V2-receptors. Invention describes a derivative of 4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine represented by the general formula (I): or its pharmaceutically acceptable salt wherein symbols have the following values: R1 represents -OH, -O-lower alkyl or optionally substituted amino-group; R2 represents lower alkyl that can be substituted with one or more halogen atoms, or halogen atom; among R3 and R4 one of them represents -H, lower alkyl or halogen atom, and another represents optionally substituted nonaromatic cyclic amino-group, or optionally substituted aromatic cyclic amino-group; R5 represents -H, lower alkyl or halogen atom. Also, invention describes a pharmaceutical composition representing agonist of arginine-vasopressin V2-receptors. Invention provides preparing new compounds possessing with useful biological properties.

EFFECT: valuable medicinal properties of compound and composition.

9 cl, 18 tbl, 13 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of carboxylic acids of the formula: wherein Y is taken independently in each case among the group comprising C(O), N, CR1, C(R2)(R3), NR5, CH; q means a whole number from 3 to 10; A is taken among the group comprising NR6; E is taken among the group comprising NR7; J is taken among the group comprising O; T is taken among the group comprising (CH2)b wherein b = 0; M is taken among the group comprising C(R9)(R10), (CH2)u wherein u means a whole number from 0 to 3; L is taken among the group comprising NR11 and (CH2)n wherein n means 0; X is taken among the group comprising CO2H, tetrazolyl; W is taken among the group comprising C, CR15 and N; R1, R2, R3 and R15 are taken independently among th group comprising hydrogen atom, halogen atom, hydroxyl, alkyl, alkoxy-group, -CF3, amino-group, -NHC(O)N(C1-C3-alkyl)-C(O)NH-(C1-C3-alkyl), -NHC(O)NH-(C1-C6-alkyl), alkylamino-, alkoxyalkoxy-group, aryl, aryloxy-, arylamino-group, heterocyclyl, heterocyclylalkyl, heterocyclylamino-group wherein heteroatom is taken among N atom or O atom, -NHSO2-(C1-C3-alkyl), aryloxyalkyl; R4 is taken among the group comprising hydrogen atom, aryl, aralkyl, benzofuranyl, dihydrobenzofuranyl, dihydroindenyl, alkyl, benzodioxolyl, dihydrobenzodioxynyl, furyl, naphthyl, quinolinyl, isoquinolinyl, pyridinyl, indolyl, thienyl, biphenyl, 2-oxo-2,3-dihydro-1H-benzimidazolyl, pyrimidinyl and carbazolyl. Other values of radicals are given in the claimed invention. Also, invention relates to pharmaceutical composition used for inhibition binding α4β1-integrin in mammal based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof in aims for treatment or prophylaxis of diseases associated with α4β1-integrin.

EFFECT: improved method for inhibition, valuable medicinal properties of compounds.

33 cl, 7 tbl, 42 ex

FIELD: organic chemistry, medicinal biochemistry, pharmacy.

SUBSTANCE: invention relates to substituted benzimidazoles of the formula (I): and/or their stereoisomeric forms, and/or their physiologically acceptable salts wherein one of substitutes R1, R2, R3 and R4 means a residue of the formula (II): wherein D means -C(O)-; R8 means hydrogen atom or (C1-C4)-alkyl; R9 means: 1. (C1-C6)-alkyl wherein alkyl is linear or branched and can be free of substituted by one-, bi- or tri-fold; Z means: 1. a residue of 5-14-membered aromatic system that comprises from 1 to 4 heteroatoms as members of the cycle that represent nitrogen and oxygen atoms wherein aromatic system is free or substituted; 1.1 a heterocycle taken among the group of oxadiazole or oxadiazolone that can be unsubstituted or substituted; 2. (C1-C6)-alkyl wherein alkyl is a linear or branched and monosubstituted with phenyl or group -OH; or 3. -C(O)-R10 wherein R10 means -O-R11, -N(R11)2 or morpholinyl; or R8 and R9 in common with nitrogen atom and carbon atom with that they are bound, respectively, form heterocycle of the formula (IIa): wherein D, Z and R10 have values given in the formula (II); A means a residue -CH2-; B means a residue -CH-; Y is absent or means a residue -CH2-; or X and Y in common form phenyl. The cyclic system formed by N, A, X, Y, B and carbon atom is unsubstituted or monosubstituted with (C1-C8)-alkyl wherein alkyl is monosubstituted with phenyl, and other substitutes R1, R2, R3 and R4 mean independently of one another hydrogen atom, respectively; R5 means hydrogen atom; R6 means the heteroaromatic cyclic system with 5-14 members in cycle that comprises 1 or 2 nitrogen atoms and can be unsubstituted or substituted. Also, invention relates to a medicinal agent for inhibition of activity of IkB kinase based on these compounds and to a method for preparing the indicated agent. Invention provides preparing new compounds and medicinal agents based on thereof for aims for prophylaxis and treatment of diseases associated with the enhanced activity of NFkB.

EFFECT: valuable medicinal properties of compounds and composition.

4 cl, 7 tbl, 224 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): and their pharmaceutically acceptable salts possessing inhibitory effect on activity of dipeptidyl peptidase IV (DPP IV) that can be used, for example, in treatment of diabetes mellitus type 2. In compounds of the formula (I) X means nitrogen atom (N) or -C-R5; R1 and R2 mean independently hydrogen atom, (C1-C6)-alkyl; R3 means saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, mono-, di- or tri-substituted independently with (C1-C6)-alkyl, (C1-C6)-alkoxy-group, perfluoro-(C1-C6)-alkyl or halogen atom, phenyl, naphthyl, phenyl or naphthyl mono-, di- or tri-substituted independently with halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, or perfluoro-(C1-C6)-alkyl; R4 means (lower)-alkyl, (lower)-alkoxy-, (lower)-alkylthio-group, saturated or aromatic 7-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings, saturated or aromatic 5-7-membered heterocyclyl comprising 1-2 heteroatoms chosen from nitrogen, sulfur and oxygen atoms, possibly condensed with 1-2 benzene rings mono-, di- or tri-substituted independently with (C1-C6)-alkyl, (C1-C6)-alkoxy-group, perfluoro-(C1-C6)-alkyl or halogen atom, phenyl, naphthyl, phenyl or naphthyl mono-, di- or tri-substituted independently with halogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-, amino-group or perfluoro-(C1-C6)-alkyl, 4-fluorophenyloxy-(C1-C6)-alkyl or (C3-C6)-cycloalkyl; R5 means hydrogen atom or (C1-C6)-alkyl. Also, invention relates to methods for synthesis of compounds of the formula (I), pharmaceutical compositions and their using for preparing medicaments used in treatment and/or prophylaxis of DPP IV-mediated diseases.

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

21 cl, 93 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel class of 5-membered heterocyclic compounds of the general formula (I): or cosmetically acceptable salts. Invention describes a compound represented by the formula (I) and its pharmaceutically or cosmetically acceptable salt wherein R1 is chosen from linear or branched (C1-C12)-alkyl, (C3-C7)-cycloalkyl, phenyl, naphthyl, C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatoms when they present are chosen independently from oxygen (O), nitrogen (N) or sulfur (S) atom and substituted optionally wherein substitutes are chosen from the first group comprising halogen atom, hydroxy0, nitro-, cyano-, amino- oxo-group and oxime, or from the second group comprising linear or branched (C1-C8)-alkyl wherein a substitute from indicated second group is optionally substituted with R10, or wherein heteroaryl is substituted with -CH2-C(O)-2-thienyl; Y is absent or chosen from the group consisting of (C1-C12)-alkyl-Z or (C2-C8)-alkyl wherein Z is chosen from sulfur, oxygen or nitrogen atom; A and B are chosen independently from nitrogen atom (N), -NH, -NR6, sulfur, oxygen atom to form heteroaromatic ring system; R2, R3 and R4 are chosen independently from the first group comprising hydrogen, halogen atom, or R3 and R4 form phenyl ring in adjacent positions; R5 is absent or chosen from the group comprising -CH2-phenyl, -CH2(CO)R7, -CH2(CO)NHR8 and -CH2(CO)NR8R9 that are substituted optionally with R10; R6, R7, R8 and R are chosen independently from the group comprising linear or branched (C1-C8)-alkyl, (C3-C7)-cycloalkyl, C5-heterocycloalkyl, benzylpiperidinyl, phenyl, naphthyl, heteroaryl, alkylheteroaryl, adamantyl, or R8 and R9 form piperidine ring, and R means 3,4-ethylenedioxyphenyl wherein substitutes in indicated group are substituted optionally with R10, and heteroaryl means C3-, C4-, C5- or C8-heteroaryl wherein one or some heteroatom when they present are chosen independently from O, N or S; R10 is chosen from halogen atom, hydroxy-, nitro-, cyano-, amino-, oxo-group, perhalogenalkyl-(C1-C6) or oxime; X means halide ion under condition that when groups/substitutes present at the same or at adjacent carbon or nitrogen atoms then can form optionally 5-, 6- or 7-membered ring optionally containing one o some double bonds and containing optionally one or some heteroatoms chosen from O, N or S. Also, invention describes a method for synthesis of these compounds, their therapeutic and cosmetic using, in particular, in regulation of age and diabetic vascular complications. Proposed compounds show effect based on the triple effect as agent destroying AGE (terminal products of enhanced glycosylation), inhibitors of AGE and scavengers of free radicals that do their suitable in different therapeutic and cosmetic using. Also, invention relates to pharmaceutical and cosmetic compositions comprising these compounds and to methods for treatment of diseases caused by accumulation of AGE and/or free radicals in body cells. Invention provides synthesis of novel compounds possessing useful biological properties.

EFFECT: valuable medicinal properties of compounds.

73 cl, 4 tbl, 63 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of novel derivatives of 4,5-dihydro-1H-pyrazole that are strong antagonists of cannabinoid (CB1) receptor and useful in treatment of diseases associated with disorders of cannabinoid system. Compounds have the general formula (Ia) or (Ib) wherein symbols are given in the invention claim. Also, invention relates to method for synthesis of these compounds, their using, intermediate compounds for synthesis of proposed compounds and to a pharmaceutical composition comprising at least one of these compounds as an active component.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 1 tbl, 100 ex

FIELD: organic chemistry, chemical technology, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of heteroaryl-substituted aminocyclohexane of the formula (I) and their pharmaceutically acceptable salts possessing the inhibitory effect on activity of 2,3-oxydosqualene-lanosterolcyclase (OSC). In the formula (I) V means a simple bond, oxygen atom (O), -CH=CH-CH2- or -C≡C-; m and n = 0-7 independently of one another and m+n = 0-7 under condition that m is not 0 if V means O; o = 0-2; A1 means hydrogen atom, lower alkyl, hydroxy-lower alkyl or lower alkenyl; A2 means lower alkyl, or A1 and A2 are bound and form 5-6-membered cycle, and -A1-A2- means (C4-C5)-alkylene; A3 and A4 mean hydrogen atom independently of one another; A5 means hydrogen atom, lower alkyl; A6 means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally substituted with one substitute chosen independently from the group including halogen atom, lower alkyl, lower alkoxy-group and 5-6-membered heteroaryl comprising nitrogen or sulfur atom as a heteroatom, Also, invention relates to a pharmaceutical composition and using proposed compound for preparing medicinal agents. Proposed compounds can be used in treatment of such diseases as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycosis, parasitic infections, cholelithiasis, tumors and/or hyperproliferative disorders, and/or in disordered tolerance to glucose and diabetes mellitus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

24 cl, 7 sch, 28 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for preparing 3,4-diaryl(hetaryl)maleimides of the formula (I): wherein R means (C1-C4)-alkyl or benzyl, or phenyl; R1 means bromine atom (Br) or aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group; Ar means aryl, such as phenyl or naphthyl substituted with alkyl, alkoxy-group or halogen atom; unsubstituted hetaryl or substituted, such as thienyl-, benzothienyl-, furyl-, benzofuryl-, pyrrolyl or indolyl- wherein substitutes represent alkyl, alkoxy-, alkylthio-group, halogen atom or trifluoromethyl group with exception for 3,4-di-(2,5-dimethyl-3-thienyl)-1-butylmaleimide. Method involves interaction of aryl(hetaryl)boronic acid of the formula: ArB(OH)2 wherein Ar has abovementioned values with N-substituted 3,4-dibromomaleimide of the formula (III): or N-substituted 3-bromo-4-aryl(hetaryl)maleimide of the formula (IV) wherein R and Ar have abovementioned values and with using palladium catalyst in the presence of base in organic solvent medium. Also, invention to some new derivatives of 3,4-diaryl(hetaryl)maleimides that show photochrome properties.

EFFECT: improved preparing method.

7 cl, 2 dwg, 14 ex

FIELD: organic chemistry, medicine, chemical-pharmaceutical industry, pharmacy.

SUBSTANCE: invention relates to a pharmaceutical composition comprising S-isomer of compound of the formula (I) or its pharmaceutically acceptable salts and solvates in common with a pharmaceutically acceptable vehicle. Also, invention relates to a method for synthesis of compound S-isomer of the formula (I), and to a method for treatment of disease relating to the group comprising respiratory diseases, allergic diseases, dermatological diseases, gastroenteric diseases and ophthalmic diseases. The composition provides avoiding adverse sedative effects in treatment of indicated diseases.

EFFECT: valuable medicinal properties of compounds.

14 cl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepines of the general formula (I):

wherein X means ordinary bond or ethynediyl group wherein if X mean ordinary bond then R1 means halogen atom or phenyl substituted with halogen atom optionally or (C1-C7)-alkyl group; in case when X means ethynediyl group then R1 mean phenyl substituted with halogen atom optionally; R2 means halogen atom, hydroxy-group, lower alkyl, lower alkoxy-group, hydroxymethyl, hydroxyethyl, lower alkoxy-(ethoxy)n wherein n = 1-4, cyanomethoxy-group, morpholine-4-yl, thiomorpholine-4-yl, 1-oxothiomorpholine-4-yl, 1,1-dioxothiomorpholine-4-yl, 4-oxopiperidine-1-yl, 4-(lower)-alkoxypiperidine-1-yl, 4-hydroxypiperidine-1-yl, 4-hydroxyethoxypiperidine-1-yl, 4-(lower)-alkylpiperazine-1-yl, lower alkoxycarbonyl, 2-di-(lower)-alkylaminoethylsulfanyl, N,N-bis-(lower)-alkylamino-(lower)-alkyl, (lower)-alkoxycarbonyl-(lower)-alkyl, (lower)-alkylcarboxy-(lower)-alkyl, lower alkoxycarbonylmethylsulfanyl, carboxymethylsulfanyl, 1,4-dioxa-8-azaspiro[4,5]dec-8-yl, carboxy-(lower)-alkoxy-group, cyano-(lower)-alkyl, 2-oxo[1,3]dioxolane-4-yl-(lower)-alkoxy-group, 2,2-dimethyltetrahydro[1,3]dioxolo[4,5-c]pyrrole-5-yl, (3R)-hydroxypyrrolidine-1-yl, 3,4-dihydroxypyrrolidine-1-yl, 2-oxooxazolidine-3-yl, carbamoylmethyl, carboxy-(lower)-alkyl, carbamoylmethoxy-, hydroxycarbamoyl-(lower)-alkoxy-, lower alkoxycarbamoyl-(lower)-alkoxy-, (lower)-alkylcarbamoylmethoxy-group; R3 means phenyl, thiophenyl, pyridinyl that are substituted with halogen atom, cyano-group, carbamoyl, imidazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl wherein groups of 1,2,3-triazolyl, 1,2,4-triazolyl or isoxazolyl are substituted optionally with (C1-C7)-alkyl or (C1-C7)-alkylsulfanyl, and to their pharmaceutically acceptable salts. Also, invention describes a medicinal agent that is antagonist of mGlu receptors of the group II based on compound of the formula (I). The medicinal agent can be used in treatment and prophylaxis of acute and/or chronic neurological disturbances including psychosis, schizophrenia, Alzheimer's disease, disturbances in cognitive ability and memory damage.

EFFECT: valuable medicinal properties of compounds.

7 cl, 1 tbl, 98 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of benzodiazepine of the general formula (I)

and their pharmaceutically acceptable acid-additive salts wherein X means a ordinary bond or ethynediyl group; when X means ordinary bond then R1 means halogen atom, (lower)-alkyl, (lower)-alkylcarbonyl, (lower)-cycloalkyl, benzoyl, phenyl substituted optionally with halogen atom, hydroxyl, (lower)-alkyl, (lower)-alkoxy-group, halogen-(lower)-alkoxy-group or cyano-group; styryl, phenylethyl, naphthyl, diphenyl, benzofuranyl, or 5- or 6-membered heterocyclic ring representing thiophenyl, furanyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl which are optionally substituted; when X means ethynediyl group then R1 means hydrogen atom, (lower)-alkyl substituted optionally with oxo-group; (lower)-cycloalkyl substituted with hydroxyl; (lower)-cycloalkenyl substituted optionally with oxo-group; (lower)-alkenyl, optionally substituted phenyl; 5- or 6-membered heterocyclic ring representing thiophenyl, thiazolyl, pyridinyl, dihydropyridinyl, tetrahydropyridinyl or dihydropyranyl and substituted optionally; R3 means phenyl, pyridyl, thiophenyl or thiazolyl which are substituted optionally. These compounds can be used for treatment or prophylaxis of acute and/or chronic neurological diseases, such as psychosis, schizophrenia, Alzheimer's disease, disorder of cognitive ability and memory disorder. Also, invention describes a medicinal agent based on these compounds and a method for preparing compounds of the formula (I).

EFFECT: improved method for preparing, valuable medicinal properties of compounds.

10 cl, 1 tbl, 173 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

FIELD: organic chemistry of natural compounds, medicine, pharmacy.

SUBSTANCE: invention relates to novel compounds of the formula (I): , wherein each R1, R2 and R3 means independently hydrogen atom or (C1-C4)-alkyl; R4 means (C1-C12)-alkyl optionally comprising from one to three substitutes chosen from group including hydroxy-group, (C1-C12)-alkoxycarbonyl, carbamoyl, (C2-C7)-alkenyl, (C6-C10)-aryl optionally comprising from one to three substitutes chosen from group including halogen atom, (C1-C12)-alkyl, (C1-C12)-alkoxy-, hydroxy-, (C1-C12)-alkylcarbonylamino-group, (C6-C10)-aryl-(C1-C12)-alkyl wherein aryl group comprises optionally from one to three substitutes chosen from group comprising halogen atom, (C1-C12)-alkyl, (C1-C12)-alkoxy-group, heterocyclyl-(C1-C12)-alkyl; R5 means hydroxy-, (C3-C7)-cycloalkylamino-group optionally substituted with phenyl, (C6-C10)-arylamino-, (C6-C10)-aryl-(C1-C4)-alkylamino-group optionally comprising from one to three substitutes chosen from group comprising sulfamoyl, (C1-C12)-alkyl, (C1-C12)-alkoxy-, hydroxy-group, heterocyclyl or benzyl, (C1-C4)-alkoxy-, benzhydrazino-group, heterocyclyl optionally comprising from one to three substitutes chosen from group including benzyl, benzhydryl, heterocyclylamino-group wherein heterocyclyl means saturated, unsaturated or aromatic monovalent cyclic radical comprising from 1 to 3 heteroatoms chosen from nitrogen (N), oxygen (O) and sulfur (S) atoms, or to their combination; n means a whole number 0, 1 or 2. Compounds of the formula (I) elicit anti-proliferative activity that allows their using in pharmaceutical composition. Also, invention describes intermediate compounds.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

30 cl, 1 tbl, 69 ex

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