Tyrosine kinase inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula I: or its pharmaceutically acceptable salt or stereoisomer, where a is independently equal to 0 or 1; b is independently equal to 0 or 1; R1 is selected from aryl, heterocyclyl and NR10R11; said aryl or heterocyclyl group is optionally substituted with between one and five substitutes, each independently selected from R8; R5 is selected from C1-6alkyl, C2-6alkenyl, -C(=O)NR10R11, NHS(O)2NR10R11 and NR10R11, each alkyl, alkenyl or aryl is optionally substituted with between one and five substitutes, each independently selected from R8; R8 independently denotes (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)aObheterocyclyl, OH, Oa(C=O)bNR10R11 or (C=O)aCbC3-C8cycloalkyl, said alkyl, aryl, heterocyclyl are optionally substituted with one, two or three substitutes selected from R9; R9 is independently selected from (C=O)aCb(C1-C10)alkyl and N(Rb)2; R10 and R11 is independently selected from H, (C=O)Cb(C1-C10)alkyl, C1-C10alkyl, SO2Ra, said alkyl is optionally substituted with one, two or three substitutes selected from R8 or R10 and R11 can be taken together with nitrogen to which they are bonded with formation of a monocyclic heterocycle with 5 members in each ring and optionally contains one or two heteroatoms, in addition to the nitrogen, selected from N and S, said monocyclic heterocycle is optionally substituted with one, two or three substitutes selected from R9; Ra is independently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and Rb is independently selected from H, (C1-C6)alkyd, as well as to a pharmaceutical composition for inhibiting receptor tyrosine kinase MET based on this compound, as well as a method of using said compound to produce a drug.

EFFECT: novel compounds which can be used to treat cell proliferative diseases, disorders associated with MET activity and for inhibiting receptor tyrosine kinase MET are obtained and described.

8 cl, 32 ex, 4 tbl

 

PRIOR art

This invention relates to compounds 5H-benzo[4,5]cyclohepta[1,2-b]pyridine, which are inhibitors of tyrosinekinase, in particular the receptor tyrosine kinase MET and are applicable in the treatment of cellular proliferative diseases, for example cancer, hyperplasia, restenosis, cardiac hypertrophy, immune disorders and inflammation.

Recently members protooncogene family MET, subfamily receptordependent attract special attention in connection with invasion and metastasis. The family MET, including METH (also known as C-Met and RON receptor can function as oncogenes like most tyrosinekinase. It is shown that METH sverkhekspressiya and/or mutated in various malignant processes. The number of METH-activating mutations, many of which are located in the tyrosine kinase domain, was found in various solid tumors and is involved in invasion and metastasis of tumor cells.

Protooncogen C-Met encodes the MET receptor tyrosinekinase. The MET receptor is a glycosylated dimeric complex of 190 kDa, composed of 50 kDa alpha chain linked by disulfide bonds with 145 kDa beta chain. The alpha chain is detected extracellular, whereas the beta chain contains extracellular, transmembrane and cytosolic domains. METH synth is Seretse as predecessor and proteoliticeski cleaved with getting a Mature alpha and beta subunits. It has structural similarities with semaphoring and placename, the ligand-receptor family, which is included in the interaction of cells.

It is known that stimulation of MET through a growth factor for hepatocytes (also known as the scattering factor, HGF/SF) leads to the abundance of biological and biochemical effects in the cell. Activation of C-Met signaling mechanism can lead to a wide variety of cellular responses, including proliferation, survival, angiogenesis, wound healing, tissue regeneration, scattering, motility, invasion and branching morphogenesis. The signaling mechanism of HGF/MET c-Met also plays a major role in invasive growth, which is found in most tissues, including cartilage, bone, blood vessels and neurons.

Various C-Met mutations have been well described in multiple solid tumors and some hematological malignant disorders. Examples of the prototypical C-Met mutations can be observed in hereditary and sporadic papillary renal carcinoma person (Schmidt, L. et al., Nat. Tenet. 1997, 16, 68-73; Jeffers, M. et al., Proc. Nat. Acad. Sci. 1997. 94, 11445-11500). Other examples of C-Met mutations include ovarian cancer, childhood hepatocellular carcinoma, metastatic squamous cell carcinoma of head and neck cancers and stomach. It is shown that the signaling mechanism of HGF/MET inhibits anoic is with, the suspension-induced programmed cell death (apoptosis) in cells of squamous cell carcinoma of the head and neck.

The signaling mechanism of MET is involved in various types of cancer, especially kidney. The link between METH and colorectal cancer was also installed. In addition, when compared with the primary tumor in 70% of colorectal cancer with metastases in the liver demonstrates overexpression of MET. METH is also involved in glioblastoma. The expression of MET in the glioma correlates with the severity of gliomas and analysis of samples of human tumor showed that malignant gliomas have a 7-fold excess of HGF content than mild gliomas. Many studies have demonstrated that human gliomas often coexpression HGF and MET, and that high levels of expression associated with the development of malignancy. Additionally, it was shown that HGF-MET is able to activate Akt and protect cell lines gliomas from apoptotic death both in vitro and in vivo.

RON shares a similar structure, biochemical characteristics and biological properties with the MET. Studies have shown the overexpression of RON a significant portion of carcinomas of the breast and colorectal adenocarcinomas, but not in normal epithelium of the mammary gland or benign lesions. Experiments on the stitching showed that RON and MET form a non-covalent is a complex on the cell surface and interact in intracellular signaling mechanism. Genes RON and MET much coexpressed in cell motility of ovarian cancer and invasiveness. This suggests that coexpress these two related receptors may provide a selective advantage to cells carcinoma of the ovary at the time of the occurrence and development of tumors.

Recently, was published a number of reviews on METH and its function as an oncogene: Cancer and Metastasis Review 22: 309-325 (2003); Nature Reviews/Molecular Cell Biology 4:915-925 (2003); Nature Reviews/Cancer 2:289-300 (2002).

Since dysregulation of the signaling mechanism of HGF/MET implicated as a factor in the Genesis of tumors and the development of disease in many tumors, it is necessary to develop different strategies for therapeutic inhibition of this important molecule RTK. Specific small molecule inhibitors against the signaling mechanism of HGF/MET and against signaling mechanism RON/MET have important therapeutic value for the treatment of cancers in which the activity Met contributes to the invasive/metastatic phenotype.

SUMMARY of the INVENTION

The present invention relates to derivatives of 5H-benzo[4,5]cyclohepta[1,2-b]pyridine, which are applicable for the treatment of cellular proliferative diseases, for treating disorders associated with the activity MET and inhibition of the receptor tyrosine kinase Met. Compounds of the invention can be represented by formula I

DETAILED description of the INVENTION

The compounds of this invention are applicable for inhibition of tyrosinekinase, in particular the receptor tyrosine kinase MET, and are illustrated by the compound of the formula I:

or its pharmaceutically acceptable salt or a stereoisomer, where

and independently is 0 or 1;

b is independently 0 or 1;

m independently is 0, 1 or 2;

R1selected from aryl, heterocyclyl and NR10R11; specified aryl or heterocyclyl group optionally substituted by one to five substituents, each Deputy is independently selected from R8;

R5selected from hydrogen, C1-6of alkyl, C2-6alkenyl, HE, -O-C1-6of alkyl, -O-C(=O)1-6of alkyl, -O-aryl, S(O)mRa, -C(=O)NR10R11, -NHS(O)2NR10R11and NR10R11each alkyl, alkenyl and aryl optionally substituted by one to five substituents, each Deputy is independently selected from R8;

R8independently is a (C=O)aObC1-C10alkyl, (C=O)aObaryl, C2-C10alkenyl,2-C10quinil, (C=O)aObheterocyclyl, CO2H, halogen, CN, IT, ObC1-C6perfluoroalkyl, Oand(C=O)bNR10R 11, S(O)mRa, S(O)2NR10R11, OS(=O)Ra, oxo, Cho, (N=O)NR10R11or (C=O)aObC3-C8cycloalkyl specified alkyl, aryl, alkenyl, quinil, heterocyclyl and cycloalkyl, optionally substituted one, two or three substituents selected from R9;

R9independently selected from: (C=O)aOb(C1-C10)alkyl, Ob(C1-C3)perfluoroalkyl, oxo, HE, halogen, CN, (C2-C10)alkenyl, (C2-C10)quinil, (C=O)aOb(C3-C6)cycloalkyl, (C=O)aOb(C0-C6)alkylaryl, (C=O)aOb(C0-C6)accelerationtime, (C=O)aOb(C0-C6)alkylene-N(Rb)2C(O)Ra, (C0-C6)alkylene-CO2RaC(O)H, (C0-C6)alkylene-CO2H, C(O)N(Rb)2, S(O)mRaand S(O)2NR10R11; specified alkyl, alkenyl, quinil, cycloalkyl, aryl and heterocyclyl optionally substituted one, two or three substituents selected from Rb, OH, (C1-C6)alkoxy, halogen, CO2H, CN, O(C=O)C1-C6alkyl, oxo, and N(Rb)2;

R10and R11independently selected from: H, (C=O)Ob(C1-C10)alkyl, (C=O)ObC3-C8cycloalkyl, (C=O)Obaryl, (C=O) bheterocyclyl, C1-C10of alkyl, aryl, C2-C10alkenyl,2-C10the quinil, heterocyclyl, C3-C8cycloalkyl, SO2Ra(C=O)NRb2these alkyl, cycloalkyl, aryl, heterocyclyl, alkenyl and quinil optionally substituted one, two or three substituents selected from R8or

R10and R11can be taken together with the nitrogen to which they are attached with the formation of the monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, these monocyclic or bicyclic a heterocycle optionally substituted by one, two or three substituents selected from R9;

Raindependently selected from (C1-C6)alkyl, (C2-C6)alkenyl, (C3-C6)cycloalkyl, aryl, -(C1-C6)alkylaryl, heterocyclyl and -(C1-C6)accelerationtime; and

Rbindependently selected from H, (C1-C6)alkyl, aryl, -(C1-C6)alkylaryl, heterocyclyl, -(C1-C6)accelerationtime, (C3-C6)cycloalkyl, (C=O)OS1-C6of alkyl, (C=O)1-C6the alkyl or S(O)2Ra.

Specific examples of joint the present invention include:

3-phenyl-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

7-ethyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

7-[(2,4-dimethoxybenzyl)amino]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

7-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

2-hydroxy-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)propanamide;

N-methyl-5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carboxamide;

7-isobutyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;

N-[5-oxo-3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;

7-(isopropylamino)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

N-[(2R)-1,4-dioxane-2-ylmethyl]-N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-]benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)sulphonamide;

N-[(2S)-1,4-dioxane-2-ylmethyl]-N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulphonamide;

the racemic mixture of N-[1,4-dioxane-2-ylmethyl]-N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulphonamide;

N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(tetrahydrofuran-3-yl)sulphonamide;

N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-({3R}tetrahydrofuran-3-yl)sulphonamide;

N-methyl-N'-[3-(1-methyl-1H-shall irsol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-({3S}tetrahydrofuran-3-yl)sulphonamide;

N-(5-oxo-3-pyridin-4-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;

N-[5-oxo-3-(1H-pyrazole-3-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;

N-[5-oxo-3-(1,3-thiazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;

N-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;

N-[5-oxo-3-(1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;

N-(3-{1-[2-(dimethylamino)ethyl]-1H-pyrazole-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;

N-{3-[1-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazole-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;

N-(4-{7-[methylsulphonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-yl}phenyl)methanesulfonamide;

N-[3-(1-cyclopentyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;

N-{3-[1-(3,3-dimethyl-2-oxobutyl)-1H-pyrazole-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;

N-[2-(1-methylpyrrolidine-2-yl)ethyl]-3-{7-[(methylsulphonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-yl}benzamide;

N,N-dimethyl-N'-[3-(1-methyl-1H-pyrazole-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulphonamide;

7-(5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

7-[(2,4-dimethoxybenzyl)amino]-3-(3-thienyl)-5H-BAA is zo[4,5]cyclohepta[1,2-b]pyridine-5-he;

7-amino-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

7-[(2,4-dimethoxybenzyl)amino]-3-(1H-pyrazole-3-yl)-5H-benzene[4,5]cyclohepta[1,2-b]pectin-5-he;

N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(tetrahydrofuran-3-yl)sulphonamide;

7-[(imidazo[1,2-a]pyridine-3-ylmethyl)amino]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

7-{[(1-methyl-5-oxopyrrolidin-2-yl)methyl]amino}-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(tetrahydro-2H-Piran-2-ylmethyl)sulphonamide;

N-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N'-(tetrahydrofuran-3-yl)sulphonamide;

N-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]morpholine-4-sulfonamide;

N-[3-(4-isopropylpiperazine-1-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;

3-(4-isopropylpiperazine-1-yl)-7-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

N-(3-morpholine-4-yl-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;

N-(3-aniline-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;

N-[3-(cyclohexylamino-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;

N-[5-oxo-3-(pyridine-4-ylamino)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]metasolv the amide;

N-(2,4-dimethoxybenzyl)-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)etranslate;

N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)etranslate;

N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-pyrrolidin-1-retensioned;

dimethyl[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H - benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]amidophosphate;

7-[(1R)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

7-[(1S)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

7-(2-hydroxyethyl)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

7-(1,2-dihydroxyethyl)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

7-[(1R)-1-methoxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

7-[(1S)-1-methoxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

tert-butyl 4-[2-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-hydroxyethyl]piperazine 1-carboxylate;

tert-butyl 4-{2-hydroxy-2-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]ethyl}piperazine 1-carboxylate;

7-(1-hydroxy-2-piperazine-1-retil)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;

or is farmacevtichesky acceptable salt or stereoisomer.

Compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E. L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190) and can occur as racemates, racemic mixtures and as individual diastereomers, with all possible isomers and mixtures, including optical isomers, all such stereoisomers are included in the present invention. Additionally, the compounds disclosed herein may exist as tautomers and imply that both tautomeric forms are covered by the scope of claims of the invention, even if depicted only one tautomeric structure.

Obviously, one or more silicon atoms (Si) can be introduced into compounds of the present invention instead of the one or more carbon atoms by a person skilled in the art to produce compounds that are chemically stable and that can be synthesized by methods known in the art from readily available starting materials. Carbon and silicon differ in their covalent radius, which leads to differences in bond length and steric arrangement, when comparing similar relationships With element and Si element. These differences lead to small changes in the size and shape of the silicon-containing compounds than the s with carbon. The person skilled in the art will understand that the differences in size and shape can lead to minor or major changes in activity, solubility, lack of target activity, packing properties, etc. (Diass, J.O. et al. Organometallics (2006) 5:1188-1198; Showell, G. A. et al. Bioorganic & Medicinal Chemistry Letters (2006) 16:2555-2558).

If any radical (for example, R7, R8, Rband so on) appears more than once in any element, its definition in each case is independent at every other case. Also, combinations of substituents and radicals are solvable only if such combinations result in stable compounds. Line drawn inside the ring systems from substituents represent that the above relationship can be attached to any of the substitutable ring atoms. If the ring system is polycyclic, imply that the link attached to any of the acceptable carbon atoms only at the proximal ring.

Assume that substituents and substitution procedure, compounds of the present invention may be selected by the person skilled in the art to produce compounds that are chemically stable and can be easily synthesized by methods known in the art, as well as those methods set forth below, from readily available source of washes the century If the Deputy himself superseded by more than one group, it is clear that these multiple groups can be on the same carbon or on different carbons, while this leads to a stable structure. The phrase “optionally substituted with one or more substituents” should be considered equivalent to the phrase “optionally substituted by at least one Deputy, and in such cases, another option implementation will have from zero to three substituents.

As used here, implies that “alkyl” includes both branched and primocane saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. For example, With1-C10as in “C1-C10alkyl”is defined as including groups having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbons in a linear or branched arrangement. For example, “C1-C10alkyl” specifically includes methyl, ethyl, n-propyl, ISO-propyl, n-butyl, t-butyl, ISO-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, etc. the Term “cycloalkyl” means a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms. For example, “cycloalkyl” includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, etc. In the embodiment, izopet is of the term “cycloalkyl” includes groups, described just above, and further includes a monocyclic unsaturated aliphatic hydrocarbon group. For example, “cycloalkyl”, as defined in this embodiment, includes cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopentyl, cyclohexyl, cyclopentenyl, cyclobutenyl etc.

The term “alkylene” means hydrocarbon diradical group having the specified number of carbon atoms. For example, “alkylene” includes-CH2-,

-CH2CH2and so on

When used in the phrases “C1-C6aralkyl” and “C1-C6heteroalkyl”, the term “C1-C6” refers to the alkyl portion of the fragment and does not describe the number of atoms in the aryl and heteroaryl portions of the fragment.

“Alkoxy” represents either a cyclic or acyclic alkyl group with the specified number of carbon atoms attached through an oxygen bridge. “Alkoxy”therefore encompasses the definitions of alkyl and cycloalkyl above.

If not defined the number of carbon atoms, the term “alkenyl” refers to non-aromatic hydrocarbon moiety, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon-carbon double bond. Preferably there is one carbon-operon what I dual link, and can attend up to four non-aromatic carbon-carbon double bonds. Thus, “C2-C6alkenyl” means alkanniny radical having from 2 to 6 carbon atoms. Alkeneamine groups include ethynyl, propenyl, butenyl, 2-methylbutanal and cyclohexenyl. Straight, branched or cyclic part alkenylphenol group may contain double bonds and may be substituted, if substituted Alchemilla group.

The term “quinil” refers to a hydrocarbon moiety, straight, branched or cyclic, containing from 2 to 10 carbon atoms and at least one carbon-carbon triple bond. Can contain up to three carbon-carbon triple bonds. Thus, “C2-C6quinil” means alkynylaryl radical having from 2 to 6 carbon atoms. Alkyline group include ethinyl, PROPYNYL, butynyl, 3-methylbutanal etc. Straight, branched or cyclic part alkenylphenol group may contain a triple bond and may be substituted, if substituted Alchemilla group.

In some cases, the substituents can be defined with an interval of hydrocarbons, which includes zero, such as (C0-C6)alkylen-aryl. If aryl is phenyl, this definition includes phenyl, and CH2Ph, -CH2CH2Ph, C(CH 3)CH2CH(CH3)Ph, etc.

As used here, implies that “aryl” shall mean any stable monocyclic or bicyclic carbon ring that contains up to 7 atoms in each ring, where at least one ring is aromatic. Examples of such aryl elements include phenyl, naphthyl, tetrahydronaphthyl, indanyl and biphenyl. In cases where the aryl Deputy is bicyclic and one ring is non-aromatic, understand that this connection occurs through the aromatic ring.

The term heteroaryl, as used here, represents a stable monocyclic or bicyclic ring containing up to 7 atoms in each ring, where at least one ring is aromatic and contains from 1 to 4 heteroatoms selected from the group consisting of O, N and S. Heteroaryl groups within the scope of the claims include, but are not limited to: acridines, carbazolyl, cinnoline, honokalani, pyrazolyl, indolyl, benzotriazolyl, furanyl, thienyl, benzothiazyl, benzofuranyl, chinoline, ethenolysis, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridinyl, pyrimidinyl, pyrrolyl, tetrahydroquinolin. As with the definition of heterocycle below, understand that heteroaryl” includes N-oxide derivative of any nitrogen-containing heteroaryl. In SL the teas, where heteroaryl Deputy is bicyclic and one ring is non-aromatic or contains no heteroatoms, understand that connection is through an aromatic ring or through the ring containing the heteroatom, respectively.

Assume that the term “heterocycle” or “heterocyclyl”, as used here, means a 3-10 membered aromatic or nonaromatic a heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups. For the purposes of this invention, the term “heterocyclic” also viewed as synonymous with the terms “heterocycle” and “heterocyclyl” and realize that they also have the definitions presented here. “Heterocyclyl”therefore includes the above heteroaryl and their dihydro and tetrahydro analogs. Additional examples of “heterocyclyl” include, but are not limited to, the following: azetidinol, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzimidazolyl, benzotriazolyl, benzothiophene, benzoxazole, carbazolyl, carbolines, cinnoline, furanyl, imidazolyl, indolinyl, indolyl, indolizinyl, indazoles, isobenzofuranyl, isoindolyl, ethanolic, isothiazolin, isoxazolyl, naphthyridine, oxadiazole, oxazole, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl,pyridazinyl, pyridopyrimidines, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, hintline, hinely, honokalani, tetrahydropyranyl, tetrahydropyranyl, tetrahydroisoquinoline, tetrazolyl, tetrasulphides, thiadiazolyl, thiazolyl, thienyl, triazolyl, 1,4-dioxane, hexahydroazepin, piperazinil, piperidinyl, pyridine-2-IMT, pyrrolidinyl, morpholinyl, thiomorpholine, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydroisoxazole, dihydrofurane, dihydroimidazole, dihydroindole, dihydroisoxazole, dihydroisoxazole, dihydroimidazole, dihydrooxazolo, dihydropyrazine, dihydropyrazolo, dihydropyridines, dihydropyrimidines, dihydropyrrole, dihydroquinoline, dihydrotetrazolo, dihydrothiazolo, dihydrothiazolo, dehydration, dihydrotriazine, dihydroisocodeine, methylenedioxybenzyl, tetrahydrofuranyl and tetrahydrothieno and their N-oxides. Join heterocyclic substituent may take place via a carbon atom or through a heteroatom.

In the embodiment, assume that the term “heterocycle” or “heterocyclyl”, as used here, means a 5-10 membered aromatic or nonaromatic a heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups. “Heterocyclyl” in this variationbetween, hence, includes the above heteroaryl and their dihydro and tetrahydro analogs. Additional examples of “heterocyclyl” include, but are not limited to, the following: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzimidazolyl, benzotriazolyl, benzothiophene, benzoxazole, carbazolyl, carbolines, cinnoline, furanyl, imidazolyl, indolinyl, indolyl, indolizinyl, indazoles, isobenzofuranyl, isoindolyl, ethanolic, isothiazolin, isoxazolyl, naphthyridine, oxadiazole, oxazole, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyrimidines, pyridazinyl, pyridyl, pyrimidyl, pyrrolyl, hintline, hinely, honokalani, tetrahydropyranyl, tetrahydropyranyl, tetrahydroisoquinoline, tetrazolyl, tetrasulphides, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidine, 1,4-dioxane, hexahydroazepin, piperazinil, piperidinyl, pyridine-2-IMT, pyrrolidinyl, morpholinyl, thiomorpholine, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydrobenzofuranyl, dihydroisoxazole, dihydrofurane, dihydroimidazole, dihydroindole, dihydroisoxazole, dihydroisoxazole, dihydroimidazole, dihydrooxazolo, dihydropyrazine, dihydropyrazolo, dihydropyridines, dihydropyrimidines, dihydropyrrole, dihydroquinoline, dihydrotetrazolo, dihydrate azolyl, dihydrothiazolo, dehydration, dihydrotriazine, dihydroisocodeine, methylenedioxybenzyl, tetrahydrofuranyl and tetrahydrothieno and their N-oxides. Join heterocyclic substituent may take place via a carbon atom or through a heteroatom.

In yet another embodiment, the heterocycle selected from 2-azapirone, benzimidazolyl, 2-diazepinone, imidazolyl, 2-imidazolidinone, indolyl, izochinolina, morpholinyl, piperidyl, piperazinil, pyridyl, pyrrolidinyl, 2-piperidine, 2-pyrimidinone, 2-pyrrolidinone, chinoline, tetrahydrofuryl, tetrahydroisoquinoline and tanila.

As will be appreciated by specialists in this field “halo” or “halogen”, as used here, is intended to include chlorine, fluorine, bromine and iodine.

Alkyl, alkanniny, alkynylaryl, cycloalkenyl, aryl, heteroaryl and heterocyclyl substituents can be substituted or unsubstituted, unless specifically defined otherwise. For example, (C1-C6)alkyl may be substituted by one, two or three substituents selected from HE, oxo, halogen, alkoxy, dialkylamino or heterocyclyl, such as morpholinyl, piperidinyl etc. In this case, if one Deputy represents oxo and the other represents IT, the following is included in the definition:

-(C=O)CH2CH(OH)CH3-(C=IS)HE, -CH2(HE)CH2CH(Oh) etc.

The fragment formed when two R8or two R9attached to one carbon atom combined with education -(CH2)uas follows:

In addition, such cyclic fragments can optionally include one or two heteroatoms. Examples of such heteroaromatic cyclic fragments include, but are not limited to:

In some cases, R10and R11defined in such a way that they can be taken together with the nitrogen to which they are attached, with the formation of the monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said heterocycle optionally substituted by one or more substituents selected from R8. Examples of the heterocycles that can be formed this way include, but are not limited to the following, keeping in mind that the heterocycle optionally substituted by one or more (in one embodiment, one, two or three) substituents selected from R8:

In the embodiment, Formula I R1is selected from aryl and heterocyclyl; criminal code of the above aryl and heterocyclyl group optionally substituted by one to five substituents, each Deputy is independently selected from R8.

In the embodiment, Formula I R5choose from C1-6of alkyl, C2-6alkenyl, HE, -O-C1-6of alkyl, -O-C(=O)1-6of alkyl, -O-aryl, S(O)mRa, -C(=O)NR10R11,

-NHS(O)2NR10R11and NR10R11each alkyl, alkenyl, quinil and aryl optionally substituted by one to five substituents, each Deputy is independently selected from R8.

In the present invention included the free form of compounds of formula I and their pharmaceutically acceptable salts and stereoisomers. Some of the specific compounds represented here in the form of examples are protonated salts of amines. The term “free form” refers to amines in mesolevel form. Covered pharmaceutically acceptable salt not only include the salts are given as examples of specific compounds described herein, but also all the typical pharmaceutically acceptable salt free form of compounds of formula I. Free form described specific salt compounds can be isolated using methods known in the art. For example, the free form can be regenerated by treatment of the salt with a suitable dilute aqueous solution of a base, such as dilute aqueous NaOH, CA carbonate is Oia, ammonia and sodium bicarbonate. Available forms may differ from their respective salt forms somewhat in their specific physical properties, such as solubility in polar solvents, but the acid and basic salts are otherwise pharmaceutically equivalent to their respective free forms for the purposes of the invention.

Pharmaceutically acceptable salts of these compounds can be synthesized from the compounds of this invention which contain a basic or acidic fragment by conventional chemical methods. In General, the salts of the basic compounds are given either ion exchange chromatography or by reaction of the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents. Similarly salts of acidic compounds formed by reactions with the corresponding inorganic or organic base.

Thus, pharmaceutically acceptable salts of the compounds of this invention include the conventional non-toxic salts of the compounds of this invention formed by the interaction of the major of the present compounds with inorganic or organic Ki is lotai. For example, conventional non-toxic salts include salts derived from inorganic acids such as hydrochloric, Hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as salts derived from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, amoeba, maleic, hydroxymaleimide, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluensulfonate, methanesulfonate, ethicality, oxalic acid, setinova, triperoxonane etc.

When the compound of the present invention is acidic, the appropriate term “pharmaceutically acceptable salt” refers to salts derived from pharmaceutically acceptable non-toxic bases, including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum salts, ammonium, calcium, copper, iron (II), iron (III), lithium, magnesium, manganese, potassium, sodium, zinc and the like, Especially preferred are salts of ammonium, calcium, magnesium, potassium and sodium. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including prirodnye substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenziletilendiaminom, diethylamin, 2-Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, geranamine, Isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polianinova resins, procaine, purines, theobromine, triethylamine, trimethylamine, Tripropylamine, tromethamine and the like

When the compound of the present invention is acidic, the term “free form” refers to the connection in his mesolevel form, so that the acid functionality is still protonated.

Getting pharmaceutically acceptable salts described above, and other typical pharmaceutically acceptable salts are more fully described in Berg et al., “Pharmaceutical Salts”, J. Pharm. Sci., 1977:66:1-19.

Will also be noted that the compounds of the present invention can potentially be an internal salt or zwitterion, since under physiological conditions deprotonirovannym acid fragment in the connection, such as a carboxyl group may be anionic, and this electronic charge can then be internally balanced against cationic charge protonated or alkylated main fragment, such as a Quaternary nitrogen atom. You elenoa connection, with the internal balance of charges, thus is not associated with intermolecular counterion may also be considered a “free form” connections.

Some abbreviations used in the schemes and examples, are defined below:

APCIChemical ionization at atmospheric pressure
DMFDimethylformamide
DMSOThe sulfoxide
EtOAcThe ethyl acetate
LCMSLiquid chromatography-mass spectrometry
MPLCLiquid chromatography medium pressure
NBSN-bromosuccinimide
TFATriperoxonane acid
TFAATriperoxonane anhydride

The compounds of this invention can be obtained by using the reactions, as shown in the following schemes, in addition to other standard manipulations that are known in the literature or presented in the ideal examples in the experimental methods. Illustrative diagrams below, therefore, are not limited to these listed compounds or by any particular substituents used for illustrative purposes. The numbering of the substituents, as shown in the diagrams, not necessarily correlate with the numbering used in the claims, and often, for clarity, only the Deputy is shown attached to the compound, where there are multiple substituents, in terms of the definitions of Formula I here above in this description.

SCHEMA

As shown in Scheme A, the reaction of the appropriately substituted 2-methylnicotinate a-1 with a strong base followed by reaction with appropriately substituted bromobenzaldehyde provides olefinic intermediate a-2. Subsequent cyclization mediated polyphosphorous acid, provides intermediate/connection of the invention a-3.

The scheme illustrates the use of intermediate a-3 in the receipt of these compounds with a variety of amine and sulfide substituents.

The scheme illustrates the introduction of R1through a combination of Suzuki respectively substituted Bronevoy acid or a complex ester Bronevoy acid chloride condensed peredelnogo rings of these compounds.

Scheme D illustrates an alternative set of reactions of these compounds in the region have the substituted amine substituents on the phenyl ring.

Receipt of these compounds, where R5represents a functionalized methyl, illustrated in Scheme E. Thus, ester F-1 is restored by providing diol E-2, which selectively protect and further oxidized with the receipt of this compound E-4. Removing protection provides the alcohol E-5, which can further be converted to many other functional groups by methods well known in this field.

Scheme F illustrates an alternative method for the formation of the tricyclic ring system of these compounds. Thus, the appropriately substituted nicotinergic F-1 is converted to the intermediate F-2, which interacts with the appropriately substituted Bronevoy acid with getting benzaldehyde F-3. Intermediate F-3 may then undergo indirect base cyclization to obtain the present compound F-4.

Getting the bearing hydroxyl alkyl side chain substituent R5illustrated in scheme G of vinyl substitute.

Scheme H illustrates obtaining appropriately substituted amide fragments for the substituent R1.

SCHEME AND

SCHEMA

SCHEME

SCHEME D

SCHEME E

SCHEME F

SCHEME G

SCHEME N

Applicability

Compounds of the invention are applicable to bind and/or modulate tyrosine kinase activity, in particular the receptor tyrosine kinase. In the embodiment, receptor tyrosinekinase is a member of the subfamily MET. In an additional embodiment, the SUBJECT is a human SUBJECT, despite the fact that the activity of the receptor tyrosinekinase from other organisms may also be modulated by the compounds of the present invention. In this context, means to modulate or increase or decrease the activity of the kinase MET. In the embodiment, compounds of the present invention inhibit the activity of the kinase MET.

Compounds of the invention find application in a variety of applications. As will be appreciated by skilled specialists in the field of technology, the kinase activity of MET can be modulated in various ways; for example, one can affect the phosphorylation/activation of MET either through modulation of the initial phosphorylation of the protein, or by modulating autophosphorylation other active sites of the protein. Alternative is, the kinase activity of MET can be modulated by affecting the binding of substrate phosphorylation MET.

Compounds of the invention are used for treatment or prevention of cell proliferative diseases. Painful condition that can be treated by the methods and compositions provided herein include, but are not limited to, cancer (further discussed below), autoimmune disease, arthritis, graft rejection, inflammatory bowel disease, proliferation induced after medical procedures, including, but not limited to, surgery, angioplasty, etc. Should be taken into account that in some cases, the cells may not be in Hyper - or hypoproliferative state (abnormal state) and still require treatment. Thus, in one embodiment, the invention involves the use of cells or regions that are affected by or can gradually become exposed to any one of these disorders or conditions.

Compounds, compositions and methods are particularly applicable to believe the treatment and prevention of cancer, including solid tumors, such as carcinoma of the skin, breast, brain, cervix, carcinoma of testis, etc. In the embodiment, these compounds are applicable is advised for the treatment of cancer. Particularly, cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to:heart: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;light: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chandraratna hamartoma, mesothelioma;gastrointestinal tract: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (running adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small intestine (adenocarcinoma, lymphoma, carcinoid tumor, sarcoma Corpse, leiomyomata, hemangioma, lipoma, neurofibroma, fibroma), the colon (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma), rectal, colorectal and colon;urinary tract: kidney adenocarcinoma, the tumor Wilma [nephroblastoma], lymphomas, leukemias, papillary renal carcinoma), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenoma the Inom), prostate adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, horiokartsinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumor, lipoma);liver: hepatoma (hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;bones: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, abnormal Ewing sarcoma, malignant lymphoma (reticular cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochondroma (osteocartlaginous exostoses), benign chondroma, chondroblastoma, chondromyxoid, osteopenia osteoma and giant cell tumors;nervous system: skull (osteoma, hemangioma, granulomas, xanthoma, osteitis deformans), meninges (meningioma, meningococcemia, gliomas), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma [pinealoma], glioblastoma multiforme, oligodendroglioma, Sanoma, retinoblastoma, congenital tumors), neurofibroma spinal cord meningioma, glioma, sarcoma);gynecologic: the uterus (endometrial carcinoma), uterine cervix (cervical carcinoma, the precancerous cervical dysplasia), ovaries (carcinoma aicn the Cove [serous cystadenocarcinoma, slizeobrazujushchej cystadenocarcinoma, unclassified carcinoma], granulato-techline cell tumor cell tumor Sertoli-cells, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoidal sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma);hematological: blood (myeloid leukemia [acute and chronic], acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin disease, non-jackinsky lymphoma [malignant lymphoma];leather: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, this form may cell carcinoma of the head and neck, sarcoma Karposi, “moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; andthe adrenal glands: neuroblastoma. Thus, the term “cancer cell”, as provided herein, includes a cell is subjected to any one of the above-mentioned conditions. In another embodiment, compounds of the present invention are applicable for the treatment or prevention of a cancer selected from: this form may cell carcinoma of the neck and on Ovi, histiocytoses lymphoma, lung adenocarcinoma, small cell lung cancer, both lung cancer, pancreatic cancer, papillary renal carcinoma, liver cancer, stomach cancer, colon cancer, multiple myeloma, glioblastomas and breast carcinoma. In another embodiment, compounds of the present invention are applicable for the treatment of cancer selected from: histiocytoses lymphoma, lung adenocarcinoma, small cell lung cancer, pancreatic cancer, liver cancer, colon cancer, multiple myeloma, glioblastomas and breast carcinoma. In another embodiment, compounds of the present invention are used to treat a cancer selected from ovarian cancer, child hepatocellular carcinoma, metastatic, this form may cell carcinomas of the head and neck, gastric cancer, breast cancer, colorectal cancer, cervical cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, glioblastomas and sarcomas.

In another embodiment, compounds of the present invention are applicable for the prevention or modulation of metastasis of cancer cells and cancer. In particular, compounds of the present invention are applicable for the prevention or modulation of metastasis of gastric cancer, de the civil hepatocellular carcinoma, metastatic this form may cell carcinomas of the head and neck, cancers of the stomach, breast cancer, colorectal cancer, cervical cancer, lung cancer, nasopharyngeal cancer, pancreatic cancer, glioblastomas and sarcomas.

The compounds of this invention can be introduced mammals, such as humans, either individually or in combination with pharmaceutically acceptable carriers, excipients or diluents in a pharmaceutical composition in accordance with standard pharmaceutical practice. The compounds can be administered orally or parenterally, including intravenous, intramuscular, intraperitoneal, subcutaneous, rectal and local routes of administration.

Pharmaceutical compositions containing the active ingredient may be in a form suitable for oral administration, for example as tablets, lozenges, pellets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use can be obtained in accordance with any method known in the manufacture of pharmaceutical compositions and such compositions may contain one or more means selected from the group consisting of sweeteners, corrigentov, dyes and konserveerimisel, in order to obtain pharmaceutically elegant and rassasyvanie drugs. Tablets contain the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients which are suitable for manufacture of tablets. These excipients may constitute, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and dezintegriruetsja tools, such as microcrystalline cellulose, croscarmellose sodium, corn starch, or alginic acid; binders, for example starch, gelatin, polyvinyl-pyrrolidone or acacia, and lubricants, for example magnesium stearate, stearic acid or talc. Tablets may be uncoated or they may be covered with well-known methods for masking the unpleasant taste of the medicine or delay disintegration and absorption in the gastrointestinal tract and thereby provide a prolonged action over a longer period. For example, there may be used water-soluble masking the taste of a substance, such as hypromellose or hydroxypropylcellulose, or providing a time delay substance, such as ethylcellulose, butyrate cellulose acetate.

Ready-made forms for oral administration can, t is the train to be presented as hard gelatin capsules, where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules where the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active substance in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspendresume agents, such as carboxymethylcellulose sodium, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, gum tragakant and gum acacia; dispersing or wetting agents may be a natural phosphated, for example lecithin, or condensation products of accelerated with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as monooleate polyoxyethylenesorbitan, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides hexitol n the example monooleate of polyoxyethylenesorbitan. Aqueous suspensions may also contain one or more preservatives, for example ethyl or n-propyl p-hydroxybenzoate, one or more dyes, one or more corrigentov and one or more sweeteners, such as sucrose, saccharin or aspartame.

Oil suspensions can be obtained in the form prepared by suspension of the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweeteners, such as above, and corrigentov can be added to provide rasskazyvaemoe oral drug. These compositions may be preserved by the addition of an antioxidant, such as bottled hydroxyanisol or alpha-tocopherol.

Dispersible powders and granules suitable for receiving the aqueous suspension by the addition of water provide the active ingredient in a mixture with dispersing or wetting agent, suspendium means and one or more preservatives. Suitable dispersing or wetting means and suspendresume means illustrated by the examples already given above. Further the s excipients, for example, sweeteners, corrigentov and dyes, can also be represented. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

The pharmaceutical compositions of the invention can also be in the form of emulsions of oil-in-water. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or mineral oil, for example liquid paraffin or mixtures thereof. Suitable emulsifying means can be a natural phosphatides, for example lecithin soybeans, and esters or partial esters derived from fatty acids and anhydrides hexitol, such as monooleate sorbitan, and condensation products of these partial esters with ethylene oxide, such as monooleate of polyoxyethylenesorbitan. The emulsion may also contain sweeteners, Corrigan, preservatives and antioxidants.

Syrups and elixirs can be obtained in the form of ready-made forms with sweeteners, such as glycerin, propylene glycol, sorbitol or sucrose. Such forms may also contain a means of reducing the irritation, preservative, corrigent and dyes and antioxidants.

Pharmaceutical compositions can also be in the form of a sterile injectable aqueous solutions. Among priemlemye and solvents, which can be used are water, ringer's solution and isotonic sodium chloride solution.

The sterile injectable preparation may also be a sterile injectable microemulsion of the oil-in-water, where the active ingredient is dissolved in the oil phase. For example, the active ingredient may be first dissolved in a mixture of soybean oil and lecithin. The oil solution is then injected into the mixture of water and glycerine and process with the formation of microemulsions.

Injectable solutions or microemulsions may be injected into the bloodstream of the patient with the help of local bolus injection. Alternatively, it may be beneficial to introduce the solution or microemulsion thus, in order to maintain a constant circulating concentration of the present compounds. To maintain this constant concentration, you can use the device for continuous intravenous delivery. An example of such device is the Deltec CADD-PLUSTMmodel 5400.

The pharmaceutical compositions can be in the form of sterile injectable aqueous or oily suspension for intramuscular and subcutaneous injection. This suspension can be obtained in the form of ready-made forms in accordance with known in the art, using suitable dispersing or wetting means and suspen arousih funds referred to above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example in the form of a solution in 1,3-butanediol. In addition, sterile fixed oils common use as a solvent or suspendida environment. For this purpose, can be used any sedative fixed oils, including synthetic mono - or diglycerides. In addition, fatty acids such as oleic acid find use in obtaining drugs for injection.

The compounds of Formula I can also be entered in the form of suppositories for rectal administration of medication. These compositions can be obtained by mixing the drug with a suitable non-irritating by excipients, which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such substances include cocoa butter, glitserinovoye gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weights and fatty acid esters of polyethylene glycol.

For local applications, the use of creams, ointments, jellies, solutions or suspensions, etc. containing the compounds of Formula I (For the purposes of this application, the local application will include rinsing the mouth and gargling.)

Compounds of the present invention can be administered in intranasal form via topical application of suitable intranasal environments and delivery devices, or via transdermal routes, using those forms of transdermal patches, which are well known to those of ordinary skill in the art. For administration in the form of a percutaneous delivery system, the dose will be, undoubtedly, more continuous than alternating throughout the dosage regimen.

The dosage using the compounds of the present invention can be selected in accordance with various factors including type, species, age, weight, sex and type of cancer to be treated; the severity (i.e. stage) of the cancer to be treated; the route of administration; the renal function and liver of the patient; and the specific compound or its salt. A physician or veterinarian of ordinary skill can readily determine and prescribe the effective amount of the drug required for treatment, for example to prevent, inhibit (fully or partially) or stop the progress of the disease.

One presents as an example the application of a suitable amount of compound administered to a mammal undergoing treatment for cancer. The introduction of a quantity in the range from about 0.1 mg/kg body weight is up to 60 mg/kg of body weight per day, preferably in the range from 0.5 mg/kg of body weight up to 40 mg/kg of body weight per day.

For example, the compounds of the present invention can be administered in a total daily dose of up to 1000 mg of the Compounds of the present invention can be administered once daily (QD) or be divided into multiple daily doses as twice daily (BID) and three times a day (TID). Compounds of the present invention can be administered in a total daily dose of up to 1000 mg, for example 200, 300, 400, 600, 800 or 1000 mg which may be administered in a single daily dose or can be divided into multiple daily doses, as described above.

In addition, the introduction may be continuous, i.e. for every day, or alternating. The terms “alternating” or “sequentially”as used here, means the stop and start with either regular or irregular intervals. For example, alternating the introduction of the compounds of the present invention may be the introduction from one to six days a week, or it may mean the introduction of cycles (e.g., daily administration for two to eight consecutive weeks, then a rest period without the introduction of up to one week), or it could mean the introduction on alternating days.

In addition, the compounds of the present invention can be administered in accordance with any of the modes described above consistently for several not the fir, with the subsequent rest period. For example, the compounds of the present invention can be administered in accordance with any of the modes described above, from two to eight weeks, followed by a rest period equal to one week, or twice daily at a dose equal to 100-500 mg for three to five days a week. In another specific embodiment, compounds of the present invention can be administered three times daily for two consecutive weeks, followed by one week of rest.

These compounds are also applicable in combination with known therapies and anti-cancer agents. For example, these compounds are applicable in combination with known anticancer agents. Examples of such tools can be found in Cancer Principles and Practice of Oncology by V. T. Devita and S. Hellma (editors), 6thedition (February 15, 2001), Lippincott Williams & Wilkins Publishers. An ordinary specialist in the art will be able to understand what combination of tools will be applicable based on the specific characteristics of the drug and treat cancers. Such anti-cancer tools include, but are not limited to the following: receptor modulators estrogen receptor modulators, androgen, the receptor modulators retinoids, a cytotoxic/cytostatic tools, antiproliferative funds inhibitors Hairdryer the l-protein transferase, inhibitors of HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and signaling pathways of survival tools that affect checkpoints of the cell cycle. These compounds are especially applicable when they are administered in conjunction with radiation therapy.

The term “cytotoxic/cytostatic funds” refers to compounds which cause cell death or inhibit cell proliferation primarily influencing directly the functioning of cells, or inhibit or affect mitosis of cells, including alkylating funds, factors, tumor necrosis, intercalatory, connections, activating hypoxia, means inhibiting microtubule/stabilizing microtubules, inhibitors of mitotic kinesins, = inhibitors of kinases involved in the development of mitosis, antimetabolites; biological response modifiers; hormonal/antihormonal therapeutic agents, hematopoietic growth factors, therapeutic agents, labeled monoclonal antibodies, topoisomerase inhibitors, proteasome inhibitors and inhibitors of ubaidillah.

Examples of cytotoxic agents include, but are not limited to, serene, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamin, prednimustine, dibromodulcitol, ranimustine, fotemustine, adpla is in, oxaliplatin, temozolomide, heptaplatin, estramustin, improsulfan toilet, trofosfamide, nimustine, dobropillia chloride, punitive, lobaplatin, satraplatin, propiomazine, cisplatin, irofulven, Taxifolin, CIS-amindian(2-methylpyridine)platinum, benzylguanine, glufosfamide, GPX100, (TRANS, TRANS, TRANS)-bis-mu-(hexane-1,6-diamine)-mu-[diaminopurine(II)]bis[diamine(chloro)platinum(II)]tetrachloride, dianisidines, arsenic trioxide, 1-(11-dodecylamino-10-hydroxyphenyl)was 3.7-dimethylxanthine, zorubicin, idarubitsin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinfed, valrubicin, amrubicin, antineoplaston, 3'-deamino-3'-morpholino-13 deoxo-10-hydroxylaminopurine, annamycin, gorovici, alienated, MEN10755 and 4 dimethoxy-3-deamino-3-aziridinyl-4-methylsulfonylbenzoyl (see WO 00/50032).

The term “introduction” and its variants (e.g., “introduction” connections) in respect of compounds of the invention means introducing the compound or prodrug of the compound into the system of an animal in need of treatment. When the compound of the invention or a prodrug is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.), “introduction” and its variants are each understood to include consistent and sequential introduction of the compound or its prodrug and other media the TV.

As used here, the term “composition” is intended to encompass a product that contains the prescribed ingredients in specified amounts, as well as any product which results, directly or indirectly, a combination of prescribed ingredients in specified amounts.

The term “therapeutically effective amount”, as used here, refers to an amount of active compound or pharmaceutical agent that exhibits a biological or medical response in a tissue, system, animal or person sought by a researcher, veterinarian, medical doctor or other Clinician.

The term “cure cancer” or “cancer treatment” refers to administration to a mammal exposed to a cancerous state, and refers to the effect that facilitates cancer by killing cancer cells, but also to the effect, which leads to inhibition of growth and/or metastasis of a cancer.

In the embodiment, the inhibitor of angiogenesis for use as the second compound is selected from a tyrosine kinase inhibitor, an inhibitor of growth factor-derived epidermis, inhibitor of growth factor-derived fibroblasts, inhibitor of growth factor-derived platelet inhibitor of MMP (matrix metalloprotease), a blocker of the integrin, interferon-α, interleukin-12, pentosanpolysulfate, an inhibitor of cyclooxygenase, carboxamidates, combretastatin a-4, squalamine, 6-O-chloroacetyl-carbonyl)fumakilla, thalidomide, angiostatin, troponin-1, or antibodies to VEGF. In the embodiment, the modulator of the receptor estrogen is tamoxifen or raloxifene.

Also in the scope of the claims included a method of treating cancer, which comprises the introduction of a therapeutically effective amount of the compounds of Formula I in combination with radiation therapy and/or in combination with a compound selected from the modulator of estrogen receptor, a modulator of androgen receptor, receptor modulator retinoids, a cytotoxic/cytostatic tools, antiproliferative funds inhibitor phenyl-protein transferase, an inhibitor of HMG-CoA reductase inhibitor of HIV protease, reverse transcriptase inhibitors, inhibitors of angiogenesis, agonist of PPAR-γ agonists of PPAR-δ; inhibitor characteristic resiliently to many drugs, protivoastmaticheskogo means, means applicable in the treatment of anemia, tools, applicable in the treatment of neutropenia, medications that strengthen the immune system, an inhibitor of cell proliferation and signaling pathways of survival tools, which affects the checkpoint of the cell cycle, and means inducing apoptosis.

<> And yet another embodiment of the invention is a method of treating cancer, which comprises the introduction of a therapeutically effective amount of the compounds of Formula I in combination with one or more therapeutic means: abarelix (Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukine®); Alemtuzumab (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamin (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacytidine (Vidaza®); bevacizumab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomib (Velcade®); busulfan intravenous (Busulfex®); busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustin (BCNU®, BiCNU®); carmustine (Gliadel®); carmustin with Polifeprosan 20 Implant (Gliadel Wafer®); celecoxib (Celebrex®); cetuximab (Erbitux®), chlorambucil (Leukeran®), cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); Clofarabine (Clolar®), cyclophosphamide (Cytoxan®, Neosar®), cyclophosphamide (Cytoxan Injection®), cyclophosphamide (Cytoxan Tablet®), cytarabine (Cytosar-U®), liposomal cytarabine (DepoCyt®), dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®); Darbepoietin Alfa (Aranesp®), daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin (Daunorubicin®); daunorubicin, daunomycin (Cerubidine®); Denileukin diftitox (Ontak®); dexrazoxane (Zinecard®); docetaxel (Taxotere®); doxorubin is in (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®), doxorubicin (Adriamycin PFS Injection®), doxorubicin liposomal (Doxil); DROMOSTANOLONE PROPIONATE (DROMOSTANOLONE®); DROMOSTANOLONE PROPIONATE (MASTERONE INJECTION®); solution Elliott (Elliott''s B Solution®), epirubicin (Ellence®); Epoetin Alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); etoposide phosphate (Etopophos®), etoposide, VP-16 (Vepesid®), exemestane (Aromasin®); Filgrastim (Neupogen®); floxuridine (intra-arterial) (FUDR®), fludarabine (Fludara®), fluorouracil, 5-FU (Adrucil®), fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®); histrelin acetate (Histrelin implant®), hydroxyurea (Hydrea®); Ibritumomab Tiuxetan (Zevalin®); idarubitsin (Idamycin®), ifosfamide (IFEX®); imatinib mesilate (Gleevec®); interferon Alfa-2A (Roferon A®), Interferon Alfa-2b (Intron A®); irinotecan (Camptosar®), lenalidomide (Revlimid®); letrozole (Femara®), leucovorin (Wellcovorin®, Leucovorin®); Leuprolide acetate (Eligard®), levamisole (Ergamisol®), lomustin, CCNU (CeeBU®), mechlorethamine, nitrogen mustard (Mustargen®), megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP (Purinethol®); mesna (Mesnex®); mesna (Mesnex tabs®); methotrexate (Levitra®); metoksalen (Uvadex®), mitomycin C (Mutamycin®); mitotane (Lysodren®), mitoxantrone (Novantrone®); nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon®); Nofetumomab (Verluma®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®), paclitaxel (Paxene®), paclitaxel (axol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®), pamidronate (Aredia®); pegademase (Adagen(PegademaseBovine)®); pegaspargase (Oncaspar®); Pegfilgrastim (Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®); pipobroman (Vercyte®); plicamycin, mithramycin (Mithracin®); porfimer sodium (Photofrin®), procarbazine (Matulane®); chinacan (Atabrine®); Rasburicase (Elitek®), Rituximab (Rituxan®); sargramostim (Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®); temozolomide (Temodar®); teniposide, VM-26 (Vumon®); testolactone (Teslac®); tioguanin, 6-TG (Thioguanine®); thiotepa (Thioplex®), topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab (Bexxar®); Tositumomab/I-131 tositumomab (Bexxar®), Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®), vincristine (Oncovin®); vinorelbine (Navelbine®) and zoledronate (Zometa®)...

And yet another embodiment of the invention is a method of treating cancer, which comprises the introduction of a therapeutically effective amount of the compounds of Formula I in combination with paclitaxel or trastuzumab.

The present invention also includes a pharmaceutical composition suitable for treatment or prevention of cancer, which contains a therapeutically effective amount of the compounds of Formula I and a compound selected from: modulator Retz is ptor estrogen, modulator of androgen receptor, receptor modulator retinoids, a cytotoxic/cytostatic tools, antiproliferative funds inhibitor phenyl-protein transferase, an inhibitor of HMG-CoA reductase inhibitor of HIV protease, reverse transcriptase inhibitors, inhibitors of angiogenesis, agonist of PPAR-γ agonists of PPAR-δ; inhibitor of cell proliferation and signaling pathways of survival tools, which affects the checkpoint of the cell cycle and means inducing apoptosis.

Any one or more of the specific dosages and dosing schedules compounds of the present invention may also be applicable to any one or more of therapeutic agents for use in combination treatment (hereafter cited as “second therapeutic agent”).

In addition, the specific dosage and dosage of the second therapeutic agent can then be changed and the optimal dose, dosing regimen and route of administration will be determined on the basis of specific second used the treatment means.

Undoubtedly, the route of administration of compounds of the present invention is independent of the route of administration of the second therapeutic agent. In the embodiment, the introduction to the compounds of the present invention is orally centuries the employer. In yet another embodiment, the introduction to the compounds of the present invention is intravenous. Thus, in accordance with these variants of the implementation of the connection of the present invention is administered orally or intravenously and the second therapeutic agent may be administered orally, parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingual, intramuscular, rectal, transbukkalno, intranasal, liposomal, via inhalation, vaginally, by intraocular, via local delivery by catheter or stent, subcutaneously, Interational, intra-articular, intrathecal or dosed in the form of slow release.

Additionally, the connection of the present invention and the second therapeutic agent can be one and the same way of introduction, that both tools are introduced, for example, orally, intravenously. However, it is also within the scope of the present invention is the introduction of the compounds of the present invention one method of administration, for example oral, and the introduction of a second therapeutic agent through another method of administration, e.g. intravenous or by any of the techniques described here above.

These and other aspects of the invention will be apparent from the recommendations contained in this description.

Is ONE of the TESTS

Compounds of the present invention described in the Examples were tested by the assays described below, and it was found that they possess inhibitory activity against MET. Other assays are known from the literature and can easily be carried out by experts in this field (see, for example, the publication of patent applications U.S. 2005/0075340 A1, April 7, 2005, pp. 18-19; and PCT publication WO 2005/028475, March 31, 2005, pp. 236-248).

I.The kinase assays in vitro

Recombinant GST-labeled cytosolic domains of human C-Met and other receptor tyrosinekinase, including murine C-Met, human Ron, KDR, IGFR, EGFR, FGFR, Mer, TrkA and Tie2, are used to determine whether modulation of enzymatic activities of these kinases by the compounds of the present invention.

Soluble recombinant GST-labeled cytosolic domains of C-Met and other receptor tyrosinekinase Express in the baculovirus system (Pharmingen) in accordance with the methodology recommended by the manufacturer. The C-DNA encoding each cytosolic domain, subcloning in the expression vector baculovirus (pGcGHLT-A, B or C, Pharmingen), containing frame 6x his-tag tag and GST tag. The resulting construct is a plasmid and BaculoGold baculovirus DNA (Pharmingen) is used to cotransfection insect cells Sf9 or Sf21. After confirming the expression of recombinant GST-labeled kinase floor is with a recombinant baculovirus of the original culture with high titer, conditions optimize expression and conduct scaled expression of rat recombinant KDR-GST. Recombinant kinase further purified from the lysate of insect cells by affinity chromatography using glutathione-agarose (Pharmingen). Purified protein cialiswhat against 50% glycerol, 2 mm DTT, 50 mm Tris-HCl (pH 7,4) and stored at-20C. The concentration of protein in recombinant proteins determined using Coomassie Plus Protein Assay (Pierce) with BSA as the standard.

Activity of the kinase C-Met and other kinases was measured using a modified version of the homogeneous divided by time analysis of tyrosine kinase described by Park et al. (1999, Anal. Biochem. 269:94-104).

The method for determining the activity of compounds in relation to inhibition of C-Met kinase includes the following stages:

1. Get 3 multiples of serial diluted solution of the compound in 100% dimethyl sulfoxide (DMSO) at 20X from the desired final concentrations in 96-well pad.

2. Get the original reaction mixture containing 6,67 mm MgCl2, 133,3 mm NaCl, 66,7 mm Tris-HCl (pH 7.4), 0.13 mg/ml BSA, 2,67 mm dithiothreitol, of 0.27 nm recombinant C-Met and 666,7 nm substrate biotinylated synthetic peptide (biotin-ahx-EQEDEPEGDYFEWLE-CONH2) (SEQ. ID. NO.:1).

3. In black analytical tablet added to 2.5 μl of a solution of the compound (or DMSO) and 37.5 ál of the reaction mixture per well. Kinase reaction the INIC is irout by adding 10 μl of 0.25 mm MgATP per well. The reaction allowed to proceed for 80 minutes at room temperature. End conditions for the reaction are: 0.2 nm c-Met, 0.5 µm of substrate, 50 μm MgATP, 5 mm MgCl2, 100 mm NaCl, 2 mm DTT, 0.1 mg/ml BSA, 50 mm Tris (pH 7.4) and 5% DMSO.

4. Kinase reaction is stopped with 50 μl of buffer stop/detection, containing 10 mm EDTA, 25 mm HEPES, 0.1% of TRITON X-100, 0,126 μg/ml Eu-chelate labeled antibody against phosphotyrosine PY20 (cat.# AD0067, PerkinElmer) and 45 mg/ml of conjugate Streptavidin-allophycocyanin (cat.# PJ25S, Prozyme).

5. Read the HTRF signals to the reader Victor (PerkinElmer) in HTRF mode after 60 minutes.

6. IC50determine the curve of the observed relationship between concentration and HTRF signal using a 4-parameter logistic equation.

Essentially the same technique is used to determine the activity of compounds on the inhibition of mouse C-Met, human Ron, KDR, IGFR, EGFR, FGFR, Mer, TrkA and Tie2, except that the concentration of enzyme changes in the individual analyses (0.2 nm murine C-Met; 2.5 nm Ron, 8 nm KDR; of 0.24 nm IGFR; of 0.24 nm EGFR; 0.14 nm FGFR; 16 nm Mer; 8 nm TrkA; 8 nm Tie2).

Connection 3-54 in the examples were tested in the above analysis, and found that they have the IC50<50 mkm.

II.Analysis of autophosphorylated C-Met on a cellular basis

Analysis type sandwich ELISA is used to assess autophosphorylation Met in cancer cells is of elude MKN45, which MET constitutively activated. Briefly, monolayer cells pre-treated with compounds or environment and then are lysed. METH cell lysate capture antibody against MET, immobilized on a plastic surface. Provide a generic binding antibodies against phosphotyrosine or one of certain specific antibodies against phospho-MET with captured MET and spend detected using HRP-conjugated secondary antibody.

The method for determining the activity of compounds in relation to inhibition of autophosphorylation MET in MKN45 cells includes the following steps.

Day 1

1. 96-well plate ELISA cover over night at 4°C With 100 µl/well of a solution of antibody capture with a concentration of 1 µg/ml (Af276, R&D).

2. A separate 96-well plates for culture seeded with cells MKN45 at 90,000 cells/well in 0.1 ml of growth medium (RPMI 1640, 10% FBS, 100 μg/ml Pen-Strep, 100 μg/ml L-glutamine and 10 mm HEPES) and cultured overnight at 37°C/5%CO2up to 80-90% confluence.

Day 2

1. Washed tablet ELISA 4X 200 µl/well of wash buffer (TBST+0,25% BSA). Incubated tablet ELISA with 200 µl/well blocking buffer (TBST+1,5% BSA) for 3-5 h at RT.

2. Prepare a series of dilutions half-length 200 compounds in DMSO. Dilute range up to 10X analytical medium (RPMI 1640, 10% FBS and 10 mm HEPES).

3. We use the t 10X solution of compound (11 μl/well) in a tablet for crops containing cells MKN45. Incubate the plate at 37°C/5%CO2. Within 60 minutes

4. Are lysed cells 100 μl/well buffer for lysis (30 mm Tris, pH 7.5, 5 mm EDTA, 50 mm NaCl, 30 mm sodium pyrophosphate, 50 mm NaF, 0.5 mm Na3VO4, 0.25 mm of potassium bespeaks(1,10-phenanthrolin)oxovanadate, 0,5% NP40, 1% Triton X-100, 10% glycerol, and a cocktail of protease inhibitors) at 4°C for 90 minutes.

5. Remove blocking buffer from the tablet ELISA, washed tablet 4 200 µl/well of wash buffer. Transfer 90 ál/well of cell lysate MKN45 of the tablet for culture in the tablet ELISA. Incubated tightly closed analytical plate at 4°C with gentle shaking overnight.

Day 3

1. Washed tablets ELISA 4 times with 200 ál/well of wash buffer.

2. Incubated with 100 µl/well of primary antibody detection (1 μg/ml in TBST + 1% BSA) for 1.5 hours at ambient temperature. Use the following primary antibodies: 4G10 from UpState, anti-pMet(1349) and anti-pMet(1369), both from Biosource.

3. Washed tablets ELISA 4 times with wash buffer. Add 100 ál/well of secondary antibody (1:1000 anti-mouse IgG-HRP diluted in TBST + 1% BSA for 4G10 or 1:1000 against rabbit IgG-HRP anti-pMet(1349) and anti-pMet(1365)). Incubated at room temperature with gentle stirring for 1.5 hours. Washed with 4×200 μl/well wash buffer.

4. Add 100 µl/well reagent Qanta Blu (Pierce) and incubated at room temperature for 8 minutes. Read fluorescence (wavelength of excitation: 314 nm, the wavelength of emission: 425 nm) onto the reader for tablets Spectramax Gemini EM (Molecular Devices).

5. IC50calculated by the curve between concentration and fluorescence signal using a 4-parameter logistic equation.

III.Analysis of cell proliferation/viability of cells MKN45

It is known that cells MKN45 gastric cancer man sverkhekspressiya constitutively activated C-met. Found that siRNA-mediated partial knockdown of C-Met induces a pronounced growth inhibition and apoptosis of MKN45 cells, suggesting a vital role of C-Met in this cell line. In the analysis described here to measure the effect of inhibitors of C-Met on the proliferation/viability of MKN45 cells. The method for determining the activity of compounds on the inhibition of proliferation/viability MKN45 includes the following stages.

On day 1 of MKN45 cells are placed in the plate at 3,000 cells/95 µl of medium (RPMI/10% FCS, 100 mm HEPES, penicillin and streptomycin) per well in 96-well plate. The tablet set in the incubator at 37°C/5%CO2. Cook 3 multiples of serially diluted solutions of the connection 1000X from the desired final concentration in DMSO.

On day 2 prepare 50X solutions connection, diluting 1000X solutions connection cf the DOI. Add 5 ál 20X solution of compound per well to the culture of MKN45 cells described above. Return the tablet to the incubator.

On day 5 add 50 ál lisanova buffer (ViaLight Reagents Kit, Catalog No. LT07-221, Cambrex): well. Are lysed cells at room temperature for 15 minutes. Next, add 50 ál detection (ViaLight Reagents Kit) and incubated for 3 minutes. The tablet read on a TOPCOUNT (PerkinElmer) in fluorescent mode. IC50calculated by the curve between the concentration and the luminescence signal using a 4-parameter logistic equation.

IV.Analysis of HGF-induced cell migration

HGF-induced cell migration HPAF pancreatic cancer evaluated using tablets BD Falcon Fluoroblock 96-Multiwell Insert (Cat # 351164, BD Discovery Labware). The tablet consists of holes, each of which is separated by a microporous membrane on the upper and lower chambers. Cancer cells of the pancreas is placed in the tablet on the top side of the membrane, and they migrate to the underside of the membrane in response to a chemoattractant, added in the lower chamber. Cells on the lower side of the membrane have been labelled with a fluorescent dye and find using a fluorescent reader for tablets. The method for determining the activity of compounds on the inhibition of cell migration involves the following is th stage:

1. Prepare solutions of the tested compounds with 1000X the final concentration in 100% DMSO.

2. Dilute the above solutions in the 50S with DMEM/10% FCS to obtain 20X solutions connection from the target concentrations.

3. Fill each of the bottom camera tablet Fluoroblock 96-Multiwell Insert 180 μl of DMEM/10% FCS and placed in tablets 8000 cells pancreatic cancer HPAF in 50 μl DMEM/10% FCS in each upper chamber.

4. 1-2 hours after placing the tablets add 2,5 ál and 10 ál of 20X solution of the compound in the upper and lower chambers, respectively. Incubate the plate at 37°C for 60 minutes and then add concentrated HGF in the lower chamber to a final concentration of HGF equal to 15 ng/ml Tablets for input incubated overnight for 20 hours.

5. An aliquot of the concentrated dye Calcein (Molecular Probes) added to each lower chamber with a final concentration of dye 5 μg/ml and cells have been labelled for 1 hour. Each of the bottom chamber was washed with 200 μl DMEM/10% FCS.

6. Read the fluorescence onto the reader Victor (PerkinElmer) in the reading mode for the bottom. The wavelength of excitation: 485 nm, the wavelength of emission: 535 nm.

7. IC50calculated by the curve between concentration and fluorescence signal using a 4-parameter logistic equation.

EXAMPLES

Pre is left examples are intended to assist in understanding the invention. Specific substances, species and conditions are intended only to illustrate the invention and not to limit the scope of the claims.

Example 1

Stage 1: Chloride 2-[(E/Z)-2-(4-bromophenyl)vinyl]-3-carboxy-5-chloropyridine

Tert-piperonyl potassium (1M solution in THF, 60 ml, 60 mmol) are added to a solution of 4-bromobenzaldehyde (5.6 g, 30 mmol) and 5-chloro-2-methylnicotinate (Marcoux, J.-F.; Marcotte, F.-A.; Wu, J.; Dormer, P. G.; Davies, I. W.; Hughes, D.; Reider, P. J. J. Org. Chem. 2001, 66, 4194-4199) (5.6 g, 30 mmol) in 200 ml THF at 0°C. the Mixture is allowed to warm to ambient temperature and stirred for 12 hours. The reaction suspension concentrate with obtaining solids yellow-orange color, then add 50 ml of water and 50 ml of 6N HCl. After stirring the resulting suspension for 30 minutes add 200 ml of EtOH and the suspension is stirred for 4 hours. The suspension is filtered and dried to obtain compound specified in the header.

1H NMR (600 MHz, DMSO-D6) δ 8,76 (d, 1H); by 8.22 (d, 1H); 8,02 (d, 1H); 7,79 (d, 1H); 7,60-rate of 7.54 (m, 4H). LRMS (APCI) calculated for C14H10BrClNO2[M+H]+, 338,0; found 337,9.

Stage 2: 7-Bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-Oh (compound 1)

Chloride 2-[(E/Z)-2-(4-bromophenyl)vinyl]-3-carboxy-5-chloropyridine (11.2 g, and 29.9 mmol) are added to 50 ml of polyphosphoric acid and heated to 200°C. After 12 hours the solution was poured into ice and we use the t 250 ml of a solution of 5N sodium hydroxide, then add a solution of 5N sodium hydroxide to reach pH 10. The mixture is diluted with 2 l of dichloromethane, was added 100 g of Celite and the suspension is stirred for 15 minutes. Solids filtered through a funnel of porous glass and discard. The liquid phase was poured into a separating funnel and the organic layer separated. The organic layer is dried with magnesium sulfate, filtered and concentrated to obtain compound 1.

1H NMR (600 MHz, CDC13) δ 8,82 (d, 1H); and 8.50 (d, 1H); to 8.41 (d, 1H); 7,80 (DD, 1H); of 7.48 (d, 1H); to 7.35 (d, 1H); then 7.20 (d, 1H). LRMS (APCI) calculated for C14H8BrClNO [M+H]+, 320,0; found 320,0.

Example 2

Stage 1: S-(4-(Were)2-methyl-5-vinylpyridin-3-carbothioate

To a solution of 2-methyl-5-phenyldiamine acid (100 mg, 0.40 mmol) at 0°C in CH2Cl2(4 ml) add oxalicacid (344 μl, 4.0 mmol). The mixture is stirred at 40°C. After 3 hours the mixture is concentrated to dryness, dissolved in benzene (2×5 ml) and again concentrated. After dissolution of the crude residue in CH2Cl2(2 ml) at 0°C. add pyridine (1 ml, 0,M in CH2Cl2), 4-dimethylaminopyridine (10 mg, 0.08 mmol) and 4-methylthiophenol (60 mg, 0.48 mmol). The mixture then allowed to warm to room temperature. After stirring for 2 hours the mixture is diluted with EtOAc, washed with 1N HCl, saturated salt solution, dried over sodium sulfate, filtered and conc is the shape. The crude residue purified flash chromatography (gradient 100-80% hexane/EtOAc) to give the compounds specified in the header.

LRMS (APCI) calculated for C20H18NOS [M+H]+, 320,1; found 320,1.

Stage 2: 2-[(2-Methyl-5-vinylpyridin-3-yl)carbonyl]benzaldehyde

S-(4-(Were)2-methyl-5-vinylpyridin-3-carbothioate (100 mg, 0.31 mmol), thiophene-2-carboxylate copper (I) (89,6 mg, 0.47 mmol), Pd2dba3CHCl3(26 mg, of 0.025 mmol), tri-2-furifosmin (17.3 mg, 0,074 mmol) and 2-formylphenylboronic acid (51,7 mg, 0.34 mmol) are combined in a dry flask. The flask was rinsed with argon and add 3.0 ml of THF. Argon bubbled through the solution for 5 minutes and the solution is stirred and heated to 50°C. After 18 hours the reaction mixture was diluted with EtOAc, washed with 1N HCl, saturated salt solution, dried over sodium sulfate, filtered, concentrated and purified flash chromatography (gradient 100-70% hexane/EtOAc) to give the compounds specified in the header.

LRMS (APCI) calculated for C20H16NO2[M+H]+, 302,1; found 302,1.

Stage 3: 3-Phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he

Flask is charged with 2-[(2-methyl-5-vinylpyridin-3-yl)carbonyl]benzaldehyde (6.2 mg, 0.02 mmol) and Meon (1 ml). Added LiHMDS (25 μl, 1.0 M in THF) and the vessel is heated in a microwave oven series Biotage Initiator for 30 minutes at 100°C. the Mixture was then diluted with EtOAc, washed with water and asystem salt solution, then dried over Na2SO4. The solution was concentrated in vacuo and purified by reversed-phase HPLC (0-100% CH3CN/water with 0.1% TFU modifier) to give the compounds specified in the header.

1H NMR (600 MHz, CD3OD) δ to 9.15 (d, 1H), 8,76 (d, 1H), of 8.25 (d, 1H), to 7.77 (m, 4H), 7,66 (t, 1H), 7,54 (t, 2H), 7,45 (m, 2H 0,7,36 (d, 1H). LRMS (APCI) calculated for C20H14NO [M+H]+, 284,1; found 283,8.

The following connections will be received, using the experimental method described above, but using correspondingly substituted 2-formylphenylboronic acid, which receive in accordance with the methods specified in literature.

Table 1
Conn. No.StructureNameMS (M+1)
27-bromo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-heRasch. 362,0 (M+H)+; found 362,0 (M+H)+

Scheme 1

Example 3

3-Chloro-7-[(2,4-dimethoxybenzyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he

7-Bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-Oh (3.0 g, 9,40 mmol), Tris(dibenzylidene is ceton)diplegia (0) (Pd 2(dba3)) (43 mg, 0,047 mmol), rac-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP) (88 mg, 0,141 mmol) and tert-piperonyl sodium (1.08 g, 11.3 mmol) are combined in a dry flask, through which argon purge. Flask is charged with 100 ml of dry dioxane, add 2,4-dimethoxybenzene (1,41 ml, 9,40 mmol) and the mixture was bubbled with argon for 5 minutes. The reaction mixture is heated at 100°C and stirred under argon. After 2 hours the reaction mixture was concentrated and dissolved in 400 ml ethyl acetate and washed with 100 ml saturated aqueous solution of ammonium chloride. The organic layer is separated, dried with magnesium sulfate, filtered and concentrated. The resulting solid is suspended in 50 ml of hot methanol, and then allowed to cool to ambient temperature. The solids are filtered and dried to obtain the connection specified in the header.

LRMS (APCI) calculated for C23H2ClN2O3[M+H]+, 407,1; found 407,1.

Example 4

7-Amino-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he

Method And

7-Bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (1,05 g, 3,30 mmol), Pd2(dba3) (8 mg, 0,00825 mmol), BINAP (15 mg, 0,0248 mmol) and benzophenone (to 0.662 ml, 3.95 mmol) are combined in a dry flask. Flask is charged with 40 ml of anhydrous toluene, followed by addition of tert-butoxide sodium (0,444 g, to 4.62 mmol). Argon Barbati the comfort through the solution for 5 minutes. The reaction solution is heated at 110°C and stirred under argon. After 2.5 hours, the reaction mixture was concentrated, add 20 ml of THF and 1 ml of 6N hydrochloric acid and the resulting solution is stirred. After 2 hours the solution is poured into 300 ml ethyl acetate, 100 ml saturated sodium bicarbonate and 200 ml of water. The organic layers separated, dried with magnesium sulfate, filtered, concentrated and purified flash column chromatography (gradient 0-30% ethyl acetate/hexane with getting a connection specified in the header.

1H NMR (600 MHz, CDC13) δ 8,77 (d, 1H); 8,55 (d, 1H); 7,58 (d, 1H); 7,44 (d, 1H); 7.18 in (d, 1H); 7,14 (d, 1H); 7,01 (DD, 1H); 4,15 (c, 2H). LRMS (APCI) calculated for C14H10ClN2O [M+H]+, 257,0; found 257,1.

Method In

3-Chloro-7-[(2,4-dimethoxybenzyl)amino]-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-Oh (1.1 g, 2.7 mmol) dissolved in 8 ml of methanol and 30 ml of dichloromethane. Next, add 10 ml triperoxonane acid and the solution stirred at ambient temperature. After 1 hour the reaction mixture was concentrated, dissolved in 500 ml ethyl acetate and washed with 200 ml saturated sodium bicarbonate. The organic layer is separated, dried with magnesium sulfate, filtered, and purified flash column chromatography (gradient 0-10% methanol/dichloromethane) and reversed-phase HPLC (gradient of 20-100% acetonitrile/water, 0.1% modifier triperoxonane acid) obtained with the em connection specified in the header.

LRMS (APCI) calculated for C14H10ClN2O [M+H]+, 257,0; found 257,1.

Example 5

N-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide

Method And

7-Bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (5,00 g, 15.7 mmol), methylsulfonate (1,49 g, 15.7 mmol), Pd2(dba3) (0,714 g, 0.78 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) (1,36 g of 2.35 mmol) and cesium carbonate (15.3 g, and 47.0 mmol) is added to a dry flask through which argon purge. In the flask is charged with 100 ml of anhydrous dioxane and argon bubbled through the solution for 10 minutes. The reaction mixture is heated at 95°C and stirred under argon. After 2.5 hours, the reaction mixture was concentrated and dissolved in 2000 ml of ethyl acetate and 1000 ml of water. The organic layer is separated and washed with 500 ml saturated salt solution, dried by magnesium sulfate, filtered and concentrated. The resulting solids are dissolved in 150 ml of a mixture of 3:1 hot dichloromethane/methanol and allowed to cool to ambient temperature with stirring. After 3 hours, add 150 ml of hexanol and the resulting suspension allowed to mix. After 12 hours add an additional 50 ml of hexanol. After 4 hours, the solids are filtered and dried to obtain the connection specified in the header.

Method In

7-Amino-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (to 0.70 g, 2.7 mmol), triethylamine (0,83 ml, 5,94 mmol) and methanesulfonamide (0,42 ml, 5.4 mmol) is added to 40 ml of dichloromethane and cooled to 0°C. the Solution is stirred and he is allowed to cool to ambient temperature. After 1 hour the reaction is quenched with saturated sodium bicarbonate solution and stirred. After 30 minutes the reaction mixture is poured into 300 ml ethyl acetate and 250 ml of water. The organic layer is separated, dried with magnesium sulfate, filtered and concentrated to obtain crude N,N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)bis-methanesulfonamide.

The crude N,N-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)bis-methanesulfonamide (1.1 g, 2.7 mmol) dissolved in 150 ml of methanol, then add 5 ml of 5N sodium hydroxide and the solution stirred at ambient temperature. After 1 hour, the reaction solution was partially concentrated and dissolved in 250 ml of ethyl acetate, 150 ml of water and 50 ml saturated aqueous solution of ammonium chloride. The organic layer is separated, dried with magnesium sulfate, filter and concentrate to obtain the connection specified in the header.

1H NMR (600 MHz, CDC13) δ 8,82 (d, 1H); 8,54 (d, 1H); 7,98 (d, 1H); of 7.70 (DD, 1H); the 7.65 (d, 1H); 7,33 (d, 1H); to 7.25 (d, 1H); 6,78 (c, 1H); 3,12 (c, 3H). LRMS (APCI) calculated for C15H12ClN2O3S [M+H]+, 335,0; found 335,1.

the example 6

3-Phenyl-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he

In a test tube, equipped with hermetically sealed tube of Teflon, load connection 2 (100.0 mg, 0.276 mmol), PdCl2(PPh3)2(10 mg, 0.014 mmol), tri-n-butylanisole (0,089 ml, 0.30 mmol) and 3 ml of dioxane. A mixture of Ar bubbled in for 10 minutes, then heated at 95°C during the night. The solution was diluted with EtOAc and washed with water and saturated saline, then dried over Na2SO4. The solution was concentrated in vacuo and purified flash column chromatography (gradient 10-70% EtOAc/hexane) to obtain white solid. This solid is dissolved in 10 ml of a mixture 1:1:1 EtOAc/dichloromethane/water and added 82 mg CsF. After 2 hours, the organic layer is separated and the aqueous layer was extracted with EtOAc and the organic layers dried over Na2SO4. The solution was concentrated in vacuo and purified flash column chromatography (stepwise gradient 0-10-20-100% EtOAc/hexane with getting a connection specified in the header 3.

1H NMR (600 MHz, CDC13) δ 9,14 (c, 1H); 8,78 (c, 1H); 8.30 to (c, 1H); 7,75 for 7.78 (m, 1H); 7,70-7,74 (m, 2H); to 7.59 (d, 1H); 7,50-of 7.55 (m, 2H); 7,40-7,47 (m, 2H); 7,30 (d, 1H); 6,85 (DD, 1H); 5,95 (d, 1H); 5,43 (d, 1H). LRMS (APCI) calculated for (C22H16NO) [M+H]+, 310,1; found 310,2.

Example 7

7-Ethyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]PI is one-5-he

In the flask is charged with compound 3 (20.0 mg, 0,065 mmol), 8 mg of 10% palladium on coal, 3 ml of EtOH, 3 ml of EtOAc and 0.5 ml of 1N HCl. To the flask and attach a balloon with hydrogen using the three-way valve, then vacuum and rinsed with hydrogen four times. After 1 hour the reaction mixture was filtered through a 0.45 µm syringe filter nylon, concentrated in vacuo and purified by reversed-phase HPLC (20-100% CH3CN/water with 0.1% TFU modifier) to give the compounds specified in the header 4.

1H NMR (600 MHz, CDC13) δ 9,13 (c, 1H); 8,75 (c, 1H); 8,13 (c, 1H); 7,70-7,73 (m, 2H); 7,49-of 7.55 (m, 4H); 7,42-7,46 (m, 1H); 7,37 (d, 1H); 7,28 (d, 1H); of 2.81 (q, 2H); to 1.31 (t, 3H). LRMS (APCI) calculated for (C22H18NO) [M+H]+, 312,1; found 312,2.

Example 8

Stage 1: (3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)baronova acid

7-Bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (1,00 g of 3.12 mmol), Pd2(dba)3(0,146 g, 0.16 mmol), tricyclohexylphosphine (0.104 g g and 0.37 mmol), bis(pinacolato)diboron (0.87 g, of 3.43 mmol) and potassium acetate (0,61 g, 6,23 mmol) are mixed in a dry flask, through which argon purge. In the flask is charged with 40 ml of anhydrous dioxane and through the solution bubbled argon for 15 minutes. The reaction mixture is heated at 95°C and stirred under argon. After 6 hours the reaction mixture is poured into 500 ml of ethyl acetate and 100 ml of saturated aqueous ammonium chloride. The organic layer is separated, with the shat magnesium sulfate, filter and concentrate to obtain the connection specified in the header.

LRMS (APCI) calculated for C14H10BClNO3[M+H]+, 286,0; found 286,1.

Stage 2: 3-Chloro-7-hydroxy-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he

(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)baronova acid and 1.00 g, 3.5 mmol) is dissolved at 0°With a solution of 25 ml THF, 25 ml of water, 0.5 ml of acetic acid and 0.5 ml of 30% (m/m) of hydrogen peroxide. The solution is stirred and allowed to warm to ambient temperature. After 6 hours the reaction mixture is partially concentrated and dissolved in 500 ml of ethyl acetate. The organic layer was washed with water (2×100 ml), dried with magnesium sulfate, filtered and concentrated to obtain solids. A solid substance was dissolved in 20 ml of dichloromethane and 60 ml of hexanol and mixed as solids crystallize from solution. After 2 hours, the crystalline solid is filtered off and dried to obtain the connection specified in the header.

1H NMR (600 MHz, DMSO-D6) δ 10,50 (c, 1H); 8,93 (c, 1H); 8,45 (c, 1H); to 7.68 (d, 1H); 7,58 (d, 1H); 7,39 (d, 1H); 7.23 percent (d, 1H); for 7.12 (d, 1H). LRMS (APCI) calculated for C14H9C1NO2[M+H]+, 258,0; found 258,1.

The following connections receive in accordance with scheme 1. Additional synthetic modification is used when receiving some connections.

Table 2
Conn. No.StructureNameMS (M+1)
57-[(2,4-dimethoxybenzyl)amino]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-heRasch. 449,2 (M+H)+; found 449,2 (M+H)+
67-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-heRasch. 299,1 (M+H)+; found 299,1 (M+H)+
72-hydroxy-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)propanamideRasch. 371,1 (M+H)+; found 371,1 (M+H)+
87-isobutyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-heRasch. 340,2 (M+H)+; found 340,2 (M+H)+
9N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-a]pyridin-7-yl)methanesulfonamide Rasch. 377,1 (M+H)+; found 377,1 (M+H)+

Example 9

N-[5-Oxo-3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide

N-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide (0,100 g, 0.30 mmol), 3-thienylboronic acid (0,077 g to 0.60 mmol), tetrakis(triphenylphosphine)palladium (0) (10 mg, 0,009 mmol) and potassium carbonate (0.124 g, 0.90 mmol) are combined in a dry flask. The flask was rinsed with argon and add 5 ml of anhydrous dioxane. Argon bubbled through the solution for 5 minutes and the solution is stirred and heated at 100°C. After 12 hours the reaction mixture is poured into 100 ml of ethyl acetate, 100 ml of water and 25 ml saturated ammonium chloride. The organic layer is separated, dried with magnesium sulfate, filtered, concentrated and purified by reversed-phase HPLC (gradient of 30-100% acetonitrile/water, 0.1% modifier triperoxonane acid) to give the compounds specified in the header.

1H NMR (600 MHz, DMSO-D6) the 10.40 δ (c, 1H); 9,34 (d, 1H); to 8.70 (d, 1H); 8,28 (c, 1H); 8,00 (d, 1H); for 7.78 (m, 2H); 7,73 (m, 1H); 7,58 (DD, 1H); 7,38 (d, 1H); 7,26 (d, 1H); is 3.08 (c, 3H). LRMS (APCI) calculated for C19H15N2O3S2[M+H]+, of 383.0; found 383,1.

Example 10

7-(Isopropylamino)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he

3-Chloro-7-(isoprop the laminitis)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (0,030 g, 0.09 mmol), Tris(dibenzylideneacetone) diplegia (0.004 g, 0.004 percent mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0,039 g 0,19 mmol), potassium fluoride (0,018 g, 0,316 mmol) and tetrafluoroborate three-tert-butylphosphine (0.003 g, 0,009 mmol) are combined in the tube for microwave ovens. The tube is rinsed with argon and add 2 ml of DMF. The solution is stirred and heated at 180°C in a microwave oven type Biotage Initiatur. After 30 minutes, add a saturated solution of ammonium chloride and the mixture extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate, filtered, concentrated in vacuo and purified by reversed-phase HPLC (gradient of 20-70% acetonitrile/water, 0.05% modifier triperoxonane acid) to give the compounds specified in the header.

1H NMR (600 MHz, CDC13) δ 8,93 (d, 1H); 8,64 (Sirs, 1H); 7,86 (c, 1H); 7,75 (c, 1H); was 7.45 (d, 1H); 7,39 (d, 1H); 7,14 (m, 2H); 6,85 (DD, 1H); 3,93 (c, 3H); 3,76 (septet, 1H); to 1.22 (d, 6H). LRMS (APCI) calculated for (C21H21N4O) [M+H]+, 345,2; found 345,2.

Example 11

N,N-Dimethyl-2- [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-yl]ethanamine

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0,250 g, 1,29 mmol), dimethylaminoethanol (0,37 g, 2.58 mmol) and potassium carbonate (0.534 g, a 3.87 mmol) was dissolved in 3 ml of anhydrous dichloromethane. The reaction mixture is heated in a microwave oven type Biotage Initiatur at 190 is C for 1 hour. The reaction mixture is poured into 300 ml ethyl acetate and 50 ml of saturated salt solution. The organic layer is separated, dried with magnesium sulfate, filter and concentrate to obtain the connection specified in the header.

1H NMR (600 MHz, CDC13) δ 7,76 (c, 1H); 7,72 (c, 1H); 4,22 (t, 2H); 2,94 (c, 3H); 2,86 (c, 3H); to 2.74 (t, 2H); 1,29 (c, 12 H).

Example 12

N'-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-[(2R)-1, 4-dioxane-2-ylmethyl-N-metilsulfate (compound 12)

Step 1: Benzyl(1,4-dioxane-2-ylmethyl)methylcarbamate

Hydrochloride of 1-(1,4-dioxane-2-yl)-N-methylmethanamine (4,g, 29 mmol) dissolved in 100 ml of dichloromethane. Add benzylaminocarbonyl (4.9 ml, 35 mmol) and triethylamine (10 ml, 72 mmol). The solution was stirred at ambient temperature. After 12 hours the solution is concentrated and then diluted with ethyl acetate and washed with saturated sodium bicarbonate and water. The organic layer is separated, dried with magnesium sulfate, filtered, concentrated in vacuo and purified by chromatography on silica (gradient 0-100% ethyl acetate/hexane) to obtain the compound indicated in heading (racemic mixture).

Racemic mixture of 6.35 g) was dissolved in 24 ml of heptane and 8 ml of isopropanol. The substance separated on a chiral column AB (15% isopropanol/heptane) to give 2.9 g of the enantiomer And [τR : 9,43 min (analytical chiral HPLC, column AO, 0.6 cm × 25 cm VD, 15% isopropanol/heptane, isocratic mode, flow rate 0.75 ml/min)] and 2.9 g of the enantiomer In [τR : 10,92 min (analytical chiral HPLC, column AB, and 0.46 cm × 25 cm VD, 15% isopropanol/heptane, isocratic mode, flow rate 0.75 ml/min)].

LRMS (APCI) calculated for (C14H20NO4) [M+H]+, 266,1; found 266,2.

Step 2: Benzyl[(2R)-1,4-dioxane-2-ylmethyl]methylcarbamate

Benzyl(1,4-dioxane-2-ylmethyl)methyl)methylcarbamate (Enantiomer A, 2.9 g, 10.6 mmol) dissolved in 50 ml of anhydrous ethanol. Add 10% (m/m) of palladium on carbon (0.29 grams) and 1.0 ml 10h HCl. The flask is hermetically closed and filled with hydrogen. Stir the solution is pressurized hydrogen from a cylinder. After 12 hours the solution is filtered through celite and concentrated in vacuo to obtain the connection specified in the header.

1H NMR (600 MHz, D6-DMSO) δ 8,64 (c, 2H); 3,82 of 3.75 (m, 2H); of 3.69 (d, 1H); to 3.64 (d, 1H); 3,59 (m, 1H); 3,44 (m, 1H); 3,22 (t, 1H); 2,94-2,84 (m, 2H); of 2.51 (c, 3H).

Step 3: Tert-butyl{[((2R)-1,4-dioxane-2-ylmethyl)(methyl)amino]sulfonyl}carbamate

Hydrochloride of 1-(1,4-dioxane-2-yl)-N-methylmethanamine (0,760 g, 4,55 mmol), N-[1-{[{tert-butoxycarbonyl)amino]sulfonyl}pyridine-4 - (N)-ilidene]-N-methylmethanamine (1.51 g, 5.00 mmol) and triethylamine (1,55 ml of 11.4 mmol) is suspended in 50 ml of dichloromethane and stirred at ambient temperature. After 12 hours the solution was concentrated in vacuo and iseut chromatography on silica (gradient 50-100% ethylacetate/hexane) to obtain the compounds specified in the header.

LRMS (APCI) calculated for (C11H22N2O6SNa) [M+Na]+, 331,1; found 333,1.

Stage 4: Triptorelin_______{[({2R)-]}-1,4-dioxane-2-ylmethyl)(methyl)amino]sulfonyl}ammonium

Tert-butyl{[(1,4-dioxane-2-ylmethyl)(methyl)amino]sulfonyl}carbamate (1.25 g, a 4.03 mmol) dissolved in 10 ml dichloromethane and 20 ml triperoxonane acid and stirred at ambient temperature. After 2 hours the solution is concentrated and subjected twice to azeotropic distillation with heptane to obtain the connection specified in the header.

LRMS (APCI) calculated for (C6H15N2O4S) [M+H]+, 211,10; found 211,1.

Stage 5: N'-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-[(2R)-1,4-dioxane-2-ylmethyl-N-methylsulfonyl

7-Bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (1,41 g, to 4.41 mmol), triptorelin {[((2R)-1,4-dioxane-2-ylmethyl)(methyl)amino]sulfonyl}ammonium (1.30 grams, to 4.01 mmol), Tris(dibenzylideneacetone)diplegia (0,183 g, 0.20 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (0,347 g to 0.60 mmol) and cesium carbonate (3,91 g, 12,0 mmol) are combined in a dry flask. Add 50 ml of anhydrous dioxane and argon bubbled through the solution for five minutes. The solution is stirred and heated at 95°C and stirred under argon. After 2 hours the solution was concentrated in vacuo, diluted with ethyl acetate and washed with water and neymann the m salt solution. The organic layer emit, dried with magnesium sulfate, filtered and concentrated in vacuo and purified by chromatography on silica (gradient 0-100% ethyl acetate/hexane with getting a connection specified in the header.

LRMS (APCI) calculated for (C20H21ClN3O5S) [M+H]+, of 450.1; of 450.1 found.

Example 13

Enantioselective_______synthesis_______benzyl [(2S)-1, 4-dioxane-2-ylmethyl]methylcarbamate

Stage 1: (2S)-2-[(Benzyloxy)methyl]-1,4-dioxane

(2R)-3-(Benzyloxy)propane-1,2-diol (2.00 g, 11.0 mmol) and tetrabutylammonium bromide (708 mg, of 2.20 mmol) is dissolved in 50 ml of 1,2-dichloroethane, and then quickly add 50 ml of 50% (m/m) aqueous solution of sodium hydroxide and the mixture is heated at 50°C. After 18 hours, add an additional 50 ml of 1,2-dichloroethane and 50 ml of 50% (m/m) aqueous solution of sodium hydroxide. After 8 hours add an additional 50 ml of 1,2-dichloroethane. After 72 hours the mixture is diluted with diethyl ether, washed with water and saturated saline, then dried over sodium sulfate and concentrated. The residue is purified flash column chromatography (silica, ethyl acetate/hexane) to obtain the compounds specified in the header.

1H NMR (600 MHz, CDCl3) δ 7,26-to 7.35 (m, 5H); 4,51-4,56 (m, 2H); 3.72 points-is 3.82 (m, 4H); 3,67-3,71 (m, 1H); to 3.58-to 3.64 (m, 1H); 3,38-of 3.48 (m, 3H).

Step 2: Benzyl[(2S)-1,4-dioxane-2-ylmethyl]methylcarbamate

In cu godonou flask is charged with (2S)-2-[(benzyloxy)methyl]-1,4-dioxane (1.77 g, 8,48 mmol), 902 mg of 10% PD/C and 50 ml of absolute ethanol. To the flask and attach a three-way valve, equipped with a balloon with hydrogen, and then the flask is evaporated and filled with hydrogen (4×) and stirred under hydrogen atmosphere overnight. The mixture is filtered through Celite and concentrated to obtain (2S)-1,4-dioxane-2-ylmethanol.

In a round bottom flask is charged with (2S)-1,4-dioxane-2-ylmethanol (115 mg, 0,973 mmol), triethylamine (0,204 ml, 1.4 to 6 mmol) and 5 ml of dichloromethane and then cooled to -10°C. Methanesulfonanilide (91 μl, of 1.17 mmol) is added by syringe and the solution stirred for 30 minutes at -10°C. the Solution was diluted with dichloromethane, washed with 1M HCl and the aqueous layer was extracted with dichloromethane (2×). The combined organic layers washed with saturated aqueous sodium bicarbonate (2×) and saturated saline, then dried over sodium sulfate and concentrated to obtain (2R)-1,4-dioxane-2-ylmethylphosphonate.

Sodium hydride (29 mg, of 0.74 mmol) are suspended in 2 ml of N,N-dimethylformamide (DMF) and cooled to 0°C. a Solution of benzylmethylamine (81 mg, 0.49 mmol) in 2 ml of DMF added by syringe. After 20 minutes with a syringe and add a solution of (2R)-1,4-dioxane-2-ylmethylphosphonate (191 mg, 0.97 mmol) in 2 ml DMF and the mixture is heated at 70°C. After 2 hours the mixture is cooled to ambient temperature, then diluted with diethyl ether, washed with water and us is on a salt solution then dried over sodium sulfate and concentrated. The residue is purified flash column chromatography (silica, ethyl acetate/hexane with getting a connection specified in the header.

LRMS (APCI) calculated for (C14H20NO4) [M+H]+, 266,1; found 266,2.

Analysis of benzyl[(2S)-1,4-dioxane-2-ylmethyl]methylcarbamate analytical HPLC [τR: 10,85 min (analytical chiral HPLC, column AD, and 0.46 cm × 25 cm and, 15% isopropanol/heptane, isocratic, flow rate = 0.75 ml/min)] and joint injection with the enantiomer of example 12 allow for the following assignment of stereochemistry for the selected enantiomers of example 12, step 2.

Enantiomer And

benzyl[(2R)-1,4-dioxane-2-ylmethyl]methylcarbamate

Enantiomer B

benzyl[(2S)-1,4-dioxane-2-ylmethyl]methylcarbamate

Example 13A

N-[(2R)-1,4-Dioxane-2-ylmethyl]-N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)sulphonamide (compound 13)

N'-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-[(2R)-1,4-dioxane-2-ylmethyl-N-metilsulfate (0,500 g, 1.11 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0,692 g of 3.33 mmol), Pd2(dba)3(0,051 g 0,056 mmol), (tBu3)PBF4(to 0.032 g, 0.11 mmol) and potassium fluoride (0,212 g, 3,66 mmol) are combined in su is th tube. Add 5 ml of anhydrous DMF and argon bubbled through the solution for five minutes. The test tube is sealed and heated in a microwave reactor type Biotage Initiator at 135°C for 20 minutes. The solution is diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, water and saturated salt solution. The organic layer is dried with magnesium sulfate, filtered, concentrated in vacuo and purified by chromatography on silica (gradient 0-100% ethyl acetate/hexane, followed by a gradient of 0-10% methanol/dichloromethane) to obtain the crude compound. The crude substance is crystallized from a mixture of 10 ml of methanol, 40 ml of dichloromethane and 70 ml of hexanol with getting the connection specified in the header.

1H NMR (600 MHz, D6-DMSO) δ 10,52 (s, 1H); 9,20 (d, 1H); 8,55 (d, 1H); to 8.45 (s, 1H); 8,13 (s, 1H); to 7.95 (d, 1H); of 7.75 (d, 1H); at 7.55 (d, 1H); to 7.32 (d, 1H); 7,22 (d, 1H); 3,88 (s, 3H); 3,64-of 3.60 (m, 2H); to 3.58-of 3.54 (m, 1H); 3,54-to 3.50 (m, 1H); 3,44 is 3.40 (m, 1H); 3,38-to 3.34 (m, 1H); 3,14-3,10 (m, 3H); 2,77 (s, 3H). LRMS (APCI) calculated for (C24H26N5O5S) [M+H]+, 496,2; found, 496,2.

N-[(2S)-1,4-Dioxane-2-ylmethyl]-N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)sulphonamide (compound 13S) are obtained by applying the procedure described in examples 12 and 13A, but substituting benzyl[(2S)-1,4-dioxane-2-ylmethyl]methylcarbamate (enantiomer from example 12 stage 1) benzyl(2R)-1,4-dioxane-2-ylmethyl]methylcarbamate in example 12, stage 2.

The racemic mixture of N-[1,4-dioxane-2-ylmethyl]-N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)sulphonamide (compound 13RS) are obtained by applying the procedure described in examples 12 and 13A, but substituting racemic benzyl[1,4-dioxane-2-ylmethyl]methylcarbamate on benzyl[(2R)-1,4-dioxane-2-ylmethyl]methylcarbamate in example 12, step 2.

Enantiomeric components of this racemic mixtures of the present compounds are divided according to the following procedure: Racemic Compound 12 RS (0.083 g) dissolved in a mixture of 2 ml of methanol and 18 ml dichloromethane. The substance separated on chiral OD column (70% isopropanol/heptane) to give the 0,030 g of enantiomer (compound 13) [τR: 12,8 min (analytical chiral HPLC, OD column, and 0.46 cm × 25 cm and, 60% isopropanol/heptane, isocratic, flow rate = 0.75 ml/min)] and was 0.026 g of enantiomer (compound 13S) [τR: 15,8 min (analytical chiral HPLC, OD column, and 0.46 cm × 25 cm and, 60% isopropanol/heptane, isocratic, flow rate = 0.75 ml/min)].

Example 14

N-Methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-(tetrahydrofuran-3-yl)sulphonamide (compound 14)

Stage 1: N-Methyl-N-(tetrahydrofuran-3-yl)sulphonamide

In the flask is charged with N-tert-butoxycarbonyl-N-[4-(dimethylethanamine is n)-1,4-dihydropyridines-1-ylsulphonyl]asanid (2,19 g, 7,27 mmol), chloride N-methyltetrahydrofuran-3-amine (1,00 g, 7,27 mmol) and triethylamine (1,01 ml, 7,27 mmol) in 10 ml of CH2Cl2. After 2 hours the solution was concentrated in vacuo and purified flash column chromatography (10-100% EtOAc/hexane) to obtain tert-butyl{[methyl(tetrahydrofuran-3-yl)amino]sulfonyl}carbamate. Tert-butyl{[methyl(tetrahydrofuran-3-yl)amino]sulfonyl}carbamate (1.47 g, 5,23 mmol) dissolved in 70 ml of CH2Cl2and 45 ml triperoxonane acid. After 1 hour the solution was concentrated in vacuo, diluted in CH2Cl2, washed with saturated aqueous NaHCO3and saturated saline, then dried over Na2SO4. The solution was concentrated in vacuo to obtain the connection specified in the header.

1H NMR (600 MHz, DMSO-d6) δ 4,25-or 4.31 (m, 1H); 3,79-a-3.84 (m, 1H); to 3.58-3,66 (m, 2H); 3,47-to 3.52 (m, 1H); 2,56 (c, 3H), 2,04 is 2.10 (m, 1H); 1,81-of 1.88 (m, 1H).

Stage 2: N'-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methyl-N-({3R}-tetrahydrofuran-3-yl)sulphonamide and N'-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methyl-N-({3R}-tetrahydrofuran-3-yl)sulphonamide

7-Bromo-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (665 mg, 2,07 mmol), N-methyl-N-(tetrahydrofuran-3-yl)sulphonamide (372 mg, of 2.06 mmol), Pd2(dba3) (95 mg, 0.10 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (XANTPHOS) (179 mg, 0,310 mmol) and cesium carbonate (2,02 g, to 6.19 mmol) is added to su is th flask, through which argon purge. In the flask is charged with 30 ml of anhydrous dioxane and argon bubbled through the solution for 10 minutes. The reaction mixture is heated at 95°C and stirred under argon. After 2 hours the mixture is cooled to ambient temperature, diluted in ethyl acetate, washed with saturated aqueous NaHCO3and saturated saline, then dried over Na2SO4. The solution is concentrated and purified flash column chromatography (silica, ethyl acetate/hexane with getting a connection specified in the header.

1H NMR (600 MHz, DMSO-d6) δ 10,59 (c, 1H); 8,97 (d, 1H); and 8.50 (d, 1H); to 7.95 (d, 1H); 7,79 (d, 1H); rate of 7.54 (DD, 1H); 7,40 (d, 1H); 7,22 (d, 1H); 4,47-a 4.53 (m, 1H); 3.75 to of 3.80 (m, 1H); 3.42 points-of 3.53 (m, 3H); 2,67 (c, 3H); 1.93 and is 2.00 (m, 1H); 1,50-1,72 (m, 1H); LRMC (APCI) calculated for (C19H19ClN3O4S) [M+H]+, 420,1; found, 420,1.

The racemic mixture is dissolved in 5 mg/ml of a mixture of 5:1 methanol/dimethylsulfoxide and shared by chiral HPLC (column Chiracel OJ-H, 21 mm × 250 mm, 40% methanol/supercritical carbon dioxide, flow rate = 50 ml/min, 100 bar outlet pressure) to obtain enantiomer A (τR=6,33 min) and enantiomer B (τR=7,9 min)

Stage 3: N-Methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-({3R}tetrahydrofuran-3-yl)sulphonamide and N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-({3S}tet is hydrofuran-3-yl)sulphonamide

Separated enantiomers are treated the same way. The method described for the enantiomer Century

N'-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-N-methyl-N-(tetrahydrofuran-3-yl)sulphonamide enantiomer (0,070 g, 0,17 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0,069 g, 0.33 mmol), Pd2(dba)3(0.008 g, 0,0085 mmol), (tBu3)PBF4(0.005 g, is 0.017 mmol) and potassium fluoride (0,032 g of 0.56 mmol) are combined in a dry test tube. Add 1.0 ml of anhydrous DMF and argon bubbled through the solution for five minutes. The test tube is sealed and heated in a microwave reactor type Biotage Initiator at 100°C for 30 minutes. The solution is diluted with ethyl acetate and washed with saturated sodium bicarbonate solution. The organic layer is dried with magnesium sulfate, filtered, concentrated in vacuo and purified by chromatography HPLC (gradient of 20-100% acetonitrile/water, 0.05% modifier triperoxonane acid) to obtain the crude compound. The crude substance is purified by chromatography on silica (gradient 0-100% ethyl acetate/hexane, followed by a gradient of 0-20% methanol/dichloromethane). The selected substance is dissolved in a minimum amount of a mixture of 25% methanol/dichloromethane and add hexane before the deposition. The precipitate is filtered off with getting the connection specified in the header.

1H NMR (600 MHz, D6 -DMSO) δ 10,55 (c, 1H); 9,20 (d, 1H); 8,58 (d, 1H); 8,46 (c, 1H); 8,13 (c, 1H); to 7.95 (d, 1H); of 7.75 (d, 1H); 7,52 (DD, 1H); to 7.32 (d, 1H); 7,22 (d, 1H); 4,48-a 4.53 (m, 1H); 3,88 (c, 3H); 3,74-of 3.80 (m, 1H); 3,42-of 3.54 (m, 3H); 2,68 (c, 3H); 1.93 and is 2.00 (m, 1H); 1,65-1,72 (m, 1H). LRMC (APCI) calculated for (C23H24N5O4S) [M+H]+, 466,2; found, 466,2.

The racemic mixture of N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(tetrahydrofuran-3-yl)sulphonamide get using the above methodology, starting from the racemic mixture from stage 2.

The following connections receive in accordance with the methods described above. Not available for sale esters of 1-H-pyrazole-Bronevoy acid obtained by the method similar to that described in example 12

Table 3
Conn. No.R1NameMS (M+1)
15N-(5-oxo-3-pyridin-4-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamideRasch. 378,1 (M+H)+; found 378,1 (M+H)+
16 N-[5-oxo-3-(1H-pyrazole-3-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamideRasch. 367,1 (M+H)+; found 367,1 (M+H)+
17N-[5-oxo-3-(1,3-thiazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamideRasch. 384,0 (M+H)+; found 384,0 (M+H)+
18N-[3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamideRasch. 381,1 (M+H)+; found 380,7 (M+H)+
18AN-[5-oxo-3-(1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamideRasch. 387,1 (M+H)+; found 366,7 (M+H)+
19N-(3-{1-[2-(dimethylamino)ethyl]-1H-pyrazole-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamideRasch. 438,2 (M+H)+; found 437,7 (M+H)+
20 N-{3-[1-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazole-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamideRasch. 494,1 (M+H)+; found 493,6 (M+H)+
21N-(4-{7-[methylsulphonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-yl}phenylmethanesulfonylRasch. 470,1 (M+H)+; found 470,1 (M+H)+
22N-[3-(1-cyclopentyl-1H-pyrazole-4-yl)]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamideRasch. 435,1 (M+H)+; found 435,1 (M+H)+
23N-{3-[1-(3,3-dimethyl-2-oxobutyl)-1H-pyrazole-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamideRasch. 465,2 (M+H)+; found 465,2 (M+H)+
24N-[2-(1-methylpyrrolidine-2-yl)ethyl]-3-{7-[(methylsulphonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-yl}benzamideRasch. 531,2 (M+H)+; found 531,0 (M+H)+

Table 3A
Conn. No.StructureNameMS (M+1)
25N,N-dimethyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulphonamideRasch. 410,1 (M+H)+; found 409,7 (M+H)+
26N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulphonamideRasch. 382,1 (M+H)+; found 382,1 (M+H)+
26A7-(5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-heRasch. 422,1 (M+H)+; found 422,1 (M+H)+
277-[(2,4-dimethoxybenzyl)amino]-3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-heRasch. 455,1 (M+H)+; found to 455.2 (M+H)+
28 7-amino-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he, isolated as the free base and 3HCl saltRasch. 303,1 (M+H)+; found 303,1 (M+H)+
297-[(2,4-dimethoxybenzyl)amino]-3-(1H-pyrazole-3-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-heRasch. 439,2 (M+H)+; found 439,2 (M+H)+
307-[(imidazo[1,2-a]pyridine-3-ylmethyl)amino]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-heRasch. 433,2 (M+H)+; found 433,2 (M+H)+
317-{[(1-methyl-5-oxopyrrolidin-2-yl)methyl]amino}-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-heRasch. level of 414.2 (M+H)+; found 414,1 (M+H)+
32N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(tetrahydro-2H-Piran-2-ylmethyl)sulphonamideRasch. 494,2 (M+H)+; is ideno 494,2 (M+H)+
33N-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N'-(tetrahydrofuran-3-yl)sulphonamideRasch. 452,1 (M+H)+; found 452,2 (M+H)+
34N-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-morpholine-4-sulfonamideRasch. 452,1 (M+H)+; found 452,2 (M+H)+

Example 15

N-[3-(4-Isopropylpiperazine-1-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide

Method And

N-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide (0,050 g, 0.15 mmol), isopropylpiperazine (0,038 g, 0.30 mmol), Pd2(dba)3(1.5 mg, 0,0015 mmol), BINAP (3.0 mg, 0,0045 mmol) and tert-piperonyl sodium (0,043 g, 0.45 mmol) is added to a dry flask through which argon purge. Add 3.0 ml of anhydrous dioxane and argon bubbled through the solution for 5 minutes. The reaction mixture is stirred and heated at 105°C. After 12 hours the reaction mixture is poured into 100 ml of ethyl acetate, 100 ml of water and 25 ml saturated ammonium chloride. The organic layer is separated, dried with magnesium sulfate, filtered, con is intronaut and purified by reversed-phase HPLC (gradient of 20-100% acetonitrile/water, 0.1% modifier triperoxonane acid) to give the compounds specified in the header.

Method In

N-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide (0,100 g, 0.30 mmol), Pd2(dba)3(6 mg, 0,006 mmol), rac-BINAP (11 mg, 0.018 mmol) and cesium carbonate (0,490 g, 1.50 mmol) are combined and mixed in a dry tube. Add isopropylpiperazine (0,170 ml, 1.20 mmol) and 0.70 ml of anhydrous dimethylformamide and the tube is hermetically closed. The reaction contents are heated in a microwave reactor type Biotage Initiator at 180°C for 15 minutes. The reaction contents partially concentrated and purified by reversed-phase HPLC (gradient 10-100% acetonitrile/water, 0.1% modifier triperoxonane acid) to give the compounds specified in the header.

1H NMR (600 MHz, CD3OD) δ 8,64 (d, 1H); 8,18 (c, 1H); of 7.96 (d, 1H); to 7.68 (d, 1H); of 7.60 (DD, 1H); then 7.20 (d, 1H); 7.18 in (d, 1H); to 3.45 (m, 4H); 3.04 from (c, 3H); 2,78 (m, 5H); to 1.14 (d, 6H). LRMS (APCI) calculated for C22H27N4O3S [M+H]+, 427,2; found 427,2.

The following compounds are given as shown above. Additional synthetic modification is used when receiving some connections.

Table 4
Conn. No.StructureCalled the e MS (M+1)
363-(4-isopropylpiperazine-1-yl)-7-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-heRasch. 410,2 (M+H)+; found 410,2 (M+H)+
37N-(3-morpholine-4-yl-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamideRasch. 386,1 (M+H)+; found 386,1 (M+H)+
38N-(3-aniline-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamideRasch. 392,1 (M+H)+; found 392,1 (M+H)+
39N-[3-(cyclohexylamino-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamideRasch. 398,2 (M+H)+; found 398,2 (M+H)+
40N-[5-oxo-3-(pyridine-4-ylamino)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamideRasch. 393,1 (M+H)+; found 393,1 (M+H)+

Example 16

N-(3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-methoxyacetate

7-Amino-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (to 0.70 g, 2.7 mmol) was dissolved in 20 ml of anhydrous dichloromethane and 5 ml of anhydrous acetonitrile. Add methoxybutanol acid (of 0.32 ml, 4.1 mmol), hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide (EDCI) (0,79 g, 4.1 mmol) and the hydrate of 1-hydroxybenzotriazole (HOBt) (0.55 g, 4.1 mmol) and the solution stirred at ambient temperature. After 12 hours the reaction solution was poured into 300 ml ethyl acetate and 100 ml of water. The organic layer is separated and washed with 100 ml saturated salt solution. The organic layer is separated, dried with magnesium sulfate, filtered, concentrated and purified flash column chromatography (gradient 0-100% ethyl acetate/hexane with getting a connection specified in the header.

1H NMR (600 MHz, CDCl3) δ 10,29 (c, 1H); to 8.94 (d, 1H); 8,58 (d, 1H); 8,46 (d, 1H); 8,10 (DD, 1H); to 7.77 (d, 1H); 7,40 (d, 1H); then 7.20 (d, 1H); 4.04 the (c, 2H); 3,36 (c, 3H). LRMS (APCI) calculated for C17H14ClN2O3[M+H]+, 329,1; found 329,1.

Example 17

N-(2,4-Dimethoxybenzyl)-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]etranslate

In the flask is charged with compound 12 (194 mg, 0,434 mmol) and 8 ml of CH2Cl2and cooled to 0°C. Add N-methylmorpholine (0,19 ml of 1.74 mmol) and 2-chloroethanol Nellore (90 μl, 0.87 mmol) and the solution is allowed to warm to room temperature. After 18 hours, the solution was diluted with EtOAc, washed with water and saturated saline, then dried over Na2SO4. The solution was concentrated in vacuo and purified flash column chromatography (gradient 10-100% EtOAc/hexane with getting a connection specified in the header 41.

1H NMR (600 MHz, CDCl3) δ 9,14 (d, 1H); 8,73 (d, 1H); 8,19 (d, 1H); 7,69-7,72 (m, 2H); 7,58 (DD, 1H); 7,49-rate of 7.54 (m, 3H); 7,44-7,47 (m, 1H); 7,39 (d, 1H); 7,19-7,25 (m, 2H); to 6.57 (DD, 1H); 6,37 (DD, 1H); 6.30-in (app d, 1H); 6,21 (d, 1H); 6,00 (d, 1H); a 4.86 (s, 2H); and 3.72 (s, 3H); the 3.65 (s, 3H). LRMS (APCI) calculated for (C31H27N2O5S) [M+H]+, 539,2; found 539,2.

Example 18

N-(5-Oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]etranslate

The connection 42 is obtained from 41 by the method described for example 4B.

1H NMR (600 MHz, DMSO-d6) δ 10,69 (c, 1H); 9,29 (257,1H); 8,68 (d, 1H); 7,98 (d, 1H); 7,86-of 7.90 (m, 2H); for 7.78 (d, 1H); 7,52-7,58 (m, 3H); 7,45-of 7.48 (m, 1H); 7,41 (d, 1H); 7,29 (d, 1H); 6,86 (DD, 1H); of 6.20 (d, 1H); 6,06-6,10 (m, 1H). LRMS (APCI) calculated for (C22H17N2O3S) [M+H]+, 389,1; found 389,1.

Example 19

N-(5-Oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-2-pyrrolidin-1-retensioned

Compound 42 (20.0 mg, 0,051 mmol) and pyrrolidine (13 μl, 0.15 mmol) dissolved in 2 ml Meon and 1 ml of CH2Cl2. After 18 hours Astor concentrated under a stream of nitrogen and purified by reversed-phase HPLC (20-100% CH 3CN/water with 0.1% modifier TFU) to obtain the connection specified in the header 43.

1H NMR (600 MHz, CDC13) δ 9,13 (d, 1H); total of 8.74 (d, 1H); 7,92 (d, 1H); 7,73 (DD, 1H); 7.68 per-7,73 (m, 2H); 7,58 (d, 1H); 7,49-7,53 (m, 2H); 7,42 was 7.45 (m, 1H); of 7.36 (d, 1H); 7.23 percent (d, 1H); 3,28-of 3.32 (m, 2H); is 3.08-of 3.12 (m, 2H); 2,60-2,65 (m, 4H); 1,88-of 1.94 (m, 4H). LRMS (APCI) calculated for (C26H26N3O3S) [M+H]+, 460,2; found 460.

Example 20

Dimethyl[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]amidophosphate (compound 44)

Compound 27A (10 mg, 0,033 mmol) and triethylamine (14 μl, 0.10 mmol) are suspended in 2 ml of dichloromethane and add dimethylaminopropan (7 μl, of 0.066 mmol). After 30 minutes, the suspension is heated to 40°C. After an additional 2 hours add dimethylaminopropan (36 μl, 0.33 mmol). After an additional 18 hours, the yellow solution was poured into ethyl acetate and the organic layer was washed with saturated aqueous sodium bicarbonate and saturated saline, dried over surfcom sodium and concentrate. The residue is purified by reversed-phase HPLC (gradient of 20-100% acetonitrile/water with 0.05% modifier triperoxonane acid) to give the compounds specified in the header.

1H NMR (600 MHz, CDCl3) δ 8,89 (d, 1H); 8,63 (c, 1H);,7,88 (c, 1H); of 7.82 (d, 1H); 7,79 (c, 1H); 7,51 (d, 1H); 7,32-7,38 (m, 2H); 7.18 in-7,22 (m, 1H); 6,06 (shirt, 1H); 3,94 (c, 3H); 3,79(c, 3H); of 3.77 (c, 3H); LRMS (APCI) RA is a matter for (C 20H20N4O4P) [M+H]+, 411,1; found 411,1.

Example 21

Stage 1: 3-chloro-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he

In a test tube with a glass Teflon membrane load connection 1 (1.0 g, 3.1 mmol), PdCl2(dppf) (0.12 g, 0.16 mmol) and vinyltrifluoroborate potassium (0,42 g, 3.1 mmol). The vacuum tube and re-filled with argon three times. Add fully degassedn-D (30 ml) followed by the addition of triethylamine (1.3 ml, 9.4 mmol). The solution is diluted with ethyl acetate and washed with water and saturated saline and dried with magnesium sulfate. The mixture is heated at 100°C for 3 hours. The solution was concentrated in vacuo and purified flash chromatography (silica, 0-25% ethyl acetate/hexane with getting a connection specified in the header.

1H NMR (600 MHz, CDC13) δ 8,80 (d, 1H); 8,53 (d, 1H); of 8.27 (d, 1H); 7,76 (DD, 1H); EUR 7.57 (d, 1H); to 7.32 (d, 1H); 7,26 (d, 1H); 6,83 (DD, 1H); 5,94 (d, 1H); 5,43 (d, 1H). LRMS (APCI) calculated for (C16H11ClNO) [M+H]+, 268,1; found 268,1.

Stage 2: 3-Chloro-7-oxiran-2-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he

3-Chloro-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (to 0.30 g, 1.12 mmol) dissolved in 17 ml of DMSO and 3.0 ml of water. Add N-bromosuccinimide (0.20 g, 1.12 mmol) and the reaction mixture is heated in an oil bath at 60°C for 1 hour, at this time add an additional 0.1 of the N-bromosuccinimide (0,56 mmol) and the mixture is stirred for additional 45 min at 60°C. The resulting mixture is diluted with water and extracted with ethyl acetate three times. The combined organic phases are washed with saturated saline solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue is dissolved in 30 ml of tetrahydrofuran and 6 ml of tert-BuOH. Tert-BuOK (2,24 ml of 1.0m in THF, 2,24 mmol) is added dropwise and the resulting orange suspension was stirred at room temperature for 45 minutes. The reaction mixture was diluted with water and extracted with ethyl acetate three times. The combined organic phases are washed with saturated saline, dried over magnesium sulfate, concentrated in vacuo, and purified flash chromatography (silica, 0-25% ethyl acetate/hexane with getting a connection specified in the header.

1H NMR (600 MHz, CDCl3) δ 8,79 (d, 1H); 8,49 (d, 1H); to 8.20 (d, 1H); EUR 7.57 (d, 1H); at 7.55 (DD, 1H); 7,27 (d, 1H); 7.23 percent (d, 1H); 3,99 (DD, 1H); 3,21 (DD, 1H); 2,84 (DD, 1H).

Stage 3: 3-Chloro-7-(1-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-ol and 3-chloro-7-(2-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-ol

3-Chloro-7-oxiran-2-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (to 0.67 g, 2.4 mmol) dissolved in 30 ml of THF. Add LiAlH4(90 mg, 2.4 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The reaction is quenched parabalym adding water after the ith slow addition of 1N HCl. The mixture is extracted with ethyl acetate. The combined organic phases are washed with saturated saline, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude mixture was used without further purification.

3-Chloro-7-(1-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-ol

LRMS (APCI) calculated for (C16H15ClNO2)[M+H]+, grass 288,1; found grass 288,1

3-Chloro-7-(2-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-ol

LRMS (APCI) calculated for (C16H15ClNO2)[M+H]+, grass 288,1; found grass 288,1.

Stage 4: 7-(1-{[tert-Butyl(dimethylsilane]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-Oh and 3-chloro-7-(2-{[tert-butyl(dimethylsilane]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he

The crude mixture of 3-chloro-7-(1-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-ol and 3-chloro-7-(2-hydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-ol (of 0.67 g, 2.4 mmol) dissolved in 30 ml of N,N'-dimethylformamide. Sequentially added imidazole (of 0.82 g, 6.0 mmol) and TBSCl (0.45 g, 3.0 mmol) and the reaction mixture was stirred at 50°C for 2 hours, at this time add additional imidazole (0,82 g, 12 mmol) and TBSCl (0.45 g, 3.0 mmol) and the reaction mixture stirred for additional 2 hours. The mixture is diluted with water and saturated aqueous ammonium chloride and extracted three times with ethyl acetate. The combined organic phases p is washed five times with saturated salt solution, dried over magnesium sulfate and concentrated in vacuo. The resulting crude substance was dissolved in 30 ml of dichloromethane. Add MnO2(4.0 g, 46.5 mmol) and the reaction mixture was stirred over night at room temperature. The resulting suspension is filtered through a substrate celite with dichloromethane, concentrated in vacuo, and purified flash chromatography (silica, 0-20% ethyl acetate/hexane) obtaining specified in Sokolovka compounds in the mixture. The connection is shared by flash chromatography (silica, 0-10% ethyl acetate/hexane).

7-(1-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he.

1H NMR (600 MHz, CDCl3) δ 8,79 (d, 1H); 8,53 (d, 1H); 8,18 (d, 1H); 7,76 (DD, 1H); 7,58 (d, 1H); 7,29 (d, 1H); 7,26 (d, 1H); free 5.01 (q, 1H); of 1.44 (d, 3 H); 0,91 (c, 9H); 0,07 (c, 3H); -0,01 (c, 3H),

7-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he.

1H NMR (600 MHz, CDCl3) δ 8,80 (d, 1H); charged 8.52 (d, 1H); to 8.12 (d, 1H); 7,58 (DD, 1H); 7,53 (d, 1H); 7.29 trend-7,27 (m, 2H); 3,86 (t, 2H); 2,96 (t, 2H); 0,84 (c, 9H); -0,04 (c, 6H).

Stage 5: 7-(1-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he

In a test tube with a glass Teflon membrane load 7-(1-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-Oh (50 mg, 0.13 mmol), PdCl2(PPh3)2(9 mg, of 0.013 mmol, 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (78 mg, 0.38 mmol) and sodium carbonate (40 mg, 0.38 mmol). The vacuum tube and re-filled with argon three times. Add fully degassed dioxane (1.2 ml) and the mixture was stirred at 100°C during the night. The solution is diluted with ethyl acetate, washed with water and saturated saline solution, dried over magnesium sulfate, concentrated in vacuo, and purified flash chromatography (silica, 20 to 100% ethyl acetate/hexane with getting a connection specified in the header.

1H NMR (600 MHz, CDCl3) δ 8,99 (d, 1H); 8,58 (d, 1H); 8,19 (d, 1H); of 7.90 (d, 1H); 7,97 (c, 1H); 7,72 (DD, 1H); 7,56 (d, 1H); to 7.32 (d, 1H); 7,22 (d, 1H); free 5.01 (q, 1H); 3,97 (c, 3H); of 1.44 (d, 3H); 0,90 (c, 9H); 0,06 (c, 3H); -0,02 (c, 3H). LRMC (APCI) calculated for (C26H32N3O2Si) [M+H]+, 446,2; found, 446,2.

Stage 6: 7-[(1R)-1-Hydroxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-Oh and 7-[(1S)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he

7-(1-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (51 mg, 0,114 mmol) dissolved in 2 ml of tetrahydrofuran. Add tetrabutylammonium fluoride (of 0.14 ml, 1.0 M in THF, 0.14 mmol) and the mixture is stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and saturated saline and washed the feast upon the major saline solution twice. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by reverse-phase HPLC (gradient 10-70% acetonitrile/water, 0.05% modifier triperoxonane acid) receive specified in the header connection. Two enantiomers shared by preparative chiral HPLC (column AS, 18% ethanol/heptane of isocratic). The absolute stereochemistry was determined through the formation of esters of Moser.

7-[(1R)-1-Hydroxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he.

1H NMR (600 MHz, CDCl3) δ 8,98 (d, 1H); 8,55 (d, 1H); 8,24 (d, 1H); 7,89 (d, 1H); 7,80 (c, 1H); 7,74 (DD, 1H); 7,58 (d, 1H); 7,34 (d, 1H); 7,22 (d, 1H); of 5.06 (q, 1H); 3,98 (c, 3H); 1.55V (c, 3H).

Hydroxyl proton not observed. LRMS (APCI) calculated for (C20H18N3O2) [M+H]+, 332,1; found 332,1. τR: 18,9 min (analytical chiral HPLC, AS a column, and 0.46 cm × 25 cm, 18% ethanol/heptane, isocratic, flow rate = 0.75 ml/min).

7-[(1S)-1-Hydroxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-it. Data1H NMR and LRMS coincide with the data for 7-[(1R)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-it. τR: 21,5 min (analytical chiral HPLC, AS a column, and 0.46 cm × 25 cm, 18% ethanol/heptane, isocratic, flow rate = 0.75 ml/min).

Example 22

7-(2-{[tert-Butyl(dimethyl)is ilil]oxy}ethyl)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-Oh (compound 47)

In a test tube with a glass Teflon membrane load 7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-Oh (50 mg, is 0.023 mmol), PdCl2(PPh3)2(2 mg, 0.02 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (14 mg, 0,068 mmol) and sodium carbonate (7 mg, 0,068 mmol). The vacuum tube and re-filled with argon three times. Add fully degassed dioxane (0.5 ml) and the mixture was stirred at 100°C during the night. The solution is diluted with ethyl acetate, washed with water and saturated saline solution, dried over magnesium sulfate, concentrated in vacuo, and purified flash chromatography (silica, 20 to 100% ethyl acetate/hexane with getting a connection specified in the header. LRMS (APCI) calculated for (C26H32N3O2Si) [M+H]+, 446,2; found 446,2.

Example 23

7-(2-Hydroxyethyl)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-Oh (Compound 48)

7-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (5 mg, to 0.011 mmol) was dissolved in 0.5 ml of tetrahydrofuran. Add tetrabutylammonium fluoride (0,013 ml of 1.0m in THF, of 0.013 mmol) and the mixture is stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate and saturated saline solution, and about what to see saturated saline solution twice. The organic layer is dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by reverse-phase HPLC (gradient 10-70% acetonitrile/water, 0.05% modifier triperoxonane acid) receive specified in the header of the connection.

1H NMR (600 MHz, CDCl3) δ 9,01 (d, 1H); 8,58 (c, 1H); is 8.16 (d, 1H); 7,92 (c, 1H); 7,81 (c, 1H); to 7.59 (DD, 1H); 7,56 (d, 1H); to 7.35 (d, 1H); from 7.24 (d, 1H); 3,99 (c, 3H); 3.96 points (t, 2H); 3,03 (t, 2H). ). Hydroxyl proton not observed. LRMC (APCI) calculated for (C20H18N3O2) [M+H]+, 332,1; found 332,1,

Example 24

3-Chloro-7-(1,2-dihydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-Oh (compound 49)

3-Chloro-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (0.10 g, of 0.37 mmol) was dissolved in 4 ml of tetrahydrofuran and 2 ml of water. Add 4 methylmorpholine N-oxide (0,105 ml of 50% m/m aqueous solution, 0.45 mmol) followed by the addition of osmium tetroxide (in 0.24 ml of 4% m/m aqueous solution 0,037 mmol). The resulting mixture was stirred at room temperature for 3 hours, then quenched by adding 10% m/m aqueous solution of sodium thiosulfate and stirred for 10 minutes. The mixture is extracted with ethyl acetate twice. The combined organic phases are dried over magnesium sulfate, filtered, concentrated in vacuo, and purified flash chromatography (silica, 20 to 100% ethyl acetate/hexane) to receive the drug connection, specified in the header.

1H NMR (600 MHz, CDCl3) δ 8,80 (d, 1H); 8,49 (d, 1H); 8,24 (d, 1H); 7,76 (DD, 1H); of 7.60 (d, 1H); to 7.32 (d, 1H); to 7.25 (d, 1H); 4,99 (DD, 1H); a 3.87 (DD, 1H); 3,70 (DD, 1H). Hydroxyl proton not observed. LRMC (APCI) calculated for (C16H13ClNO3) [M+H]+, 302,1; found 302,1.

Example 25

7-(1,2-Dihydroxyethyl)-3-(1-methyl)-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-Oh (compound 50)

In a test tube with a glass Teflon membrane load 3-chloro-7-(1,2-dihydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (9 mg, 0.03 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (12 mg, to 0.060 mmol) Pd2(dba)3(1 mg, 0.001 mmol), (tBu3)PBF4(1 mg, of 0.003 mmol) and potassium fluoride (6 mg, 0,098 mmol). The vacuum tube and re-filled with argon three times. Add fully degassed DMF (0.9 ml) and the reaction mixture is heated in a microwave oven at 180°C for 30 minutes. The reaction mixture was poured into a mixture of ethyl acetate/saturated salt solution and washed twice with saturated saline solution. The organic layer is dried over magnesium sulfate, concentrated in vacuo and purified by reversed-phase HPLC (gradient 10-70% acetonitrile/water, 0.05% modifier triperoxonane acid) to give the compounds specified in the header.

1H NMR (600 MHz, CDCl3) δ 9,00 (d, 1H); 8,58 (d, 1H); ,27 (s, 1H); to $ 7.91 (s, 1H); 7,81 (s, 1H); of 7.75 (d, 1H); to 7.61 (d, 1H); 7,38 (d, 1H); from 7.24 (d, 1H); 5,0 (DD, 1H); 3,99 (s, 3H); a 3.87 (DD, 1H); and 3.72 (d, 1H). LRMS (APCI) calculated for (C20H18N3O3) [M+H]+, 348,1; found 348,1.

Example 26

3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carbaldehyde

3-Chloro-7-(1,2-dihydroxyethyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (60 mg, 0.20 mmol) was dissolved in 1.8 ml of tetrahydrofuran and 0.9 ml of water. Add periodate sodium (51 mg, 0.24 mmol) and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture is then diluted with water and extracted with ethyl acetate three times. The combined organic layers are dried over magnesium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (silica, 10-100% ethyl acetate/hexane with getting a connection specified in the header.

1H NMR (600 MHz, CDCl3) δ 10,15 (c, 1H); cent to 8.85 (d, 1H); 8,73 (d, 1H); 8,54 (d, 1H); to 8.20 (DD, 1H); of 7.75 (d, 1H); 7,47 (d, 1H); 7,31 (d, 1H).

Example 27

3-Chloro-7-(1-hydroxypropyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he

3-Chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carbaldehyde (25 mg, 0,093 mmol) dissolved in 4 ml of hot dichloromethane. The solution is cooled to room temperature and add ethylaniline (0,047 ml, 2.0m in THF, 0,093 mmol). The reaction mixture was stirred at room temperature for 1.5 hours, at this point the e quenched by adding saturated aqueous ammonium chloride. The mixture is extracted three times with dichloromethane. The combined organic layers are dried over magnesium sulfate, filtered, concentrated in vacuo and purified by flash chromatography (5-60% ethyl acetate/hexane with getting a connection specified in the header.

1H NMR (600 MHz, CDCl3) δ 8,80 (d, 1H); charged 8.52 (d, 1H); 8,21 (d, 1H); 7,73 (DD, 1H); of 7.60 (d, 1H); to 7.32 (d, 1H); 7,27 (d, 1H); rate 4.79 (t, 1H); 1,99 (c, 1H); 1,89-to 1.79 (m, 2H); to 0.94 (t, 3H). LRMS (APCI) calculated for (C17H15ClNO2) [M+H]+, 300,1; found 300,1.

Example 28

7-[(1R)-1-Methoxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-Oh (compound 51)

7-[(1R)-1-Hydroxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (7 mg, 0.02 mmol) dissolved in 1 ml of tetrahydrofuran. Add sodium hydride (10 mg, 60% dispersion in oil) and the reaction mixture was stirred at room temperature for 2 hours. Add methyliodide (26 μl, 0.42 mmol) and the reaction mixture was stirred an additional 3 hours. The reaction mixture is then poured into a mixture of ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers are dried over magnesium sulfate, filtered, concentrated in vacuo and purified by reverse-phase HPLC (gradient 10-100% acetonitrile/water, 0.05% modifier triperoxonane the acid) to obtain the compounds specified in the header.

1H NMR (600 MHz, CDCl3) δ 9,05 (d, 1H); 8,73 (c, 1H); 8,21 (d, 1H); 7,94 (c, 1H); 7,85 (c, 1H); 7,73 (DD, 1H); the 7.65 (d, 1H); 7,51 (d, 1H); 7,34 (d, 1H); 4,47 (kV, 1H); 4,01 (c, 3H); 3.27 to (c, 3H); of 1.46 (d, 3H). LRMS (APCI) calculated for (C21H20N3O2) [M+H]+, 346,2; found 346,2.

Example 29

7-[(1S)-1-Methoxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-Oh (compound 52)

7-[(1S)-1-Hydroxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (7 mg, 0.02 mmol) dissolved in 1 ml of tetrahydrofuran. Add sodium hydride (10 mg, 60% dispersion in oil) and the reaction mixture was stirred at room temperature for 2 hours. Add methyliodide (26 μl, 0.42 mmol) and the reaction mixture was stirred an additional 3 hours. The reaction mixture is then poured into a mixture of ethyl acetate and saturated aqueous ammonium chloride. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers are dried over magnesium sulfate, filtered, concentrated in vacuo and purified by reverse-phase HPLC (gradient 10-100% acetonitrile/water, 0.05% modifier triperoxonane acid) to give the compounds specified in the header. Data1H NMR and receiver array coincide with the data of 7-[(1R)-1-methoxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-it.

Example 30

the pet-butyl 4-[2-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-hydroxyethyl]piperazine 1-carboxylate

3-Chloro-7-oxiran-2-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he (60 mg, 0.21 mmol) is suspended in 2.5 ml of methanol. Add tert-butylpiperazine-1-carboxylate (98 mg, of 0.53 mmol) and the reaction mixture is heated to boiling under reflux for 8 hours. The resulting mixture was concentrated in vacuo and purified directly by flash chromatography (15-100% ethyl acetate/hexane with getting a connection specified in the header.

1H NMR (600 MHz, CDCl3) δ 9,79 (d, 1H); 8,49 (d, 1H); by 8.22 (d, 1H); to 7.77 (DD, 1H); of 7.60 (d, 1H); 7,31 (d, 1H); to 7.25 (d, 1H); 4,91 (DD, 1H); 3,50 is-3.45 (m, 4H); 2,72 (Sirs, 2H); 2.63 in (DD, 1H); 2,50 (DD, 1H); 2,44 (Sirs, 2H); 1,46 (c, 9H). Hydroxyl proton not observed. LRMS (APCI) calculated for (C25H29ClN3O4) [M+H]+, 470,2; found 470,2.

Example 31

Tert-butyl 4-{2-hydroxy-2-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]ethyl}piperazine 1-carboxylate (compound 53)

Tert-butyl 4-[2-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-hydroxyethyl]piperazine 1-carboxylate (65 mg, was 0.138 mmol), 1-methyl-4(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (58 mg, 0.28 mol) Pd2(dba)3(6 mg, to 0.007 mmol), (tBu3)PBF4(4 mg, 0.014 mmol) and potassium fluoride (27 mg, 0.46 mmol) are combined in a sealed tube, which vacuum and filled with argon three times. Add fully on the carbonated DMF (1.5 ml). The tube placed in an oil bath at 115°C and stirred for 19 hours. The reaction mixture was poured into a mixture of ethyl acetate/saturated saline solution and extracted with ethyl acetate. The combined organic phases are dried over magnesium sulfate, filtered, concentrated in vacuo and purified by reverse-phase HPLC (gradient 10-42% acetonitrile/water, 0.05% modifier triperoxonane acid) to give the compounds specified in the header.

1H NMR (600 MHz, CDCl3) δ 9,00 (d, 1H); 8,55 (d, 1H); 8,23 (d, 1H); to $ 7.91 (c, 1H); 7,80 (c, 1H); 7,76 (DD, 1H); of 7.60 (d, 1H); 7,34 (d, 1H); 7.23 percent (d, 1H); of 4.95 (d, 1H); 3,98 (c, 3H); 3,56-3,51 (m, 4H); 2,78 of $ 2.53 (m, 6H); 1,46 (c, 9H). Hydroxyl proton not observed. LRMS (APCI) calculated for (C29H34N5O4) [M+H]+, 516,3; found 516,3.

Example 32

7-(1-Hydroxy-2-piperazine-1-retil)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-Oh (Compound 54)

Tert-butyl 4-{2-hydroxy-2-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]ethyl}piperazine 1-carboxylate (30 mg, 0,058 mmol) dissolved in 0.5 ml dichloromethane. Add triperoxonane acid (53 μl, of 0.53 mmol) and the reaction mixture was stirred at room temperature for 8 hours. The resulting mixture was concentrated in vacuo and directly purified by reverse-phase HPLC (gradient 10-100 acetonitrile/water, 0.05% modifier triperoxonane acid) to obtain the compound indicated in the title, in the form of TN salt.

1H NMR (600 MHz, CD3OD) δ 9,11 (d, 1H); 8,67 (d, 1H); 8,31 (d, 1H); 8,25 (c, 1H); with 8.05 (d, 1H); 7,83 (DD, 1H); of 7.75 (d, 1H); 7,39 (d, 1H); to 7.32 (d, 1H); 5,12 (DD, 1H); 3,97 (c, 3H); 3,39-to 3.34 (m, 4H); 3,18-and 3.16 (m, 4H); 3.04 from-2,96 (m, 2H). Hydroxyl and amine protons not observed. LRMS (APCI) calculated for (C24H26N5O2) [M+H]+, 416,2; found 416,2.

1. The compound of Formula I:

or its pharmaceutically acceptable salt, or stereoisomer,
where a is independently 0 or 1;
b is independently 0 or 1;
R1selected from aryl, heterocyclyl and NR10R11; specified aryl or heterocyclyl group optionally substituted by one to five substituents, each Deputy is independently selected from R8;
R5choose from C1-6of alkyl, C2-6alkenyl, -C(=O)NR10R11NHS(O)2NR10R11and NR10R11each alkyl, alkenyl and aryl optionally substituted by one to five substituents, each Deputy is independently selected from R8;
R8independently is a (C=O)aObC1-C10alkyl, (C=O)aObaryl, (C=O)andAboutbheterocyclyl, HE, Oa(C=O)bNR10R11or (C=O)aObC3-C8cycloalkyl, specify the initial alkyl, aryl, heterocyclyl optionally substituted one, two or three substituents selected from R9;
R9independently selected from: (C=O)aOb(C1-C10)alkyl and N(Rb)2;
R10and R11independently selected from: H, (C=O)Ob(C1-C10)alkyl, C1-C10of alkyl, SO2Rathe specified alkyl optionally substituted by one, two or three substituents selected from R8or
R10and R11can be taken together with the nitrogen to which they are attached with the formation of monocyclic heterocycle with 5 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms, selected from N and S, the specified monocyclic heterocycle optionally substituted with one, two or three substituents selected from R9;
Raindependently selected from (C1-C6)alkyl, (C2-C6)alkenyl; and
Rbindependently selected from H, (C1-C6)alkyl.

2. The compound according to claim 1, chosen from:
3-phenyl-7-vinyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-it;
7-ethyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-it;
7-[(2,4-dimethoxybenzyl)amino]-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-it;
7-amino-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-it;
2-hydroxy-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclo is EPTA[1,2-b]pyridin-7-yl)propanamide;
N-methyl-5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-7-carboxamide;
7-isobutyl-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-it;
N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;
N-[5-oxo-3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;
7-amino-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-it;
7-(isopropylamino)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-it;
N-[(2R)-1,4-dioxane-2-ylmethyl]-N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-]benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)sulphonamide;
N-[(2S)-1,4-dioxane-2-ylmethyl]-N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulphonamide;
the racemic mixture of N-[1,4-dioxane-2-ylmethyl]-N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulphonamide;
N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(tetrahydrofuran-3-yl)sulphonamide;
N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-({3R}-tetrahydrofuran-3-yl)sulphonamide;
N-methyl-N'-[3-(l-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-({3S}-tetrahydrofuran-3-yl)sulphonamide;
N-(5-oxo-3-pyridin-4-yl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;
N-[5-oxo-3-(1H-pyrazole-3-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;br/> N-[5-oxo-3-(1,3-thiazol-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;
N-[3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;
N-[5-oxo-3-(1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;
N-(3-{1-[2-(dimethylamino)ethyl]-1H-pyrazole-4-yl}-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;
N-{3-[1-(2-morpholine-4-yl-2-oxoethyl)-1H-pyrazole-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;
N-(4-{7-[methylsulphonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}phenylmethanesulfonyl;
N-[3-(1-cyclopentyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;
N-{3-[1-(3,3-dimethyl-2-oxobutyl)-1H-pyrazole-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl}methanesulfonamide;
N-[2-(1-methylpyrrolidine-2-yl)ethyl]-3-{7-[(methylsulphonyl)amino]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-3-yl}benzamide;
N,N-dimethyl-N'-[3-(1-methyl-1H-pyrazole-4-yl]-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulfonamida;
7-(5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-it;
7-[(2,4-dimethoxybenzyl)amino]-3-(3-thienyl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;
7-[(2,4-dimethoxybenzyl)amino]-3-(1H-pyrazole-3-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;
N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta,2-b]pyridin-7-yl]-N-(tetrahydrofuran-3-yl)sulphonamide;
7-[(imidazo[1,2-a]pyridine-3-ylmethyl)amino]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;
7-{[(1-methyl-5-oxopyrrolidin-2-yl)methyl]amino}-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;
N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N-(tetrahydro-2H-Piran-2-ylmethyl)sulphonamide;
N-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]-N'-(tetrahydrofuran-3-yl)sulphonamide;
N-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]morpholine-4-sulfonamide;
N-[3-(4-isopropylpiperazine-1-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;
3-(4-isopropylpiperazine-1-yl)-7-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;
N-(3-morpholine-4-yl-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;
N-(3-aniline-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)methanesulfonamide;
N-[3-(cyclohexylamino-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;
N-[5-oxo-3-(pyridine-4-ylamino)-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]methanesulfonamide;
N-(2,4-dimethoxybenzyl)-N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)etranslate;
N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)etranslate;
N-(5-oxo-3-phenyl-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-pyrrolidin-1-retensioned;
dimethyl [3-(1-methyl-1H-feast of the ol-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]amidophosphate;
7-[(1R)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;
7-[(1S)-1-hydroxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;
7-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;
7-(2-hydroxyethyl)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;
7-(1,2-dihydroxyethyl)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;
7-[(1R)-1-methoxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;
7-[(1S)-1-methoxyethyl]-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;
tert-butyl 4-[2-(3-chloro-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl)-2-hydroxyethyl]piperazine 1-carboxylate;
tert-butyl 4-{2-hydroxy-2-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]ethyl}piperazine 1-carboxylate;
7-(1-hydroxy-2-piperazine-1-retil)-3-(1-methyl-1H-pyrazole-4-yl)-5H-benzo[4,5]cyclohepta[1,2-b]pyridine-5-he;
or its pharmaceutically acceptable salt or stereoisomer.

3. Pharmaceutical composition for inhibiting the receptor tyrosine kinase MET, which contains a compound in accordance with claim 1 and a pharmaceutically acceptable carrier.

4. The method of using compounds according to claim 1 to obtain medication, applicable for the inhibition of the receptor tyrosine kinase MET in a mammal, n is idahosa in such treatment.

5. The method of using compounds according to claim 4 to obtain medication useful for treating or preventing cancer in a mammal in need of such treatment.

6. The method of using compounds according to claim 5 for receiving medication, applicable to the prevention or modulation of metastasis of cancer in a mammal in need of such treatment.

7. Application of the compound in accordance with claim 6, where the cancer is selected from squamous cell carcinoma of the head and neck, histiocytes lymphoma, lung adenocarcinoma, small cell lung cancer, non-small cell lung cancer, pancreatic cancer, papillary cell carcinoma, liver cancer, stomach cancer, colon cancer, multiple myeloma, glioblastomas and breast carcinoma.

8. The compound according to claim 1, including:

N-[(2R)-1,4-dioxane-2-ylmethyl]-N-methyl-N'-[3-(1-methyl-1H-pyrazole-4-yl)-5-oxo-5H-benzo[4,5]cyclohepta[1,2-b]pyridin-7-yl]sulphonamide
or its pharmaceutically acceptable salt.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to novel ligands, including novel compounds of general formula 1, a wide range of biological activity which simultaneously includes alpha-adrenoceptors, dopamine receptors, histamine receptors, imidazoline receptors and serotonin receptors, including serotonin 5-HT7 receptors, in form of free bases, geometric isomers, racemic mixtures or separate optical isomers, as well as in form of pharmaceutically acceptable salts and/or hydrates. In formula 1

R1 denotes hydrogen; C1-C4alkyl optionally substituted with C1-C4alkoxycarbonyl, aromatic or saturated optionally annelated or optionally substituted with a five- or six-member heterocycle containing 1-2 N heteroatoms; C1-C3acyl; saturated optionally substituted six-member N-heterocycle; C1-C4alkoxycarbonyl; optionally substituted arylsulphonyl, R2 denotes a substitute of a cyclic system, including hydrogen; halogen; optionally substituted C1-C4alkyl;CF3, CN, C1-C4alkoxy; C1-C4alkoxycarbonyl; carboxyl; unsaturated six-member N-containing heterocyclyl or optionally substituted arylsulphonyl, Ar denotes phenyl, optionally substituted with C1-C4alkyl, dimethylamino group, one or more C1-C4alkoxy groups, one or more halides, CF3 group, nitro group, carboxyl, C1-C4alkoxycarbonyl, C1-C4acylamino group, CN, optionally annelated with a saturated heterocycle; optionally annelated and optionally substituted unsaturated five- or six-member heterocycle containing one or two heteroatoms selected from nitrogen, oxygen or sulphur; W denotes an optionally substituted (CH2)m group, optionally substituted CH=CH group, optionally substituted CH2-CH=CH group, C≡C group, SO2 group; n = 1 or 2; m=1, 2 or 3, the solid line accompanied by a dotted line (---) denotes a single or double bond.

EFFECT: compounds can be used to treat and/or prevent diseases or pathological conditions of the central nervous system, whose pathogenesis is associated with hyper- or hypo-activation of said receptors, for example anxiety or cognitive disorders, neurodegenerative and psychotic diseases.

42 cl, 26 dwg, 12 tbl, 20 ex

FIELD: chemistry.

SUBSTANCE: invention relates to use of 3,11b-cis-dihydrotetrabenazine or its pharmaceutically acceptable salts to prepare a medicinal agent for preventing or treating schizophrenia. The invention also relates to compounds for use in preventing or treating psychosis, methods of preventing or treating psychosis, as well as methods of preventing or alleviating a psychotic episode.

EFFECT: use of 3,11b-cis-dihydrotetrabenazine to prepare a medicinal agent for preventing or treating schizophrenia.

34 cl, 7 ex, 6 tbl, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and pharmaceutically acceptable salts thereof, where substitutes R1-R4 are as defined in claim 1. Said compounds have 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) enzyme inhibiting activity.

EFFECT: compounds can be used in form of a pharmaceutical composition.

15 cl, 1 tbl, 94 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compound under the invention is represented by formula (I) or its pharmaceutically acceptable salt where R1 and R2 represent H or optionally substituted alkyl where substitutes are specified from -N(CH3)2, -OH, -OCH3; B represents N; Z represents N; each of W, X and Y independently represents C-H, C-J; Ar represents an optionally substituted phenyl ring where substitutes are specified from halogen, -NH-CH3; each J independently represents NR1R2; and n is equal to 0; provided the compound is not 4-[2-(5-chloro-2-fluorophenyl)pteridine-4-ylamino]nicotinamide. The compounds of formula (I) can find application in treating HCV related conditions.

EFFECT: preparation of the new compounds for making a drug for treating HCV infection.

15 cl, 2 tbl, 9 ex

Chemical compounds // 2405780

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new compounds of formula (I): , in which: R1 and R2 are independently specified from hydrogen, C1-6alkyl, C1-6alkoxy and cyclopropyl; X1, X2 and X3 independently represent =N- or =CR10; R3 and R10 are independently specified from hydrogen, halogen, nitro, cyano, amino, carboxy, carbamoyl, C1-6alkyl, N-(C1-6alkyl)amino, N,N(C1-6alkyl)2amino, C1-6alkanoylamino, C1-6alkoxycarbonyl; R4 represents hydrogen; R5 and R6 are independently specified from hydrogen, hydroxy and C1-6alkyl where R5 and R6 independently can be optionally substituted in carbon atom with one or more R16 where R16 represents hydroxy; A represents a single link or C1-2alkylene; where specified C1-2alkylene can be optionally substituted with one or more R18; the ring C represents a saturated, partially saturated or unsaturated mono- or bicyclic ring containing 5 or 6 atoms in which at least one atom can be specified from nitrogen, sulphur or oxygen which can be linked with carbon or nitrogen atom where the -CH2- group can be optionally substituted with -C(O)- and ring sulphur atom can be optionally oxidised to produce S-oxide; R7 is specified from halogen and C1-6alkyl where R7 can be optionally substituted in carbon atom with halogen; n is equal to 0.1 or 2; where R7 values can be equal or different; and R18 is independently specified from halogen and hydroxy; or its pharmaceutically acceptable salt. Also the invention refers to their pharmaceutical compositions and methods for preparation and application thereof for cancer treatment.

EFFECT: preparation of new compounds which can find application for cancer treatment.

23 cl, 96 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula where: R1 denotes -OR1', -SR1", 6-member heterocycloalkyl with one O atom and possibly one N atom, phenyl or 5-member heteroaryl with two N atoms, 6-member heteraryl with one N atom; R1'/R1" denote C1-6-alkyl, C1-6-alkyl substituted with a halogen, -(CH2)x-C3-6cycloalkyl or -(CH2)x-phenyl; R2 denotes S(O)2-C1-6-alkyl, -S(O)2NH-C1-6-alkyl, CN; denotes the group: , and where one extra N atom of the nucleus of an aromatic or partially aromatic bicyclic amine may be present in form of its oxide ; R3 - R10 denotes H, halogen, C1-6-alkyl, C3-6cycloalkyl, 4-6-member heterocycloalkyl with one N or O atom, 6-member heterocycloalkyl with two O atoms or two N atoms, 6-8-member heterocycloalkyl containing on N atom or one O or S atom, 5-member heteroaryl with two or three N atoms, 5-member heteroaryl with one S atom, in which one carbon atom may be also substituted with N or O, 6-member heteroaryl with one or two N atoms, C1-6-alkoxy, CN, NO2, NH2, phenyl, -C(O)-5-member cyclic amide, S-C1-6-alkyl, -S(O)2-C1-6-alkyl, C1-6-alkyl substituted with halogen;C1-6-alkoxy substituted with halogen, C1-6-alkyl substituted with OH, -O-(CH2)y-C1-6-alkoxy, -O(CH2)yC(O)N(C1-6-alkyl)2, -C(O)-C1-6-alkyl, -O-(CH2)x-phenyl, -O-(CH2)x-C3-6cycloalkyl, -O-(CH2)x-6-member heterocycloalkyl with one O atom, -C(O)O-C1-6-alkyl, -C(O)-NH-C1-6-alkyl, -C(O)-N(C1-6-alkyl)2, 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl or 3-oxa-8-aza-bicyclo[3.2.1]oct-8-yl; R' and R'" in group (e) together with -(CH2)2- with which it is bonded can form a 6-member ring; R, R', R" and R"' independently denote H, C1-6-alkyl; and where all groups - phenyl, cycloalkyl, cyclic amine, heterocycloalkyl or 5- or 6-member heteroaryl, as defined for R1, R1', R1" and R3 - R10, can be unsubstituted or substituted with one or more substitutes selected from OH, =O, halogen, C1-6-alkyl, phenyl, C1-6-alkyl substituted with halogen, or C1-6-alkoxy; n, m o, p, q, r, s and t = 1 , 2; x =0, 1 or 2; y = 1 , 2; and their pharmaceutically acceptable acid addition salts.

EFFECT: compounds have glycine transporter 1 inhibiting activity, which enables their use in a pharmaceutical composition.

20 cl, 2 tbl, 12 dwg, 382 ex

FIELD: medicine.

SUBSTANCE: invention refers to new derivatives of dihydro-pyrroloquinoline of formula I where values of R1, R2, R3a and R3c radicals are specified in cl. 1 of the patent claim. Also the invention refers to a method for making the compound of formula I, to its application, a composite product based on the compound of formula I and a general antimicrobial agent and a pharmaceutical composition based on the compound of formula I.

EFFECT: there are prepared new derivatives of dihydro-pyrroloquinoline exhibiting antibacterial activity.

26 cl, 4 dwg, 11 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel substituted 8-sulphonyl-2,3,4,5-tetrahydro-1H-γ-carbolines of general formula 1 or pharmaceutically acceptable salts thereof, which are ligands with a wider range of simultaneous activity towards alpha adrenoceptors, dopamine receptors, histamine receptors, imidazoline receptors, sigma receptors, norepiniphrine receptors and serotonin receptors. In compounds of general formula 1 R1 is an amino group substitute selected from hydrogen; C1-C3alkyl optionally substituted with phenyl; C1-C4alkyloxycarbonyl; R2 is a cyclic system substitute selected from hydrogen, C1-C3alkyl optionally substituted with phenyl, pyridin-(3- or 4-yl), (6-methylpyridin-3-yl); C1-C3alkenyl substituted with phenyl; or optionally substituted phenylsulphonyl; R3 is an optionally halogen-substituted phenyl, six member aromatic azaheterocycle, mono- or di-C1-C3alkylamino group, phenylamino group which is optionally substituted with halogen atoms on the phenyl ring, or a substituted six member azaheterocycle containing an additional nitrogen atom, substituted with C1-C3alkyl.

EFFECT: compounds can be used in treating and preventing diseases and pathological conditions of the central nervous system, such as anxiety disorders, cognitive disorders, neurodegenerative diseases and depression.

18 cl, 2 dwg, 6 tbl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compounds of formula IB , where radicals R1-R5 have values, given in invention formula. In range of claimed invention also described are pharmaceutical compositions, which include compounds of IB formula, and methods of application of such compounds and compositions for treatment of different malfunctions, mainly selected from immune response reactions.

EFFECT: compounds by claimed invention have inhibiting action with respect to proteinkinases and, in particular with respect to JAK-3, ROCK or Aurora kinases.

55 cl, 6 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of general formula: I, where R1 is selected from hydrogen or methoxy; R2 is selected from a group consisting of hydroxy, lower alkoxy, provided that R2 does not denoe methoxy when R1 denotes methoxy, lower alkoxy, mono- or di-substituted with a hydroxy group, benzyloxy, amino, alkylamino, dialkylamino, cyano group, unsubstituted phenyl or tetrazolyl, -O-(CH2)m-C(O)-NR8R9, where m equals 1 or 2, and where R8 and R9 are independently selected from hydrogen, lower alkyl or tetrazolyl, or R8 and R9 together with the nitrogen atom with which they are bonded form morpholinyl or piperazinyl, -O-(CH2)n-COOR10, where n equals 1 or 2 and R10 denotes hydrogen or lower alkyl, -O-(CH2)p-NH-C(O)-OR11, where p equals 1 or 2,and where R11 denotes lower alkyl, -O-SO2-R12, where R12 denotes lower alkyl, -NR13R14, where R13 denotes hydrogen or lower alkyl, and R14 denotes lower alkyl or benzyl, and -NH-CO-(CH2)q-R15, where q equals 1 or 2, and where R5 denotes tetrazolyl; R3 is selected from a group consisting of hydrogen, hydroxy, lower alkoxy, lower alkoxy which is mono- or di-substituted with a hydroxy group, alkoxy or unsubstituted phenyl, and -O-(CH2)m-C(O)-NR8R9, where m equals 1 or 2, and where R8 and R9 are independently selected from hydrogen or lower alkyl, or R8 and R9 together with the nitrogen atom with which they are bonded form morpholinyl or piperazinyl, which can be substituted with lower alkyl; R4 is or , where R5 is selected from lower alkyl; or R5 can also denote hydrogen when selected from a group consisting of -(CH2)m-C(O)-NR8R9, -O-(CH2)p-NH-C(O)-OR11, -O-SO2-R12, -NR13R14, -NH-CO-(CH2)q-R15 and lower alkoxy which is mono- or di-substituted with a group selected from hydroxy, benzyloxy, amino or cyano; R6 is selected from a group consisting of hydrogen and lower alkyl; R7 is selected from a group consisting of lower alkyl and lower halogenalkyl; and to pharmaceutically acceptable salts of said compounds. The invention also pertains to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds having DPP-IV enzyme inhibiting activity.

22 cl, 50 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds with common formulae I, II, IV and V: (I), (III), (IV), (V), values of radicals, such as provided in invention formula. Besides, proposed invention relates to pharmaceutical composition on the basis of above-described compounds, to their application, and also to method for treatment of repeated urination, incontinence and higher activity of urinary bladder, besides, to method to treat pain.

EFFECT: new compounds have been produced and described, which may be useful for treatment of diseases related to fatty-acid amide-hydrolase (FAAH), in particular to treat repeated urination and incontinence, higher activity of bladder and/or pain.

16 cl, 442 ex, 73 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrazine-2-carboxamide derivatives of general

formula , where R1 denote a 5- or 6-member ring, having a formula given in claim 1, R2 denotes H or C1-C7-alkyl; R3 denotes phenyl, pyridinyl or pyrimidinyl, possibly substituted with the following substitutes: Cl, F or Br; R4 denotes H, CI, F, Br, CF3 or C1-C7-alkyl; R5 denotes C1-C7-alkyl; as well as pharmaceutically acceptable salts thereof. Disclosed compounds are metabotropic glutamate receptor (mGLUR 5) antagonists. The invention also pertains to a medicinal agent based on disclosed compounds.

EFFECT: improved method.

17 cl, 23 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I and to its pharmaceutically acceptable salts. In formula I , R1 means hydrogen or ; is specified from phenyl, and a 5-member heteroaromatic ring containing 1 to 2 heteroatoms specified inhe group consisting of sulphur and nitrogen; X is specified from lower alkylene, cyclisated lower alkylene containing 3 to 6 carbon atoms, and hydroxy(lower alkylene); R5 and R6 are independently specified in the group including hydrogen, lower alkyl, halogen and lower alkoxygroup; R3 is specified from hydrogen and -NH-R7; R4 is specified from hydrogen and -O(CH2CH2O)y-R10; R7 means lower alkyl; R10 means lower alkyl; n means an integer within 0 to 1; and y is equal to 0; provided when n is equal to 0, and R1 means hydrogen, then R3/R4 both cannot mean hydrogen. The invention also concerns a pharmaceutical composition containing a therapeutically effective amount of the compound under the invention.

EFFECT: preparation of the new compounds which show CDK1 kinase inhibiting activity and can be effective in cancer treatment, particularly breast cancer, lung cancer, colon cancer and prostate cancer treatment.

45 cl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to a compound of formula I and to its pharmaceutically acceptable salts. In formula I , Y means -S- or -NH-; R1 is specified from hydrogen, -C(O)O-[CH2CH2O]P-R4, -C(O)-R3 and R2-(X)n-; R3 is specified from lower alkyl, cycloalkyl containing 3 to 6 carbon atoms and ; R4 means lower alkyl; X is specified from lower alkylene and cyclisated lower alkylene; R2 means ; where is specified from phenyl, and a 5 or 6-merous heteroaromatic ring containing 1 to 2 heteroatoms specified in the group consisting of sulphur and nitrogen; R5 and R6 are independently specified in the group including hydrogen, lower alkyl, halogen, perfluor (lower alkyl) and lower alkoxygroup; n means an integer within 1 to 2; and r means 0. The invention also concerns a pharmaceutical composition containing a therapeutically effective amount of the compound under the invention.

EFFECT: preparation of the new compounds which show CDK1 kinase inhibiting activity and can be effective in cancer treatment, particularly breast cancer, lung cancer, colon cancer and prostate cancer treatment.

64 cl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of general formula (I): or to any of its stereoisomers, or to any mixture of their stereoisomers, or to their pharmaceutically acceptable salts where Ra, Rb and Rc independently represent hydrogen, alkyl, cycloalkyl, alkoxy, alkoxyalkyl, arylalkyl, formyl or alkylcarbonyl; Rd represents a heteroaryl group; where said heteroaryl group means a 5-6-member aromatic heterocyclic group which contains one or two heteroatoms in the ring structure, specified from nitrogen (N) or sulphur (S) and where the heteroaryl group is optionally substituted with one or more substitutes independently specified from the group including: halogeno, hydrazino and alkoxy. Also the invention refers to a pharmaceutical composition, the application of a chemical compound under any of cl. 1-6, as well as to a method of GABAa-receptor complex modulation in the central nervous system.

EFFECT: preparation of the new biologically active compounds exhibiting gamma-amino-butyric acid (GABAa) receptor complex modulating activity in the central nervous system.

11 cl, 10 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: medicine-ligand conjugates are powerful cytotoxins in which the medicine is bonded to the ligand through a peptide, hydrazine or disulphide linker.

EFFECT: agents are highly effective.

63 cl, 8 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to compounds of formula

, in which A is a counter ion, a=1-3, b=0-3, X=1-6C alkyl, R1=1-6C alkyl, one or R2 and R3 is 1-6C alkyl and the other is XN+Hb(R1)3-b, or R2 and R3 form a methylenedioxy group, one or R4 and R5 is a halogen and the other is a halogen-substituted 1-6C alkyl, or R4 and R5 are bonded to form a 6-10C aromatic ring or a substituted 6-10C aromatic ring in which the substitute is selected from 1-6C alkoxy, halogen and halogen-substituted 1-6C alkyl. The invention also relates to a method of measuring content of analysed substance capable of ensuring proportional colour change as a result of a reaction in a biological fluid, involving the following steps: ensuring availability of the disclosed tetrazolium salt as an indicator and determination of concentration of the said analysed substance in the biological fluid using the said tetrazolium salt which is used as an indicator.

EFFECT: agents are highly effective.

24 cl, 7 dwg, 1 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula or its pharmaceutically acceptable salt, where R1 and R2 each independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a hydroxyl group, a cyano group or a lower alkoxy; R3 independently denotes a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a hydroxyalkyl, trifluoromethyl, lower alkenyl or cyano group; R4 independently denotes a hydrogen atom, a lower alkyl, a lower alkoxy, a halogen atom, trifluoromethyl, hydroxyalkyl optionally substituted with a lower alkyl, aminoalkyl optionally substituted with lower alkyl, alkanoyl, carboxyl group, lower alkoxycarbonyl or cyano group; Q denotes a nitrogen atom; R5 and R6 each independently denotes a hydrogen atom, a lower alkyl, a halogen atom, a lower alkylsulfonyl, a lower alkylsulfanyl, alkanoyl, formyl, aryl, mono- or di-(lower) alkylcarbamoyl or mono- or di-(lower) alkylsulfamoyl; and further as indicated in the formula of invention. The invention also relates to a glucokinase activator containing the compound in paragraph 1 and to a therapeutic agent based on said compounds.

EFFECT: novel compounds which can be useful in treating and preventing diabetes and obesity are obtained and described.

29 cl, 227 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I and their pharmaceutically acceptable salts. Disclosed compounds have inhibitory effect on CDK1 kinase and can be used to prepare medicinal agents for treating diseases associated with abnormal cell cycle development. In formula I , R1 is hydrogen, -C(O)OR9 or R2-(X)n-; X is (lower)alkylene, hydroxy(lower)alkylene, cyclised(lower)alkylne or mono- or dihalogen(lower)alkylene; R2 is a group, where denotes a phenyl or a 5-6-member heteroaromatic ring containing 1-2 heteroatoms selected from a group comprising oxygen, sulphur and nitrogen atoms; R5, R6 and R7 are independently selected from a group comprising hydroxy, hydrogen, (lower)alkyl, halogen and (lower)alkoxy; R4 is a halogen, , (O)k(CH2CH2O)y-R10, , -S-R12 or -O-(CH2)tR14, where denotes a phenyl, a cycloalkyl ring containing 3-6 carbon atoms, a 4-6-member heterocycloalkyl containing 3-5 carbon atoms and 1-2 heteroatoms selected from a group comprising oxygen, nitrogen and sulphur atoms; R9, R11, R15 and R16 independently denote (lower)alkyl; R10 and R12 denote (lower)alkyl; R14 denotes perfluoro(lower)alkyl or -NR15R16; R17 and R18 independently denote hydrogen, , F, OCH3 and -C(=O)CH3; n and k are equal to 0 or 1; m, w, y and z are equal an integer from 0 to 3; and t equals an integer from 0 to 6.

EFFECT: invention also relates to a pharmaceutical composition having antiproliferative activity, containing one or more of the disclosed compounds.

65 cl, 1 tbl, 49 ex

FIELD: chemistry.

SUBSTANCE: invention relates to synthetic cytoskeleton-active compounds which are from the family of natural latrunculin A or latrunculin B and have structural formulae

and described in the formula of invention. Present invention also relates to a pharmaceutical composition containing said compounds and a pharmaceutically acceptable carrier. The invention also pertains to a method of preventing or treating diseases and conditions associated with actin polymerisation. In one embodiment of the invention, high intraocular pressure, such as during primary open angle glaucoma, is treated using the method. The method involves administering a therapeutically effective amount of the cytoskeleton-active compound of formula I or II to a subject, where the said amount is sufficient for acting on a cytoskeleton, for example through actin polymerisation inhibition.

EFFECT: compounds are highly effective.

16 cl, 75 ex

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