Compounds which are erk inhibitors

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula 1.0:

,

where Q represents tetrahydropyridinyl ring substituted. R5, R1 are selected from: (1) pyridyl, substituted with substituent, selected from group, consisting of: -O-CH3, -O-C2H5, -O-CH(CH3)2, and -O-(CH2)2-O-CH3, R2 is selected from group, consisting of: -OCH3 and -SCH3; and R5 is selected from (a) substituted triazolylphenyl-, where triazolyl is substituted with one or two alkyl groups, selected from group, consisting of: -C1-C4alkyl, (b) substituted triazolylpheenyl-, wheretriazolyl is substituted on nitrogen atom with -C1-C4alkyl, (c) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with -C2alkylene-O-C1-C2alkyl, (d) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with -C2-C4alkylene-O-CH3, and (e) substituted triazolylphenyl-, where triazolyl is substituted on nitrogen atom with hydroxy-substituted -C1-C4alkyl, and where phenyl is optionally substituted with from 1 to 3 substituents, independently selected from group, consisting of halogen; and their pharmaceutically acceptable salts and solvates, which are claimed as ERK inhibitors.

EFFECT: obtaining pharmaceutically acceptable salts and solvates, claimed as ERK inhibitors.

15 cl, 2 tbl, 32 ex

 

Reference to related application

This application claims the priority of provisional patent application U.S. No. 61/030407, filed February 21, 2008

The level of technology

The process, which is associated with growth, development and metastasis of tumors is controlled by signalling pathways that are activated in cancer cells. The path of ERK plays a key role in the regulation of growth of mammalian cells by relaying extracellular signals associated with ligand tyrosinekinase receptors on the cell surface, such as the erbB family, PDGF, FGF and VEGF tyrosinekinase receptor. Activation of the ERK pathway occurs through a cascade of events fosforistye that begins with the activation of Ras. Activation of Ras leads to recruitment and activation of Raf, a serine-threonine kinase. Activated Raf then phosphorylates and activates MEK1/2, which then phosphorylates and activates ERK1/2. When activated ERK1/2 phosphorylates several downstream targets involved in many cellular events, including changes in the cytoskeleton and transcription activation. The path of ERK/MAPK is one of the most important for cell proliferation and is thought to be the path of ERK/MAPK frequently activated in many tumors. The genes of the Ras, which are located above ERK1/2, are subjected to mutations in certain types of cancer, including colorectal cancer, melanoma, tumors of the mammary glands and the pancreas is. High Ras activity is accompanied by increased activity of ERK in many tumors found in humans. Moreover, mutation of a skin disease, a serine-threonine kinase of the Raf family, are associated with increased kinase activity. Mutations in skin disease found in melanomas (60%), thyroid cancer (above 40%) and colorectal cancer. These observations suggest that the signaling pathway ERK1/2 is an attractive way for anti-cancer therapy for a wide spectrum of tumors that occur in humans.

Taking into account all the above, a valuable contribution in this area of technology would be "small molecules" (i.e., connections), which ingibiruet ERK activity (i.e. the activity of ERK1 and ERK2), small molecules which would be useful for the treatment of a wide spectrum of cancers, such as melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer and ovarian cancer. The present invention provides such a contribution.

Brief description of the invention

In the present invention are disclosed compounds that inhibit the activity of ERK1 and/or ERK2 activity.

Compounds according to the present invention also inhibit phosphorylation of ERK1 and ERK2.

Thus, the present invention provides compounds that are inhibitors of ERK (i.e., what hibitory ERK1 and/or ERK2 inhibitors), these compounds are the compounds of formula 1.0:

or their pharmaceutically acceptable salt and solvate, where: Q is tetrahydropyridine (e.g., 1,2,3,6-tetrahydropyridine) or substituted tetrahydropyridines (for example, substituted 1,2,3,6-tetrahydropyridine); and R1and R2defined below.

The present invention discloses compounds of formula 1.0.

The present invention discloses compounds of formula 1.0 in pure or selected form.

The present invention discloses pharmaceutically acceptable salts of the compounds of formula 1.0.

The present invention discloses a solvate of the compounds of formula 1.0.

The present invention discloses compounds of formula 1.0, in which one to all hydrogen atoms (H) are deuterium.

The present invention discloses compounds of formula 1.0, where at least one hydrogen atom is a deuterium.

The present invention discloses compounds of formula 1.0, where from 1 to 5 hydrogen atoms are deuterium.

The present invention discloses compounds of formula 1.0, where one hydrogen atom is a deuterium.

The present invention discloses compounds A1-A16 and A18-A48 motorway.

The present invention discloses compounds A1-A16 and A18-A30.

This is completed with the invention discloses compounds A1-A16 and A18-A26.

The present invention discloses compounds A31-A48 motorway.

The present invention discloses a pharmaceutical composition comprising an effective amount of at least one compound of formula 1.0 and a pharmaceutically acceptable carrier.

The present invention discloses a pharmaceutical composition comprising an effective amount of at least one compound of formula 1.0 and an effective amount of at least one pharmaceutically active ingredient (such as, for example, a chemotherapeutic agent) and a pharmaceutically acceptable carrier.

The present invention also discloses a method of inhibiting ERK (i.e., inhibiting the activity of ERK) in a patient who is in need of such treatment, containing the introduction to the specified patient an effective amount of at least one compound of formula 1.0.

The present invention also discloses a method of inhibiting ERK1 (i.e., inhibiting the activity of ERK1) the patient requiring such treatment, containing the introduction to the specified patient an effective amount of at least one compound of formula 1.0.

The present invention also discloses a method of inhibiting ERK2 (i.e., inhibiting the activity of ERK2) in a patient requiring such treatment, containing the introduction to the specified effective patient is positive number, at least one compound of formula 1.0.

The present invention also discloses a method of inhibiting ERK1 and ERK2 (i.e., inhibiting the activity of ERK1 and ERK2 activity) in a patient who is in need of such treatment, containing the introduction to the specified patient an effective amount of at least one compound of formula 1.0.

The present invention also discloses a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one compound of formula 1.0.

The present invention also discloses a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one compound of formula 1.0.

The present invention discloses a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one compound of formula 1.0, in combination with an effective amount of at least one chemotherapeutic agent.

The present invention also discloses a method of treating cancer in a patient, the cat the rum you need such treatment, moreover, this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one compound of formula 1.0, in combination with an effective amount of at least one chemotherapeutic agent.

The present invention also discloses a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one compound of formula 1.0, in combination with at least one inhibitor of signal transduction.

The present invention also discloses a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one compound of formula 1.0, in combination with at least one inhibitor of signal transduction.

In the methods according to the present invention the compounds according to the present invention can be administered simultaneously or sequentially (i.e., sequentially) with chemotherapeutic agents or inhibitors of signal transduction.

Methods of treating cancer described in the present is the application may, if desired, to enable the introduction of an effective quantity of radiation (i.e., methods of treating cancer described in this application, if desired, include the introduction of radiotherapy).

Detailed description of the invention

As described in this document, unless otherwise specified, the drug or compound is applied in a certain period of the treatment cycle. For example, once a day means once a day, every day of the treatment cycle. Twice a day means two times a day, every day of the treatment cycle. Once a week means once a week during the treatment cycle. Once every three weeks means once every three weeks during the treatment cycle.

Unless otherwise specified, the following abbreviations have the following meanings:

ACNacetonitrile
Asónacetic acid
Anhyanhydrous
DASTTRIFLUORIDE diethylaminoethyl
DCCdicyclohexylcarbodiimide
DCUdicyclohexylamine
DCMdichloromethane
DIdeionized water
DIADdiisopropylsalicylic
DIEAdiisopropylethylamine
DMAP4-dimethylaminopyridine
DMEdimethoxyethan
DMFdimethylformamide
DMFDMAN,N-dimethylformamide, dimethylacetal
DMSOthe sulfoxide
DTTdithiotreitol
EDCl1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
EtEthyl
EtOAcThe ethyl acetate
EtOHEthanol
HATUN,N,N',N'-Tetramethyl-O-(7-asobancaria-1-yl)Urania hexaphosphate
Hexhexane
HOBt1-hydroxybenzotriazol
HPLChigh performance liquid chromatography
IHMSliquid chromatography with mass spectrometry
LDAdiisopropylaniline
mCPBAmeta-Chloroperoxybenzoic acid
MeonMethanol
MTT(3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide, thiazolyl blue)
NMRNuclear magnetic resonance
PFPpentafluorophenol
RMVp-methoxybenzyl
Rupyridine
Pyrpyridine
Rbround-bottom flask
Rbtround-bottom flask
RT (r.t.)room temperature
EMCl 2-(trimethylsilyl)ethoxymethyl chloride
TEAthe triethylamine
Trtriphenylmethane
Trttriphenylmethane
TrCltriphenylmethane chloride
TFAtriperoxonane acid
THFtetrahydrofuran
TLCthin-layer chromatography
TMStrimethylsilyl

As used herein, unless otherwise indicated, the following terms have the following meanings:

The term "anticancer agent" means a drug (a drug or pharmaceutically active ingredient for treatment of cancer;

The term "anticancer agent" means a drug (a drug or pharmaceutically active ingredient for treatment of cancer (i.e., chemotherapeutic agent);

The phrase "at least one" in reference to the number of compounds according to the present invention means, for example, 1 to 6, usually 1 to 4, more often 1, 2 or 3 and usually Odie is one or two and more often one; thus, in one example, "at least one" means one, in another example, "at least one" means two, and in another example, "at least one" means three;

The term "chemotherapeutic agent" means a drug (a drug or pharmaceutically active ingredient)used for cancer treatment (i.e. anticancer agents);

The term "connection" when referring to anti-tumor agents, covering agents that are antibodies;

The term "simultaneously" means (1) simultaneously in time (for example, at the same time); or (2) at different times during the overall course of treatment;

The term "sequentially" means that one follows the other;

The term "different"as used in the phrase "different antitumor agents"means the agents do not represent the same compound or structure; preferably, "different", as used in the phrase "different antitumor agents", means that these agents do not belong to the same class of antitumor agents; for example, one anti-tumor agent is Texan, and the other anticancer agent is a coordination compound of platinum;

The term "effective amount" or "therapeutically effect the main amount" is intended to denote the number of compounds or compositions according to the present invention, or quantity of radiation effective for the treatment or inhibition of diseases or conditions described herein and, thus, to obtain the desired therapeutic, ameliorative, inhibitory or preventative effect; thus, for example, in methods of treating cancer described in this application "effective amount" or "therapeutically effective amount"refers to, for example, the number of connections (or drugs) or irradiation, which leads to: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) decrease the size tumor, (C) the disappearance of the tumor and/or (d) stabilization of the tumor for a long period (the retention growth); for example, in the treatment of lung cancer (e.g. small cell lung cancer), a therapeutically effective amount means an amount that reduces or leads to the disappearance of cough, shortness of breath and/or pain; also, for example, the effective amount or therapeutically effective amount of an inhibitor of ERK (i.e., compounds according to the present invention) represents such an amount that reduces the activity and phosphorylation of ERK (ERK1 and/or ERK2); the decrease in ERK activity can be detected through analysis of pharmacodynamic markers such the AK phosphorylated RSK1,2 and phosphorylated ERK1,2, using techniques well known in the art;

The abbreviation "Ex", shown in the tables means "Example";

The phrase "one or more" has the same meaning as the phrase "at least one";

The term "patient" means an animal such as a mammal (e.g. human, and preferably human);

The term "prodrug" refers to compounds that are rapidly transformed in vivo, for example, by hydrolysis in blood, in the parental compound, i.e. the compound of formula 1.0, or its salt and/or MES; they are disclosed in detail in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol.14 of the A.C.S. Symposium Series, and in Edward C. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, of these documents are incorporated herein by reference; scope of the present invention includes prodrugs of the compounds according to the present invention;

The term "sequentially" means (1) the introduction of a single connection by the method(a) the compounds according to the invention or (b) a chemotherapeutic agent, an inhibitor of signal transduction and/or radiotherapy), followed by the introduction of another component or components; after administration of one component, the next component can be administered sequentially, immediately after the first component, or the next component can be administered after an effective period of time is Yeni after the introduction of the first component; effective time means the amount of time necessary for realization of maximum benefit from the introduction of the first component; and

The term "MES" means a physical Association of a compound according to the present invention with one or more solvent molecules; this physical Association contains varying degrees of ionic and covalent bonding, including hydrogen binding; in certain cases, the MES will be able to select, for example, when one or more solvent molecules are incorporated into the crystal lattice of the crystalline solid; "MES" covers both the solution phase and allocated solvate; non-limiting examples of the solvate include ethanolate, methanolate and the like; "hydrate" is a MES, in which the solvent molecule is a molecule of water (H2O).

As used herein, unless otherwise specified, the following terms have the following meanings, unless otherwise indicated, the definitions of each term (i.e., in the case of component or Deputy) shall apply when the term is used individually or as a component of another term (for example, the term aryl has the same value in the case of aryl and in the case of aryl part of arylalkyl, Alki-larila, arylalkyl and the like:

The term "acyl" means an H-C(O)-, alkyl-C(O)-, alkenyl-C(O)-, Quinil-C(O)-, cycloalkyl-C(O)-, cycloalkenyl-C(O)- or cycloalkenyl-C(O)-group, in which different groups are groups which are defined below, (and, as disclosed hereinafter, alkyl, alkeline, alkyline, cycloalkyl, cycloalkenyl and cycloalkenyl components may have substituents); communication with the parent component is carried out through a carbonyl; preferred atilov contain lower alkyl; non-limiting examples of suitable acyl groups include formyl, acetyl, propanol, 2-methylpropanol, butanol and cyclohexanol;

The term "alkenyl" means an aliphatic hydrocarbon group (chain), containing at least one double bond in the carbon-carbon, and the chain may be straight or branched, and the specified group contains from about 2 to about 15 carbon atoms; preferred alkeneamine groups contain from about 2 to about 12 carbon atoms in the chain; and more preferably from about 2 to about 6 carbon atoms in the chain; the term "branched" means that linear alkenylphenol chain attached to one or more lower alkyl groups such as methyl, ethyl or propyl, or alkenyl groups; the term "lower alkenyl" means alkenylphenol group containing from about 2 to about 6 carbon atoms in the chain is, and the chain may be straight or branched; the term "substituted alkenyl" means that Alchemilla group substituted by one or more independently selected substituents, and each Deputy independently selected from the group consisting of: halo, alkyl, aryl, cycloalkyl, ceanography, alkoxygroup and-S(alkyl); non-limiting examples of suitable alkenyl groups include ethynyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl;

The term "alkoxy" means alkyl-O - group (i.e., communication with the parent component is performed by prostating oxygen), in which the alkyl group is unsubstituted or substituted as disclosed hereinafter; non-limiting examples of suitable alkoxygroup include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, heptose;

The term "alkoxycarbonyl" means alkyl-O-CO - group (i.e., communication with the parent component is carried out by means of carbonyl), in which the alkyl group is unsubstituted or substituted as previously disclosed; non-limiting examples alkoxycarbonyl groups include methoxycarbonyl and etoxycarbonyl;

The term "alkyl" (including the alkyl part in other components, such as triptorelin, alkyloxy) means an aliphatic hydrocarbon group (chain), which may be the nternet or branched, where the specified group contains from about 1 to about 20 carbon atoms in the chain; preferred alkyl groups contain from about 1 to about 12 carbon atoms in the chain; more preferred alkyl groups contain from about 1 to about 6 carbon atoms in the chain; the term "branched" means that linear alkyl chain attached to one or more lower alkyl groups such as methyl, ethyl or propyl; the term "lower alkyl" means a group containing from about 2 to about 6 carbon atoms in the chain, and the chain may be straight or branched; the term "substituted alkyl" means an alkyl group substituted by one or more independently selected substituents, and each Deputy independently selected from the group consisting of: halo, aryl, cycloalkyl, cyano, hydroxy, alkoxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, carboxy, -C(O)O-alkyl and-S(alkyl); non-limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, n-pentyl, heptyl, nonyl, decyl, vermeil, trifluoromethyl and cyclopropylmethyl;

The term "alkylaryl" (or alkaryl) means an alkyl-aryl group (i.e., communication with the parent component is carried out by means aryl group, where the alkyl group is unsubstituted or substituted as disclosed above, and arilje the second group is unsubstituted or substituted, as disclosed hereinafter; the preferred alkylaryl contain lower alkyl group; non-limiting examples of suitable alcylaryl groups include o-tolyl, p-tolyl and xylyl;

The term "alkylglycerol" means alkyl-heteroaryl group (i.e., communication with the parent component is carried out by a heteroaryl group, where the alkyl is unsubstituted or substituted as disclosed above, and heteroaryl group is unsubstituted or substituted as disclosed hereinafter;

The term "alkylsulfonyl" means alkyl-S(O)- group (i.e., communication with the parent component is carried out through sulfinil), where the alkyl group is unsubstituted or substituted as previously disclosed; preferred groups are groups in which the alkyl group is lower alkyl;

The term "alkylsulfonyl" means an alkyl-S(O2)- group (i.e., communication with the parent component is carried out through sulfonyl), where the alkyl group is unsubstituted or substituted as previously disclosed; preferred groups are groups in which the alkyl group is lower alkyl;

The term "alkylthio" means alkyl-S-group (i.e., communication with the parent component via sulfur), where the alkyl group is unsubstituted or substituted, campisano previously; non-limiting examples of suitable, alkylthio groups include methylthio, ethylthio, out-propylthio, Reptilia;

The term "quinil" means an aliphatic hydrocarbon group (chain), containing at least one triple bond of carbon-carbon, where the chain may be straight or branched, and where this group contains from about 2 to about 15 carbon atoms in the chain; the preferred alkyline groups contain from about 2 to about 12 carbon atoms in the chain; and more preferably from about 2 to about 4 carbon atoms in the chain; the term "branched" means that linear alkenylphenol chain attached to one or more lower alkyl groups such as methyl, ethyl or propyl; the term "lower quinil" means alkylamino group containing from about 2 to about 6 carbon atoms in the chain, and the chain may be straight or branched; non-limiting examples of suitable etkinlik groups include ethinyl, PROPYNYL, 2-butynyl, 3-methylbutyl, n-pentenyl and decenyl; the term "substituted quinil" means that Alchemilla group substituted by one or more independently selected substituents, and each Deputy independently selected from the group consisting of alkyl, aryl and cycloalkyl;

The term "amino" means a group-NH2;

The term "aralkyl" (or arylalkyl) means aryl-alkenylphenol group (that is, the light is ü maternal component through alkenylphenol group), where the aryl group is unsubstituted or substituted as disclosed hereinafter, and Alchemilla group is unsubstituted or substituted as disclosed above; preferred kalkanli contain lower alkenylphenol group; non-limiting examples of suitable kalkanli groups include 2-fentanyl and 2-naphthylamines;

The term "aralkyl" (or arylalkyl) means an aryl-alkyl group (i.e., communication with the parent component is through the alkyl group, where the aryl is unsubstituted or substituted as disclosed hereinafter, and alkyl is unsubstituted or substituted as disclosed above; preferred aralkyl contain lower alkyl group; non-limiting examples of suitable Uralkalij groups include benzyl, 2-phenethyl and naphthaleneacetic;

The term "aralkylated" (or arylalkylamine) means aralkyl-O-group (i.e., communication with the parent component is performed by prostating oxygen), where kalkilya group is unsubstituted or substituted as described earlier; non-limiting examples of suitable, aralkylated groups include benzyloxy and 1 - or 2-naphthalenyloxy;

The term "arelaxation" means aralkyl-O-C(O)-group (i.e., communication with the parent component via the carbonyl), where kalkilya group assetmanagement or substituted, as disclosed previously; a non-limiting example of a suitable alcoxycarbenium group is benzyloxycarbonyl;

The term "Uralkali" means aralkyl-S-group (i.e., communication with the parent component via sulfur), where kalkilya group is unsubstituted or substituted as previously described; a non-limiting example of a suitable, Uralkali group is benzylthio;

The term "aroyl" means an aryl-C(O)-group (i.e., communication with the parent component via the carbonyl), where the aryl group is unsubstituted or substituted as disclosed hereinafter; non-limiting examples of suitable groups include benzoyl and 1 - and 2-naphtol;

The term "aryl" (sometimes listed as "ar"means an aromatic monocyclic or multicyclonic ring system containing from about 6 to about 14 carbon atoms, preferably from about 6 to about 10 carbon atoms; aryl group optionally may be substituted by one or more independently selected substituents in the ring system" (defined below). Non-limiting examples of suitable aryl groups include phenyl and naphthyl;

The term "arylalkyl" means aryl-alkylamino group (i.e., communication with the parent component is performed by alkenylphenol group, where the aryl group I which is unsubstituted or substituted, as disclosed above, and Alchemilla group is unsubstituted or substituted as disclosed above;

The term "kilaminjaro" means aryl-amino-heteroaryl group (i.e., communication with the parent component is carried out through a heteroaryl group, where the aryl group is unsubstituted or substituted as disclosed above, and the amino group defined above (i.e., here-NH-), and heteroaryl group is unsubstituted or substituted as disclosed hereinafter;

The term "Allgeier" means aryl-heteroaryl group (i.e., communication with the parent component is carried out by a heteroaryl group, where the aryl group is unsubstituted or substituted as disclosed above, and heteroaryl group is unsubstituted or substituted as disclosed hereinafter;

The term "aryloxy" means aryl-O-group (i.e., communication with the parent component is performed by prostating oxygen), where the aryl group is unsubstituted or substituted as disclosed above; non-limiting examples of suitable, aryloxy groups include phenoxy, naphthoxy;

The term "aryloxyalkyl" means aryl-O-C(O)-group (i.e., communication with the parent component via the carbonyl), where the aryl group is unsubstituted or Sames is authorized, as previously disclosed; non-limiting examples of suitable aryloxyalkyl groups include phenoxycarbonyl and mattoxicator;

The term "arylsulfonyl" means an aryl-S(O)-group (i.e., communication with the parent component is carried out through sulfinil), where the aryl group is unsubstituted or substituted as previously disclosed;

The term "arylsulfonyl" means an aryl-S(O2)-group (i.e., communication with the parent component is carried out through sulfonyl), where the aryl group is unsubstituted or substituted as previously disclosed;

The term "aristeo" means an aryl-S-group (i.e., communication with the parent component is carried out through sulfur, where the aryl group is unsubstituted or substituted as previously disclosed; non-limiting examples of suitable aricioglu include phenylthio, naphthylthio;

The term "cycloalkenyl" means a non-aromatic monocyclic or multicyclonic ring system containing from about 3 to about 10 carbon atoms, preferably from about 5 to about 10 carbon atoms, which contains at least one double bond in the carbon-carbon bonds; preferred cycloalkenyl rings contain from about 5 to about 7 atoms in the ring; cycloalkenyl optionally may be substituted by one or more independently selected "mandated what teli in ring system" (defined below). Non-limiting examples of suitable monocyclic cycloalkenyl include cyclopentenyl, cyclohexenyl, cycloheptenyl and the like; a non-limiting example of a suitable multi cyclic cycloalkenyl is norbornylene;

The term "cycloalkyl" means a non-aromatic monocyclic or multi-cyclic ring system containing from about 3 to about 7 carbon atoms, preferably from about 3 to about 6 carbon atoms; cycloalkyl optionally may be substituted by one or more independently selected substituents in the ring system" (defined below). Non-limiting examples of suitable monocyclic cyclo-Akilov include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like; non-limiting examples of suitable multicyclonic of cycloalkyl include 1-decalin, norbornyl, substituted and the like;

The term "cycloalkenyl" means cycloalkyl-alkyl group (i.e., communication with the parent component is through the alkyl group), where cycloalkyl component is unsubstituted or substituted as disclosed above, and the alkyl component is unsubstituted or substituted as disclosed above;

The term "halo" means fluorescent, chloro, bromo or iodine group; preferred halosubstituted mean the fluorescent, the loro or bromo, and preferred means of fluorescent and chloro;

The term "halogen" means fluorine, chlorine, bromine or iodine, the preferred Halogens are fluorine, chlorine and bromine;

The term "haloalkyl" means alkyl as disclosed above, where one or more hydrogen atoms of the alkyl substituted by holography, as disclosed above;

The term "heteroalkyl" means heteroaryl-alkenylphenol group (i.e., communication with the parent component is performed by alkenylphenol group, where the heteroaryl group is unsubstituted or substituted as disclosed hereinafter, and Alchemilla group is unsubstituted or substituted as disclosed above;

The term "heteroalkyl" (or heteroaromatic) means heteroaryl-alkyl group (i.e., communication with the parent component is through the alkyl group), in which heteroaryl is unsubstituted or substituted as disclosed hereinafter, and an alkyl group is unsubstituted or substituted as disclosed above; preferred heteroalkyl contains alkyl group, which represents a lower alkyl group; non-limiting examples of suitable Uralkalij groups include pyridylmethyl, 2-(furan-3-yl)ethyl and the quinoline-3-ylmethyl;

The term "heteroalkyl" means heteroaryl-S-group, where the heteroaryl group is and is unsubstituted or substituted, as disclosed above;

The term "heteroaryl" means an aromatic monocyclic or multicyclonic ring system containing from about 5 to about 14 atoms in the ring, preferably from about 5 to about 10 atoms in the ring, in which one or more ring atoms are other than carbon, such as nitrogen, oxygen or sulfur, present themselves or in combination; the preferred heteroaryl contain from about 5 to about 6 atoms in the ring; "heteroaryl" optionally may be substituted by one or more of the substituent in ring system" (defined below); the prefix Aza, oxa or thia before the root name heteroaryl means that at least a nitrogen atom, oxygen or sulfur, respectively, present as a ring atom; the nitrogen atom of heteroaryl can optionally be oxidized to the corresponding N-oxide; non-limiting examples of suitable heteroaryl include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, isoxazolyl, isothiazolin, oxazolyl, thiazolyl, pyrazolyl, furutani, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, honokalani, phthalazine, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofuranyl, indolyl, isoindolyl, benzimidazolyl, benzothiazyl, chinoline, imidazolyl, cyanopyridyl, hintline, dienophile the sludge, pyrrolopyridine, imidazopyridine, ethenolysis, benzoxazinones, 1,2,4-triazinyl, benzothiazolyl, properidine

,

and the like;

The term "heteroarylboronic" (or heteroalkyl) means heteroaryl-alkylamino group (i.e., communication with the parent component is performed by alkenylphenol group, where the heteroaryl group is unsubstituted or substituted as disclosed above, and Akinola group is unsubstituted or substituted as disclosed above;

The term "heteroaromatic" (or heteroaryl) means heteroaryl-aryl group (i.e., communication with the parent component is carried out by means aryl group, where the heteroaryl group is unsubstituted or substituted as disclosed above, and the aryl group is unsubstituted or substituted as disclosed above;

The term "heterotrimetallic" means heteroaryl-heteroaryl group (i.e., communication with the parent component is carried out through the last heteroaryl group, where each heteroaryl group is unsubstituted or substituted as disclosed above;

The term "heteroarylboronic" means heteroaryl-SO-group, where the heteroaryl group is unsubstituted or substituted as disclosed above;

The term "heteroaryl Lionel" means heteroaryl-SO 2group, where the heteroaryl group is unsubstituted or substituted as disclosed above;

The term "heteroaromatic" means heteroaryl-S-group, where the heteroaryl group is unsubstituted or substituted as disclosed above;

The term "heterocyclyl" (or geteroseksualen) means a non-aromatic monocyclic or multicyclonic ring system containing from about 3 to about 10 ring atoms, preferably from about 5 to about 10 ring atoms in which one or more atoms in the ring system is other than carbon elements (for example, one or more heteroatoms independently selected from the group consisting of nitrogen atom, oxygen and sulfur, and which contains at least one double bond in the carbon-carbon double bond carbon-nitrogen, where the ring system no neighboring atoms oxygen and/or sulfur; Preferred heterocyclyl rings contain from about 5 to about 6 ring atoms; the prefix Aza, oxa or thia before the root name heterocyclyl means that at least one atom of nitrogen, oxygen or sulfur is present as a ring atom; heterocyclyl optionally may be substituted by one or more of the substituent in ring system" (defined below); the nitrogen atom or sulfur heterocyclyl can be n is necessarily oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide; non-limiting examples of suitable monocyclic azaheterocyclic groups include 1,2,3,4-tetrahydropyridine, 1,2-dihydropyridine, 1,4-dihydropyridin, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 2-pyrazoline and the like; non-limiting examples of suitable exegetically groups include 3,4-dihydro-2H-Piran, dihydrofurane, fordevelopment and the like; a non-limiting example of a suitable multicyclonic oxa-heterocyclyl group is a 7-oxabicyclo[2.2.1]heptenyl; non-limiting examples of suitable monocyclic together.according rings include dihydrothiophene, dihydrothiophene and the like;

The term "geterotsiklicheskikh" (or geterotsiklicheskikh) means heteroseksualci-alkyl group (i.e., communication with the parent component is through the alkyl group), where heterocytolysine group (i.e., heterocyclyl group is unsubstituted or substituted as indicated below, and the alkyl group is unsubstituted or substituted as disclosed above;

The term "heterocyclyl" (or heteroseksualci) means a non-aromatic saturated monocyclic or multicyclonic ring system containing from about 3 to about 10 stake is zevah atoms, preferably from about 5 to about 10 ring atoms in which one or more atoms in the ring system is other than carbon, such as nitrogen, oxygen or sulfur, present themselves or in combination, and in the ring system there are no adjacent oxygen atoms and/or sulfur; preferred heterocyclyl contain from about 5 to about 6 ring atoms; the prefix Aza, oxa or thia before the root name heterocyclyl means that at least one atom of nitrogen, oxygen or sulfur is present as a ring atom; heterocyclyl may not be substituted by one or more of the substituent in ring system" (defined below); the nitrogen atom or sulfur heterocyclyl may be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide; non-limiting examples of suitable monocyclic heterocycle ilen rings include piperidyl, pyrrolidinyl, piperazinil, morpholinyl, thiomorpholine, thiazolidine, 1,3-DIOXOLANYL, 1,4-dioxane, tetrahydrofuranyl, Tetra-hydrodiuril, tetrahydropyranyl and the like;

The term "hydroxyalkyl" means BUT is an alkyl group, where the alkyl group is substituted or unsubstituted, as disclosed above; preferred hydroxyalkyl contain lower alkyl; non-limiting examples of suitable Hydra is kalkilya groups include hydroxymethyl and 2-hydroxyethyl; and

The term "substituent in ring system" denotes a Deputy, which is attached to an aromatic or nonaromatic ring system, and which, for example, replaces an available hydrogen in the ring system; each substituent in the ring system is independently selected from the group consisting of: alkyl, aryl, heteroaryl, aralkyl, alkylaryl, aralkyl, heteroalkyl, alkylglycerol, heteroalkyl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, Alcoxy, acyl, Arola, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxyalkyl, arylcarbamoyl, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylsulfonyl, arylsulfonyl, heteroarylboronic, alkylthio, aaltio, heteroaromatic, Uralkali, heteroalkyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclyl, R60R65N-, R60R65N-alkyl-, R60R65NC(O)- and R60R65NSO2-where R60and R65each independently selected from the group consisting of: hydrogen, alkyl, aryl and aralkyl; the Term "substituent in ring system" means a cyclic ring containing from 3 to 7 atoms in the ring, where 1-2 of the ring atoms may be heteroatoms, attached to aryl, heteroaryl, heterocyclyl or heterocyclyl ring by means of the simultaneous substitution of two ring hydrogen atoms on the indicated aryl, heteroaryl, heterocyclyl or heterocyclyl ring; non-limiting examples include:

,and the like.

Lines that go in the ring, show that this connection can be connected with any suitable ring carbon atoms.

Any carbon or heteroatom with unsaturated valences shown in the text, schemes, examples, structural formulas, and any table disclosed herein, as expected, is the hydrogen atom or atoms of hydrogen required to saturate the valences. And any one or more of these hydrogen atoms may represent a deuterium.

One or more compounds according to the invention may also exist in the form of MES or can, if desired, be converted into MES. Getting the solvate is well known. Thus, for example, the solvate antifungal fluconazole in ethyl acetate, and water is described in M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004). In E.S. van Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and A.L. Bingham et al, Chem. Commun., 603-604 (2001) revealed similar methods of obtaining solvate, hemisulfate, hydrates and the like. Typical non-limiting method of obtaining represents the dissolution of the compounds according to the invention in the desired quantities gellately the second solvent (organic or water, or mixtures thereof)at a temperature above the ambient temperature, and cooling the solution at a rate sufficient to form crystals, which then allocate by known methods. Analytical techniques such as IR spectroscopy, allow us to determine the presence of a solvent (or water) in the form of MES (or hydrate) in crystals.

The term "pharmaceutical composition", as expected, includes both the bulk composition and individual dosage units containing more than one (e.g., two) pharmaceutically active agent, such as, for example, the connection according to the present invention, and an additional agent selected from a list of additional agents described herein, along with any pharmaceutically inactive excipients. Bulk composition and each individual dosage unit can contain fixed quantities of the above-mentioned "more than one pharmaceutically active agent". Bulk composition is a material which has not yet been formed in separate dosage units. Examples of dosage units are oral dosage forms such as tablets, capsules, pills and the like. In a similar manner described in this application, the methods of treatment of the patient by the introduction farmaceuticas the second composition according to the present invention, as is also understood, include the introduction of the above bulk composition and individual dosage forms.

Prodrugs of the compounds according to the present invention are also disclosed in this application. The term "prodrug"used in the present invention denotes a compound that is a precursor of the medicinal product, and which, when administered to a subject, undergoes chemical conversion by metabolic or chemical processes to obtain the compounds of formula 1.0, or its salts and/or MES. Prodrugs are disclosed in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of the A.C.S. Symposium Series, and Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, which is incorporated herein in full by reference.

For example, if the compound of formula 1.0, or a pharmaceutically acceptable salt, hydrate or MES compound that contains the functional group of carboxylic acid, a prodrug may include an ester formed by the replacement of the hydrogen atom of the acid group in this group, as for example, (C1-C8)alkyl, (C2-C12)alkanoyloxy, 1-(alkanoyloxy)ethyl, containing from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)ethyl, containing 5 to 10 carbon atoms, alkoxycarbonylmethyl is, containing from 3 to 6 carbon atoms, 1-(alkoxycarbonyl)ethyl, containing from 4 to 7 carbon atoms, 1-methyl-1-(alkoxycarbonyl)ethyl, containing from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl containing from 3 to 9 carbon atoms, 1-(N-(alkoxycarbonyl)amino)ethyl, containing from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotononitrile, gamma-butyrolactone-4-yl, di-N,N-(With1-C2)alkylamino(C2-C3)alkyl (such as β-dimethylaminoethyl), carbarnoyl-(C1-C2)alkyl, N,N-di(C1-C2)allylcarbamate-(C1-C2)alkyl and piperidino-, pyrrolidino or morpholino(C2-C3)alkyl, and the like.

Similarly, if a compound of formula 1.0 include functional alcohol group, a prodrug can be obtained by substitution of the hydrogen atom of the alcohol group in this group, as for example, (C1-C6)alkanoyloxy, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonylmethyl, N-(C1-C6)alkoxycarbonylmethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkenyl, ariell and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoaniline group is selected independently from the natural L-amino acids, P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2the Lee glycosyl (radical, obtained by removing hydroxyl group hemiacetal forms of carbohydrate), and the like.

If the compound of formula 1.0 include amine functional group, a prodrug can be obtained by substitution of the hydrogen atom of the amino group in this group, as for example, R70is carbonyl, R70O-carbonyl, NR70R75-carbonyl where R70and R75each independently represents a (C1-C10)alkyl, (C3-C7)cycloalkyl, benzyl, or R70-carbonyl is a natural α-aminoacyl or natural α-aminoacyl, -C(OH)C(O)OY80where Y80represents H, (C1-C6)alkyl or benzyl, -C(OY82)Y84where Y82is a (C1-C4) alkyl, and Y84is a (C1-C6)alkyl, carboxy(C1-C6)alkyl, amino(C1-C4)alkyl or mono-N - or di-N,N-(C1-C6)acylaminoalkyl, -C(Y86)Y88where Y86represents H or methyl, and Y88is a mono-n - or di-N,N-(C1-C6)alkylamino morpholino, piperidine-1-yl or pyrrolidin-1-yl and the like.

The present invention also includes compounds according to the invention in isolated and purified form.

Polymorphic forms of the compounds of formula 1.0 and salt, solvate, and prodrugs of the compounds of formula 1.0, as it is proposed is located, included in the present invention.

Certain compounds according to the present invention may exist in different isomeric forms (e.g., enantiomers, diastereoisomers, atropoisomeric). The invention includes all such isomers both in pure form and as mixtures, including racemic mixtures. Enol forms are also covered by the present invention.

All stereoisomers (for example, geometric isomers, optical isomers and the like) of the compounds according to the present invention (including stereoisomers salt, solvate, and prodrugs of the compounds as well as salts and solvate of the prodrugs), such as existing due to the asymmetric carbon of the various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotamania forms, atropoisomeric and diastereomeric forms, are included in the scope of the present invention. Individual stereoisomers of the compounds according to the invention can, for example, be essentially free of other isomers, or may be mixed, for example, in the form of racemates, or mixed with all other, or other selected stereoisomers. Chiral centers in accordance with the present invention can have the S or R configuration, defined according to the recommendations of the IUPAC 1974. The terms "salt", "MES" "proletar the creation" and the like, as implied, apply equivalent with respect to the salt, solvate and prodrugs of enantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugs of the compounds according to the invention.

Diastereomer mixture can be separated into their individual diastereomers on the basis of their physical-chemical differences using methods well known to experts in the art, such as chromatography and/or fractional crystallization. Enantiomers can be separated by turning the enantiomeric mixture in diastereomer mixture, applying the reaction with an appropriate optically active compound (e.g., chiral auxiliary substance, such as a chiral alcohol or acid chloride of Mosera), by separating the diastereomers and converting (e.g., by hydrolysis) the individual diastereomers to the corresponding pure enantiomers. Some of the compounds of formula (I) can be atropoisomeric (for example, substituted barely) and, in this case, is also considered part of the present invention. Enantiomers can also be split using chiral HPLC column.

The compounds of formula 1.0 form salts, which are also included in the scope of the present invention. Reference to compounds of formula 1.0 here, as you know, includes the mention of their salts, E. what do otherwise specified. The term "salt(s)", as used here, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when the compound of formula 1.0 contains as the main component, such as, but not limited to, pyridine or imidazole, and an acidic component, such as, but not limited to, carboxylic acids, can form zwitterions ("inner salts"), which are included in the scope of the term "salt(s)", as used in this document. Pharmaceutically acceptable salts (i.e., non-toxic, physiologically acceptable salts are preferred. Salts of compounds of formula 1.0 can be obtained, for example, by reaction of compounds of formula 1.0 with the amount of acid or base, such as an equivalent amount, in a medium such as the medium in which the salt precipitates or in an aqueous medium followed by lyophilization. Acids (and bases), which are generally considered suitable for the formation of pharmaceutically acceptable salts of the basic (or acidic) pharmaceutical compounds are disclosed, for example, by S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; in The Orange Book (Food & Drug Administratin, Washington, D.C. on their website); and P. Heinrich Stahl, Camille G. Wermuth (Eds.), Hubook of Pharmaceutical Salts: Properties, Selection, and Use, (2002) Int'l. Union of Pure and Applied Chemistry, pp.330-331. These documents are included in this application in full by reference.

Examples of salts obtained by addition of the acid include acetates, adipate, alginates, ascorbates, aspartate, benzoate, bansilalpet, bisulfate, borates, butyrate, citrates, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, econsultancy, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic, lactates, maleate, methanesulfonate, methylsulfate, 2-naphthalenesulfonate, nicotinate, nitrates, oxalates, pamoate, pectinate, persulfates, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylates, succinate, sulfates, sulfonates (such as those mentioned herein), tartarate, thiocyanates, toluensulfonate (also known as tozilaty), undecanoate and the like.

Examples of basic salts are ammonium salts, alkali metal salts, such as salts of sodium, lithium and potassium, salts of alkaline earth metals such as calcium salts and magnesium salts, aluminum salts, zinc salts, salts with organic bases (for example, organic amines)such as benzathine, diethylamin is, dicyclohexylamine, geranamine (formed with N,N-bis(dehydroabietyl)Ethylenediamine), N-methyl-D-glucamine, N-methyl-O-glucoside, t-butyl amines, piperazines, phenyl-cyclohexylamine, choline, tromethamine, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups can be stereoselectivity with agents such as halide lower Akilov (for example, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, dibutil and diamyl sulfates), long-chain halide (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), halide of Arakelov (for example, benzyl and phenethyl bromides), and others.

It is implied that all such acidic and basic salts are pharmaceutically acceptable salts included in the scope of the present invention and all acid and basic salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.

The compounds of formula 1.0, and their salts, solvate and prodrug may exist in their tautomeric form (for example, in the form amide or simple aminoether). All such tautomeric forms are considered here as part of the present invention.

In the ring systems according to the present invention, comprising a heteroatom, the carbon atoms have no hydroxyine the groups, neighboring groups N, O or S, and the carbon atoms there are no N or S groups adjacent to another heteroatom. Thus, for example, in the ring:

does not exist-IT is the group that is associated directly with carbon, designated as 2 and 5.

The compounds of formula 1.0 can exist in different tautomeric forms, and all these forms are included in the scope of the present invention. Also, for example, all keto-enol and Imin-enamine forms of the compounds included in the scope of the present invention.

Tautomeric forms, such as, for example, components:

and

in certain versions of the present invention are considered as equivalent.

The term "substituted" means that one or more hydrogen atoms at the specified atom substituted by a group selected from the indicated group, provided that under the existing conditions the normal valency of the designated atom is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. The term "stable compound" or "stable structure" means a connection that is strong enough to withstand the selection of reaction the th mixture applied to purity and become effective pharmaceutical agent.

The term "optionally substituted" means an optional substitution of specific groups, radicals or components.

The term "purified", "in purified form" or "in isolated and purified form"used in the connection, refers to the physical state of the compounds after separation from the process of synthesis or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form"as applied to the connection, refers to the physical state of the compounds after purification process or processes described herein or well known to specialists in this field of technology with the degree of purity sufficient to identify using standard analytical techniques described herein and well known to specialists in this field of technology.

When the functional group in the compound designated as "protected", this means that the group is in modified form, designed to prevent unwanted side reactions at the protected position when the compound reacts. Suitable protective groups are known to experts in the art, and are disclosed in such documents, as for example, .W. Greene et al, Protective Groups in organic Synthesis (1991), Wiley, New York.

When any the I variable (for example, aryl, heterocycle, R3and the like) more than once found in any constituent or in any compound of formula 1.0, in each case, the definition of this variable does not depend on its definition at every other case.

As used herein, the term "composition", as expected, covers the product contains certain ingredients in certain amounts, as well as any product which is obtained directly or indirectly, from the combination of certain ingredients in certain amounts.

The present invention also embraces isotopically-labeled compounds according to the present invention, which are identical to these compounds, but one or more atoms replaced by an atom having an atomic mass or mass number different from the commonly occurring atomic mass or mass number. Examples of isotopes that may be present in the connection according to the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as2H,3H,13C,14C,15N18Oh,17Oh,31P,32R35S18F and36Cl, respectively.

Certain isotopically labeled compounds of formula 1.0 (for example, labeled using3H and14C) suitable for analysis of raspredeleniya fabric connections and/or substrate. The isotope tritium (i.e.,3H) and carbon-14 (i.e.,14(C) particularly preferred due to the ease of their production and definitions. Certain isotopically labeled compounds of formula (I) can be used to obtain images for medical purposes. For example, such compounds, labeled positron-emitting isotopes, such as11With or18F, can be useful for application in Positron emission tomography (PET), and compounds labeled with isotopes that emit gamma rays, such as123I can be useful for application in single Photon emission computed tomography (SPECT). In addition, the substitution of heavier isotopes such as deuterium (i.e.,2H) may provide certain therapeutic advantages resulting from greater metabolic stability (e.g., increased half-life in vivo or reduced the required dosage) and, therefore, may be preferable under certain conditions. Isotopically labeled compounds of formula (I), in particular containing isotopes with longer half-lives (T1/2 > one day), can, in General, be obtained by the following methods similar to those disclosed in the schemes and/or in the examples below, by isotopic substitution unlabeled reagent corresponding isotopically labeled d is a Gent.

The present invention discloses compounds of formula 1.0:

or their pharmaceutically acceptable salt or solvate, where R1, R2and Q are selected independently and, where:

Q is:;

R1is selected from the group consisting of: heteroaryl and substituted heteroaryl where specified substituted heteroaryl has from one to three (preferably one) substituents independently selected from the group consisting of: HE, alkoxy, and-O-alkylene-O-alkyl;

R2is selected from the group consisting of: -O-alkyl and S-alkyl; and

R5is selected from the group consisting of:

(a) thiazolidine-,

(b) triazolinone-where specified phenyl optionally has from one to three substituents independently selected from the group consisting of: halo (e.g., Br, Cl, F, and in one example F), alkoxy (for example, C1-C6alkoxy and in one example1-C2alkoxy, and in another example-och3),

(c) substituted triazolylmethyl-where specified phenyl optionally has from one to three substituents independently selected from the group consisting of: halo (e.g., Br, Cl, F, and in one example F), alkoxy (for example, C1-C6alkoxy and in one example1-C2alkoxy, and in another example-och3), and specified triazolyl the second group has one or two substituent, independently selected from the group consisting of: alkyl, replacement of alkyl, -alkylene-O-alkyl, and amino (i.e.,- NH2),

(d) triazolylmethyl-,

(e) triazolylmethyl-where specified thienyl optionally has from one to two substituents independently selected from the group consisting of: halo (e.g., Br, Cl, F, and in one example F), alkoxy (for example, C1-C6alkoxy and in one example1-C2alkoxy, and in another example-och3),

(f) substituted triazolylmethyl-where specified thienyl optionally has from one to three substituents independently selected from the group consisting of: halo (e.g., Br, Cl, F, and in one example F), alkoxy (for example, C1-C6alkoxy and in one example, C1-C2alkoxy, and in another example-och3), and the specified thiazolidine group has one or two substituent independently selected from the group consisting of: alkyl, replacement of alkyl, -alkylene-O-alkyl, and amino (i.e.,- NH2),

(g) triazolopyridine-,

(h) triazolopyridine-where specified pyridyl optionally has from one to three substituents independently selected from the group consisting of: halo (e.g., Br, Cl, F, and in one example F), alkyl, and alkoxy (e.g., C1-C6alkoxy, and in one example, C1-C2alkoxy, and in another example-OCH3). when the the condition, that the carbon atoms adjacent to the nitrogen atom in the specified pyridine not have a Deputy halo, and

(i) substituted triazolopyridine-, where: (1) the specified pyridyl optionally has from one to three substituents independently selected from the group consisting of: halo (e.g., Br, Cl, F, and in one example F), alkyl, and alkoxy (e.g., C1-C6alkoxy and in one example, C1-C2alkoxy, and in another example-OCH3), provided that the carbon atoms adjacent to the nitrogen atom in the specified pyridine not have a Deputy halo and (2) thiazolidine group has one or two substituent independently selected from the group consisting of: alkyl, replacement of alkyl, -alkylene-O-alkyl, and amino (i.e.,- NH2),

(j) triazolylmethyl-,

(k) triazolylmethyl-where specified thiazolyl optionally has one Deputy, is independently selected from the group consisting of: halo (e.g., Br, Cl, F, and in one example F), alkyl, and alkoxy (e.g., C1-C6alkoxy and in one example, C1-C2alkoxy, and in another example-OCH3), amino (i.e., NH2), alkylamino, dialkylamino, where each alkyl is selected independently, and

(l) substituted triazolylmethyl-, where (1) the specified thiazolyl optionally has one Deputy, is independently selected from the group consisting of: halo (e.g., Br, Cl , and in one example F), alkyl, and alkoxy (e.g., C1-C6alkoxy and in one example1-C2alkoxy, and in another example-OCH3), amino (i.e., NH2), alkylamino, dialkylamino, where each alkyl is selected independently, and (2) thiazolidine group has one or two substituent independently selected from the group consisting of: alkyl, replacement of alkyl, -alkylene-O-alkyl, and amino (i.e.,- NH2),

(m) pyridinylmethyl-,

(n) pyridinylmethyl-where specified thienyl optionally has from one to two substituents independently selected from the group consisting of: halo (e.g., Br, Cl, F, and in one example F), alkoxy (for example, C1-C6alkoxy and in one example1-C2alkoxy, and in another example-OCH3), and

(o) substituted pyridinylmethyl-, where (1) thienyl optionally has from one to two substituents independently selected from the group consisting of: halo (e.g., Br, Cl, F, and in one example F), alkoxy (for example, C1-C6alkoxy and in one example1-C2alkoxy, and in another example-OCH3), and (2) pyridazinyl group has from one to three substituents independently selected from the group consisting of: =O, alkyl, amino (i.e.,- NH2), alkylamino, dialkylamino, where each alkyl is selected independently from halo, (EmOC is emer, Br, Cl, F, and in one example F), provided that the carbon atoms adjacent to the nitrogen atom in the specified pyridazinyl not have a Deputy halo, and

provided that when the specified-alkylene-O-alkyl group linked to the nitrogen atom of the specified triazolyl in (C), (f), (i) and (l) the Deputy group R5constituting alkylene specified-alkylene-O-alkyl groups does not represent a-CH2- (i.e., component alkylene has 2 or more carbon atoms in length).

The present invention discloses compounds of formula 1.0:

or their pharmaceutically acceptable salt or solvate, where:

Q represents:

;

R1is selected from the group consisting of: heteroaryl and substituted heteroaryl where specified substituted heteroaryl has from one to three (preferably one) substituents independently selected from the group consisting of: HE, alkoxy, and-O-alkylene-O-alkyl;

R2is selected from the group consisting of: -O-alkyl and S-alkyl; and

R5is selected from the group consisting of:

(a) thiazolidine-,

(b) triazolinone-where specified phenyl optionally has from one to three substituents independently selected from the group consisting of: halo (e.g., Br, Cl, F, and in one example F), alkoxy (for example, C1-C6alkoxy and ar is the first example With 1-C2alkoxy, and in another example-OCH3),

(c) substituted triazolylmethyl-where specified phenyl optionally has from one to three substituents independently selected from the group consisting of: halo (e.g., Br, Cl, F, and in one example F), alkoxy (for example, C1-C6alkoxy and in one example1-C2alkoxy, and in another example-OCH3), and the specified thiazolidine group has one or two substituent independently selected from the group consisting of: alkyl, replacement of alkyl, -alkylene-O-alkyl, and amino (i.e.,- NH2),

(d) triazolylmethyl-,

(e) triazolylmethyl-where specified thienyl optionally has from one to two substituents independently selected from the group consisting of: halo (e.g., Br, Cl, F, and in one example F), alkoxy (for example, C1-C6alkoxy and in one example1-C2alkoxy, and in another example-OCH3),

(f) substituted triazolylmethyl-where specified thienyl optionally has from one to three substituents independently selected from the group consisting of: halo (e.g., Br, Cl, F, and in one example F), alkoxy (for example, C1-C6alkoxy and in one example1-C2alkoxy, and in another example-OCH3), and the specified thiazolidine group has one or two substituent independently selected from the group SOS is oasa of: alkyl, replacement of alkyl, -alkylene-O-alkyl, and amino (i.e.,- NH2), and

provided that when the specified-alkylene-O-alkyl group linked to the nitrogen atom of the specified triazolyl in (C), (f), (i) and (l) the Deputy group R5constituting alkylene specified-alkylene-O-alkyl groups does not represent a-CH2- (i.e., component alkylene has 2 or more carbon atoms in length).

Specialists in the art it is obvious that the term "alkylene"used in the title of Vice-About-alkylene-O-alkyl and-alkylene-O-alkyl, means a divalent saturated hydrocarbon group. Thus, the example component alkylene represents-CH2-CH2-example-Of-alkylene-O-alkyl component represents-O-(CH2)2-O-CH3and example is alkylene-O-alkyl component represents -(CH2)2-O-CH3.

Specialists in the art it is obvious that the term alkylen also includes component-CH2-.

Examples R1heteroaryl groups include, but without limitation to this, pyridyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, pyridyl N-O and pyrimidinyl.

Examples R1substituted heteroaryl groups include, but without limitation to this, substituted pyridyl, substituted pyrrolyl, substituted pyrazolyl, for ewenny imidazolyl, substituted furanyl, substituted thienyl, substituted thiazolyl, substituted pyridyl N-O and substituted pyrimidinyl.

In one embodiment, the present invention R1represents pyridyl.

In another embodiment, the present invention R1represents a substituted pyridyl.

In another embodiment, the present invention R1represents pyridyl, substituted with one Deputy.

The substituents for substituted R1groups (e.g., substituted pyridyl) independently selected from the group consisting of: HE, alkoxy, and-O-alkylene-O-alkyl. Examples of alkoxygroup include, for example, C1-C6alkoxygroup (such as, for example, -O-CH3, -O-C2H5and-O-CH(CH3)2). Examples of-O-alkylene-O-alkyl groups include, for example, -O-(C1-C4)alkylen-O-(C1-C6)alkyl, -O-(C1-C2)alkylen-O-(C1-C3alkyl) and-O-(CH2)2-O-CH3).

Examples R1include, for example,

and.

In one embodiment, the present invention R1represents pyridyl, substituted alkoxygroup.

In another embodiment, the present invention R1substituted-co(CH3)2group.

In another embodiment, the n of the present invention, R 1substituted-OS2H5group.

In another embodiment, the present invention R1represents:

.

In another embodiment, the present invention R1represents:

.

In another embodiment, the present invention R1replaced by-O-alkylene-O-alkyl.

In another embodiment, the present invention R1substituted-OCH2CH2OCH3.

In another embodiment, the present invention R1represents:

.

Examples of-O-alkyl group, R2include, for example, -O-(C1-C6)alkyl, -O-(C1-C2)alkyl, and-OCH3.

Examples of-S-alkyl group, R2include, for example, -S-(C1-C6)alkyl, -S-(C1-C2)alkyl and-SCH3.

In one embodiment, the present invention R2represents-O-(C1-C2)alkyl group.

In another embodiment, the present invention R2represents-OCH3.

In another embodiment, the present invention R2represents-S-(C1-C2)alkyl group.

In another embodiment, the present invention R2represents-SCH3.

In one var is ante implementation of the present invention R 5represents triazolylmethyl component, where triazolinone component is linked to the phenyl part by a ring carbon atom triazolines component.

In one embodiment, the present invention R5is triazolylmethyl - component, such as, for example,

.

In another embodiment, the present invention R5represents triazolylmethyl - component, such as, for example,

.

In another embodiment, the present invention R5represents triazolylmethyl - component, such as, for example,

.

In another embodiment, the present invention substituted triazolinone component specified R5group substituted on the ring nitrogen atom.

When triazolinone component of R5substituted by alkyl, examples of alkyl groups include, for example, -C1-C6alkyl, -C1-C4alkyl, -C1-C2alkyl, and-CH3. In one embodiment of the present invention the alkyl substitution on triazolines component of R5and this represents an alkyl-CH3.

When triazolinone component of R5substituted-alkylene-O-alkyl groups, examples of al the ilen-O-alkyl groups include, for example, -C1-C4alkylen-O-C1-C6alkyl, -C1-C2alkylen-O-C1-C2alkyl, -C1-C4alkylen-O-CH3and-CH2CH2OCH3. In one embodiment, the present invention is alkylene-O-alkyl substitution on triazolines component of R5and this is alkylene-O-alkyl represents-CH2CH2OCH3. When the nitrogen atom triazolines component of R5substituted-alkylene-O-alkyl group, examples of alkylene-O-alkyl groups include, for example, -C2-C4alkylen-O-C1-C6alkyl, -C2alkylen-O-C1-C2alkyl, -C2-C4alkylen-O-CH3and-CH2CH2OCH3. In one embodiment, the present invention is alkylene-O-alkyl substitution on the nitrogen atom triazolines component of R5and this is alkylene-O-alkyl represents-CH2CH2OCH3.

When triazolinone component of R5replaced replacement alkyl groups, examples of the replacement of alkyl groups include, for example, replacement With1-C4alkyl, replacement-C1-C2alkyl and replacement-CH3. Examples also include, for example, -CH2SLEEP(CH3)2and-CH2CH2OH.

When phenyl be the th R 5substituted by halogen atoms, examples of halogen atoms include, for example, chlorine (Cl), fluorine (F) and bromine (Br). In one embodiment of the present invention, the halogen on the phenyl represents F. In another embodiment, the present invention phenyl substituted by one atom F.

In one embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted, and said phenyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the nitrogen atom and the phenyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the carbon atom and the phenyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the nitrogen atom and the carbon atom and the phenyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted, and the substituted phenyl.

In another embodiment, altoadige invention R 5represents a substituted triazolylmethyl-where specified triazolyl substituted on the nitrogen atom and the phenyl substituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the carbon atom and the phenyl substituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the nitrogen atom and the carbon atom and the phenyl substituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl is unsubstituted and the phenyl substituted.

In another embodiment, the present invention R5represents an unsubstituted triazolylmethyl-.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl is replaced by a group-CH2SLEEP(CH3)2on the nitrogen atom.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl is replaced by a group-CH2CH2OH on the nitrogen atom.

In another embodiment, the present invention R5represents samisen the th triazolylmethyl-, where triazolyl substituted alkyl group on the nitrogen atom.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted alkyl group on the nitrogen atom and is substituted by an alkyl group on the carbon atom, where each alkyl group is independently selected.

In another embodiment, the present invention R5represents a substituted triazolinone-where triazolyl substituted-CH3the group on the nitrogen atom.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted-CH3the group on the nitrogen atom and a-CH3the group on the carbon atom.

In another embodiment, the present invention R5component represents a substituted triazolylmethyl-where triazolyl substituted-NH2the group on the carbon atom.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted-alkylene-O-alkyl group on the nitrogen atom.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted-CH2CH2OCH3the group on the nitrogen atom.

In another embodiment, the present of the Britania R 5component represents a substituted triazolylmethyl-where the specified phenyl component substituted with halogen, and the specified triazolinone component is substituted as specified in any of the above embodiments of the invention.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component is substituted by one halogen, and the specified triazolinone component is substituted as specified in any of the above embodiments of the invention.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component is substituted by fluorine atom, and the specified triazolinone component is substituted as specified in any of the examples above.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component substituted with one fluorine atom, and the specified triazolinone component is substituted as specified in any of the above embodiments of the invention.

In another embodiment, the present invention R5represents a substituted triazolylmethyl group, phenyl where this component is replaced by the ne atom F, and the specified triazolinone component is substituted by a hydroxyl substituted alkyl group on the nitrogen atom.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component is substituted with one F atom, and the specified triazolinone component is substituted by a group CH2CH2OH on the nitrogen atom.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component is substituted with one F atom, and the specified triazolinone component substituted-alkylene-O-alkyl group on the nitrogen atom.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component is substituted with one F atom, and the specified triazolinone component substituted-CH2CH2OCH3the group on the nitrogen atom.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component substituted with halogen, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl responsibility which I substituted with one halogen, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component replaced by F, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component is substituted with one F, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5component represents a substituted triazolylmethyl-where the specified phenyl component replaced by alkoxygroup, and the specified triazolinone component substituted as described in any of the above embodiments of the invention.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component substituted with one alkoxygroup, and the specified triazolinone component substituted as described in any of the above embodiments of the invention.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component Sames the on-OCH 3group, and the specified triazolinone component substituted as described in any of the above embodiments of the invention.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component replaced one-OCH3group, and the specified triazolinone component substituted as described in any of the above embodiments of the invention.

In another embodiment, the present invention R5represents a substituted triazolylmethyl group, phenyl where this component is replaced by a one-OCH3group, and the specified triazolinone component is substituted by a hydroxyl substituted alkyl group on the nitrogen atom.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component replaced one-OCH3group, and the specified triazolinone component substituted-CH2CH2OH group on the nitrogen atom.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component replaced one-OCH3group, and the specified triazolinone component substituted-alkylene-O-alkyl group on the nitrogen atom

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component replaced one-OCH3group, and the specified triazolinone component substituted-CH2CH2OCH3the group on the nitrogen atom.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component replaced by alkoxygroup, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component substituted with one alkoxygroup, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component is substituted by a group-OCH3and specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified phenyl component is substituted by a group-OCH3and specified triazolinone component is unsubstituted.

In another embodiment in the present invention, R 5represents:

.

In another embodiment, the present invention R5represents:

.

In another embodiment, the present invention R5represents:

.

In another embodiment, the present invention R5represents:

.

In another embodiment, the present invention R5represents:

.

In another embodiment, the present invention R5represents:

In another embodiment, the present invention R5represents:

In another embodiment, the present invention R5represents:

.

In another embodiment, the present invention R5represents:

.

In another embodiment, the present invention R5represents:

.

In another embodiment, the present invention R5represents:

.

In another embodiment, the present invention 5represents a substituted triazolylmethyl-where specified triazolyl substituted, and the specified thienyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the nitrogen atom, and the specified thienyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the carbon atom, and the specified thienyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the nitrogen atom and carbon atom, and the specified thienyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted, and the specified thienyl replaced.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the nitrogen atom, and the specified thienyl replaced.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the carbon atom and asany thienyl replaced.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the nitrogen atom and carbon atom, and the specified thienyl replaced.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl is unsubstituted, and the specified thienyl replaced.

In another embodiment, the present invention R5represents unsubstituted triazolylmethyl-.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom by the group-CH2SLEEP(CH3)2.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom by the group-CH2CH2OH.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom alkyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom alkyl group and substituted on the carbon atom alkyl group, where each alkyl g is the SCP is selected independently.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom by the group-CH3.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom by the group-CH3and the carbon atom of the group-CH3.

In another embodiment, the present invention R5component represents a substituted triazolylmethyl-where triazolyl substituted on the carbon atom of the group-NH2.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom-alkylene-O-alkyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom by the group-CH2CH2OCH3.

In another embodiment, the present invention R5component represents a substituted triazolylmethyl-where the specified thienyl component substituted with halogen, and the specified triazolinone component substituted as described in any of the above embodiments of the invention.

In another embodiment, the present R 5represents a substituted triazolylmethyl-where the specified thienyl component is substituted by one halogen, and the specified triazolinone component substituted as described in any of the above embodiments of the invention.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component replaced by F, and the specified triazolinone component substituted as described in any of the above embodiments of the invention.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component is substituted with one F, and the specified triazolinone component substituted as described in any of the above embodiments of the invention.

In another embodiment, the present invention R5represents a substituted triazolylmethyl group where the specified thienyl component is substituted with one F, and the specified triazolinone component is substituted on the nitrogen atom of the hydroxyl substituted alkyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component is substituted with one F, and specified triazole the other component is substituted on the nitrogen atom by the group-CH 2CH2OH.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component is substituted with one F, and the specified triazolinone component is substituted on the nitrogen atom-alkylene-O-alkyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component is substituted with one F, and the specified triazolinone component is substituted on the nitrogen atom by the group-CH2CH2OCH3.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component substituted with halogen, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component is substituted by one halogen, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component replaced by F, and the specified triazolinone component is unsubstituted.

In another embodiment, the present is about the invention R 5represents a substituted triazolylmethyl-where the specified thienyl component is substituted with one F, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5component represents a substituted triazolylmethyl-where the specified thienyl component replaced by alkoxygroup, and the specified triazolinone component substituted as described in any of the above embodiments of the invention.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component substituted with one alkoxygroup, and the specified triazolinone component substituted as described in any of the above embodiments of the invention.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component is substituted by a group-OCH3and specified triazolinone component substituted as described in any of the above embodiments of the invention.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component is substituted by a group-OCH3and decree of the Naya triazolinone component substituted, as described in any of the above embodiments of the invention.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component is substituted by a group-OCH3and specified triazolinone component is substituted on the nitrogen atom of the hydroxyl substituted alkyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component is substituted by a group-OCH3and specified triazolinone component is substituted on the nitrogen atom by the group-CH2CH2OH.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component is substituted by a group-OCH3and specified triazolinone component is substituted on the nitrogen atom-alkylene-O-alkyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component is substituted by a group-OCH3and specified triazolinone component is substituted on the nitrogen atom by the group-CH2CH2OCH3.

In another embodiment, the present invention R5is Soboh is substituted triazolylmethyl-, where specified thienyl component replaced by alkoxygroup, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component substituted with one alkoxygroup, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component is substituted by a group-OCH3and specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thienyl component is substituted by a group-OCH3and specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5is triazolopyridine-.

In another embodiment, the present invention R5represents a

.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted, and the pyridyl is unsubstituted.

In the other the embodiment of the present invention R 5represents a substituted triazolylmethyl-where specified triazolyl substituted on the nitrogen atom, and the pyridyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the carbon atom and the pyridyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the nitrogen atom and carbon atom, and the pyridyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted, and the substituted pyridyl.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the nitrogen atom, and said pyridyl substituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the carbon atom, and said pyridyl substituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl replaced and the ome nitrogen and on the carbon atom, and the specified pyridyl substituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl is unsubstituted, and is specified pyridyl substituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom alkyl group.

When Peregrina part of the group R5substituted alkyl group, examples of alkyl groups include, for example, -C1-C6alkyl, -C1-C4alkyl, -C1-C2alkyl, and-CH3.

When Peregrina part of the group R5substituted by halogen atoms, examples of halogen atoms include, for example, Cl, F and Br, provided that the carbon atoms adjacent to the nitrogen atom in the specified pyridine, unsubstituted by halogen. In one embodiment of the present invention, the halogen on pyridine represents F. In another embodiment, the present invention pyridyl substituted with one F.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom by the group-CH2SLEEP(CH3)2and the pyridyl is unsubstituted.

In another embodiment, the present invention R5before the hat is substituted triazolylmethyl-, where triazolyl substituted on the nitrogen atom by the group-CH2CH2OH, and the pyridyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom alkyl group, and the pyridyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom alkyl group and substituted on the carbon atom alkyl group, where each alkyl group is independently selected, and the pyridyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom by the group-CH3and the pyridyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom by the group-CH3and on the carbon atom by a group-CH3and the pyridyl is unsubstituted.

In another embodiment, the present invention R5component represents a substituted triazolylmethyl-where triazolyl substituted on the carbon atom of the group-NH2and the pyridyl is unsubstituted.

Alternatively, the filling up of the present invention R 5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom-alkylene-O-alkyl group, and the pyridyl is unsubstituted, provided that Allenova component specified-alkylene-O-alkyl groups does not represent a-CH2- (that is, Allenova component has two or more carbon atoms in length).

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom by the group-CH2CH2OCH3and the pyridyl is unsubstituted.

In another embodiment, the present invention R5component represents a substituted triazolylmethyl-where the specified Peregrina component substituted with halogen, provided that the carbon atoms adjacent to the nitrogen atom in the specified pyridine, unsubstituted with halogen, and the specified triazolinone component substituted as described in any of the above embodiments of the invention, describes substituted triazolyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component is substituted by one halogen, provided that the carbon atoms adjacent to the nitrogen atom in the specified pyridine, unsubstituted ha is ogena, and the specified triazolinone component substituted as described in any of the above embodiments of the invention, describes substituted triazolyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component is substituted by F, provided that the carbon atoms adjacent to the nitrogen atom in the specified pyridine, unsubstituted specified fluorine atom, and the specified triazolinone component substituted as described in any of the above embodiments of the invention, describes substituted triazolyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component is substituted with one F, provided that the carbon atoms adjacent to the nitrogen atom in the specified pyridine, unsubstituted specified fluorine atom, and the specified triazolinone component substituted as described in any of the above embodiments of the invention, describes substituted triazolyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl group where the specified Peregrina component is substituted with one F, provided that the carbon atoms adjacent to the at the IOM nitrogen in the specified pyridine, unsubstituted specified F, and the specified triazolinone component is substituted on the nitrogen atom of the hydroxyl substituted alkyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component is substituted with one F, provided that the carbon atoms adjacent to the nitrogen atom in the specified pyridine, unsubstituted specified F, and the specified triazolinone component is substituted on the nitrogen atom by the group-CH2CH2OH.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-, provided that the carbon atoms adjacent to the nitrogen atom in the specified pyridine, unsubstituted specified F, and the specified triazolinone component is substituted on the nitrogen atom-alkylene-O-alkyl group, and Allenova component specified-alkylene-O-alkyl groups does not represent a-CH2- (that is, Allenova component has two or more carbon atoms in length).

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component is substituted with one F, provided that the carbon atoms adjacent to the nitrogen atom in the specified pyridine, unsubstituted specified F, and the specified triazolinone component of samase is and on the nitrogen atom by the group-CH 2CH2OCH3.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component substituted with halogen, provided that the carbon atoms adjacent to the nitrogen atom in the specified pyridine, unsubstituted with halogen, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component is substituted by one halogen, provided that the carbon atoms adjacent to the nitrogen atom in the specified pyridine, unsubstituted specified by halogen, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component is substituted by F, provided that the carbon atoms adjacent to the nitrogen atom in the specified pyridine, unsubstituted specified F, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component is substituted with one F, provided that the carbon atoms adjacent to the nitrogen atom in the specified pyridine, n is replaced by the specified F, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5component represents a substituted triazolylmethyl-where the specified Peregrina component replaced by alkoxygroup, and the specified triazolinone component substituted as described in any of the above embodiments of the invention describing triazolyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component substituted with one alkoxygroup, and the specified triazolinone component substituted as described in any of the above embodiments of the invention describing triazolyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component is substituted by a group-OCH3and specified triazolinone component substituted as described in any of the above embodiments of the invention describing triazolyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component is substituted by a group-OCH3and MC is connected triazolinone component substituted, as described in any of the above embodiments of the invention describing triazolyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl group where the specified Peregrina component is substituted by a group-OCH3and specified triazolinone component is substituted on the nitrogen atom of the hydroxyl substituted alkyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component is substituted by a group-OCH3and specified triazolinone component is substituted on the nitrogen atom by the group-CH2CH2OH.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component is substituted by a group-OCH3and specified triazolinone component is substituted on the nitrogen atom-alkylene-O-alkyl group, and Allenova component specified-alkylene-O-alkyl groups does not represent a-CH2- (that is, Allenova component has two or more carbon atoms in length).

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina status is engaged substituted by one group-OCH 3and specified triazolinone component is substituted on the nitrogen atom by the group-CH2CH2OCH3.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component replaced by alkoxygroup, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component substituted with one alkoxygroup, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component substituted-OCH3group, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified Peregrina component is substituted by a group-OCH3and specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted 1 or 2 groups independently selected from the group which ostoja of: (a) hydroxyl-substituted alkyl groups (for example, -CH2SLEEP(CH3)2and-CH2CH2OH), (b) alkyl (for example, -C1-C6alkyl, -C1-C4alkyl, -C1-C2alkyl, and-CH3), (s) -NH2and (d) -alkylene-O-alkyl (e.g.,- CH2CH2OCH3), provided that Allenova component specified-alkylene-O-alkyl groups does not represent a-CH2- (that is, Allenova component has two or more carbon atoms in length), when specified-alkylene-O-alkyl group linked to the nitrogen atom of the specified triazolyl; and specified pyridyl substituted with 1-3 groups independently selected from the group consisting of: (a) alkyl (for example, -C1-C6alkyl, -C1-C4alkyl, -C1-C2alkyl, and-CH3), (b) halogen (such as Cl, F and Br), and provided that the carbon atoms adjacent to the nitrogen atom in the specified pyridine, unsubstituted with halogen, and (C), alkoxy (e.g.,- OCH3).

In another embodiment, the present invention R5represents a

.

In another embodiment, the present invention R5represents triazolylmethyl-.

In another embodiment, the present invention R5represents:

.

In another embodiment, the present invention R5represents C is displaced triazolylmethyl-, where specified triazolyl substituted, and the specified thiazolyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the nitrogen atom, and the specified thiazolyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the carbon atom and the specified thiazolyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the nitrogen atom and carbon atom, and the specified thiazolyl is unsubstituted.

When thiazolidine part of the group R5substituted alkyl group, examples of alkyl groups include, for example, -C1-C6alkyl, -C1-C4alkyl, -C1-C2alkyl, and-CH3.

When thiazolidine part of the group R5substituted by halogen atoms, examples of halogen atoms include, for example, Cl, F and Br. In one embodiment, the present invention halogen on thiazolyl represents F. In another embodiment, the present invention thiazolyl substituted with one F.

When thiazolidine part of the group R5the Deputy who s alkylamino group, examples of alkylamino groups include, for example, C1-C6alkyl-NH-, C1-C2alkyl-NH-, CH3-NH - and CH3CH2-NH-.

When thiazolidine part of the group R5replaced dialkylamino group, examples of dialkylamino groups include, for example, (C1-C6alkyl)2-N-, where each alkyl independently selected, (C1-C2alkyl)2-N-, where each alkyl independently selected, (CH3)2N - (CH3CH2)2-N - (CH3)(CH3CH2)N.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted, and the specified thiazolyl replaced.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the nitrogen atom, and the specified thiazolyl replaced.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the carbon atom and the specified thiazolyl replaced.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted on the nitrogen atom and carbon atom, and the specified thiazolyl replaced.

In another embodiment, is carried out the present invention R 5represents a substituted triazolylmethyl-where specified triazolyl is unsubstituted, and is specified thiazolyl replaced.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom by alkyl, and specified thiazolyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom by the group-CH2SLEEP(CH3)2and this thiazolyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom by the group-CH2CH2OH, and the specified thiazolyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom alkyl group and substituted on the carbon atom alkyl group, where each alkyl group is independently selected, and specified thiazolyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom-CH3group, and MC is connected thiazolyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom by the group-CH3and on the carbon atom by a group-CH3and this thiazolyl is unsubstituted.

In another embodiment, the present invention R5component represents a substituted triazolylmethyl-where triazolyl substituted on the carbon atom of the group-NH2and this thiazolyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom-alkylene-O-alkyl group, provided that Allenova component specified-alkylene-O-alkyl groups does not represent a-CH2- (i.e. Allenova component has two or more carbon atoms in length), and the specified thiazolyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom by the group-CH2CH2OCH3and this thiazolyl is unsubstituted.

In another embodiment, the present invention R5component represents a substituted triazolylmethyl-where the specified thiazolidine with the bringing substituted with halogen, and the specified triazolinone component substituted as described in any of the above embodiments of the invention, describes substituted triazolyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thiazolidine component replaced by F, and the specified triazolinone component substituted as described in any of the above embodiments of the invention, describes substituted triazolyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl group where the specified thiazolidine component is substituted with one F, and the specified triazolinone component is substituted on the nitrogen atom of the hydroxyl substituted alkyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thiazolidine component is substituted with one F, and the specified triazolinone component is substituted on the nitrogen atom by the group-CH2CH2OH.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thiazolidine component is substituted with one F, and the specified triazolinone component is substituted on the nitrogen atom is-alkylene-O-alkyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thiazolidine component is substituted with one F, and the specified triazolinone component is substituted on the nitrogen atom by the group-CH2CH2OCH3.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thiazolidine component substituted with halogen, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thiazolidine component replaced by F, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5component represents a substituted triazolylmethyl-where the specified thiazolidine component replaced by alkoxygroup, and the specified triazolinone component substituted as described in any of the above embodiments of the invention, describes substituted triazolyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thiazolidine component is substituted by a group-OCH3and the specified triazolinone component substituted, as described in any of the above embodiments of the invention, describes substituted triazolyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl group where the specified thiazolidine component is substituted by a group-OCH3and specified triazolinone component is substituted on the nitrogen atom of the hydroxyl substituted alkyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thiazolidine component is substituted by a group-OCH3and specified triazolinone component is substituted on the nitrogen atom by the group-CH3CH2OH.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thiazolidine component is substituted by a group-OCH3and specified triazolinone component is substituted on the nitrogen atom-alkylene-O-alkyl group, and Allenova component specified-alkylene-O-alkyl groups does not represent a-CH2- (i.e. Allenova component has two or more carbon atoms in length).

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where are specified thiazolidine component is substituted by a group-OCH 3and specified triazolinone component is substituted on the nitrogen atom by the group-CH2CH2OCH3.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thiazolidine component replaced by alkoxygroup, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thiazolidine component is substituted by a group-OCH3and specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thiazolidine component is replaced by alkylamino group, and the specified triazolinone component substituted as described in any of the above embodiments of the invention, revealing triazolyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thiazolidine component is replaced by dialkylamino group, and the specified triazolinone component substituted as described in any of the above embodiments of the invention, revealing triazolyl group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thiazolidine component is replaced by alkylamino group, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where the specified thiazolidine component is replaced by dialkylamino group, and the specified triazolinone component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-where specified triazolyl substituted by one or two groups independently selected from the group consisting of: (a) hydroxyl-substituted alkyl groups (for example, -CH2SLEEP(CH3)2and-CH2CH2OH), (b) alkyl (for example, -C1-C6alkyl, -C1-C4alkyl, -C1-C2alkyl, and-CH3), -NH2and (s) -alkylene-O-alkyl (e.g.,- CH2CH2OCH3), provided that Allenova component specified-alkylene-O-alkyl groups does not represent a-CH2- (that is, Allenova component has two or more carbon atoms in length), when specified-alkylene-O-alkyl group linked to the nitrogen atom of the specified triazolyl; and specified enous the Lil substituted by one group, selected from the group consisting of: (a) alkyl (for example, -C1-C6alkyl, or-C1-C4alkyl or-C1-C2alkyl, or-CH3), (b) halogen (such as Cl, F or Br), (C) alkylamino (for example, C1-C6alkyl-NH - or1-C2alkyl-NH-, or CH3-NH-, or CH3CH2-NH-), and (d) dialkylamino (for example, (C1-C6alkyl)2-N-, where each alkyl is selected independently, or (C1-C2alkyl)2-N-, where each alkyl is selected independently, or (CH3)2N-, or - (CH3CH2)2-N-, or - (CH3)(CH3CH2)N-).

In another embodiment, the present invention R5represents a

.

In another embodiment, the present invention R5represents pyridinylmethyl-.

In another embodiment, the present invention R5represents a

.

When pyridinoline part of the group R5substituted by alkyl, examples of alkyl groups include, for example, -C1-C6alkyl, -C1-C4alkyl, -C1-C2alkyl, and-CH3.

When pyridinoline part of the group R5substituted by halogen atoms, examples of halogen atoms include, for example, Cl, F and Br. In one embodiment, the present image is the shadow of the halogen on pyridazinyl represents F. In another embodiment, the present invention pyridazinyl replaced by one atom of F. When pyridinoline component substituted by halogen, carbon atoms adjacent to nitrogen atoms, unsubstituted by halogen.

When pyridinoline part of the group R5replaced alkylamino group, examples of alkylamino groups include, for example, C1-C6alkyl-NH-, C1-C2alkyl-NH-, CH3-NH - and CH3CH2-NH-.

When pyridinoline part of the group R5replaced dialkylamino group, examples of dialkylamino groups include, for example, (C1-C6alkyl)2-N-, where each alkyl independently selected, (C1-C2alkyl)2-N-, where each alkyl independently selected, (CH3)2N - (CH3CH2)2-N - (CH3)(CH3CH2)N.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl substituted, and the specified thienyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl substituted by a group =O, and the specified thienyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted pyridazinyl enyl-, where specified pyridazinyl substituted alkyl group, and the specified thienyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl substituted methyl group, and the specified thienyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl substituted by a group =O and alkyl group, and the specified thienyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl substituted by a group =O and methyl group, and the specified thienyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl substituted amino group, and the specified thienyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl replaced alkylamino group, and the specified thienyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where is shown pyridazinyl replaced dialkylamino group, and the specified thienyl is unsubstituted.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl substituted, and the specified thienyl replaced.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl is unsubstituted, and the specified thienyl replaced.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl is unsubstituted, and the specified thienyl substituted with one or two independently selected Halogens.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl is unsubstituted, and the specified thienyl substituted by one or two Halogens independently selected from the group consisting of: Br, Cl and F.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl is unsubstituted, and the specified thienyl substituted with one or two independently selected alkoxygroup

In another embodiment, the present invention R5represents a substituted pyridazinedione the-, where specified pyridazinyl is unsubstituted, and the specified thienyl substituted by one or two groups-OCH3.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl substituted as described in any of the above embodiments of the invention, revealing substituted pyridazinyl group, and the specified thienyl replaced.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl substituted as described in any of the above embodiments of the invention, revealing substituted pyridazinyl group, and the specified thienyl substituted with one or two independently selected Halogens

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl substituted as described in any of the above embodiments of the invention, revealing substituted pyridazinyl group, and the specified thienyl substituted by one or two Halogens independently selected from the group consisting of: Br, Cl and F.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl substituted as described in any of the above embodiments of the invention, revealing substituted pyridazinyl group, and the specified thienyl substituted with one or two independently selected alkoxy-groups.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl substituted as described in any of the above embodiments of the invention, revealing substituted pyridazinyl group, and the specified thienyl substituted with one or two-OCH3groups.

In another embodiment, the present invention R5represents a substituted pyridinylmethyl-where specified pyridazinyl substituted by one or two groups independently selected from the group consisting of alkyl (e.g. methyl) and =O, and the specified thienyl substituted by one or two groups independently selected from the group consisting of: alkoxy (e.g.,- OCH3), halogen (such as Br, Cl and F).

In another embodiment, the present invention R5represents:

.

In another embodiment, the present invention R5represents:

.

In another embodiment, the present invention R5represents:

.

In another embodiment, the present invention R5pre is is a substituted triazolylmethyl group where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component optionally substituted on the nitrogen atom alkyl group, and the carbon atom alkyl group, (d) thiazolidine component optionally substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component optionally substituted on the nitrogen atom by one group-CH3and on the carbon atom by one group-CH3and (f) thiazolidine component optionally substituted on the carbon atom of the group-NH2or (g) thiazolidine component optionally substituted on the nitrogen atom by the group-CH2CH2OCH3; and, where specified phenyl component optionally substituted with halogen.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone sostav the maintenance optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component optionally substituted on the nitrogen atom alkyl group, and the carbon atom alkyl group, (d) thiazolidine component optionally substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component optionally substituted on the nitrogen atom by one group-CH3and on the carbon atom by one group-CH3and (f) thiazolidine component optionally substituted on the carbon atom of the group-NH2or (g) thiazolidine component optionally substituted on the nitrogen atom by the group-CH2CH2OCH3; and, where specified phenyl component substituted with halogen.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component substituted on the atom is zhota one group-CH 3and on the carbon atom by one group-CH3and (f) thiazolidine component is substituted on the carbon atom of the group-NH2or (g) thiazolidine component is substituted on the nitrogen atom by the group-CH2CH2OCH3; and, where specified phenyl component optionally substituted with halogen.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component is substituted on the nitrogen atom by one group-CH3and on the carbon atom by one group-CH3and (f) thiazolidine component is substituted on the carbon atom of the group-NH2or (g) thiazolidine component is substituted on the nitrogen atom by the group-CH2CH2OCH3; and, where specified phenyl component substituted with halogen.

In another embodiment, in the execution of the present invention R 5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component is substituted on the nitrogen atom by one group-CH3and on the carbon atom by one group-CH3and (f) thiazolidine component is substituted on the carbon atom of the group-NH2or (g) thiazolidine component is substituted on the nitrogen atom by the group-CH2CH2OCH3; and, where specified phenyl part is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component optionally substituted on the nitrogen atom alkyl g is uppoi, (C) specified triazolinone component optionally substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component optionally substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component optionally substituted on the nitrogen atom by one group-CH3and on the carbon atom by one group-CH3and (f) thiazolidine component optionally substituted on the carbon atom of the group-NH2or (g) thiazolidine component optionally substituted on the nitrogen atom by the group-CH3CH3OCH3; and, where specified phenyl component optionally substituted by alkoxygroup.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component optionally substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component optionally substituted on the nitrogen atom is Rupay-CH 3(e) specified triazolinone component optionally substituted on the nitrogen atom by one group-CH3and on the carbon atom by one group-CH3and (f) thiazolidine component optionally substituted on the carbon atom of the group-NH2or (g) thiazolidine component optionally substituted on the nitrogen atom by the group-CH2CH2OCH3; and, where specified phenyl component replaced by alkoxygroup.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component is substituted on the nitrogen atom by one group-CH3and on the carbon atom by one group-CH3and (f) thiazolidine component is substituted on the carbon atom of the group-NH2or (g) thiazolidine component substituted on the atom I is the group-CH 2CH2OCH3; and, where specified phenyl component optionally substituted by alkoxygroup.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component is substituted on the nitrogen atom by one group-CH3and on the carbon atom by one group-CH3and (f) thiazolidine component is substituted on the carbon atom of the group-NH2or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2OCH3group; and, where specified phenyl component of the substituted al Coxe group.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component optionally substituted on the nitrogen atom Deputy selected is from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component optionally substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component optionally substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component optionally substituted on the nitrogen atom by one group-CH3and on the carbon atom by one group-CH3and (f) thiazolidine component optionally substituted on the carbon atom of the group-NH2or (g) thiazolidine component optionally substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thienyl component optionally substituted with halogen.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component neobyazatel is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component optionally substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component optionally substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component optionally substituted on the carbon atom of the group-NH2or (g) thiazolidine component optionally substituted on the nitrogen atom by the group-CH2CH2OCH3; and, where indicated thienyl component substituted with halogen.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component is substituted on the nitrogen atom by one group-CH3and on the carbon atom by one group-CH3and (f) thiazolidine component is substituted on the carbon atom which kind of group-NH 2or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thienyl component optionally substituted with halogen.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component is substituted on the nitrogen atom by one group-CH3and on the carbon atom by one group-CH3and (f) thiazolidine component is substituted on the carbon atom of the group-NH2or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thienyl component substituted with halogen.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-group, where (a) the specified triazolyl the I component is substituted on the nitrogen atom Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component is substituted on the nitrogen atom by one group-CH3and on the carbon atom by one group-CH3and (f) thiazolidine component is substituted on the carbon atom of the group-NH2or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thienyl component is unsubstituted.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component optionally substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group is Oh, (d) thiazolidine component optionally substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component optionally substituted on the nitrogen atom by one group-CH3and on the carbon atom by one group-CH3and (f) thiazolidine component optionally substituted on the carbon atom of the group-NH2or (g) thiazolidine component optionally substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thienyl component optionally substituted by alkoxygroup.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component optionally substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component optionally substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component optionally substituted on the nitrogen atom by one group-CH3and on the atom ug is erode one group-CH 3and (f) thiazolidine component optionally substituted on the carbon atom of the group-NH2or (g) thiazolidine component optionally substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thienyl component replaced by alkoxygroup.

In another embodiment, the present invention R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component is substituted on the nitrogen atom by one group-CH3and on the carbon atom by one group-CH3and (f) thiazolidine component is substituted on the carbon atom of the group-NH2or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thienyl component optionally substituted by alkoxygroup.

In another embodiment, in the execution of the present invention R 5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component is substituted on the nitrogen atom by one group-CH3and on the carbon atom by one group-CH3and (f) thiazolidine component is substituted on the carbon atom of-NH2group, or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thienyl component replaced by alkoxygroup.

Other embodiments of the present invention is described below. Embodiments of the present invention have been numbered to make them easier to reference.

An embodiment of the invention No. 1 represents the compounds of formula 1.0, where R2represents-O-(C1-C2)alkyl group, and R1replaced by pyridium.

Embodiment of izobreteny the No. 2 represents the compounds of formula 1.0, where R2represents-O-(C1-C2)alkyl group, and R1represents pyridyl, substituted with one Deputy.

An embodiment of the invention No. 3 represents the compounds of formula 1.0, where R2represents-O-(C1-C2)alkyl group, and R1is selected from the group consisting of:

and.

An embodiment of the invention No. 4 represents the compounds of formula 1.0, where R2represents-O-(C1-C2) alkyl group, and R1represents:

.

An embodiment of the invention No. 5 represents the compounds of formula 1.0, where R2represents-O-(C1-C2)alkyl group, and R1represents:

An embodiment of the invention No. 6 represents the compounds of formula 1.0, where R2represents-O-(C1-C2)alkyl group, and R1represents:

where the specified alkoxygroup represents-och(CH3)2.

An embodiment of the invention No. 7 represents the compounds of formula 1.0, where R2represents-O-(C1-C2) alkyl group, and R1represents:

where the specified alkoxygroup represents-OC2H5.

An embodiment of the invention No. 8 represents the compounds of formula 1.0, where R2represents-O-(C1-C2) alkyl group, and R1represents:

.

An embodiment of the invention No. 9 represents the compounds of formula 1.0, where R2represents-O-(C1-C2) alkyl group, and R1represents:

.

An embodiment of the invention No. 10 represents the compounds of formula 1.0, where z is 1, R2represents-O-(C1-C2) alkyl group, and R1represents:

where the specified-O-alkylene-O-alkyl group represents-OCH2CH2OCH3.

An embodiment of the invention No. 11 represents the compounds of formula 1.0, where R2represents-O-(C1-C2)alkyl group, and R1represents:

.

An embodiment of the invention No. 12 represents the compounds of formula 1.0, where R2represents-OCH3and R1substituted pyridyl.

An embodiment of the invention No. 13 represents the compounds of formula 1.0, where R2represents-OCH3, R 1represents pyridyl, substituted with one Deputy.

An embodiment of the invention No. 14 represents the compounds of formula 1.0, where R2represents-OCH3and R1is selected from the group consisting of:

and.

An embodiment of the invention No. 15 represents the compounds of formula 1.0, where R2represents-OCH3and R1represents:

.

An embodiment of the invention No. 16 represents the compounds of formula 1.0, where R2represents-OCH3and R1represents;

.

An embodiment of the invention No. 17 represents the compounds of formula 1.0, where R2represents-OCH3and R1represents:

where the specified alkoxygroup represents-och(CH3)2.

An embodiment of the invention No. 18 represents the compounds of formula 1.0, where R2represents-OCH3and R1represents:

where the specified alkoxygroup represents-OC2H5.

An embodiment of the invention No. 19 is a compound of formula 1.0, where R2represents-OCH and R1represents:

.

An embodiment of the invention No. 20 is a compound of formula 1.0, where R2represents-OCH3and R1represents:

.

An embodiment of the invention No. 21 is a compound of formula 1.0, where R2represents-OCH3and R1represents:

where the specified-O-alkylene-O-alkyl group represents-OCH2CH2OCH3.

An embodiment of the invention No. 22 is a compound of formula 1.0, where R2represents-OCH3and R1represents:

.

An embodiment of the invention No. 23 is a compound of formula 1.0, where R2represents-S-(C1-C2)alkyl group, and R1replaced by pyridium.

An embodiment of the invention the number 24 represents the compounds of formula 1.0, where R2represents-S-(C1-C2)alkyl group, and R1represents pyridyl, substituted with one Deputy.

An embodiment of the invention No. 25 is a compound of formula 1.0, where R2represents-S-(C1-C2)alkyl group, and R1is selected from the group, ostoja from:

and.

An embodiment of the invention No. 26 is a compound of formula 1.0, where R2represents-S-(C1-C2)alkyl group, and R1represents:

.

An embodiment of the invention No. 27 is a compound of formula 1.0, where R2represents-S-(C1-C2)alkyl group, and R1represents:

.

An embodiment of the invention No. 28 is a compound of formula 1.0, where R2represents-S-(C1-C2)alkyl group, and R1represents:

where the specified alkoxygroup represents-och(CH3)2.

An embodiment of the invention No. 29 is a compound of formula 1.0, where R2represents-S-(C1-C2) alkyl group, and R1represents:

where the specified alkoxygroup represents-OC2H5.

An embodiment of the invention No. 30 is a compound of formula 1.0, where R2represents-S-(C1-C2) alkyl group, and R1represents:

.

Embodiment of izaberete the Oia No. 31 consists of the compounds of formula 1.0, where R2represents-S-(C1-C2)alkyl group, and R1represents:

.

An embodiment of the invention No. 32 is a compound of formula 1.0, where R2represents-S-(C1-C2)alkyl group, and R1represents:

where the specified-O-alkylene-O-alkyl group represents-OCH2CH2OCH3.

An embodiment of the invention No. 33 is a compound of formula 1.0, where R2represents-S-(C1-C2) alkyl group, and R1represents:

.

An embodiment of the invention No. 34 is a compound of formula 1.0, where R2represents-SCH3and R1replaced by pyridium.

An embodiment of the invention No. 35 is a compound of formula 1.0, where R2represents-SCH3and R1represents pyridyl, substituted with one Deputy.

An embodiment of the invention No. 36 is a compound of formula 1.0, where R2represents-SCH3and R1is selected from the group consisting of:

and.

An embodiment of the invention No. 37 represents a connection is ormula 1.0, where R2represents-SCH3and R1represents:

.

An embodiment of the invention No. 38 is a compound of formula 1.0, where R2represents-SCH3and R1represents:

.

An embodiment of the invention No. 39 is a compound of formula 1.0, where R2represents-SCH3and R1represents:

where the specified alkoxygroup represents-och(CH3)2.

An embodiment of the invention No. 40 is a compound of formula 1.0, where R2represents-SCH3and R1represents:

where the specified alkoxygroup represents-OC2H5.

An embodiment of the invention No. 41 is a compound of formula 1.0, where R2represents-SCH3and R1represents:

.

An embodiment of the invention No. 42 is a compound of formula 1.0, where R2represents-SCH3and R1represents:

.

An embodiment of the invention No. 43 is a compound of formula 1.0, where R2represents-SCH3 and R1represents:

where the specified-O-alkylene-O-alkyl group represents-OCH2CH2OCH3.

An embodiment of the invention No. 44 is a compound of formula 1.0, where R2represents-SCH3and R1represents:

.

An embodiment of the invention No. 45 represents the compounds of formula 1.0 having the formula 1.1:

An embodiment of the invention No. 46 represents any of the embodiments of the invention No. 1-44, where the compound of formula 1.0 is a compound of formula 1.1.

Other embodiments of the present invention are compounds where R5the Deputy described below. The phrase "as described in any of the embodiments of the invention No. 1-46" means that an embodiment of the invention is disclosed as suitable for each of the embodiments of the invention No. 1-46. For example, another embodiment of the present invention is a compound described in embodiment No. 1, where R5described in any of the following paragraphs. In another example, another embodiment of the present invention is a compound described in option vypolneniyasvoey No. 2, where R5described in any of the following paragraphs, and so on.

Thus, other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted by one or two alkyl groups selected from the group consisting of: -C1-C6of alkyl, -C1-C4of alkyl, -C1-C2the alkyl and -- CH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted by one or two alkyl groups selected from the group consisting of: -C1-C4of alkyl, -C1-C2the alkyl and -- CH3. Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component substituted with one or two-CH3groups.

Other embodiments of the present invention are compounds of formula 1.0, as the description is but in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom alkyl group selected from the group consisting of: -C1-C4of alkyl, -C1-C2the alkyl and -- CH3. Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom by the group-CH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom-alkylene-O-alkyl group selected from the group consisting of: -C2-C4alkylen-O-C1-C6of alkyl, -C2alkylen-O-C1-C2of alkyl, -C2-C4alkylen-O-CH3and-CH2CH2OCH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom-Ala is flax-O-alkyl group, selected from the group consisting of: -C2alkylen-O-C1-C2the alkyl and -- CH2CH2OCH3. Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom by the group-CH2CH2OCH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom replacement alkyl group selected from the group consisting of: replacement-C1-C4of alkyl, replacement-C1-C2the alkyl and replacement-CH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom replacement alkyl group selected from the group consisting of: CH2SLEEP(CH3)2and-CH2CH2OH.

Others in the ways of implementation of the present invention are compounds of formula 1.0, as described in any of the embodiments of the invention No. 1-46, where the optional halogen substituents for the phenyl component of R5independently selected from the group consisting of: Cl, F and BR.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where the optional halogen Deputy for the phenyl component of R5is a F.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where the optional halogen Deputy for the phenyl component of R5represents one F.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component optionally substituted on at the IU nitrogen alkyl group on the carbon atom alkyl group, (d) thiazolidine component optionally substituted on the nitrogen atom by the group-CH3(e) specified triazolinone component optionally substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component optionally substituted on the carbon atom of-NH2group, or (g) thiazolidine component optionally substituted on the nitrogen atom-CH2CH2OCH3group; and, where specified phenyl component optionally substituted with halogen (e.g., a halogen such as, for example, F).

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl - group, where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component optionally substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component optionally substituted Natoma nitrogen-CH 3group, (e) thiazolidine component optionally substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component optionally substituted on the carbon atom of-NH2group, or (g) thiazolidine component optionally substituted on the nitrogen atom-CH2CH2OCH3group; and, where specified phenyl component substituted with halogen (e.g., a halogen such as, for example, F).

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl - group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom-CH3group, (e) thiazolidine component is substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3gr is POI, (f) thiazolidine component is substituted on the carbon atom of-NH2group, or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2OCH3group; and, where specified phenyl component optionally substituted with halogen (e.g., a halogen such as, for example, F).

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom-CH3group, (e) thiazolidine component is substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component is substituted on the carbon atom of-NH2group, or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2 OCH3group; and, where specified phenyl component substituted with halogen (e.g., a halogen such as, for example, F).

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where the optional substituents for the phenyl component of R5independently selected from the group consisting of: alkoxy.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where the optional Deputy for the phenyl component of R5represents a group-OCH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where the optional Deputy for the phenyl component of R5represents a group-OCH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl - group, where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of:-CH 2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component optionally substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component optionally substituted on the nitrogen atom-CH3group, (e) thiazolidine component optionally substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component optionally substituted on the carbon atom of-NH2group, or (g) thiazolidine component optionally substituted on the nitrogen atom-CH3CH2OCH3group; and, where specified phenyl component optionally substituted by alkoxygroup (for example, one group-OCH3).

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl - group, where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone is leaving optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component optionally substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component optionally substituted on the nitrogen atom-CH3group, (e) thiazolidine component optionally substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component optionally substituted on the carbon atom of-NH2group, or (g) thiazolidine component optionally substituted on the nitrogen atom-CH3CH3OCH3group; and, where specified phenyl component replaced by alkoxygroup (for example, one group-OCH3).

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl - group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH3CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl groups is th, (d) thiazolidine component is substituted on the nitrogen atom-CH3group, (e) thiazolidine component is substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component is substituted on the carbon atom of-NH2group, or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2OCH3group; and, where specified phenyl component optionally substituted by alkoxygroup (for example, one group-OCH3).

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl - group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom-CH3group, (e) thiazolidine component is substituted on the nitrogen atom of one-CH3group and and the ome carbon one-CH 3group, (f) thiazolidine component is substituted on the carbon atom of-NH2group, or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2OCH3group; and, where specified phenyl component of the substituted alkoxy group (for example, one group-OCH3).

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl - group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom-CH3group, (e) thiazolidine component is substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component is substituted on the carbon atom of-NH2group, or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2OCH3/sub> group; and, where specified phenyl part is unsubstituted.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where specified substituted R5component represents a substituted triazolylmethyl where the specified triazolinone component is substituted: (a) one Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH3OH, (b) one alkyl group, (C) two alkyl groups, (d) one-CH3group, (e) two-CH3groups, (f) one-NH2group, or (g) one-CH2CH2OCH3group.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted by one or two alkyl groups selected from the group consisting of: -C1-C6of alkyl, -C1-C4alkyl, -C1-C2the alkyl and -- CH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted Tr is analytieal-, where triazolinone component is substituted by one or two alkyl groups selected from the group consisting of: -C1-C4of alkyl, -C1-C2the alkyl and -- CH3. Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component substituted with one or two-CH3groups.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom alkyl group selected from the group consisting of: -C1-C4alkyl, -C1-C2alkyl, and-CH3. Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom by the group-CH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of embodiments izobreteny the No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom-alkylene-O-alkyl group selected from the group consisting of: -C2-C4alkylen-O-C1-C6of alkyl, -C2alkylen-O-C1-C2of alkyl, -C2-C4alkylen-O-CH3and-CH2CH2OCH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom-alkylene-O-alkyl group selected from the group consisting of: -C2alkylen-O-C1-C2the alkyl and -- CH2CH2OCH3. Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom by the group-CH2CH2OCH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where diazolidinylurea substituted on the nitrogen atom replacement alkyl group, selected from the group consisting of: replacement-C1-C4of alkyl, replacement-C1-C2the alkyl and replacement group-CH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom replacement alkyl group selected from the group consisting of: CH2SLEEP(CH3)2and-CH2CH2OH.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where the optional halogen substituents for thienyl component of R5independently selected from the group consisting of: Cl, F and Br.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where the optional halogen substituents for thienyl component of R5represent F.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where optional is halogen Deputy thienyl for component R 5represents one F.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl group, where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component optionally substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component optionally substituted on the nitrogen atom-CH3group, (e) thiazolidine component optionally substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component optionally substituted on the carbon atom of-NH2group, or (g) thiazolidine component optionally substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thienyl component optionally substituted with halogen (e.g., a halogen such as, for example, F).

Other options perform in the present invention are compounds of formula 1.0, as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl group, where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2, -CH2CH2OH, (b) triazolinone component optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component optionally substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component optionally substituted on the nitrogen atom-CH3group, (e) thiazolidine component optionally substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component optionally substituted on the carbon atom of-NH2group, or (g) thiazolidine component optionally substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thienyl component substituted with halogen (e.g., a halogen such as, for example, F).

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5performance is possessing a substituted triazolylmethyl group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom-CH3group, (e) thiazolidine component is substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component is substituted on the carbon atom of-NH2group, or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thienyl component optionally substituted with halogen (e.g., a halogen such as, for example, F).

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom-CH3group, (e) thiazolidine component is substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component is substituted on the carbon atom of-NH2group, or (g) thiazolidine component is substituted on the nitrogen atom-CH3CH2OCH3group; and, where indicated thienyl component substituted with halogen (e.g., a halogen such as, for example, F).

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom alkyl group and the atom angle of the ode alkyl group, (d) thiazolidine component is substituted on the nitrogen atom-CH3group, (e) thiazolidine component is substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component is substituted on the carbon atom of-NH2group, or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thienyl component is unsubstituted.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where specified substituted R5component represents a substituted triazolylmethyl where the specified triazolinone component is substituted: (a) one Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) one alkyl group, (C) two alkyl groups, (d) one-CH3group, (e) two-CH3groups, (f) one-NH2group, or (g) one-CH2CH2OCH3group.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where the optional substituents for thienyl component of R5

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where the optional substituents for thienyl component of R5represent a group-OCH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where the optional Deputy thienyl for component R5represents a group-OCH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl group, where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component optionally substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component optionally substituted on the nitrogen atom-CH3group (s) specified triazolinone component optionally substituted on the nitrogen atom of one-CH 3the group and the carbon atom of one-CH3group, (f) thiazolidine component optionally substituted on the carbon atom of-NH2group, or (g) thiazolidine component optionally substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thienyl component optionally substituted by alkoxygroup (for example, one group-OCH3).

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl group, where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component optionally substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component optionally substituted on the nitrogen atom-CH3group, (e) thiazolidine component optionally substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) the three who zailina component optionally substituted on the carbon atom of-NH 2group, or (g) thiazolidine component optionally substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thienyl component replaced by alkoxygroup (for example, one group-OCH3).

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom-CH3group, (e) thiazolidine component is substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component is substituted on the carbon atom of-NH2group, or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thienyl optional component C is mesena alkoxygroup (for example, one group-OCH3).

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom-CH3group, (e) thiazolidine component is substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component is substituted on the carbon atom of-NH2group, or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thienyl component is substituted by an alkoxy group (for example, one group-OCH3).

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R 5represents a substituted triazolylmethyl-where triazolinone component is substituted by one or two alkyl groups selected from the group consisting of: -C1-C6of alkyl, -C1-C4of alkyl, -C1-C2the alkyl and -- CH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of embodiment of the invention, No. 1-6, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted by one or two alkyl groups selected from the group consisting of: -C1-C4of alkyl, -C1-C2alkyl and-CH3. Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component substituted with one or two-CH3groups.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom alkyl group selected from the group consisting of: -C1-C4of alkyl,-C 1-C2the alkyl and -- CH3. Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom by the group-CH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom-alkylene-O-alkyl group selected from the group consisting of: -C2-C4alkylen-O-C1-C6of alkyl, -C2alkylen-O-C1-C2alkyl, -C2-C4alkylen-O-CH3and-CH2CH2OCH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom-alkylene-O-alkyl group selected from the group consisting of: -C2alkylen-O-C1-C2the alkyl and -- CH2CH2OCH3. Other embodiments of the present invention presented is Aut a compound of formula 1.0, as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom by the group-CH2CH2OCH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom replacement alkyl group selected from the group consisting of: replacement-C1-C4of alkyl, replacement-C1-C2the alkyl and replacement group-CH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom replacement alkyl group selected from the group consisting of: CH2SLEEP(CH3)2and-CH2CH2OH.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents zameshano triazolylmethyl group where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component optionally substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component optionally substituted on the nitrogen atom-CH3group, (e) thiazolidine component optionally substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component optionally substituted on the carbon atom of-NH2group, or (g) thiazolidine component optionally substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated Peregrina component is unsubstituted.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom alkyl group, and the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom-CH3group, (e) thiazolidine component is substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component is substituted on the carbon atom of-NH2group, or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated Peregrina component is unsubstituted.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted by one or two alkyl groups selected from the group consisting of: -C1-C6of alkyl, -C1-C4alkyl, -C1-C2alkyl, and-CH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46 where R 5represents a substituted triazolylmethyl-where triazolinone component is substituted by one or two alkyl groups selected from the group consisting of: -C1-C4of alkyl, -C1-C2the alkyl and -- CH3. Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component substituted with one or two-CH3groups.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom alkyl group selected from the group consisting of: -C1-C4of alkyl, -C1-C2the alkyl and -- CH3. Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom by the group-CH3.

Other embodiments of the present invention are compounds f is rmula 1.0, as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom-alkylene-O-alkyl group selected from the group consisting of: -C2-C4alkylen-O-C1-C6of alkyl, -C2alkylen-O-C1-C2of alkyl, -C2-C4alkylen-O-CH3and-CH2CH2OCH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom-alkylene-O-alkyl group selected from the group consisting of: -C2alkylen-O-C1-C2the alkyl and -- CH2CH2OCH3. Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom by the group-CH2CH2OCH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R51-C4of alkyl, replacement-C1-C2the alkyl and replacement group-CH3.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-where triazolinone component is substituted on the nitrogen atom replacement alkyl group selected from the group consisting of: CH2SLEEP(CH3)2and-CH2CH2OH.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component optionally substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component optionally substituted on the nitrogen atom alkyl group, (C) specified triazolinone component optionally substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl is Noah band (d) thiazolidine component optionally substituted on the nitrogen atom-CH3group, (e) thiazolidine component optionally substituted on the nitrogen atom of one-CH3the group and the carbon atom of one-CH3group, (f) thiazolidine component optionally substituted on the carbon atom of-NH2group, or (g) thiazolidine component optionally substituted on the nitrogen atom-CH3CH2OCH3group; and, where indicated thiazolidine component is unsubstituted.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted triazolylmethyl-group, where (a) the specified triazolinone component is substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and-CH2CH2OH, (b) triazolinone component is substituted on the nitrogen atom alkyl group, (C) specified triazolinone component is substituted on the nitrogen atom of the alkyl group on the carbon atom alkyl group, (d) thiazolidine component is substituted on the nitrogen atom-CH3group, (e) thiazolidine component is substituted on the nitrogen atom of one-CH3g what uppoi and the carbon atom of one-CH 3group, (f) thiazolidine component is substituted on the carbon atom of-NH2group, or (g) thiazolidine component is substituted on the nitrogen atom-CH2CH2OCH3group; and, where indicated thiazolidine component is unsubstituted.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted pyridinylmethyl-where pyridinoline component is substituted by one or two groups independently selected from the group consisting of alkyl (e.g. methyl) and =O, and the said thienyl component is unsubstituted.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5represents a substituted pyridinylmethyl-where pyridinoline component is substituted by =O component, or the specified pyridazinyl group substituted by alkyl (e.g., stands), or the specified pyridazinyl substituted by =O component and alkyl (e.g., stands), and the specified thienyl component is unsubstituted.

Other embodiments of the present invention are compounds of formula 1.0, as described in the any of the embodiments of the invention No. 1-46, where R5is selected from the group consisting of:

,,,,

,,,

,,,

,,,,

,,,

,,,

and.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5is selected from the group consisting of:

,,,,

,,,

,,,

,,,,,and

.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5is selected from the group consisting of:

,,,

,,,

,,,

,,,.

Other embodiments of the present invention are compounds of formula 1.0 as described in any of the embodiments of the invention No. 1-46, where R5is selected from the group consisting of:

,,,

,,,

,,,

,and.

Other embodiments of the N. the present invention are compounds of the formula 1.1:

where:

R1and R2defined in any of the embodiments of the invention No. 1-44,

Q represents:

; and

R5is selected from the group consisting of:

,,,,

,,,

,,,

,,,,

,,,

,,,

and.

Other embodiments of the present invention are compounds of the formula 1.1:

where:

R2represents-O-(C1-C2)alkyl group, and R1represents:

,

Q represents:

; and

R5is selected from the group consisting of:

, ,,,

,,,

,,,

,,,,

,,,

,,,

and.

Other embodiments of the present invention are compounds of the formula 1.1:

where:

R2represents-S-(C1-C2)alkyl group, and R1represents:

,

Q represents:

; and

R5is selected from the group consisting of:

,,,,

,,,

,,,

, ,,,

,,,

,,,

and.

Other embodiments of the present invention are any of the above embodiments of the invention (for example, any of the embodiments of the invention No. 1-46, or any other embodiment of the invention the following variant of execution of the invention No. 46), where one or more hydrogen atoms are deuterium.

Typical representatives of the compounds according to the present invention include, but without limitation to this:

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and

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Typical representatives of the compounds according to the present invention include, but without limitation to this:

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Typical representatives of the compounds according to the present invention include, but without limitation to this:

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Typical representatives of the compounds according to the present invention, where the hydrogen was replaced by deuterium, include, but without limitation to this:

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Another embodiment of the present invention is a compound A1.

Another embodiment of the present invention is a compound A2.

Another option you have is filling up of the present invention is a compound A3.

Another embodiment of the present invention is a compound A4.

Another embodiment of the present invention is a compound A5.

Another embodiment of the present invention is a compound A6.

Another embodiment of the present invention is a compound A7.

Another embodiment of the present invention is a compound A8.

Another embodiment of the present invention is a compound A9.

Another embodiment of the present invention is an a10 connection.

Another embodiment of the present invention is a compound A11.

Another embodiment of the present invention is a compound A12.

Another embodiment of the present invention is a compound A13.

Another embodiment of the present invention is a compound A14.

Another embodiment of the present invention is a compound A15.

Another embodiment of the present invention is a compound A16.

Another embodiment of the present invention is a compound A18.

Another embodiment of the present invention, the stand is made by a compound A19.

Another embodiment of the present invention is a compound A20.

Another embodiment of the present invention is a compound A21.

Another embodiment of the present invention is a compound A22.

Another embodiment of the present invention is a compound A23.

Another embodiment of the present invention is a compound A24.

Another embodiment of the present invention is a compound A25.

Another embodiment of the present invention is a compound A26.

Another embodiment of the present invention is a compound A27.

Another embodiment of the present invention is a compound A28.

Another embodiment of the present invention is a compound A29.

Another embodiment of the present invention is a compound A30.

Another embodiment of the present invention is a compound A31.

Another embodiment of the present invention is a compound A32.

Another embodiment of the present invention is a compound A33.

Another embodiment of the present invention pre which is a compound A34.

Another embodiment of the present invention is a compound A35.

Another embodiment of the present invention is a compound A36.

Another embodiment of the present invention is a compound A37.

Another embodiment of the present invention is a compound A38.

Another embodiment of the present invention is a compound A39 motorway.

Another embodiment of the present invention is a compound A40.

Another embodiment of the present invention is a compound A41.

Another embodiment of the present invention is a compound a.

Another embodiment of the present invention is a compound A43.

Another embodiment of the present invention is a compound A44.

Another embodiment of the present invention is a compound A45.

Another embodiment of the present invention is a compound A46.

Another embodiment of the present invention is a compound A.

Another embodiment of the present invention is a compound A48 motorway.

Another embodiment of the present invention pre which is a pharmaceutically acceptable salt of compound A1.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A2.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A3.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A4.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A5.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A6.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A7.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A8.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A9.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the a10 connection.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound (A11).

Another embodiment of the present invention is a pharmaceutical is Ki acceptable salt of the compound A12.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A13.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A14.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A15.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A16.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A18.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A19.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A20.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A21.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A22.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A23.

Another embodiment of the present invention represents pharmacy is is automatic acceptable salt of the compound A24.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A25.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A26.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A27.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A28.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A29.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A30.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A31.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A32.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A33.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A34.

Another embodiment of the present invention represents pharmacy is is automatic acceptable salt of the compound A35.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A36.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A37.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A38.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A39 motorway.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A40.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A41.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound a.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A43.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A44.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A45.

Another embodiment of the present invention represents pharmacy is is automatic acceptable salt of the compound A46.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A.

Another embodiment of the present invention is a pharmaceutically acceptable salt of the compound A48 motorway.

Another embodiment of the present invention is a MES connection A1.

Another embodiment of the present invention is a MES connection A2.

Another embodiment of the present invention is a MES connection A3.

Another embodiment of the present invention is a MES connection A4.

Another embodiment of the present invention is a MES connection A5.

Another embodiment of the present invention is a MES connection A6.

Another embodiment of the present invention is a MES connections A7.

Another embodiment of the present invention is a MES A8 connection.

Another embodiment of the present invention is a MES connection A9.

Another embodiment of the present invention is a MES a10 connection.

Another embodiment of the present invention is a MES connection is 11.

Another embodiment of the present invention is a MES connection A12.

Another embodiment of the present invention is a MES connection A13.

Another embodiment of the present invention is a MES connections A14.

Another embodiment of the present invention is a MES connections A15.

Another embodiment of the present invention is a MES connection A16.

Another embodiment of the present invention is a MES connection A18.

Another embodiment of the present invention is a MES connection A19.

Another embodiment of the present invention is a MES connection A20.

Another embodiment of the present invention is a MES connection A21.

Another embodiment of the present invention is a MES connection A22.

Another embodiment of the present invention is a MES connection A23.

Another embodiment of the present invention is a MES connection A24.

Another embodiment of the present invention is a MES connection A25.

Another embodiment of nastojasih the invention is a MES connection A26.

Another embodiment of the present invention is a MES connection A27.

Another embodiment of the present invention is a MES connection A28.

Another embodiment of the present invention is a MES connection A29.

Another embodiment of the present invention is a MES connection A30.

Another embodiment of the present invention is a MES connection A31.

Another embodiment of the present invention is a MES connection A32.

Another embodiment of the present invention is a MES connection A33.

Another embodiment of the present invention is a MES connection A34.

Another embodiment of the present invention is a MES connection A35.

Another embodiment of the present invention is a MES connection A36.

Another embodiment of the present invention is a MES connection A37.

Another embodiment of the present invention is a MES connection A38.

Another embodiment of the present invention is a MES connection A39 motorway.

Another embodiment of nastojasih the invention is a MES connection A40.

Another embodiment of the present invention is a MES connection A41.

Another embodiment of the present invention is a MES connection a.

Another embodiment of the present invention is a MES connection A43.

Another embodiment of the present invention is a MES connection A44.

Another embodiment of the present invention is a MES connection A45.

Another embodiment of the present invention is a MES connection A46.

Another embodiment of the present invention is a MES connection A.

Another embodiment of the present invention is a MES A48 motorway connections.

Other embodiments of the present invention are any embodiment of the invention of formula 1.0, where the connection is clean or the selected form.

Other embodiments of the present invention are any embodiment of the invention of formula 1.0, where the connection is in a pure form.

Other embodiments of the present invention are any embodiment of the invention of formula 1.0, where the compound is selected form.

the other embodiments of the present invention are any of the compounds A1-A16 and A18-A48 motorway in the net and the selected form.

Other embodiments of the present invention are any connection from A1 to A16 and A18-A30 clean and the selected form.

Other embodiments of the present invention are any connection from A1 to A16 and A18-A26 clean and the selected form.

Other embodiments of the present invention are any connection from A31-A48 motorway in the net and the selected form.

Other embodiments of the present invention are any connection from A1 to A16 and A18-A48 motorway in pure form.

Other embodiments of the present invention are any connection from A1 to A16 and A18-A30 in pure form.

Other embodiments of the present invention are any connection from A1 to A16 and A18-A26 in pure form.

Other embodiments of the present invention are any connection from A31-A48 motorway in pure form.

Other embodiments of the present invention are any connection from A1 to A16 and A18-A48 motorway in the selected form.

Other embodiments of the present invention are any connection from A1 to A16 and A18-A30 in the selected form.

Other embodiments of the present invention are any connection from A1 to A16 and A18-A26 in the selected form.

Other embodiments of the infusion is his invention represent any connection from A31-A48 motorway in the selected form.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one connection (for example, 1, 2, or 3, or 1 or 2, or 1, and usually 1) of formula 1.0, preferably of the formula 1.1) and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of the compounds of formula 1.0, preferably of the formula 1.1) and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one connection (for example, 1, 2, or 3, or 1 or 2, or 1, and usually 1)selected from the group consisting of: A1 to A16 and A18-A48 motorway, and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one connection (for example, 1, 2, or 3, or 1 or 2, or 1, and usually 1)selected from the group consisting of: A1 to A16 and A18-A30, and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount, hence, is her least a single connection (e.g., 1, 2, or 3, or 1 or 2, or 1, and usually 1)selected from the group consisting of: A1 to A16 and A18-A26, and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one connection (for example, 1, 2, or 3, or 1 or 2, or 1, and usually 1)selected from the group consisting of: A31-A48 motorway, and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of: A1 to A16 and A18-A48 motorway, and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of: A1 to A16 and A18-A30, and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of: A1 to A16 and A18-A26, and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising effective the number of connections, selected from the group consisting of: A31-A48 motorway, and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one connection (for example, 1, 2, or 3, or 1 or 2, or 1, and usually 1) of formula 1.0, preferably of the formula 1.1), at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) other pharmaceutically active ingredient, and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of the compounds of formula 1.0, preferably of the formula 1.1), the other pharmaceutically active ingredient and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one connection (for example, 1, 2, or 3, or 1 or 2, or 1, and usually 1)selected from the group consisting of: A1 to A16 and A18-A48 motorway, at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) other pharmaceutically active ingredient and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical compositions the Oia, containing an effective amount of at least one connection (for example, 1, 2, or 3, or 1 or 2, or 1, and usually 1)selected from the group consisting of: A1 to A16 and A18-A30, at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) other pharmaceutically active ingredient and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one connection (for example, 1, 2, or 3, or 1 or 2, or 1, and usually 1)selected from the group consisting of: A1 to A16 and A18-A26, at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) other pharmaceutically active ingredient and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one connection (for example, 1, 2, or 3, or 1 or 2, or 1, and usually 1)selected from the group consisting of: A31-A48 motorway, at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) other pharmaceutically active ingredient, and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective the number of connections, selected from the group consisting of: A1 to A16 and A18-A48 motorway, the other pharmaceutically active ingredient and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of: A1 to A16 and A18-A30, the other pharmaceutically active ingredient and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of: A1 to A16 and A18-A26, and the other pharmaceutically active ingredient and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of: A31-A48 motorway, the other pharmaceutically active ingredient and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one connection (for example, 1, 2, or 3, or 1 or 2, or 1, and usually 1) of formula 1.0, preferably of the formula 1.1), at least one (e.g. 1, 2 or 3, or 1 or 2, or 1 and, as PR is usually 1) chemotherapeutic agent and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of the compounds of formula 1.0, preferably of the formula 1.1), a chemotherapeutic agent and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one connection (for example, 1, 2, or 3, or 1 or 2, or 1, and usually 1)selected from the group consisting of: A1 to A16 and A18-A48 motorway, at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one connection (for example, 1, 2, or 3, or 1 or 2, or 1, and usually 1)selected from the group consisting of: A1 to A16 and A18-A30, at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount, at the ore, a single connection (e.g., 1, 2, or 3, or 1 or 2, or 1, and usually 1)selected from the group consisting of: A1 to A16 and A18-A26, at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of at least one connection (for example, 1, 2, or 3, or 1 or 2, or 1, and usually 1)selected from the group consisting of: A31-A48 motorway, at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent, and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of: A1 to A16 and A18-A48 motorway, a chemotherapeutic agent and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of: A1 to A16 and A18-A30, chemotherapeutic agent and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition, with whom containing a series of effective number of connections, selected from the group consisting of: A1 to A16 and A18-A26, chemotherapeutic agent and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a pharmaceutical composition comprising an effective amount of a compound selected from the group consisting of: A31-A48 motorway, a chemotherapeutic agent and a pharmaceutically acceptable carrier.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, preferably of the formula 1.6).

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of one compound of formula 1.0, preferably of the formula 1.6).

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) is unity, selected from the group A1-A16 and A18-A48 motorway.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) compound selected from the group A1-A16 and A18-A30.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) compound selected from the group A1-A16 and A18-A26.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) compound selected from the group A31-A48 motorway.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of one compound, selected what about the group A1-A16 and A18-A48 motorway.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of one compound selected from the group A1-A16 and A18-A30.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of one compound selected from the group A1-A16 and A18-A26.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of one compound selected from the group A31-A48 motorway.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (1, 2, or 3, or 1, or 2, or 1, and usually 1) compound of formula 1.0, and an effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent.

Another option is done is of the present invention is a method of treating cancer in a patient, who needs such treatment, and this method includes the introduction of a specified patient an effective amount of one compound of formula 1.0, and an effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) compound selected from the group A1-A16 and A18-A48 motorway, and the effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) compound selected from the group A1-A16 and A18-A30, and an effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating cancer in a patient, which which need such treatment, moreover, this method includes the introduction of a specified patient an effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) compound selected from the group A1-A16 and A18-A26, and an effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) compound selected from the group A31-A48 motorway, and the effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of one compound selected from the group A1-A16 and A18-A48 motorway, and the effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating cancer in a patient, which required the such treatment, moreover, this method includes the introduction of a specified patient an effective amount of one compound selected from the group A1-A16 and A18-A30, and an effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of one compound selected from the group A1-A16 and A18-A26, and an effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of one compound selected from the group A31-A48 motorway, and the effective amount of at least one (1, 2, or 3, or 1 or 2, or 1, and usually 1) chemotherapeutic agent.

Compounds according to the present invention inhibit the activity of ERK1 and ERK2. Thus, the present invention also discloses a method of inhibiting ERK in mammals, especially humans, by introducing the effective number (n is an example, a therapeutically effective amount) of one or more (e.g. one) compounds according to the present invention. Introduction compounds according to the present invention to a patient in order to inhibit ERK1 and/or ERK2 useful for the treatment of cancer.

In any of the methods of treating cancer described in the present invention, unless otherwise indicated, the methods can optionally include the addition of one or more (e.g. 1, 2 or 3, or 1 or 2, or 1) chemotherapeutic agent. Chemotherapeutic agents can be administered simultaneously or sequentially with the compounds according to the present invention.

Methods of treating cancer described in the present invention include methods that use a combination of drugs (i.e. compounds or pharmaceutically active ingredients or pharmaceutical compositions) (i.e., methods of treating cancer according to the present invention include combinatorial therapy). Specialists in the art it is obvious that drugs in General are entered individually in the form of pharmaceutical compositions. The use of pharmaceutical compositions containing more than one drug, is included in the scope of the present invention.

In any of the methods of treating cancer described in the present invention, unless otherwise specified, means obazatelno may include an effective amount of radiotherapy. If radiotherapy is preferred γ-radiation

Examples of cancers that can be treated using the methods according to the present invention, include, but without limitation to this: (A) lung cancer (e.g. adenocarcinoma of the lung and non-small cell lung cancer), (B) pancreatic cancer (such as carcinoma of the pancreas, such as, for example, carcinoma of the exocrine part of the pancreas), (C) cancer of the colon (e.g. colorectal carcinomas, such as, for example, adenocarcinoma of colon cancer and adenoma of the colon), (D) myeloid leukemia (such as acute myelogenous leukemia (AML), CML and CMML), (E) thyroid cancer, (F) myelodysplastic syndrome (MDS), (G) a carcinoma of the bladder, (H) epidermal carcinoma, (I) melanoma, (J) breast cancer, (K) prostate cancer, (L) head and neck cancer (e.g. squamous cell carcinoma of the head and neck), (M) ovarian cancer, (N) brain cancer (e.g., glioma, such as glioblastoma multiforme), (O) cancer of mesenchymal origin (e.g., fibrosarcoma and rhabdomyosarcoma), (B) sarcoma, (Q) tetracalcium, (R) neuroblastoma, (S) cancer of kidney (T) hepatoma, (U) nahodkinskuju lymphoma, (V) multiple myeloma (W) anaplastic carcinoma of the thyroid gland.

Thus, another embodiment of the present izobreteny which is a method of treating lung cancer, cancer of the pancreas, cancer of the colon (e.g. colorectal cancer), myeloid leukemias (for example, AML, CML and CMML), thyroid cancer, myelodysplastic syndrome (MDS), carcinoma of the bladder, squamous cell carcinomas, melanoma, breast cancer, prostate cancer, head and neck cancer (e.g. squamous cell head and neck cancer), ovarian cancer, brain cancer (e.g., gliomas, such as glioblastoma multiforme), cancers of mesenchymal origin (e.g., fibrosarcoma and rhabdomyosarcoma, sarcoma, tetracalcium, neuroblastoma, carcinoma of the kidney, Hepatol, non-Hodgkin's lymphoma, multiple myeloma, or anaplastic carcinoma of the thyroid gland, the patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating lung cancer, pancreatic cancer, cancer of the colon (e.g. colorectal cancer), myeloid leukemias (for example, AML, CML and CMML), thyroid cancer, myelodysplastic syndrome (MDS), carcinoma of the bladder, squamous cell carcinomas, melanoma, breast cancer, prostate cancer as the drive, head and neck cancer (e.g. squamous cell head and neck cancer), ovarian cancer, brain cancer (e.g., gliomas, such as glioblastoma multiforme), cancers of mesenchymal origin (e.g., fibrosarcoma and rhabdomyosarcoma, sarcoma, tetracalcium, neuroblastoma, carcinomas of the kidney, Hepatol, non-Hodgkin's lymphoma, multiple myeloma, or anaplastic carcinoma of the thyroid gland, the patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2 and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating lung cancer, pancreatic cancer, cancer of the colon (e.g. colorectal cancer), myeloid leukemias (for example, AML, CML and CMML), thyroid cancer, myelodysplastic syndrome (MDS), carcinoma of the bladder, squamous cell carcinomas, melanoma, breast cancer, prostate cancer, head and neck cancer (e.g. squamous cell head and neck cancer), ovarian cancer, brain cancer (e.g., gliomas, such as glioblastoma multiforme), IU cancer is ehemalige origin (for example, fibrosarcoma and rhabdomyosarcoma, sarcoma, tetracalcium, neuroblastoma, carcinomas of the kidney, Hepatol, non-Hodgkin's lymphoma, multiple myeloma, or anaplastic carcinoma of the thyroid gland, the patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating lung cancer, pancreatic cancer, cancer of the colon (e.g. colorectal cancer), myeloid leukemias (for example, AML, CML and CMML), thyroid cancer, myelodysplastic syndrome (MDS), carcinoma of the bladder, squamous cell carcinomas, melanoma, breast cancer, prostate cancer, head and neck cancer (e.g. squamous cell head and neck cancer), ovarian cancer, brain cancer (e.g., gliomas, such as glioblastoma multiforme), cancers of mesenchymal origin (for example, fibrosarcoma and rhabdomyosarcoma, sarcoma, tetracalcium, neuroblastoma, carcinomas of the kidney, Hepatol, non-Hodgkin's lymphoma, multiple myeloma, or anaplastic carcinoma of the thyroid gland, the patient who think the mo such treatment, moreover, this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, when the cancer is selected from the group consisting of: melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer and ovarian cancer.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutical the agent, when the cancer is selected from the group consisting of: melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer and ovarian cancer.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, when the cancer is selected from the group consisting of: melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer and ovarian cancer.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent when the cancer is selected from the GRU is dust, consisting of: melanoma, pancreatic cancer, thyroid cancer, colorectal cancer, lung cancer, breast cancer and ovarian cancer.

Another embodiment of the present invention is a method of treating melanoma in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating melanoma in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating melanoma in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating melanoma in a patient, who needs such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating pancreatic cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating pancreatic cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating cancer Pagiel the colonic cancer in a patient, who needs such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating pancreatic cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating thyroid cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating thyroid cancer in a patient who is in need of such treatment, being the m this method includes the introduction of a specified patient an effective amount, at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating thyroid cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating thyroid cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating colorectal cancer in a patient requiring such treatment, and asany the method includes the introduction of a specified patient an effective amount, at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating colorectal cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating colorectal cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating colorectal cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2 is, usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating lung cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating lung cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating lung cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) soy is inane formula 1.0.

Another embodiment of the present invention is a method of treating lung cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating breast cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating breast cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating breast cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating breast cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating ovarian cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention pre which is a method of treating ovarian cancer in a patient, who needs such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating ovarian cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating ovarian cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least; one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Other embodiments of the present invention before the represent ways of treating breast cancer (i.e., postmenopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient requiring such treatment, and said treatment consists of the administration of an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with hormonal therapies (i.e antihormonal agents).

Other embodiments of the present invention are methods of treating breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient requiring such treatment, and said treatment consists of the administration of an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with hormonal therapies (i.e antihormonal agents).

Other embodiments of the present invention are methods of treating breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient requiring such treatment, and asanee treatment consists of the administration of an effective amount, at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with hormonal therapies (i.e., antihormonal agents) and in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Other embodiments of the present invention are methods of treating breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient requiring such treatment, and said treatment consists of the administration of an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with hormonal therapies (i.e., antihormonal agents) and in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Methods of treating breast cancer described in this application include the treatment of hormone-dependent metastatic and running breast cancer, adjuvant therapy for hormone-dependent primary and early breast cancer, in situ treatment ducktales carcino the s and in situ treatment of inflammatory breast cancer.

Treatment of hormone-dependent breast cancer can also be used to prevent breast cancer in patients with a high risk of developing breast cancer.

Thus, other embodiments of the present invention are methods of preventing breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient requiring such treatment, and said treatment consists of the administration of an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0 in combination with hormonal therapies (i.e., antihormonal agents).

Other embodiments of the present invention are methods of preventing breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient requiring such treatment, and said treatment consists of the administration of an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with hormonal therapy is mi (i.e., antihormonal agents).

Other embodiments of the present invention are methods of preventing breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient requiring such treatment, and said treatment consists of the administration of an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with hormonal therapies (i.e., antihormonal agents) and in combination with an effective amount of at least one (for example, 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Other embodiments of the present invention are methods of preventing breast cancer (i.e., post-menopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient requiring such treatment, and said treatment consists of the administration of an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with hormonal therapies (i.e., antihormonal agents), and in whom is inali with an effective amount at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating brain cancer (e.g., glioma, such as glioblastoma multiforme) the patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating brain cancer (e.g., glioma, such as glioblastoma multiforme) the patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating brain cancer (e.g., glioma, such as glioblastoma multiforme) the patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of the pharmaceutical is tion of the composition, containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating brain cancer (e.g., glioma, such as glioblastoma multiforme) the patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating brain cancer (e.g., glioma, such as glioblastoma multiforme) the patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of a chemotherapeutic agent, where the specified chemotherapeutic agent is temozolomide.

Another embodiment of the present invention the submitted is a method of treating brain cancer (e.g., glioma, such as glioblastoma multiforme) the patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of a chemotherapeutic agent, where the specified chemotherapeutic agent, is temozolomide.

Another embodiment of the present invention is a method of treating prostate cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating prostate cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another option is carried out the present invention is a method of treating prostate cancer in a patient, who needs such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating prostate cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating myelodysplastic syndrome in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating myelodysplastic syndrome in a patient, which neobhodimosti treatment, moreover, this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating myelodysplastic syndrome in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating myelodysplastic syndrome in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention before the hat is a method of treating myeloid leukemias in a patient, who needs such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method for the treatment of myeloid leukemia in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method for the treatment of myeloid leukemia in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method for the treatment of myeloid leukemia in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective number is the amount of the pharmaceutical composition, containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a treatment of acute myelogenous leukemia (AML) in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating acute myelogenous leukemia (AML) in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating acute myelogenous leukemia (AML) in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount is STV pharmaceutical composition, containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating acute myelogenous leukemia (AML) in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method for the treatment of chronic myelomonocytic leukemia (CMML) in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method for the treatment of chronic myelomonocytic leukemia (CMML) in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of at least the underwater (for example, 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method for the treatment of chronic myelomonocytic leukemia (CMML) in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method for the treatment of chronic myelomonocytic leukemia (CMML) in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating chronic myelogenous leukemia (chronic myeloid lake is AI, CML) in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating chronic myelogenous leukemia (chronic myeloid leukemia, CML) in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating chronic myelogenous leukemia (chronic myeloid leukemia, CML) in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method for the treatment of chronic myelogenous leukemi the (chronic myeloid leukemia, CML) in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method for the treatment of myeloid leukemia in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method for the treatment of myeloid leukemia in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating myeloid the th leukemia patient, who needs such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method for the treatment of myeloid leukemia in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating bladder cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating bladder cancer in a patient who is in need of such treatment, and pointed to by the second method involves the introduction of a specified patient an effective amount, at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating bladder cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating bladder cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating non-Hodgkin's lymphoma in a patient who is in need of such treatment, and the decree of the config method includes the introduction of a specified patient an effective amount, at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating non-Hodgkin's lymphoma in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating non-Hodgkin's lymphoma in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating non-Hodgkin's lymphoma in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 and and 2 and, usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3.1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating multiple myeloma in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating multiple myeloma in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Another embodiment of the present invention is a method of treating multiple myeloma in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (for example, 1, or 3, 1 or 2, and usually 1) compound of formula 1.0.

Another embodiment of the present invention is a method of treating multiple myeloma in a patient who is in need of such treatment, and this method includes the introduction of a specified patient an effective amount of a pharmaceutical composition containing an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, and usually 1) compound of formula 1.0, in combination with an effective amount of at least one (e.g. 1, 2 or 3, 1 or 2, or 1) chemotherapeutic agent.

Chemotherapeutic agents (antineoplastic agents) include, but without limitation to this: agents acting on the microtubules, alkylating agents, antimetabolites, natural products and their derivatives, hormones and steroids (including synthetic analogs), and synthetic products.

Examples of alkylating agents including nitrogen mustards, derived ethylenimine, alkyl sulphonates, nitrosoanatabine and triazine) are: Urallestorg, Chlormethine, Cyclophosphamide (Cytoxan®), Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenephosphoramide, Busulfan, Carmustin, Lomustin, Streptozocin, Dacarbazine and Temozolomide.

Examples of antimetabolites (including antagonists of folic acid analogues is of pirimidine, purine analogues and inhibitors adenozindezaminazy) are: Methotrexate, 5-Fluorouracil, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Tioguanin, Fludarabine, Pentostatin and Gemcitabine.

Examples of natural products and their derivatives (including Vinca alkaloids, antitumor antibiotics, enzymes, lymphokines and epipodophyllotoxins) are: Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubitsin, Paclitaxel (Paclitaxel is an agent acting on microtubules, and is commercially available under the trademark Taxol®), derivatives of Paclitaxel (e.g., Taxotere), Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Interferons (especially IFN-a), Etoposide, and Teniposide.

Examples of hormones and steroids (including synthetic analogs) are: 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrol acetate, Tamoxifen, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Hlortrianizen, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesterone acetate, Leuprolide, Flutamide, Toremifene and Zoladex.

Examples of synthetic substances (including inorganic complexes, such as coordination complexes cards the us) are: Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole and Hexamethylmelamine.

Examples of other chemotherapeutic agents are: Navelbine, CPT-11, Anastrazole, Letrazole, Capecitabine, Relaxation and Droloxifene.

Agents acting on microtubules (e.g., Paclitaxel, derivatives of Paclitaxel or a Paclitaxel - like compound), as used in this document represent a compound that interferes with the process of cell mitosis, that is, has antimitoticescoe effect by influencing the formation and/or operation of the microtubules. Such agents can be, for example, agents that stabilize microtubules or agents that disrupt the formation of microtubules.

Agents acting on microtubules, are useful in methods according to the present invention, well known to experts in the art and include, but without limitation to this: Alocalized (NSC 406042), Halichondrin In (NSC 609395), Colchicine (NSC 757), Colchicine derivatives (e.g., NSC 33410), Dolastatin 10 (NSC 376128), Maytansine (NSC 153858), Rhizoxin (NSC 332598), Paclitaxel (Taxol®, NSC 125973), derivatives of Paclitaxel (e.g., Taxotere, NSC 608832), Thiocolchicine (NSC 361792), Criticismin (NSC 83265), Vinblastine sulfate (NSC 49842), Vincristine sulfate (NSC 67574), Epothilone And Epothilone, Discodermolide (see the e Service, (1996) Science, 274:2009), Estramustin, Nocodazole, MAR and the like. Examples of such agents are disclosed, for example, in Bulinski (1997) J. Cell Sci. 110:3055-3064, Panda (1997) Proc. Natl. Acad. Sci. USA 94:10560-10564, Muhlradt (1997) Cancer Res. 57:3344-3346, Nicolaou (1997) Nature 387:268-272, Vasquez (1997) Mol. Biol. Cell. 8:973-985 and Panda (1996) J. Biol. Chem. 271:29807-29812.

Chemotherapeutic agents Paclitaxel - like activity include, but not limited to, Paclitaxel and derivatives of Paclitaxel (Paclitaxel - like compounds and their analogues. Paclitaxel and its derivatives (e.g., Taxol and Taxotere) is available for purchase commercially. In addition, methods of production of Paclitaxel and derivatives and analogs of Paclitaxel are known to experts in the art (see, for example, U.S. patents: 5,569,729; 5,565,478; 5,530,020; 5,527,924; 5,508,447; 5,489,589; 5,488,116; 5,484,809; 5,478,854; 5,478,736; 5,475,120; 5,468,769; 5,461,169; 5,440,057; 5,422,364; 5,411,984; 5,405,972; and 5,296,506).

More specifically, the term "Paclitaxel", as used herein, refers to a medicinal product is available commercially under the name Taxol®(NSC number: 125973). Taxol®inhibits replication of eukaryotic cells, increasing polymerization tubulinea components in stable bundles of microtubules, which can't be converted into the corresponding structures necessary for mitosis. Among the many available chemotherap whitesky drug Paclitaxel has generated a lot of interest due to its effectiveness, found in clinical trials in respect of tumors insensitive to medicines, including ovarian cancer and breast cancer (Hawkins (1992) Oncology, 6: 17-23, Horwitz (1992) Trends Pharmacol. Sci. 13: 134-146, Rowinsky (1990) J. Natl. Canc. Inst. 82: 1247-1259).

Additional agents that affect microtubules, can be examined by one or more assays known in the technical field, for example, semi-automatic analysis, which measure the tubulin-polymerized activity of analogues of Paclitaxel, in combination with cellular analysis used to measure the potential of these compounds in blocking mitosis cells (see Lopes (1997) Cancer Chemother. Pharmacol. 41:37-47).

As a rule, the activity of the test compounds is determined by contact of the cells with this compound, with subsequent determination is interrupted if the cell cycle or not, in particular, through inhibition of mitotic events. Such inhibition may be an interrupt mitotic apparatus, for example, interruption of the normal education of the spindle. The cells, which is interrupted mitosis may differ altered morphology (for example, compression of microtubules, the increased number of chromosomes and so on).

Compounds that may be able to polymerization of tubulin, was skanirovali in vitro. For example, compounds were skanirovali against the cult of wirowanych cells WR21 (derived from cell lines of mice 69-2 wap-ras), the inhibition of proliferation and/or changes in cellular morphology, compression of microtubules. You can then spend in vivo study of the compounds showed positive results, with the help of Nude mice bearing tumor cells WR21. Detailed protocols for these screening methods disclosed in Porter (1995) Lab. Anim. Sci., 45(2):145-150.

Other methods of screening compounds for desirable activity known to specialists in this field of technology. Typically, such assays include assays that allow to test the inhibition of Assembly and/or disassembly of microtubules. Analyses on microtubule Assembly are disclosed, for example, in Gaskin et al. (1974) J. Molec. Biol., 89: 737-758. U.S. patent No. 5,569,720 also discloses in vitro and in vivo assays for compounds with Paclitaxel - like activity.

Thus, in the methods according to the present invention, where used, at least one chemotherapeutic agent, examples of these chemotherapeutic agents include agents selected from the group consisting of: acting on the microtubule agents, alkylating agents, antimetabolites, natural products and their derivatives, hormones and steroids (including synthetic analogs), and synthetic products.

In the methods according to the present invention, which is applied, at least one chemotherapeutic and the UNT, examples of these chemotherapeutic agents also include: (1) taxanes, (2) coordination compounds of platinum, (3) inhibitors of the epidermal growth factor (EGF), which are antibodies, (4) "small molecules" - inhibitors of EGF (5) inhibitors of vascular endothelial growth factors (VEGF), which are antibodies, (6) "small molecules" - kinase inhibitors of VEGF, (7) antagonists of the estrogen receptor or selective modulators of estrogen receptor (SERMs), (8) antitumor nucleoside derivative, (9) epothilone, (10) topoisomerase inhibitors, (11) Vinca alkaloids, (12) antibodies that are inhibitors of αVβ3 integrins, (13) folate antagonists, (14) inhibitors ribonucleotidic reductase, (15) anthracyclines, (16) biologics; (17) inhibitors of angiogenesis and/or suppressors of tumor necrosis factor alpha (TNF-alpha)such as thalidomide (or related imide), (18) inhibitors of Bcr/abl kinase, (19) "small molecules" - inhibitors of MEK1 and/or MEK2, (20) "small molecules" - inhibitors of IGF-1 and IGF-2, (21) "small molecules" - RAF inhibitors and skin disease kinases (22) "small molecules" - inhibitors of kinase-dependent cell cycle, such as CDK1, CDK2, CDK4 and CDK6, (23) alkylating agents, and (24) inhibitors farnesyltransferase (also known as FPT inhibitors or FTI (i.e., inhibitors farnesyltransferase)).

In the methods according to the present invention, applying at least one chemotherapeutic agent, examples of such chemotherapeutic agents include:

(1) taxanes, such as Paclitaxel (Taxol®and/or Docetaxel (Taxotere®);

(2) coordination compounds of platinum, such as, for example, Carboplatin, Cisplatin and Oxaliplatin (for example, Eloxatin);

(3) EGF inhibitors that are antibodies, such as antibodies to the HER2 gene (such as, for example, Trastuzumab (Herceptin), Genentech, Inc.), Cetuximab (Erbitux, IMC-C225, ImClone Systems), EMD 72000 (Merck KGaA), anti-EFGR monoclonal antibodies AVG (Abgenix), TheraCIM h-R3 (Center of Molecular Immunology), monoclonal antibody 425 (Merck KGaA), monoclonal antibodies ICR-62 (ICR, Sutton, England); Hersam (Elan Pharmaceutical Technologies and Ribozyme Pharmaceuticals), PKI 166 (Novartis), EKB 569 (Wyeth-Ayerst), GW-572016 (GlaxoSmithKline), Cl-1033 (Pfizer Global Research and Development), conjugate Trastuzumab and maytansinoid (Genentech, Inc.), Matumona (Imclone Systems and Merck KGaA) and Melvax II (Imclone Systems and Merck KgaA);

(4) "small molecules" - EGF inhibitors, such as, Tarceva (TM) (OSI-774, OSI Pharmaceuticals, Inc.) and Iressa (ZD 1839, Astra Zeneca);

(5) VEGF inhibitors that are antibodies, such as Bevacizumab (Genentech, Inc.) and IMC-S (ImClone Systems), DC 101 (KDR VEGF Receptor 2 firm ImClone Systems);

(6) "small molecules" - kinase inhibitors of VEGF, such as: SU 5416 (Sugen, Inc.), SU 6688 (Sugen, Inc.), Bay 43-9006 (VEGF and skin disease inhibitor firm Voeg Pharmaceuticals and Onyx Pharmaceuticals);

(7) the ant who honesty estrogen receptor or selective modulators of estrogen receptor (SERMs), such as Tamoxifen, Idoxifene, RA-moxifen, TRANS-2,3-Digitalocean, Levormeloxifene, Koleksi-dryer, MDL 103,323 and Acolbifene (Schering Corp.);

(8) antitumor nucleoside derivatives such as 5-Fluorouracil, Gemcitabine, Capecitabine, Cytarabine (Ara-C), fludarabine (F-Ara-A), Decitabine and Chlorodeoxyadenosine (Cda, 2-Cda);

(9) epothilones, such as BMS-247550 (Brisl-Myers Squibb) and EPO906 (Novartis Pharmaceuticals);

(10) topoisomerase inhibitors such as Topotecan (Glaxo SmithKline) and Camptosar (Pharmacia);

(11) Vinca alkaloids, such as, Navelbine (Anvar and Fabre, France), Vincristine and Vinblastine;

(12) antibodies that are inhibitors of αVβ3 integrins, such as, LM-609 (see Clinical Cancer Research, Vol.6, page 3056-3061, August 2000, which is incorporated herein in full by reference);

(13) folate antagonists such as Methotrexate (MTX) and Pemetrexed (Kolya);

(14) inhibitors ribonucleotidic inhibitors, such as Hydroxyurea (HU);

(15) anthracyclines, such as Daunorubicin, Doxorubicin (Adriamycin) and Idarubitsin;

(16) biologics, such as interferon (e.g., intron a and Roferon), pegylated interferon (e.g., intron and pegasis) and Rituximab (Rituxan, the antibody used for the treatment of non-Hodgkin lymphoma);

(17) Thalidomide (or related imide);

(18) inhibitors of Bcr/abl kinase, such as, for example, Gleevec (STI-571), AMN-17, ONO 12380, SU 11248(Sunitinib) and BMS-354825

(19) MEK1 and/or MEK2 inhibitors, such as PD0325901 and Arry-142886 (AZD6244);

(20) "small molecules" - inhibitors of IGF-1 and IGF-2, such as, for example, NVP-AEW541;

(21) "small molecules" - RAF inhibitors and skin disease kinases, such as, for example, BAY 43-9006 (Sorafenib);

(22) "small molecules" - inhibitors of kinase-dependent cell cycle, such as CDK1, CDK2, CDK4 and CDK6, such as, for example, CYC202, BMS387032 and Flavopiridol;

(23) alkylating agents, such as, for example, Temozolomide trademarks of Temodar;

(24) inhibitors farnesyltransferase, such as, for example:

(a) Lonafarnib brand Sarasar® (i.e., 4-[2-[4-(3,10-dibromo-S-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1-piperidinyl)-2-oxoethyl]-1-piperazinecarboxamide, see, for example, U.S. patent US 5,874,442, published February 23, 1999, and U.S. patent US 6,632,455 published on October 14, 2003, which are incorporated herein by reference in full),

(b) Tipifarnib brand Zarnestra® (i.e., (R)-6-amino[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-chinoline, see for example, international application WO 97/16443, published may 9, 1997, and U.S. patent US 5,968,952, issued October 19, 1999, which are incorporated herein in full by reference), and

(c) Bristol-Myers Squibb 214662:

(see international patent application WO97/3092, published on August 28, 1997, U.S. patent US 6,011,029, issued January 4, 2000, and U.S. 6,455,523, which are incorporated herein by reference).

Inhibitors of kinase Bcr/abl inhibitors of EGF receptor and antibodies to the gene HER-2 (inhibitor of EGF receptor, which are antibodies, which appear above, also known as inhibitors of signal transduction. Therefore, chemotherapeutic agents, as used in this application, include inhibitors of signal transduction.

Typical inhibitors of signal transduction, which are chemotherapeutic agents include, but without limitation to this: (i) inhibitors of Bcr/abl kinase, such as, for example, STI 571 (Gleevec), (ii) an Inhibitor of receptor epidermiology growth factor (EGF), such as, for example, inhibitors of kinases (Iressa, OSI-774) and antibodies (ImClone: S [Goldstein et al. (1995), Clin Cancer Res. 1:1311-1318] and Abgenix: ABX-EGF), and (iii) inhibitors of receptor HER-2/neu, such as, for example, Herceptin® (Trastuzumab).

How safe and effective introduction of most of these chemotherapeutic agents known to specialists in this field of technology. In addition, these techniques are disclosed in the literature. For example, how the introduction of many chemotherapeutic agents are disclosed in the Handbook "Physicians' Desk Reference" (PDR), for example, 1996 edition (Medical Economics Company, Montvale, NJ 07645-1742, USA), th Physician''s Desk Reference, 56thEdition, 2002 (published by Medical Economics company, Inc. Montvale, NJ 07645-1742), and the Physician''s Desk Reference, 57thEdition, 2003 (published by Thompson PDR, Montvale, NJ 07645-1742); the disclosure of which is incorporated herein in full by reference.

For example, the compound of formula 1.0 (for example, the pharmaceutical composition comprising the compound of formula 1.0); may be given by mouth (for example, in the form of capsules), chemotherapeutic agents can be administered intravenously, usually in the form of intravenous solution. The use of pharmaceutical compositions containing more than one drug, is included in the scope of the present invention.

The compound of formula 1.0 and chemotherapeutic agents are introduced in therapeutically effective doses to obtain clinically acceptable results, such as, for example, reduction or disappearance of symptoms or tumor. Thus, the compound of formula 1.0 and chemotherapeutic agents can be administered simultaneously or sequentially according to the treatment Protocol. The introduction of chemotherapeutic agents can be made according to the treatment protocols, already known in this technical field.

In General, when more than one chemotherapeutic agent used in the methods according to the present invention, chemotherapeutic agents can be administered in the same day is because at the same time, or sequentially, in their standard dosage form. For example, chemotherapeutic agents are usually administered intravenously, preferably by intravenous drip infusion, using intravenous solutions, well-known in the art (e.g., isotonic saline solution (0.9% NaCl) or dextrose (for example, 5% dextrose)).

If there are two or more chemotherapeutic agent, chemotherapeutic agents, as a rule, are entered in the same day; however, specialists in the art it will be obvious that chemotherapeutic agents can be administered on different days and in different weeks. Qualified clinical doctor can enter chemotherapeutic agents according to the regimen recommended by the manufacturer of the agent, and may regulate the scheme depending on the needs of the patient, for example, taking into account the patient's response to treatment. For example, when Gemcitabine is used in combination with the coordination compound of platinum, such as, for example, Cisplatin, for the treatment of lung cancer, as Gemcitabine and Cisplatin are entered in the same day, namely on the first day of the treatment cycle, and then Gemcitabine is entered by itself in day 8 and re-introduced itself in day 15.

Compounds according to the present invention and x is Biotherapeutics agents can be introduced at the treatment Protocol, the duration of which ranges from one to seven weeks, and which, as a rule, repeated 6-12 times. Typically, the treatment Protocol is designed for a period of time from one to four weeks. Can be used treatment protocols designed for the period of time from one to three weeks. You can apply the treatment, lasting from one to two weeks. During such a treatment Protocol or cycle, the compounds according to the present invention can be administered daily, while the chemotherapeutic agent may be administered one or more times per week. Typically, the connection according to the present invention may be injected on a daily basis (i.e. once a day), and in one embodiment, a compound according to the present invention can be administered twice a day, and chemotherapeutic agent is injected once a week or once every three weeks. For example, taxanes (such as Paclitaxel (e.g., Taxol®) or Docetaxel (e.g., Taxotere®)) can be administered once a week or once every three weeks.

However, experts in the field of technology it is obvious that the treatment protocols may vary depending on the needs of the patient. Thus, the combination of compounds (drugs)used in the methods according to the present izobreteny is, may be entered in accordance with variants of the protocols disclosed above. For example, during the treatment cycle, the compounds according to the present invention can be more intermittent than continuous. Thus, for example, during the treatment cycle, the compounds according to the present invention can be administered daily during the week and then not be entered during the week, with the repetition of this introduction during the treatment cycle. Alternatively, compounds according to the present invention can be administered daily for two weeks and then not be entered during the week, with the repetition of this introduction during the treatment cycle. Thus, the compounds according to the invention can be administered daily for one or more weeks and then not be entered for one or more weeks during the treatment cycle, with the repetition of this model introduction during the treatment cycle. Such intermittent treatment may rather be based on the number of days, than a full week. For example, a daily maintenance dose within 1-6 days, and then 1-6 days without a dose, with repetition of this model introduction during the treatment Protocol. The number of days (or weeks), during which the compounds according to the present invention is not entered, must not equal the number of days (or weeks)when the compounds according to the present invention by introducing the Xia. Usually, if you use intermittent dosing Protocol, the number of days or weeks, during which the compounds according to the present invention are at least equal to or greater than the number of days or weeks, when the compounds according to the present invention is not entered.

The chemotherapeutic agent can be administered by bolus or continuous infusion. The chemotherapeutic agent can be administered from once a day to once every week or once every two weeks, or once every three weeks, or once every four weeks per cycle of treatment. In the case of daily introduction during the cycle of treatment, the daily dose may be interrupted for several weeks of the treatment cycle. For example, the introduction of dose within weeks (or days), and then a week (or several days) without a dose, with repetition of this model introduction during the treatment cycle.

Compounds according to the present invention can be administered by mouth, preferably in the form of solid dosage forms, and in one embodiment in the form of capsules, and at the same time, the total therapeutically effective daily dose may be injected through one to four or one to two hotel doses per day, as a rule, a therapeutically effective dose be administered one or two times is a day, in one embodiment, a therapeutically effective dose be administered twice a day. Compounds according to the present invention can be administered in an amount of from about 50 to about 400 mg once daily, and can be administered in an amount of from about 50 to about 300 mg once a day. Compounds according to the present invention is generally introduced in an amount of from about 50 to about 350 mg twice a day, usually from about 50 mg to about 200 mg twice a day, and in one embodiment from about 75 mg to about 125 mg, with the introduction of two times a day, and in another embodiment, about 100 mg, with the introduction of two times a day.

If the patient's response to treatment or stabilization of his condition therapeutic cycle, this therapeutic cycle can be repeated according to the assessment of the attending physician. At the completion of therapeutic cycles, the patient may continue to accept connections according to the present invention in the same doses that were administered to the treatment Protocol, or if the dose was less than 200 mg twice daily, the dose may be increased to 200 mg twice a day. This maintenance dose may be as long until the progress of the patient or the patient can no longer tolerate this dose (in this case, the dose can be reduced, and the patient will continue to make the reduced dose).

Chemotherapeutic agents used with the compounds according to the present invention, are in their normally prescribed doses during the treatment cycle (i.e., Chemotherapeutic agents are introduced in accordance with standard practice, the introduction of these drugs). For example: (a) from about 30 to about 300 mg/m2for taxan; (b) from about 30 to about 100 mg/m2for Cisplatin; (C) AUC from about 2 to about 8 for Carboplatin; (d) from about 2 to about 4 mg/m2for EGF inhibitors that are antibodies; (e) from about 50 to about 500 mg/m2for "small molecules" - EGF inhibitors; (f) from about 1 to about 10 mg/m2for kinase inhibitors of VEGF, which are antibodies; (g) from about 50 to about 2400 mg/m2for "small molecules" - VEGF inhibitors; (h) from about 1 to about 20 mg for SERMs; (i) from about 500 to about 1250 mg/m2antitumor nucleosides 5-Fluorouracil, Gemcitabine and involving capecitabine; (j) to anticancer nucleoside Tsitarabina (Ara-C): 100-200 mg/m2/day for 7-10 days, every 3-4 weeks, and high doses in refractory leukemia and lymphoma, i.e., 1-3 mg/m2within one hour, every 12 hours for 4 to 8 doses every 3-4 weeks; (k) anti-tumor nucleoside Fludarabine (F-ara-A): 10-25 mg/m2/day every 3-4 weeks; (l) anti-tumor nucleoside On zitouna: 30-75 mg/m 2for three days every 6 weeks, with a maximum of 8 cycles; (m) anti-tumor nucleoside Chlorodeoxyadenosine (CdA, 2-CdA): 0.05-0.1 mg/kg/day as a continuous infusion for up to 7 days, every 3-4 weeks; (n) from about 1 to about 100 mg/m2for epothilones; (a) from about 1 to about 350 mg/m2for topoisomerase inhibitors; (b) from about 1 to about 50 mg/m2for Vinca alkaloids; (q) for the folate antagonist Methotrexate (MTX) 20-60 mg/m2by mouth, intravenously or intramuscularly, every 3-4 weeks, the injection mode, the intermediate dose is 80-250 mg/m2intravenously over 60 minutes every 3-4 weeks, the high dose is 250-1000 mg/m2intravenous introduction with Leucovorin every 3-4 weeks; (r) for folate antagonist of Pemetrexed (Kolya): 300-600 mg/m2(10 minutes intravenous infusion on day 1) every 3 weeks; (s) for inhibitor ribonucleotidic reductase of Hydroxyacetone (HU): 20-50 mg/kg/day (as it is necessary to reduce the number of blood cells); (t) steering the platinum compound Oxaliplatin (Eloxatin) is introduced in the amount of 50-100 mg/m2every 3-4 weeks (preferably used for solid tumors, such as non-small cell lung cancer, colorectal cancer and ovarian cancer); (u) for anthracycline of Daunorubicin: 10-50 mg/m2/day intravenously for 3-5 days, each the e 3-4 weeks; (v) to anthracycline Doxorubicin (Adriamycin): 50-100 mg/m2, intravenous continuous infusion for 14 days, every 3-4 weeks, or 10-40 mg/m2intravenously, weekly; (w) to anthracycline Idarubitsin: 10-30 mg/m2daily, within 1-3 days by slow intravenous infusion over 10-20 minutes every 3-4 weeks; (x) for biological interferon (intron-a, Roferon): 5-20 million immunizing units, three times a week; (u) for biological pegylated interferon (PegIntron, pegasis): 3-4 mg/kg/day, constantly, subcutaneously (to relapse or loss of activity); (z) for biological Rituximab (Rituxan) (the antibody used for non-Hodgkin's lymphoma): 200-400 mg/m2intravenously weekly for 4-8 weeks, for 6 months; (AA) to the alkylating agent temosolomida: 75 mg/m2250 mg/m2for example, 150 mg/m2or, for example, 200 mg/m2as for example 200 mg/m2within 5 days; and (bb) for an inhibitor of MEK1 and/or MEK2 PD0325901: 15 mg, 30 mg, 15 mg daily for 21 days every 4 weeks.

Gleevec can be used by mouth in amounts of from about 200 to about 800 mg/day.

Thalidomide (and related imides) can be used by mouth in amounts from about 200 to about 800 mg/day, and may be injected continuously or applied to relapse or toxicness is. See, for example, Mitsiades et al., "Apoptotic signaling induced by immunomodulatory thalidomide analoqs in human multiple myeloma cells; therapeutic implications", Blood, 99(12):4525-30, June 15, 2002, the disclosure of which is incorporated herein by reference.

The FPT inhibitor Sarasar® (Lonafarnib) may be given by mouth (for example, in the form of capsules), in quantities of from about 50 to about 200 mg, twice a day, or in amounts from about 75 to about 125 mg, twice a day, or in amounts from about 100 to about 200 mg, twice a day, or in an amount of about 100 mg twice a day

Paclitaxel (e.g., Taxol®for example, you can enter once a week, in the amount of from about 50 to about 100 mg/m2and in another example from about 60 to about 80 mg/m2. In another example, Paclitaxel (e.g., Taxol®you can enter once every three weeks, in amounts of from about 150 to about 250 mg/m2and in another example from about 175 to about 225 mg/m2.

In another example, Docetaxel (e.g., Taxotere®) may be injected once a week, in the amount of from about 10 to about 45 mg/m2. In another example, Docetaxel (e.g., Taxotere®) may be given once every three weeks in an amount of from about 50 to about 100 mg/m2.

In another example, Cisplatin can be administered once per week in an amount of from about 20 to about 40 mg/m2. In another example, C is splitin may be given once every three weeks, in the amount of from about 60 to about 100 mg/m2.

In another example, Carboplatin can be administered once a week, in the amount necessary to ensure AUC from about 2 to about 3. In another example, Carboplatin can be administered once every three weeks, in an amount necessary to ensure AUC from about 5 to about 8.

Other embodiments of the present invention are any of the methods of treatment of cancer, where the compounds of formula 1.0 and chemotherapeutic agents are introduced in the form of a pharmaceutical composition containing an effective amount of the compounds of formula 1.0, the effective amount of chemotherapeutic agents, and a pharmaceutically acceptable carrier.

Other embodiments of the present invention provide a method for treatment of cancer, where the chemotherapeutic agent is selected from the group consisting of: Paclitaxel, Docetaxel, Carboplatin, Cisplatin, Gemcitabine, Tamoxifen, Herceptin, Cetuximab, Tarceva, Iressa, Bevacizumab, navelbine under maintenance Protocol, IMC-S, SU5416 and SU6688.

Other embodiments of the present invention provide a method for treating cancer using chemotherapeutic agent, and a chemotherapeutic agent selected from the group consisting of: Paclitaxel, Docetaxel, Carboplatin, Cisplatin, navelbine under maintenance Protocol, Gemcitabine and Herceptin.

p> Other embodiments of the present invention provide a method for treating cancer using chemotherapeutic agent, and a chemotherapeutic agent selected from the group consisting of: Cyclo-phosphamide, 5-Fluorouracil, Temosolomida, Vincristine, Cisplatin, Carboplatin and Gemcitabine.

Other embodiments of the present invention provide a method for treating cancer using chemotherapeutic agent, and a chemotherapeutic agent selected from the group consisting of: Gemcitabine, Cisplatin and Carboplatin.

The present invention also discloses a method of treating cancer in a patient requiring such treatment, and said treatment includes the introduction of the indicated patient a therapeutically effective amount of at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, and a therapeutically effective amount of at least one (e.g. 1, 2 or 3, or 1 or 2, or 2, or 1) chemotherapeutic agent selected from the group consisting of: (1) taxan, (2) coordination compounds of platinum, (3) inhibitors of the epidermal growth factor (EGF), which are antibodies, (4) "small molecules" - EGF inhibitors, (5) inhibitors of vascular endothelial growth factors (VEGF), which are the antibodies is a, (6) "small molecules" - kinase inhibitors of VEGF, (7) antagonists of the estrogen receptor or selective modulators of estrogen receptor (SERMs), (8) antitumor nucleoside derivatives, (9) epothilones, (10) topoisomerase inhibitors, (11) Vinca alkaloids, (12) antibodies that are inhibitors of αVβ3 integrins, (13) folate antagonists, (14) inhibitors ribonucleotidic reductase (15) anthracyclines, (16) biologics; (17) inhibitors of angiogenesis and/or suppressors of tumor necrosis factor alpha (TNF-alpha)such as Thalidomide (or related imide), (18) inhibitors of Bcr/abl kinase, (19) "small molecules" - inhibitors MEK and/or MEK, (20) "small molecules" inhibitors of IGF-1 and IGF-2, (21) "small molecules" - RAF inhibitors and skin disease kinases (22) "small molecules" inhibitors of kinase-dependent cell cycle, such as CDK1, CDK2, CDK4 and CDK6, (23) alkylating agents, and (24) inhibitors farnesyltransferase (also known as FPT inhibitors or FTI (i.e., inhibitors farnesyltransferase)).

The present invention also discloses a method of treating cancer in a patient requiring such treatment, and said treatment includes the introduction of the indicated patient a therapeutically effective amount of at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, and a therapeutically effective to the richest, at least two (for example, 2 or 3, or 2, and usually 2) different antineoplastic agents selected from the group consisting of: (1) taxan, (2) coordination compounds of platinum, (3) inhibitors of the epidermal growth factor (EGF), which are antibodies, (4) "small molecules" - EGF inhibitors, (5) inhibitors of vascular endothelial growth factors (VEGF), which are antibodies, (6) "small molecules" - kinase inhibitors of VEGF, (7) antagonists of the estrogen receptor or selective modulators of estrogen receptor (SERMs), (8) antitumor nucleoside derivatives, (9) epothilones, (10) topoisomerase inhibitors, (11) Vinca alkaloids, (12) antibodies that are inhibitors of αVβ3 integrins, (13) folate antagonists, (14) inhibitors ribonucleotidic reductase (15) anthracyclines, (16) biologics; (17) inhibitors of angio-Genesis and/or suppressors of tumor necrosis factor alpha (TNF-alpha)such as thalidomide (or related imide), (18) inhibitors of Bcr/abl kinase, (19) "small molecules" - inhibitors MEK and/or MEK, (20) "small molecules" inhibitors of IGF-1 and IGF-2, (21) "small molecules" - RAF inhibitors and skin disease kinases (22) "small molecules" inhibitors of kinase-dependent cell cycle, such as CDK1, CDK2, CDK4 and CDK6, (23) alkylating agents, and (24) inhibitors farnesyltransferase (also known as Inga is itory FPT or FTI (i.e., inhibitors farnesyltransferase)).

The present invention also discloses a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient therapeutically effective amounts of at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, and antitumor agent selected from the group consisting of: (1) EGF inhibitors that are antibodies, (2) "small molecules" - EGF inhibitors, (3) VEGF inhibitors that are antibodies and (4) "small molecules" - VEGF inhibitors. Radiotherapy can also be used in combination with the above combinatorial therapy, that is, the above method using a combination of compounds according to the invention and an antitumor agent, may also include the introduction of a therapeutically effective amount of radiation.

The present invention also discloses a method for the treatment of leukemia (e.g. acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) in a patient who is in need of such treatment, and this method includes the introduction of a specified patient therapeutically effective amounts of at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, and: (1) the Glivec or interferon is La treat CML; (2) Gleevec or pegylated interferon to treat CML; (3) the Gleevec treatment for CML; (4) antineoplastic nucleoside derivative (e.g., Ara-C) for the treatment of AML; or (5) antitumor nucleoside derivative (e.g., Ara-C) in combination with anthracyclines for the treatment of AML.

The present invention also discloses a method of treating non-Hodgkin's lymphoma in a patient who is in need of such treatment, and this method includes the introduction of a therapeutically effective amount of at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 and: (1) biological product (e.g., Rituxan); (2) a biological product (e.g., Rituxan) and anti-tumor nucleoside derivative (e.g., fludarabine); or (3) of Genasense (antisense against BCL-2).

The present invention also discloses a method of treating multiple myeloma in a patient who is in need of such treatment, and this method includes the introduction of a specified patient therapeutically effective amounts of at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 and: (1) proteosome inhibitor (e.g., PS-341 from Millenium); or (2) Thalidomide (or related IMID).

The present invention also discloses a method of treating cancer in a patient requiring such treatment which s, moreover, this method includes the introduction of a specified patient therapeutically effective amounts of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, and (b)at least one (e.g. 1, 2 or 3, or 1 or 2, or 2, or 1) antineoplastic agent selected from the group consisting of: (1) taxan, (2) coordination compounds of platinum (3) EGF inhibitors that are antibodies, (4) "small molecules" - EGF inhibitors, (5) VEGF that are antibodies, (6) "small molecules" - kinase inhibitors of VEGF, (7) antagonists of the estrogen receptor or selective modulators of estrogen receptor, (8) antitumor nucleoside derivatives, (9) epothilones, (10) topoisomerase inhibitors, (11) Vinca alkaloids, (12) antibodies that are inhibitors of αVβ3 integrins.

The present invention also discloses methods of treating non-small cell lung cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient therapeutically effective amounts of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, and (b)at least one (e.g. 1, 2 or 3, or 1 or 2, or 2, or 1) antineoplastic agent selected from the group consisting of: (1) the aksanov, (2) coordination compounds of platinum, (3) EGF inhibitors that are antibodies, (4) "small molecules" - EGF inhibitors, (5) VEGF that are antibodies, (6) "small molecules" - kinase inhibitors of VEGF, (7) antagonists of the estrogen receptor or selective modulators of estrogen receptor, (8) antitumor nucleoside derivatives, (9) epothilones, (10) topoisomerase inhibitors, (11) Vinca alkaloids, (12) antibodies that are inhibitors of αVβ3 integrins.

The present invention also discloses a method of treating non-small cell lung cancer in a patient who is in need of such treatment, and this method includes the introduction of a specified patient therapeutically effective amounts of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, and (b)at least one (e.g. 1, 2 or 3, or 1 or 2, or 2, or 1) antineoplastic agent selected from the group consisting of: (1) taxan, (2) coordination compounds of platinum, (3) antitumor nucleoside derivatives, (4) inhibitors of topoisomerase and (5) of the Vinca alkaloids.

The present invention also discloses methods of treating non-small cell lung cancer in a patient who is in need of such treatment, and this method includes the introduction of therapeutically is effectivnogo quantities: (a) at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, (b) carboplatin and (C) of paclitaxel.

The present invention also discloses a method of treating non-small cell lung cancer in a patient who is in need of such treatment, and this method includes the introduction of the indicated patient a therapeutically effective amount of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, (b) Cisplatin and (C) gemcitabine.

The present invention also discloses a method of treating non-small cell lung cancer in a patient who is in need of such treatment, and this method includes the introduction of a therapeutically effective amount of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, (b) carboplatin and (C) gemcitabine.

The present invention also discloses a method of treating non-small cell lung cancer in a patient who is in need of such treatment, and this method includes the introduction of a therapeutically effective amount of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, (b) carboplatin and (C) of docetaxel.

The present invention also discloses a method of treating cancer in a patient, which required the such treatment, moreover, this method includes the introduction of a therapeutically effective amount of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, and (b) antineoplastic agent selected from the group consisting of: (1) EGF inhibitors that are antibodies, (2) "small molecules" - EGF inhibitors, (3) VEGF inhibitors that are antibodies, (4) "small molecules" - inhibitors kinase VEGF.

The present invention also discloses a method of treating squamous cell cancer of the head and neck of the patient requiring such treatment, and this method includes the introduction of a specified patient therapeutically effective amounts of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, and (b)at least one (e.g. 1, 2 or 3, or 1 or 2 or 2 or 1) antineoplastic agent selected from the group consisting of: (1) taxan and (2) coordination compounds of platinum.

The present invention also discloses a method of treating squamous cell cancer of the head and neck of the patient requiring such treatment, and this method includes the introduction of a specified patient therapeutically effective amounts of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound is ormula 1.0, and (b)at least one (e.g. 1, 2 or 3, or 1 or 2 or 2 or 1) antineoplastic agent selected from the group consisting of: (1) taxan, (2) coordination compounds of platinum and (3) antitumor nucleoside derivatives (for example, 5-Fluorouracil).

The present invention also discloses a method of treating CML in a patient requiring such treatment, and this method includes the introduction of a therapeutically effective amount of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, (b) Gleevec and (C) interferon (e.g., intron-A).

The present invention also discloses a method of treating CML in a patient requiring such treatment, and this method includes the introduction of a therapeutically effective amount of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, (b) Gleevec and (C) pegylated interferon (e.g., intron and pegasis).

The present invention also discloses a method of treating CML in a patient requiring such treatment, and this method includes the introduction of a therapeutically effective amount of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 and (b) of Glivec.

The present invention also rusk which indicates the method for the treatment of CMML patients who needs such treatment, and this method includes the introduction of a therapeutically effective amount of at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0.

The present invention also discloses a method of treating AML in a patient requiring such treatment, and this method includes the introduction of a specified patient therapeutically effective amounts of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 and (b) antitumor nucleoside derivative (e.g., Cytarabine (i.e., Ara-C)).

The present invention also discloses a method of treating AML in a patient requiring such treatment, and this method includes the introduction of a specified patient therapeutically effective amounts of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, (b) antitumor nucleoside derivative (e.g., Cytarabine (i.e., Ara-C)) and (C) anthracycline.

The present invention also discloses a method of treating non-Hodgkin's lymphoma in a patient who is in need of such treatment, and this method includes the introduction of a specified patient therapeutically effective amounts of: (a)at least one (e.g. 1, 2 or 3, or 1 ili, or 1, and usually 1) compound of formula 1.0 and (b) Rituximab (Rituxan).

The present invention also discloses a method of treating non-Hodgkin's lymphoma in a patient who is in need of such treatment, and this method includes the introduction of a specified patient therapeutically effective amounts of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, (b) Rituximab (Rituxan) and (C) antitumor nucleoside derivative (e.g., fludarabine (i.e., F-ara-A).

The present invention also discloses a method of treating non-Hodgkin's lymphoma in a patient who is in need of such treatment, and this method includes the introduction of a specified patient therapeutically effective amounts of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 and (b) of Genasense (antisense against BCL-2).

The present invention also discloses a method of treating multiple myeloma in a patient who is in need of such treatment, and this method includes the introduction of a therapeutically effective amount of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 and (b) proteasome inhibitor (e.g., PS-341 (Millenium)).

The present invention also discloses pic is b the treatment of multiple myeloma patients who needs such treatment, and this method includes the introduction of a specified patient therapeutically effective amounts of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 and (b) Thalidomide or related IMID.

The present invention also discloses a method of treating multiple myeloma in a patient who is in need of such treatment, and this method includes the introduction of a therapeutically effective amount of: (a)at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 and (b) of Thalidomide.

The present invention is directed to methods of treating cancer described in this application, especially disclosed above, where in addition to the introduction of the compounds of formula 1.0 and antitumor agents also introduced radiotherapy in the period before, during or after a treatment cycle.

The present invention also discloses a method of treating cancer (e.g., lung cancer, prostate cancer and myeloid leukemia) in a patient who is in need of such treatment, and this method includes the introduction of a specified patient: (1) an effective amount of at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0, in combination with (2)at least one (e.g. 1, 2 or 3, or 1 or 2, or 2, or 1) antineoplastic agent, an agent acting on microtubules and/or radiotherapy.

The present invention also discloses a method of treating cancer in a patient requiring such treatment, and this method includes the introduction of a specified patient an effective amount of at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) compound of formula 1.0 in combination with an effective amount of at least one (e.g. 1, 2 or 3, or 1 or 2, or 1, and usually 1) inhibitors of signal transduction.

Thus, in one example (e.g., treatment of non-small cell lung cancer): (1) compound of formula 1.0 is introduced in an amount of from about 50 mg to about 200 mg twice a day, and in another example is introduced from about 75 mg to about 125 mg twice a day, and in yet another example is introduced about 100 mg twice a day, (2) Paclitaxel (e.g., Taxol®) is injected once a week, in the amount of from about 50 to about 100 mg/m2and in another example from about 60 to about 80 mg/m2and (3) Carboplatin is injected once a week, in the amount necessary to ensure AUC from about 2 to about 3.

In another example (e.g., treatment of non-small cell lung cancer): (1) compound of formula 1.0 is introduced in an amount of from about 50 mg to about 200 mg twice a day, and in another example introduces the I from about 75 mg to about 125 mg twice a day, in one example, is entered about 100 mg twice a day, (2) Paclitaxel (e.g., Taxol®injected once a week, in the amount of from about 50 to about 100 mg/m2and in another example from about 60 to about 80 mg/m2and (3) Cisplatin is injected once a week, in the amount of from about 20 to about 40 mg/m2.

In another example (e.g., treatment of non-small cell lung cancer): (1) compound of formula 1.0 is introduced in an amount of from about 50 mg to about 200 mg twice a day, and in another example the compound of formula 1.0 is introduced in an amount of from about 75 mg to about 125 mg twice a day, and in yet another example, the compound of formula 1.0 is introduced in an amount of about 100 mg twice a day, (2) Docetaxel (e.g., Taxotere®) is injected once a week, in the amount of from about 10 to about 45 mg/m2and (3) Carboplatin is injected once a week, in the amount necessary to ensure AUC from about 2 to about 3.

In another example (e.g., treatment of non-small cell lung cancer): (1) compound of formula 1.0 is introduced in an amount of from about 50 mg to about 200 mg twice a day, and in another example the compound of formula 1.0 is introduced in an amount of from about 75 mg to about 125 mg twice a day, and in yet another example, the compound of formula 1.0 is introduced in an amount of about 100 mg twice a day, (2) Docetaxel (e.g., Taxotere®put one of the AZ in a week, in the amount of from about 10 to about 45 mg/m2and (3) Cisplatin is injected once a week, in the amount of from about 20 to about 40 mg/m2.

In another example (e.g., treatment of non-small cell lung cancer): (1) compound of formula 1.0 is introduced in an amount of from about 50 mg to about 200 mg twice a day, and in another example the compound of formula 1.0 is introduced in an amount of from about 75 mg to about 125 mg twice a day, and in yet another example, the compound of formula 1.0 is introduced in the amount of 100 mg twice a day, (2) Paclitaxel (e.g., Taxol®) is injected once every three weeks, in amounts of from about 150 to about 250 mg/m2and in another example from about 175 to about 225 mg/m2and in yet another example -175 mg/m2and (3) Carboplatin is injected once every three weeks, in an amount necessary to ensure AUC from about 5 to about 8, and in another example - AUC 6.

In another example, the treatment of non-small cell lung cancer: (1) compound of formula 1.0 is introduced in the amount of 100 mg twice a day, (2) Paclitaxel (e.g., Taxol®) is injected once every three weeks, in the amount of 175 mg/m2and (3) Carboplatin is injected once every three weeks, in an amount necessary to ensure AUC 6.

In another example (e.g., treatment of non-small cell lung cancer): (1) compound of formula 1.0 is introduced in an amount of from about 50 mg to the Colo 200 mg twice a day, in another example, the compound of formula 1.0 is introduced in an amount of from about 75 mg to about 125 mg twice a day, and in yet another example, the compound of formula 1.0 is introduced in an amount of about 100 mg twice a day, (2) Paclitaxel (e.g., Taxol®) is injected once every three weeks, in amounts of from about 150 to about 250 mg/m2and in another example from about 175 to about 225 mg/m2and (3) Cisplatin is injected once every three weeks in an amount of from about 60 to about 100 mg/m2.

In another example (e.g., treatment of non-small cell lung cancer): (1) compound of formula 1.0 is introduced in an amount of from about 50 mg to about 200 mg twice a day, and in another example the compound of formula 1.0 is introduced in an amount of from about 75 mg to about 125 mg twice a day, and in yet another example, the compound of formula 1.0 is introduced in an amount of about 100 mg twice a day, (2) Docetaxel (e.g., Taxotere®) is injected once every three weeks in an amount of from about 50 to about 100 mg/m2and (3) Carboplatin is injected once every three weeks, in an amount necessary to ensure AUC from about 5 to about 8.

In another example (e.g., treatment of non-small cell lung cancer): (1) compound of formula 1.0 is introduced in an amount of from about 50 mg to about 200 mg twice a day, in another example, the compound of formula 1.0 is introduced in an amount of from about 75 meters is up to about 125 mg twice a day, in one example, the compound of formula 1.0 is introduced in an amount of about 100 mg twice a day, (2) Docetaxel (e.g., Taxotere®) is injected once every three weeks in an amount of from about 50 to about 100 mg/m2and (3) Cisplatin is injected once every three weeks in an amount of from about 60 to about 100 mg/m2.

In another example, for the treatment of non-small cell lung cancer, using the compounds of formula 1.0, Docetaxel and Carboplatin: (1) compound of formula 1.0 is introduced in an amount of from about 50 mg to about 200 mg twice a day, and in another example the compound of formula 1.0 is introduced in an amount of from about 75 mg to about 125 mg twice a day, and in yet another example, the compound of formula 1.0 is introduced in an amount of about 100 mg twice a day, (2) Docetaxel (e.g., Taxotere®) is injected once every three weeks in an amount of about 75 mg/m2and (3) Carboplatin is injected once every three weeks, in an amount necessary to ensure AUC of about 6.

In another example, the treatment of non-small cell lung cancer, described above, Docetaxel (e.g., Taxotere®) and Cisplatin, Docetaxel (e.g., Taxotere®and Carboplatin, Paclitaxel (e.g., Taxol®and Carboplatin, or Paclitaxel (e.g., Taxol®) and Cisplatin are entered in the same day.

In another example (e.g., CML): (1) compounds is their formula 1.0 is introduced in an amount of from about 100 mg to about 200 mg twice a day, (2) Gleevec is introduced in an amount of from about 400 to about 800 mg/day by mouth, and (3) interferon (intron-A) is introduced in an amount of from about 5 to about 20 million immunizing units, three times a week.

In another example (e.g., CML): (1) compound of formula 1.0 is introduced in an amount of from about 100 mg to about 200 mg twice a day, (2) Gleevec is introduced in an amount of from about 400 to about 800 mg/day by mouth, and (3) pegylated interferon (PegIntron or pegasis) is introduced in an amount of from about 3 to about 6 micrograms/kg/day.

In another example (e.g., non-Hodgkin's lymphoma): (1) compound of formula 1.0 is introduced in an amount of from about 50 mg to about 200 mg twice a day, and in another example the compound of formula 1.0 is introduced in an amount of from about 75 mg to about 125 mg twice a day, and in yet another example, the compound of formula 1.0 is introduced in the amount of 100 mg twice a day, and (2) Genasense (antisense against BCL-2) is administered by continuous intravenous infusion at a dose of from about 2 to about 5 mg/kg/day (for example, 3 mg/kg/day)for 5-7 days every 3-4 weeks.

In another example (e.g., multiple myeloma): (1) compound of formula 1.0 is introduced in an amount of from about 50 mg to about 200 mg twice a day, and in another example the compound of formula 1.0 is introduced in an amount of from about 75 mg to about 125 mg twice a day, and it is one example of the compound of formula 1.0 is introduced in the amount of 100 mg twice a day, and (2) proteosome inhibitor (e.g., PS-341 - Millenium) is introduced in an amount of from about 1.5 mg/m2twice a week, within two weeks following each other, when a break in one week.

In another example (e.g., multiple myeloma): (1) compound of formula 1.0 is introduced in an amount of from about 50 mg to about 200 mg twice a day, and in another example the compound of formula 1.0 is introduced in an amount of about 75 mg to about 125 mg twice a day, and in yet another example, the compound of formula 1.0 is introduced in an amount of about 100 mg twice a day, and (2) Thalidomide (or related imide) is inserted through the mouth, in the amount of from about 200 to about 800 mg/day, and the dose is unchanged until signs of relapse or toxicity.

In one embodiment, the methods of treating cancer according to the invention, the chemotherapeutic agents are selected from the group consisting of: Paclitaxel, Docetaxel, Carboplatin, Cisplatin, Gemcitabine, Tamoxifen, Herceptin, Cetuximab, Tarceva, Iressa, Bevacizumab, navelbine under maintenance Protocol, IMC-1C11, SU5416 and SU6688.

In another embodiment, the methods of treating cancer according to the invention, the chemotherapeutic agents are selected from the group consisting of: Paclitaxel, Docetaxel, Carboplatin, Cisplatin, navelbine under maintenance Protocol, Gemcitabine and Herceptin.

Thus, one embodiment of the invention is a method Leche is of cancer, introducing the patient requiring such treatment, a therapeutically effective amount of the compounds of formula 1.0, taxane and coordination compounds of platinum.

Another embodiment of the invention is a method of treating cancer, which contains the introduction to the patient requiring such treatment, a therapeutically effective amount of the compounds of formula 1.0, taxane and coordination compounds of platinum, where the aforementioned compound of formula 1.0 is injected every day, specified Texan injected once per week per cycle, and the specified coordination compound of platinum is injected once per week per cycle. In another embodiment, the treatment occurs within one to four weeks per cycle.

Another embodiment of the invention is a method of treating cancer, which contains the introduction to the patient requiring such treatment, a therapeutically effective amount of the compounds of formula 1.0, taxane and coordination compounds of platinum, where the aforementioned compound of formula 1.0 is injected every day, specified taxon is injected once every three weeks per cycle, and the specified coordination compound of platinum is injected once every three weeks per cycle. In another embodiment, the treatment occurs within one to three weeks per cycle.

The etc is another embodiment of the invention is a method of treatment of cancer, introducing the patient requiring such treatment, a therapeutically effective amount of the compounds of formula 1.0, Paclitaxel and Carboplatin. In another embodiment of the invention, the said compound of formula 1.0 is injected every day, specified Paclitaxel injected once per week per cycle, and said Carboplatin is injected once per week per cycle. In another embodiment, the treatment occurs within one to four weeks per cycle.

Another embodiment of the invention is a method of treating cancer, which contains the introduction to the patient requiring such treatment, a therapeutically effective amount of the compounds of formula 1.0, Paclitaxel and Carboplatin. In another embodiment of the invention, the said compound of formula 1.0 is injected every day, specified Paclitaxel is injected once every three weeks per cycle, and said Carboplatin is injected once every three weeks per cycle. In another embodiment, the treatment occurs within one to three weeks per cycle.

Another embodiment of the invention is a method of treating non-small cell lung cancer in a patient who is in need of such treatment, containing daily administration of therapeutically effective amounts of compounds of formula 1.0, introduction Ter is piticescu effective amount Carboplatin once per week per cycle, and the introduction of a therapeutically effective amount of Paclitaxel once a week per cycle, where the treatment is carried out within one to four weeks per cycle. In another embodiment, a specified compound of formula 1.0 is injected twice a day. In another embodiment, a specified Carboplatin and specified Paclitaxel are entered in the same day, and in another embodiment, a specified Carboplatin and specified Paclitaxel are entered sequentially, and in another embodiment, a specified Carboplatin is inserted after the specified Paclitaxel.

Another embodiment of the invention is a method of treating non-small cell lung cancer in a patient who is in need of such treatment, containing daily administration of therapeutically effective amounts of compounds of formula 1.0, introduction therapeutically effective amount Carboplatin once every three weeks per cycle, and the introduction of a therapeutically effective amount of Paclitaxel once every three weeks per cycle, where the treatment is administered for one to three weeks. In another embodiment, a compound of formula 1.0 is injected twice a day. In another embodiment, a specified Carboplatin and specified Paclitaxel are entered in the same day, and in another embodiment, a specified Carboplatin and specified Paclitaxel is entered sequentially, in another embodiment, a specified Carboplatin is inserted after the specified Paclitaxel.

Another embodiment of the invention directed to a method of treating non-small cell lung cancer in a patient who is in need of such treatment, introducing from about 50 to about 200 mg of the compounds of formula 1.0, twice a day, introduction Carboplatin once per week per cycle in an amount necessary to ensure AUC from about 2 to about 8 (and in another embodiment from about 2 to about 3), and the introduction of once per week per cycle of Paclitaxel in an amount of from about 60 to about 300 mg/m2(and in another embodiment about 50 to 100 mg/m2and in yet another embodiment, from about 60 to about 80 mg/m2), and the treatment is carried out within one to four weeks per cycle. In another embodiment, a specified compound of formula 1.0 is introduced in an amount of from about 75 to about 125 mg twice a day, and in another embodiment about 100 mg twice a day. In another embodiment, a specified Carboplatin and specified Paclitaxel are entered in the same day, and in another embodiment, a specified Carboplatin and specified Paclitaxel are entered sequentially, and in another embodiment, the image is etenia specified Carboplatin is inserted after the specified Paclitaxel.

In another embodiment, the invention is directed to a method of treating non-small cell lung cancer in a patient who is in need of such treatment, introducing from about 50 to about 200 mg of the compounds of formula 1.0, twice a day, introduction Carboplatin once every three weeks per cycle in an amount necessary to ensure AUC from about 2 to about 8 (in another embodiment, from about 5 to about 8, and in another embodiment, a - 6), and the introduction of once every three weeks per cycle of Paclitaxel in an amount of from about 150 to about 250 mg/m2(and in another embodiment from about 175 to about 225 mg/m2and in another embodiment, the invention is 175 mg/m2), and the treatment is carried out within one to three weeks. In another embodiment, a specified compound of formula 1.0 is introduced in an amount of from about 75 to about 125 mg twice a day, and in another embodiment about 100 mg twice a day. In another embodiment, a specified Carboplatin and specified Paclitaxel are entered in the same day, and in another embodiment, a specified Carboplatin and specified Paclitaxel are entered sequentially, and in another embodiment, a specified Carboplatin is inserted after the specified PA what metaxalon.

Other embodiments of the invention are methods of treating cancer as described in the above versions of the invention (that is, embodiments of the invention, intended for the treatment of cancer and the treatment of non-small cell lung cancer using taxane and coordination compounds of platinum), except that instead of Paclitaxel and Carboplatin, taxanes and coordination compounds of platinum, used together in ways that are: (1) Docetaxel (Taxotere®) and cisplatin; (2) Paclitaxel and cisplatin; and (3) Docetaxel and Carboplatin. In another embodiment, the methods according to the present invention Cisplatin is used in an amount from about 30 to about 100 mg/m2. In another embodiment, the methods according to the invention Docetaxel is used in amounts from about 30 to about 100 mg/m2.

In another embodiment, the invention is directed to a method of treating cancer, which contains the introduction to the patient requiring such treatment, a therapeutically effective amount of the compounds of formula 1.0, taxane and EGF inhibitor that is an antibody. In another embodiment, the invention is applied taxon represents Paclitaxel, and inhibitor of EGF is a HER2 antibody (in one embodiment, Herceptin) Il is Cetuximab, in another embodiment, the invention is applied Herceptin. The duration of treatment and number and the introduction of the compounds of formula 1.0 and taxane are as described in embodiments of carrying out the invention disclosed above. The EGF inhibitor that is an antibody is injected once per week per cycle, and in another embodiment, the invention is introduced on the same day that taxon, and in another embodiment, the invention is inserted in series with taxonom. For example, Herceptin is introduced in a shock dose of from about 3 to about 5 mg/m2(in another embodiment, about 4 mg/m2), and then put into a maintenance dose of about 2 mg/m2once a week per cycle, for the remaining part of the treatment cycle (cycle is usually 1-4 weeks). In one embodiment, the cancer to be treated is breast cancer.

In another embodiment, the invention is directed to a method of treating cancer, which contains the introduction to the patient requiring such treatment therapeutically effective amounts of: (1) the compounds of formula 1.0, (2) taxane and (3) antineoplastic agent selected from the group consisting of: (a) "small molecules" - EGF inhibitor, (b) VEGF inhibitor that is an antibody, and (C) "small molecule - inhibitor Keene is s VEGF. In another embodiment, the invention is applied Texan Paclitaxel or Docetaxel. In another embodiment, the anticancer agent is selected from the group consisting of: Tarceva, Iressa, Bevacizumab, SU5416, SU6688 and BAY 43-9006. The duration of treatment and number and the introduction of the compounds of formula 1.0 and taxane are as described in versions of the invention above. The kinase inhibitor of VEGF, which is an antibody, usually given once per week per cycle. "Small molecules" - inhibitors of EGF and VEGF are usually put in a daily cycle. In another embodiment, the VEGF inhibitor that is an antibody is introduced into one and the same day that taxon, and in another embodiment, the invention is introduced simultaneously with taxonom. In another embodiment of the invention, "small molecule - inhibitor EGF or a small molecule inhibitor of VEGF, is introduced into one and the same day that taxon, or typed simultaneously with taxonom. The kinase inhibitor of VEGF or EGF, typically administered in an amount of from about 10 to about 500 mg/m2.

In another embodiment, the invention is directed to a method of treating cancer, which contains the introduction to the patient requiring such treatment, a therapeutically effective amount of the compounds of formula 1.0, protivoopujolevy the howling nucleoside derivative and coordination compounds of platinum.

Another embodiment of the invention is a method of treating cancer, which contains the introduction to the patient requiring such treatment, a therapeutically effective amount of the compounds of formula 1.0, anti-tumor nucleoside derivative, and coordination compounds of platinum, where the aforementioned compound of formula 1.0 is injected every day, specified antitumor nucleoside derivative is injected once per week per cycle, and the specified coordination compound of platinum is injected once per week per cycle. Although the treatment may be carried out within one to four weeks per cycle, in one embodiment, the treatment is carried out for one to seven weeks per cycle.

Another embodiment of the invention is a method of treating cancer, which contains the introduction to the patient requiring such treatment, a therapeutically effective amount of the compounds of formula 1.0, anti-tumor nucleoside derivative, and coordination compounds of platinum, where the aforementioned compound of formula 1.0 is injected every day, specified antitumor nucleoside derivative is injected once per week per cycle, and the specified coordination compound of platinum is injected once every three weeks per cycle. Although the treatment may be carried out within one to four weeks per cycle, about which Mr. embodiment, the invention is carried out for one to seven weeks per cycle.

Another embodiment of the invention is a method of treating cancer, which contains the introduction to the patient requiring such treatment, a therapeutically effective amount of the compounds of formula 1.0, gemcitabine and cisplatin. In another embodiment of the invention, the said compound of formula 1.0 is introduced every day, the gemcitabine is injected once per week per cycle, and the specified cisplatin injected once per week per cycle. In one embodiment, the treatment is for one to seven weeks per cycle.

Another embodiment of the invention is a method of treating cancer, which contains the introduction to the patient requiring such treatment, a therapeutically effective amount of the compounds of formula 1.0, gemcitabine and cisplatin. In another embodiment of the invention, the said compound of formula 1.0 is introduced every day, the gemcitabine is injected once per week per cycle, and the specified Cisplatin injected once every three weeks per cycle. In another embodiment, the treatment is carried out for one to seven weeks per cycle.

Another embodiment of the invention is a method of treating cancer, which contains the introduction to the patient requiring such treatment, a therapeutically effective amount of the compound form is s 1.0, gemcitabine and carboplatin. In another embodiment, a specified compound of formula 1.0 is introduced every day, the gemcitabine is injected once per week per cycle, and said Carboplatin is injected once per week per cycle. In another embodiment, the treatment is for one to seven weeks per cycle.

Another embodiment of the invention is a method of treating cancer, which contains the introduction to the patient requiring such treatment, a therapeutically effective amount of the compounds of formula 1.0, gemcitabine and carboplatin. In another embodiment, a specified compound of formula 1.0 is introduced every day, the gemcitabine is injected once per week per cycle, and said Carboplatin is injected once every three weeks per cycle. In another embodiment, the treatment is carried out for one to seven weeks per cycle.

In the above versions of the invention, using gemcitabine, the compound of formula 1.0 and the coordination compound of platinum are introduced, as disclosed above for the embodiment of the invention using taxanes. Gemcitabine is administered amount of from about 500 to about 1250 mg/m2. In one embodiment, gemcitabine is administered the same day as the coordination compound dps is Tina, in another embodiment, consistently with the coordination compound of platinum, and in another embodiment, gemcitabine is given after the coordination compounds of platinum.

Another embodiment of the present invention is a method of treating cancer in a patient requiring such treatment, containing the introduction to the specified patient, the compounds of formula 1.0 and antitumor agent selected from: (1) EGF inhibitors that are antibodies, (2) "small molecules" - EGF inhibitors (3) VEGF inhibitors that are antibodies, and (4) "small molecules" - kinase inhibitors of VEGF, all of which are described above. The treatment is carried out for one to seven weeks per cycle, and usually within one to four weeks per cycle. The compound of formula 1.0 is introduced in the same manner as disclosed above for other embodiments of the invention. Antineoplastic agents, in the form of small molecules, as a rule, are introduced daily, and antitumor agents in the form of antibodies, usually injected once per week per cycle. In one embodiment, the antineoplastic agents are selected from the group consisting of: Herceptin, Cetuximab, Tarceva, Iressa, Bevacizumab, IMC-S, SU5416, SU6688 and BAY 43-9006.

In other embodiments, execution nastojasih the invention, where applicable coordination compound of platinum, as well as at least one other anticancer agent, and these medicines are introduced sequentially, the coordination compound of platinum, typically administered after other antitumor agents that have already been entered.

Other embodiments of the present invention include the introduction to the patient a therapeutically effective amount of radiation in addition to the compounds of formula 1.0 and anticancer agents in versions of the invention disclosed above. Irradiation is introduced according to the methods and modes well known to specialists in this field of technology.

Another embodiment of this invention is a pharmaceutical composition comprising at least two different chemotherapeutic agent and a pharmaceutically acceptable carrier for intravenous administration. Preferably pharmaceutically acceptable carrier is an isotonic saline solution (0.9% NaCl) or dextrose (for example, 5% dextrose).

Another embodiment of this invention is a pharmaceutical composition comprising the compound of formula 1.0 and at least two different antineoplastic agent and a pharmaceutically acceptable carrier for nutrion the th introduction. Preferably pharmaceutically acceptable carrier is an isotonic saline solution (0.9% NaCl) or dextrose (for example, 5% dextrose).

Another embodiment of this invention is a pharmaceutical composition comprising the compound of formula 1.0 and at least one antineoplastic agent and a pharmaceutically acceptable carrier for intravenous administration. Preferably pharmaceutically acceptable carrier is an isotonic saline solution (0.9% NaCl) or dextrose (for example, 5% dextrose).

Other embodiments of the present invention are the use of a combination of at least one (e.g., one) compound of formula 1.0 and medicines for the treatment of breast cancer, that is, the present invention is directed to combinatorial therapy for the treatment of breast cancer. Specialists in the art it will be obvious that the compounds of formula 1.0 and drugs, as a rule, are administered as separate pharmaceutical compositions. The use of pharmaceutical compositions containing more than one drug, is included in the scope of the present invention.

Thus, another embodiment of the present invention is a method of treatment or prevention is treatment) breast cancer (i.e., postmenopausal and premenopausal breast cancer, e.g., hormone-dependent breast cancer) in a patient requiring such treatment, which contains the introduction of the indicated patient a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and a therapeutically effective amount of at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors, (b) antiestrogens, and (C) LHRH analogues; and, moreover, said treatment necessarily includes the introduction of at least one chemotherapeutic agent.

The compound of formula 1.0, preferably introduced through the mouth, and in one embodiment, the invention is introduced in the form of a capsule.

Examples of aromatase inhibitors include, but without limitation to this: Anastrozole (such as arimidex), Letrozole (e.g., femara), Exemestane (Aromasin), Fadrozole and Formestane (for example, Lentaron).

Examples of antiestrogens are, but without limitation to this: Tamoxifen (for example, Nolvadex), Fulvestrant (e.g., Faslodex), Raloxifene (for example, Evista) and Acolbifene.

Examples of LHRH analogues are, but without limitation to this: Goserelin (for example, Zoladex) and Leuprolide (for example, Leuprolide Acetate, such as Lupron or Lupron On the pot).

Examples of chemotherapeutic agents include, but without limitation to this: Trastuzumab (e.g., Herceptin), Gefitinib (for example, Iressa), Erlotinib (for example, Erlotinib HCl, such as Tarceva), Bevacizumab (e.g., Avastin), Cetuximab (for example, Erbitux) and Bortezomib (for example, Velcade).

Preferably, when used in more than one antihormonal agent, and each agent is selected from the different categories of agents. For example, one agent is an aromatase inhibitor (for example, Anastrozole, Letrozole, or Exemestane), and the other agent is antiestrogen (e.g., Tamoxifen or Fulvestrant).

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors, (b) antiestrogens, and (C) LHRH analogues; and introduction of an effective amount of at least one chemotherapeutic agent.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient, which is necessary for such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors, (b) antiestrogens, and (C) LHRH analogues.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors and (b) antiestrogens.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors and (b) antiestrogens; and at least one chemotherapeutic agent.

Another embodiment of the invention is a pic the b of treating or preventing breast cancer in a patient, who needs such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and at least one aromatase inhibitor.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, at least one aromatase inhibitor and at least one chemotherapeutic agent.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of: (1)at least one (e.g., one) compound of formula 1.0; and (2)at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors that are selected from the group consisting of Anastrozole, Letrozole, Exemestane, Fadrozole and Formestane, (b) antiestrogens that are selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene and Acolbifene and (C) LHRH analog is, selected from the group consisting of: Goserelin and Leuprolide; and introduction of an effective amount of at least one chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of: (1)at least one (e.g., one) compound of formula 1.0; and (2)at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors that are selected from the group consisting of Anastrozole, Letrozole, Exemestane, Fadrozole and Formestane, (b) antiestrogens that are selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene and Acolbifene and (C) LHRH analogues, which are selected from the group consisting of: Goserelin and Leuprolide.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of: (1)at least one (e.g. one) Conn is of formula 1.0; and (2)at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors that are selected from the group consisting of Anastrozole, Letrozole, Exemestane, Fadrozole and Formestane and (b) antiestrogens that are selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene and Acolbifene.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of: (1)at least one (e.g., one) compound of formula 1.0; and (2)at least one antihormonal agent selected from the group consisting of: (a) aromatase inhibitors that are selected from the group consisting of Anastrozole, Letrozole, Exemestane, Fadrozole and Formestane, (b) antiestrogens that are selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene and Acolbifene; and introduction of an effective amount of at least one chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer W is Lesa patient, who needs such treatment, where said treatment includes the introduction of a therapeutically effective amount of: (1)at least one (e.g., one) compound of formula 1.0; and (2)at least one aromatase inhibitor selected from the group consisting of Anastrozole, Letrozole, Exemestane, Fadrozole and Formestane.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of: (1)at least one (e.g., one) compound of formula 1.0; (2)at least one aromatase inhibitor, which is selected from the group consisting of Anastrozole, Letrozole, Exemestane, Fadrozole and Formestane; and (3) introducing an effective amount of at least one chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of: (1)at least one (e.g. one) link the formula 1.0; (2)at least one aromatase inhibitor and (3)at least one LHRH analogue.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of:(1)at least one (e.g., one) compound of formula 1.0; (2)at least one antiestrogen; and (3)at least one LHRH analogue.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of: (1)at least one (e.g., one) compound of formula 1.0; (2)at least one aromatase inhibitor, which is selected from the group consisting of Anastrozole, Letrozole, Exemestane, Fadrozole and Formestane; and (3)at least one LHRH analogue, which is selected from the group consisting of: Goserelin and Leuprolide.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of: (1, at least one (e.g., one) compound of formula 1.0; (2)at least one antiestrogen is selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene and Acolbifene; and (3)at least one LHRH analogue, which is selected from the group consisting of: Goserelin and Leuprolide.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and Anastrozole.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and Letrozole.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and Exemestane.

Another option in the execution of the invention is a method of treating or preventing breast cancer in a patient, who needs such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and Fadrozole.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and Formestane.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and Tamoxifen.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 Fulvestrant.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient, to the mu need such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and Raloxifene.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and Acolbifene.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and Goserelin.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and Leuprolide.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where asanee treatment includes the introduction of a therapeutically effective amount, at least one (e.g., one) compound of formula 1.0, Anastrozole and antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene and Acolbifene.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Letrozole and antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene and Acolbifene.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Exemestane and antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene and Acolbifene.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least, one of the CSOs (for example, one) compound of formula 1.0, Fadrozole and antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene and Acolbifene.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Formestane and antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene and Acolbifene.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Anastrozole and Tamoxifen.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Letrozole and Tamoxifen.

Another embodiment of the invention submitted is a method of treating or preventing breast cancer in a patient, who needs such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Exemestane and Tamoxifen.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Fadrozole and Tamoxifen.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Formestane and Tamoxifen.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Anastrozole and Fulvestrant.

Another embodiment of the invention is a method of treatment or is the avoiding breast cancer in a patient, who needs such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Letrozole and Fulvestrant.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Exemestane and Fulvestrant.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Fadrozole and Fulvestrant.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Formestane and Fulvestrant.

Another embodiment of the invention is a method for the treatment of libradtran breast cancer in a patient, who needs such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Anastrazole and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Letrozole and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Exemestane and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another option, issue the log of the invention is a method of treating or preventing breast cancer in a patient, who needs such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Fadrozole and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Formestane and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Tamoxifen, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another version of the imp is the implementation of the invention is a method of treating or preventing breast cancer in a patient, who needs such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Fulvestrant and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Raloxifene, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Acolbifene and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another option in the execution of the invention is a method of treating or preventing breast cancer in a patient, who needs such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Goserelin and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Leuprolide and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Anastrozole, antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene and Acolbifene, and a chemotherapeutic agent selected from the group consisting of the: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Letrozole, antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene and Acolbifene, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Exemestane, antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene and Acolbifene, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or predot who stop breast cancer in a patient, who needs such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Fadrozole, antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene and Acolbifene, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Formestane, antiestrogen selected from the group consisting of: Tamoxifen, Fulvestrant, Raloxifene and Acolbifene, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., real is) the compounds of formula 1.0, The anastrozole, Tamoxifen, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Letrozole, Tamoxifen, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Exemestane, Tamoxifen, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment,where said treatment includes the introduction of a therapeutically effective amount, at least one (e.g., one) compound of formula 1.0, Fadrozole, Tamoxifen, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Formestane, Tamoxifen, and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Anastrozole, Fulvestrant and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method for the treatment or prevention of cancer is breast cancer in a patient, who needs such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Letrozole, Fulvestrant and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Exemestane, Fulvestrant and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Fadrozole, Fulvestrant and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab the a and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Formestane, Fulvestrant and a chemotherapeutic agent selected from the group consisting of: Trastuzumab, Gefitinib, Erlotinib, Bevacizumab, Cetuximab, and Bortezomib.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Goserelin and Tamoxifen.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Goserelin and Fulvestrant.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient, which clean the Dimo such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Goserelin and Raloxifene.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Goserelin and Acolbifene.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Leuprolide and Tamoxifen.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Leuprolide and Fulvestrant.

Another embodiment of the invention is a method of treating or preventing breast cancer oupatient, who needs such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Leuprolide and Raloxifene.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Leuprolide and Acolbifene.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Goserelin and Anastrozole.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Goserelin and Letrozole.

Another embodiment of the invention is a method of treatment or before the rotation of breast cancer in a patient, who needs such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Goserelin and Exemestane.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Goserelin and Fadrozole.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Goserelin and Formestane.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Leuprolide and Anastrozole.

Another embodiment of the invention is a method of treatment or before the rotation of breast cancer in a patient, who needs such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Leuprolide and Letrozole.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Leuprolide and Exemestane.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Leuprolide and Fadrozole.

Another embodiment of the invention is a method of treating or preventing breast cancer in a patient requiring such treatment, where said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Leuprolide and Formestane.

Another embodiment of the invention is the treatment or predotvrasheniye breast cancer in a patient, who needs such treatment, and said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and Anastrozole.

Another embodiment of the invention is the treatment or prevention of breast cancer in a patient requiring such treatment, and said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and Letrozole.

Another embodiment of the invention is the treatment or prevention of breast cancer in a patient requiring such treatment, and said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and Exemestane.

Another embodiment of the invention is the treatment or prevention of breast cancer in a patient requiring such treatment, and said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and Tamoxifen.

Another embodiment of the invention is the treatment or prevention of breast cancer in a patient, which required the such treatment, and said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0 and Fulvestrant.

Another embodiment of the invention is the treatment or prevention of breast cancer in a patient requiring such treatment, and said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Anastrozole and Fulvestrant.

Another embodiment of the invention is the treatment or prevention of breast cancer in a patient requiring such treatment, and said treatment includes the introduction of a therapeutically effective amount of at least one compound of formula 1.0 (e.g., one), Letrozole and Fulvestrant

Another embodiment of the invention is the treatment or prevention of breast cancer in a patient requiring such treatment, and said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Exemestane and Fulvestrant.

Another embodiment of the invention is the treatment or prevention of breast cancer in a patient, which it is odimo such treatment, and said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Anastrozole and Tamoxifen.

Another embodiment of the invention is the treatment or prevention of breast cancer in a patient requiring such treatment, and said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Letrozole and Tamoxifen.

Another embodiment of the invention is the treatment or prevention of breast cancer in a patient requiring such treatment, and said treatment includes the introduction of a therapeutically effective amount of at least one (e.g., one) compound of formula 1.0, Exemestane and Tamoxifen.

Other embodiments of the present invention are any of the above embodiments for the treatment of breast cancer, where the chemotherapeutic agent is a Trastuzumab.

Other variants of the present invention are any of the above embodiments for the treatment or prevention of breast cancer, where the method is directed to the treatment of breast cancer.

The connection is ormula 1.0, antihormone tools and chemotherapeutic agents can be administered simultaneously or sequentially.

Antihormone tools and chemotherapeutic agents are introduced in accordance with the protocols, doses and dosage forms that are well known to experts in the art (for example, Physician''s Desk Reference or published literature). For example, Tamoxifen, Fulvestrant, Raloxifene, Anastrozole, Letrozole, Exemestane, Leuprolide and Goserelin, see Physician''s Desk Reference, 57thEdition, 2003, published by Thomas PDR at Montvale, N.J. 07645-1742, which is incorporated herein in full by reference.

In General, in versions of the invention directed to methods of treatment for breast cancer: (1) compound of formula 1.0 can be administered daily (e.g., once a day, and in one embodiment, a compound of formula 1.0 can be administered twice a day), (2) aromatase inhibitors can be introduced by known protocols used for aromatase inhibitors (for example, once a day), (3) antiestrogens may be introduced by known protocols used for antiestrogen (for example, from once per day to once per month) (4) LHRH analog may be administered by known Protocol used for LHRH analogue (e.g., from once a month to one of razgadai three months) and (5) a chemotherapeutic agent may be administered by known protocols used for chemotherapeutic agent (e.g., from once a day to once a week).

Radiotherapy, in the case of the introduction of the above treatments for breast cancer, typically entered by known protocols prior to the introduction of the compounds of formula 1.0, antihormone tools and optional chemotherapeutic agents.

The treatment methods of breast cancer treatment is continuous (i.e., on a continuous dosing scheme). The treatment is carried out to achieve a complete response, or until an experienced clinical doctor determines that the patient is not benefiting from treatment (for example, when the disease progresses).

Continuous treatment Protocol for breast cancer can be replaced by intermittent treatment regimen, if according to the assessment of experienced clinical doctor, the patient will benefit from intermittent regimens with one or more injected drugs. For example, the compound of formula 1.0 can be administered by intermittent regimens, whereas the remaining drugs used in the treatment are entered as described here. An example of intermittent treatment Protocol, with the introduction of the compounds of formula 1.0 is a repeating cycle of three weeks with the introduction of the compounds of formula 1.0, followed by one week without the introduction of the compounds of formula 1.0.

Once achieved a complete response to cured the e breast cancer, supportive therapy can be carried out using the compounds of formula 1.0, at the dosage described in the method according to the present invention. Supportive therapy may also include the introduction of antihormone funds, using the dosage described in the methods according to the present invention. Supportive therapy can be carried out only with the help of antihormone funds. For example, once achieved a complete response, the aromatase inhibitor (for example, Anastrozole, Letrozole or Exemestane) may be entered within five years. Alternatively, for example, an antiestrogen such as Tamoxifen, can be applied after achieving complete response during the period, the duration of which is up to five years, with the subsequent use of aromatase inhibitor (for example, Anastrozole, Letrozole or Exemestane) over a period of time, the duration of which is up to five years.

In versions of the invention, aimed at the treatment of breast cancer, as disclosed above, the compound of formula 1.0 is introduced continuously at a total daily dose from about 100 mg to about 600 mg this is Usually the total number is entered in the form of individual doses, and in one embodiment, this number is entered twice a day. In one embodiment, a compound of formula was twice a day, in the amount from about 50 mg to about 300 mg per dose. In another embodiment, a compound of formula 1.0 is injected twice a day, in the amount from about 100 mg to about 200 mg per dose. Examples include the compound of formula 1.0, which is injected twice a day, in the amount of 100 mg per dose. Examples include a compound of formula 1.0, which is injected twice a day, in the amount of 200 mg per dose.

Anastrozole is introduced through the mouth, once a day, in the amount of from about 0.5 to about 10 mg per dose, and in one embodiment in an amount of about 1.0 mg per dose.

Letrozole is introduced through the mouth, once a day, in the amount of from about 1.0 to about 10 mg per dose, and in one embodiment in an amount of about 2.5 mg per dose.

Exemestane is introduced through the mouth, once a day, in the amount of from about 10 to about 50 mg per dose, and in one embodiment in an amount of about 25 mg per dose.

Fadrozole introduced by mouth, twice a day, in the amount of from about 0.5 to about 10 mg per dose, and in one embodiment in an amount of about 2.0 mg per dose.

Formestane is injected once every two weeks, intramuscularly, in the amount of from about 100 to about 500 mg per dose, and in one embodiment in an amount of about 250 mg per dose.

Tamoxife is introduced through the mouth, once a day, in the amount of from about 10 to about 100 mg per dose, and in one embodiment in an amount of about 20 mg per dose.

Fulvestrant is administered intramuscularly, once a month, in the amount of from about 100 to about 1000 mg per dose, and in one embodiment of the invention, in an amount of about 250 mg per dose.

Raloxifene is introduced through the mouth, once a day, in the amount of from about 10 to about 120 mg per dose, and in one embodiment in an amount of about 60 mg per dose.

Acolbifene introduced by mouth, once a day, in the amount of from about 5 to about 20 mg per dose, and in one embodiment in an amount of about 20 mg per dose.

Goserelin subcutaneously, once a month or once every three months, in the amount of from about 2 to about 20 mg per dose, and in one embodiment in an amount of about 3.6 mg per dose at introduction once a month, and in another embodiment in an amount of about 10.8 mg per dose, with the introduction of once every three months.

Leuprolide administered subcutaneously once a month or once every three months, in the amount of from about 2 to about 20 mg per dose, and in one embodiment of the invention, in an amount of about 3.75 mg per dose, with the introduction of once a month, and in another embodiment, the quantity is as about 11.25 mg per dose, with the introduction of once every three months.

Trastuzumab is injected intravenously, once a week, in the amount of from about 2 to about 20 mg/kg per dose, and in one embodiment in an amount of about 2 mg/kg dose. Trastuzumab, as a rule, first introduced in shock dose, which, as a rule, two weekly doses. Thus, for example, is injected dose, 4 mg/kg, and then put 2 mg/kg per dose for a week.

Gefitinib introduced by mouth, once a day, in the amount of from about 100 to about 1000 mg per dose, and in one embodiment in an amount of about 250 mg per dose.

Erlotinib introduced by mouth, once a day, in the amount of from about 100 to about 500 mg per dose, and in one embodiment in an amount of about 150 mg per dose.

Bevacizumab is injected intravenously once every two weeks, in amounts of from about 2.5 to about 15 mg per kilogram of body weight per dose, and in one embodiment in an amount of about 10 mg per kilogram per dose.

Cetuximab is injected intravenously, once a week, in the amount of from about 200 to about 500 mg per square meter per dose, and in one embodiment in an amount of about 250 mg per square meter per dose.

Bortezomib is administered intravenously way is, twice a week, for two weeks and then 10 days off (treatment cycle is 21 days), with a maximum of 8 cycles of treatment, in an amount of from about 1.0 to about 2.5 mg per meter square per dose, and in one embodiment in an amount of about 1.3 mg per square meter per dose.

Thus, in one embodiment, the present invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0 by mouth, in the amount of from about 50 mg to about 300 mg per dose, and each dose is given twice a day, and (2) of Anastrozole oral by, in the amount of from about 0.5 to about 10 mg per dose, and each dose is given once a day.

In another embodiment, the present invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, by mouth, in the amount of from about 100 to about 200 mg per dose, and each dose is given twice a day, and (2) of Anastrozole in an amount of about 1.0 mg per dose, and each dose is given once a day.

In another embodiment, the present invention breast cancer is treated (or predotvrashayetsya) in a patient, who needs such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, by mouth, in the amount of from about 50 mg to about 300 mg per dose, and each dose is given twice a day, and (2) Letrozole, by mouth, in the amount of from about 1.0 to about 10 mg per dose, and each dose is given once a day.

In another embodiment, the present invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, by mouth, in an amount of about 100-200 mg per dose, and each dose is given twice a day, and (2) Letrozole, by mouth, in an amount of about 2.5 mg per dose, and each dose is given once a day.

In another embodiment, the present invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, by mouth, in the amount of from about 50 mg to about 300 mg per dose, and each dose is given twice a day, and (2) Exemestane, by mouth, in the amount of from about 10 to about 50 mg per dose, and each dose is given once a day.

In other variations is the implementation of the present invention breast cancer is treated (or prevented) in a patient, who needs such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, by mouth, in an amount of about 100-200 mg per dose, and each dose is given twice a day, and (2) Exemestane in an amount of about 25 mg per dose, and each dose is given once a day.

In another embodiment of this [Invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, by mouth, in the amount of from about 50 mg to about 300 mg per dose, and each dose is given twice a day, and (2) Fulvestrant, intramuscularly, in the amount of from about 100 to about 1000 mg per dose, and each dose is given once a month.

In another embodiment, the present invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, by mouth, in an amount of about 100-200 mg per dose, and each dose is given twice a day, and (2) Fulvestrant, intramuscularly, in the amount of about 250 mg per dose, and each dose is given once a month.

In another embodiment, the present invention RA is breast cancer is treated (or prevented) in a patient, who needs such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, by mouth, in the amount of from about 50 mg to about 300 mg per dose, and each dose is given twice a day, and (2) Tamoxifen, oral, in the amount of from about 10 to about 100 mg per dose, and each dose is given once a day.

In another embodiment, the present invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, by mouth, in an amount of about 100-200 mg per dose, and each dose is given twice a day, and (2) of Tamoxifen oral by, in an amount of about 20 mg per dose, and each dose is given once a day.

In other embodiments, execution of the present invention breast cancer is treated by a patient who is in need of such treatment, when said treatment consists of the administration of the compounds of formula 1.0, one of the aromatase inhibitors (e.g. Anastrozole, Letrozole or Exemestane, and in one embodiment of the invention Anastrozole), and one of antiestrogens (for example, Fulvestrant or Tamoxifen), where the compound of formula 1.0, aromatase inhibitor and an antiestrogen is introduced in doses disclosed above

Thus, for example, in another embodiment, the present invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, by mouth, in the amount of from about 50 mg to about 300 mg per dose, and each dose is given twice a day, (2) of Anastrozole oral by, in the amount of from about 0.5 to about 10 mg per dose, and each dose is given once a day, and (3) Fulvestrant, intramuscularly, in the amount of from about 100 to about 1000 mg per dose, and each dose is given once a month.

In another embodiment, the present invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, by mouth, in an amount of about 100-200 mg per dose, and each dose is given twice a day, (2) of Anastrozole oral by, in an amount of about 1.0 mg per dose, and each dose is given once a day, and (3) Fulvestrant, intramuscularly, in the amount of about 250 mg per dose, with each the dose is given once a month.

In another embodiment, the present invention breast cancer is treated (or prevented) in a patient, which which need such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0 by mouth, in the amount of from about 50 mg to about 300 mg per dose, and each dose is given twice a day, (2) Letrozole, by mouth, in the amount of from about 1.0 to about 10 mg per dose, and each dose is given once a day, and (3) Fulvestrant, in the amount of from about 100 to about 1000 mg per dose, and each dose is given once a month.

In another embodiment, the present invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, by mouth, in an amount of about 100-200 mg per dose, and each dose is given twice a day, (2) Letrozole, by mouth, in an amount of about 2.5 mg per dose, and each dose is given once a day, and (3) Fulvestrant, intramuscularly, in the amount of about 250 mg per dose, with each the dose is given once a month.

In another embodiment, the present invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, by mouth, in the amount of from about 50 mg to about 300 mg per dose, presentada dose given twice a day, (2) Exemestane, by mouth, in the amount of from about 10 to about 50 mg per dose, and each dose is given once a day, and (3) Fulvestrant, intramuscularly, in the amount of from about 100 to about 1000 mg per dose, and each dose is given once a month.

In another embodiment, the present invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, by mouth, in an amount of about 100-200 mg per dose, and each dose is given twice a day, (2) Exemestane, by mouth, in an amount of about 25 mg per dose, and each dose is given once a day, and (3) Fulvestrant, intramuscularly, in the amount of about 250 mg per dose, with each the dose is given once a month.

In another embodiment, the present invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0 in amount from about 50 mg to about 300 mg per dose, by mouth, with each dose given twice a day, (2) Anastrozole in an amount of from about 0.5 to about 10 mg per dose, oral route, and each dose is given once a day, and (3) of Tamoxifen in to the Icesave from about 10 to about 100 mg per dose, through the mouth, and each dose is given once a day.

In another embodiment, the present invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0 in an amount of about 100-200 mg per dose by mouth, with each dose given twice a day, (2) Anastrozole in an amount of about 1.0 mg per dose, oral route, and each dose is given once a day, and (3) of Tamoxifen in an amount of about 20 mg per dose by mouth, with each dose enter once a day.

In another embodiment, the present invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0 in amount from about 50 mg to about 300 mg per dose, by mouth, with each dose given twice a day, (2) Letrozole in the amount of from about 1.0 to about 10 mg per dose, oral route, and each dose is given once a day, and (3) of Tamoxifen in the amount of from about 10 to about 100 mg per dose, oral route, and each dose is given once a day.

In another embodiment, the present invention breast cancer is not the Xia (or prevented) in a patient, who needs such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, in an amount of about 100-200 mg per dose by mouth, with each dose given twice a day, (2) Letrozole in an amount of about 2.5 mg per dose, oral route, and each dose is given once a day, and (3) of Tamoxifen in an amount of about 20 mg per dose, oral route, and each dose is given once a day.

In another embodiment, the present invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, in the amount of from about 50 mg to about 300 mg per dose, by mouth, with each dose given twice a day, (2) Exemestane, in the amount of from about 10 to about 50 mg per dose, oral route, and each dose is given once a day, and (3) Tamoxifen, in the amount of from about 10 to about 100 mg per dose, oral route, and each dose is given once a day.

In another embodiment, the present invention breast cancer is treated (or prevented) in a patient requiring such treatment, when said treatment includes the introduction of a specified patient: (1) the compounds of formula 1.0, in an amount of about 10-200 mg per dose, by mouth, with each dose given twice a day, (2) Exemestane in an amount of about 25 mg per dose, oral route, and each dose is given once a day, and (3) Tamoxifen, in an amount of about 20 mg per dose, oral route, and each dose is given once a day.

Specialists in the art it is obvious that when using other combinations antihormonal agents, private antihormonal agent is used in quantities above a separate antihormonal agent.

Other treatment options for breast cancer are the ways to treat breast cancer, disclosed above, where the compounds of formula 1.0 is injected twice a day, in an amount of about 100 mg per dose.

Other treatment options for breast cancer are the ways to treat breast cancer, disclosed above, where the compounds of formula 1.0 is injected twice a day, in an amount of about 200 mg per dose.

Other treatment options for breast cancer are the ways to treat breast cancer, disclosed above, where the chemotherapeutic agent is introduced in addition to the compound of formula 1.0 and antihormonal agent (or antihormonal agents). In these versions of the invention the spacing of the doses of the compounds of formula 1.0 and antihormonal agents is s are such as disclosed above for combinatorial therapies, or such as is disclosed above for the individual compounds of formula I and antihormonal agents, and dosages of chemotherapeutic agents are as disclosed above for a single chemotherapeutic agent. Doses of chemotherapeutic agents are well known in the prior art.

Other embodiments of the present invention are pharmaceutical compositions containing the compound of formula 1.0 and at least one antihormonal agent and a pharmaceutically acceptable carrier.

Other embodiments of the present invention are pharmaceutical compositions containing the compound of formula 1.0, at least one antihormonal agent, at least one chemotherapeutic agent and a pharmaceutically acceptable carrier.

Other variants of the present invention are pharmaceutical compositions containing the compound of formula 1.0, at least one chemotherapeutic agent and a pharmaceutically acceptable carrier.

Specialists in the art it will be obvious that the compounds (drugs)used in the methods according to the invention is available to a qualified clinical doctor in pharmaceutical compositions (formulations) from about the of voditelei and used in these compositions. So, the casting compound or class of compounds in the above-described methods may be replaced by bringing a pharmaceutical composition containing a specific compound or class of compounds. For example, an embodiment of the invention directed to a method of treating cancer, which contains the introduction to the patient requiring such treatment, a therapeutically effective amount of the compounds of formula 1.0, taxane and coordination compounds of platinum, covers a method of treating cancer, comprising the administration to a patient who is in need of such treatment, a therapeutically effective amount of a pharmaceutical composition containing the compound of formula 1.0, pharmaceutical compositions containing Texan, and pharmaceutical compositions containing coordination compound of platinum.

Specialists in the art it is obvious that the exact dosage and protocols introduction, used in the methods according to the present invention, may vary depending on the assessment of a qualified clinical medical doctor. The exact applied dose may vary depending on the needs of the patient and the severity of the condition to be treated. Identifying the appropriate dose for a particular case is within the competence of a person skilled in the art. Determining how argirov the th dose and treatment protocols, can be done after a qualified clinical doctor will consider such factors as age, condition and weight of the patient, and the severity of the cancer to be treated, and the response of the patient to treatment.

The number and frequency of introduction of the compounds of formula 1.0 and chemotherapeutic agents will be regulated according to the assessment of a qualified clinical doctor (primary care physician), taking into account such factors as age, condition and weight of the patient, as well as the severity of the cancer to be treated.

The chemotherapeutic agent can be administered for therapeutic protocols well known to specialists in this field of technology. Specialists in the art it is obvious that the introduction of the chemotherapeutic agent may vary depending on the type of cancer to be treated, and the effects provided chemotherapeutic agent for the disease. Also, based on the knowledge of a qualified clinical doctor, therapeutic protocols (e.g., the size of the dose and number of injections) can vary depending on the observed effects exerted on the patient by introduction of therapeutic agents, and depending on the observed response of the cancer to the introduction of therapeutic agents.

The initial introduction can be carried out on the plant and in the field of technology protocols, and then the dose, route of administration and the number of injections can vary qualified clinical doctor depending on the observed effects.

The specific choice of the chemotherapeutic agent will depend on the diagnosis of the treating physician and his assessment of the patient and the appropriate treatment Protocol.

Determination of the order of introduction and the number of repetitions of the introduction of the chemotherapeutic agent in the implementation of the treatment Protocol is the responsibility of the attending physician, and occurs after the evaluation of the cancer to be treated, and the condition of the patient.

Thus, the attending physician, based on his experience and knowledge, can modify each Protocol for the introduction of the chemotherapeutic agent, depending on the needs of the individual patient, as the treatment proceeds. All such modifications are within the scope of the present invention.

The specific choice antihormonal agents, optional chemotherapeutic agents, and optional exposure depends on the diagnosis of the attending physician and his assessment of the patient and the appropriate treatment Protocol.

Determination of the order of introduction and the number of repetitions of the introduction of antihormonal agents, optional chemotherapeutic agents, and optional radiation treatment Protocol is the responsibility of the attending physician when choosing the appropriate evaluation of breast cancer, to be treated, and the condition of the patient.

Thus, the attending physician, based on his experience and knowledge, can modify each Protocol for the introduction of antihormonal agents, optional chemotherapeutic agents, and optional exposure, depending on the needs of the individual patient, as the treatment proceeds. All such modifications are within the scope of the present invention.

Doctor, when assessing the effectiveness of treatment when injected dose, will examine the overall health of the patient, as well as more specific indicators, such as the relief of symptoms caused by cancer (e.g., pain, cough (lung cancer) and shortness of breath (lung cancer)), inhibition of tumor growth, the actual compression of the tumor or inhibition of metastasis. Tumor size can be measured by standard means, such as a radiological study, for example, CAT or MRI scan, and serial measurements can be used to assess whether tumor growth is slowed down or even prevented or not. Relief of symptoms associated with the disease, such as pain, and improvement in General condition can also be used to assess the effectiveness of treatment.

Compounds according to the present invention can be obtained by the methods disclosed in US 2007/0191604, published on August 16, 2007, U.S. No. 11/810282, filed June 2007, as well as by the methods described below. US 2007/0191604 and U.S. No. 11/810282 incorporated herein in full by reference.

The following conditions apply JHMS: (1) C-18 oblashtovana column, 5 μm, 4.6×50 mm, (2) MS:PE Sciex API-150EX, and (3) HPLC: Shimadzu LC-10 ADvp, 1 ml/min, linear gradient of 10% acetonitrile in water to 95% acetonitrile in water, both containing 0.05% TFA.

Example 1

Synthesis of 3-Methoxy-1-(2-{4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-pyrrolidin-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide

Synthesis of 2-chloro-1-{4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-ethanone

Stage 1: Obtain 4-bromo-benzimidazol acid complex ethyl ester

4-Bromo-benzonitrile (5 g) is suspended in absolute EtOH (100 ml) and cooled to 0-5°C. was Barbotirovany HCl gas, first intensively, and then slowly for 5 hours. The resulting solution was stirred overnight. A large part of the solvent was removed and the precipitate was filtered, washed twice EtOH and dried to obtain compound VN (4.1 g) as a solid white color.

Stage 2: Getting Connection VN

4-Bromo-benzimidazol acid complex ethyl ester (2.12 g, 8 mmol) was dissolved in pyridine (20 ml). When mixing on bavili methylhydrazine (640 μl, 12 mmol), the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, was added diethyl ether, filtered, washed three times with diethyl ether and dried to obtain compound VN (2.2 g).

Stage 3: Obtain 3-(4-bromo-phenyl)-1-methyl-1H-[1,2,4]triazole

The mixture of compounds VN (2.2 g) in formic acid (30 ml) was boiled under reflux and then concentrated. The residue was treated with saturated NaHCO, and was extracted three times with EtOAc. The combined organic phase was dried over MgSO4. After concentrating the received connection NR 4 in the form of colorless crystals (1.39 g). (It should be noted that it was found that the reaction should be conducted for no more than two hours. Large-scale synthesis it is necessary to use 10% NaOH instead of NaHCO3).

Stage 4: Obtain 4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ether complex

In a large flask of high pressure loaded connection NR 4 (13.3 g, 55.9 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (19 g, 61.5 mmol), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (2.3 g, 2.8 mmol), K2CO3(2.2 g, 168 mmol) and DME/water (5:1, 120 ml). The mixture was quickly degirolami argon (Ar) for about 0.5 minutes, covered and stirred at 80°C overnight. After cooling, the reaction mixture was diluted with EtOAc and brine solution. The organic layer was isolated and dried (MgSO4). After concentration the residue was purified on silica gel. Carrying out elution with Meon/EtOAc (0-10%) gave the desired product VN (13.9 g, 73%).

Stage 5: Obtain 4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-1,2,3,6-tetrahydro-pyridine hydrochloride

The first group can be removed by treating the compound WN a solution of 4N HCl in dioxane at room temperature for two hours. Removal of solvent in vacuo gave the opportunity to get connection VN.

Step 6: Obtain 2-chloro-1-{4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-ethanone

To a cooled solution (0°C) 4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-1,2,3,6-tetrahydro-pyridine 6 EXT (13.7 g, 44 mmol) in dichloromethane (450 ml) was dropwise added TEA (37 ml, 264 mmol). After stirring at 0°C for 10 minutes to the reaction mixture was added chloro-acetyl chloride (10.5 ml, 132 mmol). The resulting mixture was stirred at 0°C for one hour and extinguished with water (165 ml). The reaction mixture was diluted with dichloromethane (600 ml). The organic layer was separated and washed salt dissolve the Ohm, dried over MgSO4. The reaction mixture was concentrated to about 50 ml, was added diethyl ether, and the solid was filtered to give the desired product VN (8.74 g).

Synthesis of 3-Methoxy-pyrrolidin-3-carboxylic acid complex of methyl ether

Stage 1: Obtain methyl α,α-dimethoxypropionate

Followed the methodology Ernest Wenkert, et al. (JACS, 1983, 105, 2021-2029). The solution methylpiruvate (44 g), triethylorthoformate (62 ml), concentrated H2SO4(0.2 ml) in the Meon (120 ml) was boiled under reflux for 4 hours. In the next hour person to distil the solvent (80 ml). The reaction mixture was cooled to 10°C., poured into a solution of KOH (1.2 g KOH in 600 ml of water and was extracted with diethyl ether (3×). The combined diethyl ether extracts were washed with brine and dried (MgSO4). After concentration the residue person to distil under vacuum obtaining acetal (VN) (40 g, 62%, 40-and 43C/1 Torr).

Stage 2: Getting 2-ethoxyacrylate

Followed the methodology Ernest Wenkert, et al. (JACS, 1983, 105, 2021-2029). Odnogolosy flask downloaded α,α-dimethoxypropionate (8 HV) (150 g) and toluensulfonate acid monohydrate (3 g), and joined the distiller for molecular distillation. The mixture was heated to 140°C (temperature of the water bath), and the methanol evaporated first. is the product (76 g) (WN) person to distil after as the oil bath temperature exceeded 190°C.

Stage 3: Obtain 1-benzyl-3-methoxy-pyrrolidin-3-carboxylic acid complex of methyl ether

To a stirred solution of methyl 2-ethoxyacrylate (20.8 g, 179 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (55 ml, 215 mmol) in dichloromethane (160 ml) at 0°C was added a solution triperoxonane acid (2 ml) in dichloromethane (10 ml). The resulting solution was heated to room temperature and stirred overnight. After concentration the crude product was purified by column chromatography on silica gel, was suirable with a mixture of ethyl acetate/hexane/Et3N (1000:3000:4-1000:1000:3) to give the compounds whose name is stated in the title, (VN), (17.7 mg, 40%). (It should be noted that the addition of Et3N it is important to ensure deep division.)

Stage 4: Getting salt of 3-methoxy-pyrrolidin-3-carboxylic acid complex methyl ester and tartaric acid

1-Benzyl-3-methoxy-pyrrolidin-3-carboxylic acid methyl ester (VN) (2.49 g) was hydrogenosomal in ethanol using 10% Pd/C at 55 psi of hydrogen for 24 hours Filtration on Pd/C, followed by evaporation of the ethanol gave 1.6 g of the crude dibenzylamino product (VN). The crude product was dissolved in 95 ml of methanol, and added and 1.35 g of L-tartaric acid. After 24 hours the crystals were filtered and recrystallize from methanol to obtain 13.4 g of the product (VN), the name of which is specified in the title.

Stage 5: Obtain 3-Methoxy-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ether complex

To a cooled solution (0°C) connection VN (28 g, 90.52 mmol) in dry CH2Cl2(250 ml) was added triethylamine (31.5 ml, 226.32 mmol, 2.5 equiv.), and then (Re)2O (25.7 g, 117.68 mmol, 1.3 equiv.). The resulting mixture was stirred at a temperature of from 0°C. to room temperature overnight, and then diluted CH2Cl2, the resulting mixture was washed with a saturated aqueous solution of NaHCO3and with brine, dried (MgSO4) and concentrated. Chromatography on silica gel (hexane/ethyl acetate, 4:1) allowed to obtain a connection VN (23.5 mg, 90.52 mmol, 100%) as a colourless oil.

To a stirred solution of compound VN (23.5 mg, 90.52 mmol) in THF/MeOH (175 ml 175 ml) was added 135 ml of LiOH (1M in H2O, 135 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature overnight, then added 135 ml of 1N HCl. The resulting mixture was stirred for another 15 minutes and then concentrated, azeotropically with dioxane (150 ml × 3) to obtain the compound VN (42.32 g) as a solid white color that was used in the next stage without further the cleaning.

The alternate connection VN can be obtained in the following way:

To an ice-cold solution of 3-oxo-pyrrolidin-1-carboxylic acid benzyl complex ester 1A (250 g, 1.14 mol) in 3.5 l of anhydrous dichloromethane was added KCN (7.5 g, 0.12 mol)are then added 18-crown-6 (30 g, 0.11 mol), despite the incomplete dissolution, slowly added TMSCN (183 ml, 1.37 mol) over 20 minutes. The reaction mixture was stirred at ambient temperature overnight. Polynesians solution of NaHCO3(2 l) was added at 15°C was stirred for 10 minutes, and then the organic layer was separated, dried over magnesium sulfate, filtered, and boiled away with 3-Cyano-3-trimethylsilyloxy-pyrrolidin-1-carboxylic acid benzyl complex ester 2A, 422 g (>100%).

3-Cyano-3-trimethylsilyloxy-pyrrolidin-1-carboxylic acid complex benzyl ether 2A (422 g) in 4 l of anhydrous Meon added 2.2 l of a solution of 4N HCl in dioxane. The reaction mixture is boiled under reflux for 13 hours and was stirred at ambient temperature overnight. Removed the solvent, and then suspended in 5 l of CH2Cl2, washed 4+3 liters of water, set pH 6-7 with aqueous NaHCO3, dried over magnesium sulfate, filtered, and boiled away with 3-hydroxy-pyrrolidine-1,3-dicarboxylic acid 1-b is solovovo of ester 3-methyl ether complex 3A, 278 g (Stage 2, 87%).

To a suspension of NaH (52 g, 1.3 mol) in 2.2 l of anhydrous DMF at 8°C was added a solution of 3-hydroxy-pyrrolidine-1,3-dicarboxylic acid 1-benzyl complex ester 3-methyl ether complex 3A (278 g, 1.0 mol) in 700 DMF, the reaction temperature was maintained below 11°C. After complete addition (about 20 minutes), remove the ice bath, stirred it up at 16-18°C for one hour and then at ambient temperature for one hour. Was cooled to 15°C., slowly added Mel (81 ml, 1.3 mol). The reaction mixture was stirred at ambient temperature overnight. Then the reaction mixture is poured into cold water (4 l) and then was extracted with Et2O (6 l) and EtOAc (2 l), washed the organic layer with water (5 l), saline solution (700 ml), dried over magnesium sulfate, filtered, and boiled away to obtain crude 3-methoxy-pyrrolidine-1,3-dicarboxylic acid 1-benzyl complex ester 3-methyl ether complex 4A 289 g (99% yield of the crude product that contains mineral oil) (mixing/separation by washing with pentane gave compound 4A, 268.2 g (92%).

To 3-methoxy-pyrrolidine-1,3-dicarboxylic acid 1-benzyl complex ester 3-methyl ether complex 4A in the Meon (2200 ml) was added 14 g of 10% Pd/C (50% in water). The reaction mixture was hydrogenosomal using H2at a pressure of about 55 psi (valve is open)all night. The reaction mixture was filtered, dried to obtain 3-methoxy-pyrrolidin-3-carboxylic acid complex methyl ester IN 126 g (total yield for the four stages amounted to 70%, without column purification).

Synthesis of 3-methoxy-pyrrolidin-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide

Stage 1:

5-Bromo-1H-pyridone 1BI (100 g, 0.58 mol), sodium carbonate (238 g, 1.73 mol) and 2-iodopropane (86 ml, 0.86 mol) was stirred in DMF (1 l) at room temperature for one day. The mixture was diluted with ethyl acetate and water, the layers were separated. The separated organic layer was washed with water (x2), dried (MgSO4) and was filtered. The solvents were removed in vacuo, and purification by column [5% ethyl acetate in hexano] gave the first of the less polar 5-isopropoxypyridine 2BIa (73 g, 59%) as a colourless liquid. Further elution of [50% ethyl acetate in hexano] gave the more polar 5-bromo-1-isopropylpyridine 2BIb in a solid white color (22 g, 18%).

Stage 2:

5-Isopropoxypyridine 2BIa (10 g, 0.046 mol), bis(pinacolato)LIBOR (14.1 g, 0.056 mol), potassium acetate (13.6 g, 0.14 mol) and PdCl2(dppf)2.CH2Cl2(3.78 g, 0.0046 mol) was weighed in a 2-throat-neck flask with a volume of 1 l, equipped with a water cooler. Added DMSO (100 ml)and the mixture was purged with nitrogen for 15 minutes. The mixture naked is evali at 100°C. in a nitrogen atmosphere, within two hours. After cooling to room temperature, added water (100 ml), toluene (100 ml), ethanol (100 ml), potassium carbonate (32 g, 0.23 mol) and brominated 3BI (22.4 g, 0.046 mol). The mixture was purged with nitrogen for 10 minutes at room temperature, and added Pd(Ph3P)4(5.35 g, 0.0046 mol). The resulting mixture was heated at 100°C for two hours and cooled to room temperature. Added water and ethyl acetate. The solids were filtered through celite. The layers were separated, and the separated organic layer was washed with water (x2). The combined aqueous layers were subjected to reversible extraction with ethyl acetate (X1). The combined organic layers were dried (MgSO4), filtered, and removed solvent in vacuo. Purification by column [Hexane-ethyl acetate = 9:1 (V/V)] gave isopropoxyethanol 4BI (20 g, 80%) as a solid yellow color.

Stage 3:

Isopropoxyethanol 4BI (20 g, 0.037 mol) and Pd/C (10%, 50%, 7.8 g, 0.0037 mol) was stirred in toluene (100 ml) and 2-propanol (200 ml) in an atmosphere of H2(rubber Luggage) at room temperature for one day. The solid catalyst was filtered through celite, and the solvents were removed in vacuum to obtain aminoindazole 5BI (Qty.) in a solid off-white color.

Stage 4:

Aminoindazole 5BI (39 g, 0.076 mol) is pyrrolidinecarbonyl acid VN (32 g, 0.069 mol) was dissolved in DMF (300 ml) at room temperature. Added HATU (29 g, 0.076 mol) and theniPr2NEt (14.5 ml, 0.083 mol). The mixture was stirred at room temperature overnight and diluted with ethyl acetate and water. The layers were separated. The separated organic layer was washed with water (x2), dried (MgSO4) and was filtered. Concentrated in vacuo and then purified on a column of [hexane-ethyl acetate = 4:1 (V/V)] to obtain the crude compound 7BI in the form of foam off-white color.

Stage 5:

The crude substance 7BI was stirred in a mixture of dichloromethane (300 ml), triperoxonane acid (100 ml) and water (50 ml) at room temperature overnight. The mixture was cooled at 0°C and carefully extinguished saturated aqueous sodium bicarbonate. The solvents were removed in vacuum. Diluted with water and ethyl acetate. The layers were separated, and the separated aqueous layer was extracted with ethyl acetate (X3). The combined organic layers were dried (MgSO4), filtered, and the solvents were removed in vacuum. Purification on a column of [5-10% Meon (7N ammonia) in dichloromethane] to give pyrrolidin 8BI (23 g, 84%) as a solid off-white color.

Alternative:

Boronat 1BJ (1.0 g, 3.80 mmol), brominate 2BJ (1.84 g, 3.80 mmol), sodium bicarbonate (1.21 g, 11.4 mmol) was loaded into zapasaemoi tube. D. bavili toluene (30 ml), ethanol (30 ml) and water (15 ml). The suspension was purged with nitrogen for 15 minutes and added Pd(Ph3P)4(439 mg, 0.38 mmol) in one portion. The mixture was heated in a sealed tube at 90°C overnight. After cooling to room temperature, added water and ethyl acetate, and the layers were separated. The separated organic layer was washed with water, dried (MgSO4) and was filtered. The solvents were removed in vacuum. The residue was dissolved in toluene (100 ml). Added methanol (100 ml) and then Pd/C (809 mg, 0.38 mmol, 50%). The mixture was stirred in an atmosphere of H2(rubber Luggage) all night. The catalyst was filtered, the solvents were removed in vacuum. Purification by column [hexane-ethyl acetate = 2:1 (V/V)] gave aniline 5BI (1.2 g, 61%, Stage 2) in a solid off-white color.

Synthesis of 3-Methoxy-1-(2-{4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl)-2-oxo-ethyl)-pyrrolidin-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide

The mixture of compounds VN (7.88 g, at 24.93 mmol), compound 8BI (9.86 g, at 24.93 mmol) and DIEA (26.1 ml, 149.62 mmol) in DMF (200 ml) was stirred at room temperature for 5 hours. The reaction was held at about 89% in accordance with GHMC. The reaction mixture then was heated at 50°C overnight (16 hours). IHMS showed completion of reaction. DMF was removed under reduced pressure. The crude product Rast is orily in 700 ml of DCM and once washed with 35 ml of water. The aqueous layer was extracted with 20%MeOH/DCM (2×120 ml). The combined organic extracts homogenized using Meon and dried over MgSO4. The solvent was removed and the crude product was purified by column chromatography using 20%MeOH/EtoAc to obtain the desired product A1 in the form of a solid yellow (70%). (IHMS M+1=674, retention time = 2.91 min)1H NMR (400 MHz, CD3OD): δ 8.67 (s, 1H), 8.42 (s, 1H), 8.35 (s, 1H), 8.15-8.19 (m, 1H), 7.94 (DD, 2H, J=8.4 & 10 Hz), 7.64 (m, 1H), 7.49 (m, 3H), 6.84 (m, 1H), 6.20 (d, 1H, J=11.2 Hz), 5.3 (m, 1H), 4.28 (s, 1H), 4.23 (m, 1H), 3.97 (s, 3H), 3.8 (m, 2H), 3.56 (d, 1H, 2.4 Hz), 3.52 (d, 1H, 6.4 Hz), 3.31 (s, 3H), 3.17 (t, 1H, J=10 Hz), 3.07 (t, 1H, J=12 Hz), 2.81 (m, 1H), 2.81 (m, 1H), 2.65 (s, 1H), 2.58 (s, 1H), 2.43 (m, 1H), 2.17 (m, 1H), 1.32 (d, 6N, J=6.4 Hz)

Example 2

Synthesis of 3-methoxy-1-(2-{4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-pyrrolidin-3-carboxylic acid [3-(6-hydroxy-pyridin-3-yl)-1H-indazol-5-yl]-amide

The above compound (A20) identified after the disintegration di-HCl salt of 3-methoxy-1-(2-{4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-pyrrolidin-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide.

IHMS M+1 634, retention time = 2.28 min1H-NMR (400 MHz, DMSO-d6): δ 13.09 (ush, 1H), 11.84 (ush, 1H), 10.02 (s, 1H), 8.51 (s, 1H), 8.37 (s, 1H), 8.02 (DD, 1H, J=9.5 Hz & 2.5 Hz), 7.95 (m, 2H), 7.82 (d, 1H, J=1.9 Hz), 7.71 (m, 1H), 7.51(m, 3H), 6.52 (d, 1H, J=9.5 Hz), 6.27 (m, 1H), 4.08-4.34 (m, 2H), 3.92 (s, 3H), 3.70 (m, 2H), 3.49 (m, 2H), 3.24 (s, 3H), 3.16 (d, 1H, J=5.2 Hz), 2.84-3.13 (m, 3H), 2.55-2.76 (m, 2H), 2.36 (m, 1H), 2.05 (m, 1H).

Example 3

Synthesis of 1-(2-{4-[4-(1,5-Dimethyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-3-methoxy-pyrrolidin-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide

Synthesis of (S)-1-(2-(4-(4-(1,5-dimethyl-1H-1,2,4-triazole-3-yl)phenyl)-5,6-dihydropyridines-1(2H)-yl)-2-oxoethyl)-N-(3-(6-isopropoxypyridine-3-yl)-1H-indazol-5-yl)-3-ethoxypyrrolidine-3-carboxamide

Stage 1: Obtain 3-(4-bromo-phenyl)-1,5-dimethyl-1H-[1,2,4]triazole

A mixture of the hydrochloride of 4-bromo-N'-methylbenzimidazole 1 (1.7 g) (obtained according to the method of synthesis of Sch-1499895) in acetic anhydride (10 ml) was heated at 100°C for 0.5 hours. After cooling and concentration under reduced pressure the residue was dissolved in EtOAc, washed twice with saturated NaHCO3, with brine and dried (MgSO4). After evaporation of the solvent the residue was purified on silica gel. Elution with EtOAc gave 3-(4-bromophenyl)-1,5-dimethyl-1H-[1,2,4]-triazole 2BK (1.04 g).

Stage 2: Obtain tert-butyl 4-(4-(1,5-dimethyl-1H-1,2,4-triazole-3-yl)phenyl)-5,6-dihydropyridines-1(2H)-carboxylate

In a test-tube high-pressure loaded connection 2BK (252 mg, 1 mmol), 4-(4,4,5,5-Tetra is ethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (403 mg, 1.3 mmol), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (41 mg, 0.05 mmol), K2CO3(410 mg, 3 mmol) and DME/water (5:1, 6 ml). The mixture was quickly degirolami with argon for about half a minute, it was covered and stirred at 100°C overnight. After cooling, the reaction mixture was diluted with EtOAc and brine solution. The organic layer was isolated and dried (MgSO4). After concentration the residue was purified on silica gel. Elution with Meon/EtOAc (0-10%) allowed to obtain the target product 3BK (332 mg).

Stage 3: Obtain 4-(4-(1,5-dimethyl-1H-1,2,4-triazole-3-yl)phenyl)-1,2,3,6-tetrahydropyridine hydrochloride

The Boc group can be removed by processing the connection 3BK a solution of 4N HCl in dioxane at room temperature for two hours. Removal of solvent in vacuo gave the opportunity to get connection 4BK.

Stage 4: Obtaining (S)-tert-butyl 2-(3-(3-(6-isopropoxypyridine-3-yl)-1H-indazol-5-ylcarbonyl)-3-ethoxypyrrolidine-1-yl)acetate

To a solution of compound 5BK (3.5 g, 6.6 mmol) (obtained according to the methodology in the synthesis of Sch-1499895) in acetonitrile (26 ml) was added DIEA (5.7 ml, 32.9 mmol). The solution was cooled to 0°C. and dropwise added 0.47 ml (3.29 mmol) of tert-BUTYLCARBAMATE. After stirring for 4 hours at 0°C again added 0.47 ml (3.29 mmol) of tert-butyl is aracataca. The solution was stirred for one hour at 0°C and then warmed to room temperature. After stirring overnight at room temperature, dissolved in EtOAc (200 ml) and washed NaHCO3(1×50 ml), water (1×50 ml) and with brine (1×50 ml). The organic extracts were dried over MgSO4, and the solvent removed. The crude product was purified by column chromatography using 20% Meon/EtOAC to obtain the desired product WK (2.4 g).

Stage 5: Obtaining (S)-2-(3-(3-(6-isopropoxypyridine-3-yl)-1H-indazol-5-ylcarbonyl)-3-ethoxypyrrolidine-1-yl)acetic acid

Connection 6BK (2.4 g) was treated with 40 ml of TFA for 45 minutes at room temperature. TFA was removed under reduced pressure, and the solid is washed with diethyl ether to obtain compound 7BK as TFA salt (4.4 g, 95%).

Step 6: Obtaining (S)-1-(2-(4-(4-(1,5-dimethyl-1H-1,2,4-triazole-3-yl)phenyl)-5,6-dihydropyridines-1(2H)-yl)-2-oxoethyl)-N-(3-(6-isopropoxypyridine-3-yl)-1H-indazol-5-yl)-3-ethoxypyrrolidine-3-carboxamide

To a mixture of compound 7BK (0.12 mmol), HATU (46 mg, 0.12 mmol) in DMF (2 ml) was added compound 4BK (39 mg, 0.12 mmol) and DIEA (0.063 ml). The mixture was stirred for twenty minutes and directly purified by HPLC to obtain compound A14. Mass when ECTR: GHMS M+1=690, retention time = 3.25 minutes;

1H NMR A14 HCl salt (400 MHz, DMSO-d6): δ 10.5 (ush, 1H), 10.23 (d, J=17.6 Hz, 1H), 8.7 (m, 1H), 8.45 (d, J=1.2 Hz, 1H), 8.18 (m, 1H), 7.94 (m, 2H), 7.75 (DD, J=8.8, 2.0 Hz, 1H), 7.56 (m, 3H), 6.93 (m, 1H), 6.3 (m, 1H), 5.3 (m, 1H), 4.6-4.53 (m, 2H), 4.2-4.0 (m, 3H), 3.82 (s, 3H), 3.7-3.5 (m, 5H), 3.3 (s, 3H), 2.67-2.54 (m, 3H), 2.44 (s, 3H), 2.4(m, 1H), 1.33 (d, J=6.4 Hz, 6N).

Example 4

Synthesis of 1-[2-(4-{3-Fluoro-4-[1-(2-methoxy-ethyl)-1H-[1,2,4]triazole-3-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-yl)-2-oxo-ethyl]-3-methoxy-pyrrolidin-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide

Synthesis of (S)-1-[2-(4-{3-fluoro-4-[1-(2-methoxy-ethyl)-1H-[1,2,4]triazole-3-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-yl)-2-oxo-ethyl]-3-methoxy-pyrrolidin-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide

Stage 1: Obtain 4-bromo-2-fluoro-benzamide

At 0°C in parts was added 1,1'-carbonyldiimidazole (8.8 g, 54.3 mmol) to a stirred mixture of 4-bromo-2-fermenting acid (6 g, 27.3 mmol) in dichloromethane (100 ml). Twenty minutes later received a clear solution. Added ammonium hydroxide (28%, 30 ml)and the mixture was stirred overnight. The aqueous layer was separated and was extracted twice with dichloromethane. The combined organic extracts were washed with water, twice 1 N HCl, water, brine solution and dried (MgSO4). The solvent was removed under vacuum, and the solid is washed what Aksana to obtain 4-bromo-2-fermentated 2BL (5.56 g).

Stage 2: Getting connection 3BL

The mixture of compounds 2BL (4.66 g, 21.48 mmol), Et3OPF6(6.4 g, 25.77 mmol) in dichloromethane (86 ml) was boiled under reflux for one hour. The solvent was removed under reduced pressure. The crude substance was cooled to 0°C, ground into powder with diethyl ether and filtered to obtain the target product 3BL (7.5 g).

Stage 3: Getting connection 4BL

Connection 3BL (1.96 g) was dissolved in pyridine (10 ml). Added hydroxyethylhydrazine (0.51 ml) under stirring, and the resulting mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure to get crude product 4BL in the form of a yellow resin, which was directly used in the next stage of the synthesis without further purification.

Stage 4: Getting connection 5BL

A mixture of the crude compound 4BL from the previous stage in formic acid (30 ml) was boiled under reflux overnight and then concentrated under reduced pressure. The residue was treated with saturated NaHCO3and thrice was extracted with EtOAc. The combined organic layers were dried over MgSO4. After concentration the residue of the compound was purified on silica gel. Elution using EtOAc allowed recip is th connection 6BL (1.1 g), venture connection 5BL (183 mg).

Connection 6BL can easily be converted into a compound 5BL by means of a water main hydrolysis.

Stage 5: Getting connection 7BL

A solution of compound 5BL (429 mg, 1.5 mmol) in DMF (3 ml) was added with stirring to the flask containing NaH (60%, 66 mg, 1.65 mmol). After stirring for 30 minutes slowly added Mel (0.103 ml, 1.65 mmol). After 30 minutes the reaction mixture was diluted with EtOAc, washed three times with water, with brine and dried (MgSO4). After concentration the residue was purified on silica gel. Elution using 10% Meon/EtOAc allowed to obtain a connection 7BL (88 mg).

Stage 6: Getting connection A16

Connection A16 received from the connection 7BL, following a methodology similar to the methodology for the synthesis of (S)-1-(2-(4-(4-(1,5-dimethyl-1H-1,2,4-triazole-3-yl)phenyl)-5,6-dihydropyridines-1(2H)-yl)-2-oxoethyl)-N-(3-(6-isopropoxypyridine-3-yl)-1H-indazol-5-yl)-3-ethoxypyrrolidine-3-carboxamide (A14, Example 3).

Mass spectrum: GHMS M+1=738, retention time = 4 minutes.

1H NMR A16 HCl salt (400 MHz, DMSO-d6): δ 10.45 (ush, 1H), 10.23 (d, J=16.8 Hz, 1H), 8.7 (m, 1H), 8.6 (m, 1H), 8.46 (m, 1H), 8.18 (m, 1H), 8.0 (m, 1H), 7.74 (d, J=8 Hz, 1H), 7.57 (d, J=8 Hz, 1H), 7.42 (m, 1H), 6.93 (m, 1H), 6.43 (m, 1H), 5.3 (m, 1H), 4.6-4.5 (m, 2H), 4.41 (m, 2H), 4.21-4.01 (m, 4H), 3.8-3.6 (ush, 7H), 3.33 (m, 3H), 3.25 (m, 2H), 2.67-2.54 (m, 3H), 2.4 (m, 1H), 1.33 (d, J=6.4 Hz, 6N).

Example 5

C the Proc. of 1-(2-{4-[4-(1-Ethyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-3-methoxy-pyrrolidin-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide

Synthesis of 4-[4-(1-ethyl-1H-[1,2,4]triazole-3-yl)-phenyl]-1,2,3,6-tetrahydropyridine hydrochloride

Stage 1: Obtain 4-bromo-benzimidazol acid complex ethyl ester

4-Bromo-benzonitrile (5 g) is suspended in absolute EtOH (100 ml) and cooled to 0-5°C. was Barbotirovany gas HCl, at first intensely for several minutes, and then slowly for 5 hours. The resulting solution was stirred overnight. A large part of the solvent was removed and the precipitate was filtered, washed twice EtOH and dried to obtain compound VM (4.1 g) as a solid white color.

Stage 2: Getting connection VM

4-bromo-benzimidazol acid complex ethyl ester (1 g) was dissolved in pyridine (20 ml). Added acylhydrazone (550 mg) with stirring, and the resulting mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, was added diethyl ether, filtered, washed three times with diethyl ether and dried to obtain compound VM (1 g).

Stage 3: Obtain 3-(4-bromo-phenyl)-1-ethyl-1H-[1,2,4]triazole

The mixture of compounds VM (1 g) in formic acid (10 ml) was boiled under reflux overnight and then concentrated. The residue was treated with saturated NaHCO3and three times extragear the Wali EtOAc. The combined organic layers were dried over MgSO4. After concentrating the received connection 4 VM in the form of colorless crystals (0.9 g).

Stage 4: Obtain 4-[4-(1-ethyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid complex tert-butyl methyl ether

In a large flask of high pressure loaded connection VM (400 mg), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid complex tert-butyl ester (540 mg), Pd(PPh3)4(180 mg), Na2CO32N (3 ml) and Dioxane/EtOH/water (7:3:2, 10 ml). The mixture was quickly degirolami with argon for about half a minute, covered and placed in a microwave reactor at 120°C for 20 minutes. After cooling, the reaction mixture was diluted with EtOAc and brine solution. The organic layer was separated and dried (MgSO4). After concentration the residue was purified on silica gel. Elution with Meon/EtOAc (0-10%) allowed to obtain the target product VM (310 mg).

Stage 5: Obtain 4-[4-(1-ethyl-1H-[1,2,4]triazole-3-yl)-phenyl]-1,2,3,6-tetrahydro-pyridine hydrochloride

The Boc group can be removed by processing the connection VM a solution of 4N HCl in dioxane at room temperature for two hours. Removal of the solvent under reduced pressure allowed to obtain connection is out VM.

Synthesis of 1-(2-{4-[4-(1-Ethyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-3-methoxy-pyrrolidin-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide

Unpeeled connection MM (5.9 mmol) was stirred in a mixture of dichloromethane/Meon (1:1, 20 ml), oxo-acetic acid complex ethyl ether (10 ml, 50%) and NaBH(OAc)3(10 ml) at room temperature overnight. The mixture was repaid by saturated aqueous sodium bicarbonate. The solvents were removed in vacuum. Diluted with water and ethyl acetate. The layers were separated, and the separated aqueous layer was extracted with ethyl acetate (X3). The combined organic layers were dried (MgSO4), filtered, and the solvents were removed in vacuum. Purification by column allowed us to obtain a connection VM in the form of a yellow oil.

The crude compound VM (2.35 g) was stirred in a solution of LiOH (1 m, 10 ml) and THF (10 ml) at room temperature overnight. In a mixture of established pH 3. The solvents were removed in vacuum. The product was used in the next stage without purification.

The crude product VM (49 mg), 4-[4-(1-Ethyl-1H-[1,2,4]triazole-3-yl)-phenyl]-1,2,3,6-tetrahydro-pyridine (25.4 mg), HATU (45 mg) and triethylamine (0.1 ml) was stirred in DMF (1 ml) at room temperature, overnight). The mixture was purified by HPLC, to receive the of compound A3 in the form of a yellow oil. Mass spectrum: GHMS M+1=690, retention time = 3.47 minutes.

Example 6

Synthesis of 4-[4-(1-isopropyl-1H-[1,2,4]triazole-3-yl)-phenyl]-1,2,3,6-tetrahydro-pyridine hydrochloride

Stage 1: Obtain 4-bromo-benzimidazol acid complex ethyl ester

4-Bromo-benzonitrile (5 g) is suspended in absolute EtOH (100 ml) and cooled to 0-5°C. was Barbotirovany gas HCl, slowly at first for a few minutes, and then intensively for 5 hours. The resulting solution was stirred overnight. A large part of the solvent was removed and the precipitate was filtered, washed twice EtOH and dried to obtain compound 2BN (4.1 g) as a solid white color. (It should be noted that when conducting large-scale synthesis may need more time to complete the reaction. It is better to monitor the disappearance of the starting reagents for the detection of the endpoint of the reaction.)

Stage 2: Getting connection 3BN

4-Bromo-benzimidazol acid complex ethyl ester (1 g) was dissolved in pyridine (20 ml). Added isopropylpyrazine (550 mg) with stirring, and the resulting mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, was added diethyl ether, filtered, washed three times with diethyl ether and dried with the teachings connection 3BN (0.9 g).

Stage 3: Obtain 3-(4-bromo-phenyl)-1-isopropyl-1H-[1,2,4]triazole

The mixture of compounds 3BN (1 g) in formic acid (10 ml) was boiled under reflux overnight and then concentrated. The residue was treated with saturated NaHCO3and thrice was extracted with EtOAc. The combined organic layers were dried over MgSO4. After concentrating the connection 4BN received in the form of colorless crystals (0.9 g).

Stage 4: Obtain 4-[4-(1-isopropyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid complex tert-butyl methyl ether

In the bulb of a high pressure loaded connection 4BN (500 mg), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid complex tert-butyl ester (583 mg), Pd(PPh3)4(112 mg), Na2CO32N (3 ml) and Dioxane (10 ml). The mixture was quickly degirolami with argon for about half a minute, it was covered and stirred at 100°C overnight. After cooling, the reaction mixture was diluted with EtOAc and brine solution. The organic layer was separated and dried (MgSO4). After concentration the residue was purified on silica gel. Elution using Meon/EtOAc (0-10%) allowed to obtain the target product 5BN (410 mg).

Stage 5: Obtain 4-[4-(1-isopropyl-1H-[1,2,4]triazole-3-yl)-phenyl]-1,2,3,6-tetrahydro-pyridine hydrochloride

The first group can be removed by processing the connection 5BN a solution of 4N HCl in dioxane at room temperature for two hours. Removal of the solvent under reduced pressure gave the opportunity to get connection 6BN.

Synthesis of 1-(2-{4-[4-(1-Isopropyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-3-methoxy-pyrrolidin-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide

The crude compound 8BN (5.9 mmol) was stirred in a mixture of dichloromethane/Meon (1:1, 20 ml), oxo-acetic acid complex ethyl ether (10 ml, 50%) and NaBH(OAc)3(10 ml) at room temperature overnight. The mixture was repaid by saturated aqueous sodium bicarbonate. The solvents were removed in vacuum. Diluted with water and ethyl acetate. The layers were separated, and the separated aqueous layer was extracted with ethyl acetate (X3). The combined organic layer was dried (MgSO4), filtered, and the solvents were removed in vacuum. Purification by column allowed us to obtain a connection 9BN in the form of a yellow oil, with a yield of 65%.

The crude compound 9BN (2.35 g) was stirred in a solution of LiOH (1 m, 10 ml) and THF (10 ml) at room temperature overnight. In a mixture of established pH 3. The solvents were removed in vacuum. The product was used in the next stage without purification, the quantitative output is output.

The crude substance 10BN (60 mg), 4-[4-(1-isopropyl-1H-[1,2,4]triazole-3-yl)-phenyl]-1,2,3,6-tetrahydro-pyridine (35 mg), HATU (52 mg) and triethylamine (0.1 ml) was stirred in DMF (1 ml) at room temperature overnight. The mixture was purified by HPLC to obtain compound A5 in the form of a yellow oil. Mass spectrum: GHMS M+1=704, retention time = 3.56 minutes.

Example 7

Synthesis of 1-(2-{4-[4-{1-Isopropyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-3-methoxy-pyrrolidin-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide

Synthesis of 4-[4-(1-isopropyl-1H-[1,2,4]triazole-3-yl)-phenyl]-1,2,3,6-tetrahydropyridine hydrochloride

Stage 1: Obtain 4-bromo-benzimidazol acid complex ethyl ester

4-Bromo-benzonitrile (5 g) is suspended in absolute EtOH (100 ml) and cooled to 0-5°C. was Barbotirovany gas HCl, at first intensely for several minutes, and then slowly for five hours. The resulting solution was stirred overnight. A large part of the solvent was removed and the precipitate was filtered, washed twice, using EtOH, and dried to obtain compound VA (4.1 g) as a solid white color.

Stage 2: Getting connection WO

4-Bromo-benzimidazol acid complex ethyl EF the R (1 g) was dissolved in pyridine (20 ml). Added isopropylpyrazine (550 mg) with stirring, and the resulting mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, was added diethyl ether, filtered, washed three times with diethyl ether and dried with precept connection VO (0.9 g).

Stage 3: Obtain 3-(4-bromo-phenyl)-1-isopropyl-1H-[1,2,4]triazole:

The mixture of compounds VA (1 g) in formic acid (10 ml) was boiled under reflux and cooled. The residue was treated with saturated NaHCO3and thrice were extracted using EtOAc. The combined organic layers were dried over MgSO4. After concentrating the received connection VO in the form of colorless crystals (0.9 g). (It should be noted that it was found that the reaction should be conducted for no more than two hours. Large-scale synthesis it is necessary to use 10% NaOH instead of NaHCO3).

Stage 4: Obtain 4-[4-(1-isopropyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid complex tert-butyl methyl ether

In a large flask of high pressure loaded connection VO (500 mg), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid complex tert-butyl ester (583 mg), Pd(PPh3)4(112 mg), Na2CO32N (3 ml) and Dioxane (10 ml). The mixture of fast which was degirolami with argon for about half a minute, covered and stirred at 100C for the whole night. After cooling, the reaction mixture was diluted with EtOAc and brine solution. The organic layer was separated and dried (MgSO4). After concentration the residue was purified on silica gel. Elution using Meon/EtOAc (0-10%) allowed to obtain the target product VO (410 mg).

Stage 5: Obtain 4-[4-(1-isopropyl-1H-[1,2,4]triazole-3-yl)-phenyl]-1,2,3,6-tetrahydropyridine hydrochloride

The first group can be removed by processing the connection WE a solution of 4N HCl in dioxane at room temperature for two hours. Removal of the solvent under reduced pressure allowed to obtain compound 6.

Obtaining and chiral separation of 3-Methylsulfanyl-pyrrolidine-3-carboxylic acid complex methyl ester WR

Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester VR (4.3 g, 20 mmol) was dissolved in 28 ml of toluene and 3.5 ml of methanol. 2N solution trimethylsilyldiazomethane in hexano (13 ml, 26 mmol) was added dropwise at 0 C and the reaction mixture was stirred for 10 min at ambient temperature. The mixture is boiled away with obtaining 4.3 g of oil.

Oil 2VR (0.5 g, 2.1 mmol)dissolved in tetrahydrofuran (15 ml), dropwise added 1.2 ml of a 2N solution of diisopropylamide lithium in hexano, and the reaction mixture was peremeci the Ali for one hour at -78 C. Slowly added dimethyl disulfide (0.48 ml, 5.4 mmol)and the reaction mixture was allowed to gradually warm to ambient temperature. The reaction mixture was stirred for 18 hours. Added a saturated solution of ammonium chloride (25 ml)and the reaction mixture was stirred for 5 minutes. The reaction mixture was extracted three times with ethyl acetate (3×25 ml), dried over magnesium sulfate, filtered, and boiled away with getting after column chromatography 0.386 g of the product 3VR, the name of which is specified in the title.

3-Methylsulfanyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl complex ester 3-methyl ester (2.15 g, 8.8 mmol) was dissolved in 20 ml of 50% triperoxonane acid/dichloromethane and stirred for 2 hours. The reaction mixture is evaporated to obtain 3.35 g of 3-methylsulfanyl-pyrrolidine-3-carboxylic acid complex of methyl ester of 4 BP in the form of a viscous solid.

Alternatively, the product VR can be obtained in the following way:

2-Methylsulfanyl-propionic acid complex methyl ether VR (25 g, 0.1 mol), dissolved in chloroform, slowly added sulfurylchloride (15.1 ml, 0.1 mol) at 0°C. the Reaction mixture was stirred at 0°C for 30 minutes, and the mixture is then boiled under reflux at 65°C for 30 minutes. Reacciona the mixture was then concentrated to dryness to obtain 23.75 g of 2-methylsulfanyl-acrylic acid complex methyl ester VR in liquid form.

To a stirred solution of 2-ethoxyacrylate 2-methylsulfanyl-acrylic acid complex methyl ester VR (136 g, 1.03 mol) and benzyl methoxymethyl-trimethylsilylmethyl-amine VR (290 g, 1.22 mol) in dichloromethane (2.7 l) at 0°C was added a solution triperoxonane acid (26 ml, 0.3 mol). The resulting solution was heated to room temperature and stirred overnight. The crude product was purified by column chromatography on silica gel, elwira solution of ethyl acetate in hexane (1:4) to give 1-benzyl-3-methylsulfanyl-pyrrolidine-3-carboxylic acid complex methyl ester VR (131 g, 47%).

To 1-benzyl-3-methylsulfanyl-pyrrolidine-3-carboxylic acid complex methyl ether VR (131 g, 493.7 mmol)dissolved in dichloroethane (2.6 l)at 0°C was added N,N,N',N'-tetramethyl-naphthalene-1,8-diamine VR (31.8 g, 0.144 mmol) and then added 2-chloro-propionate VR (64 ml, 593.1 mmol). The reaction mixture was stirred overnight at ambient temperature and then concentrated to dryness. The residue was dissolved in 2.8 l of methanol and boiled under reflux at 65°C for 3.5 hours. The reaction mixture was then concentrated to dryness, and the residue was purified by column chromatography on silica gel, elwira solution of methanol in dichloromethane (1:9), with 3-methylsulfanyl-pyrrolidine-3-carboxylic acid complex is th methyl ester VR (75 g, 86%).

Chiral separation of 3-methylsulfanyl-pyrrolidine-3-carboxylic acid complex methyl ester WR

3-Methylsulfanyl-pyrrolidine-3-carboxylic acid complex ethyl ester VR (42.9 g, 244.8 mmol) and L-tartaric acid (36.7 g, 244.8 mmol) was placed in a round bottom flask, 1 liter, and dissolved with methanol (250 ml). The flask is then attached to a rotary evaporator at 75°C. the Flask was gently rotated at this temperature for about 20 minutes to ensure complete dissolution. After formation of a transparent solution, added about 10 mg of crystals of 3-methylsulfanyl-pyrrolidine-3-carboxylic acid complex methyl ester VR (for seed and crystal formation) and allowed to gently settle for crystal formation. After three days was filtered 19.4 g of crystals, which are then washed with cold methanol (20-30 ml) to obtain 18.2 g of crystalline 3-methylsulfanyl-pyrrolidine-3-carboxylic acid complex methyl ester VR.

Chiral purity crystals of 3-methylsulfanyl-pyrrolidine-3-carboxylic acid complex methyl ester VR was determined by obtaining derivatives with 4-nitrobenzenesulfonate and research them using analytical HPLC (Chiral column AD) in terms of use of the solvent system of 20% isopropanol/hexane with a flow rate of 1 ml/min ODA is divided purity was > 99.9% with a retention time 16.58 minutes.

Obtaining 3-Methylsulfanyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ether complex

To a cooled (0°C.) solution VR (28 g, 90.52 mmol) in dry CH2Cl2(250 ml) was added triethylamine (31.5 ml, 226.32 mmol, 2.5 equiv.) and then added (BOC)2O (25.7 g, 117.68 mmol, 1.3 equiv). The resulting mixture was stirred at a temperature of from 0°C. to room temperature overnight, and then diluted using CH2Cl2, washed saturated aqueous NaHCO3and with brine, dried (MgSO4) and concentrated. Chromatography on silica gel (hexane/ethyl acetate, 4:1) allowed to obtain a connection VR (23.5 mg, 90.52 mmol, 100%) as a colourless oil.

To peremeshannom solution of the substance VR (23.5 mg, 90.52 mmol) in THF/MeOH (175 ml 175 ml) was added 135 ml of LiOH (1M in H2O, 135 mmol, 1.5 equiv.). The reaction mixture was stirred at room temperature overnight, added 135 ml of 1N HCl. The resulting mixture was stirred for another 15 min and then concentrated, to obtain the compounds VR.

Stage 1:

Aminoindazole 5BI (39 g, 0.076 mol) and pyrrolidinecarbonyl acid 14 BP (32 g, 0.069 mol) was dissolved in DMF (300 ml) at room temperature. Added HATU (29 g, 0.076 mol) and then addediPr2NEt (14.5 ml, 0.083 mol). The mixture displaced ivali at room temperature overnight and diluted with ethyl acetate and water. The layers were separated. The separated organic layer was washed with water (x2), dried (MgSO4) and was filtered. Concentrated in vacuo, followed by purification on column [hexane-ethyl acetate = 4:1 (V/V)] to obtain the crude compound 7 in the form of foam off-white color.

Stage 2:

The crude substance 7 was stirred in a mixture of dichloromethane (300 ml), triperoxonane acid (100 ml) and water (50 ml) at room temperature overnight. The mixture was cooled at 0°C and carefully extinguished saturated aqueous sodium bicarbonate. The solvents were removed in vacuum. Diluted with water and ethyl acetate. The layers were separated, and the separated aqueous layer was extracted with ethyl acetate (X3). The combined organic layers were dried (MgSO4), filtered, and the solvents were removed in vacuum. Purification on a column of [5-10% Meon (7N ammonia) in dichloromethane] allowed to get pyrrolidin VO (23 g, 84%) as a solid off-white color.

Synthesis of 1-(2-{4-[4-(1-isopropyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-3-methylsulfanyl-pyrrolidine-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide

The crude substance VO (5.9 mmol) was stirred in a mixture of dichloromethane/Meon (1:1, 20 ml), oxo-acetic acid complex ethyl ether (10 ml, 50%) and NaBH(Oc) 3(10 ml) at room temperature overnight. The mixture was repaid by saturated aqueous sodium bicarbonate. The solvents were removed in vacuum. Diluted with water and ethyl acetate. The layers were separated, and the separated aqueous layer was extracted with ethyl acetate (X3). The combined organic layers were dried (MgSO4), filtered, and the solvents were removed in vacuum. Purification by column allowed us to obtain the substance VO in the form of a yellow oil.

The crude substance VO (2.35 g) was stirred in a solution of LiOH (1 m, 10 ml) and THF (10 ml) at room temperature overnight. In a mixture of established pH 3. The solvents were removed in vacuum. The product was used in the next stage without purification.

The crude compound VA (60 mg), 4-[4-(1-isopropyl-1H-[1,2,4]triazole-3-yl)-phenyl]-1,2,3,6-tetrahydropyridine (35 mg), HATU (52 mg) and triethylamine (0.1 ml) was stirred in DMF (1 ml) at room temperature overnight. The mixture was purified by HPLC to obtain compound air defense in the form of a yellow oil. Mass spectrum: GHMS M+1=720, retention time = 3.68 minutes.

Example 8

Obtaining 1-[2-(4-{4-[1-(2-hydroxy-2-methyl-propyl)-1H-[1,2,4]triazole-3-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-yl)-2-oxo-ethyl]-3-methoxy-pyrrolidin-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]amide

Synthesis of 2-the ENT-1-{4-[4-(1-ethyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-ethanone

Stage 1: Obtain 4-bromo-benzimidazol acid complex ethyl ester

4-Bromo-benzonitrile (5 g) is suspended in absolute EtOH (100 ml) and cooled to 0-5°C. was Barbotirovany gas HCl, at first intensely for several minutes, and then slowly for 5 hours. The resulting solution was stirred overnight. A large part of the solvent was removed and the precipitate was filtered, washed EtOH twice and dried to obtain compound VA (4.1 g) as a solid white color.

Stage 2: Getting connection 3BQ:

4-Bromo-benzimidazol acid complex ethyl ester (1.68 g) was dissolved in pyridine (10 ml). 1 Hydrazino-2-methyl-propane-2-ol (1 g) was added under stirring, and the resulting mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and added diethyl ether, filtered, washed three times with diethyl ether and dried to obtain compound 3BQ (1 g).

Stage 3: Obtain 1-[3-(4-bromo-phenyl)-[1,2,4]triazole-1-yl]-2-methyl-propane-2-ol:

The mixture of compounds 3BQ (1 g) in formic acid (10 ml) was boiled under reflux overnight and then concentrated. The residue was treated with saturated NaHCO3, and was extracted with EtOAc three times. The combined organic layers were dried over MgSO4. After koncentrira is of connection 4BQ received in the form of colorless crystals (0.9 g).

Stage 4: Obtain 4-{4-[1-(2-hydroxy-2-methyl-propyl)-1H-[1,2,4]triazole-3-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ether complex

In a large flask of high pressure loaded 4BQ (400 mg), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (540 mg), Pd(PPh3)4(180 mg), 2N Na2CO3(3 ml) and dioxane/EtOH/water (7:3:2, 10 ml). The mixture was quickly degirolami with argon for about half a minute, covered and placed in a microwave reactor at 120C for 20 minutes. After cooling, the reaction mixture was diluted with EtOAc and brine solution. The organic layer was separated and dried (MgSO4). After concentration, the residue was purified on silica gel. Elution using Meon/EtOAc (0-10%) allowed to obtain the target product 5BQ (310 mg).

Stage 5: Obtain 2-methyl-1-{3-[4-(1,2,3,6-tetrahydro-pyridine-4-yl)-phenyl]-[1,2,4]triazole-1-yl}-propan-2-ol

The first group can be removed by treating the compound 5BQ 4N HCl solution in dioxane at room temperature for two hours. Removal of the solvent under vacuum gave the opportunity to get connection 6BQ.

Synthesis of 1-[2-(4-{4-[1-(2-hydroxy-2-methyl-propyl)-1H-[1,2,4]triazole-3-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-yl)-2-oxo-ethyl]-3-methoxy-pyrrolidin-3-carboxylic acid [3-(isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide

The crude compound 8BN (5.9 mmol) was stirred in a mixture of dichloromethane/Meon (1:1, 20 ml), oxo-acetic acid complex ethyl ether (10 ml, 50%) and NaBH(OAc)3(10 ml)at room temperature overnight. The mixture was repaid by saturated aqueous sodium bicarbonate. The solvents were removed in vacuum. Diluted with water and ethyl acetate. The layers were separated, and the separated aqueous layer was extracted with ethyl acetate (X3). The combined organic layers were dried (MgSO4), filtered, and the solvent was boiled away under vacuum. Purification by column allowed us to obtain a connection VM in the form of a yellow oil.

The crude compound VM (2.35 g) was stirred in a solution of LiOH (1 m, 10 ml) and THF (10 ml) at room temperature overnight. To a mixture of established pH 3. The solvents were removed in vacuum. The product was used in the next stage without purification.

The crude compound 10BN (60 mg), 2-methyl-1-{3-[4-(1,2,3,6-tetrahydropyridine-4-yl)-phenyl]-[1,2,4]triazole-1-yl}-propan-2-ol (38 mg), HATU (50 mg) and triethylamine (0.1 ml) was stirred in DMF (1 ml) at room temperature overnight. The mixture was purified by HPLC, which allowed to obtain a connection to the A9 in the form of a yellow oil, yield 50%. Mass spectrum: GHMS M+1=734, retention time = 3.32 minutes.

Example 9

Obtaining 3-methox is-1-(2-{4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-pyrrolidin-3-carboxylic acid {3-[6-(2-methoxy-ethoxy)-pyridine-3-yl]-1H-indazol-5-yl}-amide

Synthesis of 3-methoxy-pyrrolidin-3-carboxylic acid {3-[6-(2-methoxy-ethoxy)-pyridine-3-yl]-1H-indazol-5-yl}-amide

Stage 1:

In the bulb of a high pressure loaded connection 1BR (1.75 g), the connection 2BR (0.5 g), Pd(PPh3)4(210 mg), Na2CO32N (10 ml) and dioxane (10 ml). The mixture was quickly degirolami with argon for about half a minute, it was covered and stirred at 100°C overnight. After cooling, the reaction mixture was diluted with EtOAc and brine solution. The organic layer was separated, and dried (MgSO4). After concentration the residue was purified on silica gel. Elution was possible to obtain the target product 3BR (0.8 g).

Stage 2:

The mixture of compounds 3BR (1.8 g), 2-methoxy-ethanol (1 g), DEAD (0.8 g) and PPh3(1.2 g) in THF (10 ml) was stirred overnight at room temperature and concentrated. The residue was purified on silica gel, which allowed to obtain the target product 4BR (0.8 g).

Stage 3:

Connection 4BR (0.5 g) in Meon (20 ml) was recovered in the flow reactor H-cube with Pd/C (10%) column.

Stage 4:

Aminoindazole 5BR (80 mg) and pyrrolidinecarbonyl acid VN (38 mg) was dissolved in DMF (1 ml) at room temperature. Added HATU (69 mg) and theniPr2NEt (0.1 ml). The mixture was stirred pikantnoi temperature overnight and diluted with ethyl acetate and water. The layers were separated. The separated organic layer was washed with water (x2), dried (MgSO4) and was filtered. Concentration under vacuum, allowed to obtain the crude compound 7BR in the form of foam off-white color.

Stage 5:

The crude compound 7BR was stirred in a mixture of dichloromethane (1 ml), triperoxonane acid (1 ml)at room temperature for 1 hour. The mixture was cooled at 0°C and switched off carefully with saturated aqueous sodium bicarbonate solution. The solvents were removed in vacuum. Diluted with water and ethyl acetate. The layers were separated, and the separated aqueous layer was extracted with ethyl acetate (X3). The combined organic layers were dried (MgSO4), filtered, and the solvents were removed in vacuum, which allowed us to obtain pyrrolidin 8BR in a solid off-white color.

Synthesis of 3-methoxy-1-(2-N-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-pyrrolidin-3-carboxylic acid {3-[6-(2-methoxy-ethoxy)-pyridine-3-yl]-1H-indazol-5-yl}-amide

The mixture of compounds VN (52 mg), compounds 8BR (62 mg) and DIEA (0.3 ml) in DMF (1.5 ml) was stirred at room temperature overnight. IHMS showed completion of reaction. DMF was removed under reduced pressure. The crude compound was purified by HPLC. (IHMS M+=692, retention time = 3.00 minutes)1H NMR (400 MHz, CDCl3): δ 11.92 (s, 1H), 11.11 (s, 1H), 9.14 (s, 1H), 8.58 (s, 1H), 8.03 (s, 1H), 7.99 (d, 1H, J=8.4 Hz), 7.90 (t, 2H, J=6.8), 7.39 (s, 2H), 7.20 (s, 3H), 6.76 (d, 1H, J=8.0 Hz), 5.85 (d, 1H, J=20 Hz), 4.4 (s, 4H), 4.05 (q, 4H, J=7.2 Hz), 3.8 (s, 3H), 3.50-3.56 (m, 6N), 2.34-2.62 (m, 5H), 2.0 (s, 2H), 1.64-1.49 (m, 3H).

Example 10

Obtaining 1-[2-(4-{4-[1-(2-hydroxy-ethyl)-1H-[1,2,4]triazole-3-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-yl)-2-oxo-ethyl]-3-methoxy-pyrrolidin-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide

Obtain {3-[3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-ylcarbonyl]-3-methoxy-pyrrolidin-1-yl}-acetic acid

To a solution of compound 8BI (3.5 g, 6.6 mmol) in acetonitrile (26 ml) was added DIEA (5.7 ml, 32.9 mmol). The solution was cooled to 0°C. and dropwise added 0.47 ml (3.29 mmol) of the compound 13BS. After stirring for 4 hours at 0°C again added 0.47 ml (3.29 mmol) of the compound 13BS. Was stirred for one hour at 0°C and then warmed to room temperature. After stirring overnight at room temperature, dissolved in EtOAc (200 ml) and washed NaHCO3(1×50 ml), water (1×50 ml) and with brine (1×50 ml). The organic extracts were dried over MgSO4, and the solvent removed. The crude compound was purified by column chromatography using 20%Meon/EtOAc with getting a the new product 14BS (2.4 g).

Connection 14BS (2.4 g) was processed using 40 ml of TFA for 45 minutes at room temperature. TFA was removed under reduced pressure, and the solid was washed with ether to obtain the target compounds 15BS as TFA salt (4.4 g, 95%). Connection 15BS turned into the HCl salt by adding 4N HCl in water.

Synthesis of 2-{3-[[4[(1,2,3,6-tetrahydro-pyridine-4-yl)-phenyl]-[1,2,4]triazole-1-yl}-ethanol hydrochloride

Getting 4-bromo-N'-(2-hydroxyethyl)benzimidate hydrochloride

Complex ethyl ester 4-bromo-benzimidazol acid VN (5 g) was dissolved in pyridine (100 ml). Hydroxyethyl hydrazine (1.92 ml) was added under stirring, and the resulting mixture was stirred overnight. The precipitate was collected by filtration, and the mother liquid was concentrated to dryness and added diethyl ether. The solid is collected by filtration. The combined solid was twice washed with diethyl ether and dried, to obtain the compounds 18BS (5.1 g).

Getting 2-(3-(4-bromophenyl)-1H-1,2,4-triazole-1-yl)ethanol

The mixture of compounds 18BS (3 g) in formic acid (50 ml) was stirred at room temperature for 30 minutes, at 100°C for 1.5 hours and concentrated. The residue was treated with saturated NaHCO3and was extracted with EtOAc three times. The combined organic extracts were dried over MgSO . After concentration the crude compound was purified on silica gel. Elution using EtOAc allowed to obtain a connection 20BS (2 g) and the connection 19BS (262 mg).

Connection 20BS can easily be converted into a compound 19BS by water hydrolysis

Getting 4-[4-(1-(2-hydroxy-ethyl)-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ether complex

In a large flask of high pressure loaded 19BS (1.5 g, 5.6 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (1.9 g, 6.2 mmol), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complex with dichloromethane(1:1) (0.22 g, 0.28 mmol), K2CO3(2.32 g, 16.8 mmol) and DME/water (5:1, 12 ml). The mixture was quickly degirolami with argon for about half a minute, it was covered and stirred at 80°C overnight. After cooling, the reaction mixture was diluted with EtOAc and washed with water (1X) and with brine (1x). The organic layer was separated and dried over MgSO4. After concentration the residue was purified on silica gel. Elution using Meon/EtOAc (0-10%) allowed to obtain the target product 21 BS (1.4 g, 73%).

Getting 2-{3-[[4[(1,2,3,6-tetrahydro-pyridine-4-yl)-phenyl]-[1,2,4]triazole-1-yl}-ethanol hydrochloride

The Boc group can be removed by processing the soedineniya 21BS 4H HCl solution in dioxane, at room temperature for two hours. Removal of the solvent under vacuum gave the opportunity to get connection 22BS.

Obtaining 1-[2-(4-{4-[1-(2-hydroxy-ethyl)-1H-[1,2,4]triazole-3-yl]-phenyl}-3,6-dihydro-2H-pyridine-1-yl)-2-oxo-ethyl]-3-methoxy-pyrrolidin-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide

The mixture of compounds 10BN (0.49 g, 1 mmol), 1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (0.38 g, 2 mmol) and 1-hydroxybenzotriazole (0.14 g, 1 mmol) was dissolved in DMF (3 ml). After stirring for 20 minutes at room temperature was added compound 16BS (0.34 g, 1 mmol) and DIEA (0.7 ml, 4 mmol). After stirring overnight at room temperature, diluted, using DCM (45 ml), and washed NaHCO3(1×7 ml), water (3×7 ml) and with brine (1×10 ml). The organic layer was dried over MgSO4. After concentration, the residue was purified on silica gel. Elution using 2% NH320%Meon/EtOAc allowed to obtain the target product A2 (0.3 g). This compound was converted to the HCl salt by adding 4N HCl in 1,4-dioxane. (JHMS: M+1=706, retention time = 3.13 min),1H NMR (400 MHz, DMSO-d6): δ=10.5 and 10.8 (m, 1H), 10.25 (d, 1H, J=19.2 Hz), 8.60-8.75 (m, 2H), 8.43 (m, 1H), 8.18 (m, 1H), 7.98 (m, 2H), 7.78 (d, 2H, J=20 Hz), 7.5-7.6 (m, 4H), 6.9 (m, 2H), 6.3 (m, 1H), 5.3 (m, 1H), 4.5-4.6 (m, 2H), 4.15-4.3 (m, 4H), 4.0-4.15 (m, 2H), 3.75 (t, 4H, 5.2 Hz), 3.5-3.6 (m, 2H), 3.4-3.3 (m, 1H), 3.29 (s, 2H) 2.5-2.7 (m, 3H), 2.3-2.4 (m, 1H), 1.3 (d, 6N, J=6.4 Hz).

Example 11

Synthesis of 3-methoxy-1-(2-{4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-pyrrolidin-3-carboxylic acid [3-(6-ethoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide (Example 1)

Stage 1:

A mixture of 6-ethoxypyridine-3-Bronevoy acid (2.5 g, 14.97 mmol), bro-indazole 3BI (7.25 g, 14.97 mmol), potassium carbonate (6.2 g, 44.91 mmol), PdCl2(dppf)2.CH2Cl2(1.22 g, 1.497 mmol), 1,4-dioxane (40 ml) and water (10 ml) was purged with nitrogen for 15 min at room temperature and then was heated at 90°C for 18 hours and cooled to room temperature. Added water (100 ml) and ethyl acetate (300 ml). The solids were filtered through celite. The layers were separated, and the separated organic layer was washed with water (100 ml). The combined organic layers were dried (Na2SO4), filtered, and the solvents removed under vacuum. Purification by column [Hexane-ethyl acetate = 9:1 (V/V)] allowed us to obtain a connection 2BU (7 g, 89%).

Stage 2:

Connection 2BU (2 g, 3.8 mmol) and Pd/C (10%, 50 wt.%, 0.7 g) was stirred in toluene (30 ml) and Meon (15 ml)in an atmosphere of H2(rubber Luggage), at room temperature for 18 hours. The solid catalyst was filtered through celite, and the solvents were removed in vacuumized on the column using 4%MeOH/CH 2Cl2allowed to obtain a connection 3BU (1.6 g, 85%).

Stage 3:

Connection 3BU (1.46 g, 3.22 mmol) and pyrrolidinecarbonyl acid VN (0.56 g, 3.22 mmol) was dissolved in DMF (300 ml) at room temperature. Added HATU (1.68 g, 4.83 mmol) and theniPr2NEt (0.78 ml, 4.83 mmol). The mixture was stirred at room temperature overnight and diluted with ethyl acetate (200 ml) and water (100 ml). The layers were separated. The separated organic layer was washed with water (100 ml), dried (Na2SO4) and was filtered. Concentration in vacuum with subsequent column purification [hexane - ethyl acetate = 9:1 (V/V)] allowed us to obtain the product 4BU.

Stage 4:

Connection 4BU (1.6 g) was stirred in a mixture of dichloromethane (30 ml), triperoxonane acid (4 ml) and several chapels water, at room temperature, overnight. The mixture was cooled at 0°C and carefully extinguished 7% Meon (NH3)/CH2Cl2. The solvents were removed in vacuum. Diluted with water (100 ml) and ethyl acetate (200 ml). The layers were separated. The organic layer was dried (Na2SO4), filtered, and the solvents were removed in vacuum. Purification by column [7% Meon (7N ammonia) in dichloromethane], we were able to get a connection 5BU (0.44 g, 49%), which was turned into monosol HCl, by processing 4N HCl/dioxane and evaporating the solution to dryness.

p> Stage 5:

The mixture of compounds VN (46 mg, 0.144 mmol), compound 5BU (60 mg, 0.144 mmol), DMF (2 ml) and N,N-diisopropylethylamine (0.076 ml, 0.432 mmol) was stirred at room temperature for 18 hours. Was diluted with EtOAc (100 ml) and washed with water (2×100 ml). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel, elwira using 4% Meon (NH3)/CH2Cl2with obtaining the target product 6BU (40 mg, 42%).

IHMS M+1=662 at retention time 2.57 min

Example 12

Synthesis of 3-methylsulfanyl-1-(2-{4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-pyrrolidin-3-carboxylic acid [3-(6-methoxy-pyridin-3-yl)-1H-indazol-5-yl]-amide

Stage 1:

Connection 8BU received from the connection 3IN1, using essentially the same methodology as described for connection 2BU from the connection 3IN1 (Example 11, step 1), using the 6-methoxypyridine-3-Bronevoy acid instead of 6-ethoxypyridine-3-Bronevoy acid.

Stage 2:

Connection 8BU (3 g, 3.8 mmol) and Pd/C (10%, 50 wt.%, 1.2 g) was stirred in toluene (30 ml) and Meon (15 ml) in an atmosphere of H2(rubber Luggage), at room temperature for 18 hours. The solid crystals were filtered across the celite, and the solvents were removed in vacuum, obtaining connection 10BU (2.8 g, 100%).

Stage 3:

Connection 10BU (0.6 g, 1.24 mmol) and pyrrolidinecarbonyl acid VR (0.33 g, 1.24 mmol) was dissolved in DMF (5 ml) at room temperature. Added HATU (0.71 g, 1.86 mmol), and then addediPr2NEt (00.66 ml, 3.72 mmol). The mixture was stirred at room temperature overnight and diluted with ethyl acetate (200 ml) and water (100 ml). The layers were separated. The separated organic layer was washed with water (100 ml), dried (Na2SO4) and was filtered. Concentration in vacuo followed by purification on a column of [hexane-ethyl acetate = 9:1 (V/V)] allowed us to obtain the product 12BU (0.65 g, 72%).

Stage 4:

Connection 12BU (0.65 g) was stirred in a mixture of dichloromethane (30 ml), triperoxonane acid (4 ml) and few drops of water at room temperature overnight. The mixture was cooled at 0°C and carefully extinguished, using 7% Meon (NH3)/CH2Cl2. The solvents were removed in vacuum. Diluted with water (100 ml) and ethyl acetate (200 ml). The layers were separated. The organic layer was dried (Na2SO4), filtered, and the solvents were removed in vacuum. Purification on a column of [15% Meon (7N ammonia) in dichloromethane], we were able to get a connection 13BU (0.22 g, 34%).

Stage 5:

The mixture of compounds is Oia VN (40 mg, 0.126 mmol), compound 13BU (50 mg, 0.126 mmol), DMF (2 ml) and N,N-diisopropylethylamine (0.045 ml, 0.25 mmol) was stirred at room temperature for 18 hours. Was diluted with EtOAc (100 ml) and washed with water (2×100 ml). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel, elwira 3% Meon (NH3)/CH2Cl2with obtaining the target product A19 (50 mg, 60%).

IHMS M+1=664 at retention time 2.88 min

Example 13

Synthesis of 3-methoxy-1-(2-{4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-pyrrolidin-3-carboxylic acid [3-(2-methoxy-pyridine-4-yl)-1H-indazol-5-yl]-amide

Stage 1:

Synthesis of 3-(2-fluoro-pyridine-4-yl)-5-nitro-1-trityl-1H-indazole

3-Bromo-5-nitro-1-trityl-1H-indazol 3BI (15.64 g, 32.3 mmol), 2-fluoro-4-pyridine-Bronevoy acid 2BV (5.0 g, 35.5 mmol), K3PO4(17.1 g, 80.7 mmol) and Pd(dppf)Cl2(2.64 g, 3.23 mmol) were mixed in dioxane/H2(240 ml/60 ml) at room temperature and was heated at 80°C overnight. The reaction mixture was cooled to room temperature and concentrated to small volume. The residue was distributed between ethyl acetate (200 ml) and with brine (150 ml). The organic layer was washed with brine, dried (MgSO4) and was filtered. The obtained filtrate is concentrated is Ali, and the residue was purified on silikagelevye column, sequentially elwira hexane, 5% ethyl acetate in hexano, 10% ethyl acetate in hexano, obtaining solid yellow 3BV (3.33 g, 64%).

Stage 2:

Obtaining 3-(2-methoxy-pyridine-4-yl)-5-nitro-1-trityl-1H-indazole

In the pressure vessel with a volume of 250 ml, 3-(2-fluoro-pyridine-4-yl)-5-nitro-1-trityl-1H-indazol 3BV (5.005 g, 10.0 mmol) was dissolved in N KOCH3/Meon/Toluene (Acros, 150 ml, 15.0 mmol) in an atmosphere of dry gas N2. The pressure vessel was soldered and heated under stirring at 70°C. for 24 hours. Vessel high pressure cooled to 0°C in an ice bath before opening. The contents of the pressure vessel was transferred into a round bottom flask, 500 ml, and boiled away to dryness. The obtained solid substance was dissolved in CH2Cl2and washed with saturated solution of NaCl and dried over MgSO4. The solvent is boiled away to dryness and dried under high vacuum to obtain compound 4BV in a solid brown color (5.12 g, 100%).

Stage 3:

Obtaining 3-(2-methoxy-pyridine-4-yl)-1-trityl-1H-indazol-5-ylamine

To a stirred suspension of 3-(2-methoxy-pyridine-4-yl)-5-nitro-1-trityl-1H-indazole 4BV (5.125 g, 10.0 mmol) in Meon/toluene (50 ml/50 ml) was added 10% Pd/C (Degussa type, 0.5 g) when the room is Noah temperature in an atmosphere of dry gas N 2. The mixture was degirolami and mixed in a rubber chamber filled with gas H2all night. The catalyst was filtered through a microfiber filter and washed Meon and CH2Cl2. The filtrate is boiled away to dryness, and the obtained solid brown 5BV (5.0 g).

Stage 4

Obtain 3-methoxy-3-[3-(2-methoxy-pyridine-4-yl)-1-trityl-1H-indazol-5-ylcarbonyl]-pyrrolidin-1-carboxylic acid tert-butyl ether complex

To a stirred suspension of 3-methoxy-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ether complex 6BV (4.16 mmol, crude) in DMF/DCM (25 ml/25 ml) was added 3-(2-methoxy-pyridine-4-yl)-1-trityl-1H-indazol-5-ylamine 5BV (2.008 g, 4.16 mmol) and Et3N (2.9 ml, 21 mmol) at room temperature in an atmosphere of dry gas N2and then added HATU (3.16 g, 8.32 mmol). The mixture was stirred at room temperature in an atmosphere of dry gas N2the whole night. The mixture was distributed between 1:1 EtOAc and a saturated solution of NaHCO3. The organic phase is separated, washed with brine, dried over MgSO4and boiled away to dryness. The crude compound in the form of a solid substance was purified on 120 g RediSep cartridge, elwira 10-25% EtOAc/Hexane, getting a solid brown color 7BV (2.95 g, 100%).

Stage 5

Obtain 3-methoxy-Pirro is one-3-carboxylic acid [3-(2-methoxy-pyridine-4-yl)-1H-indazol-5-yl]-amide

To a stirred solution of 3-methoxy-3-[3-(2-methoxy-pyridine-4-yl)-1-trityl-1H-indazol-5-ylcarbonyl]-pyrrolidin-1-carboxylic acid tert-butyl ether complex 7BV (2.95 g, 4.16 mmol) in DCM (50 ml) at room temperature was added triethylsilane (1.00 ml, 6.24 mmol)and then TFA (10 ml). The mixture was stirred at room temperature in an atmosphere of dry gas N2within 4-5 hours. The mixture is boiled away to dryness and co boiled away with dry toluene (2×75 ml). The crude solid was purified on 120 g RediSep cartridge, elwira 2.5%-6% 2M NH3-Meon/CH2Cl2, getting a solid off-white color 8BV (1.23 g, 80%).

Stage 6

Synthesis of 3-methoxy-1-(2-{4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-pyrrolidin-3-carboxylic acid [3-(2-methoxy-pyridine-4-yl)-1H-indazol-5-yl]-amide

The mixture of compounds 8BV (40 mg, 0.11 mmol), compound 9BV (41.6 mg, 0.13 mmol) and triethylamine (0.1 ml) in DMF (3 ml) was heated at 45°C., with stirring, overnight. The reaction mixture was then concentrated in vacuo, and the crude material was purified on silikagelevye column, elwira 2% and 4% 2N NH3/Meon in CH2Cl2allocating solid yellow A21 (39.6 mg, 55%). (IHMS M+1=648, retention time = 2.34 min)1H-NMR (400 MHz, CDCl 3): δ 10.54 (ush, 1H), 9.51 & 9.44 (s, 1H), 8.46 (DD, 1H, J=8.2 Hz & 1.4 Hz), 8.27 (d, 1H, J=5.3 Hz), 8.07 (s, 1H), 8.05 (m, 2H), 7.76 (m, 1H), 7.54 (m, 1H), 7.44 (m, 3H), 7.37 (ush, 1H), 6.20 & 6.11 (t, t, 1H, J=2.5 Hz), 4.27 (m, 2H), 4.00 & 3.98 (s, C, 6N), 3.96 & 3.86 (m, m, 1H), 3.74 (m, 1H), 3.47-3.60 (m, 2H), 3.453 & 3.446 (s, 3H), 3.32 (d, 1H, 9.9 Hz), 3.02 (m, 1H), 2.97 (DD, 1H, J=10.1 Hz & 1.0 Hz), 2.91 (m, 1H), 2.64 (m, 2H), 2.47 (m, 1H), 2.19 (m, 1H).

Example 14

Synthesis of 3-methylsulfanyl-1-(2-{4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-pyrrolidin-3-carboxylic acid [3-(2-ethoxy-pyridin-4-yl)-1H-indazol-5-yl]-amide

Stage 1:

Obtaining 3-(2-Ethoxy-pyridin-4-yl)-5-nitro-1-trityl-1H-indazole

In the pressure vessel with a volume of 150 ml, to a stirred solution of 3-(2-fluoro-pyridine-4-yl)-5-nitro-1-trityl-1H-indazole 3BV (2.0 g, 4.0 mmol) in anhydrous EtOH (40 ml) was added solid tert-piperonyl potassium (12 g, 10.0 mmol) in an atmosphere of dry gas N2. The pressure vessel was tightly soldered and was heated at 80°C for 24 hours. The pressure vessel was cooled to 0°C in an ice bath before opening. The contents of the pressure vessel was transferred into a round bottom flask with a volume of 250 ml, and concentrated to small volume. The resulting mixture was distributed between EtOAc and H2O. the Organic phase was separated, washed with saturated solution of NaCl and dried over MgSO4. Rast is oritel boiled away to dryness, obtaining the crude solids 11BV (1.5 g, 71%).

Stage 2:

Obtaining 3-(2-ethoxy-pyridin-4-yl)-1-trityl-1H-indazol-5-ylamine

Connection 12BV received, using essentially the same method as in example 13, step 3, except for the application 11BV instead 4BV.

Stage 3:

Obtain 3-[3-(2-ethoxy-pyridin-4-yl)-1-trityl-1H-indazol-5-ylcarbonyl]-3-methylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ether complex

Connection 14BV, with the release of 88%was obtained using essentially the same method as in example 13, step 4, except for the application 12BV and VR instead 5BV and 6BV.

Stage 4:

Obtaining 3-methylsulfanyl-pyrrolidine-3-carboxylic acid [3-(2-ethoxy-pyridin-4-yl)-1H-indazol-5-yl]-amide

Connection 15BV, with yields of 80%, obtained using essentially the same method as in example 13, step 5, except for the application 14BV instead 7BV.

Stage 5:

Obtaining 3-methylsulfanyl-1-(2-{4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-pyrrolidin-3-carboxylic acid [3-(2-ethoxy-pyridin-4-yl)-1H-indazol-5-yl]-amide

The mixture of compounds 15BV (40 mg, 0.10 mmol), compound 7 NR (41.6 mg, 0.13 mmol) and triethylamine (0.1 ml) in DMF (3 ml) was heated at 45°C, PR is stirring, the whole night. The reaction mixture was then concentrated in vacuo, and the crude material was purified on silikagelevye column, elwira 2% and 4% 2N NH3/Meon in CH2Cl2emitting solid yellow A22 (36.0 mg, 53%). (IHMS M+1=678, retention time = 2.41 minutes).1H-NMR (400 MHz, CDCl3): δ 10.55 (ush, 1H), 10.01 & 9.84 (s, 1H), 8.50 & 8.44 (d, d, 1H, J=1 Hz), 8.25 (d, 1H, J=5.2 Hz), 8.08 (s, 1H), 8.04 (d, 1H, J=8.2 Hz), 8.00 (d, 1H, J=8.2 Hz), 7.75 (m, 1H), 7.53 (m, 1H), 7.43 (d, 1H, J=8.2 Hz), 7.39 (m, 2H), 7.34 (d, 1H, J=5.2 Hz), 6.18 &6.11 (t, t, 1H, J=2.5 Hz), 4.42 (q, 2H, J=7.0 Hz), 4.35 & 4.30 (m, m, 1H), 4.22 (m, 1H), 3.99 (s, 3H), 3.92 (t, 1H, J=5.6 Hz), 3.72 (m, 3H), 3.42 (m, 1H), 3.12 (m, 1H), 2.84 (q, 1H, J=7.9 Hz), 2.76 (d, 1H, J=9.9 Hz), 2.70 (m, 1H), 2.63 (m, 2H), 2.15 (s, 3H), 2.11 (m, 1H), 1.44(t, 3H, J=7.0 Hz).

Example 15

Synthesis of 3-methoxy-1-(2-{4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl)-2-oxo-ethyl)-pyrrolidin-3-carboxylic acid [3-(2-isopropoxy-pyridin-4-yl)-1H-indazol-5-yl]-amide

Stage 1:

Getting 4-bromo-2-isopropoxy-pyridine

To a stirred solution of 4-bromo-2-fluoro-pyridine 17BV (4.12 g, 23.41 mmol) in 50 ml of anhydrous IPA pressure vessel with a volume of 150 ml, was added 2.627 g (23.41 mmol) of solid tert-butoxide potassium in the atmosphere of dry gas N2. The pressure vessel was tightly soldered and was heated at 80°C for 3 hours. The pressure vessel was cooled whom to 0°C in an ice bath, before opening. The contents of the pressure vessel was transferred into a round bottom flask with a volume of 250 ml, and concentrated to small volume. The resulting mixture was distributed between EtOAc and H2O. the Organic phase was separated, washed with saturated solution of NaCl and dried over MgSO4. The solvent is boiled away, and the resulting clear oil was purified on 80 g RediSep cartridge, elwira 20:1 Hexane/EtOAc, to obtain a clear oil 18BV (4.2 g, 83%).

Stage 2

Obtaining 3-(2-isopropoxy-pyridin-4-yl)-5-nitro-1-trityl-1H-indazole

To a stirred solution of 4.20 g (19.4 mmol) of 4-bromo-2-isopropoxy-pyridine 18BV in 150 ml of anhydrous DMSO, 7.39 g (29.1 mmol) (pinacolato)Debora added 5.704 g (58.2 mmol) of potassium acetate and 1.584 g (1.94 mmol) of Pd(dppf)Cl2at room temperature, in an atmosphere of dry gas N2. The mixture was degirolami a couple of times with dry gas N2. A mixture of dark orange was heated at 100°C for 2 hours. The mixture of dark color was cooled to room temperature and added to 75 ml of H2O and then added 9.396 g (19.4 mmol) of 1-trityl-5-nitroindazole, 13.401 g (96.96 mmol) of potassium carbonate and 2.246 g (1.94 mmol) of Tetrakis(Triphenylphosphine)palladium, at room temperature, in an atmosphere of dry gas N2. The mixture was degirolami a couple of times with dry gas N2. A mixture of dark colors was heated at 100°C overnight. A mixture of Oh is adili to room temperature and diluted with a mixture of H 2O/EtOAc 1:1. The diluted mixture was filtered through celite, and the celite washed EtOAc. The content was transferred into a separating funnel and well stirred. The organic phase is separated and washed a couple of times with saturated NaCl solution, dried over MgSO4and boiled away to dryness. Resin, painted in a dark color, purified on a 330 g RediSep cartridge, elwira Hexane, 5% EtOAc/Hexane and 10% EtOAc/Hexane, which allowed us to obtain 3.24 g (31%) solids 19BV pale yellow color.

Stage 3

Obtaining 3-(2-isopropoxy-pyridin-4-yl)-1-trityl-1H-indazol-5-ylamine

Connection 20BV, with the release of untreated substance 100%, was obtained using essentially the same method as in example 13, step 3, except for the application 19BV instead 4BV.

Stage 4:

Obtain 3-[3-(2-isopropoxy-pyridin-4-yl)-1-trityl-1H-indazol-5-ylcarbonyl]-3-methoxy-pyrrolidin-1-carboxylic acid tert-butyl ether complex

Connection 21BV received, using essentially the same method as in example 13, step 4, except for the application 20BV instead 5BV.

Stage 5:

Obtain 3-methoxy-pyrrolidin-3-carboxylic acid [3-(2-isopropoxy-pyridin-4-yl)-1H-indazol-5-yl]-amide

Connection 22BV received, using essentially the same method as in example 13, step 5, except use 21BV instead 7BV.

Step 6:

Obtain 3-methoxy-1-(2-{4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-pyrrolidin-3-carboxylic acid [3-(2-isopropoxy-pyridin-4-yl)-1H-indazol-5-yl]-amide

The mixture of compounds 22BV (40 mg, 0.10 mmol), compound 7 NR (41.6 mg, 0.13 mmol) and triethylamine (0.1 ml) in DMF (3 ml) was heated at 45°C., with stirring, overnight. The reaction mixture was then concentrated in vacuo, and the crude material was purified on silikagelevye column, elwira 2% and 4% 2N NH3/Meon in CH3Cl2allocating solid yellow 23BV (35.0 mg, 52%). IHMS M+1=676, retention time = 2.45 min1H-NMR (400 MHz, CDCl3): δ 10.42 (ush, 1H), 9.41 & 9.34 (s, 1H), 8.43 (DD, 1H, J=10.7 Hz & 1.2 Hz), 8.25 (d, 1H, J=5.2 Hz), 8.07 (s, 1H), 8.05 (m, 2H), 7.74 (m, 1H), 7.49 (m, 1H), 7.44 (m, 3H), 7.29 (ush, 1H), 6.20 & 6.11 (t, t, 1H, J=2.5 Hz), 5.37 (m, 1H), 4.27 (m, 2H), 3.98 (s, 3H), 3.80-3.98 (m, 1H), 3.74 (m, 1H), 3.53 (d, 1H, J=6.6 Hz), 3.49 (ush, 1H), 3.47 & 3.46 (s, 3H), 3.28 (d, 1H, J=10 Hz), 3.02 (m, 2H), 2.88 (m, 1H), 2.64 (m, 2H), 2.47 (m, 1H), 2.19 (m, 1H), 1.40 (d, 6N, J=6.1 Hz).

Example 16

Synthesis of 3-methylsulfanyl-1-(2-{4-[5-(1-methyl-1H-[1,2,4]triazole-3-yl)-thiophene-2-yl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-pyrrolidin-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide

Synthesis of 2-chloro-1-{4-[5-(1-methyl-1H-[1,2,4]triazole-3-yl)-thiophene-2-yl]-3,dihydro-2H-pyridine-1-yl)-ethanone

Stage 1:

Getting 5-bromo-thiophene-2-carboxylic acid amide

5-Bromo-thiophene-2-carboxylic acid (1BW) (6 g) suspended in dichloromethane (30 ml) and thionyl chloride (30 ml). The resulting solution was boiled under reflux overnight at 80°C. the Solvent was removed under reduced pressure, and the residue was dissolved in dichloromethane, was added dropwise to a chilled solution of ammonia in methanol (100 ml), the reaction was controlled by TLC and IHMS. The solvent was removed under reduced pressure to obtain 5-bromo-thiophene-2-carboxylic acid amide (2BW).

Stage 2:

Getting 5-bromo-thiophene-2-carboximidic acid complex ethyl ester

5-Bromothiophene-2-carboxylic acid amide (2BW) (7 g, 34.1 mmol) was dissolved in dichloromethane (170 ml). Added triethyloxonium hexaflurophosphate (10.16 g, 40.97 mmol)and the resulting mixture is boiled under reflux for one hour at 90°C. the Reaction mixture was concentrated under reduced pressure and used directly in the next stage.

Stage 3:

Getting 5-bromo-thiophene-2-carboxamide-N'-methyl-hydrazide

5-Bromo-thiophene-2-carboximidic acid complex ethyl ester (3BW) (13 g, 34.3 mmol) was dissolved in pyridine (100 ml). Methylhydrazine (2.7, 51.45 mmol) was added at paramesh the processes, and the resulting mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and added diethyl ether, filtered, washed three times with diethyl ether and dried to obtain compound whose name is stated in the title (4BW) (13 g).

Stage 4:

Obtain 3-(5-bromo-thiophene-2-yl)-1-methyl-1H-[1,2,4]triazole

A mixture of compound 5-bromo-thiophene-2-carboxamide-N'-methyl-hydrazide (4BW) (13 g) in formic acid (100 ml) was boiled under reflux overnight and then concentrated. The residue was treated with saturated NaHCO3and thrice was extracted with EtOAc. The combined organic layers were dried over MgSO4. After concentration, the connection 5BW purified on a column using 80% EtoAc/hexane, to obtain a solid substance, painted in light yellow color.

Stage 5:

Getting 4-[5-(1-methyl-1H-(1,2,4]triazole-3-yl)-thiophene-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ether complex

In a large flask of high pressure loaded 3-(5-bromo-thiophene-2-yl)-1-methyl-1H-[1,2,4]triazole (3.1 g, 12.8 mmol) (5BW), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (3.6 g, 11.65 mmol), [1,1'-bis(diphenylphosphino)-ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.475 g, 0.89 mmol), Na2 CO3(8.5 ml) and dioxane (40 ml). The mixture was quickly degirolami with argon for about half a minute, it was covered and stirred at 80°C overnight. After cooling, the reaction mixture was diluted with EtOAc and brine solution. The organic layer was separated and dried MgSO4. After concentration the residue was purified on silica gel. Elution using EtOAc (100%) allowed to obtain the target product (6BW) (3.5 g).

Step 6:

Getting 4-[5-(1-methyl-1H-[1,2,4]triazole-3-yl)-thiophene-2-yl]-1,2,3,6-tetrahydropyridine hydrochloride

VOS group on 6BW can be removed by treating the compound 4-[5-(1-methyl-1H-[1,2,4]triazole-3-yl)-thiophene-2-yl]-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ether complex with 4N HCl in dioxane at room temperature for two hours. Removal of the solvent under vacuum, followed by washing with diethyl ether allowed to obtain the target compound (7BW).

Step 7:

Getting 2-chloro-1-{4-[5-(1-methyl-1H-[1,2,4]triazole-3-yl)-thiophene-2-yl]-3,6-dihydro-2H-pyridine-1-yl}-ethanone

To a cooled (0°C.) solution of 4-[5-(1-methyl-1H-[1,2,4]triazole-3-yl)-thiophene-2-yl]-1,2,3,6-tetrahydropyridine (7BW) (1.5 g, 4.72 mmol) in dichloromethane (50 ml) was dropwise added TEA (4.5 ml, 28.32 mmol). After stirring at 0°C for 10 minutes to the reaction mixture was added chlorocatechol (1.12 ml, 14.2 mmol) the resulting mixture was stirred at 0°C for one hour and extinguished with water (15.6 ml). The reaction mixture was diluted with dichloromethane (200 ml). The organic layer was separated and washed with brine, dried over MgSO4. The reaction mixture was concentrated to about 50 ml, was added diethyl ether, and the solid was filtered to obtain the target product (8BW).

Step 8:

Synthesis of 3-methoxy-1-(2-{4-[4-(1-methyl-1H-[1,2,4]triazole-3-yl)-phenyl]-3,6-dihydro-2H-pyridine-1-yl}-2-oxo-ethyl)-pyrrolidin-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide

A mixture of 2-chloro-1-{4-[5-(1-methyl-1H-[1,2,4]triazole-3-yl)-thiophene-2-yl]-3,6-dihydro-2H-pyridine-1-yl}-ethanone (8BW) (0.522 g, 0.863 mmol), 3-methylsulfanyl-pyrrolidine-3-carboxylic acid [3-(6-isopropoxy-pyridine-3-yl)-1H-indazol-5-yl]-amide (VA) (0.463 g, 0.95 mmol),and DIEA (0.9 ml, 5.2 mmol) in DMF (10 ml) was stirred at room temperature overnight. DMF was removed under reduced pressure. The crude reaction mixture was besieged in 30 ml of ice water, filtered, dried and purified by column chromatography using 10% Meon/EtOAc, to obtain the target product A24 in the form of a solid yellow (70%). (IHMS M+1=698, retention time = 3.6 minutes)1H NMR (400 MHz, DMSO): δ 8.67 (s, 1H), 8.64 (s, 1H), 8.36 (s, 1H), 8.15 (s, 1H), 7.64 (d, 1H, J=8.8 Hz), 7.52 (s, 1H), 7.49 (d, 1H, J=5.2 Hz), 7.40(d, 1H, J=8.8 Hz), 7.02 (m, 1H), 6.18 (d, 1H, J=18.8 Hz), 5.08 (m, 1H), 4.41 (d, 2H, J=7.6 Hz), 4.34 (d, 1 is, J=6.4 Hz), 4.12(s, 1H), 3.96 (s, 2H), 3.84 (s, 3H), 3.76 (s, 2H), 3.52(s, 2H), 2.76 (s, 1H), 2.58 (d, 2H, J=20.4 Hz), 2.13 (s, 3H), 1.94 (t, 2H, J=2.8 Hz), 1.39 (d, 6N, J=4.8 Hz).

Examples 17-25

Connection A4, A6, A8, a10-A12, A18, A25 and A26 obtained by following the methods specified in Table 1 below.

EHMS data for compounds in Table 1, are shown in Table 2 below.

EXAMPLE 26

Obtain (S)-N-(3-(6-isopropoxypyridine-3-yl)-1H-indazol-5-yl)-3-methoxy-1-(2-(4-(5-(1-methyl-1H-1,2,4-triazole-3-yl)pyridine-2-yl)-5,6-dihydropyridines-1(2H)-yl)-2-oxoethyl)pyrrolidin-3-carboxamide:

Stage 1: Methyl 6-chloronicotinamide (VH)

The sodium methoxide (725 mg, 13.42 mmol) was added to a solution of 2-chloropyridin-5-carbonitrile (1.8 g, 13.04 mmol) in Meon: dioxane (40 ml, 1:1) at 0°C, then stirred for 30 minutes at 0°C and 1 hour at room temperature. The reaction mixture was diluted with EtOAc (200 ml) and H2O (100 ml), the organic layer separated and dried over Na2SO4was filtered, and the solvent is boiled away, getting connection VH in a solid white color (2.6 g, 100%). MS (MN 171).

Stage 2: 6-chloro-N'-methylnicotinamide (2 I)

Methylhydrazine (750 mg, 16.30 mmol) was added to a solution of methyl 6-chloronicotinamide (VH) (2.6 g, 15.29 mmol) is pyridine (10 ml) at room temperature, then was stirred for one hour. The solvent is boiled away, and the precipitate in the form of a solid substance was treated with cold diethyl ether (2×10 ml), to obtain the product VH in the form of a yellow powder (2.4 g, 85%). MS (MN, 185)

Stage 3: 2-chloro-5-(1-methyl-1H-1,2,4-triazole-3-yl)pyridine (VH)

A solution of 6-chloro-N'-methylnicotinamide (VH) (2.4 g, 13 mmol) in formic acid (99%, 10 ml) was stirred at room temperature for one hour. The reaction mixture is cooled, and the solvent is boiled away. The precipitate was extracted using EtOAc (100 ml) and aqueous NaHCO3(50 ml), the organic layer was separated, dried over Na2SO4was filtered, and the solvent is boiled away. The precipitate was chromatographically on silica gel, elwira 10% MeOH:CH2Cl2by acquisition of the product as a solid (1.8 g, 72%). MS (MN, 195).

Stage 4: Tert-butyl 4-(5-(1-methyl-1H-1,2,4-triazole-3-yl)pyridine-2-yl)-5,6-dihydropyridines-1(2H)-carboxylate (VH)

A mixture of 2-chloro-5-(1-methyl-1H-1,2,4-triazole-3-yl)pyridine (VH) (400 mg, 2.0 mmol); N-tert-butoxycarbonyl-1,2,3,6-tetrahydropyridine-4-Bronevoy acid complex pincavage ester (1.4 g, 4.53 mmol), cesium carbonate (2.3 g, 7.07 mmol) and PdCl2dppf (100 mg) in dioxane/H2O (on/about 10:1, 20 ml)was stirred at 100°C for 2 hours. The reaction mixture is cooled, Razavi and, using CH2Cl2(300 ml) and H2O (100 ml), the organic layer was separated, dried over Na2SO4was filtered, and the solvent is boiled away with obtaining a precipitate, which was chromatographically on silica gel, elwira EtOAc, product VH whose name is stated in the title, in the form of a solid (400 mg, 57%). MS (MN, 342).

Stage 5: 5-(1-methyl-1H-1,2,4-triazole-3-yl)-2-(1,2,3,6-tetrahydropyridine-4-yl)pyridine dihydrochloride (VH)

4M HCl in dioxane (20 ml) was added to a solution of tert-butyl 4-(5-(1-methyl-1H-1,2,4-triazole-3-yl)pyridine-2-yl)-5,6-dihydropyridines-1(2H)-carboxylate (VH) (4 g, 11.67 mmol) in CH2Cl2(50 ml) at room temperature. The mixture was stirred for three hours, then the solvent is boiled away, getting a product whose name is stated in the title, in the form of a solid white color (3.8 g).

Step 6: 2-chloro-1-(4-(5-(1-methyl-1H-1,2,4-triazole-3-yl)pyridine-2-yl)-5,6-dihydropyridines-1(2H)-yl)alanon (VH)

1N NaOH (50 ml, 50 mmol) and chloroacetyl chloride (3 ml, 37.7 mmol) in CH2Cl2(50 ml) was dropwise added to a solution of 5-(1-methyl-1H-1,2,4-triazole-3-yl)-2-(1,2,3,6-tetrahydropyridine-4-yl)pyridine dihydrochloride (VH) (1 g, 3.60 mmol) in CH2Cl2(50 ml) at 0°C., maintaining the pH>12. The mixture was stirred for two hours at 0°C., then the reaction mixture Rabba is or CH 2Cl2(200 ml) and N2O (100 ml). The organic layer was separated, washed H2O (50 ml), dried (Na2SO4), filtered, and the solvent is boiled away with obtaining a product whose name is stated in the title, in the form of a solid white color (1.1 g, 100%). MS (MN, 318).

Stage 7

A solution of 2-chloro-1-(4-(5-(1-methyl-1H-1,2,4-triazole-3-yl)pyridine-2-yl)-5,6-dihydropyridines-1(2H)-yl)ethanone (VH) (0.85 g, 2.68 mmol) in CH2Cl2(10 ml) was added to a solution of indazole (1 g, 2.53 mmol) in DMF (10 ml) at room temperature, then was stirred at 50°C for three hours. The reaction mixture was diluted with EtOAc (300 ml) and H2O (100 ml)then the organic layer was separated, dried over Na2SO4was filtered, and boiled away the solvent. The precipitate was chromatographically on silica gel, elwira 10% V/V MeOH/CH2Cl2/NH4OH, obtaining product A27 in a solid white color (1.3 g, 76%). MS (MN, 677).

IHMS, elution = 2.61 minutes

EXAMPLE 27

Obtain (S)-N-(3-(6-isopropoxypyridine-3-yl)-1H-indazol-5-yl)-3-methoxy-1-(2-(4-(5-(1-methyl-1H-1,2,4-triazole-3-yl)thiazol-2-yl)-5,6-dihydropyridines-1(2H)-yl)-2-oxoethyl)pyrrolidin-3-carboxamide:

Stage 1

To a stirred mixture of 2-chlorothiazole-carbonitrile (1 g, 6.92 mmol) in Meon added NaOMe (745 mg, 1.8 mmol, 2 equiv.), and the reaction mixture was stirred at 0°C for 15 min and warmed up to room temperature for another 15 min, extinguished with water, was extracted using EtOAc. The combined organic layer was washed with brine, dried over Na2SO4and concentrated to obtain the crude substance 2BY (1.2 g) as a yellow oil. To a stirred solution of the crude substances 2BY in pyridine (1 ml) was added methylhydrazine (363 μl, 6.9 mmol, 1 equiv.), the resulting mixture was stirred at 0°C for 15 min and repaid using HCOOH (5 ml). The resulting mixture is then moved in zapasaemoi a test tube and stirred at 110°C. overnight, cooled to room temperature and added water. The resulting mixture was extracted using CH2Cl2. The combined organic layer was washed with brine, dried and concentrated, to obtain the solid yellow color, which was filtered and washed using CH2Cl2. The obtained solid yellow (375 mg) is a target product 4BY. The filtrate was concentrated and optionally further purified on a column, with more product.

Stage 2

The mixture of compounds 4BY (130 mg) in POCl3was stirred in an atmosphere of N2at 120°C for two days. The original is heterogeny the mixture turned into a clear solution brown which was concentrated and purified on silica gel (CH2Cl2/MeOH, 50/1), with connections 5BY (143 mg) as a solid yellow color.

Stage 3

The mixture of compounds 5BY (118 mg, 0.59 mmol), compound 6BY (274 mg, 0.89 mmol, 1.5 equiv.), 2 M Na2CO3(590 μl, 1.18 mmol, 2 equiv.) and Pd(PPh3)4(34 mg, 0.05 equiv.) in benzene/Meon (5 ml, 4/1) was degirolami and stirred in an atmosphere of N2at 80°C overnight. The reaction mixture was then concentrated and purified on silica gel (CH2Cl2/MeOH, 30/1), with connections 7BY (150 mg) as a solid yellow color.

Stage 4

The mixture of compounds 7BY (150 mg, 0.43 mmol) and TFA (1.5 ml) was stirred at room temperature for one hour and concentrated. Chromatography on silica gel (CH2Cl2/MeOH, 15/1) allowed to obtain a connection 8BY (98 mg). To a stirred mixture of compound 8BY (98 mg, 0.4 mmol) and triethylamine (335 μl, 2.4 mmol, 6 equiv.) in CH2Cl2/MeOH (6 ml, 2/1) at 0°C was added chlorocatechol (126 μl, 1.6 mmol, 4 equiv.). The reaction mixture was stirred at 0°C for one hour and concentrated. Chromatography on silica gel (CH2Cl2/MeOH, 25/1) allowed to obtain a connection 9BY (103 mg) as a solid white color.

Stage 5

Connection 9BY replaced by connection VN in Example 15 on Stage 6, in order to obtain a connection A28. IHMS MN=683.4, retention Time = 2.77 minutes

EXAMPLE 28

Obtain (S)-N-(3-(6-isopropoxypyridine-3-yl)-1H-indazol-5-yl)-3-(methylthio)-1-(2-oxo-2-(4-(5-(6-oxopiperidin-1(6N)-yl)-5,6-dihydropyridines-1(2H)-yl)ethyl)pyrrolidin-3-carboxamide) (A29)

Stage 1: Obtain 2-(5-bromothiophene-2-yl)pyridazin-3(2H)-it

A mixture of 2,5-dibromothiophene (1.5 g, 6.2 mmol), pyridazin-3(2H)-she (0.4 g, 4.1 mmol), copper iodide (I) (0.24 g, 1.2 mmol), potassium carbonate (1.7 g, 12.4 mmol), TRANS-N,N'-dimethylcyclohexane-1,2-diamine (0.2 ml, 1.2 mmol) and toluene (15 ml) was degirolami for 15 minutes and then was heated in a sealed tube at 110°C for 18 hours. Cooled to room temperature, filtered through celite and washed using EtOAc. The filtrate was washed with water (100 ml × 2). The organic layer was dried over Na2SO4, filtered, and concentrated to obtain the target product 2BZ (0.9 g, 90%). The residue was purified on silica gel, elwira 80% EtOAc/hexane, to obtain the target product 2BZ (0.7 g, 67%).

Stage 2: Obtain tert-butyl 4-(5-(6-oxopiperidin-1(6N)-yl)thiophene-2-yl)-5,6-dihydropyridines-1(2H)-carboxylate

The mixture of compounds 2BZ (0.7 g, 2.7 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-is ihydro-2H-pyridine-1-carboxylic acid tert-butyl ether complex (0.84 g, 2.7 mmol), 2M aqueous sodium carbonate solution (6.8 ml, 13.6 mmol), Pd(PPh3)4(0.31 g, 0.27 mmol) and 1/1 /toluene/ethanol (20 ml) was degirolami within 15 minutes. Then was heated at 90°C overnight. Cooled to room temperature and diluted using EtOAc (200 ml). The organic layer was washed with water (100 ml), dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel, elwira 60% EtOAc/hexane to obtain the target product 3BZ (0.63 g, 65%).

Stage 4: Getting 2-(5-(1,2,3,6-tetrahydropyridine-4-yl)thiophene-2-yl)pyridazin-3(2H)-it

The mixture of compounds 3BZ (0.63 g, 1.75 mmol), CH2Cl2(20 ml) and TFA (23 ml) was stirred at room temperature for 18 hours. Concentrated and purified on silica gel, elwira 5% Meon (NH3)/ CH3Cl2obtaining the target product 4BZ (0.4 g, 89%).

Stage 5: Obtain 2-(5-(1-(2-chloroacetyl)-1,2,3,6-tetrahydropyridine-4-yl)thiophene-2-yl)pyridazin-3(2H)-it

To a mixture of compound 4BZ (0.62 g, 2.39 mmol), CH2Cl2(10 ml), Meon (3 ml) and triethylamine (0.67 ml, 4.78 mmol) at -78°C was added chlorocatechol (0.19 ml, 2.39 mmol). The reaction mixture was stirred at -78°C for 10 minutes, then warmed to 0°C and was stirred for one hour. Diluted using CH3Cl2(100 ml)and washed with saturated aqueous dissolve the om NaHCO 3(100 ml). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was dissolved in CH2Cl2and added diethyl ether. The obtained solid was filtered and washed with diethyl ether, and dried to obtain the target product 5BZ (0.56 g, 70%).

Stage 6

The mixture of compounds 5BZ (0.04 g, 0.12 mmol), compound 6BZ (0.05 g, 0.12 mmol), DMF (2 ml) and N,N-diisopropylethylamine (0.042 ml, 0.24 mmol) was stirred at room temperature for 18 hours. Diluted using EtOAc (100 ml), and washed with water (2×100 ml). The organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified on silica gel, elwira 3% Meon (NH3)/CH2Cl2obtaining the target product A29 (0.083 g, 97%).

IHMS MN=711, retention Time = 3.26 minutes.

EXAMPLE 29

Obtain (S)-N-(3-(6-isopropoxypyridine-3-yl)-1H-indazol-5-yl)-1-(2-(4-(5-(3-methyl-6-oxopyrimidine-1(6H)-yl)thiophene-2-yl)-5,6-dihydropyridines-1(2H)-yl)-2-oxoethyl)-3-(methylthio)pyrrolidin-3-carboxamide (A30)

Connection A30 received, using a methodology similar to the methodology described in Example 28, except for the adoption of 6-methylpyridazin-3(2H)-it instead pyridazin-3(2H)-she is in Stage 1.

IHMS MN=725, retention Time = 3.21 minutes.

EXAMPLE 30

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Connection VO (4.25 g, 10.33 mmol) was dissolved in N,N-dimethylformamide (40 ml) at room temperature. Then added diisopropylethylamine (5.1 ml, 30.99 mmol), and then the connection VN (3.27 g, 10.33 mmol). The reaction mixture was stirred for 1 hour at ambient temperature. In the reaction mixture was added brine, and then was extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts were dried over magnesium sulfate, filtered, and boiled away to obtain the crude product, the name of which is specified in the title. The crude product was chromatographically to obtain 4.95 g (69%) of the product, the name of which is specified in the title (A6) (10% 2N NH3in MeOH:CH2Cl2).

EXAMPLE 31

To a solution of compound CA (140 mg, 1.4 mmol) in CH3Ph (3 ml) was added a drop of DMF, and then added oxalicacid (0.14 ml, 1.6 mmol) at room temperature. After 30 minutes, the obtained transparent solution was added to a solution of compound CA (240 mg, 1 mmol) and triethylamine (0.5 ml) in CH2Cl2. After stirring at room temperature for 30 minutes, the reaction repaid saturated NaHCO3, were extracted using CH2Cl2and concentrated, to obtain the crude product SA (312 mg) as a solid white color that was used the right near St is significant in the following reactions. In SA, SA, and SA "D" stands for deuterium.

Join the A31 and A32, was obtained in a manner similar to the method of obtaining the compounds A1 and A6, replacing SA on WN. Join A45 and A48 motorway was obtained in a manner similar to the method of obtaining compounds A23 and A25, replacing SA on WN. In A31, A32, A45 and A48 motorway "D" stands for deuterium.

IHMS 3.95 min M+1=694.4

IHMS 4.24 min M+1=678.4

IHMS 3.94 min M+1=674

IHMS 3.61 min M+1=664

Example 32

If you follow a methodology similar to the methodology described in Example 31, the Connection A33-A44, A46 and A below will be obtained. In A33-A44, A46 and A "D" stands for deuterium.

,

,

,

,

,

,

,

,

,

,

,

,

and

.

and

In A33-A44, A46 and A "D"stands for deuterium.

Tests

Dual analyses ERK2:

Actively the TB compounds in respect of inactive ERK2 tested, applying MAR paired analysis MEK1/ERK2, as follows: the Compounds were diluted to 25-fold the final test concentration in 100% DMSO. 14 μl of kinase buffer (10 mm Tris. HCl pH 7.2, 10 mm MgCl2, 0.01% Tween-20, 1 mm DTT)containing 0.4 ng nefosfaurilirovanna murine ERK2 protein was added to each well of a black 384-well analytical tablet. 1 μl of compound at 25 times the concentration added to each well and incubated at room temperature for 30 minutes to allow connection to communicate with the inactive enzyme. During the primary incubation, the concentration of DMSO was 6.7%. The activity of ERK2, as defined, was insensitive to DMSO concentrations up to 20%. ERK2 is then activated, and its kinase activity was measured by adding 10 μl of kinase buffer with the following components (final concentration per reaction): 2 ng of active (phosphorylated) human MEK1 protein and 4 µm (total) IMAP ERK2 substrate proteins (3.9 ám its IPTTPITTTYFFFK-CONH2and 100 nm IPTTPITTTYFFFK(5-carboxyfluorescein)-CONH2) and 30 μm ATP. The concentration of DMSO in the activation of ERK was 4%. After one hour the reaction was stopped by adding 60 μl IMAP detectionin beads in binding buffer (Molecular devices). Binding given the opportunity to balanced for 30 minutes before reading the tablet on a tablet reader LJ Analyst Fluorescence Polarizationr. Inhibition compound was calculated relative to DMSO and a fully-inhibited standards. The active compounds can re-examine in an independent analysis.

Analysis of active ERK2:

The activity of activated ERK2 also identified in the format analysis IMAP, using the methodology described above. 1 μl of Compound at 25-fold concentration was added to 14 μl of kinase buffer containing 0.25 ng fully phosphorylated active murine ERK2 protein. 30 minutes after the start of incubation, the reactions were initiated by adding 10 μl of kinase buffer containing 1 μm IMAP substrate protein ERK2 (0.9 ám its IPTTPITTTYFFFK-CONH2and 100 nm IPTTPITTYFFFK(5-carboxyfluorescein)-CONH2) and 30 μm ATP. The reaction proceeded for 30 minutes before they were completed by adding 60 ál IMAP detectionin beads in binding buffer. The tablet reads as noted above, after equilibration of binding within 30 minutes. The active connection is re-examined in an independent analysis.

Analysis on solid agar:

For oncogenic cell lines characterized by substrate-independent growth. Tumor cells can be suspended in the medium for growth, containing 0.3% agarose and the indicated concentration of inhibitor farnesyltransferase. The solution is applied to the environment for growth, utverzhdennuyu 0.6% agarose, the content is concerned the same concentration of the inhibitor of ERK1 and ERK2, as the top layer. After the top layer was solid, tablets incubated at 37°C for 10-16 days, in an atmosphere of 5% CO2for growth of colonies. After incubation, colonies were stained by covering the agar solution of MTT (3-[4,5-dimethyl-thiazol-2-yl]-2,5-diphenyltetrazolium bromide, Thiazolyl blue) (1 mg/ml in phosphate-saline buffer solution). Colonies can be counted and IC50 can be determined.

AUC (area under the curve of the dependence of concentration on time during the first 6 hours (KL ACC6h) was determined using the Protocol Cassette progressive rapid screening rats (CARRS)

Dosing of animals and obtaining samples

Rats-males line Sprague, doli (Charles River Co.) pre was Coulibaly (femoral artery) in order to arrive at precise moments of taking blood samples and to reduce the load on animals caused by serial blood sampling. Two rats, which during the night was not given food, oral introduced by one connection at a dose of 10 mg/kg, the dose volume 5 ml/kg for each animal at time 0.5, 1, 2, 3, 4, and 6 hours after a dose of serially collected blood in heparin-containing tubes and concentrated to collect the plasma. Plasma, 100 μl, was collected in separate moments of time. Plasma samples were stored at -20°C until analysis.

Obtaining a sample of plasma and built the e calibration curve

Set of 12 plasma samples of rats were collected for each NCE (new chemical entity) (i.e., 6 time points and n=2 rats). These 12 plasma samples were combined for the two rats at each time point, obtaining six combined samples (one sample for one time) for each NCE. The combined samples were analyzed in the format of cassettes with six branches (a total of 36 samples)to obtain data on the six compounds. Aliquots with a volume of 50 μl, were selected from 36 samples of plasma were placed in individual wells of 96-hole tablet. Additional connection (often a structural analogue of test compounds) was taken as internal standard. For each of the analyzed compounds were prepared mini-calibration curve (three plus zero point). Free drug plasma of rats was measured, when the volume of the aliquot of 1 ml, and each aliquot was injected at a known concentration of compounds with obtaining standards with the desired concentrations. Concentrations of the standards were chosen so that they match the expected concentrations of the combined samples, based on data obtained from previously conducted studies for other compounds. For this work the standards contained concentrations of 25, 250 and 2500 ng MCE/ml plasma. The standards of the plasma along with the samples was subjected to precipitation vdvoh instances. The precipitation of the protein occurred after adding to each sample well 150 μl of acetonitrile containing the internal standard at a concentration of 1 ng/ml, using the system Tomtec Quadra 96. Precipitated samples and standards were shaken and centrifuged on a 96-well pad. About 50-100 μl of the supernatant was removed and placed in a fresh 96-well plate, using the system Tomtec Quadra 96. 5-10 μl of the Supernatant was used for analysis by HPLC-MS/MS. Mini-calibration curve was run twice, once before and after samples. Thus, for each compound analyzed all 14 samples for the study of the plus standards. In addition, the solvents as standard was injected before and after each set of 14 samples and after the highest calibration standard for each connection, thus, only 103 of the injection was made in each HPLC system for each set of six compounds. Multiple injection solvent as a standard could be made from the same wells. Twelve holes with solvent as standard were identified in each 96-well pad. Thus, one series (cassette) six NCEs was obtained and analyzed using a 96-well plate.

HPLC-MS/MS analysis

All compounds were analyzed by means of selective monitoring of reactions (SM) with LC/MS/MS instruments. Once the development was completed quickly analyzed using the standard model of sequential injection analysis CARRS.

Compounds A1-A16, A18, A20, A21, A23, A25, A26, and A27-A30 showed IC50 for AERK2 in the range of 1.2-50 nm.

Compounds A1-A3, A6, A8-A11, A13-A16, A20-A24, A26, and A27-A30 showed an AUC in the range of 36-50,999 nm. hour analysis CARRS.

For preparing pharmaceutical compositions from the compounds described in this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid form. Drugs in solid form include powders, tablets, dispersible granules, capsules, starch capsules and suppositories. The powders and tablets may contain from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, such as magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, starch capsules and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of obtaining the various compositions disclosed in A.Gennaro (ed.), Remington: The Science and Practice of Pharmacy, 20thEdition, (2000), Lippincott Williams & Wilkins, Baltimore, MD.

Drugs in liquid form include solutions, suspensions and emulsions. In the case of the decree is ü water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and radiopaque substances for oral solutions, suspensions and emulsions. Drugs in liquid form can also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which can be combined with a pharmaceutically acceptable carrier such as an inert compressed gas, for example nitrogen.

The present invention also includes preparations in solid form, which is supposed to become, immediately before use, to liquid form, either for oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

Compounds according to the invention can also be delivered transdermal. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as is conventional in the art for these purposes.

Preferably, the compound is administered orally by.

Preferably, the pharmaceutical preparation is in the form of dosage forms. In this form, the drugs are divided into standard dose of a suitable size containing appropriate quantities of the active component, for example, the amount effective to achieve the desired goal.

The number of active connections in the standard dose of the drug may vary or be from about 0.01 mg to about 1000 mg, preferably from about 0.01 mg to about 750 mg, more preferably from about 0.01 mg to about 500 mg, and most preferably from about 0.01 mg to about 250 mg, depending on the particular application.

The exact applied dose may vary depending on the needs of the patient and the severity of the condition to be treated. Determination of an appropriate dosage regimen for a particular case is within the competence of a person skilled in the art. For convenience, the total daily dose may be divided for the introduction of the parts during the day, as the need arises.

The number and frequency of injection of the compounds according to the invention and/or their pharmaceutically acceptable salts will be regulated in accordance with the assessment of the treating physician, taking into account such factors as age, condition and weight of the patient, and the severity of symptoms to be treated. A typical recommended daily regimen for oral administration can be in the range from about 0.04 mg/day to about 4000 mg/day, in two to four doses per day.

Although the present invention is disclosed above with specific embodiments of the invention, and is defined above, many alternatives, modifications and variations of the present invention will be obvious to experts in the given field of technology. All such alternatives, modifications and variations, as is implied, covered entity and the scope of the present invention.

1. The compound of formula 1.0:

or its pharmaceutically acceptable salt, where R1, R2and Q are independently chosen, and where:
Q represents:

R1selected from the group consisting of:
(1) pyridyl, substituted Deputy selected from the group consisting of: -O-CH3, -O-C2H5, -O-CH(CH3)2and-O-(CH2)2-O-CH3;
(2)
;
(3)
;
(4)

R2selected from the group consisting of: -co3and-SCH3;
R5selected from the group consisting of:
(a) substituted triazolylmethyl-where triazolyl substituted by one or two alkyl groups selected from the group consisting of: -C1-C4of alkyl,
(b) substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom of-C1-C4the alkyl,
(c) substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom of-C2alkylen-O-C1-C2the alkyl,
(d) substituted triazolylmethyl-, DG is triazolyl substituted on the nitrogen atom of-C 2-C4alkylen-O-CH3and
(e) substituted triazolylmethyl-where triazolyl substituted on the nitrogen atom of hydroxy-substituted-C1-C4the alkyl, and
where phenyl optionally substituted from 1 to 3 substituents, independently selected from the group consisting of a halogen.

2. The compound according to claim 1, having the formula:

3. The compound according to claim 1 or 2, where the optional halogen substituents for the phenyl fragment R5represent F.

4. The compound according to claim 1, where:
(a) the specified triazolyl substituted on the nitrogen atom by a Deputy selected from the group consisting of: -CH2SLEEP(CH3)2and CH2CH2HE
(b) the specified triazolyl substituted on the nitrogen atom-CH3group
(c) the specified triazolyl substituted on the nitrogen atom of one-CH3group, and the carbon atom of one-CH3group, or
(d) the specified triazolyl substituted on the nitrogen atom-CH2CH2OCH3group;
and where phenyl optionally substituted with halogen.

5. Compounds according to claim 1, where:
R5selected from the group consisting of:

6. The compound according to claim 1, where R5selected from the group consisting of:
.

7. A compound selected from the group consisting of:
,
,
,


and
,
and its pharmaceutically acceptable salts.

8. The compound according to claim 1, which represents the

or its pharmaceutically acceptable salt.

9. The compound according to claim 1, which represents the

or its pharmaceutically acceptable salt.

10. The compound according to claim 1, which represents the

or its pharmaceutically acceptable salt.

11. The compound according to claim 1, which represents the

or its pharmaceutically acceptable salt.

12. The compound according to claim 1, which represents the

or its pharmaceutically acceptable salt.

13. The compound according to claim 1, which represents the

or its pharmaceutically acceptable salt.

14. Pharmaceutical compose, have anticancer activity, containing at least one compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier.

15. The use of compounds according to claim 1 for obtaining a medicinal product for the treatment of cancer.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds or their pharmaceutically acceptable salts, where compound has formula 1-a, in which R1 and R3 are absent, m represents integer number from 1 to 2, n represents integer number from 1 to 3, A represents , B represents or , where X2 represents O or S, R4a is absent, R4b is selected from the group, consisting of: , , , , and ; Rk is selected from C1-6alkyl and C1-6halogenalkyl, L and E are such as given in i.1 of the invention formula; or compound is such as given in b) of i.1 of the invention formula. Invention also relates to pharmaceutical composition, which contains said compounds.

EFFECT: compounds by i1, possessing inhibiting activity with respect to anti-apoptosis protein Bcl-XL.

27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I) or pharmaceutically acceptable salts thereof, where Alk is an C1-C6alkyl group; G is C=O and Q is CR51R52 or NR51, where R51 and R52, being identical or different, independently denote H, C1-C6alkyl, optionally substituted with a substitute selected from a group comprising carboxy, phenoxy, benzyloxy, C1-C6alkoxy or hydroxy; C3-C6cycloalkylC1-C6alkyl; phenylC1-C6alkyl, optionally substituted with a halogen; phenylamidoC1-C6alkyl; phenylC1-C6alkylamidoC1-C6alkyl, optionally substituted with a C1-C6alkoxy group; or R51 and R52, together with a carbon atom with which they are bonded form a C=O or C2-C6alkenyl group, optionally substituted with a phenyl; M1 is CR49, where R49 is H; M2 is CR50, where R50 is H; R38 is H, C1-C6alkyl, substituted with a phenoxy group; C3-C6cycloalkylC1-C6alkyl; arylC1-C6alkyl, optionally substituted with 1 or 2 substitutes selected from a group comprising C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, carboxyl, N-methylamido, hydroxy, C1-C6alkoxyC1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphanyl, cyano, halogen, perfluoroC1-C6alkyl, nitro, formyl, hydroxyC1-C6alkyl and amino, wherein the aryl moiety is a phenyl or naphthyl; and heteroarylC1-C6alkyl, where the heteroaryl moiety is pyridinyl, optionally substituted with 1 or 2 groups selected from C1-C6alkoxy or hydroxyC1-C6alkyl, pyrazolyl or isoxazolyl, substitute with 1 or 2 C1-C6alkyl groups; R47 and R48 is C1-C6alkyl. The invention also relates to specific compounds, a method of reducing or weakening bitter taste, a composition of a food/non-food product or beverage or drug for reducing or lightening bitter taste and a method of producing a compound of formula (I).

EFFECT: obtaining novel compounds which are useful as bitter taste inhibitors or taste modulators.

37 cl, 6 dwg, 12 tbl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of structural formula or a salt thereof, where each of Z1, Z2 and Z3 is independently selected from N and C(R9), where not more than one of Z1, Z2 and Z3 is N; each R9 is hydrogen; and is a second chemical bond between either W2 and C(R12), or W1 and C(R12); W1 is -N=, and W2(R14) is selected from -N(R14)- and -C(R14)=, such that when W1 is -N=, W2(R14) is -N(R14)- and is a second chemical bond between W1 and C(R12); R11 is selected from phenyl and a heterocycle which is selected from a saturated or aromatic 5-6-member monocyclic ring, which contains one or two or three heteroatoms selected from N, O and S, or an 8-member bicyclic ring which contains one or more heteroatoms selected from N, O and S, where R11 is optionally substituted with one or two substitutes independently selected from halogen, C1-C4 alkyl, =O, -O-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from -C1-C4alkyl; or two R13 together with a nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, optionally containing an additional heteroatom selected from NH and O, where if R13 is an alkyl, the alkyl is optionally substituted with one or more substitutes selected from -OH, fluorine, and if two R13 together with the nitrogen atom to which they are bonded form a 5-6-member saturated heterocycle, the saturated heterocycle is optionally substituted on any carbon atom with fluorine; R12 is selected from phenyl, a 4-6-member monocyclic saturated ring and a heterocycle, which is selected from an aromatic 5-6-member monocyclic ring which contains one or two heteroatoms selected from N and S, where R12 is optionally substituted with one or more substitutes independently selected from halogen, -C≡N, C1-C4 alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4 alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen, C1-C4 alkyl, C1-C4 fluorine-substituted alkyl, C1-C4 alkyl-N(R13)(R13), C1-C4 alkyl-C(O)-N(R13)(R13); and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, -NH-S(=O)2-†, where † denotes the point where X1 is bonded to R11. The invention also relates to a pharmaceutical composition having sirtuin modelling activity based on said compounds.

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine to treat a subject suffering from or susceptible to insulin resistance, metabolic syndrome, diabetes or complications thereof.

18 cl, 2 tbl, 52 ex

Organic compounds // 2518462

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and

,

where X represents S or O, one of X1 and X2 represents CR3' and second represents N or independently CR3', n represents integer number 1, 2 or 3; R1 represents C1-6 halogenalkyl, R2 is selected from halogen and C1-C6-halogenalkyl; R3' represents H, C1-C6-alkyl, halogen, cyanogroup, or phenyl, non-substituted or substituted with halogen, C1-C6-alcoxygroup, C1-C6-halogenalcoxygroup, C1-C6-halogenalkyl group; Z represents halogen, Q radical or group -C(O)-NR5R6; R5 represents H or C1-C4-alkyl, R6 represents H; Q', C1-C6-alkyl, non-substituted or substituted with halogen, cyanogroup, C1-C4-alcoxygroup, C1-C4-alkoxycarbonyl, C2-C4-alkanoyl, aminocarbonyl, N-mono- or N,N-di-C1-C2-alkylaminocarbonyl, C1-C4-alkylthiogroup, group -C(O)NHR7 or radical Q"; or C3-C6-cycloalkyl, substituted with group -C(O)NHR7; or C2-C4-alkinyl; Q, Q' and Q" are such as given in the invention formula; R7 represents C1-C6-alkyl, which is non-substituted or substituted with halogen, cyanogroup, pyridyl; or represents C2-C4-alkinyl. Invention also relates to composition for fighting ectoparasites, containing compound of formula (Ia) or (Ib), and to application of compounds of formula (Ia) or (Ib) for composition production.

EFFECT: compounds of formula (Ia) and (Ib), possessing activity against ectoparasites.

11 cl, 4 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein R1 represents an alkoxy group or halogen; each U and V independently represents CH or N; "----" means a bond or is absent; W represents CH or N, or if "----" is absent, then W represents CH2 or NH, provided not all U, V and W represent N; A represents a bond or CH2; R2 represents H, or provided A means CH2, then it also can represent OH; each m and n are independently equal to 0 or 1; D represents CH2 or a bond; G represents a phenyl group that is single or double substituted in meta- and/or para-position(s) by substitutes specified in alkyl, C1-3alkoxy group and halogen, or G represents one of the groups G1 and G2: wherein each Z1, Z2 and Z3 represents CH; and X represents N or CH and Q represents O or S; it should be noted that provided each m and n are equal to 0, then A represents CH2; or a pharmaceutically acceptable salt of such compound. Besides, the invention refers to a pharmaceutical composition for treating a bacterial infection containing an active ingredient presented by a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert additive.

EFFECT: preparing the oxazolidine compounds applicable for preparing a drug for treating and preventing the bacterial infections.

14 cl, 8 dwg, 2 tbl, 33 ex

Cetp inhibitors // 2513107

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I, or its pharmaceutically acceptable salt where: X stands for -O-; Z stands for -C(=O)-; Y stands for -(CRR1)-, where R1 is selected from -C1-C2alkyl; R stands for H or -C1-C5alkyl; R5 stands for H; R2 and B each is selected from A1 and A2, where one of R2 and B stands for A1, and the other from R2 and B stands for A2; where A1 has structure (a); A2 is selected from the group, which includes phenyl, pyridyl, pyrazolyl, thienyl, 1,2,4-triazolyl and imodazolyl; A3 is selected from the group including phenyl, thiazolyl and pyrazolyl; A4 is selected from the group, including phenyl, pyridyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and asetidinyl; A2 is optionally substituted with 1-3 substituents, independently selected from halogen atom, -OCH3 and -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A3 is substituted with one A4 group and is optionally substituted with 1-2 substituents, independently selected from halogen atom, -OH, -OCH3, -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A4 is optionally substituted with 1-3 substituents, independently selected from the group, which includes: (a) -C1-C5alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with group -OH, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) halogen atom, (j) -CN, (k) -NO2, (l) -C(=O)NR3R4, (m) -OC1-C2alkyleneOC1-C2alkyl, (n) -OC1-C3alkyl, optionally substituted with 1-3 halogen atoms, (o) -C(=O)OC1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (q) -NR3R4 and (r) -S(O)xNR3R4, on condition that A4 stands for heterocyclic group, attached to A3 by means of ring carbon atom in A4, at least, one substituent in A4 must be selected from Re, where Re is selected from the group including: (a) -C1-C5alkyl, substituted with -OH group and optionally substituted with 1-3 halogen atoms, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) -CN, (j) -NO2, (k) -C(=O)NR3R4, (l) -OC1-C2alkyleneOC1-C2alkyl, (m) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (n) -NR3R4(=O)OC1-C2alkyl, (o) -NR3R4 and (p) -S(O)xNR3R4; p equals 0, 1 or 2; and Ra is selected from halogen atom, -CH3, -CF3, -OCH3 and -OCF3; R3 and R4 each is independently selected from H and CH3; and x equals 0, 1 or 2.

EFFECT: formula (I) compound is applied for medication, which possesses properties of CETP inhibitor, for increase of HDL-C and for reduction of LDL-C Technical result is compounds, inhibiting cholesterol ether transferring protein (CETP).

10 cl, 140 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where A is a 6-member heteroaryl, having 1 nitrogen atom as a heteroatom, substituted with 2-3 substitutes such as indicated in the claim, R5 is a halogen atom, cyano or C1-C6alkyl, optionally substituted with a halogen atom; R6 is C1-C6 alkyl, optionally substituted with OH; C1-C3 alkenyl; a 5-member heteroaryl, having 2-4 heteroatoms, each independently selected from N, O or S, substituted with 0-2 substitutes such as indicated in the claim, R10 is a 5-member heteroaryl, having 2-3 heteroatoms, each selected from N, O or S, substituted with 0-2 substitutes, which are C1-C3 alkyl; R7, R8, R17 denote a hydrogen or halogen atom. The invention also relates to a pharmaceutical composition, having BK B2 receptor inhibiting activity, which contains compounds of formula (I), a method of inhibiting, a method of localising or detecting the BK B2 receptor in tissue, use of the compounds of compositions to produce a medicinal agent and methods for treatment.

EFFECT: compounds of formula (I) as BK B2 receptor inhibitors.

22 cl, 1 tbl, 54 ex

FIELD: biotechnologies.

SUBSTANCE: invention refers to a compound of formula (I):

,

where R1 represents NR7C(O)R8 or NR9R10; R2 represents hydrogen; R3 represents halogen; R4 represents hydrogen, halogen, cyano, hydroxy, C1-4alkyl, C1-4alkoxy, CF3, OCF3, C1-4alkylthio, S(O)(C1-4alkyl), S(O)2(C1-4alkyl), CO2H or CO2(C1-4alkyl); R5 represents C1-6alkyl (replaced with NR11R12 or heterocyclyl that represents nonaromatic 5-7-membered ring containing 1 or 2 heteroatoms independently chosen from a group containing nitrogen, oxygen or sulphur); R6 represents hydrogen, halogen, hydroxy, C1-4alkoxy, CO2H or C1-6alkyl (possibly replaced with NR15R16 group, morpholinyl or thiomorpholinyl); R7 represents hydrogen; R8 represents C3-6cycloalkyl (possibly replaced with NR24R25 group), phenyl or heteroaryl, which represents aromatic 5- or 6-membered ring containing 1 to 3 heteroatoms independently chosen from the group containing nitrogen, oxygen and sulphur, and which is probably condensed with one 6-membered aromatic or nonaromatic carbocyclic ring or with one 6-membered aromatic heterocyclic ring, where the above 6-membered aromatic heterocyclic ring includes 1 to 3 heteroatoms independently chosen from a group containing nitrogen, oxygen and sulphur; R9 represents hydrogen or C1-6alkyl (possibly replaced with pyrazolyl); R10 represents C1-6alkyl (possibly replaced with phenyl or heteroaryl group, which represents aromatic 5- or 6-membered ring containing 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur, and which is possibly condensed with one 6-membered heterocyclic ring, where the above 6-membered aromatic heterocyclic ring contains 1 or 2 heteroatoms independently chosen from the group containing nitrogen, oxygen or sulphur; where the above phenyl and heteroaryl groups in R8, R9 and R10 are possibly independently replaced with the following group: halogen, hydroxy, C(O)R42, C1-6alkyl, C1-6hydroxyalkyl, C1-6halogenoalkyl, C1-6alkoxy(C1-6)alkyl or C3-10cycloalkyl; unless otherwise stated, heterocyclyl is possibly replaced with group of C1-6alkyl, (C1-6alkyl)OH, (C1-6alkyl)C(O)NR51R52 or pyrrolidinyl; R42 represents C1-6alkyl; R12, R15 and R25 independently represent C1-6alkyl (possibly replaced with hydroxy or NR55R56 group); R11, R16, R24, R51, R52, R55 and R56 independently represent hydrogen or C1-6alkyl; or to its pharmaceutically acceptable salts.

EFFECT: new compounds are obtained, which can be used in medicine for treatment of PDE4-mediated disease state.

10 cl, 2 tbl, 202 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to organic chemistry and specifically to 5-phenyl-1H-pyrazin-2-one derivatives of general formula II or pharmaceutically acceptable salts thereof, where R denotes -R1 or - R1-R2-R3; R1 denotes aryl or heteroaryl, and is optionally substituted with one or two R1'; where each R1' independently denotes C1-6alkyl, halogen or C1-6halogenalkyl; R2 denotes -C(=O), -CH2-; R3 denotes R4; where R4 denotes an amino group or heterocycloalkyl, and is optionally substituted with one or two substitutes selected from C1-6alkyl, hydroxy group, oxo group, C1-6hydroxyalkyl, C1-6alkoxy group; Q denotes CH2; Y1 denotes C1-6alkyl; Y2 denotes Y2b; where Y2b denotes C1-6alkyl, optionally substituted with one Y2b'; where Y2b' denotes a hydroxy group, n and m are equal to 0; Y4 denotes Y4c or Y4d; where Y4c denotes lower cycloalkyl, optionally substituted with halogen; and Y4d denotes an amino group, optionally substituted with one or more C1-6alkyl; where "aryl" denotes phenyl or naphthyl, "heteroaryl" denotes a monocyclic or bicyclic radical containing 5 to 9 atoms in the ring, which contains at least one aromatic ring containing 5 to 6 atoms in the ring, with one or two N or O heteroatoms, wherein the remaining atoms in the ring are carbon atoms, under the condition that the binding point of the heteroaryl radical is in the aromatic ring, "heterocycloalkyl" denotes a monovalent saturated cyclic radical consisting of one ring containing 5 to 6 atoms in the ring, with one or two ring heteroatoms selected from N, O or SO2. The invention also relates to use of the compound of formula II or a pharmaceutical composition based on the compound of formula II.

EFFECT: obtaining novel compounds that are useful for modulating Btk activity and treating diseases associated with excessive activity of Btk.

7 cl, 2 tbl, 53 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I in which R1 represents halogen, methoxy group or cyano group; each of Y1 and Y2 represents CH, and one or two from U, V, W and X represent N, and each remaining one represents CH, or in case X, cam also represent CRa, or Ra represents halogen; A represents CH2CH(OH), CH2CH(NH2), CH(OH)CH(NH2) or CH(NH2)CH2, B represents CH2CH2, CH2NH or CONH, and D represents CH2, or A represents CH(OH)CH2, and B represents CH2NH, N(R2)CO or CONH, and D represents CH2, or B represents N(R2a)CH2, and D represents CH(OH), or A represents CH(OH)CH(OH), B represents CH2NH or CONH and D represents CH2, or A represents CH2CH2, and B represents CH2CH2, CH2NR3, NHCO, CONR4, CH2O, COCH2 or CH2CH2NH, and D represents CH2, or B represents CH2NH, and D represents CO, or A also represents CH2CH2, B represents NR4bCH2 and D represents CH(OH), or A represents CH=CH, B represents CH2NR5 or CONR6, and D represents CH2, or A represents C≡C, B represents CH2NH and D represents CO, or A represents COCH2, B represents CONH and D represents CH2, or A represents CH2N(R7), and B represents CH2CH2, a D represents CH2, or B represents CH2CH(OH), a D represents CH(OH), or A represents NHCH2, and B represents CH2NH, a D represents CH2, or B represents CH2NH, a D represents CO, or A represents NHCO, B represents CH(R8)NH or CH2CH2, and D represents CH2, or A represents OCH2, B represents CH=CH or CONH, and D represents CH2; R2 represents (C1-C4)alkyl; R2a represents hydrogen; R3 represents hydrogen, CO-(CH2)p-COOR3', (CH2)p-COOR3, (C2-C5)acyl or amino(C1-C4)alkyl, or also R3 represents (C1-C4)alkyl, which can be one or two times substituted with hydroxygroup, p stands for integer number from 1 to 4, and R3 represents hydrogen or (C1-C4)alkyl; R4 represents hydrogen or (C1-C4)alkyl; R4b represents hydrogen; R5 represents hydrogen or (C2-C5)acyl; R6 represents hydrogen or (C1-C4)alkyl; R7 represents hydrogen or (C1-C4)alkyl, which can be one or two times substituted with group, independently selected from hydroxygroup and aminogroup, R8 represents hydrogen or (C1-C4)alkyl; E represents one of the following groups (a-a1) where Z represents CH or N, and Q represents O or S, or E represents phenyl group, which is one or two times substituted in meta- and/or para-position with substituents, each of which is independently selected from group, including halogen, (C1-C3)alkyl and trifluoromethyl; or pharmaceutically acceptable salt of such compound. Formula I compound or its pharmaceutically acceptable salt is applied for obtaining medication or pharmaceutical composition for prevention or treatment of bacterial infection.

EFFECT: derivatives of oxazolidine antibiotics for obtaining medication for treatment of bacterial infections.

15 cl, 2 tbl, 214 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I) or pharmaceutically acceptable salts thereof, where Alk is an C1-C6alkyl group; G is C=O and Q is CR51R52 or NR51, where R51 and R52, being identical or different, independently denote H, C1-C6alkyl, optionally substituted with a substitute selected from a group comprising carboxy, phenoxy, benzyloxy, C1-C6alkoxy or hydroxy; C3-C6cycloalkylC1-C6alkyl; phenylC1-C6alkyl, optionally substituted with a halogen; phenylamidoC1-C6alkyl; phenylC1-C6alkylamidoC1-C6alkyl, optionally substituted with a C1-C6alkoxy group; or R51 and R52, together with a carbon atom with which they are bonded form a C=O or C2-C6alkenyl group, optionally substituted with a phenyl; M1 is CR49, where R49 is H; M2 is CR50, where R50 is H; R38 is H, C1-C6alkyl, substituted with a phenoxy group; C3-C6cycloalkylC1-C6alkyl; arylC1-C6alkyl, optionally substituted with 1 or 2 substitutes selected from a group comprising C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, carboxyl, N-methylamido, hydroxy, C1-C6alkoxyC1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphanyl, cyano, halogen, perfluoroC1-C6alkyl, nitro, formyl, hydroxyC1-C6alkyl and amino, wherein the aryl moiety is a phenyl or naphthyl; and heteroarylC1-C6alkyl, where the heteroaryl moiety is pyridinyl, optionally substituted with 1 or 2 groups selected from C1-C6alkoxy or hydroxyC1-C6alkyl, pyrazolyl or isoxazolyl, substitute with 1 or 2 C1-C6alkyl groups; R47 and R48 is C1-C6alkyl. The invention also relates to specific compounds, a method of reducing or weakening bitter taste, a composition of a food/non-food product or beverage or drug for reducing or lightening bitter taste and a method of producing a compound of formula (I).

EFFECT: obtaining novel compounds which are useful as bitter taste inhibitors or taste modulators.

37 cl, 6 dwg, 12 tbl, 186 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where A is a 6-member heteroaryl, having 1 nitrogen atom as a heteroatom, substituted with 2-3 substitutes such as indicated in the claim, R5 is a halogen atom, cyano or C1-C6alkyl, optionally substituted with a halogen atom; R6 is C1-C6 alkyl, optionally substituted with OH; C1-C3 alkenyl; a 5-member heteroaryl, having 2-4 heteroatoms, each independently selected from N, O or S, substituted with 0-2 substitutes such as indicated in the claim, R10 is a 5-member heteroaryl, having 2-3 heteroatoms, each selected from N, O or S, substituted with 0-2 substitutes, which are C1-C3 alkyl; R7, R8, R17 denote a hydrogen or halogen atom. The invention also relates to a pharmaceutical composition, having BK B2 receptor inhibiting activity, which contains compounds of formula (I), a method of inhibiting, a method of localising or detecting the BK B2 receptor in tissue, use of the compounds of compositions to produce a medicinal agent and methods for treatment.

EFFECT: compounds of formula (I) as BK B2 receptor inhibitors.

22 cl, 1 tbl, 54 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyranyl aryl methylbenzoquinazolinone compounds of formula (I), which are positive allosteric modulators of the M1 receptor and which can be used to treat diseases associated with the M1 receptor, such as Alzheimer's disease, schizophrenia, pain disorders or sleep disturbance. In formula (I) X-Y are selected from a group comprising (1) -O-CRARB-, (2) -CRARB-O-, (3) -CRARB-SRC-, (4) -CRARB-NRC- and (5) -NRC-CRARB-, where each RA and RB is a hydrogen atom, and RC is selected from a group comprising (a) hydrogen, (b) -C(=O)-C1-6alkyl, (c) -C1-6alkyl, (d) -C(=O)-CH2-C6H5, (e) -S(=O)2-C1-6 alkyl, R1 is a hydroxy group, R2 is selected from a group comprising (1) -phenyl, (2) - heteroaryl, where the phenyl or heteroaryl group R2 is optionally substituted; the rest of the values of the radicals are given in the claim.

EFFECT: obtaining novel pyranyl aryl methylbenzoquinazolinone compounds.

28 cl, 12 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (1) or a salt thereof, where D1 is a single bond, -N(R11)- or -O-, where R11 is a hydrogen atom or C1-C3 alkyl; A1 is C2-C4 alkylene, or any of divalent groups selected from the following formulae , and ,

where n1 equals 0 or 1; n2 equals 2 or 3; n3 equals 1 or 2; R12 and R13 are each independently a hydrogen atom or C1 -C3 alkyl; v is a bond with D1; and w is a bond with D2; D2 is a single bond, C1-C3 alkylene, -C(O)-, S(O)2-, -C(O)-N(R15)-, or -E-C(O)-, where E is C1-C3 alkylene, and R15 is a hydrogen atom; R1 is a hydrogen atom, C1-C6 alkyl, a saturated heterocyclic group which can be substituted with C1-C6 alkyl groups, an aromatic hydrocarbon ring which can be substituted with C1-C3 alkyl groups, C1-C4 alkoxy groups, halogen atoms, cyano groups, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or the following formula ,

where n1 equals 0, 1 or 2; m2 equals 1 or 2; D12 is a single bond, -C(O)- or -S(O)2-; R18 and R19 denote a hydrogen atom; R17 is a hydrogen atom or C1-C3 alkyl; and x is a bond with D2; under the condition that when R17 denotes a hydrogen atom, D12 denotes a single bond; under the condition that when D1 denotes a single bond, A1 denotes a divalent group of said formula (1a-5) or (1a-6); when D1 denotes -N(R11)-, -O-, or -S(O)2-, A1 denotes a single bond, C2-C4 alkylene, or any of divalent groups selected from formulae (1a-1)-(1a-3), where, when A1 denotes a single bond, D2 denotes -E-C(O)-; and D3 is a single bond, -N(R21)-, -N(R21)-C(O) - or -S-, where R21 is a hydrogen atom; and R2 denotes a group of formula ,

where Q denotes an aromatic hydrocarbon ring, a monocyclic aromatic heterocyclic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, a condensed polycyclic aromatic ring containing one or two heteroatoms selected from a group consisting of a nitrogen atom, a sulphur atom and an oxygen atom, or a partially unsaturated monocyclic or a condensed bicyclic carbon ring and a heterocyclic ring; and y denotes a bond with D3; and R23, R24 and R25 each independently denotes a hydrogen atom, a halogen atom, a cyano group, C1-C3 alkyl, which can be substituted with hydroxyl groups, halogen atoms or cyano groups, C1-C4 alkoxy group, which can be substituted with halogen atoms, alkylamino group, dialkylamino group, acylamino group, or the formula ,

where D21 denotes a single bond or C1-C3 alkylene; D22 denotes a single bond or -C(O)-; R26 and R27 each independently denotes a hydrogen atom or C1-C3 alkyl; and z denotes a bond with Q; under the condition that when D22 denotes a single bond, R27 is a hydrogen atom. The invention also relates to specific compounds, a pharmaceutical composition based on the compound of formula , a IKKβ inhibitor, a method of inhibiting IKKβ, a method of preventing and/or treating an NF-kB-associated or IKKβ-associated disease, and intermediate compounds of formulae and .

EFFECT: obtaining novel isoquinoline derivatives, having useful biological properties.

46 cl, 3 dwg, 38 tbl, 89 ex

FIELD: chemistry.

SUBSTANCE: described are racemic- or enantiomer-rich 3-substituted piperidine compounds of formula (I) or pharmaceutically acceptable salts thereof, where A denotes phenyl, naphthyl, optionally substituted, or benzothiophenyl; B denotes an azole selected from a group consisting of triazole, benzotriazole, 5-methyl- or 5-phenyltetrazole; Y-CH2 and X- N-R, where R denotes hydrogen or C1-4alkyl, pharmaceutical compositions containing said compounds, and methods of treating depression, anxiety or pain disorder in mammals.

EFFECT: high efficiency of using compounds.

11 cl, 4 tbl, 126 ex

FIELD: chemistry.

SUBSTANCE: invention relates to substituted indole derivatives of formula , where A and B are independently CH2 or C=O, X is indolyl, unsubstituted or mono- or polysubstituted; T is (CR5a-cR6a-c)n, n=1 or 2. Q is (CR7a-cR8a-c)m, m=0, 1 or 2, the values of the rest of the radicals are given in claim 1, which act on the ORL1 receptor.

EFFECT: improved method.

13 cl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel pyrrole compounds of formula I or pharmaceutically acceptable salts thereof: I, where: Ar denotes phenyl, thiophenyl; R1 denotes imidazolyl, imidazolyl substituted with C1-C6alkyl, chlorine, bromine, fluorine, hydroxy group, methoxy group; R2 denotes H, CH3, Cl, F, OH, OCH3, OC2H5, propoxy group, carbamoyl, dimethylamino group, NH2, formamide group, CF3; X denotes CO and SO2. The compounds inhibit S-nitrosoglutathione reductase (GSNOR).

EFFECT: using the compound to produce a pharmaceutical composition and for treating asthma.

17 cl, 1 tbl, 14 dwg, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzodiazepine compounds of general formula , wherein each R1, R2, R3 and R4 independently represent hydrogen or alkyl, or R2 and R3 together represent lower alkylene; A1 is lower alkylene optionally substituted by hydroxy; and R5 is a fragment of formula , wherein each R6 and R7 independently represents hydrogen, lower alkyl, cycloalkyl, phenyl, furyl, thienyl, pyrazolyl, etc.; each XA and XB independently represents a bond, lower alkylene, -CO-, -SO2- etc., a pharmaceutical composition containing them, and using the above compound as the pharmaceutical composition or for preparing the same.

EFFECT: new compounds may be used for preventing and treating cardiac arrhythmia.

8 cl, 1047 ex, 78 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds being aspartyl protease inhibitors applicable for treating cardiovascular, neurodegenerative disorders and fungal infection of formula , wherein W represents -C(=O)-; X represents -NH-; U represents -C(R6)(R7)-; R1 represents methyl, R2, R3 and R6 represent H, R4 and R7 represent optionally substituted phenyl, as well as tautomers and pharmaceutically acceptable salts thereof.

EFFECT: there are presented new effective aspartyl protease inhibitors specified in rennin, cathepsin D, BACE-1, for treating cardiovascular diseases, cognitive and neurodegenerative diseases, as well as fungal infections.

67 cl, 1 tbl, 4393 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a specific list of various novel azaazulene compounds, which contain 6,5-condensed heterocycle of an indole type, benzimidazole type, purine type, 3H-imidaso[4,5-b]pyrene,3H-imidaso[4,5-c] pyridine, etc., which can be described by the general formula , where R1 is =O; R2 is H or diethylaminoalkyl; R3-R7 is H; other variables in the formula (I) are given in the specific structural formulas of the described compounds. A pharmaceutical composition which contains thereof is also described.

EFFECT: compounds possess an anti-tumour activity and can be used for treatment of cancer, such as breast cancer, lung cancer, pancreas cancer, cancer of large intestine, and acute myeloid leukemia.

5 cl, 2 dwg, 6 tbl, 14 ex

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