Diaminotriazole compounds used as protein kinase inhibitors

FIELD: chemistry.

SUBSTANCE: described are novel diaminotriazole compounds of general formula

(values of radicals are given in the claim), pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds, a method of inhibiting JAK2 and JAK3 kinase activity and use of the novel compounds to produce a medicinal agent for treating several diseases.

EFFECT: high efficiency of the compounds.

19 cl, 3 tbl, 26 ex

 

The SCOPE of the INVENTION

The present invention relates to compounds that can be used as inhibitors of Janus kinases (JAK). The present invention also relates to compounds that can be used as inhibitors of Aurora kinase-2, kinase Flt3, kinases GSK-3 and KDR. The invention also includes pharmaceutically acceptable compositions containing the compounds of the invention and methods of using the compositions in the treatment of various disorders.

The LEVEL of TECHNOLOGY

The Janus kinase (JAK) family of tyrosine kinases, including JAK1, JAK2, JAK3 and TYK2. The JAK kinase play an important role in signal transduction by cytokines. Substrates of kinases of the JAK family, downstream in the cascade, are the carrier proteins signal and activators of transcription (STAT). JAK/STAT signaling mediates many types of abnormal immune responses such as allergies, asthma, autoimmune diseases, as well as graft rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as solid and hematologic malignancies such as leukemia and lymphoma. JAK2 also involved in the development of myeloproliferative disorders, including true polycythemia, essential trombozitemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, x is oncesi myeloid leukemia, chronic monocytic myeloid leukemia, chronic eosinophilic leukemia syndrome hypereosinophilia and systemic mastocytosis.

WO2004/046120 reveals diametricaly that can be used as inhibitors of protein kinases, including Flt3, FMS, c-Kit, DERIVED, JAK, subfamily of AGC protein kinases, CDK, GSK, Src, ROCK, and/or Syk. However, there is a need to develop compounds that are more selective inhibitors of protein kinases, in particular inhibitors of Aurora-2, Flt3, KDR, JAK2 and JAK3. Particularly desired is development of compounds that can be used as inhibitors of kinases of the JAK family.

The INVENTION

It is known that the compounds of the present invention, and pharmaceutically acceptable compositions on their basis, effective as inhibitors of protein kinases. In some embodiments, the compounds of the present invention and pharmaceutically acceptable compositions on their basis effective as inhibitors of protein kinases GSK-3, JAK-2, JAK-3, Flt3, KDR, or Aurora-2. In preferred embodiments of these compounds of the present invention and pharmaceutically acceptable compositions are inhibitors of JAK 2 and JAK-3. These compounds have the General formula I:

or their pharmaceutically acceptable derivatives with different values is amestitelj, specified in the present description.

These compounds and pharmaceutical compositions based on them applicable for the treatment or prevention of various diseases, including, without limitation, allergies, asthma, autoimmune diseases such as transplant rejection, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, as well as solid and hematologic malignancies such as leukemias and lymphomas. Compounds and pharmaceutical compositions based on them can also be used for the treatment or prevention of myeloproliferative disorders, including true polycythemia, essential trombozitemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic monocytic myeloid leukemia, chronic eosinophilic leukemia syndrome hypereosinophilia and systemic mastocytosis.

DETAILED description of the INVENTION

Definitions and General terminology

As used in the present description, the following definitions will be presented, unless otherwise defined. For the implementation of the objectives of the present invention, the chemical elements are identified in accordance with the Periodic system of elements Mendeleev, CAS version, Handbook of Chemistry and Physics, 75thEd. Additionally, General principles of organic chemistry and described in "Organic Chemistry", Thomas Sorrell, University Science Books, Sausalito: 1999; "March's Advanced Organic Chemistry, 5thEd., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001; "Encyclopedia of Organic Transformations"; Ed.: Richard C. Larock, John Wiley & Sons, New York: 1999; "Encyclopedia of Reagents for Organic Synthesis", Ed.: Leo A. Paquette, John Wiley & Sons, New York: 1995; T.W. Greene & P.G.M Wutz, "Protective Groups in Organic Synthesis", 3rdEdition, John Wiley & Sons, Inc. (1999)(and earlier editions), the full contents of which are herewith incorporated by reference.

As shown in the present description, the compounds according to the invention can optionally be substituted with one or more substituents, such as generally provided for above, or as shown by separate classes, subclasses and groups according to the invention. It is determined that the expression "optionally substituted" is used interchangeably with the expression "substituted or unsubstituted". In General, the term "substituted", or preceded by the term "optionally" or not, refers to the replacement of hydrogen radicals in the established structure of the specific radical substituent. Unless otherwise indicated, optionally substituted group may have a Deputy for each appropriate position of the group, and when more than one position in any of the installed structure can be replaced by more than one Deputy, selected from a specific group, the Deputy may be either the same or different on each one is ogenyi. Combinations of substituents represented by the present invention are preferred, because the result is the formation of a stable or chemically feasible compounds. The term "stable"as it is used in the present invention refers to compounds that do not significantly change in requirements, definitions, and preferably their separation, purification, and use for one or more of the purposes disclosed in the present invention. In some embodiments, a stable compound or chemically feasible compound that does not change significantly when the temperature is 40°C or less in the absence of moisture or other chemically reactive conditions, at least during the week.

The term "aliphatic" or "aliphatic group", as used in the present description, means a straight (i.e. unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or which contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of nancysinatra, but which is not aromatic (also specified in the present from which reenie as the terms "carbocycle", "cycloaliphatic" or "cycloalkyl"), which is the only place of connection to the remainder of the molecule. Unless otherwise specified, aliphatic groups contain 1-20 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-10 aliphatic carbon atoms. In other embodiments aliphatic groups contain 1-8 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-6 aliphatic carbon atoms, and in yet other embodiments aliphatic groups contain 1-4 aliphatic carbon atoms. In some embodiments, the term "cycloaliphatic" (or "carbocycle", or "cycloalkyl"refers to monocyclic3-8the hydrocarbon or bicyclic C8-12the hydrocarbon that is completely saturated or that contains one or more units of nancysinatra, but which is not aromatic, that has a single connection point to the rest of the molecule, where any individual ring in the specified bicyclic ring system has 3-7 members. Suitable aliphatic groups include, but without limitation, linear or branched, substituted or unsubstituted alkyl, alkeline, alkyline groups and their hybrids, such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

The term "hetero is alifaticheskii", as it is used in the present invention, means an aliphatic group in which one or two carbon atoms are independently substituted with one or more atoms of oxygen, sulfur, nitrogen, phosphorus or silicon. Heteroaromatics groups can be substituted or unsubstituted, branched or unbranched, cyclic or acyclic, and include "heterocycle", "heterocyclyl", "heterocyclizations" or "heterocyclic" group.

The term "heterocycle", "heterocyclyl", "geterotsiklicheskikh" or "heterocyclic", as used in the present description, means non-aromatic, monocyclic, bicyclic or tricyclic ring system in which one or more ring members is independently selected from a heteroatom. In some embodiments, the "heterocycle", "heterocyclyl", "geterotsiklicheskikh" or "heterocyclic" group has from three to fourteen ring members in which one or more ring members is a heteroatom independently selected from oxygen, sulfur, nitrogen, or phosphorus, and each ring in the system contains 3 to 7 ring members.

Examples of heterocyclic rings include benzimidazole (for example, 3-1H-benzimidazole-2-it, 3-(1-alkyl)-benzimidazole-2-one), tetrahydrofuranyl (for example, 2-tetrahydrofuranyl, 3-then it is carbonated shall Returnil), tetrahydrothiophene (for example, 2-tetrahydrothiophene, 3-tetrahydrothiophene), morpholine (for example, 2-morpholino, 3-5 morpholino, 4-morpholino), thiomorpholine (for example, 2-thiomorpholine, 3 thiomorpholine, 4-thiomorpholine), pyrrolidinyl (for example, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl), tetrahydropyranyl (for example, 1-tetrahydropyranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl), piperidinyl (for example, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl), pyrazolyl (for example, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl), diazolidinyl (for example, 2-thiazolidine, 3-thiazolidine, 4-thiazolidine), imidazolidinyl (for example, 1-imidazolidinyl, 2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl), indolinyl, tetrahydropyranyl, tetrahydroisoquinoline, benzothiophen, benzodithiol and dihydroimidazole-2-he (1,3-dihydroimidazole-2-one).

The term "heteroatom" means one or more atoms of oxygen, sulfur, nitrogen, phosphorus, or silicon (including, any oxidized form of nitrogen atoms, sulfur, phosphorus or silicon; and stereoselectivity form of any basic nitrogen atom or a substituted nitrogen atom of the heterocyclic ring, for example N (as in 3,4-dihydro-2N-pyrrolyl), NH (as in pyrrolidinyl) or NR+(as in N-substituted pyrrolidinyl)).

The term "unsaturated"as used in the present from which reenie, means that the remainder is one or more units of nancysinatra.

The term "alkoxy" or "thioalkyl"as it is used in the present invention, refers to an alkyl group as previously defined, attached to the main carbon chain through an oxygen atom ("alkoxy") or sulfur atom ("thioalkyl").

The terms "halogenated", "halogenoalkanes and halogenoalkane" mean alkyl, alkenyl or alkoxy that may be substituted with one or more halogen atoms. The term "halogen" means F, Cl, Br or I.

The term "aryl"used alone or as part of a large balance, both in terms of "aralkyl", "arakaki" or "aryloxyalkyl", refers to monocyclic, bicyclic and tricyclic ring systems having, as a rule, from five to fourteen ring members, where at least one ring in the system is aromatic and where each ring in the system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring". The term "aryl" also refers to a heteroaryl ring system, as defined in the present description below.

The term "heteroaryl"used by itself or as part of a large balance, both in terms of "heteroalkyl" or "heteroaromatics", refers to monocyclic, bicyclic and tricyclic ring is a diversified systems having, as a rule, from five to fourteen ring members, where at least one ring in the system is aromatic, at least one ring in the system contains one or more heteroatoms, and where each ring in the system contains 3 to 7 ring members. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

Examples of heteroaryl rings include furanyl (for example, 2-furanyl, 3-furanyl), imidazolyl (for example, N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl) benzimidazole, isoxazolyl (for example, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), oxazolyl (for example, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl), pyrrolyl (for example, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl), pyridyl (e.g. 2-pyridyl, 3-pyridyl, 4-pyridyl), pyrimidinyl (for example, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl), pyridazinyl (for example, 3-pyridazinyl), thiazolyl (for example, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl), tetrazolyl (for example, 5-tetrazolyl), triazolyl (for example, 2-triazolyl and 5-triazolyl), thienyl, (for example, 2-thienyl, 3-thienyl), benzofuran, thiophenyl, benzothiophene, indolyl (e.g., 2-indolyl), pyrazolyl (for example, 2-pyrazolyl), isothiazolin, oxadiazolyl (e.g., 1,2,3-oxadiazolyl), oxadiazolyl (e.g., 1,2,5-oxadiazolyl), oxadiazolyl (for example, 1,2,4-oxadiazolyl), triazolyl (for example, 1,2,3-triazolyl), thiadiazolyl (e.g., 1,2,3-thiadiazolyl), thiadiazolyl (e.g., 1,3,4-thiadiazolyl), thiadiazolyl (e.g., 1,2,5-thiadiazolyl), purinol, pyrazinyl, triazinyl (for example, 1,3,5-triazinyl), chinoline (for example, 2-chinoline, 3-chinoline, 4-chinoline) and ethenolysis (for example, 1-ethenolysis, 3-ethenolysis or 4-ethenolysis).

Aryl (including aralkyl, Alcoxy, aryloxyalkyl and the like) or heteroaryl (including heteroalkyl, heteroaromatics and the like) group may contain one or more substituents. Suitable substituents on the unsaturated carbon atom aryl or heteroaryl group selected from halogen; -R°; -OR°; -SR°; 1,2-methylenedioxy; 1,2-Ethylenedioxy; phenyl (Ph)optionally substituted with R°; -O(Ph)optionally substituted with R°; -(CH2)1-2(Ph), optionally substituted with R°; -CH=CH(Ph), optionally substituted with R°; -NO2; -CN; -N(R°)2; -NR°C(O)R°; -NR°C(S)R°; -NR°C(O)N(R°)2; -NR°C(S)N(R°)2; -NR°CO2R°; -NR°NR°C(O)R°; -NR°NR°C(O)N(R°)2; -NR°NR°CO2R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -CO2R°; -C(O)R°; -C(S)R°; -C(O)N(R°)2; -C(S)N(R°)2; -C(=NH)-N(R°)2, -OC(O)N(R°)2; -OC(O)R°; -C(O)N(OR°)R°; -C(NOR°)R°; -S(O)2R°; -S(O)3R°; -SO2N(R°)2; -S(O)R°; -NR°SO2N(R°)2; -NR°SO2R°; -N(OR°)R°; -C(=NH)-N(R°)2or -(CH2)0-2NHC(O)R°, where ka is the home of the independent occurrence of R° is selected from hydrogen, optionally substituted C1-6aliphatic, an unsubstituted 5-6 membered heteroaryl or heterocyclic ring, phenyl, -O(Ph), or-CH2(Ph), or, notwithstanding, as defined above, two independent occurrences of R°, on one and the same Deputy or different substituents, taken together with the atom(atoms)to which each R° group is bound, forms a 5-8-membered heterocycle, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Optional substituents on the aliphatic group of R° is selected from NH2, NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, OH, O(C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), - O(halogen C1-4aliphatic group) or a halogen(C1-4aliphatic group), where each of the above C1-4aliphatic groups of R° is unsubstituted.

Aliphatic or heteroaromatics group or non-aromatic heterocyclic ring may contain one or more substituents. Suitable substituents on the saturated carbon of aliphatic or heteroaromatics group or non-aromatic heterocyclic ring select the districts of those listed above for the unsaturated carbon aryl or heteroaryl group and additionally include the following: =O, =S, =NNHR*, =NN(R*)2, =NNHC(O)R*, =NNHCO2(alkyl), =NNHSO2(alkyl), or =NR*, where each R* is independently selected from hydrogen or optionally substituted C1-6aliphatic group. Optional substituents on the aliphatic group of R* are selected from NH2, NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, OH, O(C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), - O(halogen C1-4aliphatic group) or a halogen(C1-4aliphatic group), where each of the above C1-4aliphatic groups of R* is unsubstituted.

Optional substituents on the nitrogen atom nonaromatic heterocyclic ring selected from R+,-N(R+)2, -C(O)R+, -CO2R+, -C(O)C(O)R+, -C(O)CH2C(O)R+, -SO2R+, -SO2N(R+)2, -C(=S)N(R+)2, -C(=NH)-N(R+)2or-NR+SO2R+; where R+represent hydrogen, optionally substituted C1-6aliphatic group, optionally substituted phenyl, optionally substituted-O(Ph), optionally substituted-CH2(Ph), optionally C is displaced -(CH 2)1-2(Ph); optionally substituted-CH=CH(Ph) or unsubstituted 5-6 membered heteroaryl or heterocyclic ring, having from one to four heteroatoms independently selected from oxygen, nitrogen or sulfur, or, notwithstanding, as defined above, two independent occurrence of R+at one and the same Deputy or different substituents, taken together with the atom(atoms)to which each R+the group is linked, form a 5-8-membered heterocycle, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Optional substituents on the aliphatic group or the phenyl ring of R+selected from NH2, NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, OH, O(C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), - O(halogen C1-4aliphatic group) or a halogen(C1-4aliphatic group), where each of the above C1-4aliphatic groups of R+is unsubstituted.

The term "alkylidene chain" refers to a straight or branched carbon chain, which may be fully saturated or have one or more units of unsaturation, and have two points p is soedineniya to the rest of the molecule.

As defined above, in some embodiments, two independent occurrence of R° (or R+or any other variable similarly defined in the present invention), taken together with the atom(atoms)to which each variable is bound, form a 5-8-membered heterocycle, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur. Examples of rings that are formed when two independent occurrences of R° (or R+or any other variable similarly defined in the present invention), taken together with the atom(atoms)to which each variable is bound include, but without limitation, the following: a) two independent occurrence of R° (or R+any other variable similarly defined in the present invention)that are linked to the same atom and are taken together with that atom to form a ring, for example N(R°)2where both the occurrence of R°, taken together with the nitrogen atom, form a piperidine-1-silt, piperazine-1-silt or morpholine-4-silt group; and b) two independent occurrence of R° (or R+any other variable similarly defined in the present invention)that are associated with different atoms and are taken together with both of those atoms to form a ring, for example, where the phenyl gruppotoscano with two substituents OR°

,

these two occurrences of R°, taken together with the oxygen atoms to which they are linked, form a condensed 6-membered ring containing an oxygen atom ring

.

You must understand that can be formed in a variety of other rings, when two independent occurrence of R° (or R+any other variable similarly defined in the present invention) taken together with the atom(atoms)to which each variable is associated, and examples of which are specified above, are not intended to limit.

Unless otherwise provided, the structure described in the present invention is also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example R and S configurations for each asymmetric center, (Z) and (E) isomers with double bonds and (Z) and (E) conformational isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric and geometric (or conformational) of the mixture of the presented compounds are within the borders of the present invention. Unless otherwise specified, all tautomeric forms of the compounds according to the invention are within the borders of the present invention. In addition, unless otherwise provided, the structure described in the present invention, it also means the inclusion of compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of hydrogen by deuterium or tritium, or the replacement of12C carbon using13C or14C carbon are within the borders of the present invention. Such compounds are useful, for example, as analytical tools or samples in biological experiments.

The description of the compounds according to the invention

The invention provides a compound of formula I:

or its pharmaceutically acceptable salt, derivative or prodrug,

where A represents N or CR1;

R1represents H, halogen or1-6alkyl;

RXselected from the

RYselected from the

whenever R it independently selected from hydrogen or C1-6aliphatic group, optionally substituted with J or J'; and

R' is independently selected from hydrogen or a group selected from C1-8aliphatic group, optionally substituted with up to three substituents J or J', C6-10aryl, optionally substituted with POM is using up to three substituents J, heteroaryl ring having 5-10 ring atoms, optionally substituted with up to three substituents J, or heterocyclic ring having 3-10 ring atoms, optionally substituted with up to three substituents J or J', or where R and R', taken together, form a 5-8-membered cycloalkyl, heterocycle, aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, each ring optionally and independently substituted with up to three substituents J;

at each occurrence R" it independently selected from hydrogen or a group selected from C1-8aliphatic group, optionally substituted with up to three substituents J or J', C6-10aryl, optionally substituted with up to three substituents J, a heteroaryl ring having 5-10 ring atoms, optionally substituted with up to three substituents J, or heterocyclic ring having 3-10 ring atoms, optionally substituted with up to three substituents J or J'

or, where R and R", taken together, form a 5-8-membered cycloalkyl, heterocycle, aryl or heteroaryl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen or sulfur, each ring optionally and independently substituted with up to three batch is of Italy J;

whenever J it independently selected from halogen; -R°; -OR°; -SR°; 1,2-methylenedioxy; 1,2-Ethylenedioxy; phenyl (Ph)optionally substituted with R°; -O(Ph)optionally substituted with R°; -(CH2)1-2(Ph), optionally substituted with R°; -CH=CH(Ph), optionally substituted with R°; -NO2; -CN; -N(R°)2; -NR°C(O)R°; -NR°C(S)R°; -NR°C(O)N(R°)2; -NR°C(S)N(R°)2; -NR°CO2R°; -NR°NR°C(O)R°; -NR°NR°C(O)N(R°)2; -NR°NR°CO2R°; -C(O)C(O)R°; -C(O)C(O)OR°, -C(O)C(O)N(R°)2, -C(O)CH2C(O)R°; -CO2R°; -C(O)R°; -C(S)R°; -C(S)OR°, -C(O)N(R°)2; -C(S)N(R°)2; -C(=NH)-N(R°)2, -OC(O)N(R°)2; -OC(O)R°; -C(O)N(OR°)R°; -C(NOR°)R°; -S(O)2R°; -S(O)3R°; -SO2N(R°)2; -S(O)R°; -NR°SO2N(R°)2; -NR°SO2R°; -N(OR°)R°; -C(=NH)-N(R°)2; C(=NOR°)R°; (CH2)0-2NHC(O)R°; -P(O)2R°; -PO(R°)2; -OPO(R°)2or-P(O)(H)(OR°);

where at each independent occurrence of R° it is chosen from hydrogen, optionally substituted C1-6aliphatic group, optionally substituted 5-6-membered heteroaryl or heterocyclic ring, optionally substituted phenyl (Ph); optionally substituted-O(Ph); optionally substituted -(CH2)1-2(Ph); optionally substituted-CH=CH(Ph); or, two independent occurrence of R°, on one and the same Deputy or different substituents, taken together with the atom(atoms), to the which each R° group is bound, form a 5-8-membered heterocycle, aryl, or heteroaryl ring or a 3-8-membered cycloalkyl ring having 0-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

where the Deputy for the aliphatic group of R° represents optionally substituted heteroaryl, optionally substituted heterocyclic group, NH2, NH(C1-6aliphatic group), N(C1-6aliphatic group)2, halogen, C1-6aliphatic group, OH, O(C1-6aliphatic group), NO2CN, CO2H, CO2(C1-6aliphatic group), - O(halogen With1-6aliphatic group) or a halogen(C1-6aliphatic group), where each of these aliphatic groups of R° is unsubstituted;

where the Deputy for phenyl, heteroaryl or heterocyclic group of R° represents a C1-6aliphatic group, NH2, NH(C1-4aliphatic group), N(C1-6aliphatic group)2, halogen, C1-6aliphatic group, OH, O(C1-6aliphatic group), NO2CN, CO2H, CO2(C1-6aliphatic group), - O(halogen C1-6aliphatic group) or a halogen(C1-6aliphatic group), where each of the specified C1-6aliphatic groups of R° is unsubstituted;

whenever J' his independent Vybrat of =O, =S, =NNHR*, =N(R*) 2, =NNHC(O)R*, =NNHCO2(alkyl), =NNHSO2(alkyl), or =NR*, where each R* is independently selected from hydrogen or optionally substituted C1-6aliphatic group; where the aliphatic group of R* is optionally substituted with NH2, NH(C1-4aliphatic group), N(C1-4aliphatic group)2, halogen, C1-4aliphatic group, OH, O(C1-4aliphatic group), NO2CN, CO2H, CO2(C1-4aliphatic group), - O(halogen C1-4aliphatic group) or a halogen(C1-4aliphatic group), where each of C1-4aliphatic group R is unsubstituted.

In certain embodiments, RXselected from the

In certain embodiments according to the invention RYrepresents a

In certain embodiments A is N.

In other embodiments A is a CR2. In further embodiments A represents CH.

In some embodiments, RXselected from the

In further embodiments, R' represents a C1-6aliphatic group, phenyl, or 5-8-membered heteroaryl group, where R' is optionally substituted with up to one substituent J. In further embodiments, R' is a C1-63and where R° is1-3aliphatic group. In still further embodiments, R' is a methyl, ethyl, propyl, isopropyl, -CH2-isopropyl, butyl,tert-butyl, -CH2tert-butyl or cyclohexyl, where R' is optionally substituted with-COOR°, -OR°, or R°. In certain embodiments, R represents hydrogen or methyl.

In some embodiments, RXselected from the

In further embodiments, R" is independently selected from C1-6aliphatic group, phenyl, or 5-8-membered heterocyclic group, where R" is optionally substituted with up to one substituent J. In further embodiments, R" is independently selected from C1-6aliphatic group, or phenyl, where R" is optionally substituted with up to one substituent J, where J is selected from halogen, -CF3, -CN, -COOR°, -COR° or°R° represents a C1-3aliphatic group. In still further embodiments, R" is a methyl, ethyl, propyl, isopropyl, -CH2-isopropyl, butyl,tert-butyl or-CH2tert-butyl, where R" is optionally substituted with-CN, -COOR° or°. In certain embodiments R pre whom represents a hydrogen or methyl.

A specific embodiment RXpresents for compounds in Table 1 (see end of description).

In some embodiments, RYselected from the

or

In further embodiments, R" is independently selected from C1-6aliphatic group, phenyl, or 5-8-membered heterocyclic group, where R" is optionally substituted with up to one substituent J. In further embodiments, R" is independently selected from C1-6aliphatic group, phenyl, where R" is optionally substituted with up to one substituent J, where J is selected from halogen, -CF3, -CN, -COOR°, -COR° or°R° represents a C1-3aliphatic group. In still further embodiments, R" is a methyl, ethyl, propyl, isopropyl, -CH2-isopropyl, butyl,tert-butyl or-CH2tert-butyl, where R" is optionally substituted with CN, -COOR° or°. In certain embodiments, R represents hydrogen or methyl.

A specific embodiment RYrefer to compounds in Table 1.

Typical examples of compounds of formula I are presented in Table 1.

General synthesis technique

Compounds of the present invention can be obtained using techniques well-known professional in this blastedly similar compounds, using the techniques presented below, using the General synthesis schemes and with the help of examples of the preparation, which are presented below. Processes for producing compounds of the present invention described in the schemes and in the examples. On the schema variables are as described for compounds (for example, the formula (I) according to the invention, or are actually recognizable with links to these compounds.

Scheme 7 describes the synthesis of a number of exemplary compounds where Ar1and Ar2are replaced.

General conditions: solvent, a base, a suitable binding agent, for example: A. DMF, DIEA, RCOCl; B. DMF, DEA, isocyanate; C. DMF, DIEA, charformat; D. DMF, DIEA, 1SO2R; E. iPrOH, alkylhalides, the heat.

Scheme 7 reflects the route to obtaining the compounds of the present invention, where

Ar1substituted with amine derivative, in particular, where R2is a (T)nAr1and Ar1substituted with amine derivative. Figure 7 amine group interacts in normal conditions of binding, to provide the amine derivative. It should be clear that the described synthesis can be modified in a way that also provides other amine derivatives. Additionally, there may be used other bonding conditions than those described. Such techniques are well known with what ecialist average in this area (see for example, Greene, or Greene & Wutz, Protective Groups in Organic Synthesis; WO 01/81330). It should be clear that the conditions should be selected to be compatible (i.e. inert) with the remaining substituents (for example, -NR1R2).

Figure 1: the Route of obtaining diametrically derivatives

Scheme 2: the Route of obtaining derivatives diametrically compounds

Method A: DMF, DIEA, room temperature, carboxylated.

Method B: DMF, DIEA, room temperature, the isocyanate.

Method C: DMF, DIEA, room temperature, chloroformiate.

Scheme 3: the Route of obtaining diametrically derivatives

(a) N-cyano-N'-aryl-O-phenylazomethine, NMP (N-organic, DIEA, M.V., 160-220°C, 6-15 minutes; (b) HNR1R2NMP, M.V., 220-250°C, 6-15 minutes; (c) 6N HCl, 95°C; METHOD A: ClCO2R (charformat), DIEA, DMF; METHOD B: OCN-R (isocyanate), DIEA (diisopropylethylamine), DMF; METHOD C: RCO2H (carboxylic acid), DCC (dicyclohexylcarbodiimide), DCM (dichloromethane) or RCOCl (acid chloride acid), DIEA, or pyridine, DMF.

Another common direction to the compounds of the present invention is depicted in Scheme 3. Although specific reagents depicted in Scheme 3, the professional in this field should understand that there can be and is used other stages and reagents, to implement depicts the synthesis. Schemes 4 and 5 below, reflect this General pattern, more specifically.

Although certain typical embodiments described and depicted above and in the description, should be taken into account that the compounds according to the invention can be obtained in accordance with the methods depicted in General above, using appropriate starting materials using methods generally available to the professional in this field.

The use of drugs and the introduction of

Pharmaceutically acceptable composition

As indicated above, the present invention encompasses compounds that are inhibitors of protein kinases, and, accordingly, the compounds of the present invention can be used for the treatment of diseases, disorders and conditions, including, among others, allergic diseases, proliferative diseases, autoimmune diseases, conditions associated with transplantation, inflammatory diseases, immunologically-mediated diseases, viral diseases or destructive bone disease (such as disorders of bone resorption). Thus, another aspect of the present invention encompasses pharmaceutically acceptable compositions that contain any of the compounds described above, as well as heart and soul is on contain a pharmaceutically acceptable carrier, adjuvant or excipient. In some embodiments, these compositions contain, in addition, one or more additional therapeutic agents.

Also should be taken into account that the specific compounds of the present invention can exist in free form or, where appropriate, in the form of their pharmaceutically acceptable derivatives. In the present invention, pharmaceutically acceptable derivatives include, without limitation, pharmaceutically acceptable salts, esters, salts of these esters, or any other product or accession or derivative which upon administration to a patient is capable, directly or indirectly, to ensure the presence in the body of the compounds described in the present description, or its metabolite or residue.

Used in the present description, the term "pharmaceutically acceptable salt" refers to those salts, which on the basis of competent medical opinion can be used in contact with the tissues of humans and lower animals without showing excessive toxicity, hypersensitivity, allergic response, and similar events, as well as with an acceptable ratio of benefit/risk. "Pharmaceutically acceptable salt" means any non-toxic salt or salt of ester compounds of the present invention, which in the appointment of the recipient is capable of is especial directly or indirectly, a compound of the invention, its metabolite or residue that inhibits the selected kinase, including Aurora-2, Flt3, KDR, JAK2 and JAK3. In specific embodiments, the compound or its pharmaceutically acceptable salt inhibits JAK2 or JAK3.

Pharmaceutically acceptable salts are well known to experts in the relevant field. For example, S. M. Berge and other details to describe pharmaceutically acceptable salts inJ.Pharmaceutical Sciences, 1977, 66, 1-19included in this description by reference. Pharmaceutically acceptable salts of the compounds of the present invention include both derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable non-toxic salts with acidic residues are salts that are formed by the interaction of amino groups with inorganic acids such as hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, as well as using other methods used in this field, such as ion exchange.

Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, bansilalpet, benzoate, bisulfate, borate, butyrate, comfort, imporantant, citrate, cyclopentanepropionate, digluconate, dodecyl sulphate, aconsultant, formate, fumarate, glucoheptonate, glycerol, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-econsultant, lactobionate, lactate, laurate, lauryl, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluensulfonate, undecanoate, and valerianate like that. Salts derived from appropriate bases include alkali metal salts, alkaline earth metals, ammonium and N+(C1-4alkyl)4.

The present invention also covers the quaternization of any basic nitrogen-containing groups of the compounds presented in this description. Water - or fat-soluble or dispersible products may be obtained by quaternization. Typical salts of alkaline or alkaline-earth metals include sodium, lithium, potassium, calcium, magnesium and the like. Moreover, pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, Quaternary ammonium, and amine cations, which are obtained using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, nih is alkilany sulfonate and arylsulfonate.

As stated above, the pharmaceutically acceptable compositions of the present invention optionally contain a pharmaceutically acceptable carrier, adjuvant or excipient, which, in this case, include any and all solvents, diluents, or other liquid carriers, dispersing or suspendresume tools, surface active agents, isotonic agents, thickeners or emulsifiers, preservatives, solid binders, lubricants and the like, that correspond to specific desired dosage forms. Remington''s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in the preparation of pharmaceutically acceptable compositions and known techniques for their preparation. Use any of the traditional media, except those that are incompatible with the compounds of the present invention due to the development of any undesirable biological effects or other harmful interactions with other component(s) of the pharmaceutically acceptable composition, is considered in the framework of the present invention.

Some examples of substances suitable as pharmaceutically acceptable carriers include, without limitation, ion exchange substance, alumina, aluminum stearate, lecithin, plasma proteins, t is such as human plasma albumin, buffer substances such as phosphates, glycine, sorbic acid or potassium sorbate, a mixture of partial glycerides of saturated vegetable fatty acids, water, salts or electrolytes, such as Protamine sulfate, centripetal, dailypost, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene copolymers, lanolin, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as carboxymethylcellulose sodium, ethylcellulose and acetylcellulose; chopped tragakant; malt; gelatin; talc; forming substances, such as cocoa butter and wax for suppositories; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol or polyethylene glycol; esters, such as etiloleat and tillaart; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic; ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible lubricants, such as sodium lauryl sulfate and magnesium stearate, as well as dyes, antiadhesive, prophetic the tion of the shell, sweeteners, flavorings and fragrances, preservatives and antioxidants can also be present in the composition in accordance with the decision of the pharmacist.

The use of compounds and pharmaceutically acceptable compositions

Another aspect of the present invention encompasses a method of treating or reducing the severity of allergic diseases, proliferative diseases, autoimmune diseases, conditions associated with transplantation, inflammatory diseases, immunologically-mediated diseases, viral diseases or kostnadsstrukturen diseases (such as diseases of bone resorption), including the introduction of an effective amount of a compound or pharmaceutically acceptable composition to a subject, which needs treatment. In specific embodiments of the present invention by "effective amount" of a compound or pharmaceutically acceptable composition understand the amount effective to treat or reduce the severity of the disease, disorder, or pathological condition that requires treatment. Compounds and compositions relating to the method of the present invention, can be entered using any amount and any route of administration effective for treating or reducing the severity of the disease, disorder or condition requiring the treatment. The required amount varies from subject to subject, depending on species, age, General condition of the subject, the severity of the infection, the particular agent, its mode of administration and the like, Compounds of the present invention is preferably administered in the form of a form for a single admission for ease of administration and uniformity of dosage. The expression "shape for the single dose used in the present description, refers to physically discrete form of the agent designated for the patient undergoing treatment. However, it should be understood that the total daily dose of the compounds or compositions of the present invention is prescribed by the attending physician on the basis of competent medical opinion. Individual dose for any particular patient or organism will depend upon a variety of factors, including disease, about which treatment, the severity of this disorder; activity of the specific compound; the specific composition; the age, weight, General health, sex and diet of the patient; the time of administration, route of administration and rate of excretion of the specific compound; the duration of the treatment; drugs used in combination or in conjunction with a specific connection, and similar factors well known is e specialists in the relevant field. The term "patient"used in the present description, means animals, preferably mammals, most preferably humans.

Pharmaceutically acceptable compositions of the present invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intrawaginalno, administered intraperitoneally, locally (powders, ointments or drops), hominids, in the form of an oral or nasal spray or similar, depending on the severity of infection, about which treatment is carried out. In specific embodiments, the compounds of the present invention may be prescribed orally or parenterally in doses of from about 0.01 mg/kg to about 50 mg/kg, preferably from about 1 mg/kg to about 25 mg/kg of body weight of the subject per day, one or more techniques to achieve the desired therapeutic effect.

Liquid dosage forms for oral assignments include but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert fillers, most commonly used in this field, such as water or other solvents to increase the solubility of the agents and emulsifiers such as ethyl alcohol, isopropyl the new alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, butter, wheat germ, olive, castor and Kungaeva oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol and fatty acid esters and sorbitol, and mixtures thereof. Addition of inert fillers in compositions for oral administration can be added adjuvants, such as wetting agents, emulsifiers and suspendresume agents, sweeteners, flavorings and fragrances.

Preparations for the injection, for example a sterile aqueous or oily suspension for injection, can be prepared using well-known in this area acceptable dispersing or wetting agents and suspendida agents. Sterile preparations for injection can also be a sterile injectable solution, suspension or emulsion in a nontoxic, acceptable for parenteral administration the carrier or solvent, for example a solution in 1,3-butanediol. Acceptable carriers and solvents that can be used are water, ringer's solution, solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are traditionally used in image quality is as a medium for dissolution or suspension. For this purpose, can be used any soft fixed oils, including synthetic mono - and diglycerides. In addition, these fatty acids, as oleic acid, is used for the preparation of injection preparations.

Preparations for the injection may be sterilized, for example, by filtration through a bacterial filter or by adding sterilizing agents to the sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile environment, suitable for injection, before the introduction.

In order to extend the effect of the compounds of the present invention, it is desirable slow suction connection from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous substances poorly soluble in water. The absorption rate of the connection in this case will depend on its rate of dissolution which, in turn, depends on the size of crystals and crystalline structures. Alternatively, delayed absorption of parenteral input connection is achieved by dissolution or suspension of the compounds in the oil solvent. Injectable depot forms are obtained by forming microcapsule matrix connection is as biodegradable polymers, such as polylactide-polyglycolide. Depending on the ratio of the compounds and polymers, as well as the nature of the particular polymer used, may be regulated by the rate of release of connection. Examples of other biodegradable polymers include poly(orthoevra) and poly(anhydrides). Injectable depot forms are also prepared by the conclusion of the compounds in liposomes or microemulsions that are compatible with body tissues.

Compositions for rectal or vaginal introduction mainly are suppositories which can be prepared by mixing the compounds of the present invention with acceptable not cause irritation fillers or carriers such as cocoa butter, polyethylene glycol or wax for suppositories, which are in solid state at room temperature but become liquid at body temperature and, as a consequence, melt in the rectum or vagina, and release the active compound.

Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid forms of active compound are mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as citrate or dicalcium phosphate and/or a) fillers or dry diluents, such as starch, lactose, glucose,mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum Arabic, C) humectants such as glycerol, d) dezintegriruetsja agents, such as agar-agar, calcium carbonate, potato starch or starch from tapioca, alginic acid, certain silicates and sodium carbonate, e) slow dissolving agents, such as paraffin, f) substances that accelerate the absorption, such as Quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glycerol monostearate, h) adsorbents, such as kaolin and bentonite clay, and I) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and a mixture thereof. In the case of capsules, tablets and pills, the dosage form may also contain buffering agents.

Solid compositions of a similar type may also be enclosed in soft and hard gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and other Solid dosage forms such as tablets, coated tablets, capsules, pills and granules can be prepared with coatings and shells such as enteric shell and other shell, well known to experts in the field of pharmacy. They m who may need to contain opalescent agents and also include compositions which release the active(s) component(s) only or preferably in a particular part of the gastrointestinal tract as needed in slow motion. Examples of "embedded" compositions, which can be used include polymeric substances and waxes. Solid compositions of a similar type may also be enclosed in soft and hard gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compounds can also be in the form of microcapsules with one or more fillers described above. Solid dosage forms such as tablets, coated tablets, capsules, pills and granules can be prepared with coatings and shells such as enteric shell, shell, controlling the release of drugs and other shell, well known to experts in the field of pharmacy. In such solid dosage forms the active compound may be mixed with at least one inert filler, such as sucrose, lactose or starch. Such dosage forms are also typically may contain additional substances addition of inert fillers, such as lubricants for tablets and other excipients for tablets, such as magnesium stearate and Mick is kristallicheskaja cellulose. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents. They may need to keep opalescent agents and also include compositions which release the active(s) component(s) only or preferably in a particular part of the gastrointestinal tract as needed in slow motion. Examples of "embedded" compositions, which can be used include polymeric substances and waxes.

Dosage forms for local or percutaneous use of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalers or patches. The active ingredient in sterile form is mixed with a pharmaceutically acceptable carrier and any needed preservatives or buffers, if required. Ophthalmological preparations, ear drops and eye drops are also considered as included in the scope of the present invention. In addition, the present invention includes the use of transdermal patches, which have the additional advantage of providing controlled delivery of the drug into the tissue. Such dosage forms can be prepared by dissolving and dispersing the compound in an appropriate environment. Accelerators suction can be used to increased the I of penetration of compounds through the skin. The speed can be adjusted using the speed control membranes, and through the distribution of compounds in a polymer matrix or gel.

As indicated above, the compounds of the present invention can be used as inhibitors of protein kinases. In one embodiments of the compounds and compositions of the present invention are inhibitors of one or more kinases such as Aurora-2, Flt3, KDR, JAK2 and JAK3. In some preferred embodiments, the compounds of the present invention are effective as inhibitors of JAK2 and JAK3. Thus, it is not limited to any particular theory, the compounds and compositions are particularly useful for treating or reducing the severity of the disease, pathological condition, or disorder, the development of which is associated with the activation of one or more protein kinases, including Aurora kinase-2, Flt3, KDR, JAK2 and JAK3. In the case when activation of the kinase Aurora-2, Flt3, KDR, JAK2 and JAK3 entails a specific disease, pathological condition, or disorder; a disease, pathological condition, or disorder may also be designated as "Aurora-2, Flt3, KDR, JAK2 or JAK3-mediated disease or symptom of the disease. Thus, in another aspect, the present invention encompasses a method of treating or reducing the severity of the disease, pathological condition, or disorder, g is e in the development of a pathological state involved in the activation of one or more protein kinases, including Aurora kinase-2, Flt3, KDR, JAK2 and JAK3.

The potency of the compound used in the invention as an inhibitor of protein kinases, can be examinedin vitro, in vivoor cell lines. In vitrostudies include studies that determine how phosphorylase activity and ATPase activity, for example, kinases, Aurora-2, FltS, KDR, JAK2 and JAK3. In the alternative researchin vitroquantify the ability of the inhibitor to bind the protein kinase. The binding of the inhibitor can be measured by incorporation of radioactive label in the inhibitor prior to binding, followed by separation of the complex of the inhibitor/enzyme and measuring the amount of bound radioactive label. Alternative binding of the inhibitor can be determined by experiment with competitive linking, where new inhibitors are incubated with, for example, kinases, Aurora-2, Flt3, KDR, JAK2 and JAK3 associated with famous radio.

The term "measured inhibition"as used in this description, means the measured difference kinase activity between a sample containing composition and a kinase and an equivalent sample containing the kinase without composition.

The term "FLT-3-mediated disease", as used in the present description, means any disease or pathological condition, about which it is known, Thu is in its development plays the role of the family kinases FLT-3. State data include, without limitation, hematopoietic diseases, in particular acute myeloid leukemia (AML), acute promyelocytic leukemia (APL) and acute lymphocytic leukemia (ALL).

The term "JAK-mediated disease", as used in the present description, means any disease or pathological condition, about which it is known that in its development the role played by the family of JAK kinases. State data include, among other things, immune reactions, such as allergic or type I hypersensitivity reactions, asthma, autoimmune diseases such as transplant rejection, diseases, graft versus host disease, rheumatoid arthritis, amyotrophic lateral sclerosis and multiple sclerosis, neurodegenerative diseases, such as familial amyotrophic lateral sclerosis (FALS), as well as solid and hematological tumors, such as leukemias and lymphomas. State, which plays the role of JAK2 include myeloproliferative diseases such as polycythemia Vera, essential thrombocythemia, chronic idiopathic myelofibrosis, chronic myelogenous leukemia, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia, chronic eosinophilic leukemia and systemic mastocytosis.

The term "AUR-mediated for Alemania" or "AUR-mediated condition", used in the present description, means any disease or pathological condition, about which it is known that in its development plays the role of the family kinases AUR. These States include, among others, allergic diseases, especially asthma.

You must understand that the compounds and pharmaceutically acceptable compositions of the present invention can be used in combination therapy, which means that the compounds and pharmaceutically acceptable compositions can be assigned simultaneously, before or after one or more of the drug or medical procedure. The specific combination of therapeutic effects (drugs or procedures) for use in the mode of combined treatment should be performed taking into account the compatibility of the selected drugs and/or procedures and the desired effect. Also it should be clear that the drugs can lead to the expected effect in respect of the same disease (e.g., a compound of the invention may be appointed concurrently with another agent used to treat the disease), or they may cause other effects (e.g., control of any adverse effects). In the present description additional therapeutic agents that are commonly prescribed for the treatment or prevention of a specific disease were evania or pathological condition, designated as "suitable for diseases or pathological conditions for which treatment".

For example, chemotherapeutic agents or other anti-proliferative agents may be combined with the compounds of the present invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include without limitation any other drugs or anticancer agents that may be used in combination with anticancer agents of the present invention, including surgery, radiation therapy (including gamma radiation, radiation therapy beam neutron, proton therapy, brachytherapy, and systemic radioactive isotopes, etc), endocrine therapy, biological response modifiers (interferons, interleukins, and tumor necrosis factor (TNF), etc), hyperthermia and cryotherapy, agents that weaken any side effects (e.g., antiemetics), and other proven chemotherapeutic drugs, including, but not limited to, alkylating drugs (mechlorethamine, chlorambucil, cyclophosphamide, melphalan, ifosfamide), antimetabolites (metotrexat), purine antagonists and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabin, gemcitabine), inhibitors of the faith of the s division (vinblastine, vincristine, vinorelbine, paclitaxel), podophyllotoxins (etoposide, irinotecan, topotecan), antibiotics (doxorubicin, bleomycin, mitomycin), drugs nitrosoanatabine (carmustin, lomustin), inorganic ions (cisplatin, carboplatin), enzymes (asparaginase), and hormones (tamoxifen, leuprolide, flutamide, and megestrol), Gleevec, adriamycin, dexamethasone, and cyclophosphamide. For more comprehensive information about modern methods of cancer treatment see http://www.nci.nih.gov/, section FDA dedicated to Oncology drugs on the page http://www.fda.gov/cder/cancer/druglistframe.htm and The Merck Manual, the seventeenth Ed. 1999, the full content of which is incorporated by reference.

Other examples of agents that can be combined inhibitors of the present invention include, without limitation, drugs for the treatment of Alzheimer's disease, such as aricept and Exelon, drugs to treat Parkinson's disease such as L-DOPA/carbidopa, entacapone, ropinirol, pramipexol, parlodel, pergolid, trihexyphenidyl and amantadine; agents for treating multiple sclerosis, such as beta interferon (e.g., Avonex and Rebif), Copaxone and mitoxantrone; medications for asthma such as albuterol and singulair; agents for treating schizophrenia such as zyprexa risperdal, quetiapine, and haloperidol; anti-inflammatory agents such as corticosteroids, the BUT-blockers, IL-1 RA, azathioprine, cyclophosphamide and sulfasalazin; immunomodulatory and immunosuppressive agents such as cyclosporine, tacrolimus, rapamycin, mycophenolate, interferons, corticosteroids, cyclophosphamide, azathioprine and sulfasalazin; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, blockers of ion channels, riluzole, and anti-Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons and anti-viral agents; agents for treating blood disorders such as corticosteroids, protivoanemicheskoe agents and growth factors; and agents for treating immunodeficiency, such as gamma globulin.

The amount of additional therapeutic agent present in the compositions of the present invention should be not more than the amount that is usually administered in a composition containing as the active agent only this therapeutic agent. Preferably the amount of additional therapeutic agent disclosed in this description of the composition should range from about 50% to 100% of the amount, Oba is but present in the composition, containing the agent as the sole therapeutically active agent.

Compounds of the present invention or its pharmaceutically acceptable salt may also be included in compositions for "covered" implantable medical devices such as prostheses, artificial valves, vascular prostheses, stents and catheters. Thus, the present invention, in another aspect, includes a composition for coating an implantable device containing the compound of the present invention described earlier, and the paragraphs and subparagraphs of this description, and a carrier suitable for coating these implantable devices. In another aspect of the present invention includes an implantable device coated with a composition comprising a compound of the present invention, as described previously, as well as in paragraphs and subparagraphs of this description, as well as the media, suitable to cover these implantable devices.

Vascular stents, for example, used to prevent the development of restenosis (re-narrowing of the lumen of the artery after the intervention). However, in patients using stents or other implantable devices, an increased risk of forming blood clots or activated platelets. Adverse effects can be prevented or attenuated pre-coated with the em device pharmaceutically acceptable composition, containing the kinase inhibitor. Acceptable coatings and manufacturing principles "covered" implantable devices are described in US Patents 6099562; 5886026 and 5304121. Materials coatings are typically biocompatible materials, such as polymer hydrogel, polymethylsiloxane, polycaprolactone, polyethylene glycol, polylactic acid, ethylene vinyl acetate and mixtures thereof. On the cover as necessary may be additionally marked with a suitable top coat from Versiliana, polysaccharides, polyethylene glycol, phospholipids or combinations thereof to impart to the composition the properties of a controlled release.

Another aspect of the present invention relates to the inhibition proteinkinases (for example, Aurora-2 activity in a biological sample or in a patient; the method comprises the administration to the patient or contact with a specified biological sample of the compounds of formula I or compositions containing this compound. The term "biological sample", as used in the present description, including, without limitation, cell cultures and their extracts; material for biopsy obtained from a mammal or extracts; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts.

The inhibition of the activity of kinases, including the kinase activity of Aurora-2, Flt3, KDR, JAK2 and JAK3, in biological samples is scah can be used for a large number of targets, well-known experts in this field. Examples of such purposes include, among other things, blood transfusion, transplantation of organs, storage of biological specimens and biological research.

EXAMPLES

Compounds of General formula I receive in accordance with the General methods described in the schemes and the examples of the present invention.

Example 1. Getting 4-chloro-6-(3S,5R)for 3,5-dimethylpiperazine-1-yl)pyrimidine (1)

To a solution of 4,6-dichloropyrimidine (14.9 g, 100.0 mmol) in 150 ml of anhydrous acetonitrile, add (2S,6R)-2,6-dimethylpiperazine (22,8 g, 200.0 mmol) in portions over about 10 minutes. The reaction mixture is left at room temperature using a water bath, and stirred for another 20 minutes. The solid precipitates from the solution as the reaction. The solid is removed by filtration. The filtrate is concentrated to obtain an oily product. The resulting product was dissolved in EtOAc (300 ml)and the organic layer washed with water (100 ml×3). The organic layer is dried over Na2SO4. Removal of the solvent provides oil product in the form of the desired product that is installed using LC/MS (MS+1=227,1). The product weighs 22.1 g (yield of 97.6%).

Example 2. Obtaining 1-((2S,6R)-4-(6-chloropyrimidine-4-yl)-2,6-dimethy the piperazine-1-yl)ethanone (2)

To a solution of 4-chloro-6-((3S,5R)for 3,5-dimethylpiperazine-1-yl)pyrimidine (l, 10,29 g of 45.4 mmol) and DIEA (8,80 g, 68,1 mmol, 1.50 equiv.) in 100 ml of dichloromethane added portions acetylchloride (a 4.03 ml, of 56.7 mmol, 1.25 EQ.) at room temperature for about 10 minutes. The reaction mixture was stirred at room temperature for another 30 minutes. To the reaction mixture an aqueous solution of NaHCO3and the organic layer was washed with NaHCO3(100 ml×2)and then saturated aqueous NaCl. The organic layer is dried over Na2SO4. Removal of the solvent yields a yellow oil colors. The obtained oily product is ground to powder in diethyl ether to obtain a solid white color. The solid is collected by filtration and washed again with diethyl ether. The solid is dried in vacuum, and weight determine equal 11,95, the Output is of 98.2%. LC/MS (M+1=269,1).

Example 3. Getting 3

To a solution of 1-((2S,6R)-4-(6-chloropyrimidine-4-yl)-2,6-dimethylpiperazine-1-yl)ethanone (2, being 9.61 g, 35,7 mmol) in 75 ml anhydrous THF added hydrazine (5,72 g, the ceiling of 5.60 ml, 178,8 mmol, 5.0 EQ.). Solid precipitates out of solution as the reaction. The reaction mixture is stirred and refluxed overnight. Reactio the ing the mixture is cooled to room temperature. The solid is collected by filtration and washed with cold methanol (25 ml×3)to get rid of excess hydrazine and its HCl salt. The solid is dried in vacuum, and weight determine the equal of 8.95 g (83,3% yield). LC/MS (M+1=265,2).

Example 4. Gettingtert-butyl 4-((Z)-1-cyano-2-finelytuned)phenylcarbamate(4)

To a suspension of diphenylcarbonate (11,04 g of 46.4 mmol) in 130 ml of isopropanol addtert-butyl4-aminophenylarsonic (9,20 g, a 44.2 mmol). The reaction mixture was stirred at room temperature overnight, and the solid is collected by filtration. The solid is dried in vacuum, and it weighs 10,85 g (69,7% yield). LC/MS (M+1=353,2).

Example 5. Getting connection 5

To a solution of compound3(3,17 g, 12,0 mmol) andtert-butyl4-((Z)-1-cyano-2-finelytuned)phenylcarbamate (4, to 3.52 g, 10.0 mmol) in 6 ml of NMP was added 1 ml of DIEA. The reaction mixture was sealed in a reaction flask for microwave irradiation and heated in a reactor with microwave irradiation at 180°C for about 6 minutes. The reaction mixture is cooled to room temperature and distributed between ethyl acetate and water. The organic layer was washed with water twice and dried over Na2SO4. Removal of the solvent yields a solid substance is altago color. The obtained solid is washed with dichloromethane, to obtain a solid white color. NMR: DMSO-d6: 8,98 (users, 1H); to 8.94 (s, 1H); scored 8.38 (s, 1H); 7,72 (users, 2H); was 7.45 (d, 2H); to 7.25 (d, 2H); 6.73 x (s, 1H); 4,60-4,10 (m, 4H); 3,20 (m, 2H); 2,02 (s, 3H); of 1.40 (s, 9H); to 1.15 (m, 6H). LC/MS (M+1=523,3).

Example 6. Obtaining 1-((2S,6R)-4-(6-(3-(4-aminophenylamino)-5-amino-1N-1,2,4-triazole-1-yl)pyrimidine-4-yl)-2,6-dimethylpiperazine-1-yl)ethanone(6)

To a solution of compound6(2.0 g, a 3.83 mmol) in 15 ml dichloromethane add 5 ml triperoxonane acid. The reaction mixture was stirred at room temperature for about 30 minutes. HPLC indicates complete reaction. The solvent is removed in vacuum and the resulting oily product is partitioned between dichloromethane and aqueous solution of NaHCO3. The organic layer was washed with aqueous solution of NaHCO3several times and dried over Na2SO4. Removal of solvent gives 1.56 g of the desired product (yield is a 96.9%).

Example 7. A common method of formation of the carbamate. In the following seems to be a typical example of the formation of the carbamate. Receiving compound I-76

To a solution of 1-((2S,6R)-4-(6-(3-(4-aminophenylamino)-5-amino-1N-1,2,4-triazole-1-yl)pyrimidine-4-yl)-2,6-dimethylpiperazine-1-yl)ethanone (21 mg, 0.05 mmol) in 2 ml of DMF add atillah RMIT (6.5 mg, 0.06 mmol, 1.2 EQ.). To the reaction mixture add a drop of DIEA. The reaction mixture was stirred at room temperature for about 20 minutes. The reaction crude product is injected by P-HPLC, and 18 mg of the desired product is obtained as a salt triperoxonane acid.

Example 8. A common way to generate molecules derived urea

In the following seems to be a typical example of the formation of molecules derived urea:

To a solution of 1-((2S,6R)-4-(6-(3-(4-aminophenylamino)-5-amino-1H-1,2,4-triazole-1-yl)pyrimidine-4-yl)-2,6-dimethylpiperazine-1-yl)ethanone (21 mg, 0.05 mmol) in 2 ml of DMF add isocyanurate (4.2 mg, 0.06 mmol, 1.2 EQ.). To the reaction mixture add a drop of DIEA. The reaction mixture was stirred at room temperature for about 20 minutes. The reaction crude product is injected by P-HPLC, and 17 mg of the desired product is obtained as a salt triperoxonane acid.

Example 9. Obtaining the compound (9)

To a solution of compound3(1,58 g, 12,0 mmol) andtert-butyl 4-(4-((Z)-1-cyano-2-finelytuned)phenyl)piperazine-1-carboxylate (2.10 g, 5.0 mmol) in 6 ml of NMP was added 1 ml of DIEA. The reaction mixture was sealed in a reaction flask for microwave irradiation and heated in a reactor with microwave irradiation at te is the temperature of 180 degrees for about 6 minutes. The reaction mixture is cooled to room temperature and distributed between ethyl acetate and water. The organic layer was washed with water twice and dried over Na2SO4. Removal of the solvent yields a solid yellow color. The obtained solid substance Privat dichloromethane, to obtain a solid white color. NMR in DMSO-d6: 8,86 (s, 1H); scored 8.38 (s, 1H); 7,70 (users, 2H); of 7.48 (d, 2H); 6.90 to (d, 2H); 6,70 (s, 1H); 4,65-to 4.15 (m, 4H); to 3.45 (m, 4H); 3,18 (m, 2H); 2,98 (m, 4H); of 2.20 (s, 3H); to 1.38 (s, 9H); 1,22 (m, 6H); LC/MS (M+1=592,3).

Example 10. Obtaining 1-((2S,6R)-4-(6-(3-(4-(piperazine-1-yl)phenylamino)-5-amino-1N-1,2,4-triazole-1-yl)pyrimidine-4-yl)-2,6-dimethylpiperazine-1-yl)ethanone (10)

To a solution of compound9(1.0 g, 1.70 mmol) in 15 ml dichloromethane add 5 ml triperoxonane acid. The reaction mixture was stirred at room temperature for about 30 minutes. HPLC indicates complete reaction. The solvent is removed in vacuum and the resulting oily product is partitioned between dichloromethane and aqueous solution of NaHCO3. The organic layer was washed with aqueous solution of NaHCO3several times and dried over Na2SO4. Removal of solvent gives 805 mg of the desired product (yield is a 96.9%).

Example 11. Receiving compound I-113

A common way of formation of the deposits molecule carbamate in accordance with the methodology similar to the method described to obtain compound I-113.

Example 12. Receiving compound I-60

A common way to generate molecules derived urea in accordance with the method similar to the method described to obtain compound I-60.

Figure 4: Route of obtaining diametrically connections.

(a) N-cyano-N'-(4-acetamidophenyl)-O-phenylazomethine, NMP, DIEA, M.V., 220°C; (b) i:CIS-2,6-dimethylpiperazine, NMP, MV, 250°C, ii: Ac2O the base; (c) 6N HCl, 95°C; METHOD a: isopropylcarbamate, DIEA, DMF; METHOD B: isopropyltoluene, DIEA, DMF; METHOD C: isovalerianic acid, dicyclohexylcarbodiimide, dichloromethane.

Figure 5: the Route of obtaining diametrically connections.

1-(2-chloropyridin-4-yl)-hydrazine, NMP, M.V., 220°C; (b)CIS-2,6-dimethylpiperazine, NMP, MV, 250°C.

Example 13

N-{4-[5-Amino-1-(2-chloro-pyridin-4-yl)-1H-[l,2,4]triazole-3-ylamino]-phenyl}-ndimethylacetamide.The reaction flask for microwave irradiation load of 1.34 g (2-chloropyridin-4-yl)-hydrazine (of 7.48 mmol, 1.1 EQ.) and 2.00 g of N-cyano-N'-(4-acetamidophenyl)-O-phenylazomethine (6,80 mmol, 1 EQ.). Solids are dissolved in 40 ml of NMP and 8 ml of DIEA. Sealed flask was heated to a temperature of 220 the C for 6 minutes under microwave irradiation. After cooling the resulting solution was poured into 200 ml saturated sodium bicarbonate solution. The precipitate is collected and washed with 3×100 ml of water. After drying by azeotropic distillation (3×50 ml of acetonitrile) solid dark yellow (2.0 g, 5,80 mmol, 85% yield) used without further purification.1H NMR (500 MHz, DMSO-d6) δ 9,68 (1H, s), of 9.00 (1H, s), 8,40 (1H, d), to 7.67 (2H, m)to 7.50 (2H, d), 7,40 (2H, d), to 6.95 (2H, s), 2,0 (3H, s) ppm LC/MS: 2.16 min/343,95 (M+H).

Example 14. Receiving compound I-35

N-(4-{-1-[2-(4-Acetyl-3,5-dimethylpiperazine-1-yl)-pyridin-4-yl]-5-amino-1N-[l,2,4]triazole-3-ylamino}-phenyl)-ndimethylacetamide.To a solution of 100 mgN-{4-[5-amino-1-(2-chloro-pyridin-4-yl)-1N[1,2,4]triazole-3-ylamino]-phenyl}-ndimethylacetamide (0,291 mmol, 1 EQ.) in 5 ml of NMP was added 100 mgCIS-2,6-dimethylpiperazine (0,877 mmol, 3.0 EQ.). Stir the solution is heated to a temperature of 250°C under microwave irradiation for 15 minutes. The reaction mixture is concentrated by evaporation in a vacuum and then dissolved in 5 ml of CH2Cl2and 5 ml of DMF. In the mixed solution is added successively 1 ml of base Janiga and 100 μl of acetic anhydride. After 3 hours at 25°C the reaction mixture was concentrated to a dark oil color and purified using flash-chromatography (EtOAc), which in turn yields 15 mgN-(4-{-1-[2-(4-acetyl-3,5-dimethyl who piperazin-1-yl)-pyridin-4-yl]-5-amino-1 H-[l,2,4]triazole-3-ylamino}-phenyl)-ndimethylacetamide (0,0323 mmol, 11% yield) as a solid yellow color.

Example 15. Receiving compound I-41

Connection A: 223,4 mg (0.48 mmol) of compound I-7 was dissolved in 2.0 ml of 6N HCl. The reaction mixture is heated to a temperature of 95 degrees. After one hour the reaction mixture is allowed to cool down to room temperature. All volatiles are removed under reduced pressure. The last trace amounts of water azeotrope removed by co-distillation with toluene. The residue is distilled at high vacuum over night. Output: the expected 100%.1H NMR (500 MHz, DMSO-d6) δ at 8.36 (users, 1H), 8,11 (users, 1H), 7,25 (users, 2H), 6.90 to (userd, 2H), 6,53 (userd, 4H), 4,59-3,98 (m, 6H), 3.04 from (users, 2H), 2,03 (m, 3H), 1,20 (users, 6H), LC/MS: LC/MS: 1.51 min/422,2 (M+H).

Example 16. Receiving compound I-103

METHOD A: compound I-103: 46,0 mg (0.10 mmol) of compound I-7, 80 μl (0.46 mmol) of DIEA and 120 μl of a 1.0 M solution of isopropylcarbamate (0.12 mmol) dissolved in 1.0 ml DMF. The reaction mixture is allowed the opportunity to mix at room temperature over night. The reaction mixture was diluted with 2.0 ml of H2O and filtered through 0.45 µm plate. The resulting solution was then injected on cooked HPLC system (2 volume) and elute with a mixture of 5-95% acetonitrile/in the Yes. Output: 8,8 mg, about 14%.

Example 17. Receiving compound I-107

METHOD B: compound I-107: 55,0 mg (0.12 mmol) of compound I-7, 100 ál (0,56 mmol) DIEA and 12.3 mg (0.14 mmol) isopropylmalate dissolved in 1.0 ml DMF. The reaction mixture is allowed the opportunity to mix at room temperature over night. The reaction mixture was diluted with 2.0 ml of H2O and filtered through 0.45 µm plate. The resulting solution was then injected on cooked HPLC system (2 volume) and elute with a mixture of 5%-95% acetonitrile/water. Output: 35,3 mg, approximately 47%.

Example 18. Receiving compound I-111

METHOD C: compound I-111: to 31.2 mg (0.30 mmol) isovalerianic acid are dissolved in 850 μl of CH2Cl2. Add 150 μl (0.15 mmol) of 1.0 M solution dicyclohexylcarbodiimide in CH2C12. After stirring for 15 minutes at room temperature the solution is filtered by 55.6 mg (0,121 mmol) of compound I-7. The product filtrate is washed through 2.0 ml DMF. The resulting reaction mixture is allowed the opportunity to mix at room temperature over night. The reaction mixture was diluted with 2.0 ml of H2O and filtered through 0.45 µm plate. The resulting solution was then injected on cooked HPLC system (2 volume) and elute with a mixture of 10%-90% acetonitrile/water. Output: 3.6 mg, approximately 40 %.

Example 19. Receiving compound I-111

Connection(8): 5,25 g (13.3 mmol) of the compound (7), of 3.78 g (17.5 mmol) (2-chloropyridin-4-yl)-hydrazine and 13.3 ml (74,7 mmol) DIEA suspended on 26.6 ml of NMP. The reaction mixture is sealed and heated to 220°C under microwave irradiation. After 6 minutes the reaction mixture is allowed to cool down to room temperature. The reaction mixture is then poured on saturated aqueous sodium bicarbonate solution. The resulting aqueous phase was diluted with EtOAc and the layers separated. The organic layer is dried over MgSO4, filtered and evaporated to dryness. The resulting crude product chromatographic with 6-inch silica gel and elute with a mixture of 5-9% MeOH/CH2Cl2. Still relatively crude product is recrystallized from a mixture of EtOAc/hexane. Output: 1,38 g, approximately 23%.

Example 20. Receiving compound I-113

Compound I-55: 603,6 mg (1,36 mmol) of the compound (9) and 622,5 mg (5.5 mmol) of 2,6-dimethylpiperazine suspended in NMP. The reaction mixture is heated to a temperature of 250 ° C. under microwave irradiation. After 15 minutes the reaction mixture is allowed to cool down to room temperature. Add 130 μl (1.6 mmol) of pyridine, and then 1.3 ml (to 13.8 mmol) of acetic anhydride. After 30 minutes the reaction mixture is added slowly to asystem solution of sodium bicarbonate. The product is extracted with EtOAc, dried over MgSO4, filtered and evaporated to dryness. The resulting crude product chromatographic with 6-inch silica gel and elute with a mixture of 5-9% MeOH/CH2Cl2. Yield: 108 mg, about 14%.

Example 21. NMR and Mass spectrometry connections

Analytical data for certain compounds of the present invention collect and record the following way. Data proton NMR collected using the instrument Bruker AMX 500 and a suitable solvent. For LC/MS method using column Hypersil BDS C18, 5 μm to 2.1×50 mm, with a flow rate of 1.0 ml/min with a suitable gradient. Mass spectrometry samples will be analyzed by MicroMass ZQ or Quattro II mass spectrometer operates in single MS mode using electrospray ionization. Samples contribute to the mass spectrometer using flow injection (FIA) or chromatography. Mobile phase for all mass spectrometric analyses contains acetonitrile-water mixture. In some cases, triperoxonane acid. Table 2 (see end of description) depicts a typical LC mass spectrometric data (LC/MS), delay time (RT) and1H-NMR data for certain compounds of the present invention, where the number of compounds in Table 2 corresponds to the compounds described in Table 1 (empty cells indicate that no testing is rodilas).

Example 22. Inhibition of FLT-3

Compounds studied for their ability to inhibit the activity of FLT-3 using a radiometric filter-binding studies. In this study tracked the inclusion of33P in the substrate poly(Glu, Tyr) 4:1 (pE4Y). The reaction is carried out in solution containing 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 1 mm DTT, 0.01% of BSA and 2.5% DMSO. The final substrate concentration in the study is 90 μm ATP and 0.5 mg/ml pE4Y (both reagent from Sigma Chemicals, St Louis, MO). The final concentration of the compounds is usually in the range from 0.01 to 5 μm. Typically, 12-point titration is carried out by preparing serial dilutions of the original 10 mm solution of the test compound in DMSO. The reaction was performed at room temperature. Solution 1 contains 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 1 mg/ml pE4Y and 180 μm ATP (containing 0.3 µci [Y33P]ATP for each reaction). Solution 2 contains 100 mm HEPES (pH 7.5), 10 mm MgCl2, 25 mm NaCl, 2 mm DTT, 0.02% of BSA and 3 nm FLT-3. The research is conducted on 96-well tablet by mixing 50 μl of solution 1 and 2.5 ml of the test compounds. Reactions trigger solution 2. After incubation for 20 minutes at room temperature the reaction is stopped with 50 μl of 20% TCA containing 0.4 mm ATP. The entire reaction volume is then transferred to a filter plate and washed with 5% TCA using the device Harvester-600 from TOMTEC (Hamden, CT). The value of including33P pE4y analyzed by scintillation counter Packard TopCount Microplate Scintillation Counter (Meriden, CT). Data cheated by using the Prism program to calculate values IC50or Ki.

Many compounds of the invention, including compounds in table 1, inhibit FLT-3.

Example 23 Inhibition of AUR-2

Compounds evaluated in the following manner for their ability to inhibit Aurora-2 using a standard pair of enzymatic studies (Fox et al (1998)Protein Sci7,2249). In the original buffer solution studies, containing 0.1 M HEPES of 7.5, 10 mm MgCl2, 1 mm DTT, 25 mm NaCl, 2.5 mm of phosphoenolpyruvate, 300 mm NADH, 30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 40 mm ATP, and 800 μm peptide (LRRASLG, American Peptide, Sunnyvale, CA), add a solution of the compound of the present invention in DMSO to a final concentration of 30 μm. The resulting mixture was incubated at 30°C for 10 minutes. The initiate reaction by adding 10 ál of stock solution Aurora-2 to obtain the final concentrations in the study, 70 nm. The reaction rate is calculated by monitoring the absorption intensity at 340 nm for 5-minute period at 30°C using a tablet reader BioRad Ultramark (Hercules, CA). The Ki values determined according to the speed as a function of the concentration of the inhibitor.

Many compounds of the invention, including compounds in table 1, in the will eurout AUR-2 with Ki values of less than 50 nm.

Example 24: Inhibition of KDR

Compounds evaluated for their ability to inhibit KDR using the standard pairwise enzyme studies (Fox et al., Protein Sci, (1998) 7, 2249). Studies conducted in a mixture of 200 mm HEPES of 7.5, 10 mm MgC12, 25 mm NaCl, 1 mm DTT and 1.5% DMSO. The final substrate concentration in the study are 300 μm ATP (Sigma Chemicals) and 10 μm poly E4Y (Sigma). Studies conducted at 37°C and 30 nm KDR. The final concentrations of the components of the system paired enzymes 2.5 mm phosphoenolpyruvate, 200 μm NADH, 30 μg/ml pyruvate kinase and 10 μg/ml lactate dehydrogenase. Uterine buffer solution studies are containing all of the reagents listed above, with the exception of ATP and test the connection. 177 μl stock solution is placed in a 96-well plate, and then add 3 μl of 2 mm stock solution of DMSO containing test compound (final concentration 30 μm). The tablet is pre-incubated for approximately 10 minutes at 37°C and the reaction initiated by adding 20 μl of ATP (final concentration 300 μm). The reaction rate is determined using the reader tablet devices Molecular Devices (Sunnyvale, CA) for 5 minutes period has read at 37°C. Compounds exhibiting more than 50%inhibition relative to control wells containing a mixture of research and DMSO bestestimate connection titrated to determine the IC50 values.

Some compounds of the invention, including compounds in table 1, inhibit KDR with Ki values of less than 50 nm.

Example 25. The study of inhibition of JAK3

Compounds evaluated for their ability to inhibit JAK with the above studies. The reaction is carried out in kinase buffer containing 100 mm HEPES (pH of 7.4), 1 mm DTT, 10 mm MgCl2, 25 mm NaCl and 0.01% BSA.

The concentration of substrates in the study are 5 μm ATP (200 µci/µmol ATP) and 1 μm poly(Glu)4Tyr. The reaction is carried out at 25°C and 1 nm JAK3.

In each well of 96-well polycarbonate tablet add 1,5 µl of a suspected inhibitor of JAK3 with 50 μl of kinase buffer containing 2 μm poly(Glu)4Tyr and 10 μm ATP. Then the reaction mix, and 50 μl of kinase buffer containing 2 nm JAK3 enzyme, is added to start the reaction. After 20 minutes incubation at room temperature (25°C) the reaction is stopped with 50 μl of 20% trichloroacetic acid (TCA), which also contains 0.4 mm ATP. All the contents of each well are then transferred into 96-well plates with glass fiber filter using a device TomTek Cell Harvester. After laundering add 60 μl of scintillation fluid to determine the inclusion of33P using counter Perkin Elmer TopCount.

Example 26. The study of inhibition of JAK2

Researched what I spend the same way as described above in example 25, except that the used enzyme JAK-2, the final concentration of poly(Glu)4Tyr is 15 μm, final concentration of ATP is 12 microns.

Table 3 reflects these inhibition of JAK2 and JAK3 (Ki) of the compounds of the sample. The numbers of the compounds in table 3 correspond to the numbers in table 1. In table 3, "A" means a Ki value less than 0.05 μm, "B" means the value of Ki in the range of 0.05 to 0.5 μm for the indicated enzyme.

Table 3
Conn.#JAK2JAK3Conn.#JAK2JAK3Conn.#JAK2JAK3
1InA60AA119AAnd
2AA61AA120 AAnd
3AA62AA121AAnd
4AA63AA122AAnd
5AA64AA123AAnd
6AA65AA124AAnd
7AA66AA125A And
8AA67AA126AAnd
9AA68AA127AAnd
10AA69AA128AAnd
11AA70AA129AAnd
12AA71AA130AAnd
13AA72AA131AAnd
14InIn73AA132AAnd
15AA74AA133AAnd
16AA75AA134AAnd
17AA76AA135AAnd
18 AA77AA136AAnd
19AA78AA137AAnd
20AA79AA138AAnd
21AA80AA139AAnd
22AA81AA140AAnd
23A A82AIn141
24AA83AN142AAnd
25InIn84AA143AAnd
26AA85AA144InIn
27AA86AA145InIn
28AA 87AA146InIn
29AA88AA147InIn
30AA89AA148InIn
31AA90AA149InIn
32AA91AA150InIn
33AA92 AA151InIn
34AA93AA152InIn
35AA94AA153InIn
36AA95AA154InIn
37AA96AA155InIn
38AA97In In156InIn
39AA98InIn157InIn
40AA99AA158InIn
41AA100AA159InIn
42AA101AA160InIn
43AA102AA 161InIn
44AA103AA162InIn
45AA104AA163InIn
46AA105AA164InIn
47AA106AA165InIn
48AA107AA166 AndAnd
49AA108AA167AndAnd
50AA109AA168InIn
51AA110AA169InIn
52AA111AA170InIn
53AA112AA171In And
54AA113AA172InAnd
55AA114AA173InAnd
56AA115AA174InIn
57AA116AA175InIn
58AA117AA176InIn
59AA118AA119AndAnd

While a number of embodiments of the present invention are described, it is obvious that basic examples can be modified for other embodiments that use the compounds and methods of the present invention. Therefore, it should be understood that the scope of the present invention is largely determined by the attached claims than private embodiments, which are presented for illustrative purposes.

Table 1. Examples of compounds of formula 1.

1. The compound of the formula I

or its pharmaceutically acceptable salt, where
And represents N or CR1;
R1represents H;
RXselected from

;
in each case R is independently selected from hydrogen or C1-6of alkyl;
RYselected from


R represents a C1-6alkyl; and
R' is independently selected from hydrogen or a group selected from C1-8the alkyl, optionally substituted C1-6alkoxycarbonyl,3-7cycloalkyl, optionally substituted C1-6the alkyl or C1-6alkoxy, phenyl, optionally substituted C1-6the alkyl, CF3With1-6alkoxy, or phenyl, optionally disubstituted with halogen, heterocyclic rings having 6 atoms in the ring atom O as heteroatom, pyridinyl or furanyl;
R" is independently selected from C1-8the alkyl, optionally substituted C1-6alkoxycarbonyl,3-7cycloalkyl, phenyl, optionally substituted C1-6the alkyl, or phenyl, optionally disubstituted with halogen, or heterocyclic ring having 5-6 atoms in the ring atom O as heteroatom.

2. The compound according to claim 1, where RYselected from

3. The compound according to claim 1, where RYrepresents a
;

4. The compound according to any one of claims 1 to 3, where a represents N.

5. The compound according to any one of claims 1 to 3, where a represents CH.

6. The compound according to any one of claims 1 to 3, where R' represents a C1-6alkyl, phenyl, pyridinyl or furanyl.

7. The connection according to claim 6, where R' represents a C1-6alkyl, optionally substituted C1-6alkoxycarbonyl, or phenyl, optionally substituted C1-6the alkyl, CF3C1-6alkoxy.

8. The connection according to claim 7 wherein R' represents methyl, ethyl, propyl, isopropyl,
-CH2-isopropyl, butyl, tert-butyl, -CH2tert-butyl or cyclohexyl, optionally substituted C1-6alkoxycarbonyl, or cyclohexyl and an atom Of as heteroatom.

9. The compound according to any one of claims 1 to 3, where R is Rxrepresents hydrogen or methyl.

10. The compound according to any one of claims 1 to 3, where each R" is independently selected from C1-8the alkyl, optionally substituted C1-6alkoxycarbonyl, phenyl, optionally substituted C1-6the alkyl, or phenyl, optionally disubstituted with halogen, or 6-membered courtesans is a cyclic group, with O as the heteroatom.

11. The connection of claim 10, where each R" is independently selected from C1-6the alkyl, optionally substituted C1-6alkoxycarbonyl, or phenyl, optionally disubstituted by halogen.

12. Connection claim 11, where each R" represents a methyl, ethyl, propyl, isopropyl, -CH2-isopropyl, butyl, tert-butyl or-CH2tert-butyl, optionally substituted C1-6alkoxycarbonyl.

13. A compound selected from one of compounds represented in Table 1:















































































































































































14. The pharmaceutical composition inhibiting the protein kinase GSK-3, JAK-2, JAK-3, FLT-3, KDR, or AURORA-2 and containing the compound according to any one of claims 1 to 13 and a pharmaceutically acceptable carrier, adjuvant or the binder.

15. The pharmaceutical composition according to 14, characterized in that, in addition, contains additional therapeutic agent selected from a chemotherapeutic or anti-proliferative agent, an anti-inflammatory agent, an immunomodulatory or immunosuppressive agent, a neurotrophic factor, an agent for treating cardiovascular disease, an agent for treating diabetes, an agent for treating immunodeficiency disorders.

16. The pharmaceutical composition according to item 15, distinguish what the lasting themes the specified therapeutic agent is an immunomodulatory or immunosuppressive agent.

17. A method of inhibiting the activity of kinases JAK2 or JAK3 in a biological sample, comprising contacting the above-mentioned biological sample with a compound according to any one of claims 1 to 13 or a composition based on it.

18. The use of compounds according to any of claims 1 to 13 or a composition based on it for the manufacture of a medicinal product for treating or alleviating the severity of the disease or pathological condition, such as allergies, asthma, autoimmune disease, graft rejection (AML disease Lou Gehrig's disease (als), multiple sclerosis (MS), solid cancer, hematological cancer or myeloproliferative disease.

19. Use p, where the disease or disorder is allergic or hypersensitivity type I, asthma, amyotrophic lateral sclerosis (AML, disease, Lou Gehrig's disease (als), multiple sclerosis (MS), graft rejection, graft versus host disease, rheumatoid arthritis, leukemia, lymphoma, exclude polycythemia Vera, essential trombozitemia, chronic idiopathic myelofibrosis, myeloid metaplasia with myelofibrosis, chronic myeloid leukemia, chronic myelomonocytic leukemia is m, chronic eosinophilic leukemia, hypereosinophilic syndrome or systemic mastocytosis.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds selected from a group consisting of compounds of formula: and or to their pharmaceutically acceptable salts. Also, the invention refers to a pharmaceutical composition, as well as to using at least one compound under cl.1 and/or its pharmaceutically acceptable salts.

EFFECT: preparing new biologically active compounds which exhibit the properties of cycline-dependent kinase inhibitors.

11 cl, 86 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula (I)

, where A denotes -CH2-, -O- or -NR'-, in which R' denotes hydrogen or C1-6alkyl, or R' and R4 form C2-5alkylene; R1 denotes hydrogen, amine group, C1-6alkyl, hydroxy group, -NR'R", (C0-6alkylene)-NR'R", where R' and R" are independently selected from a group comprising hydrogen, C1-6alkyl, heteroalkyl, formyl, C1-6alkylcarbonyl, arylcarbonyl optionally substituted with halogenalkyl, C1-6alkylsulphonyl, arylsulphonyl or -(C0-6alkylene)-OR', where R' denotes hydrogen, C1-6alkyl, formyl or C1-6alkylcarbonyl; R2 , R2 and R2 independently denote hydrogen, halogen, C1-6alkyl or C1-6alkoxy group; R3 denotes hydrogen, C1-6alkyl, aryl-C1-6alkyl, aryl optionally substituted with halogen, or heteroaryl, where the heteroaryl is a monocyclic or bicyclic ring containing 5-6 ring atoms and at least one aromatic ring containing one or three ring heteroatoms selected fron N, O and S, where the remaining ring atoms are carbon atoms, and the bonding site of the heteroaryl radical must be on the aromatic ring; R4 denotes hydrogen, C1-6alkyl, aryl, C3-7cycloalkyl-C1-6alkyl, aryl-C1-6alkyl; R5 denotes hydrogen or C1-6alkyl; or R4 and R5 together with the carbon atom to which they are bonded, form an optionally substituted C3-7cycloalkyl ring; R6 denotes hydrogen or C1-6alkyl; and pharmaceutically acceptable salts thereof, where the term "aryl" denotes phenyl or naphthyl. The invention also relates to a pharmaceutical composition based on compounds of formula I and having a inhibitory activity towards chymase.

EFFECT: novel compounds which can inhibit chymase are obtained and can be used as medicinal agents.

22 cl, 79 ex, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described novel compounds of formula (I), where R1 represents hydroxymethyl; R2 is selected from -C(O)NR4R5; HET-1 represents 5- or 6-member heteroaryl ring, bound by atom C; R3 represents halogeno; R4 and R5 together with nitrogen atom, to which they are bound, can form heterocyclyl ring system, as it is defined for HET-3; HET-3 represents possibly substituted azetidinyl; m equals 1; n equals 0, 1 or 2; or their pharmaceutically acceptable salt, which can be applied as glucokinase (GLK) activators or active ingredient of pharmaceutical compositions, also described are methods of obtaining them.

EFFECT: creation of novel compounds applied as glucokinase (GLK) activators in treatment of diabetes.

13 cl, 40 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of formula I , in which A denotes hydrogen, B denotes methyl or B is in a trans-position relative oxygen; X denotes CH2; Y denotes a group of formula , , ,

, or ;

, in which the left-hand bond is to an oxygen atom, and the right-hand bond is to the group R; R denotes 5-indolyl; in form of a free base or an acid addition salt. The invention also relates to a pharmaceutical composition, to use of compounds in any of claims 1-7, to a method of preventing and treating psychiatric and neurodegenerative disorders in a person, as well as a method of treating and preventing diseases or pathological condition in which α7 nAChR activation plays a role.

EFFECT: obtaining novel biologically active compounds having α7 nAChR agonist activity.

16 cl, 4 ex

FIELD: medicine.

SUBSTANCE: invention refers to new compounds which are N-substituted 1,4-diazabicyclo[2.2.2.]octane derivatives. The offered compounds exhibit antiviral activity and can find application in medicine as active components for the development of dosage forms used for treating viral diseases.

EFFECT: higher antiviral activity of the compound.

7 dwg, 4 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: in the formula (I) , R1 is metoxymethyl; R2 is selected out of -C(O)NR4R5, -SO2NR4R5, -S(O)PR4 and HET-2; R3 is selected out of halogeno, fluoromethyl, metoxy and cyano; HET-1 is 5- or 6-member heteroaryl ring linked by C atom and containing nitrogen atom in 2 position and possibly 1 or 2 additional ring heteroatoms selected independently out of O, N and S, which is possible substituted at available carbon atom or at ring nitrogen atom by 1 substitute selected independently out of R6, provided that it would not cause ring quaternisation. The other radicals are indicated in the invention claim. Also invention refers to pharmaceutical composition containing claimed compound as active component, and methods of obtaining compound of the formula (I).

EFFECT: compounds with glucokinase inhibition effect.

19 cl, 2 tbl, 61 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new compounds of formulae and , in which radicals and symbols assume values defined in the formula of invention, e.g. to 1H-indazoles, 1,2-benzisoxazoles and 1,2-benzisothiazoles. Said compounds are receptor ligands of the α-7 nAChR subtype. The invention also relates to a pharmaceutical composition containing the said compounds.

EFFECT: possibility of using the said compounds to make medicinal agents for treating diseases associated with impaired functioning of nicotinic acetylcholine receptors and their abnormal functioning, primarily in brain cells.

46 cl, 85 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of structural formula I and their pharmaceutically acceptable salts. In structural formula I , X is oxygen; Y is oxygen; Y1 Y2, R7 and R4 represent H; X1 and X2 are independently selected from a group consisting of hydrogen, an alkyl group containing 1 to 5 carbon atoms, in which one or more hydrogen atoms of the alkyl group can be substituted with a halogen, aryl group containing 6 to 10 carbon atoms or a cycloalkyl group containing 3 to 9 carbon atoms, or a 5-9-member heterocyclic group with 2 heteroatoms selected from N and O, or a cycloalkyl group containing 5 to 9 carbon atoms; values of the rest of the radicals are given in the formula of invention. The invention also pertains to a pharmaceutical composition having properties of selective inhibitors of type IV phosphodiesterase, containing a therapeutically effective amount of the invented compound.

EFFECT: increased effectiveness of the compounds.

6 cl, 23 ex

FIELD: chemistry.

SUBSTANCE: described is a compound selected from formulae , , , , and , where X1 denotes CH; X2-X5 each independently denotes CH or C-, where -C represents the point where group B is bonded and where one of X2-X5 denotes -C; X7-X10 each independently denotes CH or CR2; X18-X21 each independently denotes CH or CR5; X22 and X23 each independently denotes CH or CR12, where at least one of X22 and X23 denotes CR12; X24 denotes CH; B denotes CH2 or C=O; B1 denotes CH; Y denotes oxygen or sulphur; Z denotes O; m equals 2; R denotes hydrogen or R denotes each indendently (C1-C6)alkyl, (C3-C8)cycloalkyl, halogen, imidazolyl substituted with (C1-C6)alkyl and/or an oxo group or OR9; R9 denotes hydrogen, (C1-C6)alkyl which is unsubstituted or substituted with once or several times with fluorine, or (C4-C8)cycloalkylalkyl; R12 denotes a (C1-C6)alkoxy group which is substituted once or several times with fluorine, unsubstituted thiazolyl, thiazolyl which is substituted with (C1-C6)alkyl, unsubstituted oxazolyl, dihydropyranyl, tetrahydropyranyl or tetrahydropyranyloxy, and pharmaceutically acceptable salts of the said compounds. Described also are pharmaceutical compositions containing the said compounds.

EFFECT: invention relates to ligands of nicotinic acetylcholine receptors (nAChR), activation of nAChRs and treatment of diseases associated with defective or with functional disorders of nicotinic acetylcholine receptors, especially in the brain.

69 cl, 55 ex

FIELD: chemistry.

SUBSTANCE: described is a compound selected from a group consisting of formula II formula III and formula IV , or its salt or ester, where G1 is selected from a group which includes - (CR1R2)n-, n equals 0 or 1; R1 and R2 are independently selected from a group which includes hydrogen; X1, X2 and X3 are independently selected from a group consisting of hydrogen, optionally substituted lower alkyl, halogen, optionally substituted lower alkoxy, G2 is a heterocycloalkyl linker optionally substituted with X4 and X5, where the heterocycloalkyl linker is selected from a group consisting of piperazinyl, 3,6-dihydro-2N-pyridinyl, [1,4]diazepanyl, 3,9-diazabicyclo[3,3,1]nonyl; X4 and X5 are independently selected from a group consisting of hydrogen and optionally substituted lower alkyl; CO2R; R is selected from a group consisting of optionally substituted lower alkyl and hydrogen; G3 is a bond; G4 is selected from a group consisting of hydrogen, aryl, selected from phenyl which is optionally substituted with a lower alkyl, halogen, lower haloalkyl or lower haloalkoxy; heteroaryl selected from pyridinyl which is optionally substituted with a halogen or lower haloalkyl; and optionally substituted cycloheteroalkyl selected from 1,3-benzodioxolyl. Described also are specific compounds and a pharmaceutical composition.

EFFECT: disclosed compounds are used as modulators of receptors activated by a peroxisomal proliferator.

5 cl, 2 tbl, 117 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I:

or pharmaceutically acceptable salts thereof, in which Q is a divalent or trivalent radical selected from C6-10aryl and heteroaryl; where said aryl or heteroaryl in Q is optionally substituted up to 3 times with radicals independently selected from halogen, C1-6 alkyl, C1-6 alkyl substituted with halogen, C1-6 alkoxy group, C1-6 alkoxy group substituted with halogen, -C(O)R20 and -C(O)OR20; where R20 is selected from hydrogen and C1-6 alkyl; and where optionally, the carbon atom neighbouring W2 can be bonded through CR31 or O with a carbon atom of Q to form a 5-member ring condensed with A and Q rings; where R31 is selected from hydrogen and C1-6 alkyl; W1 and W2 are independently selected from CR21 and N; where R21 is selected from hydrogen and -C(O)OR25; where R25 denotes hydrogen; ring A can contain up to 2 carbon ring atoms substituted with a group selected from -C(O)-, -C(S)- and -C(=NOR30)- and can be partially unsaturated and contain up to 2 double bonds; where R30 denotes hydrogen ; L is selected from C1-6alkylene, C2-6alkenylene, -OC(O)(CH2)n-, -NR26(CH2)n- and -O(CH2)n-; where R26 is selected from hydrogen and C1-6 alkyl; where n is selected from 0, 1, 2, 3 and 4; q is selected from 0 and 1; t1, t2, t3 and t4 are each independently selected from 0, 1 and 2; R1 is selected from -X1S(O)0-2X2R6a, -X1S(O)0-2X2OR6a, -X1S(O)0-2X2C(O)R6a, -X1S(O)0-2X2C(O)OR6a, -X1S(O)0-2X2OC(O)R6a and -X1S(O)0-2NR6aR6b; where X1 is selected from a bond, O, NR7a and C1-4alkylene; where R7a is selected from hydrogen and C1-6alkyl; X2 is selected from a bond and C1-6alkylene; R6a is selected from hydrogen, cyanogroup, halogen, C1-6alkyl, C2-6alkenyl, C6-10aryl, heteroaryl, heterocycloalkyl and C3-8cycloalkyl; where said aryl, heteroaryl, cycloalkyl and heterocycloalkyl in R6a is optionally substituted with 1-3 radicals independently selected from hydroxy group, halogen, C1-6alkyl, C1-6alkyl substituted with a cyano group, C1-6alkoxy group and C6-10aryl-C1-4alkoxy group; and R6b is selected from hydrogen and C1-6alkyl; R3 is selected from hydrogen, halogen, hydroxy group, C1-6alkyl, C1-6alkyl substituted with halogen, C1-6alkyl substituted with a hydroxy group, C1-6alkoxy group, C1-6alkoxy group substituted with halogen, -C(O)R23 and -C(O)OR23; where R23 is selected from hydrogen and C1-6alkyl; R4 is selected from R8 and -C(O)OR8; where R8 is selected from C1-6alkyl, heteroaryl, C3-8cycloalkyl and heterocycloalkyl; where said heteroaryl, cycloalkyl or heterocycloalkyl in R8 is optionally substituted with 1-3 radicals independently selected from halogen, C1-6alkyl, C3-8cycloalkyl and C1-6alkyl substituted with halogen; R5 is selected from hydrogen, C1-6alkyl substituted with a hydroxy group, and a C1-6alkoxy group; heteroaryl denotes a monocyclic or condensed bicyclic aromatic ring complex containing 5-9 carbon atoms in the ring, where one or more ring members are heteroatoms selected from nitrogen, oxygen and sulphur, and heterocycloalkyl denotes a saturated monocyclic 4-6-member ring in which one or more said carbon atoms in the ring are substituted with a group selected from -O-, -S- and -NR-, where R denotes a bond, hydrogen or C1-6alkyl. The invention also relates to pharmaceutical compositions containing said compounds, and methods of using said compounds to treat or prevent diseases or disorders associated with GPR119 activity, such as obesity, type 1 diabetes, type 2 sugar diabetes, hyperlipidemia, type 1 autopathic diabetes, latent autoimmune diabetes in adults, type 2 early diabetes, child atypical diabetes, adult diabetes in children, malnutrition-associated diabetes and diabetes in pregnant women.

EFFECT: improved properties of compounds.

27 cl

FIELD: chemistry.

SUBSTANCE: invention relates to 6-piperidinyl-substituted isoquinoline derivatives of formula (I)

, where values of radicals are given in the claim, and compositions containing said compounds.

EFFECT: said compounds and compositions can be useful in treating and preventing diseases associated with Rho-kinase and mediated by Rho-kinase through myosin light chain phosphatase phosphorylation.

31 cl, 378 ex, 12 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to an immunodepressant based on a heterocyclic compound of formula

or to its pharmaceutically acceptable salt where X represents a nitrogen atom or CH, both or one of R1 or R2 represents a hydrogen atom, hydroxyl, a halogen atom, an amino group, C1-C6 alkoxy or C1-C6 alkyl: R3 represents a hydrogen atom, difluoromethyl, an amino group, methyl or hydroxymethyl; R4 or R5 represents a hydrogen atom or C1-C6 alkyl; R6 represents morpholino (optionally substituted by one or two C1-C6 alkyl groups), pyrrolidinyl (optionally substituted by hydroxy C1-C6 alkyl), piperidine (which is optionally substituted by an oxygen atom, hydroxyl, formyl or C1-C6 alkyl), piperazinyl (optionally substituted by one or two oxygen atoms, where a nitrogen atom in position 4 is optionally substituted by a substitute selected from a groups consisting of formyl, C1-C6 hydroxyalkyl, C1-C6 alkoxycarbonyl, C1-C6 oxoalkyl, furoyl, benzoyl, methoxybenzoyl, benzylcarbonyl, dimethylcarbamoyl, diethylcarbamoyl, morpholinocarbonyl and methoxyacetyl) or 1,4-diazepano (optionally substituted by one oxygen atom where a nitrogen atom in position 4 is optionally substituted by a substitute selected from a group consisting of formyl, C1-C6 oxoalkyl). Also, the invention refers to a heterocyclic compound of general formula

and to an anticancer drug based on the compound of formula (II).

EFFECT: there are produced new immunodepressant based on the compound of formula (I) and compound of formula (II) which can be used as anticancer drugs.

12 cl, 8 tbl, 60 ex

FIELD: chemistry.

SUBSTANCE: invention refers to the compounds of formula (I): where R denotes cycloalkyl, heterocyclil, aryl, alkyl-O-C(O)-, alkanoyl or alkyl where each cycloalkyl, heterocyclil and aryl does not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, cyano group, alkoxy group, alkyl-O-C(O)-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil, and where each alkyl-O-C(O)-, alkyl, alkoxy group and heterocyclil does not necessarily have additional 1 to 3 substitutes chosen from the group including a hydroxy group, alkyl, halogen, carboxy group, alkoxy group, alkyl-O-C(O)-, alkanoyl, alkyl-SO2-, amino group, mono- or disubstituted by alkyl amino group and heterocyclil; R2 denotes alkyl, cycloalkyl, cycloalkylalkyl- or alkoxy group where alkyl does not necessarily contain from 1 to 3 substitutes chosen from the alkoxy group or halogen; R3 denotes R8-O-C(O)-, (R8)(R9)N-C(O)-, R8-C(O)-, where R8 and R9 independently denote alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- or nonaromatic heterocyclil where each alkyl, cycloalkyl, aryl, arylalkyl-, cycloalkylalkyl- and nonaromatic heterocyclil do not necessarily contain from 1 to 3 substitutes chosen from the group including a hydroxy group, carboxy group, alkyl-O-C(O)-, alkyl-C(O)-O- and alkanoyl; R4 and R5 independently denote hydrogen, alkyl, alkynyl, alkoxy group, cycloalkyl, arylalkyl-, cycloalkylalkyl-, heteroarylalkyl-, monoalkylamino-C(O)-, dialkylcmino-C(O)- or dialkylamino-C(O)-alkyl-, where both these alkyl groups do not necessarily form a ring and where each alkyl, alkynyl, cycloalkyl, arylalkyl-, cycloalkylalkyl- heteroarylalkyl-, monoalkylamino-C(O)-, dialkylamino-C(O)- or dialkylamino-C(O)-alkyl- do not necessarily contain from 1 to 3 substitutes chosen from the group including alkyl, hydroxy group, halogen, carboxy group and alkoxy group; R6 and R7 independently denote hydrogen, halogenalkyl, halogen, dialkylamino group, alkoxy group, halogenalkoxy group, heteroaryl or alkyl-S(O)2- where each heteroaryl does not necessarily contain from 1 to 3 substitutes chosen from alkyl; where "heterocyclil" denotes fully saturated or nonsaturated aromatic or nonaromatic cyclic group that is represented by 5- or 6-membered monocyclic ring system containing at least one heteroatom chosen from nitrogen, oxygen and sulphur atoms; "heteroaryl" denotes 5- or 6-membered monocyclic ring system containing from 1 to 4 heteroatoms chosen from N, O and S; or to their pharmaceutically acceptable salts and their optical isomers, or to mixtures of the optical isomers. The invention also refers to the method of inhibition of the specimen's CETP activity, to the way of treatment of the specimen's abnormality or disease mediated by CETP or responsive to CETP inhibition, to the pharmaceutical composition, and to application of the formula (I) compounds.

EFFECT: production of new bioactive compounds that inhibit the CETP.

10 cl, 71 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to new compounds of formula I-9 where q is represented by 1; R11 is represented by C3-8-alkyl; C3-8-cycloalkyl or C3-8-cycloalkyl-C1-3-alkyl; A is represented by phenyl substituted by one or more substituting groups independently chosen from R12; and R12 is represented by -(CH2)-NR13R14; R13 is represented by C1-6-alkylcarbanil; and R14 is represented by hydrogen; and to the pharmaceutically acceptable salts of such compounds and to the pharmaceutical compositions based on such compounds. It has been revealed that the compounds of formula I-9 are histamine NZ-receptor antagonists and thus that they can be used in treatment of diseases connected with expression of such receptors.

EFFECT: compounds of formula I-9 can be used in treatment of diseases connected with expression of histamine NZ-receptors.

6 cl, 216 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I): where R1 and R2 represent hydrogen and a group which is hydrolysed in a physiological environment, optionally substituted lower alkanoyl or aroyl; X represents a methylene group; Y represents oxygen atom; n represents the number 0, 1, 2 or 3 and m represents the number 0 or 1; R3 represents a group of pyridine N-oxide according to formula A, B or C which is attached as shown by an unmarked linking: where R4, R5, R6 and R7 independently represent aryl, heterocycle, hydrogen, C1-C6-alkyl, C1-C6-alkylthio, C6-C12-aryloxy or C6-C12-arylthio group, C1-C6-alkylsulphonyl or C6-C12-arylsulphonyl, halogen, C1-C6-haloalkyl, trifluoromethyl, or heteroaryl group; or where two or more residues R4, R5, R6 and R7 taken together represent an aromatic ring, and where P represents a central part, preferentially chosen from regioisomers 1,3,4-oxadiazol-2,5-diyl, 1,2,4-oxadiazol-3,5-diyl, 4-methyl-4H-1,2,4-triazol-3,5-diyl, 1,3,5-triazine-2,4-diyl, 1,2,4-triazine-3,5-diyl, 2H-tetrazol-2,5-diyl, 1,2,3-thiadiazol-4,5-diyl, 1-alkyl-3-(alkoxycarbonyl)-1R-pyrrol-2,5-diyl, where alkyl is presented by methyl, thiazol-2,4-diyl, 1H-pyrazol-1,5-diyl, pyrimidine-2,4-diyl, oxazol-2,4-diyl, carbonyl, 1H-imidazol-1,5-diyl, isoxazol-3,5-diyl, furan-2,4-diyl, benzole-1,3-diyl and (Z)-1-cyanoethene-1,2-diyl, and where the regioisomers of the central part include both regioisomers produced by exchanging the nitrocatechol fragment and the -(X)n-(Y)m-R3 fragment. Also, the invention refers to a method for making a compound of formula I, as well as to a method for treating an individual suffering central and peripheral nervous system disorders, to a pharmaceutical composition based on the compounds of formula I, and also to their application for preparing the drug and as COMT inhibitor.

EFFECT: there are produced and described new compounds which show a potentially effective pharmaceutical properties in treating a number of central and peripheral nervous system disorders.

25 cl, 64 ex, 3 tbl

Mglur5 modulators // 2439068

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel compounds of general formula I:

(where values R1-R5, X and Z are defined in invention description), pharmaceutical composition, which contains them, and application of claimed compounds as MGLUR5 modulators for inhibition of transient relaxations of lower esophageal sphincter or for treatment or prevention of gastroesophageal reflux disease.

EFFECT: obtaining compounds for treatment or prevention of gastroesophageal reflux disease.

14 cl, 87 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazolidinone derivatives of formula and pharmaceutically acceptable salts thereof, where X denotes N or CH; R1 denotes a lower alkyl, fluoro-lower alkyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-lower alkyl, phenyl, naphthyl, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of a halide, lower alkyl, fluoro-lower alkyl, lower alkoxy group and fluoro-lower alkoxy group; R2 denotes lower alkyl, halide-lower alkyl, lower alkenyl, C3-C6-cycloalkyl, pheny, phenyl-lower alkyl, tetrahydropyran, pyridine, where the phenyl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide; R3 denotes phenyl or heteroaryl (pyridinyl, thienopyridinyl, benzoisothiazolyl, benzooxazolyl, tetrahydropyrazinyl, pyrazinyl), where the phenyl or heteroaryl can be optionally substituted with 1-2 substitutes independently selected from a group consisting of halide, CN, lower alkyl, fluoro-lower alkyl, lower alkoxy group; R4, R5, R6, R7, R8, R9, R10 and R11 independently denote hydrogen or lower alkyl. The invention also relates to a pharmaceutical composition based on compounds of formula I.

EFFECT: obtaining novel imidazolidinone derivatives, having LXRalpha or LXRbeta receptor agonist activity.

26 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula where: R1 denotes COORa1, CONRa2Ra2', CONRa4ORa4', where: each of Ra1 and Ra4 denotes a hydrogen atom; each of Ra2 and Ra2' denotes a hydrogen atom; Ra4' denotes a lower alkyl; or R1 denotes a heterocyclic group selected from the following groups, where Y2 denotes a hydrogen atom or a lower alkyl: R2 denotes O, S, SO, SO2; R3 denotes a phenyl which is substituted with 2 substitutes selected from halogen, CF3; X2 denotes CH or N; W denotes the following residue: where: W1 denotes CH or S; W2 denotes CH; W3 denotes C or N; and at least one of W1, W2 and W3 denotes a carbon atom; or pharmaceutically acceptable salt or ester thereof. The invention also relates to a pharmaceutical composition having Avrora A selective inhibitory action, which, along with a pharmaceutically acceptable carrier or diluent, contains at least one compound of formula I a an active ingredient.

EFFECT: aminopyridine or aminopyrazine derivatives which inhibit growth of tumour cells based on Avrora A kinase selective inhibitory action.

11 cl, 3 tbl, 24 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel diarylamine-containing compounds of formula (I) or formula (4b), pharmaceutically acceptable salts thereof, which have c-kit inhibiting properties. In formulae (I) and (4b), each R1 independently denotes H, -C(O)OH and -L1-C1-6alkyl, where L1 denotes -O- or -C(O)O-, or any two neighbouring R1 groups can together form a 5-6-member heterocyclic ring containing a nitrogen atom or an oxygen atom as a heteroatom, a 6-member heterocyclic ring with one or two nitrogen atom s as heteroatoms, optionally substituted with a C1-4alkyl, and R5 denotes hydrogen or C1-C6alkyl; values of radicals Ar and Q are given in the claim. The invention also relates to a pharmaceutical composition containing said compounds, and a method of treating diseases whose development is promoted by c-kit receptor activity.

EFFECT: more effective use of the compounds.

17 cl, 3 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 6-piperidinyl-substituted isoquinoline derivatives of formula (I)

, where values of radicals are given in the claim, and compositions containing said compounds.

EFFECT: said compounds and compositions can be useful in treating and preventing diseases associated with Rho-kinase and mediated by Rho-kinase through myosin light chain phosphatase phosphorylation.

31 cl, 378 ex, 12 tbl

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