Jak kinase-modulating quinazoline derivatives and methods of applying thereof

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where R1 and R2 have the following values: (i) R1 and R2 together form =O; (ii) R1 and R2 together with carbon atom, which they are bound with, form duoxacycloalkyl; R1 represents hydrogen or halogen; and R2 represents halogen; (iv) R1 represents C1-6alkyl, where alkyl is optionally substituted with cyano, -RxS(O)qRv or -RxNRyRz; and R2 represents hydrogen; (v) R1 represents -OR12 or -NR13R14; and R2 represents hydrogen, deutero or phenyl, which is optionally substituted with halogen; R3 represents hydrogen, halogen, C1-6alkyl, cyano, halogen C1-6alkyl, C3-10cycloalkyl or C1-6alkoxy; R4 and R5 represent hydrogen; R6 is independently selected from halogen, C1-6alkyl, halogenC1-6alkyl, -RxOR18 and -RxS(O)qRv; R7 independently represents halogen or -RxORw; R12 is selected from hydrogen and C1-6alkyl, R13 represents hydrogen; R14 is selected from hydrogen, C3-10cycloalkyl, -C(O)Rv and -C(O)ORw; R18 represents hydrogen, C1-6alkyl, or pyperidinyl, where R18 is optionally substituted with 1-3 Q1 groups, each Q1 is independenly selected from hydroxyl, C1-6alkoxy, C1-6alkoxycarbonyl, carboxyl and morpholinyl; Rx independently represents C1-6alkylene or simple bond; Rv and Rw represent hydrogen or C1-6alkyl; Ry and Rz represent hydrogen; n has value 0-4; p has value 0-5; and each q independently has value 0, 1 or 2. Invention also relates to compounds of formula (II) , where substituents have values, given in the invention formula, to pharmaceutical composition, possessing inhibiting activity with respect to JAK kinases, containing compounds of formula (I) or (II), methods of treating JAK-modulated disease, and application of compounds of formula (I) or (II).

EFFECT: compounds of formula (I) or (II) as inhibitors of JAK kinases.

32 cl, 6 dwg, 2 tbl, 84 ex

 

Related applications

The present application claims priority over provisional application U.S. No. 61/156447, filed February 27, 2009, 61/294083 filed January 11, 2010, and 61/294490 filed January 13, 2010. The disclosure of the above applications is incorporated into the present application by reference in their entirety.

The scope of the invention

In this application presents compounds that are modulators of JAK kinases, compositions comprising such compounds, and methods of their use. Presented compounds are useful for treatment, prevention or relief of diseases or disorders associated with JAK, including JAK2, JAK3 or TYK2 kinase, or one or more symptoms associated with such diseases or disorders. In addition, the methods of treatment of cancer, including hematological and solid tumors.

Background of the invention

The JAK family of kinases is a family of cytoplasmic protein kinases, including such members as JAK1, JAK2, JAK3 and TYK2. The receptors of growth factors or cytokines for recruitment JAK kinases include receptor interferon receptors of interleukins (receptors for cytokines IL-2, IL-7, IL-9 IL-13, IL-15, IL-23), receptors for various hormones (erythropoietin receptor (Epo)receptor thrombopoetin (Tpo), the leptin receptor, the insulin receptor, the receptor PR is " Lactina " (PRL), the receptor for granulocyte colony-stimulating factor (G-CSF) and receptor growth hormone receptor tyrosine kinases (such as EGFR and DERIVED) and receptors for other growth factors, such as factor inhibiting leukemia (LIF), Oncostatin M (OSM), IFNα/β/γ, Granulocyte-macrophage colony-stimulating factor (GM-CSF), Ciliary neurotrophic factor (CNTF), cardiotrophin-1 (CT-1)(See, Rane, S. G. and E.P. Reddy, Oncogene 2000 19, 5662-5679).

Phosphorylated receptors serve as dock sites for other SH-2 domain containing signaling molecules that interact with JAK, such as the STAT family of transcription factors, Src family kinases, MAP kinase, PI3 kinase and patientinitiated (Rane S.G. and E.P. Reddy, Oncogene 2000 19, 5662-5679). The family of latent cytoplasmic transcription factors, STAT, is the most well characterized are present along this path substrates for JAK. STAT proteins bind to phosphorylated cytokine receptors through their SH2 domains to implement their phosphorylation by JAK, what leads to their dimerization and release and, ultimately, translocation to the nucleus, where they activate gene transcription. Different members of the STAT, which have been identified to date represent STAT1, STAT2, STAT3, STAT4, STAT5 (including STAT5a and STAT5b and STAT6.

JAK kinase may play an important role in signaling through these receptors, disorders of lipid metabolism, growth disturbances and disorders of the immune system - all are potential therapeutic targets.

JAK kinase and JAK2 mutations involved in myeloproliferative disorders, cancers, including hematological and solid tumors. Examples of disorders include chronic myelogenous leukemia (CML), malignant polycythemia (PV), essential trombozitemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), chronic myelomonocytic leukemia (CMML) and systemic mastocytosis (SM). It is believed that myeloproliferative disorders arise either from mutations purchasing functions JAK as such, any of activation oncoprotein BCR-ABL, which specifically activates the path JAK2. Some literary sources describe the role of JAK2 mutations in various disorders. See, Samanta et al. Cancer Res 2006, 66(13), 6468-6472, Sawyers et al. Cell, 1992, 70, 901-910, Tefferi N. Eng J. Med. (2007) 356(5): 444-445) Baxter et al. Lancet (2005) 365: 1054-1056, Levine et al. Blood (2006, Jones et al. Blood (2005) 106:2162-2168) 107:4139-4141, Campbell et al. Blood (2006) 107(5): 2098-2100, Scott et al. N Eng J Med 2007 356(5): 459-468, Mercher et al. Blood (2006) 108(8): 2770-2778, Lacronique et al. Science (1997) 278: 1309-1312, Lacronique et al. Blood (2000) 95:2535-2540, Griesinger F. et al. Genes Chromosomes Cancer (2005) 44:329-333, Bousquet et al. Oncogene (2005) 24:7248-7252, Schwaller et al. Mol. Cell. 2000 6,693-704, Zhao et al. EMBO 2002 21(9), 2159-2167.

Literary sources indicate that JAK can also serve as a target for cancer pre is Stateline gland, including androgen-resistant prostate cancer. See, Barton et al. Mol. Canc. Ther. 2004 3(1), 11-20, Blume-Jensen et al. Nature (2001) 411(6835):355-356 and Bromberg J Clin Invest. (2002) 109(9): 1139-1142, Rane Oncogene (2000) 19(49):5662-5679. JAK as a significant mediator of the transmission signal of cytokines is considered a therapeutic target for inflammation and graft rejection. See, Borie et al., Transplantation (2005) 79(7):791-801, and Milici et al., Arthritis Research (2008) 10(14): 1-9

Given the large number of different diseases associated with dysregulation of the signaling activity of JAK, currently under development are many small molecule inhibitors of JAK. Examples of the compounds are in preclinical stages of development, include TG101209 (TargeGen), examples of the compounds present in the clinical stages of the study include INCBO 18424 Incyte), XL019 (Exelixis) and TG101348 (TargeGen). See, Pardanani et al. Leukemia 2007, 21: 1658-1668; and Pardanai, A. Leukemia 2008 22:23-20.

However, there is still a need for new classes of compounds that are useful as inhibitors of enzymes in the signaling pathway JAK.

Brief description of the invention

In this application presents the compounds of formula (I)

or their pharmaceutically acceptable salt, solvate or hydrate, where

R1and R2selected from (i), (ii), (iii), (iv) and (v) and have the following meanings:

(i) R1and R2the place form =O, =S, =NR9or =CR10R11;

(ii) R1and R2both are-OR8or R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;

(iii) R1represents hydrogen or halogen; and R2is a halogen;

(iv) R1represents alkyl, alkenyl, quinil, cycloalkyl or aryl, where alkyl, alkenyl, quinil, cycloalkyl or aryl optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents selected from halogen, cyano, alkyl, -RXORW, -RxS(O)qRv, -RxNRyRzand-C(O)ORW; and R2represents hydrogen, halogen or-OR8; and

(v) R1represents halogen, deutero, -OR12, -NR13R14or-S(O)qR15; and R2represents hydrogen, deutero, alkyl, alkenyl, quinil, cycloalkyl or aryl, where alkyl, alkenyl, quinil, cycloalkyl or aryl optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents selected from halogen, cyano, alkyl, -RXORW, -Rx S(O)qRvand RxNRyRz;

R3represents hydrogen, halogen, alkyl, cyano, halogenated, cycloalkyl, cycloalkenyl, hydroxy or alkoxy;

R4and R5each independently represents hydrogen or alkyl;

each R6independently selected from halogen, alkyl, alkenyl, quinil, halogenoalkane, cycloalkyl, -RXOR18, -RXNR19R20and RxS(O)qRv;

each R7independently represents halogen, alkyl, halogenated or-RXORW;

R8represents alkyl, alkenyl or quinil;

R9represents hydrogen, alkyl, halogenated, hydroxy, alkoxy or amino;

R10represents hydrogen or alkyl;

R11represents hydrogen, alkyl, halogenated or-C(O)OR8;

R12selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, -C(O)RV, -C(O)ORWand-C(O)NRyRzwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl and heteroaryl, each optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment animtree, in one variant of embodiment one, two or three substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio;

R13and R14selected as follows:

(i) R13represents hydrogen or alkyl; and R14selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, alkoxy, -C(O)RV, -C(O)ORW, -C(O)NRyRzand-S(O)qRvwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaryl, each optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio; or

(ii) R13and R14together with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl where heterocyclyl or heteroaryl substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents, independently selected from halogen, alkyl, hydroc and, alkoxy, amino, alkylthio, and where heterocyclyl optionally substituted by oxo group;

R15represents alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, -C(O)NRyRzor-NRyRzwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaryl, each optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio;

R18represents hydrogen, alkyl, halogenated, hydroxys2-6alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaromatic; where R18optionally substituted by 1-3 groups Q1every Q1independently selected from alkyl, hydroxyl, halogen, halogenoalkane, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyl, carboxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogenfree and amino;

R19and R20selected as follows:

(i) R19and R20Hep is the first independent, represents hydrogen or alkyl; or (ii) R19and R20together with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl, which is optionally substituted by 1-2 groups, each of which is independently selected from halogen, alkyl, halogenoalkane, hydroxyl and alkoxy;

each Rxindependently represents alkylene or a simple bond;

Rvrepresents hydrogen, alkyl, alkenyl or quinil;

Rwindependently represents hydrogen, alkyl, alkenyl, quinil or halogenated;

Ryand Rzselected as follows:

(i) Ryand Rzeach independently represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl or halogenated;

(ii) Ryand Rztogether with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl, are not substituted by 1-2 groups, each of which is independently selected from halogen, alkyl, halogenoalkane, hydroxyl and alkoxy;

n has a value of 0-4;

p has a value of 0-5; and

each q, independently, is 0, 1 or 2.

In some embodiments the embodiment of the compounds have activity modulators JAK kinases, including JAK2 kinase. The compounds are useful in medical treatment, pharmaceutical compositions and methods of modulating the activity of a JAK kinase, including : the wild-type and/or mutated forms of the JAK kinase. In some embodiments the embodiment of the compounds presented in this invention have the activity of JAK2 kinase modulators. In some embodiments the embodiment of the compounds are inhibitors of JAK kinases, including JAK2 kinase. In some embodiments the embodiment of the compounds are inhibitors of JAK kinases, including JAK2 and TYK2 kinases.

In one variant embodiment, the compounds for use in the compositions and methods presented in this application are compounds of formula (I).

In one variant embodiment of the connection presented in this invention is a compound of formula (I). In one variant embodiment of the connection presented in this invention is a pharmaceutically acceptable salt of the compounds of formula (I). In one variant embodiment of the connection presented in this invention is a MES the compounds of formula (I). In one variant embodiment of the connection presented in this invention is a hydrate of the compound of formula (I).

Also provided pharmaceutical compositions formulated for the introduction of a proper way and manner, containing effective concentrations of one or more compounds presented in this invention, or their pharmaceutically acceptable with the lei, the solvate and hydrate, and optionally comprising at least one pharmaceutical carrier.

Such pharmaceutical compositions are delivered amount effective for treating, preventing or alleviating diseases or disorders, which include, without limitation, myeloproliferative disorders such as polycythemia Vera (PCV), essential thrombocythemia (ET), primary myelofibrosis (PMF), chronic eosinophilic leukemia (CEL), chronic myelomonocytic leukemia (CMML), systemic mastocytosis (SM) and idiopathic myelofibrosis (IMF); leukemia such as myeloid leukemia, including chronic myeloid leukemia (CML), imatinib-resistant forms of CML, acute myeloid leukemia (AML) and the subtype of AML, acute megacaryoblastic leukemia (AMKL); lymphoproliferative diseases, such as myeloma; cancer, such as head and neck cancer, prostate cancer, breast cancer, ovarian cancer, melanoma, lung cancer, brain tumors, pancreatic cancer, and kidney cancer; and inflammatory diseases or disorders related to immune dysfunction, immunodeficiency, immunomodulation, autoimmune disease, tissue graft rejection, disease graft-versus-host, wound healing, kidney disease, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, psoriasis allergic Rin is t, inflammatory bowel disease, including Crohn's disease and ulcerative colitis (UC), systemic lupus erythematosus (SLE), arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma, chronic obstructive pulmonary disease (COPD) and dry eye syndrome (or keratoconjunctivitis sicca (KCS)). In one variant embodiment, such disease or disorder modulated, or have any other impact JAK kinases, including JAK2, JAK3 or TYK2.

Also in this application presents a combination therapy with one or more compounds or compositions provided in the present invention, or their pharmaceutically acceptable salts, solvate or hydrate in combination with other pharmaceutically active means for the treatment of diseases and disorders described in this application.

In one variant embodiment, such additional pharmaceutical agents include one or more chemotherapeutic agents, antiproliferative funds, antiinflammatory agents, immunomodulating agents or immunosuppressive funds.

The compounds or compositions provided in the present invention, or their pharmaceutically acceptable salt, solvate or hydrate, can be administered simultaneously with introduction, before or after administration of one or more of the above environments, the TV. Also provided pharmaceutical compositions containing the compound, presented in this invention, and one or more of the above tools.

In some embodiments, embodiments in the present application presents methods of treatment, prevention or relief of a disease or disorder that is modulated JAK kinases or is otherwise affected by JAK kinases, including JAK2 kinase, such as wild type and/or mutant JAK2 kinase, or one or more symptoms or causes. In another variant embodiment, the present application presents methods of treatment, prevention or relief of diseases or disorders by modulating JAK2 kinase selective manner compared with JAK3 kinase. In the following variant embodiment, the present application presents methods of treatment, prevention or relief of diseases or disorders by modulating JAK3 kinase selective manner compared with JAK2 kinase. In another variant embodiment, the present application presents methods of treatment, prevention or relief of diseases or disorders by modulating both kinases JAK2 and JAK3. In one variant embodiment of the methods of treatment of cancer, including hematological and solid tumors.

In the implementation in practice of the methods, effective amounts connected the th or compositions, containing therapeutically effective concentrations of the compounds are formulated for systemic delivery, including parenteral, oral or intravenous delivery, or for local or topical application, enter the subject, which are the symptoms of the disease or disorder to be treated. Amounts are effective to alleviate or eliminate one or more symptoms of diseases or disorders.

These and other aspects of the invention described in this application will be apparent when referring to the below detailed description.

Brief description of drawings

Fig. 1 represents the in vivo data showing the response to the dose of the compounds of formula I in models of type II collagen-induced arthritis (CIA) in rats.

Fig. 2 represents the effects of varying doses of the compounds of formula I and the control of body weight in the model of type II collagen-induced arthritis (CIA) in rats.

Fig. 3 represents the survival analysis Kaplan-Meier estimates for the firm connection Ambit intended for internal use only, TGEN101348 and control in the mouse model TELJAK.

Fig. 4 represents the survival analysis Kaplan-Meier estimates for the firm connection Ambit intended only for internal use, the compounds of formula I and control the I in murine models TELJAK.

Fig. 5 represents the survival analysis Kaplan-Meier estimates for the firm connection Ambit intended only for internal use, the compounds of formula I and control in HELV617F mouse model of liquid tumors.

Fig. 6 represents the survival analysis Kaplan-Meier estimates for the firm connection Ambit intended for internal use only, TGEN101348 and control HELV617F mouse model of liquid tumors.

Detailed description of the invention

In this application presents the compounds of formula (I), which have activity as modulators of JAK kinases, including JAK2 kinase. In addition, the methods of treatment, prevention or relief of diseases which are modulated JAK kinases, including JAK2 kinase, and pharmaceutical compositions and dosage forms useful for such methods. Methods and compositions are described in detail in the following sections.

In some embodiments the embodiment of the compounds presented in this application, are selective against JAK2, i.e. compounds bind or interact with JAK2 at much lower concentrations compared to their binding or interaction with other JAK receptors, including JAK3 receptor, at the same concentration. In some embodiments, embodiments of compounds associated with JAK3 receptor PR is the binding constant, at least about 3 times, about 5 times higher, about 10 times, about 20 times, about 25 times greater, about 50 times higher, about 75 times higher, about 100 times higher, about 200 times higher, about 225 times greater, about 250 times higher, or about 300 times higher compared with their binding to JAK2 receptor.

In some embodiments the embodiment of the compounds presented in this application, are selective against JAK3, i.e. compounds bind or interact with JAK3 at much lower concentrations compared to their binding or interaction with other JAK receptors, including JAK2 receptor, at the same concentration. In some embodiments, embodiments of compounds associated with JAK2 receptor with a binding constant of at least about 3 times, about 5 times higher, about 10 times, about 20 times, about 25 times greater, about 50 times higher, about 75 times higher, about 100 times higher, about 200 times higher, about 225 times greater, about 250 times higher, or about 300 times higher compared with their binding to JAK3 receptor.

In some embodiments the embodiment of the compounds presented in this invention, bind or interact with TYK2. In some embodiments the embodiment of the compounds presented in the present the invention, have a Kd of less than 20 nm, less than 40 nm, less than 50 nm, less than 75 nm, less than 80 nm, less than 90 nm or less than 100 nm against TYK2. In some embodiments the embodiment of the compounds presented in this invention have a Kd greater than about 10 nm, 20 nm, 25 nm, 40 nm, 50 nm or 70 nm against the kinase Aurora B. Methods for determining Kd compounds against protein kinases, such as TYK2 and Aurora B kinase, known to specialists in this field. Illustrative methods are described in provisional application U.S. No. 61/294413 and Fabian et al., Nature Biotechnology 2005, 23,329-336.

Definitions A.

If not stated otherwise, all technical and scientific terms used in this application have common values, which are known to experts in this field. All patents, applications, published applications and other publications are incorporated by reference in their entirety. When in the description there are several definitions of the term, the advantage of have the definitions stated in this section, unless otherwise noted.

"Alkyl" refers to a group with a linear or branched hydrocarbon chain consisting solely of carbon atoms and hydrogen, do not contain any unsaturation, containing from one to ten, one to eight, one to six or one to four carbon atoms, and which is attached to the rest of the molecule by SIP the soup simple communication for example, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl) and the like.

"Alkenyl" refers to a group with a linear or branched hydrocarbon chain consisting solely of carbon atoms and hydrogen, containing at least one double bond, in some embodiments of the incarnation, containing from 2 to 10 carbon atoms, from 2 to 8 carbon atoms or from 2 to 6 carbon atoms, and which is attached to the rest of the molecule via a simple link or a double bond, for example ethynyl, prop-1-enyl, but-1-enyl, Penta-1-enyl, Penta-1,4-dienyl and similar.

"Quinil" refers to a group with a linear or branched hydrocarbon chain consisting solely of carbon atoms and hydrogen, containing at least one triple bond containing from two to ten carbon atoms, and which is attached to the rest of the molecule via a simple link or a triple bond, such as ethinyl, prop-1-inyl, but-1-inyl, Penta-1-inyl, Penta-3-inyl and the like.

"Alkylene" and "Allenova chain" refers to a linear or branched divalent hydrocarbon chain consisting solely of carbon and hydrogen that does not contain any unsaturation and contains from one to eight carbon atoms, such as methylene, ethylene, propylene, the-butylene and the like. Allenova chain can be attached to the rest of the molecule through any two carbon atoms in the chain.

"Alkoxy" refers to a group having the formula-OR, where R is an alkyl or halogenated, where alkyl optionally may be substituted by one or more substituents, in one variant of embodiment one, two or three substituents, independently selected from the group comprising nitro, halogen, hydroxyl, alkoxy, oxo, thioxo, amino, carbonyl, carboxy, azido, cyano, cycloalkyl, heteroaryl and heterocyclyl.

"Alkoxyalkyl" refers to a group having the formula-RhOR, where Rhrepresents a linear or branched alkylenes chain and OR is an alkoxy, as defined above.

"Alkylthio" refers to a group having the formula-SR, where R is an alkyl or halogenated.

"Aryloxy" refers to the group-OR where R represents an aryl, including lower aryl, such as phenyl.

"Amine" or "amino" refers to a group having the formula-NR'r R", where R' and R", each independently, represent hydrogen, alkyl, halogenated, hydroxyalkyl or alkoxyalkyl, or where R' and R" together with the nitrogen atom to which they are bound, form heterocyclyl, optionally substituted with halogen, oxo, hydroxy or alkoxy.

"Aminoalkyl" refers to a group having the formula-Rh/sub> NR'R", where Rhrepresents a linear or branched alkylenes chain, and where R NR'r" represents the amino defined above.

"Aminocarbonyl" refers to a group having the formula-C(O)R NR'r", NR'r R" is amino, the above-defined.

"Aryl" refers to a group representing a carbocyclic ring system, including monocyclic, bicyclic, tricyclic, tetracyclic C6-C18ring system, where at least one of the rings is aromatic. The aryl may be fully aromatic, examples of which are phenyl, naphthyl, anthracene, acenaphthylene, azulene, fluorene, indenyl and pyrenyl. The aryl may also contain an aromatic ring in combination with a non-aromatic ring, examples of which are arenafan, inden and fluoren. The term includes both substituted and unsubstituted groups. Aryl group may be substituted by any of the described group, including, but not limited to, one or more groups selected from the group comprising halogen (fluorine, chlorine, bromine or iodine), alkyl, hydroxyl, amino, alkoxy, aryloxy, nitro and cyano.

"Carboxyl" refers to a group having the formula-C(O)OH.

"Cycloalkyl" refers to a suitable monovalent monocyclic or bicyclic hydrocarbon group, consisting iscrucial the but of atoms of carbon and hydrogen, containing from three to ten carbon atoms and which is saturated and attached to the rest of the molecule via a simple link, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, decaline, norbornane, norbornene, substituted, bicyclo[2,2,2]octane and the like.

"Cycloalkenyl" refers to a group of the formula-RaRdwhere Rarepresents an alkyl group as defined above, and Rdrepresents cycloalkyl group that is defined above. Alkyl group and cycloalkyl group optionally can be substituted, as defined in this application.

"Deutero" or "deuterium" refers to an isotope of hydrogen to deuterium, which has the chemical designation D or2H.

"Halogen", "halo" or "halogen" refers to F, Cl, Br or I.

"Halogenated" refers to an alkyl group, in some embodiments of the incarnation1-6alkyl group in which one or more hydrogen atoms replaced by halogen. Such groups include, but are not limited to, chloromethyl, trifluoromethyl, 1-chloro-2-foretel, 2,2-dottorati, 2-forprofit, 2-forproper-2-yl, 2,2,2-triptorelin, 1,1-dottorati, 1,3-debtor-2-methylpropyl, 2,2-divorcecare, (trifluoromethyl)cyclopropyl, 4,4-diverticulosis and 2,2,2-Cryptor-1,1-dimethylethyl.

"Heterocyclyl" refers to a suitable 3-15 membered Kohl the eve group, which consists of carbon atoms and from one to five heteroatoms selected from the group comprising nitrogen, oxygen and sulfur. In one variant embodiment, a group that represents a heterocyclic ring system may be a monocyclic, bicyclic or tricyclic or tetracyclic ring system, which may include condensed or linked bridge connection ring systems; and the nitrogen atoms or sulfur in the heterocyclic ring system, optionally, can be oxidized; the nitrogen atom, optionally, can be stereoselectivity; and heterocyclyl group may be partially or fully saturated or aromatic. Heterocyclic ring system may be attached to the main structure at any heteroatom or carbon atom that provides obtaining a suitable connection. Examples of heterocyclic radicals include, azetidine, benzopyranones, benzopyranyl, bettererererer, betterregulation, bromanil, chromones, coumarinyl, decahydroquinoline, dibenzofurans, dihydromethysticin, dihydroergotoxine, dihydrofuran, dihydropyran, DIOXOLANYL, dihydropyrazine, dihydropyridines, dihydropyrazolo, dihydropyrimidines, dihydropyrrole, DIOXOLANYL, 1,4-ditional, isobenzofuranyl, isobenzofurandione, isopropanol, isocoumarins, benzo[1,3]dioxol-5-yl, benzodioxolyl, 1,3-dioxolane-2-yl, DIOXOLANYL, morpholinyl, octahedrally, activitiesunder, tetrahydrofuran, oxazolidin-2-IMT, oxazolidinones, piperidinyl, piperazinil, pyranyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydroisoquinoline, tetrahydropyranyl, tetrahydrofuryl, pyrrolidinyl, oxathiolanes and pyrrolidinyl.

"Heteroaryl" refers to heterocyclyl group, as defined above, which is aromatic. Heteroaryl group may be attached to the main structure at any heteroatom or carbon atom that provides obtaining a suitable connection. Examples of such heteroaryl groups include, but are not limited to: acridines, benzimidazolyl, bunzendahl, benzisoxazole, benzo[4,6]imidazo[1,2-α]pyridinyl, benzofuranyl, benzenepropanal, benzothiadiazoles, benzothiazolyl, benzothiophene, benzotriazolyl, benzothiophene, benzoxazines, benzoxazolyl, benzothiazolyl, β-carbolines, carbazolyl, cinnoline, dibenzofurans, furanyl, imidazolyl, imidazopyridines, imidazothiazoles, indazoles, indolizinyl, indolyl, isobenzofuranyl, isoindolines, ethenolysis, isothiazolinones, isothiazolin, naphthyridine, octahedrally, activitiesunder, oxazolidinones, oxazolidinyl, oxazolopyridine, OK is azolyl, isoxazolyl, oxiranyl, pyrimidinyl, phenanthridines, phenanthrolines, phenarsazine, phenazines, phenothiazines, phenoxazines, phthalazine, pteridine, purinol, pyrazinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyrimidines, pyrimidinyl, pyrrolyl, hintline, chinoline, honokalani, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, triazinyl and triazolyl.

"Aralkyl" refers to a group of the formula-RaRbwhere Rarepresents an alkyl group as defined above, substituted by Rb, aryl group, as defined above, e.g. benzyl. As the alkyl and aryl group optionally can be substituted, as defined in this application.

"Heteroalkyl" refers to a group of the formula-RaRfwhere Rarepresents an alkyl group as defined above, and Rfis a heteroaryl group that is defined in this application. Alkyl group and heteroaryl group optionally can be substituted, as defined in this application.

"Geterotsiklicheskikh" refers to a group of the formula-RaRewhere Rarepresents an alkyl group as defined above, and Rerepresents heterocyclyl group that is defined in this application, where the alkyl group Racan be attached to any carbon atom or heteroa the WMD heterocyclyl group R e. Alkyl group and heterocyclyl group optionally can be substituted, as defined in this application.

"Alkoxycarbonyl" refers to a group having the formula-C(O)OR where R is alkyl, including lower alkyl.

The term "dioxocyclohexa as used in this application means a heterocyclic group containing two ring oxygen atom and two or more ring carbon atoms.

"Oxo" refers to a group =O, attached to the carbon atom.

"Thioalkyl" refers to a group having the formula-RhSRiwhere Rhrepresents a linear or branched alkylenes chain, and Rirepresents an alkyl or halogenated.

"Thioxo" refers to the group =S, attached to the carbon atom.

"IR50" refers to the amount, concentration or dosage of a particular test compound that provides 50% inhibition of a maximal response, such as cell growth or proliferation, measured using any in vitro or cellular analysis described in this application.

If not specified or not specifically described in the present description, it should be clear that the substitution can occur on any atom alkyl, alkenylphenol, alkenylphenol, cycloalkyl, heterocyclyl, aryl or heteroaryl g is uppy.

Pharmaceutically acceptable salts include, but are not limited to, salts of mineral acids, such as hydrochloride; and organic acid salts, such as, but not limited to, mesilate, Eilat, toilet, besylate, brasilit, camphorsulfonate, hydrobromide, phosphate, sulfate, triptorelin, acetate, benzoate, fumarate, malate, maleate, oxalate, succinate and tartrate.

As used in this application, and if not specified otherwise, the term "hydrate" means a compound that is represented in the present invention, or its salt, which, in addition, includes a stoichiometric or non-stoichiometric amount of water bound non-covalent intermolecular bonds.

As used in this application, and if not specified otherwise, the term "MES" means the MES, formed by the Association of one or more molecules of a solvent with a compound represented by the present invention. The term "MES" includes hydrates (e.g., monohydrate, dihydrate, trihydrate, tetrahydrate and the like).

As used in this application, "essentially pure" means a substance that looks quite homogeneous and does not contain impurities, which can be easily determined by standard methods of analysis, such as thin layer chromatography (TLC), gel electrophoresis, high performance liquid chromatogra the Oia (HPLC) and mass spectrometry (MS), used by experts in this field to assess such purity, or sufficiently pure so that additional cleaning can not detectable change of physical and chemical properties of substances, such as enzymatic and biological activity. The methods of cleaning compounds to obtain essentially chemically pure compounds known to specialists in this field. However, essentially chemically pure compound can be a mixture of stereoisomers. In such cases, additional cleaning can increase the specific activity of the connection.

Unless specifically stated otherwise, when the connection can take alternative tautomeric, regioisomeric and/or stereoisomeric form, it is assumed that all alternative isomers covered by the scope of the claimed invention. For example, when the connection is described as having one of the two tautomeric forms, it is assumed that both tautomer covered by the present invention. Thus, the compounds presented in this invention may be enantiomerically pure, or may be a stereoisomeric or diastereomeric mixture.

It should be clear that the compounds presented in this invention may contain chiral centers. Such chiral centers can be either (R)or (S) configuration, or it could be a mixture.

Optically active (+) and (-), (R)- and (S)- or (D)and (L)-isomers can be obtained using chiral synthesis or chiral reagents, or by separation using traditional methods such as reversed-phase HPLC or crystallization.

As used in this application, the term "enantiomerically pure" or "pure enantiomer" means that the compound includes more than 75 wt. -%, more than 80% of the mass, more than 85% wt., more than 90% of the mass, more than 91% of the mass, more than 92 wt. -%, more than 93 wt. -%, more than 94% of the mass, more than 95 wt. -%, more than 96% of the mass, more than 97 wt. -%, more than 98 wt. -%, more than 98.5% of mass., more than 99% of the mass, more than 99.2% of mass., more than 99.5% of the mass, and more than 99.6% of mass., more than 99.7% of mass., more than 99.8% of the mass. or more than 99.9% of the mass. the desired enantiomer.

When the amount of any present Deputy is not specified (for example, halogenated), may contain one or more substituents. For example, "halogenated" may include one or more identical or different from each other Halogens.

In this application the description, if there is any discrepancy between the chemical name and chemical structure, in this case, defining, preferably, is the structure.

As used in this application,the term "isotopic composition" refers to the amount of each present isotope for a given atom, and "natural isotopic composition" refers to naturally occurring isotopic composition or the relative isotopic composition for a given atom. Atoms with their natural isotopic composition, can also be specified as "raw" atoms. Unless otherwise stated, the atoms of the compounds described in this application represent any stable isotope of that atom. For example, unless otherwise stated, when a position specifically designated as "H" or "hydrogen", I mean that this provision includes the hydrogen at its natural isotopic composition.

As used in this application, the term "isotopically enriched" refers to the atom having the isotopic composition different from the natural isotopic composition of this atom. "Isotopically enriched" may also refer to a compound containing at least one atom having an isotopic composition different from the natural isotopic composition of the atom.

As used in this application, the term "isotopic enrichment" refers to the percentage of inclusion of a particular isotope in a given atom in the molecule instead of the natural isotopic composition of this atom. For example, the deuterium enrichment of 1% at the specified position means that 1% of the molecules in the sample contain deuterium at the specified position. Because the natural distribution is of deuterium is about 0,0156%, the enrichment of deuterium in any position in the compound synthesized using unenriched source substances, is about 0,0156%. The isotopic enrichment of the compounds presented in this invention, can be determined using conventional analytical methods, known to any specialist in this field, with average qualifications, including mass spectrometry and spectroscopy nuclear magnetic resonance.

"Anticancer funds" refers to anti-metabolites (for example, 5-fluoro-uracil, methotrexate, fludarabine), means against the formation of microtubules (e.g., Vinca alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel, docetaxel), alkylating agents (e.g. cyclophosphamide, melphalan, carmustine, means on the basis of nitrosamine, such as mechlorethamine and hydroxyurea), tools platinum-based (e.g., cisplatin, carboplatin, oxaliplatin, JM-216 or satraplatin, CI-973), anthracyclines (e.g., doxorubicin, daunorubicin), antitumor antibiotics (e.g., mitomycin, idarubitsin, adriamycin, daunomycin), topoisomerase inhibitors (e.g. etoposide, camptothecin), means against angiogenesis (e.g., Sutent® and Bevacizumab) or any other cytotoxic funds (estramustine phosphate, etc is nimustine), hormones or agonists, antagonists, partial agonists or partial antagonists hormones, inhibitors of kinases and radiation therapy.

"Anti-inflammatory agent" refers to inhibitors of matrix metalloproteinases, inhibitors of Pro-inflammatory cytokines (e.g., anti-TNF molecules, soluble receptors of TNF and IL1), nonsteroidal anti-inflammatory drugs (NSAID), such as inhibitors prostaglandins (e.g., choline magnesium salicylate, salicylsalicylic acid), inhibitors of COX-1 or COX-2) or glucocorticoid receptor agonists, such as corticosteroids, methylprednisone, prednisone or cortisone.

As used in this application, the abbreviations for any protective groups, amino acids and other compounds, unless otherwise stated, consistent with their normal use or are known abbreviations, including acronyms, which can be found in J. Org. Chem. 2007 72(1): 23A-24A, or the abbreviations established by IUPAC-IUB Commission on Biochemical Nomenclature (see Biochem. 1972, 77:942-944).

B. Connections

In this application presents the compounds of formula (I) or their pharmaceutically acceptable salt, solvate or hydrate, where

R1and R2selected from (i), (ii), (iii), (iv) and (v) and have the following meanings:

(i) R1and R2together form =O, =S, =NR9or =CR10R11;

(i) R 1and R2both are-OR8or R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;

(iii) R1represents hydrogen or halogen; and R2is a halogen;

(iv) R1represents alkyl, alkenyl, quinil, cycloalkyl or aryl, where alkyl, alkenyl, quinil, cycloalkyl or aryl optionally substituted by one or more substituents selected from halogen, alkyl, -RXORW, -RxS(O)qRv, -RxNRyRzand-C(O)ORW; and R2represents hydrogen, halogen or-OR8; and

(v) R1represents a halogen, -OR12, -NR13R14or-S(O)qR15; and R2represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl or aryl, where alkyl, alkenyl, quinil, cycloalkyl or aryl optionally substituted by one or more substituents selected from halogen, alkyl, -RXORW, -RxS(O)qRvand RxNRyRz;

R3represents hydrogen, halogen, alkyl, cyano, halogenated, cycloalkyl, cycloalkenyl, hydroxy or alkoxy;

R4and R5each independently represents hydrogen or alkyl; each R6independently selected from halogen, alkyl, alkenyl, quinil, halogenoalkane, is cloacina, -RXOR18and RXNR19R20; each R7independently represents halogen, alkyl, halogenated or-RXORW;

R8represents alkyl, alkenyl or quinil;

R9represents hydrogen, alkyl, halogenated, hydroxy, alkoxy or amino;

R10represents hydrogen or alkyl;

R11represents hydrogen, alkyl, halogenated or-C(O)OR8;

R12selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, -C(O)RV, -C(O)ORWand-C(O)NRyRzwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl and heteroaryl, each optionally substituted by one or more substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio;

R13and R14selected as follows:

(i) R13represents hydrogen or alkyl; and R14selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, alkoxy, -C(O)RV, -C(O)ORW, -C(O)NRyRzand-S(O)qRvwhere alkyl, alkenyl, Ala the Nile, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaryl, each optionally substituted by one or more substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio; or

(ii) R13and R14together with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl where heterocyclyl or heteroaryl optionally substituted by one or more substituents, independently selected from halogen, alkyl, hydroxy, alkoxy, amino, alkylthio, and where heterocyclyl also optionally substituted by oxo group;

R15represents alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, -C(O)NRyRzor-NRyRzwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaryl, each optionally substituted by one or more substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio;

R18represents hydrogen, alkyl, halogenated, hydroxys2-6alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaromatic; where R18optionally substituted by 1-3 groups Q1every Q1independently selected from alkyl, hydroxyl, halogen, halogenoalkane, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, carboxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogenfree and amino;

R19and R20selected as follows:

(i) R19and R20each independently represents hydrogen or alkyl; or

(ii) R19and R20together with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl, which is optionally substituted by 1-2 groups, each of which is independently selected from halogen, alkyl, halogenoalkane, hydroxyl and alkoxy;

each Rxindependently represents alkylene or a simple bond;

Rvrepresents alkyl, alkenyl or quinil;

Rwindependently represents hydrogen, alkyl, alkenyl, quinil or halogenated;

Ryand Rzselected as follows:

(i) Ryand Rzeach independently represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl or halogenated;

(ii) Ryand Rztogether with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl, which is optionally substituted by 1-2 groups, each of which is independently selected from halogen, alkyl, halogenoalkane, hydroxyl and alkoxy;

n has a value of 0-4;

p has a value of 0-5; and

each q, independently, is 0, 1 or 2.

In some embodiments, embodiments in the present application is represented by the compounds of formula (II)

or their pharmaceutically acceptable salt, solvate or hydrate, where R1and R2selected from (i), (ii), (iii), (iv) and (v) and have the following meanings:

(i) R1and R2together form =O, =S, =NR9or =CR10R11;

(ii) R1and R2both are-OR8or R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;

(iii) R1represents hydrogen or halogen, and R2is a halogen;

(iv) R1represents alkyl, alkenyl, quinil, cycloalkyl or aryl, where alkyl, alkenyl, quinil, cycloalkyl or aryl optionally substituted by one or more substituents selected from halogen, alkyl, -RXORW, -RxS(O)qRvand RxNRyRzand R2represents hydrogen, halogen, and-OR8; and

(v) R1represents a halogen, -OR12, -NR13R14, -S(O)qR15or-R17C(O)OR12and R2represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl or aryl, where alkyl, alkenyl, quinil, cycloalkyl or aryl is obazatelno substituted by one or more substituents, selected from halogen, alkyl, -RXORW, -RxS(O)qRvand RxNRyRz;

R3represents hydrogen, alkyl or cycloalkyl,

R4and R5each independently represents hydrogen or alkyl;

R6a, R6b, R6cand R6deach independently selected from hydrogen, halogen, alkyl, halogenoalkane, RxS(O)qRvand RXOR18; each R7independently represents halogen, alkyl, halogenated or-RXORW;

R8represents alkyl, alkenyl or quinil;

R9represents hydrogen, alkyl, halogenated, hydroxy, alkoxy or amino;

R10represents hydrogen or alkyl;

R11represents hydrogen, alkyl, halogenated or-C(O)OR8; each R12independently represents hydrogen, alkyl, halogenated, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, geterotsiklicheskikh or-C(O)NRyRz;

R13and R14selected as follows:

(i) R13represents hydrogen or alkyl, and R14selected from hydrogen, alkyl, halogenoalkane, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, geterotsiklicheskikh, -C(O)RV, -C(O)ORW, -C(O)NRyRzand-S(O)qRv; or

(ii) R13and R14together with the volume of nitrogen, with which they are linked, form heterocyclyl, optional zameshannyj one or more substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio;

R15selected from hydrogen, alkyl, halogenoalkane, hydroxyalkyl, alkoxyalkyl, aminoalkyl, thioalkyl, geterotsiklicheskikh, -C(O)NRyRzor-NRyRz;

R18represents hydrogen, alkyl, halogenated, hydroxyalkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaromatic; where R18optionally substituted by 1-3 groups Q1every Q1independently selected from alkyl, hydroxyl, halogen, halogenoalkane, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, carboxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogenfree and amino;

Rvrepresents hydrogen, alkyl, alkenyl or quinil;

each Rxindependently represents alkylene or a simple bond;

Rwindependently represents hydrogen or alkyl;

Ryand Rzselected as follows:

(i) Ryand Rzeach independently represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl or halogenated;

(ii) Ryand Rztogether with the nitrogen atom to which they are connected, is formed will heterocyclyl or heteroaryl, which is optionally substituted by 1-2 groups, each of which is independently selected from halogen, alkyl, halogenoalkane, hydroxyl and alkoxy; and each q, independently, is 0, 1 or 2.

In some embodiments, embodiments in the present application is represented by the compounds of formula (III) or (IIIa)

their pharmaceutically acceptable salt, solvate or hydrate, where

R3represents hydrogen, alkyl, halogenated or cycloalkyl;

each R6independently selected from halogen, alkyl, halogenoalkane, -RxS(O)qRvand RXOR18;

each R7independently represents halogen, alkyl, halogenated or-RXORW;

p is 1 or 2;

other variables have the meaning given in this application.

In some embodiments, embodiments in the present application is represented by the compounds of formula (III), (IIIa) or their pharmaceutically acceptable salt, solvate or hydrate, where

R3represents hydrogen, alkyl, halogenated or cycloalkyl;

each R6independently selected from halogen, alkyl, halogenoalkane, -RxS(O)qRvand RXOR18;

each R7independently represents halogen, alkyl, halogenated or-RXORW;

other variables have the meaning assigned to the present application.

In some embodiments, embodiments in the present application is represented by the compounds of formula (III), (IIIa) or their pharmaceutically acceptable salt, solvate or hydrate, where

R3represents hydrogen or alkyl or cycloalkyl;

each R6independently selected from halogen, alkyl, halogenoalkane and RXOR18;

each R7independently represents halogen, alkyl, halogenated or-RXORW;

other variables have the meaning given in this application.

In some embodiments, embodiments in the present application is represented by the compounds of formula (III), (IIIa) or their pharmaceutically acceptable salt, solvate or hydrate, where

R3represents hydrogen or alkyl;

each R6independently selected from halogen, alkyl, alkenyl, quinil, halogenoalkane, cycloalkyl, -RXOR18, -RxS(O)qRvand RXNR19R20;

each R7independently represents halogen, alkyl, halogenated or-RXORW;

p has a value of 1;

other variables have the meaning given in this application.

In some embodiments, embodiments in the present application is represented by the compounds of formula (III), (IIIa) or their pharmaceutically acceptable salt, solvate or hydrate, where

R3represents hydrogen or Ala is l;

each R6independently selected from halogen, alkyl, halogenoalkane and RXOR18;

each R7independently represents halogen, alkyl, halogenated or-RXORW;

other variables have the meaning given in this application.

In some embodiments, embodiments in the present application is represented by the compounds of formula (III), (IIIa) or their pharmaceutically acceptable salt, solvate or hydrate, where

R3represents hydrogen, alkyl or halogenated;

each R6independently selected from halogen, alkyl, halogenoalkane, -RxS(O)qRvand RXOR18;

each R7independently represents halogen, alkyl, halogenated or-RXORW;

other variables have the meaning given in this application.

In some embodiments, embodiments in the present application is represented by the compounds of formula (III), (IIIa) or their pharmaceutically acceptable salt, solvate or hydrate, where

R3represents hydrogen, alkyl, cycloalkyl, hydroxyl or alkoxy;

each R6independently selected from halogen, alkyl, halogenoalkane and RXOR18;

each R7independently represents halogen, alkyl, halogenated or-RXORW;

other variables have the meaning given in the present is awke.

In some embodiments, embodiments in the present application is represented by the compounds of formula (III), (IIIa) or their pharmaceutically acceptable salt, solvate or hydrate, where

R3represents hydrogen, alkyl, cycloalkyl, hydroxyl or alkoxy;

each R6independently selected from halogen, alkyl, alkenyl, quinil, halogenoalkane, cycloalkyl, -RXOR18and RXNR19R20;

each R7independently represents halogen, alkyl, halogenated or-RXORW;

other variables have the meaning given in this application.

In one variant embodiment, R1and R2selected from (i), (ii), (iii), (iv) and (v) and have the following meanings:

(i) R1and R2together form =O, =S, =NR9or =CR10R11;

(ii) R1and R2both represent alkoxy, or R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;

(iii) R1represents hydrogen or halogen; and R2is a halogen; and

(iv) R1represents alkyl, alkenyl, quinil or cycloalkyl, where the alkyl, alkenyl, quinil or cycloalkyl substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three batch is italiani, selected from halogen, cyano, alkyl, -RXORW, -RxS(O)qRv, -RxNRyRzand-C(O)ORW; and R2represents hydrogen, halogen or hydroxy; and

(v) R1represents halogen, deutero, hydroxy or amino; and R2represents hydrogen, deutero, alkyl, alkenyl, quinil or cycloalkyl, where the alkyl, alkenyl, quinil or cycloalkyl, optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents selected from halogen, cyano, alkyl, -RXORW, -RxS(O)qRvand RxNRyRz;

other variables have the meaning given in this application.

In other variant embodiments, R1and R2selected from (i), (ii), (iii), (iv) and (v) and have the following meanings:

(i) R1and R2together form =O;

(ii) R1and R2both represent alkoxy, or R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;

(iii) R1represents hydrogen or halogen; and R2is a halogen; and

(iv) R1represents alkyl, alkenyl, quinil or cycloalkyl, where the alkyl, alkenyl, quinil or cycloalkyl substituted one is m or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents selected from halogen, cyano, alkyl, -RXORW, -RxS(O)qRv, -RxNRyRzand-C(O)ORW; and R2represents hydrogen, halogen or hydroxy; and

(v) R1represents halogen, deutero, hydroxy or amino; and R2represents hydrogen, deutero, alkyl, alkenyl, quinil or cycloalkyl, where the alkyl, alkenyl, quinil or cycloalkyl, optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents selected from halogen, cyano, alkyl, -RXORW, -RxS(O)qRvand RxNRyRz;

other variables have the meaning given in this application.

In one variant embodiment, R1and R2selected from (i), (ii), (iii), (iv) and (v) and have the following meanings:

(i) R1and R2together form =O, =S, =NR9or =CR10R11;

(ii) R1and R2both represent alkoxy, or R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;

(iii) R1represents water is od or halogen and R 2is a halogen;

(iv) R1represents alkyl, alkenyl, quinil, cycloalkyl or aryl and R2represents hydrogen, halogen, hydroxy and alkoxy; and

(v) R1represents deutero, hydroxyl, alkoxy, amino, alkoxycarbonyl or-NHC(O)H and R2represents hydrogen, deutero, alkyl, aryl or halogenared.

In one variant embodiment, R1and R2selected from (i), (ii), (iii), (iv) and (v) and have the following meanings:

(i) R1and R2together form =O, =S, =NR9or =CR10R11;

(ii) R1and R2both represent alkoxy, or R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;

(iii) R1represents hydrogen or halogen, and R2is a halogen;

(iv) R1represents alkyl, alkenyl, quinil, cycloalkyl or aryl, and R2represents hydrogen, halogen, hydroxy and alkoxy; and

(v) R1represents a hydroxyl, alkoxy, amino or alkoxycarbonyl, and R2represents hydrogen, alkyl, aryl or halogenared.

In one variant embodiment, R1and R2selected from (i), (ii), (iii), (iv) and (v) and have the following meanings:

(i) R1and R2together form =O, =S, =NR9or =CR10R11;

(ii) R1and R both represent alkoxy, or R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;

(iii) R1represents hydrogen or halogen, and R2is a halogen;

(iv) R1represents alkyl, cianelli, alkenyl, quinil, cycloalkyl or aryl, and R2represents hydrogen, halogen, hydroxy and alkoxy; and

(v) R1represents a hydroxyl, alkoxy, amino or alkoxycarbonyl, and R2represents hydrogen, alkyl, aryl or halogenared.

In one variant embodiment, R1and R2selected from (i), (ii), (iii) and (iv) and shall have the following meanings:

(i) R1and R2together form =O;

(ii) R1and R2both represent alkoxy, or R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;

(iii) R1represents hydrogen or halogen, and R2is a halogen; and

(iv) R1represents a hydroxyl, alkoxy, amino or alkoxycarbonyl, and R2represents hydrogen, alkyl, aryl or halogenared.

In one variant embodiment, R1and R2together form =O.

In one variant embodiment, R1represents hydrogen, halogen or deutero, and R2represents a halogen or dei the EPO.

In one variant embodiment, R1and R2selected from (i), (ii), (iii) and (iv) and shall have the following meanings:

(i) R1and R2together form =O;

(ii) R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;

(iii) R1represents hydrogen or halogen; and R2is a halogen; and

(iv) R1represents halogen, deutero or hydroxyl, and R2represents hydrogen or deutero;

where other variables have the meaning given in this application.

In one variant embodiment, R1and R2selected from (i) and (ii) and shall have the following meanings:

(i) R1and R2both represent alkoxy, or R1and R2together form =O; and

(ii) R1represents hydroxyl, -OR12or-NR13R14; and R2represents hydrogen, alkyl, aryl or halogenared;

R12selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, -C(O)RV, -C(O)ORWand-C(O)NRyRzwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl and heteroaryl, each optionally substituted by one or more substituents independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio;

R13and R14selected as follows:

(i) R13represents hydrogen or alkyl, and R14selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, alkoxy, -C(O)RV, -C(O)ORW, -C(O)NRyRzand-S(O)qRvwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaryl, each optionally substituted by one or more substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio; or

(ii) R13and R14together with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl where heterocyclyl or heteroaryl optionally substituted by one or more substituents, independently selected from halogen, alkyl, hydroxy, alkoxy, amino, alkylthio, and where heterocyclyl also optionally substituted by oxo group;

Rvrepresents hydrogen, alkyl, alkenyl or quinil;

Rwindependently represents hydrogen, alkyl, alkenyl, quinil or halogenated;

Ryand Rzselected as follows:

(i) Ryand Rzeach independently represents the t of a hydrogen, alkyl, alkenyl, quinil, cycloalkyl or halogenated;

(ii) Ryand Rztogether with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl, which is optionally substituted by 1-2 groups, each of which is independently selected from halogen, alkyl, halogenoalkane, hydroxyl and alkoxy; and each q, independently, is 0, 1 or 2.

In one variant embodiment, R1and R2selected from (i) and (ii) and shall have the following meanings:

(i) R1and R2both represent alkoxy, or R1and R2together form =O; and

(ii) R1represents hydroxyl, -OR12or-NR13R14; and R2represents hydrogen, alkyl, aryl or halogenared;

R12selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, -C(O)RV, -C(O)ORWand-C(O)NRyRzwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaryl, each optionally substituted by one or more substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio;

R13and R14selected as follows:

(i) R13represents hydrogen or alkyl, in which R 14selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, alkoxy, -C(O)RV, -C(O)ORW, -C(O)NRyRzand-S(O)qRvwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaryl, each optionally substituted by one or more substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio; or

(ii) R13and R14together with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl where heterocyclyl or heteroaryl optionally substituted by one or more substituents, independently selected from halogen, alkyl, hydroxy, alkoxy, amino, alkylthio, and where heterocyclyl also optionally substituted by oxo group;

Rvrepresents alkyl, alkenyl or quinil;

Rwindependently represents hydrogen, alkyl, alkenyl, quinil or halogenated;

Ryand Rzselected as follows:

(i) Ryand Rzeach independently represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl or halogenated;

(ii) Ryand Rztogether with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl, which is optionally substituted by 1-2 groups, each of which is independently selected from halogen, alkyl, halogenoalkane, hydroxyl and alkoxy; and each q, independently, is 0, 1 or 2.

In other variant embodiments, R12represents hydrogen or alkyl; R13represents hydrogen or alkyl, and R14represents alkyl, cycloalkyl, -C(O)Rvor-C(O)ORWwhere Rvand Rweach independently represents hydrogen or alkyl.

In other variant embodiments, R12represents hydrogen or alkyl; R13represents hydrogen or alkyl, and R14represents alkyl, cycloalkyl or-C(O)ORWwhere Rvand Rweach independently represents hydrogen or alkyl.

In one variant embodiment, R1and R2selected from (i), (ii) and (iii) and shall have the following meanings:

(i) R1and R2together form =O;

(ii) R1and R2both represent alkoxy; and

(iii) R1represents hydroxy or alkoxy, and R2represents hydrogen.

In one variant embodiment, R1and R2selected from (i) and (ii) and shall have the following meanings:

(i) R1and R2together form =O; and

(ii) R1represents hydroxy or alkoxy, and R2represents hydrogen.

In one of variantology, R1represents-OR12or-NR13R14and R2represents hydrogen, where R12selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, -C(O)RV, -C(O)ORWand-C(O)NRyRzwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl and heteroaryl, each optionally substituted by one or more substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio;

R13and R14selected as follows:

(i) R13represents hydrogen or alkyl, and R14selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, alkoxy, -C(O)RV, -C(O)ORW, -C(O)NRyRzand-S(O)qRvwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaryl, each optionally substituted by one or more substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio; or

(ii) R13and R14together with the nitrogen atom, to which m they are connected, form heterocyclyl or heteroaryl where heterocyclyl and heteroaryl optionally substituted by one or more substituents, independently selected from halogen, alkyl, hydroxy, alkoxy, amino, alkylthio, and where heterocyclyl also optionally substituted by oxo group;

Rvrepresents alkyl, alkenyl or quinil;

Rwindependently represents hydrogen, alkyl, alkenyl, quinil or halogenated;

Ryand Rzselected as follows:

(i) Ryand Rzeach independently represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl or halogenated;

(ii) Ryand Rztogether with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl, which is optionally substituted by 1-2 groups, each of which is independently selected from halogen, alkyl, halogenoalkane, hydroxyl and alkoxy; and each q, independently, is 0, 1 or 2.

In other variant embodiments, R12represents hydrogen or alkyl; R13and R14selected as follows:

(i) R13represents hydrogen or alkyl, and R14represents alkyl, cycloalkyl or-C(O)ORW; or

(ii) R13and R14together with the nitrogen atom to which they are bound, form heterocyclyl.

In other variant embodiments, R12is dared or alkyl; R13represents hydrogen or alkyl, and R14represents alkyl, cycloalkyl, -C(O)Rvor-C(O)ORWwhere Rvand Rweach independently represents hydrogen or alkyl.

In other variant embodiments, R12represents hydrogen or alkyl; R13represents hydrogen or alkyl, and R14represents alkyl, cycloalkyl or-C(O)ORW. In one variant embodiment, R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa.

In one variant embodiment, R1represents hydrogen or halogen, and R2represents a halogen. In one variant embodiment, R1represents hydrogen or fluorine, and R2represents fluorine. In one variant embodiment, R1represents fluorine, and R2represents fluorine.

In one variant embodiment, R1represents a hydroxyl, alkoxy, amino or alkoxycarbonyl, and R2represents hydrogen, alkyl, aryl or halogenared. In one variant embodiment, R1represents a hydroxyl or alkoxy, and R2represents hydrogen. In one variant embodiment, R1represents hydroxyl, and R2represents hydrogen. In one variant embodiment, R1represents the t an alkoxy, and R2represents hydrogen. In one variant embodiment, R1represents hydroxyl, methoxy, amino or methoxycarbonylamino, and R2represents hydrogen, phenyl or forfinal.

In one variant embodiment, R3represents hydrogen, alkyl, cycloalkyl or alkoxy. In other variant embodiments, R3represents hydrogen, alkyl or cycloalkyl. In one variant embodiment, R3represents hydrogen, alkyl or alkoxy. In the following variant embodiment, R3represents hydrogen or alkyl. In other variant embodiments, R3represents hydrogen or methyl. In one variant embodiment, R3represents hydrogen, methyl or cyclopropyl.

In one variant embodiment, R3represents alkyl, cycloalkyl or cyano. In one variant embodiment, R3represents methyl, cyclopropyl or cyano. In one variant embodiment, R3represents an alkyl or cycloalkyl. In one variant embodiment, R3represents methyl or cyclopropyl.

In one variant embodiment, each R6independently selected from halogen, alkyl, alkenyl, quinil, halogenoalkane, cycloalkyl and-OR18where R18represents hydrogen, alkyl, halogenated, hydroxyalkyl, alkenyl, quinil, qi is loukil, cycloalkenyl, heterocyclyl or geterotsiklicheskikh; where R18optionally substituted by 1-3 groups Q1every Q1independently selected from alkyl, hydroxyl, cyano, halogen, halogenoalkane, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, carboxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogenfree and amino.

In one variant embodiment, each R6independently selected from halogen, alkyl, alkenyl, quinil, halogenoalkane, hydroxyalkyl; cycloalkyl, -RxS(O)qRvand-OR18where Rxrepresents a simple bond or alkylene; Rvrepresents hydrogen or alkyl; q is 1 or 2; R18represents hydrogen, alkyl, halogenated, hydroxyalkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl or geterotsiklicheskikh; where R18optionally substituted by 1-3 groups Q1every Q1independently selected from alkyl, hydroxyl, halogen, halogenoalkane, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, carboxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogenfree and amino.

In one variant embodiment, each R6independently selected from halogen, alkyl, halogenoalkane and-OR18; where R18represents hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, geterotsiklicheskikh or heterocy is poured, where R18optionally substituted by 1-3 groups Q1every Q1independently selected from alkyl, hydroxyl, halogen, halogenoalkane, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, carboxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogenfree and amino. In one variant embodiment, R18represents hydrogen, alkyl, halogenated, hydroxys2-6alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaromatic; where R18optionally substituted by 1-3 groups Q1every Q1independently selected from alkyl, hydroxyl, halogen, halogenoalkane, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, carboxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogenfree and amino.

In one variant embodiment, each R6independently selected from halogen, alkyl, halogenated and RXOR18; where R18represents hydrogen, alkyl, halogenated, hydroxyalkyl or heterocyclyl; where R18optionally substituted by a group Q1where Q1selected from hydroxyl, cyano, alkoxy, alkoxycarbonyl, carboxyl, heterocyclyl and amino. In one variant embodiment, R18represents hydrogen or alkyl. In other variant embodiments, R18is ogorodili methyl.

In one variant embodiment, each R6independently selected from hydrogen, alkyl, halogen, hydroxy or alkoxy. In one variant embodiment, each R6independently selected from fluorine, iodine, methyl, trifloromethyl and-OR18; where R18represents hydrogen, methyl, hydroxyethyl, hydroxypropyl, morpholinoethyl, methoxyethyl, tert-butyloxycarbonyl, carboxymethyl or piperidinyl.

In one variant embodiment, R6arepresents a hydrogen or halogen. In one variant embodiment, R6brepresents hydrogen or alkoxy. In one variant embodiment, R6crepresents hydrogen, halogen, alkyl, halogenated, -RxOR18, -RxS(O)qRvwhere Rxrepresents a simple bond or alkylene; Rvrepresents hydrogen or alkyl; q is 1 or 2; R18represents hydrogen, alkyl, halogenated, hydroxyalkyl or heterocyclyl; where R18optionally substituted by a group Q1where Q1selected from hydroxy, alkoxy, alkoxycarbonyl, carboxyl, heterocyclyl and amino. In one variant embodiment, R6crepresents hydrogen, halogen, alkyl, hydroxy or alkoxy. In one variant embodiment, R6drepresents a hydrogen or halogen.

In one variant embodiment, R6aisone hydrogen or halogen. In one variant embodiment, R6brepresents hydrogen or alkoxy. In one variant embodiment, R6crepresents hydrogen, halogen, alkyl, halogenated, -RxOR18; where R18represents hydrogen, alkyl, halogenated, hydroxyalkyl or heterocyclyl; where R18optionally substituted by a group Q1where Q1selected from hydroxy, alkoxy, alkoxycarbonyl, carboxyl, heterocyclyl and amino. In one variant embodiment, R6crepresents hydrogen, halogen, alkyl, hydroxy or alkoxy. In one variant embodiment, R6drepresents a hydrogen or halogen.

In one variant embodiment, R6arepresents a hydrogen or halogen. In one variant embodiment, R6arepresents a hydrogen or fluorine. In one variant embodiment, R6brepresents hydrogen or methoxy. In one variant embodiment, R6crepresents hydrogen, fluorine, iodine, methyl, trifluoromethyl or-OR18; where R18represents hydrogen, methyl, hydroxyethyl, hydroxypropyl, morpholinoethyl, methoxyethyl, tert-butyloxycarbonyl, carboxymethyl or piperidinyl. In one variant embodiment, R6drepresents a hydrogen or fluorine.

In one variant embodiment, each R7independently represents halogen, alkyl, Gal is penalcol or-R XORWwhere Rwrepresents hydrogen or alkyl. In one variant embodiment, each R7independently represents a fluorine or methoxy. In one variant embodiment, R7represents a halogen. In one variant embodiment, R7represents fluorine.

In one variant embodiment, Rxrepresents a simple bond. In one variant embodiment, n has a value of 0-4. In one variant embodiment, n is 0, 1, 2 or 3. In one variant embodiment, n has a value of 1. In one variant embodiment, n is 0. In one variant embodiment, n is set to 2. In one variant embodiment, p is 0, 1 or 2. In one variant embodiment, p is 1 or 2. In one variant embodiment, p is set to 1.

In some embodiments, embodiments in the present application is represented by the compounds of formula (III) or (IIIa), where

R1and R2selected from (i), (ii), (iii) and (iv) and shall have the following meanings:

(i) R1and R2together form =O;

(ii) R1and R2both represent-OR8or R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;

(iii) R1represents hydrogen or halogen, and R2is a halogen; and

(iv) R1represents a hydroxyl, alkoxy, cianelli,amino, alkoxycarbonyl or-NHC(O)H, and R2represents hydrogen, alkyl, aryl or halogenared;

R3represents hydrogen or alkyl; each R6independently selected from halogen, alkyl, halogenoalkane and RxOR18; where R18represents hydrogen, alkyl, halogenated, hydroxyalkyl or heterocyclyl; where R18optionally substituted by a group Q1where Q1selected from hydroxyl, alkoxy, alkoxycarbonyl, carboxyl, heterocyclyl and amino; each R7independently represents halogen, alkyl, halogenated, hydroxy or alkoxy; and

R8represents alkyl, alkenyl or quinil.

In some embodiments, embodiments in the present application is represented by the compounds of formula (III) or (IIIa), where

R1and R2selected from (i), (ii), (iii) and (iv) and shall have the following meanings:

(i) R1and R2together form =O;

(ii) R1and R2both represent-OR8or R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;

(iii) R1represents hydrogen or halogen, and R2is a halogen; and

(iv) R1represents a hydroxyl, alkoxy, amino or alkoxycarbonyl, and R2represents hydrogen, alkyl, aryl or halogenared; R3is own the th hydrogen or alkyl; each R6independently selected from halogen, alkyl, halogenoalkane and RxOR18; where R18represents hydrogen, alkyl, halogenated, hydroxyalkyl or heterocyclyl; where R18optionally substituted by a group Q1, Q1selected from hydroxyl, alkoxy, alkoxycarbonyl, carboxyl, heterocyclyl and amino; each R7independently represents halogen, alkyl, halogenated, hydroxy or alkoxy; and R8represents alkyl, alkenyl or quinil.

In some embodiments, embodiments in the present application is represented by the compounds of formula (III) or (IIIa), where

R1and R2selected from (i), (ii) and (iii) and shall have the following meanings:

(i) R1and R2together form =O;

(ii) R1represents hydrogen or halogen, and R2is a halogen; and

(iii) R1represents a hydroxyl, alkoxy, amino, -NHCH(O) or alkoxycarbonyl, and R2represents hydrogen or alkyl; R3represents hydrogen or alkyl; each R6independently selected from halogen, alkyl, halogenoalkane, -RXOR18and RxS(O)qRvwhere Rxrepresents a simple bond or alkylene; Rvrepresents hydrogen or alkyl; q is set to 2; R18represents hydrogen, alkyl, halogenated, hydroxyalkyl is or heterocyclyl; where R18optionally substituted by a group Q1, Q1selected from hydroxyl, alkoxy, alkoxycarbonyl, carboxyl, heterocyclyl and amino; R7is a halogen; and p has the value 1.

In some embodiments, embodiments in the present application is represented by the compounds of formula (III) or (IIIa), where

R1and R2selected from (i), (ii) and (iii) and shall have the following meanings:

(i) R1and R2together form =O;

(ii) R1represents hydrogen or halogen, and R2is a halogen; and

(iii) R1represents a hydroxyl, alkoxy, amino, -NHCH(O) or alkoxycarbonyl, and R2represents hydrogen or alkyl;

R3represents hydrogen or alkyl;

each R6independently selected from halogen, alkyl, halogenoalkane, -RXOR18and RxS(O)qRvwhere Rxrepresents a simple bond or alkylene; Rvrepresents alkyl; q is set to 2; R18represents hydrogen, alkyl, halogenated, hydroxyalkyl or heterocyclyl; where R18optionally substituted by a group Q1where Q1selected from hydroxyl, alkoxy, alkoxycarbonyl, carboxyl, heterocyclyl and amino;

R7is a halogen; and

p has a value of 1.

In some embodiments, in the present embodiment C is the turnout represented by the compounds of formula (IV) or (IVa)

or their pharmaceutically acceptable salt, solvate or hydrate, where the variables have the meanings given in this application. In one variant embodiment, R7represents a halogen. In one variant embodiment, R7represents fluorine.

In some embodiments, embodiments in the present application is represented by the compounds of formula (V) or (Va)

or their pharmaceutically acceptable salt, solvate or hydrate, where the variables have the meanings given in this application. In some embodiments, embodiments in the present application is represented by the compounds of formula (V) or (Va), where

R1and R2selected from (i), (ii) and (iii) and shall have the following meanings:

(i) R1and R2together form =O;

(ii) R1represents hydrogen or halogen, and R2is a halogen; and

(iii) R1represents a hydroxyl, alkoxy, amino, -NHCH(O) or alkoxycarbonyl, and R2represents hydrogen or alkyl;

R3represents hydrogen or alkyl; and

R4represents hydrogen;

R5represents hydrogen;

R6selected from halogen, alkyl, halogenoalkane, -RXOR18and RxS(O)qRvwhere Rxrepresents a simple bond or alkylene; R vrepresents alkyl; q is set to 2; R18represents hydrogen, alkyl, halogenated, hydroxyalkyl or heterocyclyl; where R18optionally substituted by a group Q1where Q1selected from hydroxyl, alkoxy, alkoxycarbonyl, carboxyl, heterocyclyl and amino.

In some embodiments, embodiments in the present application is represented by the compounds of formula (VI)

or their pharmaceutically acceptable salt, solvate or hydrate, where the variables have the meanings given in this application. In one variant embodiment, R1represents a hydroxyl, amino, alkoxy or alkoxycarbonyl; R2represents hydrogen, halogen or halogenared; each R6independently selected from halogen, alkyl, halogenoalkane, -RxS(O)qRvand RXOR18; where Rxrepresents a simple bond or alkylene; Rvrepresents hydrogen or alkyl; q is 1 or 2; R18represents hydrogen, alkyl, halogenated, hydroxyalkyl or heterocyclyl; R18optionally substituted by a group Q1selected from hydroxyl, alkoxy, alkoxycarbonyl, carboxyl, heterocyclyl and amino; n is 0 or 1; and R3represents hydrogen or alkyl. In one variant embodiment, R1the stand is made by a hydroxyl; and R2represents hydrogen; n is 0, and R3represents alkyl.

In some embodiments, embodiments in the present application is represented by the compounds of formula (VII)

or their pharmaceutically acceptable salt, solvate or hydrate, where the variables have the meanings given in this application. In one variant embodiment, each R6independently selected from halogen, alkyl, halogenoalkane, -RxS(O)qRvand RXOR18; where Rxrepresents a simple bond or alkylene; Rvrepresents hydrogen or alkyl; q is 1 or 2; where R18represents hydrogen, alkyl, halogenated, hydroxyalkyl or heterocyclyl; R18optionally substituted by a group Q1selected from hydroxyl, alkoxy, alkoxycarbonyl, carboxyl, heterocyclyl and amino; n is 0 or 1; each R7independently represents halogen, alkyl, halogenated, hydroxy or alkoxy; p is 1; and R3represents hydrogen, alkyl or alkoxy.

In some embodiments, embodiments in the present application is represented by the compounds of formula (VII) or their pharmaceutically acceptable salt, solvate or hydrate, where n has the value 0, and the other variables have the meaning given in this application.

In n which are variants of the embodiments in the present application is represented by the compounds of formula (VIII)

or their pharmaceutically acceptable salt, solvate or hydrate, where the variables have the meanings given in this application. In one variant embodiment, each R6independently selected from halogen, alkyl, halogenoalkane, -RxS(O)qRvand RXOR18; where Rxrepresents a simple bond or alkylene; Rvrepresents hydrogen or alkyl; q is 1 or 2; where R18represents hydrogen, alkyl, halogenated, hydroxyalkyl or heterocyclyl; R18optionally substituted by a group Q1selected from hydroxyl, alkoxy, alkoxycarbonyl, carboxyl, heterocyclyl and amino; n is 0 or 1; each R7independently represents halogen, alkyl, halogenated, hydroxy or alkoxy; p is 1; and R3represents hydrogen, alkyl or cycloalkyl.

In some embodiments, embodiments in the present application is represented by the compounds of formula (IX)

or their pharmaceutically acceptable salt, solvate or hydrate, where the variables have the meanings given in this application. In one variant embodiment, each R6independently selected from halogen, alkyl, halogenoalkane, -RxS(O)qRvand RXOR18; where Rxis simply the second link or alkylene; Rvrepresents hydrogen or alkyl; q is 1 or 2; where R18represents hydrogen, alkyl, halogenated, hydroxyalkyl or heterocyclyl; R18optionally substituted by a group Q1selected from hydroxyl, alkoxy, alkoxycarbonyl, carboxyl, heterocyclyl and amino; n is 0 or 1; each R7independently represents halogen, alkyl, halogenated, hydroxy or alkoxy; p is 1; and R3represents hydrogen or alkyl. In one variant embodiment, the present application presents the compounds of formula (IX) or pharmaceutically acceptable salt, solvate or hydrate, where R3represents alkyl; R7is a halogen; n has a value of 0, and p has a value of 1.

In some embodiments, embodiments in the present application is represented by the compounds of formula (X)

or their pharmaceutically acceptable salt, solvate or hydrate, where the variables have the meanings given in this application. In one variant embodiment, each R6independently selected from halogen, alkyl, halogenoalkane, -RxS(O)qRvand RXOR18; where Rxrepresents a simple bond or alkylene; Rvrepresents hydrogen or alkyl; q is 1 or 2; where R18is the battle hydrogen, alkyl, halogenated, hydroxyalkyl or heterocyclyl; R18optionally substituted by a group Q1selected from hydroxyl, alkoxy, alkoxycarbonyl, carboxyl, heterocyclyl and amino; n is 0 or 1; each R7independently represents halogen, alkyl, halogenated, hydroxy or alkoxy; p is 1; and R3represents hydrogen or alkyl.

In some embodiments, embodiments in the present application is represented by the compounds of formula (XI)

or their pharmaceutically acceptable salt, solvate or hydrate, where R1and R2selected from (i), (ii), (iii), (iv) and (v) and have the following meanings:

(i) R1and R2together form =O, =S, =NR9or =CR10R11;

(ii) R1and R2both are-OR8or R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;

(iii) R1represents hydrogen or halogen; and R2is a halogen; and

(iv) R1represents alkyl, alkenyl, quinil, cycloalkyl or aryl, where alkyl, alkenyl, quinil, cycloalkyl or aryl optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituent and, selected from halogen, cyano, alkyl, -RXORW, -RxS(O)qRv, -RxNRyRzand-C(O)ORW; and R2represents hydrogen, halogen or-OR8; and

(v) R1represents halogen, deutero, -OR12, -NR13R14or-S(O)qR15; and R2represents hydrogen, deutero, alkyl, alkenyl, quinil or cycloalkyl, where the alkyl, alkenyl, quinil or cycloalkyl optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents selected from halogen, cyano, alkyl, -RXORW, -RxS(O)qRvand RxNRyRz;

R3represents halogen, alkyl, halogenated, hydroxy or alkoxy;

R4and R5each independently represents hydrogen or alkyl;

R6a, R6b, R6cand R6deach independently selected from hydrogen, halogen, alkyl, alkenyl, quinil, halogenoalkane, cycloalkyl, -RXOR18, -RXNR19R20and RxS(O)qRv; each R7independently represents halogen, alkyl, halogenated or-RXORW;

R8represents alkyl, alkenyl or quinil;

R9is the Wallpaper hydrogen, alkyl, halogenated, hydroxy, alkoxy or amino;

R10represents hydrogen or alkyl;

R11represents hydrogen, alkyl, halogenated or-C(O)OR8;

R12selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, -C(O)RV, -C(O)ORWand-C(O)NRyRzwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl and heteroaryl, each optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio;

R13and R14selected as follows:

(i) R13represents hydrogen or alkyl; and R14selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, alkoxy, -C(O)RV, -C(O)ORW, -C(O)NRyRzand-S(O)qRvwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl and heteroalkyl, is each, optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio; or

(ii) R13and R14together with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl where heterocyclyl or heteroaryl optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents, independently selected from halogen, alkyl, hydroxy, alkoxy, amino, alkylthio, and where heterocyclyl also optionally substituted by oxo group;

R15represents alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, -C(O)NRyRzor-NRyRzwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaryl, each optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituent and, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio;

R18represents hydrogen, alkyl, halogenated, hydroxys2-6alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaromatic; where R18optionally substituted by 1-3 groups Q1every Q1independently selected from alkyl, hydroxyl, halogen, halogenoalkane, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyl, carboxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogenfree and amino;

R19and R20selected as follows:

(i) R19and R20each independently represents hydrogen or alkyl; or

(ii) R19and R20together with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl, which is optionally substituted by 1-2 groups, each of which is independently selected from halogen, alkyl, halogenoalkane, hydroxyl and alkoxy;

each Rxindependently represents alkylene or a simple bond;

Rvrepresents hydrogen, alkyl, alkenyl or quinil;

Rwindependently represents hydrogen, alkyl, alkenyl, quinil or halogenated;

Ryand Rzselected as follows:

(i) Ryand Rzka is each independently represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl or halogenated;

(ii) Ryand Rztogether with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl, which is optionally substituted by 1-2 groups, each of which is independently selected from halogen, alkyl, halogenoalkane, hydroxyl and alkoxy;

p has a value of 0-5; and

each q, independently, is 0, 1 or 2; provided that when R1and R2together form =O, then R6aand R6drepresent hydrogen, R6bselected from hydrogen, alkyl, alkenyl, quinil, halogenoalkane, cycloalkyl, -RXOR18, -RXNR19R20and RxS(O)qRv, R6cselected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, hydroxy, -RXNR19R20and RxS(O)qRvand the other variables have the meaning given in this application.

In another variant embodiment, when R1and R2together form =O, then R6aand R6represent hydrogen, R6and R6ceach independently selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, hydroxy, -RXNR19R20and RxS(O)qRvand the other variables have the meaning given in this application.

In another variant embodiment, when R1and R2 together form =O, then R6a, R6band R6drepresent hydrogen, and R6cselected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, hydroxy, -RXNR19R20and RxS(O)qRvand the other variables have the meaning given in this application.

In another variant embodiment, when R1and R2together form =O, then R6a, R6band R6drepresent hydrogen, and R6cselected from hydrogen, alkyl, cycloalkyl and hydroxy.

In other variant embodiments, R6arepresents hydrogen, and R6b, R6cand R6deach independently selected from hydrogen, halogen, alkyl, alkenyl, quinil, halogenoalkane, cycloalkyl, -RXOR18, -RXNR19R20and RxS(O)qRvprovided that when R1and R2together form =O, then R6band R6drepresent hydrogen, and R6cselected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, -RXOR18, -RXNR19R20and RxS(O)qRvand the other variables have the meaning given in this application.

In other variant embodiments, R6a, R6band R6deach represent hydrogen, and R6cindependently selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, RXOR1 , -RXNR19R20and RxS(O)qRvand the other variables have the meaning given in this application. In the following variant embodiment, R6a, R6band R6deach represent hydrogen, and R6crepresents hydrogen, alkyl, cycloalkyl or-RxOR18and the other variables have the meaning given in this application. In other variant embodiments, R6a, R6b, R6cand R6drepresent hydrogen. In another variant embodiment, p is set to 2, and each R7independently selected from halogen, hydroxy and alkoxy. In the following variant embodiment, p is 1, and R7represents a halogen.

In one variant embodiment, R6aand R6drepresent hydrogen, and R6band R6ceach independently selected from hydrogen, halogen, alkyl, alkenyl, quinil, halogenoalkane, cycloalkyl, -RXOR18, -RXNR19R20and RxS(O)qRvprovided that when R1and R2together form =O, R6cselected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, -RXOR18, -RXNR19R20and RxS(O)qRvwhere other variables have the meaning given in this application.

In some embodiments, embodiments in the present application is to provide the Lena compounds of the formula (XII)

or their pharmaceutically acceptable salt, solvate or hydrate, where the other variables have the meaning given in this application. In one variant embodiment, R7represents a halogen.

In some embodiments, embodiments in the present application is represented by the compounds of formula (XIII)

or their pharmaceutically acceptable salt, solvate or hydrate, where R1and R2selected from (i), (ii), (iii), (iv) and (v) and have the following meanings:

(i) R1and R2together form =O, =S, =NR9or =CR10R11;

(ii) R1and R2both are-OR8or R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;

(iii) R1represents hydrogen or halogen; and R2is a halogen; and

(iv) R1represents alkyl, alkenyl, quinil or cycloalkyl, where the alkyl, alkenyl, quinil or cycloalkyl optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents selected from halogen, cyano, alkyl, -RXORW, -RxS(O)qRv, -RxNRyRzand-C(O)ORW; and R2is own the th hydrogen, halogen or-OR8; and

(v) R1represents halogen, deutero, -OR12, -NR13R14or-S(O)qR15; and R2represents hydrogen, deutero, alkyl, alkenyl, quinil or cycloalkyl, where the alkyl, alkenyl, quinil or cycloalkyl, optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents selected from halogen, cyano, alkyl, -RXORW, -RxS(O)qRvand RxNRyRz;

R3represents halogen, alkyl, halogenated, cycloalkyl, cycloalkenyl, hydroxy or alkoxy;

R4and R5each independently represents hydrogen or alkyl;

R6a, R6b, R6cand R6deach independently selected from hydrogen, halogen, alkyl, alkenyl, quinil, halogenoalkane, cycloalkyl, -RXOR18, -RXNR19R20and RxS(O)qRv;

R7, R7cand R7each independently selected from hydrogen, halogen, alkyl, halogenated and RXORW;

R8represents alkyl, alkenyl or quinil;

R9represents hydrogen, alkyl, halogenated, hydroxy, alkoxy or amino;

R10represents a hydrogen Il is alkyl;

R11represents hydrogen, alkyl, halogenated or-C(O)OR8;

R12selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, -C(O)RV, -C(O)ORWand-C(O)NRyRzwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaryl, each optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio;

R13and R14selected as follows:

(i) R13represents hydrogen or alkyl; and R14selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, alkoxy, -C(O)RV, -C(O)ORW, -C(O)NRyRzand-S(O)qRvwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaryl, each optionally substituted by one or more, in one variant embodiment of the one-ceterm is, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio; or

(ii) R13and R14together with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl where heterocyclyl or heteroaryl optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents, independently selected from halogen, alkyl, hydroxy, alkoxy, amino, alkylthio, and where heterocyclyl also optionally substituted by oxo group;

R15represents alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, -C(O)NRyRzor-NRyRzwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaryl, each optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio;

p> R18represents hydrogen, alkyl, halogenated, hydroxys2-6alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaromatic; where R18optionally substituted by 1-3 groups Q1every Q1independently selected from alkyl, hydroxyl, halogen, halogenoalkane, alkoxy, aryloxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonyl, carboxyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, halogenfree and amino;

R19and R20selected as follows:

(i) R19and R20each independently represents hydrogen or alkyl; or

(ii) R19and R20together with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl, which is optionally substituted by 1-2 groups, each of which is independently selected from halogen, alkyl, halogenoalkane, hydroxyl and alkoxy; each Rxindependently represents alkylene or a simple bond;

Rvrepresents hydrogen, alkyl, alkenyl or quinil;

Rwindependently represents hydrogen, alkyl, alkenyl, quinil or halogenated;

Ryand Rzselected as follows:

(i) Ryand Rzeach independently represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl or halogen the keel;

(ii) Ryand Rztogether with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl, which is optionally substituted by 1-2 groups, each of which is independently selected from halogen, alkyl, halogenoalkane, hydroxyl and alkoxy;

p has a value of 0-5; and

each q, independently, is 0, 1 or 2; and provided that when R1and R2together form =O, then R7cneither R7dcan't be a-ORW. In one variant embodiment, R7drepresents hydrogen. In one variant embodiment, R7drepresents hydrogen, and R7band R7ceach independently selected from hydrogen, halogen, alkyl, halogenoalkane and RXORW. In other variant embodiments, R7bis a halogen, R7bselected from hydrogen, halogen, alkyl, halogenoalkane and RXORWand R7crepresents hydrogen. In other variant embodiments, R7cand R7drepresent hydrogen.

In another variant embodiment, the present application presents the compounds of formula (XIV)

or their pharmaceutically acceptable salt, solvate or hydrate, where:

R1and R2selected from (i), (ii), (iii), (iv) and (v) and have the following meanings:

(i) R1and R2together form =O, =S, =NR9or =CR10 11;

(ii) R1and R2both are-OR8or R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;

(iii) R1represents hydrogen or halogen; and R2is a halogen; and

(iv) R1represents alkyl, alkenyl, quinil or cycloalkyl, where the alkyl, alkenyl, quinil or cycloalkyl optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents selected from halogen, cyano, alkyl, -RXORW, -RxS(O)qRv, -RxNRyRzand-C(O)ORW; and R2represents hydrogen, halogen or-OR8; and

(v) R1represents halogen, deutero, -OR12, -NR13R14or-S(O)qR15; and R2represents hydrogen, deutero, alkyl, alkenyl, quinil or cycloalkyl, where the alkyl, alkenyl, quinil or cycloalkyl, optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents selected from halogen, cyano, alkyl, -RXORW, -RxS(O)qRvand RxNRyRz;/p>

R3represents hydrogen, halogen, alkyl, halogenated, cycloalkyl, hydroxy or alkoxy;

R4and R5each independently represents hydrogen or alkyl;

R6a, R6b, R6drepresent hydrogen;

R6crepresents hydrogen, halogen, alkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkylsulfonyl, alkoxy, hydroxyalkoxy or alkoxyalkane,

R7brepresents halogen, and R7crepresents hydrogen, halogen, hydroxy or alkoxy;

R8represents alkyl, alkenyl or quinil;

R9represents hydrogen, alkyl, halogenated, hydroxy, alkoxy or amino;

R10represents hydrogen or alkyl;

R11represents hydrogen, alkyl, halogenated or-C(O)OR8;

R12selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, -C(O)RV, -C(O)ORWand-C(O)NRyRzwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl and heteroaryl, each optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment of the one-three, one Varian is e one embodiment, two or three substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio;

R13and R14selected as follows:

(i) R13represents hydrogen or alkyl; and R14selected from hydrogen, alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, alkoxy, -C(O)RV, -C(O)ORW, -C(O)NRyRzand-S(O)qRvwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaryl, each optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio; or

(ii) R13and R14together with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl where heterocyclyl or heteroaryl optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents, independently selected from halogen, alkyl, hydroxy, alkoxy, amino, and al is ylthio, and where heterocyclyl also optionally substituted by oxo group;

R15represents alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl, heteroalkyl, -C(O)NRyRzor-NRyRzwhere alkyl, alkenyl, quinil, cycloalkyl, cycloalkenyl, heterocyclyl, geterotsiklicheskikh, aryl, aralkyl, heteroaryl or heteroaryl, each optionally substituted by one or more, in one embodiment, the embodiments one to four, in one variant embodiment, one to three, in one variant of embodiment one, two or three substituents, independently selected from halogen, oxo, alkyl, hydroxy, alkoxy, amino, alkylthio; each Rxindependently represents alkylene or a simple bond;

Rvrepresents hydrogen, alkyl, alkenyl or quinil;

Rwindependently represents hydrogen, alkyl, alkenyl, quinil or halogenated;

Ryand Rzselected as follows:

(i) Ryand Rzeach independently represents hydrogen, alkyl, alkenyl, quinil, cycloalkyl or halogenated;

(ii) Ryand Rztogether with the nitrogen atom to which they are bound, form heterocyclyl or heteroaryl, which is optionally substituted by 1-2 groups, each of which is independently selected from halogen, is of Lila, halogenoalkane, hydroxyl and alkoxy; provided that when R3represents hydrogen, then R6cis other than halogen.

In another variant embodiment, the present application presents the compounds of formula (XIV) or their pharmaceutically acceptable salt, solvate or hydrate, where

(i) R1and R2together form =O, =S, =NR9or =CR10R11;

(ii) R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;

(iii) R1represents hydrogen or halogen; and R2is a halogen; and

(iv) R1represents halogen, deutero, hydroxyl, and R2represents hydrogen or deutero;

R3represents hydrogen, halogen, alkyl, halogenated, cycloalkyl, hydroxy or alkoxy;

R4and R5each independently represents hydrogen or alkyl;

R6a, R6b, R6drepresent hydrogen;

R6crepresents hydrogen, halogen, alkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkylsulfonyl, alkoxy, hydroxyalkoxy or alkoxyalkane,

R7bis a halogen and R7crepresents hydrogen; provided that when R3represents hydrogen, then R6cis other than halogen.

In other options, the ante embodiment, R3represents halogen, alkyl, cycloalkyl, halogenated, hydroxy or alkoxy. In the following variant embodiment, R3represents alkyl, halogenated, cycloalkyl, hydroxy or alkoxy. In the following variant embodiment, R3represents alkyl, cycloalkyl or alkoxy. In other variant embodiments, R6crepresents hydrogen, fluorine, chlorine, hydroxy, alkyl, hydroxyalkyl, alkoxyalkyl, alkylsulfonyl, alkoxy, hydroxyalkoxy or alkoxyalkane. In other variant embodiments, R6crepresents hydrogen, fluorine, chlorine, hydroxy, methyl, hydroxymethyl, hydroxyethyl, methoxymethyl, ethoxymethyl, methylsulfonylmethyl, ethylsulfonyl, methoxy, ethoxy, propyloxy, hydroxypropoxy, hydroxyethoxy, hydroxyethoxy, methoxyethoxy or ethoxyethoxy. In the following variant embodiment, R6crepresents hydrogen, alkyl, hydroxy, hydroxyalkyl, alkoxyalkyl, alkylsulfonyl, hydroxyalkoxy or alkoxyalkane.

In one variant embodiment, the present invention presents a compound selected from the following:

(4-chlorination-2-yl)(3-forfinal)methanon;

(4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(3-forfinal)methanon;

(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon;

(4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-ftoh the Nile)methanon;

(4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(2-methoxyphenyl)methanon;

(4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol;

2-(fluoro(4-forfinal)methyl)-N-(1H-pyrazole-3-yl)hinzelin-4-amine;

2-(diftar(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;

2-(diftar(4-forfinal)methyl)-N-(1H-pyrazole-3-yl)hinzelin-4-amine;

N-(5-cyclopropyl-1H-pyrazole-3-yl)-2-(diftar(4-forfinal)methyl)hinzelin-4-amine;

3-(2-(4-perbenzoic)hinzelin-4-ylamino)-1H-pyrazole-5-carbonitrile;

(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;

2-((4-forfinal)(methoxy)methyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;

2-(amino(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;

3-(2-((4-forfinal)(hydroxy)methyl)hinzelin-4-ylamino)-1H-pyrazole-5-carbonitrile;

(5-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol;

(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(trifluoromethyl)hinzelin-2-yl)methanon;

(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(trifluoromethyl)hinzelin-2-yl);

(7-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanon;

2-(diftar(4-forfinal)methyl)-7-fluoro-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;

2-(diftar(4-forfinal)methyl)-7-fluoro-N-(1H-pyrazole-3-yl)hinzelin-4-amine;

(4-(1H-pyrazole-3-ylamino)-7-iodination-2-yl)(4-forfinal)methanon;

(4-(1H-pyrazole-3-ylamino)-7-iodine is insulin-2-yl)(4-forfinal)methanol;

(4-forfinal)(7-methyl-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon;

(4-forfinal)(7-methyl-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;

2-(diftar(4-forfinal)methyl)-7-methyl-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;

2-(diftar(4-forfinal)methyl)-7-methyl-N-(1H-pyrazole-3-yl)hinzelin-4-amine;

(4-(1H-pyrazole-3-ylamino)-7-methoxyquinazoline-2-yl)(4-forfinal)methanon;

(4-(1H-pyrazole-3-ylamino)-7-methoxyquinazoline-2-yl)(4-forfinal)methanol;

(4-forfinal)(7-methoxy-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon;

(4-forfinal)(7-methoxy-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;

2-(diftar(4-forfinal)methyl)-7-methoxy-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;

2-(diftar(4-forfinal)methyl)-7-methoxy-N-(1H-pyrazole-3-yl)hinzelin-4-amine;

2-(diftar(4-forfinal)methyl)-8-fluoro-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;

(4-(1H-pyrazole-3-ylamino)-8-methoxyquinazoline-2-yl)(4-forfinal)methanon;

2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-ol;

(4-forfinal)(7-hydroxy-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon;

(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(2-morpholinoethoxy)hinzelin-2-yl)methanol;

2-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)ethanol;

3-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yl) - Rev. XI)propan-1-ol;

(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(piperidin-4-yloxy)hinzelin-2-yl)methanol;

(4-forfinal)(7-(2-methoxyethoxy)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;

tert-butyl 2-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)acetate;

2-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)acetic acid;

methyl ester {(4-fluoro-phenyl)-[4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl]methyl}carbamino acid; and

bis-(4-fluoro-phenyl)-[4-(5-methyl-1H-pyrazole-3-ylamino)-hinzelin-2-yl]methanol.

In one variant embodiment, the present invention presents a compound selected from the following:

(R,S)-methyl-(4-forfinal)(4-(5-methyl-4H-pyrazole-3-ylamino)hinzelin-2-yl)methylcarbamate;

(R,S)-(4-forfinal)(8-methyl-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;

(R,S)-(7-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol;

(4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)bis(4-forfinal)methanol;

(2-(diftar(4-forfinal)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yl)methanol;

2-(diftar(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3-yl)-7-(methylsulfonylmethyl)hinzelin-4-amine;

2-(Diftar(4-forfinal)methyl)-7-(ethoxymethyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;

(R,S)(7-chloro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol

(6-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanon(R,S)-(6-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol;

(R,S)-(4-(1H-pyrazole-3-ylamino)-6-florinopolis-2-yl)(4-forfinal)methanol;

(7-bromo-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanon;

(7-bromo-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol;

(R,S)-(4-(1H-pyrazole-3-ylamino)-7-bromination-2-yl)(4-forfinal)methanol;

2-(2-(4-forfinal)-1,3-dioxolane-2-yl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;

(8-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanon;

(R,S)-(8-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol;

(2-methoxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon;

(R,S)-(2-methoxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;

(3-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;

N-((4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methyl)formamide;

(R,S)-(3,4-differenl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;

(3-chloro-4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;

3-(4-forfinal)-3-(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)propanenitrile;

2-((cyclopropylamino)(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;

2-(1-(4-forfinal)-2-(methylsulphonyl)ethyl)-N-(5-meth is l-1H-pyrazole-3-yl)hinzelin-4-amine;

2-(3-amino-1-(4-forfinal)propyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;

(R,S)(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol, 1-d;

(4-forfinal)(4-(5-methoxy-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon;

(R,S)-(4-(5-ethyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol;

(4-Forfinal)(4-(5-methoxy-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;

(4-fluoro-3-methoxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon;

(4-fluoro-3-hydroxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon; and

(R,S)-(2-fluoro-5-(hydroxy(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methyl)enolacetate.

Also in this application presents isotopically-enriched analogs of compounds presented in this invention. Isotopic enrichment (for example, deteriora) for pharmaceutical substances for improving the pharmacokinetic properties ("PK"), pharmacodynamic properties ("PD") profile and toxicity has been demonstrated previously with some classes of drugs. See, for example, Lijinsky et al., Food Cosmet. Toxicol, 20: 393 (1982); Lijinsky et al., J. Nat. Cancer Inst., 69: 1127 (1982); Mangold et al., Mutation Res. 308: 33 (1994); Gordon et al., Drug Metab. Dispos., 15: 589 (1987); Zello et al., Metabolism, 43: 487 (1994); Gately et al., J. Nucl Med., 27: 388 (1986); Wade D, Chem. Biol Interact. 117: 191 (1999).

The isotopic enrichment of medicines can be used, for example, to (1) reduce or eliminate relately metabolites, (2) increase the half-life of the original medicinal product, (3) reduce the number of doses needed to achieve the desired effect, (4) reduction of the dosed quantity is needed to achieve the desired effect, (5) increasing the formation of active metabolites, if they are formed, and/or (6) reduce the production of harmful metabolites in specific tissues and/or create more effective drugs and/or safer drugs for combination therapy, regardless of whether combination therapy is desirable or not.

The substitution of an atom of one of its isotopes often leads to a change in the reaction rate of the chemical interaction. This phenomenon is known as the Kinetic Isotope Effect (KIE"). For example, if C-H bond is broken in determining the speed stage in a chemical reaction (i.e. the phase with the highest energy transition), the substitution of deuterium for such hydrogen will cause the decrease of reaction rate and slow process. This phenomenon is known as the Kinetic Isotope Effect of Deuterium ("DKIE"). (See, for example, Foster et al., Adv. Drug Res., vol. 14, pp. 1-36 (1985); Kushner et al., Can. J. Physiol. Pharmacol, vol. 77, pp. 79-88 [in Russian] (1999)).

Tritium (T) is a radioactive isotope of hydrogen used in scientific experiments, fusion reactors, neutron generators and R is biopharmaceutically tools. Tritium is a hydrogen atom that has 2 neutrons in the nucleus and has an atomic mass close to 3. In the natural environment it occurs in very low concentrations, most commonly present as T2O. Tritium decays slowly (half-life = 12.3 years) and emits a beta particle with low energy, which cannot penetrate the outer layer of human skin. The main danger is internal to the impact associated with this isotope, although it would need to be ingested in large quantities to cause a significant risk to health. Compared to deuterium, less amount of tritium to achieve dangerous effect. The substitution of hydrogen with tritium (T) leads to a stronger connection than the substitution of deuterium, and gives a significantly large isotope effects. Similarly, the isotopic substitution of other elements, including, but not limited to,13C or14C for carbon,33S34S or36S to sulfur,15N for nitrogen and17O or18O for oxygen, will give a similar kinetic isotope effects.

C. the Formulation of pharmaceutical compositions

In this application presents a pharmaceutical composition comprising the compound in the present invention, for example, the compound of formula I, as sports is an ingredient or its pharmaceutically acceptable salt, MES or hydrate; in combination with a pharmaceutically acceptable excipient, carrier, diluent or excipient or their mixture.

The connection is made in the present invention, can be entered separately or in combination with one or more other compounds presented in this invention. Pharmaceutical compositions that include the compound in the present invention, for example, the compound of formula I, can be formulated in various dosage forms for oral, parenteral or local administration. Pharmaceutical compositions can also be formulated in dosage forms with modified release, including dosage form, delayed, extended, prolonged, lengthy, pulsed, controlled, accelerated and rapid, directional, programmable release and held in the stomach. These dosage forms can be obtained in accordance with the traditional methods and procedures, which are known to experts in this field (see, Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Deliver Technology, Rathbone et al., Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc.: New York, NY, 2003; Vol. 126).

In one variant embodiment, is provided a pharmaceutical composition in dosage form for oral administration, which is luchot connection, in the present invention, for example, the compound of formula I or its pharmaceutically acceptable salt, MES or hydrate; and one or more pharmaceutically acceptable excipients or carriers.

In another variant embodiment, is provided a pharmaceutical composition in dosage form for parenteral administration, which comprise a compound provided in the present invention, for example, the compound of formula I or its pharmaceutically acceptable salt, MES or hydrate; and one or more pharmaceutically acceptable excipients or carriers.

In the following variant of the embodiment are provided pharmaceutical compositions in a dosage form for topical administration, which comprise a compound provided in the present invention, for example, the compound of formula I, or its pharmaceutically acceptable salt, MES or hydrate; and one or more pharmaceutically acceptable excipients or carriers.

Pharmaceutical compositions provided in the present invention, can be provided in the dosage form is a standard dose, or in mnogochasovoj dosage form. Dosage form is a standard dose, as used in this application, refers to a physically discrete unit suitable DL is the introduction to the subject, such as a person or animal, and individually Packed, as it is known from the prior art. Each standard dose contains a predetermined quantity of active ingredient(ingredient), sufficient to produce the desired therapeutic effect, in Association with the required pharmaceutical carriers or excipients. Examples of dosage forms, including the standard dose, including ampoule, syringe, and individually packaged pill and capsule. Dosage form, representing the standard dose, you can enter as divided into parts or shares. Mnogozonovaya dosage form is a multiple identical standard doses Packed in one container, for administration in the form of a separate unit dosage forms. Examples mnogochasovoj dosage forms include a bottle, a bottle of tablets or capsules or bottle containing a pint or a gallon medicines.

Pharmaceutical compositions provided in the present invention, it is possible to enter a one or in several stages with defined time intervals. It should be clear that the specific dose and duration of treatment can vary depending on age, weight and condition of the patient receiving treatment, and can be defined is mpirical by using known testing protocols or by extrapolating data from in vivo or in vitro tests or diagnostic data. In addition, it should be clear that for any individual specific scheme of injection drugs should over time be adjusted in accordance with the needs of the individual and the professional judgment of the person making the introduction of, or controlling the introduction of drugs.

In one variant embodiment, therapeutically effective dose is from about 0.1 mg to about 2000 mg per day of the compounds presented in this invention. Therefore, the pharmaceutical compositions should provide a dose of from about 0.1 mg to about 2000 mg of the compound. In some embodiments of the incarnation standard pharmaceutical dosage forms get so that they provide from about 1 mg to about 2000 mg, from about 10 mg to about 1000 mg, from about 20 mg to about 500 mg, or from about 25 mg to about 250 mg of active of active ingredient or combination of active ingredients on the standard dosing unit. In some embodiments of the incarnation standard pharmaceutical dosage forms get so that they can provide about 10 mg, 20 mg, 25 mg, 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg or 2000 mg of active active ingredient.

Oral administration

Pharmaceutical compositions obespechenie in the present invention may be presented in solid, semi-solid is whether liquid dosage form for oral administration. As used in this application, oral administration also includes buccal, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, bistratose tablets, chewable tablets, capsules, pills, pills, pellets, lozenges, sachets, granules containing the drug chewing gum, loose powders, effervescent or nishiuchi powders or granules, solutions, emulsions, suspensions, pills, powders, elixirs and syrups. In addition to the active ingredient(or ingredients), pharmaceutical compositions can contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrating agents, wetting agents, lubricants, slip agents, dyes, inhibitors migration of dyes, sweeteners and flavouring agents.

Binders or granulating agents impart cohesive properties to the tablet so that the tablet is not destroyed in the pressing. Suitable binders or granulating agents include, but are not limited to, starches such as corn starch, potato starch, and pre-gelatinizing starch (such as STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, IU the ACCA and lactose; natural and synthetic gums, such as Arabian gum, alginic acid, alginates, extract caragana, panwar gum,gum, ghatti, gummy extract of the huskisabgol, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, erbogachan larch, powder tragakant and guar gum; cellulose, such as ethylcellulose, acetate cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methylcellulose, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hypromellose (HPMC); microcrystalline cellulose such as AVICEL-PH-101, AVICEL-PH-103, AVICEL RC-581, AVICEL-PH-105 (FMC Corp., Marcus Hook, PA); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, powdered cellulose, dextrine, kaolin, mannitol, silicic acid, sorbitol, starch, pre-gelatinizing starch and mixtures thereof. In the pharmaceutical compositions, obspechivaya in the present invention, a binder or a filler may be present in an amount of from about 50 to about 99% of the mass.

Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, Inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch and powdered Saha is. Some diluents such as mannitol, lactose, sorbitol, sucrose and Inositol, when they are present in sufficient quantities, can give some properties extruded tablets that make it possible decay in the mouth during chewing. Such molded tablets can be used as chewable tablets.

Suitable disintegrating agents include, but are not limited to, agar, bentonite; cellulose, such as methylcellulose and carboxymethylcellulose; wood products; natural sponge; cation-exchange resin; alginic acid; gums, such as guar gum and Veegum HV; citrus pulp; cross-linked cellulose, such as crosscarmellose; cross-linked polymer such as crosspovidone; cross-linked starches; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; polacrilin potassium; starches such as corn starch, potato starch, tapioca starch and pre-gelatinizing starch; clays; algae; and mixtures thereof. The amount of baking powder in pharmaceutical compositions, obspechivaya in the present invention varies depending on the type of drug, and it can easily determine specialist with average skills. Pharmaceutical compositions obespechenie in the present invention may contain from about 0.5 to about 15% or from about 1 to OK the lo 5% of the mass. baking-powder.

Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerin; sorbitol; mannitol; glycols, such as glycerinated and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oil, including peanut oil, cotton seeds, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; zinc stearate; etiloleat; ailleret; agar; starch; Likopodija; silica or silica gels, such as AEROSIL®200 (W.R. Grace Co., Baltimore, MD) and CAB-O-SIL®(Cabot Co. of Boston, MA); and mixtures thereof. Pharmaceutical compositions provided by the present invention may contain about 0.1 to about 5% of the mass. lubricant.

Suitable slip agents include colloidal silica, CAB-O-SIL®(Cabot Co. of Boston, MA) and not containing asbestos talc. Dyes include any of the approved for use of certified water soluble FD&C dyes insoluble in water, FD&C dyes suspended in the hydrate of aluminum and colored varnishes, and mixtures thereof. Colored nail Polish is a combination by adsorption of water-soluble dye with a heavy metal hydroxide, giving an insoluble form of the dye. Odorants in luchot natural odorants, extracted from plants, such as fruits, and synthetic blends of compounds which give a pleasant taste sensations, such as peppermint and methyl salicylate. Sweeteners include sucrose, lactose, mannitol, syrups, glycerin and artificial sweeteners, such as saccharin and aspartame. Suitable emulsifying agents include gelatin, Arabic gum, tragakant, bentonite, and surfactants, such as polyoxyethylene sorbitan monooleate (TWEEN®20), polyoxyethylene sorbitan monooleate 80 (TWEEN®80) and triethanolamine. Suspendresume and dispersing substances include sodium carboxymethyl cellulose, pectin, tragakant, Veegum, Arabian gum, sodium salt of carbometalation, hypromellose and polyvinylpyrrolidone. Preservatives include glycerin, methyl - and propylparaben, benzoic acid, sodium benzoate and alcohol. Wetting agents include the propylene glycol monostearate, servicemanual, diethylene glycol monolaurate and lauric ester of polyoxyethylene. Solvents include glycerin, sorbitol, ethyl alcohol, and syrup. Examples of non-aqueous liquids used in emulsions, include mineral oil and oil seeds. Organic acids include citric and tartaric acid. Sources of carbon dioxide include sodium bicarbonate, and carbonate on the model.

It should be clear that many carriers and excipients can perform several functions, even in the same composition.

Pharmaceutical compositions obespechenie in the present invention, can be represented in the form of compressed tablets, RUB in the powder tablets, chewing bread, quick-dissolving tablets, multipressure tablets or tablets with enterosalivary coating, sugar coating or film coating. Tablets with enterosalivary cover are extruded tablets covered with substances that are resistant to gastric acid, but is dissolved or decomposed in the intestine, thus protecting the active ingredients from the acidic environment of the stomach. Enterosgelya coatings include, but are not limited to, fatty acids, fats, fenilsalitsilat, waxes, shellac, ammonium, shellac and acetamidate cellulose. Tablets with sugar coating are pressed tablets, surrounded by sugar coating that may best way to mask unpleasant tastes or odors and protect tablets from oxidation. Tablet film-coating are pressed tablets that are coated with a thin layer or film of water-soluble material. Film coating include, but are not limited to the I, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000 and acetated cellulose. Film coating gives the same General properties as sugar coating. Multipressure tablets are compressed tablets obtained with the use of more than one cycle of pressing, including multi-layer tablets and tablets with a press-coated or dry floor.

The dosage form in tablet form can be obtained from the active ingredient in powdered, crystalline or granular form, alone or in combination with one or more carriers or excipients, as described in this application, including binders, disintegrating agents, polymers, providing controlled release, lubricants, diluents and/or dyes. Flavors and sweeteners are especially useful for obtaining chews and biscuits.

Pharmaceutical compositions obespechenie in the present invention, can be represented in the form of soft or hard capsules, which can be made of gelatin, methylcellulose, starch or calcium alginate. Hard gelatin capsule, also known as capsule dry seeding (DFC), consists of two sections, where one section surrounds the other, thus completely enclosing in itself Akti is hydrated ingredient. Soft elastic capsule (SEC) is a soft spherical shell, such as gelatin shell which is plasticized by the addition of glycerin, sorbitol, or a similar polyol. Soft gelatin shell may contain a preservative to prevent the growth of microorganisms. Suitable preservatives are those that are described in this application, including methyl - and propylparaben and sorbic acid. Liquid, semi-solid and solid dosage forms presented in this invention can be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions or suspensions in propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions can be obtained, as described in U.S. Patent No. 4328245; 4409239; and 4410545. Capsules may also have a coating method known to specialists in this field, to modify or delay the dissolution of the active ingredient.

Pharmaceutical compositions obespechenie in the present invention, can be presented in liquid and semi-solid dosage forms, including emulsions, solutions, suspensions, elixirs and syrups. Emulsion is a two-phase system in which one liquid is dispersed as small droplets in the other liquid, the cat heaven can be an emulsion of oil-in-water or water-in-oil. The emulsion can include pharmaceutically acceptable non-aqueous liquid or solvent, emulsifier and preservative. Suspension may include pharmaceutically acceptable suspendisse agent and preservative. Aqueous alcoholic solutions may include pharmaceutically acceptable acetal, such as di(lower alkyl)acetal lower alkylenediamine, for example, acetaldehyde diethylacetal; and miscible with water, the solvent containing one or more hydroxyl groups such as propylene glycol and ethanol. Elixirs are clear, sweetened and Vodopyanova solutions. Syrups are concentrated aqueous solutions of sugar, for example sucrose, and may also contain a preservative. As for liquid dosage forms, for example, a solution in polyethylene glycol can be diluted with a sufficient amount of pharmaceutically acceptable liquid carrier, e.g. water, is more convenient for measuring the dose for injection.

Other useful liquid and semi-solid dosage forms include, but are not limited to, dosage forms containing the active ingredient(ingredients)in the present invention, and dialkylamines mono - or polyalkyleneglycol, including, 1,2-dimethoxymethane, diglyme, trislim, tetralin, polyethylene glycol-350-dimethyl ether, polietilen icol-550-dimethyl ether, the polyethylene glycol-750-dimethyl ether, where 350, 550 and 750 refer to the approximate average molecular weight of polyethylene glycol. These compositions can optionally include one or more antioxidants, such as bottled hydroxytoluene (BHT), bottled hydroxyanisol (BHA), propylgallate, vitamin E, hydroquinone, hydroxycoumarins, ethanolamine, lecithin, cephalin, ascorbic acid, malic acid, sorbitol, phosphoric acid, bisulfite, sodium metabisulfite, thiodipropionic acid and its esters and dithiocarbamate.

Pharmaceutical compositions obespechenie in the present invention for oral administration, can also be represented in the form of liposomes, micelles, microspheres or nanosystems. Dosage forms in the form of micelles can be obtained, as described in U.S. Patent No. 6350458.

Pharmaceutical compositions obespechenie in the present invention, can be represented as nishiuchi or effervescent granules and powders for restructuring in liquid dosage form. Pharmaceutically acceptable carriers and excipients used in nishiuchi granules or powders may include diluents, sweeteners and wetting agents. Pharmaceutically acceptable carriers and excipients used in the effervescent granules or powders may include organic acids and the source is ioxide carbon.

The dyes and perfumes can be used in all the above dosage forms.

Pharmaceutical compositions obespechenie in the present invention can be formulated into dosage forms for immediate or modified release, including delayed, long-term, pulsed, controlled, directed and programmed release.

Pharmaceutical compositions obespechenie in the present invention may be formulated together with other active ingredients which do not report the desired therapeutic action, or with substances that Supplement the desired action.

Parenteral administration

Pharmaceutical compositions obespechenie in the present invention, can be entered by parenteral inyecci, infusion or implantation, for local or systemic administration. Parenteral administration, as the term is used in this application includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesically and subcutaneous administration.

Pharmaceutical compositions obespechenie in the present invention may be formulated in any dosage form, which is s are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solution or suspension in liquid prior to injection. Such dosage forms can be obtained in accordance with conventional methods known to experts in the field of pharmaceuticals (see, Remington: The Science and Practice of Pharmacy, supra).

Pharmaceutical compositions intended for parenteral, Vvedenie may include one or more pharmaceutically acceptable carriers and excipients, including, but not limited to, water media, mixed water media, non-aqueous media, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, substances that enhance the solubilization, isotonic agents, buffering agents, antioxidants, local anesthetics, suspendresume and dispersing agents, wetting agents or emulsifying agents, complexing agents, airing or hepatoblastoma substances createsite substances lisamarie substances, thickeners, are substances that regulate pH, and inert gases.

Suitable aqueous media include, but are not limited to, water, saline, physiological saline or phosphate-buffered saline (PBS), sodium chloride solution for injection, ringer's solution of kleinheksel, isotonic dextrose injection, sterile water for injection, dextrose and containing lactate ringer's solution for injection. Non-aqueous carriers include, but are not limited to, non-volatile vegetable oils, castor oil, corn oil, cotton seeds, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil and having an average chain length triglycerides of coconut oil and oils from the seeds of palm trees. Mixed water media include, but are not limited to, ethanol, 1,3-butanediol, liquid polyethylene glycol (e.g. polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerin, N-methyl-2-pyrrolidone, N,N-dimethylacetamide and dimethylsulfoxide.

Suitable antimicrobial agents or preservatives include, but are not limited to, phenols, Cresols, mercury compounds, benzyl alcohol, chlorobutanol, methyl - and propyl p-hydroxybenzoate, thimerosal, benzalconi chloride (for example, benzenehexachloride), methyl - and propylparaben and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerin and dextrose. Suitable buffering agents include, but are not limited to phosphate and citrate. Suitable antioxidants are those that are described in this application, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspendresume and dispersing agents are those that are described in this application, including sodium carboxymethyl cellulose, hypromellose and polyvinylpyrrolidone. Suitable emulsifying agents include substances described in this application, including polyoxyethylenesorbitan, polyoxyethylene sorbitan monooleate 80 and triethanolamine. Suitable airing or hepatoblastoma substances include, but are not limited to EDTA. Suitable substances that regulate the pH include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid and lactic acid. Suitable complex-forming substances include, but are not limited to, cyclodextrins, including α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, sulfobutyl ether-β-cyclodextrin and sulfobutyl ester of 7-β-cyclodextrin (CAPTISOL®, CyDex, Lenexa, KS).

Pharmaceutical compositions obespechenie in the present invention may be formulated for administration using a single dose or multiple doses. Song DL the dose is packaged in a vial, the vial or syringe. Mnogorazovye parenteral composition should contain an antimicrobial agent in bacteriostatic or fungistatic concentrations. All parenteral compositions should be sterile, as is known and practiced in the field.

In one variant embodiment, pharmaceutical compositions are provided in a ready to use sterile solutions. In other variant embodiments, pharmaceutical compositions are provided in the form of a sterile dry soluble products, including freeze-dried powders and hypodermic tablets, to restructure the media before use. In the following variant embodiment, pharmaceutical compositions are provided in a ready to use sterile suspensions. In the following variant embodiment, pharmaceutical compositions are provided in the form of a sterile dry soluble products for restructuring the media before use. In another variant embodiment, pharmaceutical compositions are provided in a ready to use sterile emulsions.

Pharmaceutical compositions obespechenie in the present invention can be formulated into dosage forms for immediate or modified release, including delayed, the longer the CSOs, pulsed, controlled, directed and programmed release.

The pharmaceutical compositions can be formulated in the form of suspensions, solids, semi-solid substances, or thixotropic liquid for administration in the form of implantable depot of the drug. In one variant embodiment, the pharmaceutical compositions provided in this application, dispersed in a solid inner matrix, which is surrounded by the outer polymeric membrane, which is insoluble in the fluids of the body, but provides the possibility of diffusion through her active ingredient contained in the pharmaceutical compositions.

Suitable internal matrix include polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene-vinyl acetate copolymers, silicone rubbers, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers such as hydrogels of esters of acrylic and methacrylic acid, collagen, crosslinked polyvinylalcohol and cross-linked partially hydrolyzed polyvinyl acetate.

Suitable external polymeric membranes include polyethylene, polypropylene, these the ene/propylene copolymers, the ethylene/ethylacrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubbers, polydimethylsiloxane, neoprene rubber, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride with vinyl acetate, vinylidenechloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrine rubber, copolymer of ethylene/vinyl alcohol, terpolymer ethylene/vinyl acetate/vinyl alcohol and a copolymer of ethylene/vinyloxyethyl.

Local introduction

Pharmaceutical compositions obespechenie in the present invention, can be entered locally on the skin, holes or mucous membrane. Local injection, as the term is used in this application, includes (intra)dermal, conjunctiva, intracorneal, intraocular, ophthalmic, ear, percutaneous, nasal, vaginal, urethral, respiratory and rectal administration.

Pharmaceutical compositions obespechenie in the present invention may be formulated in any dosage forms that are suitable for local injection for local or systemic effect, including emulsions, solutions, suspensions, creams, gels, hydrogels, ointments, fine powders, dressings, elixirs, lotions, suspensions, tinctures, pastes, foams, films, aerosols, medicines for the roshaniya, sprays, suppositories, bandages, dermal patches. Pharmaceutical compositions formulated for topical administration, obespechenie in the present invention may also include liposomes, micelles, microspheres, nanosystems, and mixtures thereof.

Pharmaceutically acceptable carriers and excipients suitable for use in compositions for topical administration, presented in this invention include, but are not limited to, water media, mixed water media, non-aqueous media, antimicrobial agents or preservatives against the growth of microorganisms, stabilizers, substances that enhance the solubilization, isotonic agents, buffering agents, antioxidants, local anesthetics, suspendresume and dispersing funds, wetting agents or emulsifying agents, complexing agents, airing or hepatoblastoma agents, penetration enhancers, createsite substances lisamarie substances, thickening agents, and inert gases.

Pharmaceutical compositions can also enter local by using electroporation, iontophoresis, phonophoresis, sonophoresis or microneedles or Bezuglova injections, such as POWDERJECT™ (Chiron Corp., Emeryville, CA), and BIOJECT™ (Bioject Medical Technologies Inc., Tualatin, OR).

Pharmaceutical compositions obespechenie in the present invention, can be represented in the forms of the ointments, creams and gels. Suitable carrier materials for ointments include oil or hydrocarbon media, including lard, betonirovannoy lard, olive oil, cotton seed and other oils, vaseline; emulsifiable or absorbent media, such as hydrophilic petrolatum, hydroxystanozolol and anhydrous lanolin; sadogashima media, such as hydrophilic ointment; water-soluble carriers for ointments, including glycols with different molecular weight; emulsified media, either in the form of emulsion, water-in-oil (W/O)or in the form of emulsions of oil-in-water (O/W), including cetyl alcohol, glycerylmonostearate, lanolin and stearic acid (see, Remington: The Science and Practice of Pharmacy, supra). These carriers are emollients, but usually require the addition of antioxidants and preservatives.

Suitable basis for the cream can be an oil-in-water or water-in-oil. Media for creams can be water-washable, and contain an oil phase, an emulsifier and the aqueous phase. The oil phase is also called the "inner" phase, which usually consists of petroleum butter and fatty alcohol such as cetyl or stearyl alcohol. The aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and usually contains a wetting agent. The emulsifier in the composition of the cream may be own the th non-ionic, anionic, cationic or amphoteric surface-active substance.

Gels are semisolid systems type of suspension. Single-phase gels contain organic macromolecules distributed essentially uniformly in the liquid medium. Suitable gel-forming substances include crosslinked polymers of acrylic acid, such as carbomer, carboxypolymethylene, CARBOPOL®; hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers and polyvinyl alcohol; Celulose polymers such as hydroxypropylcellulose, hydroxyethylcellulose, hypromellose, phthalate of hydroxypropylmethylcellulose and methyl cellulose; gums such as tragakant and xanthan gum; sodium alginate; and gelatin. To obtain a homogeneous gel can be added dispersing agents such as alcohol or glycerin, or gel-forming substance can be atomized by grinding into powder, mechanical mixing and/or stirring.

Pharmaceutical compositions obespechenie in the present invention, it is possible to enter rectal, urethral, vaginal or perivaginal in the form of suppositories, pessaries, sticks, poultices or compresses, pastes, powders, dressings, creams, plasters, contraceptives, ointments, solutions, emulsions, suspensions, tampons, gels, foams, is praew or clysm. These dosage forms can be obtained using traditional methods, as described in Remington: The Science and Practice of Pharmacy, supra.

Rectal, urethral and vaginal suppositories are solid dosage forms for insertion into body orifices, which are solid at ordinary temperatures but melt or soften at body temperature to release the active ingredient(ingredients) inside these holes. Pharmaceutically acceptable carriers used in rectal and vaginal suppositories include bases or carriers, such as hardeners, which provide a melting point close to body temperature, when formulating their pharmaceutical compositions, obespechivanie in the present invention; and antioxidants described in this application, including bisulfite and sodium metabisulfite. Suitable carrier materials include, but are not limited to, cocoa butter (cocoa butter), glycerin-gelatin, carbowax (polyoxyethyleneglycol), spermaceti, paraffin, white and yellow wax, and appropriate mixtures of mono-, di - and triglycerides of fatty acids, hydrogels such as polyvinyl alcohol, hydroxyethylmethacrylate, polyacrylic acid; glitserinovoye gelatin. You can use a combination of different media. Rectal and vaginal suppositories can be obtained by way of pressing the Lee formation. Typical mass rectal and vaginal suppository is from about 2 to about 3,

Pharmaceutical compositions obespechenie in the present invention, it is possible to enter ophthalmic through in the form of solutions, suspensions, ointments, emulsions, gel-forming solutions, powders for dilution, gels, eye inserts and implants.

Pharmaceutical compositions obespechenie in the present invention, it is possible to enter intranasally or by inhalation into the respiratory tract. The pharmaceutical compositions can be provided in the form of an aerosol or solution for the delivery of the container in which created pressure, pump, spray, atomizer, such as an atomizer using electrohydrodynamics to produce thin spray or nebulizer, alone or in combination with a suitable propellant, such as 1,1,1,2-Tetrafluoroethane or 1,1,1,2,3,3,3-Heptafluoropropane. Pharmaceutical compositions can also be presented as a dry powder for insufflation, alone or in combination with an inert carrier such as lactose, or a phospholipid; and nasal drops. For intranasal use, the powder may include bioadhesive substance, including chitosan, or a cyclodextrin.

Solutions or suspensions for use in a pressurized container, pump, spray, atomizer, or nebulae is zere can be formulated as follows, to contain ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilization, or extending release of the active ingredient in the present invention, the propellant as the solvent; and/or surfactant, such as sarbatorile, oleic acid or oligobrachia acid.

Pharmaceutical compositions obespechenie in the present invention, can be crushed to a particle size suitable for delivery by inhalation, such as about 50 μm or less, or about 10 microns or less. Particles of such sizes can be obtained using the grinding method, well-known experts in this field, such as spiral jet milling, jet milling in the fluidized bed, speratically liquid handling with the formation of the nanoparticles, high pressure homogenization, or spray drying.

Capsules, blisters and cartridges for use in an inhaler or insufflator can be formulated to contain a powder mixture including pharmaceutical compositions, obespechenie in the present invention; appropriate basis for powder, such as lactose or starch; and modifying additive, such as L-leucine, mannitol, or magnesium stearate. Lactose can b shall be anhydrous or in the form of a monohydrate. Other suitable excipients or carriers include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose. Pharmaceutical compositions obespechenie in the present invention, for administration by inhalation/intranasal may additionally include a suitable odorant, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium.

Pharmaceutical compositions obespechenie in the present invention for local injection may be formulated for immediate release or modified release, including slow-motion, long, pulsating, controlled, targeted and programmed release.

Modified-release

Pharmaceutical compositions obespechenie in the present invention, can bitstormlite in the form of a pharmaceutical form modified-release. As used in this application, the term "modified release" refers to the dosage form, in which the rate or place of release of the active ingredient(ingredient) differ from the dosage form immediate release with the introduction in the same way. Pharmaceutical form modified release include forms of delayed -, extended -, prolonged, long inogo, pulsed, controlled, accelerated and rapid, directional, programmable release and held in the stomach dosage forms. Pharmaceutical compositions for dosage forms of the modified release can be obtained using various devices and methods modified release, which are known to experts in this field, including, but not limited to, matrix devices of the controlled release device osmotically controlled release, a controlled release device, comprising particles of different shape and size, ion-exchange resins, enterosgelya coating, multilayer coatings, microspheres, liposomes, and combinations thereof. The rate of release of the active ingredient(ingredient) also can be modified by changing the particle size and polymorphism of the active ingredient(ingredient).

Examples of modified release include, but are not limited to, those described in U.S. Patents№№: 3845770; 3916899; 3536809; 3598123; 4008719; 5674533; 5059595; 5591767; 5120548; 5073543; 5639476; 5354556; 5639480; 5733566; 5739108; 5891474; 5922356; 5972891; 5980945; 5993855; 6045830; 6087324; 6113943; 6197350; 6248363; 6264970; 6267981; 6376461; 6419961; 6589548; 6613358; and 6699500.

1. Matrix devices controlled release

Pharmaceutical compositions obespechenie in this izaberete the AI for pharmaceutical form modified-release can be obtained using a matrix device of supervised release, known to specialists in this field (see, Takada et al. "Encyclipedia of Controlled Drug Delivery," Vol. 2, Mathiowitz Ed., Wiley, 1999).

In one variant embodiment, the pharmaceutical compositions obespechenie in the present invention for pharmaceutical form modified-release is obtained using erodible matrix device, which is nabukenya, erodible or water soluble polymers, including synthetic polymers and natural polymers and derivatives, such as polysaccharides and proteins.

Substances useful for the formation of erodible matrix include, but are not limited to, chitin, chitosan, dextran & pullulan; resinous agar, Arabic gum, gum karaya, gum fruit Robinia, gum tragakant, Cartagena, gum, ghatti, guar gum, xanthan gum and scleroglucan; starches such as dextrin and maltodextrin; hydrophilic colloids such as pectin; phosphatides, such as lecithin; alginates; propylene glycol alginate; gelatin; collagen; and derivative cellulose, such as ethylcellulose (EC), metilcellulose (MEC), carboxymethylcellulose (CMC), CMEC, hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), cellulose acetate (CA), cellulose propionate (CP), cellulose butyrate (CB), ACET butyrate cellulose (CAB), CAP, CAT, hypromellose (HPMC), HPMCP, HPMCAS, the acetate hypromellose trimellitate (HPMCAT) and metilgidroxiatilzelllozu (EHEC); polyvinylpyrrolidone; polyvinyl alcohol; polyvinyl acetate; esters of fatty acids of glycerol; polyacrylamide; polyacrylic acid; copolymers metacrilato acid or methacrylic acid (EUDRAGIT®, Rohm America, Inc., Piscataway, NJ); poly(2-hydroxyethyl-methacrylate); polylactide; copolymers of L-glutamic acid and ethyl-L-glutamate; degradable copolymers of lactic acid-glycolic acid; poly-D-(-)-3-hydroxipropionic acid; and other derivatives of acrylic acid, such as homopolymers and copolymers of butyl methacrylate, methyl methacrylate, ethyl methacrylate, ethyl acrylate, (2-dimethylaminoethyl)methacrylate, and (trimethylaminoethyl)methacrylamide.

In the following variants embodiment, the pharmaceutical compositions are formulated with the imperishable matrix device. Active ingredient(the ingredient) dissolved or dispersed in an inert matrix, and it is released primarily by diffusion through an inert matrix after injection. Substances suitable for use as a nondestructive matrix devices include, but are not limited to, insoluble plastics, such as polyethylene, polypropylene, polyisoprene, polyisobutylene, polybutadiene, polymetylmetacrylate, polybutylmethacrylate, chlorinated polyethylene, polyvinyl chloride, copolymers of methyl acrylate-methyl methacrylate, copolymers of ethylene-vinyl acetate, ethylene/propylene copolymers, copolymers of ethylene/ethyl acrylate, copolymers of vinyl chloride with vinyl acetate, vinylidenechloride, ethylene and propylene, ionomer polyethylene terephthalate, butyl rubber, epichlorohydrine rubber, copolymer of ethylene/vinyl alcohol, terpolymer ethylene/vinyl acetate/vinyl alcohol and a copolymer of ethylene/vinyloxyethyl, polyvinylchloride, plasticized nylon, plasticized polyethyleneterephthalate, natural rubber, silicone rubbers, polydimethylsiloxane, siliconcarbide copolymers and hydrophilic polymers, such as ethylcellulose, cellulose acetate, crosspovidone and cross-linked partially hydrolyzed the polyvinyl acetate; fatty compounds, such as Carnauba wax, microcrystalline wax, and triglycerides.

In the matrix system for the controlled release of the desired release kinetics can be controlled, for example, by the type of polymer, the viscosity of the polymer, the particle size of the polymer and/or active ingredient(ingredient), the relationship of the active ingredient(ingredients) to the polymer and other excipients or carriers in the compositions.

Pharmaceutical compositions, obspechivaya the s in the present invention for pharmaceutical form modified-release can be obtained by methods known to experts in this field, including direct compression, dry or wet granulation followed by pressing, granulation of the melt, followed by pressing.

2. Device osmotically controlled release

Pharmaceutical compositions obespechenie in the present invention for pharmaceutical form modified-release, can be obtained by using the device osmotically controlled release, including the single-chamber system, two-chamber system, a method of asymmetric membranes (AMT) and extruding core (ECS). Typically, such devices have at least two components: (a) the core which contains an active ingredient(the ingredient); and (b) partially permeable membrane with at least one aperture for delivery, which encapsulates the core. Partially permeable membrane controls the flow of water to the core from an aqueous environment, causing the release of drug through extrusion through the opening(s) for delivery.

In addition to the active ingredient(ingredient), the core device for osmotically controlled release optionally includes an osmotic agent, which generates driving the DRS to transport water from the environment into the core of the device. One class of osmotic agents are water-nabukenya hydrophilic polymers, which are also called "cosmopolitanly" and "hydrogels", including, but not limited to, hydrophilic vinyl and acrylic polymers, polysaccharides such as calcium alginate, polyethylene oxide (PEO), polyethylene glycol (PEG), polypropyleneglycol (PPG), poly(2-hydroxyethylmethacrylate), poly(acrylic)acid, poly(methacrylic) acid, polyvinylpyrrolidone (PVP), crosslinked PVP, polyvinyl alcohol (PVA), PVA/PVP copolymers, PVA/PVP copolymers with hydrophobic monomers such as methyl methacrylate and vinyl acetate, hydrophilic polyurethanes containing a large number of PEO units, the sodium croscarmelose, carrageen, hydroxyethyl cellulose (HEC), hydroxypropylcellulose (HPC), hypromellose (HPMC), carboxymethylcellulose (CMC) and carboximetilzellulozu (CEC), sodium alginate, polycarbophil, gelatin, xanthan gum and matrikamantra.

Another class of osmotic agents are cosmogeny, which are able to absorb water, affecting the osmotic pressure gradient across the barrier of the surrounding coating. Suitable omogeni include, but are not limited to, inorganic salts such as magnesium sulfate, magnesium chloride, calcium chloride, sodium chloride, lithium chloride, potassium sulfate, potassium phosphate, sodium carbonate, sulfite intothree is, the lithium sulfate, potassium chloride and sodium sulfate; sugars such as dextrose, fructose, glucose, Inositol, lactose, maltose, mannitol, raffinose, sorbitol, sucrose, trehalose, and xylitol; organic acids such as ascorbic acid, benzoic acid, fumaric acid, citric acid, maleic acid, sabotinova acid, sorbic acid, adipic acid, detinova acid, glutamic acid, p-toluensulfonate acid, succinic acid and tartaric acid; urea; and mixtures thereof.

Osmotic agents with different rates of dissolution can be used to influence how quickly the active ingredient(ingredients) is initially delivered from the dosage form. For example, amorphous sugars, such as MANNOGEM EZ (SPI Pharma, Lewes, DE) can be used to ensure expedited shipping during the first two hours, to provide the desired therapeutic effect, and gradually and continually release other amounts to maintain the desired level of therapeutic or prophylactic effect over an extended period of time. In this case, the active ingredient(ingredients) are released with such speed to compensate metabolized by or derived from an organism, the amount of the active ingredient.

The core also includes a large diversity, the connector of the other excipients and carriers, described in this application, to enhance the effect of the dosage form or improve stability or workability.

Substances useful for obtaining a partially permeable membrane include various grades of acrylics, vinyls, ethers, polyamides, polyesters and celulosic derivatives that are water-permeable and water-insoluble at physiologically relevant pH values, or they can be made insoluble in water by chemical changes, such as stitching. Examples of suitable polymers useful for coating include plasticized, unplasticized and reinforced cellulose acetate (CA), cellulose diacetate, cellulose triacetate, CA propionate, cellulose nitrate, acetylbutyrate cellulose (CAB), CA ethylcarbamate, CAP, CA methylcarbamate, CA succinate, cellulose acetate trimellitate (CAT), CA diethylaminoacetate, CA ethylcarbonate, CA CHLOROACETATE, CA ethylacetat, CA methylsulfonate, CA butylsulfonyl, CA p-toluensulfonate, agar acetate, amylose triacetate, betaglucans, betaglucosilated, acetaldehyde dimethylacetal, triacetate gum fruit Robinia, ethylene gidroksilirovanii-vinyl acetate, EC, PEG, PPG, PEG/PPG copolymers, PVP, HEC, HPC, CMC, CMEC, HPMC, HPMCP, HPMCAS, HPMCAT, poly(acrylic) acids and esters and poly-(methacrylic) acids and esters and their copolymers, starch, dextran, dextrin, chitosan, is ollagen, gelatin, polyalkene, polyesters, polysulfones, polyethersulfones, polystyrenes, polyvinylchloride, simple and complex polyvinyl ethers, natural waxes and synthetic waxes.

Partially permeable membrane may also be a hydrophobic microporous membrane, where the pores, essentially, filled with gas and is not wetted by the water environment, but are permeable to water vapor, as disclosed in U.S. Patent No. 5798119. Such hydrophobic, but permeable to water vapor, the membrane typically consists of hydrophobic polymers, such as polyalkene, polyethylene, polypropylene, polytetrafluoroethylene, derivatives of polyacrylic acid, polyethers, polysulfones, polyethersulfones, polystyrenes, polyvinylchloride, polyvinylidene fluoride, simple and complex polyvinyl ethers, natural waxes and synthetic waxes.

Available in semi-permeable membrane of the opening(s) for delivery may be formed after the formation of the coating by mechanical or laser drilling. The opening(s) for delivery can also be formed in situ by erosion of the layer of water-soluble substances or break the thinner part of the casing above embedded in her core. In addition, the hole for delivery may be formed in the coating process, as in the case of asymmetric membranes is s coating type, disclosed in U.S. Patent No. 5612059 and 5698220.

The total amount of active ingredients(ingredients)that is emitted and the rate of release, in essence, can be modulated with regard to the thickness and porosity of the semi-permeable membrane, the composition of the core and the number, size and position of holes for delivery.

Pharmaceutical compositions for pharmaceutical form osmotically controlled release can optionally include additional conventional excipients or carriers as described in this application, to improve the action or the workability of the composition.

Dosage forms with osmotically controlled release can be obtained in accordance with the traditional methods and procedures, which are known to experts in this field (see, Remington: The Science and Practice of Pharmacy, supra; Santus and Baker, J. Controlled Release 1995, 35, 1-21; Verma et al., Drug Development and Industrial Pharmacy 2000, 26, 695-708; Verma et al., J. Controlled Release 2002, 79, 7-27).

In some embodiments, embodiments of the pharmaceutical compositions presented in this application are formulated into dosage forms with AMT controlled-release, which includes asymmetric osmotic membrane that coats a core comprising the active ingredient(the ingredients), and other pharmaceutically acceptable excipients or carriers. Cm. U.S. patent No. 5612059 and WO 2002/17918. Dosage forms with AMT controlled-release can be obtained in accordance with the traditional methods and procedures, which are known to experts in this field, including direct compression, dry granulation, wet granulation and method of coating by dipping.

In some embodiments, embodiments of the pharmaceutical compositions presented in this application are formulated into dosage forms with ESC controlled-release, which covers the core comprising the active ingredient(the ingredient), hydroxyethylcellulose and other pharmaceutically acceptable excipients or carriers.

3. Devices controlled release comprising particles of various shapes and sizes

Pharmaceutical compositions obespechenie in the present invention for pharmaceutical form modified-release, can be obtained in the form of a controlled release device with particles of various shapes and sizes, which includes many particles, granules or pellets with a size from about 10 microns to about 3 mm, from about 50 μm to about 2.5 mm, or from about 100 μm to about 1 mm in diameter. Such compositions in the form of many different particles can be obtained by methods known to experts in this field, including wet and dry of granulares the tion, extrusion/spheronization, roller compaction, solidification of the melt and by coating method, spray on grain core. See, for example, Multiparticulate Oral Drug Delivery, Marcel Dekker: 1994; and Pharmaceutical Pelletization Technology, Marcel Dekker: 1989.

Other excipients or carriers as described in this application can be mixed with pharmaceutical compositions for easier handling and education of many particles. The obtained particles can form a device, comprising many different particles, or they can be coated using various film-forming substances, such as intersolubility polymers, vodosnabzhenie and water-soluble polymers. Composition consisting of many different particles can be further processed to obtain capsules or tablets.

4. Targeted delivery

Pharmaceutical compositions obespechenie in the present invention can also be formulated to target a particular tissue, receptor, or other area of the body of the subject to be treated, including liposomal delivery system, the delivery system based on the release of red blood cells and antibodies. Examples include, but are not limited to, U.S. Patents№№ 6316652; 6274552; 6271359; 6253872; 6139865; 6131570; 6120751; 6071495; 6060082; 6048736; 6039975; 6004534; 5985307; 5972366; 5900252; 5840674; 5759542; and 5709874.

D. assessment of the activity of the compounds

Standard physiological, pharmacological and biochemical procedures are available for testing the compounds to identify those that possess biological activities that modulate the activity of a JAK kinase, including wild-type and mutant JAK kinase. Such assays include, for example, biochemical assays, such as assays of binding, see, Fabian et al., Nature Biotechnology 2005, 23,329-336, the analyses include radioactivity, as well as various cellular assays.

Examples of methods of cellular analysis include measurement of STAT5A phosphorylation, for example, by the method of enzyme-linked immunosorbent assay (ELISA), or the measurement of proliferation in leukemic cell lines, such as TF-1 or HEL-2, for example, by incorporation of BrdU, a method for fluorescent labeling or by analysis of the reporter, activated transcription factor STAT5. Cells that are useful for such assays include cells with JAK wild type, such as TF-1, or with the mutated JAK, such as cell line HEL-2, which Express a constitutively active JAK2 with V617F mutation. Suitable cells include cells obtained by culturing cells from samples taken from the patient, as well as cells obtained using routine molecular biology techniques, for example, retroviral transduction, transfection, the mutagen is and etc.

E. Methods of using the compounds and compositions

Also in this application presents methods of using the disclosed compounds and compositions, or pharmaceutically acceptable salt, solvate or hydrate for the treatment, prevention or relief of a disease or disorder that is mediated or otherwise affected by the activity of the JAK kinases, including JAK2 kinase, or one or more symptoms of diseases or disorders that are mediated or otherwise affected by the activity of the JAK kinases, including JAK2 kinase. JAK kinase may represent a form of wild type and/or mutant form of JAK2 kinase. As described above, such diseases or disorders include, without limitation: myeloproliferative disorders such as polycythemia Vera (PCV), essential thrombocythemia and idiopathic myelofibrosis (IMF); leukemia such as myeloid leukemia, including chronic myeloid leukemia (CML), imatinib-resistant forms of CML, acute myeloid leukemia (AML) and the subtype of AML, acute megacaryoblastic leukemia (AMKL); lymphoproliferative diseases, such as myeloma; cancer, including head and neck cancer, prostate cancer, breast cancer, ovarian cancer, melanoma, lung cancer, brain tumor, pancreatic cancer and carcinoma of the kidney; and inflammatory the e disease or disorder, related to immune dysfunction, immunodeficiency, immunomodulation, autoimmune disease, tissue graft rejection, disease graft-versus-host, wound healing, kidney disease, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, psoriasis, allergic rhinitis, inflammatory bowel disease, including Crohn's disease and ulcerative colitis (UC), systemic lupus erythematosus (SLE), arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD) and dry eye syndrome (or keratoconjunctivitis sicca (KCS)).

In some embodiments, embodiments in the present application presents methods of using the disclosed compounds and compositions, or pharmaceutically acceptable salt, solvate or hydrate for the treatment, prevention or relief of diseases or disorders selected from myeloproliferative disorders such as polycythemia Vera (PCV), essential thrombocythemia and idiopathic myelofibrosis (IMF) and hypereosinophilic syndrome (HES); leukemia such as myeloid leukemia, including chronic myeloid leukemia (CML), imatinib-resistant forms of CML, acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and the subtype of AML, acute megacaryoblastic leukemia (AMKL); lymphoproliferative diseases, such as myeloma; cancer, including the Aya cancer of the head and neck, prostate cancer, breast cancer, ovarian cancer, melanoma, lung cancer, brain cancer, pancreatic cancer, stomach cancer, thyroid cancer, carcinoma of the kidney, Kaposi's sarcoma, a disease of Castellana, melanoma; and inflammatory diseases or disorders related to immune dysfunction, immunodeficiency or immune modulation, such as a tissue graft rejection, disease graft-versus-host, wound healing, kidney disease; autoimmune diseases such as multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, psoriasis, allergic rhinitis, atopic dermatitis, malignant myasthenia gravis, inflammatory bowel disease, including Crohn's disease and ulcerative colitis (UC), systemic lupus erythematosus (SLE), arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma and chronic obstructive pulmonary disease (COPD), inflammatory eye diseases, including conjunctiva, uveitis, iritis, scleritis, inflammatory diseases of the upper respiratory tract, including the upper respiratory tract, such as rhinitis and sinusitis, and inflammatory diseases of the lower respiratory tract including bronchitis, inflammatory myopathy, such as myocarditis, other inflammatory diseases, such as ischemic reperfusion lesions, associated with inflammatory ischemic FDS is a tie, such as shock or cardiac arrest, and other inflammatory conditions, such as the system inflammatory response syndrome (SIRS) and sepsis.

In some embodiments the embodiment of the JAK-oborudovanie diseases and disorders include restenosis, fibrosis and scleroderma. In some embodiments the embodiment of the JAK-oborudovanie diseases include viral diseases such as Epstein-Barr (EBV), hepatitis (hepatitis B or hepatitis C, human immunodeficiency virus (HIV), T-lymphotropic virus type 1 human (HTLV-I), varicella zoster virus, and papilloma virus human (HPV).

F. Combination therapy

In addition, professionals in this field should be clear that the compounds, isomers and pharmaceutically acceptable salts, solvate or hydrate presented in this invention, including pharmaceutical compositions and compositions containing these compounds, can be used in various methods of combination therapy for the treatment of conditions and diseases described above. Thus, the present invention also provides use of the compounds, isomers and pharmaceutically acceptable salts, solvate or hydrate presented in this invention, in combination with other active pharmaceutical for the treatment of diseases/conditions described in this application.

In some embodiments, embodiments of anticancer tools include anti-metabolites (for example, 5-fluorouracil, cytarabine, methotrexate, fludarabine, and others), means against the formation of microtubules (e.g., Vinca alkaloids such as vincristine, vinblastine; taxanes such as paclitaxel and docetaxel), alkylating tools (e.g., cyclophosphamide, melphalan, carmustine, means on the basis of nitrosamine, such as mechlorethamine and hydroxyurea), the funds on the basis of platinum (for example, cisplatin, carboplatin, oxaliplatin, satraplatin and CI-973), anthracyclines (e.g., doxorubicin and daunorubicin), antitumor antibiotics (e.g., mitomycin, idarubitsin, adriamycin and daunomycin), topoisomerase inhibitors (e.g. etoposide and camptothecin), anti-angiogenesis (e.g., Sutent®, sorafenib and Bevacizumab) or any other cytotoxic funds (for example, estramustine phosphate, prednimustine), hormones or agonists, antagonists, partial agonists or partial antagonists hormones, inhibitors is Inez (such as imatinib) and radiation therapy.

In some embodiments the embodiment of anti-inflammatory agents include inhibitors of matrix metalloproteinases, inhibitors of Pro-inflammatory cytokines (e.g., anti-TNF molecules, soluble receptors of TNF and IL1), nonsteroidal anti-inflammatory drugs (NSAIDs), such as inhibitors prostaglandins (for example, helenmary salicylate and salicylsalicylic acid), inhibitors of COX-1 or COX-2 or agonists of the glucocorticoid receptor, such as corticosteroids, methylprednisone, prednisone or cortisone.

The compound or composition provided in the present invention, or their pharmaceutically acceptable salt, solvate or hydrate, can be administered simultaneously with introduction, before or after administration of one or more of the above tools.

Also provided pharmaceutical compositions containing the compound in the present invention, or its pharmaceutically acceptable salt, solvate or hydrate and one or more of the above tools.

It also provides a combination therapy which provides treatment or preventing symptoms or associated complications of cancer and similar diseases and disorders, comprising the administration to a subject in need this, one of the compounds or compositions disclosed in the present is her application, or their pharmaceutically acceptable salts, solvate or hydrate, with one or more anticancer agents.

G. Obtaining compounds

The initial substance in the examples of the synthesis presented in this application are either available from commercial sources or can be obtained by using known literature procedures (for example, March's Advanced Organic Chemistry: Reactions, Mechanisms and Structure, (1992) 4th Ed.; Wiley Interscience, New York). All commercially available compounds were used without further purification unless otherwise stated. Spectra 300 MHz proton (1(H) nuclear magnetic resonance (NMR) were recorded on Bruker Avance 300 NMR spectrometer. Significant peaks represented in the form of tabular data, and they typically are included: the number of protons and multipletness (s - singlet; d - doublet; t - triplet; square - Quartet, m - multiplet; users broadened singlet). Chemical shifts are indicated in ppm (δ) relative to tetramethylsilane. Mass spectra of low-resolution (MS) were obtained in the form of mass spectra ionization electrospray (ESI), which were recorded on the device Shimadzu HPLC/MS using reversed-phase conditions (acetonitrile/water, 0.05% of acetic acid). Preparative reversed-phase HPLC is usually carried out using HPLC Varian system equipped with a column with reversed phase Phenomenex phenylhexa, henomenex Luna C18 or Varian Pursuit diphenyl; typical elution conditions included the use of the gradient, including increasing the composition of the organic co-solvent is 0.05% HOAc/CH3CN or 0.05% HOAc/MeOH) to an aqueous co-solvent (0,05% aqueous HOAc). Chromatography on silica gel was carried out either manually, usually following a published procedure, flash chromatography (Still et al. (1978) J. Org. Chem. 43:2923)or on an automated system (for example, Biotage SP instrument) using columns with a nozzle made of silica gel.

It should be clear that in the following description, combinations of substituents and/or variables in the presented formulas are valid only in the case when it comes to suitable compounds under standard conditions.

Also, specialists in this area should be clear that the method described below, it may be necessary to protect functional groups of intermediate compounds suitable protective groups. Such functional groups include hydroxy, amino, mercapto and carboxylic acid. Suitable protective groups for hydroxy include trialkylsilyl or diarylethylenes (for example, tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl and the like. Suitable protective groups for amino, amidino and guanidino include tert-butoxycarbonyl, benzyloxycarbonyl and such is. Suitable protective groups for mercapto include-C(O)-R (where R is an alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable protective groups for carboxylic acids include alkilany, arrowy or Uralkaliy esters.

Protective groups can be added or removed in accordance with standard methods that are well known to specialists in this field, as specified in this application. The use of protective groups are described in Green, T. W. and P.G.M. Wutz, Protective Groups in Organic Synthesis (1991), 2nd Ed., Wiley-Interscience.

The specialist in this area with average skills will be able to easily determine what options for each Deputy are suitable for the reaction conditions of each Scheme. In addition, substituents selected from the components, as described above, and may be attached to the original substances, intermediate compounds and/or end products, in accordance with the scheme, known to specialists with average skills.

Also it should be clear that the compounds presented in this invention can exist as one or more isomers, which are E/Z isomers, enantiomers and/or diastereomers.

The compounds of formula (I) can be obtained as shown in the following schemes, unless otherwise indicated, and a variety of the substituents defined in this application in its other sections.

In this application used standard abbreviations and acronyms defined in J. Org. Chem. 2007 72(1): 23A-24A. Other abbreviations and acronyms used in this application, have the following meanings:

DCMDichloromethane
DIEADiisopropylethylamine
EDCIThe hydrochloride of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide
EtOACThe ethyl acetate
EtOHEthanol
FBSFetal bovine serum
HATUHexaphosphate O-(7-asobancaria-1-yl)-N,N,N',N'-tetramethylurea
HOAcAcetic acid
HOBtN-hydroxybenzotriazole
MeOHMethanol
TEAthe triethylamine
Trailtriphenylmethyl

The compounds presented in this application, Sintesi is ovale in accordance with the following diagrams and descriptions. Scheme 1 illustrates the General path of a key synthetic intermediate compounds and the compounds presented in this invention, through substituted anthranilamide 5. On the basis of substituted benzoic acid, nitration under standard conditions, for example, the nitric acid treatment in acid conditions when heated, if necessary, provides appropriate nitrobenzoic acid 2, which is separated from any undesired regioisomers by chromatography or crystallization. The restoration of the nitro group under standard conditions, for example, using hydrogen gas and a catalyst based on a noble metal in a solvent such as water, lower alcohol, EtOAc or DMF; metallic Sn or Fe in acidic conditions; or SnCl2in a solvent such as EtOH or DMF gives the corresponding Anthranilic acid 4. Conversion of the carboxyl group 4 in carboxamido group 5 is carried out by any of numerous standard methods, including treatment with ammonia or ammonium chloride in the presence of binding reagents, such as HATU, EDCI (hexaphosphate benzotriazol-1 yloxy)Tris(dimethylamino)phosphonium, dicyclohexylcarbodiimide and the like, or, alternatively, via the acid chloride of the acid in the processing of the acid with thionyl chloride or phosphorylchloride or the like, with subsequent is by adding a suitable form of ammonia, such as ammonia in MeOH or ammonium hydroxide. Anthranilamide 5 then condensed with a suitably activated carboxylic acid derivative 6 with subsequent dehydrating the cyclization, promoted, for example, by heating or TMSCl in the presence of a tertiary amine base such as TEA, DIEA, or pyridine, to obtain the 4-hydroxyquinazoline 8. The hydroxyl group of 4-hydroxyquinazoline 8 then converted into a group to delete. Examples of such conversions include the processing of halogenation agent such as phosphorylcholine, obtaining hintline 9 (Z = halogen), or sulphonylchloride with getting hintline 9 (Z = sulfonyloxy derived), or halogenation agent, then the organic mercaptan, followed by oxidation of sulphur compounds 7 (Z = alvinlee or sulfonylurea derived). Hinzelin 9 then subjected to interaction with a suitable pyrazolines (pyrazole-NH2) in a suitable solvent, such as DMF or dimethylacetamide, optionally in the presence of an ion source of iodine, for example, potassium iodide or tetrabutylammonium iodide, optionally under heating, to obtain, after separation, connection 10.

Scheme 1

It should be clear that at appropriate stages of the synthesis method, such that shown in Scheme 1, one or several who are R 6groups of formula 1-10 may serve as a precursor of the modified R6group end connection is provided in the present invention. For example, when the connection 1 R6=CO2Me, methoxycarbonyl group can be converted to a suitable stage of the synthesis, for example, carboxyl group by hydrolysis, amide by hydrolysis and subsequent activation of carboxypropyl and processing Amin, hydroxymethylene group by recovery in tertiary carbinol by treatment with two equivalents of Grignard reagent, aminomethyl group by restoring to hydroxymethylene group with subsequent oxidation to the aldehyde and subsequent by reductive amination with a suitable amine in the presence of a selective reducing agent, such as triacetoxyborohydride sodium. Similarly, when R6=OCH2Ph, then R6can be converted to OH by hydrolytic cleavage of the benzyl group, followed by alkylation of the obtained phenolic hydroxyl group by using optionally substituted alkylhalogenide or optionally substituted alkylsulfonate to obtain the corresponding aromatic ether.

Similarly, some of the R groups in the intermediate compounds 8, 9, or 10 can be included, as shown n the figure 1, and then converted to alternative R group.

In Scheme 2, anthranilamide 5, obtained in accordance with Scheme 1, treated with activated derivatives of oxalic acid, such as dialkylamines, either in pure form or in a suitable solvent such as EtOH or HOAc; or anthranilamide 5 is treated with chloride monoalkyl ester of oxalic acid in a suitable solvent such as DCM, in the presence of a base such as TEA, and, optionally, in the presence of a catalyst, such as DMAP; or anthranilamide 5 process monoalkylated air cyanoacetate when heated in a suitable solvent, such as acetonitrile or DMF, in the presence of a base, such as TEA. Similar to the methods described in Scheme 1, the subsequent processing of the products obtained in dehydrating conditions, for example by heating with or without TMSCl in the presence of a suitable base, such as DIEA, in a suitable solvent such as DCE, gives the bicyclic product 11. In addition, a slightly modified procedure output to the intermediate compound (11) is described in patent application WO2004/20441, incorporated by reference in its entirety. Conditions for the conversion of compound 11 to compound 12, the conversion of compound 12 compound 13 compound 14 and to convert the connection 13 connection 15 are similar to those which the quiet described in Scheme 1 for similar transformations. Alkoxycarbonyl group in 2-position chineselanguage ring compounds 12 or connection 14 can be treated with metallocenes, for example, abillities connection or aryl Grignard reagent in a suitable solvent, such diethyl ether, THF or other volatile solvent, to obtain the ketone 13 or 15, respectively. Although it is not shown in Scheme 2, the intermediate compound 11 can similarly be treated with metallwaren to obtain the corresponding arylketones, which can then be converted to compound 15 by converting 4-hydroxy-group in the group that you want, for example, chlorine, followed by substitution of the chlorine group suitably substituted 3-aminopyrazoles using reagents and conditions similar to those described for similar transformations in Scheme 1.

Scheme 2

M represents a metal

Figure 3 illustrates how to convert ketones 15, obtained in accordance with Scheme 2, the following compounds provided in the present invention. Treatment of compound 15 with a suitable reducing agent, for example, hydride reagent, such as borohydride sodium in an alcohol solvent or borohydride lithium in ether solvent or appropriate borohydride or aluminohydrides reagent in p is Chadasha system solvent, restores the ketone to the corresponding carbinol 16. Treatment of ketone 15 alkyl or abillities or mineralogically reagent gives a tertiary carbinol 17. Alternatively, treatment of ketone 15 O-substituted or O-unsubstituted hydroxylamine in a suitable solvent, such as alcohol or mixture of alcohol/water, optionally in the presence of acid or alkaline catalyst, gives the oxime 18. The oxime can be subjected to further processing in reducing conditions, for example, borane-aminoven complex in the presence of a strong acid when heated for prolonged reaction times or under conditions of hydrogenolysis (H2the catalyst based on a noble metal, optionally in the presence of organic or mineral acids) for extended periods of time with getting amine 19. Alternatively, the use of milder conditions such as lower temperatures, shorter reaction times or more soft acid, if present, gives alkoxyamine or hydroxylamine 20.

Scheme 3

Alternatively, amines 19 can be obtained in accordance with the sequence of the synthesis illustrated in Scheme 4. In figure 4, a hydroxyl group, carbinol 16 transform in the deleted group Z by processing, for example, a halide of phosphorus obtained with the em connection 21 (Z = halogen), or by treatment with sulphonylchloride in a suitable solvent such as DCM in the presence of a halogen acceptor such as a tertiary amine such as DIEA, or pyridine, to obtain compound 21 (Z = sulfonyloxy derived). For the latter reaction, in case of accidental sulfonylamine one or more other parts of the molecule, foreign sulfonylurea group is removed at a young Posta stage by processing a nucleophile such as hydroxide, ammonia or hydrazine.

As shown in Scheme 4, intermediate connection 21 is subjected to further conversion to azide 22 by replacing the deleted group Z azide ion, for example, by treatment of compound 21 azide of an alkali metal in a suitable solvent, such as a dipolar aprotic solvent, for example DMF or DMSO, at a temperature ranging from about 0°C to about 100°C. the Recovery of the azide with the help of a reducing agent, such as triphenylphosphine, followed by processing in the conditions of hydrolysis or hydrogenolysis (H2the catalyst based on a noble metal) in a suitable solvent, such as alcohol or DMF, gives the amine 23.

Figure 4 also illustrates that amines 23 can be further modified to produce 24 of the present invention, where one of the hydrogen atoms of the amino group substituted by a group R14. Education is denied amine 23 allermuir agent, such as the acid chloride of the acid or acid anhydride, usually in the presence of a base and optionally in the presence of an acylation catalyst, such as DMAP or pyridine, in a suitable solvent, such as EtOAc, DCM, DMF or THF, provides products 24 (R14= acyl). Alternatively, amine 23 is treated with alkylchlorosilanes, for example, ethyl - or isopropylcarbamate, in the presence of a base and optionally in the presence of an acylation catalyst, such as DMAP or pyridine, in a suitable solvent, such as EtOAc, DCM, DMF or THF, to obtain the corresponding carbamate 24 (R14=-C(O)OR12). Alternatively, amine 23 is treated with sulphonylchloride, for example methane - or benzosulphochloride, in the presence of a base and optionally in the presence of an acylation catalyst, such as DMAP or pyridine, in a suitable solvent, such as EtOAc, DCM, DMF or THF, to obtain the corresponding sulfonamida 23 (R14=-SO2R12). Alternatively, amine 23 in a suitable solvent, such as MeOH, EtOH, or DME, is treated with aldehyde in dehydrating conditions, for example, in the presence of molecular sieves or triethylorthoformate, optionally in the presence of an acid catalyst such as acetic acid or hydrochloric acid, to obtain the intermediate iminovogo connection, and the mixture is processing the feed, either simultaneously or sequentially, a selective reducing agent, such as cyanoborohydride sodium or triacetoxyborohydride sodium or (especially in the case of pre-treatment with aldehyde) borohydride sodium, to obtain a new amine 23 (R14= alkyl or aryl, each of which is optionally substituted).

Scheme 4

A representative method is illustrated in Scheme 5 for the conversion of ketone 15 in additional connections provided in the present invention. Ketone 15 in a suitable solvent, such as THF, DME, diglyme, or DMSO, is treated with anion formed in the processing trialkylphosphates strong base such as sodium hydride, lithium amide, dimethylsulfoxide (DMSO) anion or the like, at a suitable temperature ranging from about 0°C to about 100°C to give, after final processing and separation, α,β-unsaturated complex ester 25. Treatment of compound 25 in suitable reducing conditions, for example, H2in the presence of a catalyst based on a noble metal in a suitable solvent, such as alcohol or DMF, gives ester 26. The reduction of the ester group of compound 19 can be realized by processing hydride reduction system, such as LiAlH4/THF, LiBH4/THF or Ca(BH4 2/EtOH/THF, to obtain the primary alcohol 27. Hydroxyl group of the alcohol 27 is converted into a group to delete Z using the method well known in the prior art, for example, by treatment of compound 20 phosphorylchloride getting connection 28 (Z = halogen), or by processing the connection 27 sulphonylchloride getting connection 28 (Z = sulfonyloxy derived). The intermediate connection 28 can then be processed by a nucleophile with a connection 29. For example, treatment of compound 28 mercaptides the nucleophile gives compound 29 (Y=S); process connection 28 alkoxides the nucleophile gives compound 29 (Y=O); process connection 28 aminoven the nucleophile gives compound 29 (Y=NH or NRX).

Scheme 5

A complementary approach to the conversion of alcohol 27 in the compounds provided in the present invention, is illustrated in Scheme 6. Alcohol 27 is first treated with a suitable oxidation system, such as pyridine chlorproma/DCM or reagent Swarna (DMSO/oxalicacid/TEA/DCM) or DMSO/complex of pyridine-sulfur trioxide/TEA or periodinane Dess-Martin (1,1,1-triacetoxy)-1,1-dihydro-1,2-benzodioxol-3-(1H)-he/DCM)to obtain the aldehyde 30. Treatment of aldehyde 30 primary or secondary amine in the presence of a selective reducing agent, such as triacetoxyborohydride the d sodium or cyanoborohydride sodium, in a suitable solvent, such as alcohol, optionally in the presence of catalytic amount of acid such as acetic acid, gives the amine 31.

Scheme 6

The invention has been described in an illustrative manner, and it should be clear that the terminology used is intended to reveal the essence of the invention and not for limitation. Thus, professionals in this field should be understood that terms, such as choice of solvent, reaction temperature, volume, time of reaction may vary, provided that they provide the desired compounds. In addition, professionals in this field should also be clear that many of the reagents are presented in the following examples, may be replaced by other suitable reagents. See, for example, Smith & March, Advanced Organic Chemistry, 5thed. (2001). Such changes and modifications, including without limitation, those related to used chemical structures, substituents, derivatives, intermediates compounds, synthesis, compositions and/or methods provided in the present invention can be made without departure from the essence and scope of the present invention. The U.S. patents and publications referenced in this description are incorporated by reference.

EXAMPLES

Variation voploscheni is, described above should be considered only as examples, and specialists in this field must be known, or they can be determined using no more than routine experimentation, various equivalents of specific compounds, substances and procedures. All such equivalents are contemplated as included within the scope of the claimed invention and covered by the attached claims.

Example 1

Receive (3-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon

Stage A: To a suspension of ethyl 4-chlorination-2-carboxylate (237 mg, 1 mmol) in THF (5 ml) was added dropwise 1M solution of 3-performancebased in THF (2 ml, 2 mmol) at -20°C. the Reaction mixture was stirred at -20°C for 4 hours. The mixture was suppressed by addition of 0.5 n HCl solution (5 ml) and the biphasic mixture was extracted using EtOAc (2×10 ml). The combined organic layers were washed with saturated saline and was dried over MgSO4. (4-chlorination-2-yl)(3-forfinal)methanon received in the form of a yellow solid (190 mg, 66%).LC-MS (ESI) m/z 287 (M+H)+.

Stage B: (3-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon received, following a similar procedure as described for the synthesis of (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone in Example 3 with use the of (4-chlorination-2-yl)(3-forfinal)methanone as educt. Purification was performed using HPLC without finishing (26% yield).1H NMR (300 MHz, DMSO-d6) δ are 2.19 (s, 3H), is 6.54 (s, 1H), 7,60 (m, 2H), of 7.70 (m, 1H), 7,83-a 7.92 (m, 4H), up 8.75 (m, 1H), of 10.73 (s, 1H), 12,24 (s, 1H); LC-MS (ESI) m/z 348 (M+H)+.

Example 2

Obtain (4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(3-forfinal)methanone

To a solution of (4-chlorination-2-yl)(3-forfinal)methanone Example 1 (57 mg, 0.20 mmol) in DMF (3 ml) was added DIEA (0,069 ml, 0.4 mmol) and 1H-pyrazole-3-amine (83 mg, 1 mmol). The mixture was stirred at 50°C for 2 hours. The reaction was suppressed by the addition of water and the precipitate was filtered. The crude solid was purified using preparative TLC using DCM/MeOH as mobile phase to obtain (4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(3-forfinal)methanone (18 mg, 27%).1H NMR (300 MHz, DMSO-d6) δ to 6.80 (s, 1H), to 7.67-to 7.61 (m, 4H), 7,92-to 7.84 (m, 4H), 8,78 (m, 1H), was 10.82 (s, 1H), 12,54 (s, 1H); LC-MS (ESI) m/z 334 (M+H)+.

Example 3

Receive (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone

Stage A: To a solution of ethyl 4-chlorination-2-carboxylate (0.6 g, of 2.53 mmol) in THF (6 ml) at -40°C was added dropwise a 1 M solution of 4-performancebased in THF (3 ml, 3.0 mmol, 1.2 EQ.). The mixture was stirred at -40°C for 4 hours. The reaction was suppressed by addition of 0.5 n HCl solution (5 ml) and the mixture was extracted with is using EtOAc (2×10 ml). The combined organic layers were washed with saturated saline and was dried over MgSO4. The crude product was purified on a column of silica gel using a mixture of EtOAc-hexane as eluent. (4-chlorination-2-yl)(4-forfinal)methanon was obtained as a pale yellow solid (440 mg, 60%).1H NMR (300 MHz, DMSO-d6) δ 7,45-7,40 (m, 2H), 8.07-a 8,03 (m, 1H), 8.17-a 8,13 (m, 2H), 8,23 (m, 2H), 8,42 (d, 1H); LC-MS (ESI) m/z 287 (M+H)+.

Stage B: To a solution of (4-chlorination-2-yl)(4-forfinal)methanone (84 mg, 0.30 mmol) in DMF (3 ml) was added DIEA (0,103 ml, 0.6 mmol) and 5-methyl-1H-pyrazole-3-amine (88 mg, 0.9 mmol) at room temperature. The reaction mixture was heated at 40°C during the night. The reaction was suppressed by the addition of water and the yellow precipitate was collected by filtration and washed with water. The crude product was purified by chromatography on silica gel, elwira a mixture of DCM/MeOH to obtain (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone (30 mg, 29%).1H NMR (300 MHz, DMSO-d6) δ are 2.19 (s, 3H), is 6.54 (s, 1H), 7,40 (m, 2H), 7,68 (t, 1H), from 7.9 to 7.7 (m, 2H), 8,08 (m, 2H), total of 8.74 (d, 1H), 10,66 (s, 1H), 12,20 (s, 1H); LC-MS (ESI) m/z 348 (M+H)+.

Example 4

Obtain (4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone

(4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanon was obtained by following the procedure described in Example 3 for the synthesis of (4-forfinal)(4-(5-methyl-1H-piraso the-3-ylamino)hinzelin-2-yl)methanone, substituting 5-methyl-1H-pyrazole-3-amine in Example 3 1H-pyrazole-3-amine (30% yield).1H NMR (300 MHz, DMSO-d6) δ is 6.78 (s, 1H), 7,39 (t, 2H), of 7.70 (m, 2H), of 7.90 (m, 2H), 8,10 (m, 2H), 8,77 (d, 1H), 10,84 (s, 1H), 12,56 (C, H); LC-MS (ESI) m/z 334,3 (M+H)+.

Example 5

Obtain (4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(2-methoxyphenyl)methanone

Stage A: To a solution of ethyl 4-chlorination-2-carboxylate (0,250 g, 1.05 mmol) in DMF (2.5 ml) at room temperature in an argon atmosphere was added potassium iodide (0,192 g of 1.16 mmol), DIEA (0,238 ml, 1.37 mmol) and 1H-pyrazole-3-amine (0,113 g, 1.37 mmol). The mixture was stirred at room temperature for 5 hours and diluted with the help of H2O (5 ml). The precipitate was collected by filtration, washed using H2O and dried under high vacuum for several hours to obtain ethyl 4-(1H-pyrazole-3-ylamino)hinzelin-2-carboxylate in the form of a rusty-brown solid (0,190 g, 64%).1H NMR (300 MHz, DMSO-d6) δ to 12.52 (s, 1H), of 10.58 (s, 1H), 8,72 (d, 1H), of 7.90 (d, 2H), 7,78 (s, 1H), 7,68 (m, 1H), 7,18 (s, 1H), 4,48 (square, 2H), 1,48 (t, 3H); LC-MS (ESI) m/z 284 (M+H)+.

Stage B: To a suspension of ethyl 4-(1H-pyrazole-3-ylamino)hinzelin-2-carboxylate (0,110 g 0,39 mmol) in THF (5 ml) in an argon atmosphere at -40°C was added (2-methoxyphenyl)minibrain (0.5 M solution in THF; 2,32 ml of 1.16 mmol). The mixture was stirred at -40°C for 3 hours and extinguished 0,5 N. HCl solution (10 ml). The organic is the second layer was separated. The aqueous layer was washed using 10% MeOH/CH2Cl2(50 ml ×2). The combined organic layers were washed with saturated brine (25 ml), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified using preparative HPLC (column Phenomenex phenylhexa with reversed phase, suirable with a gradient of solvent B=0.05% OF HOAC/CH3CN and solvent A=0.05% Of HOAc/H2O) to obtain (4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(2-methoxyphenyl)methanone in the form of a yellow solid (0,023 g, 17%).1H NMR (300 MHz, DMSO-d6) δ 3,50 (s, 3H), return of 6.58 (s, 1H), 7,15 (m, 2H), 7,70-to 7.50 (m, 4H), 7,88 (m, 2H), up 8.75 (d, 1H), is 10.68 (s, 1H), 12,42 (s, 1H); LC-MS (ESI) m/z 346 (M+H)+.

Example 6

Receiving (R,S)-(4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol

To a solution of (4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone from Example 4 (375 mg, 1.12 mmol) in a mixture of 1:1 MeOH/THF (10 ml) at 0°C was added NaBH4(64 mg, was 1.69 mmol). The reaction mixture was stirred at 0°C for 3 hours. The reaction mixture was suppressed by the addition of water and the solid collected by filtration. The crude product was purified using reverse-phase HPLC to obtain (R,S)-(4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol as a white solid (130 mg, 34%).1H NMR (300 MG IS, DMSO-d6) δ 5,67 (m, 1H), 5,79 (m, 1H), 6,85 (s, 1H), 7,11 (t, 2H), 7,55 (m, 3H), of 7.70 (s, 1H), 7,80 (m, 2H), 8,61 (d, 1H), 10,50 (s, 1H), 12,46 (s, 1H); LC-MS (ESI) m/z 336 (M+H)+.

Example 7

Receiving (R,S)-2-(fluoro(4-forfinal)methyl)-N-(1H-pyrazole-3-yl)hinzelin-4-amine

To a solution of (R,S)-(4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol from Example 6 (88 mg, 0,238 mmol) in a mixture of DCM/THF (18 ml, 2:1) was added TRIFLUORIDE bis(2-methoxyethyl)-amino)sulfur (of 0.066 ml, 0.22 mmol) at room temperature. The reaction mixture was stirred at 50°C during the night. The reaction mixture was suppressed by the addition of acetone (0.1 ml), the solvent evaporated and the residue was purified using HPLC. (R,S)-2-(Fluoro(4-forfinal)methyl)-N-(1H-pyrazole-3-yl)hinzelin-4-amine was obtained as a white powder (12 mg, 15%).1H NMR (300 MHz, DMSO-d6) δ 6,46 (s, 1H), is 6.61 (s, 1H), 6,86 (s, 1H), 7,22 (m, 2H), of 7.64-7,56 (m, 2H), of 7.70 (s, 1H), 7,82 (m, 2H), 8,65 (d, 1H), 10,63 (s, 1H), 12,50 (s, 1H); LC-MS (ESI) m/z 338 (M+H)+.

Example 8

Getting 2-(diftar(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine

Stage A: 2,2-Debtor-2-(4-forfinal)acetic acid was obtained according to Middleton et al., J. Org. Chem., 1980, 45(14): 2883-2887) by reacting ethyl 2-(4-forfinal)-2-oxoacetate with TRIFLUORIDE (diethylamino)sulfur and subsequent saponification of ester.

Stage B: To a solution of 2,2-debtor-2-(4-forfinal)acetic acid is you (1,33 g, 7,0 mmol) in DCM (50 ml) was added oxalicacid (0,640 ml, 7.5 mmol) and catalytic amount of DMF. After stirring for 3 hours the mixture was concentrated under reduced pressure to obtain 2.2-debtor-2-(4-forfinal)acetylchloride. To a solution of 2-aminobenzamide (0,857 g, 6.3 mmol) and TEA (1,04 ml, 0,0075 mol) in DCE (100 ml) at room temperature was added 2,2-debtor-2-(4-forfinal)acetylchloride above, in DCE (100 ml) and the reaction mixture was stirred over night. After addition of EtOAc (200 ml) and the mixture was washed 1 N. HCl solution, a saturated solution of NaHCO3and saturated salt solution. The organic solution was concentrated to obtain not quite white solid (0,989 mg, 51%).1H NMR (300 MHz, DMSO-d6) δ to 7.15 (t, 1H), 7,27 (m, 2H), 7,54 (m, 1H), 7,74 (m, 2H), 7,92 (m, 2H), 8,44 (d, 2H), 13,37 (s, 1H).

Stage C: To a solution of 2-(2,2-debtor-2-(4-forfinal)acetamido)benzamide (0.95 g, is 3.08 mmol) in DCE (25 ml) was added TEA (17,2 ml, 0,123 mol) and chlorotrimethylsilane (of 5.84 ml, 0,0462 mol) at room temperature. The reaction mixture was stirred at 85°C during the night. After cooling to room temperature, the solid was filtered and the filtrate was concentrated to dryness. The residue was purified on a column of silica gel using DCM/MeOH as eluent. 2-(Diftar(4-forfinal)methyl)hinzelin-4-ol was obtained as a not-quite-white solid (0,668 g, 75%).1H NMR (30 MHz, DMSO-d6) δ 7,39 (t, 2H), 7.62mm (m, 1H), 7,78-7,71 (m, 3H), to 7.84 (m, 1H), 8,16 (m, 1H), 13,11 (s, 1H).

Stage D: 4-Chloro-2-(diftar(4-forfinal)methyl)hinzelin received in accordance with the procedure described in Example 26 to obtain 4-chloro-2-(diftar(4-forfinal)methyl)-7-methylinosine, substituting 2-(diftar(4-forfinal)methyl)-7-methylpyrazole-4-ol in Example 26 2-(diftar(4-forfinal)methyl)hinzelin-4-I (95% yield). LC-MS (ESI) m/z 308 (M+H)+.

Stage E: To a solution of 4-chloro-2-(diftar(4-forfinal)methyl)hintline (0,150 g, 0,487 mmol) in DMF (2 ml) at room temperature was added potassium iodide (of 0.081 g, 0,487 mmol), DIEA (0,093 ml, 0,535 mmol) and 5-methyl-1H-pyrazole-3-amine (0,048 g, 0,487 mmol). After stirring the reaction mixture at room temperature overnight the reaction was suppressed by addition of water (15 ml). The precipitate was collected by filtration and washed using H2O. the Crude solid was ground into powder with MeOH. 2-(Diftar(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine was obtained in the form of not-quite-white solid (0.125 g, 69%).1H NMR (300 MHz, DMSO-d6) δ 2,24 (s, 3H), of 6.31 (s, 1H), 7,34 (m, 2H), 7,68 (m, 3H), 7,87 (m, 2H), 8,68 (m, 1H), 10,69 (s, 1H), 12,20 (s, 1H); LC-MS (ESI) m/z 370 (M+H)+.

Example 9

Getting 2-(diftar(4-forfinal)methyl)-N-(1H-pyrazole-3-yl)hinzelin-4-amine

2-(Diftar(4-forfinal)methyl)-N-(1H-pyrazole-3-yl)hinzelin-4-amine was obtained using the receiving procedures similar to that described in Example 8, using 1H-pyrazole-3-amine instead of 5-methyl-1H-pyrazole-3-amine used in Example 8 stage E (61% yield).1H NMR (300 MHz, DMSO-d6) δ 6,77 (s, 1H), 7,32 (m, 2H), to 7.77-7,63 (m, 4H), 7,88 (m, 2H), 8,71 (d, 1H), was 10.82 (s, 1H), 12,55 (s, 1H); LC-MS (ESI) m/z 356 (M+H)+.

Example 10

Obtaining N-(5-cyclopropyl-1H-pyrazole-3-yl)-2-(diftar(4-forfinal)methyl)hinzelin-4-amine

N-(5-cyclopropyl-1H-pyrazole-3-yl)-2-(diftar(4-forfinal)methyl)hinzelin-4-amine was obtained using a procedure similar to that described in Example 8 using 5-cyclopropyl-1H-pyrazole-3-amine instead of 5-methyl-1H-pyrazole-3-amine used in Example 8 stage E (68% yield).1H NMR (300 MHz, DMSO-d6) δ 0,637 (m, 2H), 0,96 (m, 2H), 1.91 a (m, 1H), of 6.20 (s, 1H), of 7.70 (m, 2H), 7,80 (m, 3H), of 7.90 (m, 4H), to 8.70 (d, 1H), is 10.68 (s, 1H), 12,20 (s, 1H); LC-MS (ESI) m/z 396 (M+H)+.

Example 11

Obtaining 3-(2-(4-perbenzoic)hinzelin-4-ylamino)-1H-pyrazole-5-carbonitrile

Stage A: To a solution of 5-nitro-3-pyrazolylborate acid (6,28 mg, 40 mmol) in DMF (30 ml) was added carbonyldiimidazole (12,96 mg, 80 mmol). The mixture was left to stir for 30 minutes and was added a solution of ammonia in MeOH (2M, 60 ml). The reaction mixture was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to get crude product is one which is then washed with ether to obtain 3-nitro-1H-pyrazole-5-carboxamide (3.0 g, 48%)which was used directly in the next stage without additional purification. LC-MS (ESI) m/z 155 (M-H)-.

Stage B: 3-nitro-1H-pyrazole-5-carboxamide (3.0 g, 19.2 mmol) in pyridine (30 ml) was treated with phosphorus oxychloride (5.9 g) and the resulting solution was stirred for 3 hours at room temperature. The reaction mixture was diluted with ice, then was extracted using DCM (100 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude 3-nitro-1H-pyrazole-5-carbonitrile, which was used directly in the next stage without additional purification. LC-MS (ESI) m/z 137 (M-H)-.

Stage C: To a solution of 3-nitro-1H-pyrazole-5-carbonitrile (1000 mg, from 7.24 mmol) in AcOH (10 ml) and H2O (2 ml) was added zinc powder (2.35 mg, 36,24 mmol) at 0°C. the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was filtered, the pH was brought to 8 with ammonium hydroxide and then the mixture was extracted using EtOAc (30 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to get crude product 3-amino-1H-pyrazole-5-carbonitrile (200 mg, 28%)which was used directly in the following article the Hai without additional purification. LC-MS (ESI) m/z 107 (M+H)+.

Stage D: a Mixture of (4-chlorination-2-yl)(4-forfinal)methanone from Example 3 (580 mg, 2.02 mmol) and 3-amino-1H-pyrazole-5-carbonitrile (218 mg,2.02 mmol) in DMF (5 ml) was stirred at room temperature overnight. Then to this mixture was added MeOH (10 ml) and the precipitate was filtered, washed using MeOH and dried to obtain 3-(2-(4-perbenzoic)hinzelin-4-ylamino)-1H-pyrazole-5-carbonitrile (170 mg, 23.4 per cent).1H NMR (300 MHz, DMSO-d6) δ 6.89 in (s, 1H), 7,40 (d, 2H), 7,83 (s, 1H), 7,98 (m, 2H), 8,11 (m, 2H), 8,56 (s, 1H), 11,18 (s, 1H), at 13.84 (s, 1H); LC-MS (ESI) m/z 359 (M+H)+.

Example 12

Obtaining hydrochloride (R,S)-(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol

To a solution of (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone of Example 3 (60 mg, 0,172 mmol) in a mixture of 1:1 MeOH/THF (10 ml) at 0°C was added NaBH4(64 mg, was 1.69 mmol). The reaction mixture was stirred at 0°C for 1.5 hours. The reaction mixture was suppressed by adding a few drops of acetone and concentrated to dryness. The crude solid was purified using HPLC to obtain (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol (18 mg, 30%);1H NMR (300 MHz, DMSO-d6) δ of 2.25 (s, 3H), 5,67 (s, 1H), of 5.83 (users, 1H), 6,40 (users, 1H), 7,13 (m, 2H), 7,55-7,53 (m, 3H), 7,79 (s, 2H), 8,57 (users, 1H), 10,43 (s, 1H), 12,12 (users, 1H); LC-MS (ESI) m/z 350 (M+H)+.

To susp is nsii (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone (2.3 g) in 30% MeOH/DCM (60 ml) at 0°C was added dropwise a solution of 4M HCl/l,4-dioxane (10 ml). After complete dissolution of all solids, and the mixture was concentrated under reduced pressure and to the residue was added a 30% solution of CH3CN/H2O (80 ml) and the mixture was treated with ultrasound to dissolve all solids. The mixture was frozen and liofilizirovanny during the night with obtaining hydrochloride (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol (100%).1H NMR (300 MHz, DMSO-d6) δ of 2.25 (s, 3H), of 6.02 (s, 1H), of 6.20 (s, 1H), 7,27 (t, 2H), 7,60 (Qut, 2H), 7,80 (t, 1H), 8,08 (t, 1H), 8,23 (d, 1H), 8,83 (d, 1H), 12,16 (s, 1H), 14,51 (user., 1H); LC-MS (ESI) m/z 350 (M+H)+.

Example 13

Receiving (R,S)-2-((4-forfinal)(methoxy)methyl)-N-(5-methyl-1H - pyrazole-3-yl)hinzelin-4-amine

Stage A: To a solution of (R,S)-2-bromo-2-(4-forfinal)acetic acid (2,02 g, 8,66 mmol) in DCM (15 ml) and DMF (0.15 ml) was added oxalicacid (0.8 ml, 9.1 mmol), then the mixture was left for stirring for 30 minutes at room temperature. The reaction mixture was then cooled to 0°C and slowly added 2-aminobenzamide (1.12 g, 8,23 mmol) in pyridine (2 ml). The mixture was brought to room temperature for ~ 1 hour and then evaporated. Kneading the powder with a mixture of 2n HCl/methanol/water gave the crude (R,S)-2-(2-bromo-2-(4-forfinal)acetamido)benzamide, which was used without further purification (2,13 g, 73%). LC-MS (ESI) m/z 351 (M+H)+.

Stage B: (R,S)-2-(2-bromo-2-(4-CFT is henyl)acetamido)benzamide (0.52 g, 1.48 mmol) in MeOH (4 ml) was added sodium methoxide in MeOH (25%, of 0.64 ml, 2,96 mmol) and the resulting solution was stirred overnight at 65°C. the Reaction mixture was distributed between EtOAc and 2 N. HCl solution, the EtOAc layer was dried with sodium sulfate and then evaporated. The crude product was then ground into powder with ether to obtain (R,S)-2-((4-forfinal)(methoxy)methyl)hinzelin-4-ol, which was used without further purification (260 mg, 62%). LC-MS (ESI) m/z 285 (M+H)+.

Stage C: To a solution of (R,S)-2-((4-forfinal)(methoxy)methyl)hinzelin-4-ol (200 mg, 0.7 mmol) in DCM (2 ml) was added DMAP (8 mg, 0.07 mmol) and TEA (of 0.39 ml, 2.8 mmol), followed by the addition of 2,4,6-triisopropylbenzene-1-sulphonylchloride (211 mg, of 0.91 mmol) and the reaction mixture was stirred for 30 minutes at room temperature. The crude mixture was purified using chromatography on silica gel, elwira using 0-50% EtOAc and hexane, to obtain the (R,S)-2-((4-forfinal)(methoxy)methyl)hinzelin-4-yl 2,4,6-triisopropylbenzenesulfonyl (320 mg, 83%). LC-MS (ESI) m/z 573 (M+Na)+.

Stage D: (R,S)-2-((4-forfinal)(methoxy)methyl)hinzelin-4-yl-2,4,6-triisopropylbenzenesulfonyl (77 mg, 0.14 mmol) in DMF (2 ml) was added 5-methyl-1H-pyrazole-3-amine (20 mg, 0.2 mmol), TEA (of 0.02 ml, 0.14 mmol) and potassium iodide (33 mg, 0.2 mmol) and the reaction mixture was stirred at 50°C for 1 hour, followed by heating at 70°C for 2 hours. Then add the Yali additional amount of 5-methyl-1H-pyrazole-3-amine (45 mg) and the mixture was heated at 50°C during the night. The mixture was evaporated and purified via chromatography on silica gel, elwira using 0-12% MeOH in DCM. Purified fractions were evaporated and then were subjected to additional purification using preparative HPLC (column Phenomenex C-18 reversed-phase, suirable with a gradient of solvent B=0.05% Of HOAc/CH3CN and solvent A=0.05% Of HOAc/H2O), then using preparative thin layer chromatography (10% MeOH in DCM) to give (R,S)-2-((4-forfinal)(methoxy)methyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine (5 mg, 10%).1H NMR (300 MHz, DMSO-d6) δ of 2.28 (s, 3H), of 3.32 (s, 3H), lower than the 5.37 (s, 1H), 6,56 (s, 1H), 7,15 (d, 2H), EUR 7.57 (m, 3H), 7,81 (m, 2H), 8,59 (d, 1H), 10,48 (s, 1H), 12,09 (s, 1H); LC-MS (ESI) m/z 364 (M+H)+.

Example 14

Receiving (R,S)-2-(amino(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine

Stage A: To a solution of 2-amino-2-(4-forfinal)acetic acid (5 g, 29.5 mmol) in THF (50 ml) at 50°C was added triphosgene (8,77 g, 29.5 mmol), and then continued heating for 3 hours. The reaction mixture is then filtered and evaporated to approximately 10 ml, followed by addition of 150 ml of hexane. The mixture was slightly heated and then cooled to -20°C for 1 hour. The crude suspension was filtered to obtain 4-(4-forfinal)oxazolidin-2,5-dione (of 5.03 g, 87%)which was used without further purification.

Stage B: To a solution of 4-4-forfinal)oxazolidin-2,5-dione (2.5 g, 12.8 mmol) in THF (30 ml), cooled to -25°C, was added benzylchloride (2,3 ml of 16.6 mmol) followed by slow addition (~10 minutes) N-methylmorpholine (2,11 ml, 19.2 mmol) in solution in THF (5 ml). The solution was stirred at this temperature for 1 hour and then was allowed to warm to room temperature over night. The resulting solution was filtered through Celite and the filtrate was concentrated. The crude substance was recrystallized from a mixture of 2:2:1 tert-butyl methyl ether:hexane:THF to obtain benzyl 4-(4-forfinal)-2,5-dioxoimidazolidin-3-carboxylate (2.7 g, 64%)which was used without further purification.

Stage C: To a solution of 2-aminobenzamide (591 mg, 4,34 mmol) in THF (10 ml) was added benzyl 4-(4-forfinal)-2,5-dioxoimidazolidin-3-carboxylate (1,43 g, 4,34 mmol) and the reaction mixture was heated at 50°C for 2 hours. Added an additional 5 ml of THF and continued heating for 0.5 hours. Then was added sodium methoxide in MeOH (25%, of 1.87 ml, 8,68 mmol) and the reaction mixture was heated to 65°C for 2 hours. Then was added HOAc (0.4 ml), the solution was evaporated and the crude mixture was purified by chromatography on silica gel, elwira mixture of 0-10% MeOH in DCM, to obtain the (R,S)-(4-forfinal)(4-hydroxyquinazoline-2-yl)methylcarbamate (1.1 g, 63%). LC-MS (ESI) m/z 404 (M+Na)+.

Stage D: To a solution of (R,S)-(4-forfinal)(4-hydroxyI azolin-2-yl)methylcarbamate (451 mg, 1.11 mmol) in DCM (5 ml) was added DMAP (7 mg, 0.05 mmol), TEA (and 0.61 ml, 4.4 mmol) and 2,4,6-triisopropylbenzene-1-sulphonylchloride (440 mg, 1,45 mmol). The reaction mixture was stirred at room temperature for 0.5 hours and then was evaporated. The residue was purified by chromatography on silica gel, elwira mixture of 0-50% EtOAc in hexane, to obtain the (R,S)-2-((benzyloxycarbonylamino)(4-forfinal)methyl)hinzelin-4-yl 2,4,6-triisopropylbenzenesulfonyl (580 mg, 75%). LC-MS (ESI) m/z 692 (M+Na)+.

Stage E: (R,S)-2-((benzyloxycarbonylamino)(4-forfinal)methyl)hinzelin-4-yl-2,4,6-triisopropylbenzenesulfonyl (216 mg, 0.32 mmol)in DMA (2 ml) was added 5-methyl-1H-pyrazole-3-amine (198 mg, 2.04 mmol) and potassium iodide (140 mg, 0.83 mmol) and the mixture was stirred at 55°C for 4 hours. The crude mixture was distributed between EtOAc and a saturated solution of sodium bicarbonate. The EtOAc layer was dried with sodium sulfate and then evaporated to obtain oil. Half of the crude oil was dissolved in MeOH (5 ml) was added 10% palladium hydroxide on carbon (50 mg). The resulting solution was stirred in an atmosphere of hydrogen for 6 hours, then filtered. Purification using preparative HPLC (column reversed-phase Varian diphenyl and then Phenomenex C-18, was suirable with a gradient of solvent B=0.05% OF HOAC/CH3CN and solvent A=0.05% Of HOAc/H2O) gave (R,S)-2-(amino(4-forfinal)methyl)-N-(5-METI what-1H-pyrazole-3-yl)hinzelin-4-amine in the form of its acetate salt (5 mg, 9%).1H NMR (300 MHz, DMSO-d6) δ 1,89 (s, 3H), of 2.25 (s, 3H), 5,07 (s, 1H), 6.35mm (s, 1H), 7,12 (t, 2H), 7,51 (m, 3H), to 7.77 (m, 2H), 8,56 (d, 1H), 10,55 (s, 1H); LC-MS (ESI) m/z 349 (M+H)+.

Example 15

Receiving (R,S)-3-(2-((4-forfinal)(hydroxy)methyl)hinzelin-4-ylamino)-1H-pyrazole-5-carbonitrile

To a solution of 3-(2-(4-perbenzoic)hinzelin-4-ylamino)-1H-pyrazole-5-carbonitrile from Example 11 (107 mg, 0.3 mmol) in MeOH (4 ml) and THF (4 ml) was added borohydride sodium (22.7 mg, 0.6 mmol) at 0°C and the mixture was stirred over night at room temperature. The mixture was poured into H2O (20 ml), the result was the formation of a precipitate. After filtering received solid, which was purified using preparative HPLC, to obtain the (R,S)-3-(2-((4-forfinal)(hydroxy)methyl)hinzelin - 4-ylamino)-1H-pyrazole-5-carbonitrile (30 mg, 29%).1H NMR (300 MHz, DMSO-d6) δ of 5.81 (s, 1H), 6,34 (users, 1H), to 6.88 (s, 1H), 7,17 (t, 2H), 7,58 (m, 3H), 7,81 (s, 2H), of 8.37 (m, 1H); LC-MS (ESI) m/z 361 (M+H)+.

Example 16

Receiving (R,S)-(5-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol

Stage A: 5-(4-forfinal)-1,3-dioxolane-2,4-dione was obtained in accordance with JACS, 2002 2870-2871. To 2-amino-6-perbenzoic (550 mg, 3.5 mmol) in THF (15 ml) was added 5-(4-forfinal)-1,3-dioxolane-2,4-dione (1049 mg, to 5.35 mmol) and the mixture was heated at 50°C during the night. The solvent in perivale to obtain crude 2-(2,2-debtor-2-(4-forfinal)acetamido)-4-methoxybenzamide and the crude mixture was dissolved in ethanol (12 ml), was added an aqueous solution of potassium carbonate and the reaction mixture was heated at 80°C during the night. The crude mixture was extracted using EtOAc and water and the EtOAc layer was concentrated in vacuum to obtain (R,S)-5-fluoro-2-((4-forfinal)(hydroxyl)methyl)hinzelin-4-ol (650 mg, %). LC-MS (ESI) m/z 290 (M+Na)-.

Stage B: (R,S)-5-fluoro-2-((4-forfinal)(hydroxy)methyl)hinzelin-4-Olu (650 mg, 2.25 mmol) was added periodinane Dess-Martin (1140 mg, 2.7 mmol) in acetonitrile (15 ml) and the mixture was stirred at room temperature for 30 minutes. To the crude mixture was added an aqueous solution of sodium bicarbonate and the mixture was stirred for 0.5 hours. The obtained brown precipitate was collected and washed with diethyl ether (650 mg, quantitative); LC-MS (ESI) m/z 287 (M+Na)+.

Stage C: phosphorus oxychloride (7 ml) was added (5-fluoro-4-hydroxyquinazoline-2-yl)(4-forfinal)methanon (650 mg, and 2.26 mmol) followed by addition of DMA (1 drop). The solution was heated at 85°C for 3 hours and then the mixture was concentrated. The residue was cooled in a -20°C cooling bath and diluted with cold EtOAc. The solution was washed with saturated aqueous sodium bicarbonate solution and saturated saline solution. Removal of solvent gave a brown solid. Cleaning chromatographia (gradient elution 0-40% EtOAc in hexane) gave a yellow solid (300 mg, 44%); LC-MS (ESI) m/z 305 (M+Na)+.

With the adiya D: To (4-chloro-5-florinopolis-2-yl)(4-forfinal)methanone (300 mg, 0.98 mmol) in dimethylformamide (8.0 ml) was added DIEA (0.17 ml, 0.98 mmol), 5-methyl-1H-pyrazole-3-amine (240 mg, 2.5 mmol) and potassium iodide (162 mg, 0.98 mmol) and the mixture was stirred at room temperature for 1 hour. To the reaction mixture were added water and the precipitate was collected by filtration. The precipitate was washed with diethyl ether to obtain a yellow solid (280 mg, 78%); LC-MS (ESI) m/z 366 (M+Na)+.

Stage E: (5-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone (280 mg, from 0.76 mmol) in 1:1 mixture of MeOH and THF (8 ml) at 0°C was added NaBH4(43 mg, to 1.14 mmol). After stirring for 1 hour at 0°C was added 10 drops of water. The solvents were removed under vacuum and the residue was dissolved in EtOAc (15 ml), washed with saturated saline and dried over Na2SO4. The crude product was purified using reverse-phase preparative HPLC (gradient elution from 40 to 90% acetonitrile in water with 0.05% of acetic acid) to give (R,S)-(5-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol as a white solid.1H NMR (300 MHz, DMSO-d6) δ ppm 2,2 (s, 3 H) to 5.7 (s, 1H) 5,9 (s,lH) 6,55 (s, 1 H), and 7.1 to 7.2 (m, 2H) 7,35 to 7.9 (m, 4H) a 8.9 (s, 1H) 12,25 (s, 1 H) LC-MS (ESI) m/z 368 (M+H)+.

Example 17

Receive (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(trifluoromethyl)hinzelin-2-yl)methanone

Stage A: 2-neither the ro-4-(trifluoromethyl)benzamide (1000 mg, 4,27 mmol) in MeOH (15 ml) was added palladium hydroxide 20% of the mass. (230 mg) and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through Celite washing with the aid of MeOH. The crude mixture was concentrated in vacuum to obtain 2-amino-4-(trifluoromethyl)benzamide (840 mg, 96%). LC-MS (ESI) m/z 205 (M+Na)+.

Stage B: 2-amino-4-(trifluoromethyl)benzamide (840 mg, 4,16 mmol) in THF (15 ml) was added 5-(4-forfinal)-1,3-dioxolane-2,4-dione from Example 16 (1225 mg, 6,24 mmol) and the mixture was heated at 50°C for 4 hours. The solvent is evaporated and the crude 2-(2-(4-forfinal)-2-hydroxyacetamido)-4-(trifluoromethyl)benzamide was dissolved in MeOH (10 ml), was added a solution of 0.5 M sodium methoxide in MeOH (2.5 ml, 1.25 mmol) and the reaction mixture was heated at 50°C for 1 hour. The solvent is evaporated and then added 1 n hydrochloric acid. The mixture was extracted using EtOAc and the organic phase was dried over sodium sulfate and concentrated in vacuum to obtain crude 2-((4-forfinal)(hydroxy)methyl)-7-(trifluoromethyl)hinzelin-4-ol, which was used in the next reaction without purification. LC-MS (ESI) m/z 339 (M+Na)+.

Stage D: 2-((4-forfinal)(hydroxy)methyl)-7-(trifluoromethyl)hinzelin-4-Olu (2000 mg, of 5.89 mmol) was added periodinane Dess-Martin (3000 mg, 7,07 mmol) in acetonitrile (25 ml) and the mixture was stirred at room temperature in ECENA 2 hours. To the crude mixture was added an aqueous solution of sodium bicarbonate and the mixture was stirred for 0.5 hours. The resulting brown precipitate was collected, washed with diethyl ether and dried under high vacuum to obtain (4-forfinal)(4-hydroxy-7-(trifluoromethyl)hinzelin-2-yl)methanone (to 2.57 g, quantitative yield); LC-MS (ESI) m/z 336 (M+Na)+.

Stage E: phosphorus oxychloride (6 ml) was added (4-forfinal)(4-hydroxy-7-(trifluoromethyl)hinzelin-2-yl)methanon (1280 mg, of 3.80 mmol) followed by addition of DMA (1 drop). The solution was heated at 85°C overnight and then the mixture was concentrated. The crude (4-chloro-7-(trifluoromethyl)hinzelin-2-yl)(4-forfinal)methanon used in the next stage without purification. LC-MS (ESI) m/z 305 (M+Na)+.

Stage F: (4-chloro-7-(trifluoromethyl)hinzelin-2-yl)(4-forfinal)methanone (1 g, 2.82 mmol) in DMF (10 ml) was added DIEA (0,49 ml, 2.82 mmol), 5-methyl-1H-pyrazole-3-amine (823 mg, of 8.47 mmol) and potassium iodide (468 mg, 2.82 mmol) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added water, followed by extraction using EtOAc. The organic phase was dried over sodium sulfate. The solvent was concentrated and the residue was dried under high vacuum over night. The crude solid (240 mg) was purified using reverse-phase preparative HPLC (gradientnoi elution 4090% acetonitrile in water with 0.05% of acetic acid) to give (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(trifluoromethyl)hinzelin-2-yl)methanone in the form of a yellow solid (40 mg, 16%).1H NMR (300 MHz, DMSO-d6) δ ppm 2,2 (s, 3H) 6,55 (s, 1H) of 7.35-7.5(m, 3H) of 7.9 to 8.0 (m, 1H) 8,05 to 8.3 (m, 4H) 11,1 (s, 1H) 12,25 (s, 1H); LC-MS (ESI) m/z 416 (M+H)+.

Example 18

Receiving (R,S)-(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(trifluoromethyl)hinzelin-2-yl)

To (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(trifluoromethyl)hinzelin-2-yl)methanone (500 mg, 1.2 mmol) in 1:1 mixture of MeOH/THF (10 ml) at 0°C was added NaBH4(68 mg, to 1.79 mmol). After stirring for 10 minutes at 0°C was added 10 drops of water. The solvents were removed under vacuum and the residue was dissolved in 1:1-mixture of water and EtOAc (20 ml), washed with saturated saline solution and dried over sodium sulfate. The crude product (360 mg) was purified using reverse-phase preparative HPLC (gradient elution from 40 to 90% acetonitrile in water with 0.05% of acetic acid) to give (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(trifluoromethyl)-hinzelin-2-yl)methanol as a white solid (140 mg, 40%).1H NMR (300 MHz, DMSO-d6) δ ppm 2,2 (s, 3H) 5,9(s, 1H) 6,55 (s, 1H) of 7.35-7.5(m, 3H) of 7.9 to 8.0(m, 1H) 8,05 to 8.3 (m, 4H) 11,1 (users, 1H) 12,25 (users, 1H); LC-MS (ESI) m/z 418 (M+H)+.

Example 19

Obtaining (7-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone

Stage A: To a solution of 2-bromo-2-(4-forfinal)acetic acid (425 mg, 1.82 mmol) in DCM (5 ml) DMF (0.05 ml) was added oxalicacid (0.17 ml, at 1.91 mmol) and the solution was stirred for 0.75 in hours. The solution is then cooled to 0°C was added a solution of 2-amino-4-fermentated (267 mg, at 1.73 mmol) in pyridine (1 ml). The solution was stirred at room temperature for 1 hour and then evaporated. The crude residue was distributed between EtOAc and 2 N. HCl solution. The EtOAc layer was evaporated to obtain 2-(2-bromo-2-(4-forfinal)acetamido)-4-fermentated in the form of crude oil that was used without additional purification. (420 mg, 62%). LC-MS (ESI) m/z 369 (M-H)-.

Stage B: 2-(2-bromo-2-(4-forfinal)acetamido)-4-perbenzoic (420 mg, 1.1 mmol) in diglyme (5 ml), was added 1 ml of 10% aqueous potassium carbonate solution and the solution was heated at 95°C for 6 hours, then at 60°C over night. The crude residue was distributed between EtOAc and 2 N. HCl solution. The EtOAc layer was evaporated and the crude mixture was purified using chromatography on silica gel (0-10% MeOH in DCM) to give the benzyl 7-fluoro-2-((4-forfinal)(hydroxy)methyl)hinzelin-4-ol (98 mg, 31%). LC-MS (ESI) m/z 289 (M+H)+.

Stage C: To a solution of 7-fluoro-2-((4-forfinal)(hydroxy)methyl)hinzelin-4-ol (98 mg, 0.33 mmol) in acetonitrile (4 ml) was added periodinane Dess-Martin (168 mg, 0.4 mmol) and the reaction mixture was stirred at room temperature for a period of 0.75 hours. Then was added a saturated solution of sodium bicarbonate and the solution was stirred for 1 hour. This rastvoritel was filtered and the obtained solid substance was dried. To this crude solid substance was added phosphorus oxychloride (2 ml) and DMA (0,02 ml) and the resulting solution was heated at 85°C in a period of 0.75 hours. The solvent is evaporated and then added DCM and the solution was filtered through a plug of silica gel washing with the help of DCM. The solvent is evaporated to obtain (4-chloro-7-florinopolis-2-yl)(4-forfinal)methanone (27 mg, 27%)which was used without further purification. LC-MS (ESI) m/z 305 (M+H)+.

Stage D: a solution of 5-methyl-1H-pyrazole-3-amine (13 mg, 0.13 mmol), potassium iodide (15 mg, 0,088 mmol) and DIEA (0,016 ml, 0,088 mmol) in DMF (2 ml) was added to (4-chloro-7-florinopolis-2-yl)(4-forfinal)methanone (0,027 mg, 0,088 mmol). The resulting solution was stirred at room temperature overnight and then purified using preparative HPLC (column Varian diphenyl reversed-phase, suirable with a gradient of solvent B=0.05% OF HOAC/CH3CN and solvent A=0.05% Of HOAc/H2O) to give (7-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone (10 mg, 31%).1H NMR (300 MHz, DMSO-d6) δ to 2.18 (s, 3H), 6.48 in (s, 1H), was 7.36 (t, 2H), 7,60 (m, 2H), 8,09 (m, 2H), 8,29 (t, 1H), 10,78 (s, 1H), 12,23 (s, 1H); LC-MS (ESI) m/z 366 (M+H)+.

Example 20

Getting 2-(diftar(4-forfinal)methyl)-7-fluoro-N-(5-methyl-1H - pyrazole-3-yl)hinzelin-4-amine

Stage A: 2,2-debtor-2-(4-forfinal)acetylchloride received, as is written in Example 8 stage B. To a solution of 2-amino-4-fermentated (0,330 g, 2.14 mmol) and TEA (0,395 ml of 2.83 mmol) in DCE (15 ml) was added a solution of 2,2-debtor-2-(4-forfinal)acetylchloride (0,460 mg, 2.2 mmol) in DCE (4 ml) at room temperature and the reaction mixture was stirred over night. After addition of EtOAc (20 ml) and the mixture was washed with water, saturated aqueous NaHCO3and saturated salt solution. The organic solution was concentrated to obtain not quite white solid (0,650 g, 84%). LC-MS (ESI) m/z 327 (M+H)+.

Stage B: To a solution of 2-(2,2-debtor-2-(4-forfinal)acetamido)-4-fermentated (0,650 g, 1.9 mmol) in DCE (14 ml) was added TEA (to 10.6 ml, 76 mmol) and chlorotrimethylsilane (3,78 ml, and 29.9 mmol) at room temperature. The reaction mixture was stirred at 85°C during the night. After cooling to room temperature, the solid was filtered and the filtrate was concentrated to dryness. The residue was dissolved in a mixture of EtOAc/THF (1:1) and washed with water and saturated salt solution. The organic phase was dried over MgSO4. The crude product was purified on a column of silica gel using a mixture of DCM/MeOH as eluent to obtain 2-(diftar(4-forfinal)-7-florinopolis-4-ol (0,668 g, 75%).1H NMR (300 MHz, DMSO-d6) δ 7,40 (t, 2H), of 7.48 (dt, 1H), 7,56 (DD, 1H), to 7.77 (DD, 2H), 8,21 (DD, 1H), 13,25 (s, 1H).

Stage C: a solution of 2-(diftar(4-forfinal)-7-florinopolis-4-ol (0,350 g, 1.13 mmol) in POCl3(5 ml) heating the whether at 105°C for 4 hours. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in anhydrous toluene. The toluene was concentrated under reduced pressure. The residue was dissolved in a small volume of DCM and passed through a short plug of silica gel, elwira using DCM. 4-Chloro-2-(diftar(4-forfinal)methyl)-7-florinopolis received in the form of a pale yellow solid (325 mg, 88.5 percent). LC-MS (ESI) m/z 327 (M+H)+

Stage D: To a solution of 4-chloro-2-(diftar(4-forfinal)methyl)-7-ftorhinolona (0,160 g, 0,492 mmol) in DMF (2 ml) at room temperature was added potassium iodide (0,082 g, 0,492 mmol), DIEA (0,094 ml, 0,541 mmol) and 5-methyl-1H-pyrazole-3-amine (0,048 g, 0,492 mmol). After stirring the reaction mixture at 50°C overnight the mixture was cooled to room temperature and was added H2O (15 ml). The precipitate was collected by filtration and washed using H2O. the Crude product was purified using HPLC (column with reversed phase Phenomenex phenylhexa, suirable with a gradient of solvent B=0.05% Of HOAc/CH3CN and solvent A=0.05% Of HOAc/H2O) to give 2-(diftar(4-forfinal)methyl)-7-fluoro-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine as a white powder (36 mg, 19%).1H NMR (300 MHz, DMSO-d6) δ and 2.26 (s, 3H), 6,27 (s, 1H), 7,35 (m, 2H), 7,56 (m, 1H), 7,72-763 (m, 3H), 8,78 (m, 1H), was 10.82 (s, 1H), 12,23 (s, 1H); LC-MS (ESI) m/z 388 (M+H)+.

Example 21

Getting 2-(diftar(4-forfinal)m is Teal)-7-fluoro-N-(1H-pyrazole-3-yl)hinzelin-4-amine

2-(Diftar(4-forfinal)methyl)-7-fluoro-N-(1H-pyrazole-3-yl)hinzelin-4-amine was obtained according to the procedure described in Example 20 to obtain 2-(diftar(4-forfinal)methyl)-7-fluoro-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine, substituting 5-methyl-1H-pyrazole-3-amine in Example 20 1H-pyrazole-3-amine (11% yield).1H NMR (300 MHz, DMSO-d6) δ 6,74 (s, 1H), 7,32 (m, 2H), 7,72-of 7.55 (m, 5H), 8,81 (m, 1H), 10,95 (s, 1H), 12,58 (s, 1H); LC-MS (ESI) m/z 374 (M+H)+.

Example 22

Obtain (4-(1H-pyrazole-3-ylamino)-7-iodination-2-yl)(4-forfinal)methanone

Stage A: To a solution of 2-amino-4-iodobenzoyl acid (2.5 g, 9.50 mmol) in DMF (10 ml) at room temperature in an argon atmosphere was added EDCI (2,18 g, 11,40 mmol), 1-hydroxybenzotriazole (1.54 g, 11,40 mmol), DIEA (1,98 ml, 11,40 mmol) and ammonia (7,0 n solution in MeOH; 1.90 ml, 13,30 mmol). The dark solution was stirred at room temperature overnight and diluted with the help of H2O to sediment. The precipitate was isolated by filtration, washed using H2O and dried under high vacuum for several hours to obtain 2-amino-4-iodobenzene in the form of a rusty-brown solid (1.3 g, 52%). LC-MS (ESI) m/z 263 (M+H)+.

Stage B: To a solution of 2-amino-4-iodobenzene (1.0 g, 3.61 mmol) in glacial acetic acid (10 ml) at room temperature was added di is tilokarat (5 ml). The mixture was heated at 120°C for 24 hours. The mixture was cooled to room temperature and was diluted using H2O to sediment. The precipitate was removed by filtration, washed using H2O and dried under high vacuum for several hours to obtain ethyl 7-iodine-4-oxo-3,4-dihydroquinazolin-2-carboxylate (1.0 g, 76%) as a tan solid.1H NMR (300 MHz, DMSO-d6) δ of 1.36 (t, 3H), 4,48 (square, 2H), of 7.90 (d, 1H), 7,95 (d, 1H), to 8.20 (d, 1H), 8,28 (s, 1H), 12,78 (s, 1H); LC-MS (ESI) m/z 330 (M+H)+.

Stage C: a Suspension of ethyl 7-iodine-4-oxo-3,4-dihydroquinazolin-2-carboxylate (1.0 g, 2,90 mmol) in phosphorus oxychloride (10 ml) was heated at 110°C in argon atmosphere for 12 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified column chromatography on silica gel, elwira a mixture of 30% EtOAc/hexane, to obtain ethyl 4-chloro-7-iodination-2-carboxylate as a white solid (0,510 g, 48%).1H NMR (300 MHz, DMSO-d6) δ of 1.32 (t, 3H), 4,48 (square, 2H), 7,88 (d, 1H), 7,92 (d, 1H), of 8.25 (s, 1H); LC-MS (ESI) m/z 363 (M+H)+.

Stage D: To a solution of ethyl 4-chloro-7-iodination-2-carboxylate (was 0.138 g, 0.38 mmol) in DMF (2 ml) at room temperature in an argon atmosphere was added potassium iodide (0,069 g, 0.42 mmol), DIEA (0,079 ml, 0.45 mmol) and 1H-pyrazole-3-amine (0,038 g, 0.46 mmol). The mixture was stirred at room Tempe is the atur during the night, then was diluted using H2O (15 ml). The precipitate was collected by filtration, washed using H2O and dried under high vacuum for several hours to obtain ethyl 4-(1H-pyrazole-3-ylamino)-7-iodination-2-carboxylate as a yellow solid (0,130 g, 84%).1H NMR (300 MHz, DMSO-d6) δ of 1.34 (t, 3H), of 4.38 (square, 2H), 7,14 (m, 1H), 7,72 (m, 1H), 7,94 (d, 1H), 8,28 (d, 1H), 8,48 (d, 1H), 10,92 (s, 1H), 12,58 (s, 1H); LC-MS (ESI) m/z 410 (M+H)+.

Stage E: To a suspension of ethyl 4-(lH-pyrazole-3-ylamino)-7-iodination-2-carboxylate (0,130 g, 0.31 mmol) in THF (5 ml) at -40°C was added (4-forfinal)minibrain (a 1.0 M solution in THF, 0,797 ml of 0.79 mmol). The mixture was stirred at -40°C for 5 hours, extinguished 1,0 N. HCl solution (2.0 ml) and concentrated under reduced pressure. The residue was purified using preparative HPLC (column Phenomenex phenylhexa with reversed phase, suirable with a gradient of solvent B=0.05% Of HOAc/CH3CN and solvent A=0.05% Of HOAc/H2O) to obtain (4-(1H-pyrazole-3-ylamino)-7-iodination-2-yl)(4-forfinal)methanone in the form of a yellow solid (0,050 g, 34%).1H NMR (300 MHz, DMSO-d6) δ 6,72 (s, 1H), 7,35 (m, 2H), to 7.64 (s, 1H), 8,00 (d, 1H), 8,08 (DD, 2H), 8,28 (s, 1H), 8,55 (d, 1H), 10,88 (s, 1H), 12,55 (s, 1H); LC-MS (ESI) m/z 460 (M+H)+.

Example 23

Receiving (R,S)-(4-(1H-pyrazole-3-ylamino)-7-iodination-2-yl)(4-forfinal)methanol

To suspe the Ziya (4-(1H-pyrazole-3-ylamino)-7-iodination-2-yl)(4-forfinal)methanone from Example 22 (0,032 g, 0.07 mmol) in a mixture of 1:1 THF/MeOH (2 ml) at 0°C in an argon atmosphere was added NaBH4(0.004 g, 0.10 mmol). The mixture was stirred at 0°C for 3 hours, was suppressed by the addition of two drops of acetone and concentrated under reduced pressure. The residue was purified using preparative HPLC (column Phenomenex phenylhexa with reversed phase, suirable with a gradient of solvent B=0.05% Of HOAc/CH3CN and solvent A=0.05% Of HOAc/H2O) to obtain (R,S)-(4-(1H-pyrazole-3-ylamino)-7-iodination-2-yl)(4-forfinal)methanol as a white solid (0,020 g, 63%).1H NMR (300 MHz, DMSO-d6) δ 5,64 (s, 1H), 5,88 (users, 1H), 6,80 (users, 1H), 7,15 (t, 2H), 7,52 (m, 2H), 7,65 (s, 1H), 7,80 (d, 1H), 8,12 (users, 1H), 8,35 (users, 1H), to 10.62 (users, 1H), 12,50 (users, 1H); LC-MS (ESI) m/z 462 (M+H)+.

Example 24

Receive (4-forfinal)(7-methyl-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone

Stage A: To a solution of 2-amino-4-methylbenzamide (3 g, 20.0 mmol) in THF (40 ml) was added 5-(4-forfinal)-1,3-dioxolane-2,4-dione from Example 16 (4.7 g, 24 mmol) and the solution was stirred for 2 hours at 50°C. Then was added sodium methoxide in MeOH (25%, to 5.2 ml, 24 mmol) and the solution was stirred at 50°C during the night. The reaction solution was concentrated, added 2 HCl solution and the mixture was filtered. The collected solid was dried to obtain 2-((4-forfinal)(hydroxy)methyl)-7-METI hinzelin-4-ol (5,14 g, 91%)which was used without further purification. LC-MS (ESI) m/z 285 (M+H)+.

Stage B: To a solution of 2-((4-forfinal)(hydroxy)methyl)-7-methylpyrazole-4-ol (3 g, 10,56 mmol) in acetonitrile (45 ml) was added periodinane Dess-Martin (lower than the 5.37 g, 12,67 mmol) and the mixture was stirred at room temperature for 5 hours. Then was added a saturated solution of sodium bicarbonate and the mixture was stirred at room temperature overnight. The resulting suspension is then filtered and the obtained solid was dried to obtain crude (4-forfinal)(4-hydroxy-7-methylisatin-2-yl)methanone (2.65 g, 89%). LC-MS (ESI) m/z 283 (M+H)+.

Stage C: To a solution of (4-forfinal)(4-hydroxy-7-methylisatin-2-yl)methanone (650 mg, 2.3 mmol) in DCM (4 ml) was added TEA (1.23 ml, 9.2 mmol), DMAP (15 mg, 0.05 mmol) and 2,4,6-triisopropylbenzene-1-sulphonylchloride (905 mg, 3.0 mmol) and the mixture was stirred at room temperature for 0.5 hours. The crude mixture was concentrated and the residue was purified by chromatography on silica gel, elwira mixture of 0-50% EtOAc in hexane, to obtain 2-(4-perbenzoic)-7-methylpyrazole-4-yl 2,4,6-triisopropylbenzenesulfonyl (790 mg, 63%)which was used without further purification. LC-MS (ESI) m/z 571 (M+Na)+.

Stage D: a solution of 5-methyl-1H-pyrazole-3-amine (225 mg, 2,31 mmol), potassium iodide (188 mg, 0,088 mmol) and 2-(4-perbenzoic)-7-methylpyrazole-4-yl 2,4,6-triisopropylbenzene sulfonate (380 mg, 0.69 mmol) in DMA (2 ml) was stirred at 50°C for 6 hours, then added water and the solution was filtered. The solid is then dried and ground into powder with acetonitrile to obtain (4-forfinal)(7-methyl-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone (36 mg, 14%).1H NMR (300 MHz, DMSO-d6) δ to 2.18 (s, 3H), of 2.50 (s, 3H), 6,53 (s, 1H), 7,38 (m, 2H), 7,51 (d, 2H), 7,66 (s,lH), 8,08 (m, 2H), to 8.62 (d, 1H), 10,57 (s, 1H), 12,18 (s, 1H); LC-MS (ESI) m/z 362 (M+H)+.

Example 25

Receiving (R,S)-(4-forfinal)(7-methyl-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol

To a suspension of (4-forfinal)(7-methyl-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone (40 mg, 0.11 mmol) in MeOH (2 ml), cooled to 0°C, was added borohydride sodium (30 mg, 0.8 mmol). The solution was given to slowly warm to room temperature and was stirred for 2 hours. Then added 1 HCl solution, the solution was stirred for 10 minutes and then filtered. The crude solid was purified using preparative HPLC (column Varian diphenyl reversed-phase, suirable with a gradient of solvent B=0.05% OF HOAC/CH3CN and solvent A=0.05% Of HOAc/H2O) to obtain (R,S)-(4-forfinal)(7-methyl-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol (17 mg, 42%).1H NMR (300 MHz, DMSO-d6) δ 2,24 (s, 3H), 2,47 (s, 3H), 5,64, (s, 1H), of 5.82 (users, 1H), 6,36 (s, 1H), 7,14 (t, 2H), 7,34 (d, 1H), ,54 (m, 3H), to 8.45 (d, 1H), accounted for 10.39 (s, 1H), 12,18 (s, 1H); LC-MS (ESI) m/z 364 (M+H)+.

Example 26

Getting 2-(diftar(4-forfinal)methyl)-7-methyl-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine

Stage A: 2,2-debtor-2-(4-forfinal)acetylchloride was obtained as described in Example 8 stage B. To a solution of 2-amino-4-methylbenzamide (4.0 g, was 0.026 mol) and TEA (4,35 ml, 0,0312 mol) in DCE (60 ml) was added a solution of 2,2-debtor-2-(4-forfinal)acetylchloride (4,90 g of 0.025 mol) in DCE (10 ml) at room temperature and the reaction mixture was stirred over night. After addition of EtOAc (200 ml) and the mixture was washed with water, saturated aqueous NaHCO3and saturated salt solution. The organic solution was concentrated to obtain not quite white solid (5,85 g, 69%). LC-MS (ESI) m/z 305 (M+H)+.

Stage B: To a solution of 2-(2,2-debtor-2-(4-forfinal)acetamido)-4-methylbenzamide (5,85 g, 0,0181 mol) in DCE (120 ml) was added TEA (from 91.5 ml, 0,724 mol) and chlorotrimethylsilane (34,4 ml, 0,272 mol) at room temperature. The reaction mixture was stirred at 85°C during the night. After cooling to room temperature, the solid was filtered and the filtrate was concentrated to dryness. Was carried out by absorption of a precipitate in a mixture of EtOAc/THF (1:1) and washed with water and saturated salt solution. Pure product was obtained after crystallization from hot EtOAc (2,02 g, 37%); LC-MS (ESI) m/z 305 (M+H)+.

stage C: a Solution of 2-(diftar(4-forfinal)methyl)-7-methylpyrazole-4-ol (0,304 g, 1 mmol) in POCl3(5 ml) was heated at 105°C during the night. The reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in anhydrous toluene. The toluene was concentrated under reduced pressure. The residue was dissolved in a small volume of DCM and passed through a short bed of silica gel, using DCM as solvent. 4-Chloro-2-(diftar(4-forfinal)methyl)-7-florinopolis received in the form of a pale yellow solid (308 mg, 95%).1H NMR (300 MHz, DMSO-d6) δ 2,61 (s, 3H), 7,33 (t, 2H), 7,73 (m, 2H), 7,82 (DD, 1H), 8,01 (s, 1H), 8,23 (d, 1H).

Stage D: 2-(Diftar(4-forfinal)methyl)-7-methyl-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine was obtained according to the procedure described in Example 20 to obtain 2-(diftar(4-forfinal)methyl)-7-fluoro-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine, substituting 4-chloro-2-(diftar(4-forfinal)methyl)-7-florinopolis in Example 20 4-chloro-2-(diftar(4-forfinal)methyl)-7-methyldiazonium (13% yield).1H NMR (300 MHz, DMSO-d6) δ and 2.26 (s, 3H), of 2.50 (s, 3H), 6.30-in (s, 1H), 7,34 (t, 2H), 7,47 (m, 1H), 7,71-7,66 (m, 3H), 8,56 (d, 1H), 10,59 (s, 1H), 12,20 (users, 1H); LC-MS (ESI) m/z 384 (M+H)+.

Example 27

Getting 2-(diftar(4-forfinal)methyl)-7-methyl-N-(1H-pyrazole-3-yl)hinzelin-4-amine

2-(Diftar(4-forfinal)methyl)-7-methyl-N-(1H-pyrazole-3-yl)hinzelin-4-amine was obtained according to the procedure described in Example 20 is La obtain 4-chloro-2-(diftar(4-forfinal)methyl)-7-ftorhinolona, substituting 4-chloro-2-(diftar(4-forfinal)methyl)-7-florinopolis in Example 20 4-chloro-2-(diftar(4-forfinal)methyl)-7-methyldiazonium and replacing 5-methyl-1H-pyrazole-3-amine in Example 20 1H-pyrazole-3-amine (6% yield).1H NMR (300 MHz, DMSO-d6) δ 2.50 each (s, 3H), 6.75 in (s, 1H), 7,32 (m, 2H), of 7.48 (m, 1H), 7,71-7,66 (m, 4H), 8,69 (d, 1H), of 10.72 (s, 1H), 12,51 (C, 1); LC-MS (ESI) m/z 370 (M+H)+.

Example 28

Obtain (4-(1H-pyrazole-3-ylamino)-7-methoxyquinazoline-2-yl)(4-forfinal)methanone

Stage A: 2-amino-4-methoxybenzoic acid (10,00 g to 59.82 mmol) in DMF (150 ml) at room temperature was added DIEA (16.2 ml, 71,79 mmol), 2 n solution of ammonia in MeOH (41,8 ml, 83,75 mmol), 1-EDCI (13,76 g, 71,79 mmol) and 1-hydroxybenzotriazole (9,70 g, 71,79 mmol). The solution was stirred at room temperature in argon atmosphere. After 20 hours the solution was concentrated, diluted with water and was extracted seven times with EtOAc. EtOAc was concentrated to reduce the volume and the solution was washed with saturated saline solution. The EtOAc fraction was concentrated and diluted with diethyl ether. The precipitate was collected and dried in vacuum to obtain a rusty-brown solid (9.8 g, 91%).1H NMR (300 MHz, DMSO-d6) δ ppm at 3.69 (s, 3H) 6,06 (DD, J=8,76, of 2.54 Hz, 1H) to 6.19 (d, J=2,64 Hz, 1H) 6,72 (users, 2H) of 7.48 (d, J=8,67 Hz, 1H); LC-MS (ESI) m/z 167 (M+H)+.

Stage B: 2-amino-4-methoxybenzamide (6.0 g, 36,11 mmol) in DCM (200 ml) d is balali DIEA (8.2 ml, 46,94 mmol). The solution was cooled to 0°C followed by the addition dropwise of etylchlorhydrine(of 4.44 ml, 39,72 mmol) in DCM (50 ml). Then was added DMAP (20 mg) followed by removal of the cooling bath. After stirring for 20 hours at room temperature in Ar atmosphere, and the mixture was concentrated and the addition of water resulted in the formation of a precipitate, which was filtered and washed with water. Drying in vacuo gave a solid (6.9 g, 72%).1H NMR (300 MHz, DMSO-d6) δ ppm of 1.31 (t, 3H) 3,82 (s, 3H) 4,30 (square, 7=7,10 Hz, 2H) 6,80 (DD, J=cent to 8.85, of 2.64 Hz, 1H) to 7.64 (users, 1H) 7,89 (d, J=cent to 8.85 Hz, 1H) 8,20 (d, J=2,64 Hz, 2H) 13,53 (s, 1H); LC-MS (ESI) m/z 250, 289, 330.

Stage C: ethyl 2-(2-carbarnoyl-5-methoxybenzylamine)-2-oxoacetate (6,9 g, 25,92 mmol) in DCE (300 ml) at room temperature was added TEA (144 ml, 1.04 mol) followed by the addition of tributyltinchloride (49 ml, 388,7 mmol). The heterogeneous mixture was heated to boiling point under reflux in an atmosphere of Ar. After 20 hours the solution was cooled and poured into ice/water. The organic layer was separated and concentrated, and then added to the aqueous fraction. The mixture was acidified to pH 4 and the precipitate was collected and dried in vacuum to obtain a rusty-brown white solid (5.4 g, 85%).1H NMR (300 MHz, DMSO-d6) δ ppm of 1.35 (t, 7=7,16 Hz, 3H) to 3.92 (s, 3H) to 4.38 (square, 7=7,16 Hz, 2H) 7,21 (DD, 7=8,76, of 2.54 Hz, 1H) 7,30 (d, 7=2,64 Hz, 1H) 8,07 (d, 7=8,67 Hz, 1H) 12,48 (users, 1H); LC-MS (ESI) m/z 249 (M+H)+.

Article is Diya D: phosphorus oxychloride (5 ml) was added ethyl 7-methoxy-4-oxo-3,4-dihydroquinazolin-2-carboxylate (1.0 g, a 4.03 mmol) followed by the addition of dimethylformamide (4 drops). The solution was heated to 85°C for 2 hours and then concentrated. The residue was cooled in a -20°C cooling bath and diluted with cold EtOAc. The cooled solution was washed with cold water, saturated aqueous sodium bicarbonate and saturated saline solution. Removal of solvent gave a white solid (1.2 g, 100%.). LC-MS (ESI) m/z 267 (M+H)+.

Stage E: To ethyl 4-chloro-8-methoxyquinazoline-2-carboxylate (500 mg, 1.88 mmol) in DMF (20 ml) was added DIEA (determined as 0.720 ml, 4.14 mmol), 3-aminopyrazole (309 mg, 3,76 mmol) and potassium iodide (312 mg, 1.88 mmol) at room temperature. After stirring for 18 hours and 6 hours at 40°C the solution was concentrated. The addition of water resulted in the formation of a precipitate, which was collected and washed with water. Drying in vacuo gave a solid (475 mg, 81%).1H NMR (300 MHz, DMSO-d6) δ ppm of 1.36 (t, 3H) 3,94 (s, 3H) 4,39 (square, 2H) 7,16 (s, 1H) 7,28 (m, 1H) 7,34 (m, 1H) 7,74 (users, 1H) 8,65 (m, 1H) 10,65 (s, 1H) 12,50 (s, 1H); LC-MS (ESI) m/z 314 (M+H)+.

Stage F: To ethyl 4-(1H-pyrazole-3-ylamino)-7-methoxyquinazoline-2-carboxylate (30 mg, 0.10 mmol) in anhydrous DMA (2.5 ml), cooled to -20°C cooling bath, was added dropwise 4-performancebased in THF (0,306 ml, 0,306 mmol). After 2 hours, was added an additional amount of 1 n solution of 4-performancebased (0,050 ml). After 2 hours the reaction is th mixture was suppressed by adding a saturated solution of ammonium chloride. The solution was concentrated and added H2O. the Precipitate was washed with water and purified using preparative thin layer chromatography on silica gel, elwira using 10% MeOH/DCM, to obtain a solid (21 mg, 60%).1H NMR (300 MHz, DMSO-d6) δ ppm 3,93 (s, 3H) 6.73 x (users, 1H) 7,29 (m, 2H) 7,38 (m, 2H) 7,63 (users, 1H) 8,08 (m, 2H) 8,64 (m, 1H) 10,63 (users, 1H) 12,47 (users, 1H); LC-MS (ESI) m/z 364 (M+H)+.

Example 29

Receiving (R,S)-(4-(1H-pyrazole-3-ylamino)-7-methoxyquinazoline-2-yl)(4-forfinal)methanol

To (4-(1H-pyrazole-3-ylamino)-7-methoxyquinazoline-2-yl)(4-forfinal)methanone (50 mg, 0.14 mmol) in a mixture of 2:1 MeOH/DMF (4.5 ml) at room temperature was added borohydride sodium (8 mg, 0.21 mmol) in one portion. After stirring for 40 minutes was added a solution of LiOH (60 mg) in H2O (1 ml) and stirring was continued for 45 minutes. The solution was concentrated and diluted with water, which led to the formation of a white precipitate (32 mg). The precipitate was collected and purified preparative thin-layer chromatography on silica, elwira using 10% MeOH/DCM, to obtain the (R,S)-(4-(1H-pyrazole-3-ylamino)-7-methoxyquinazoline-2-yl)(4-forfinal)methanol as a white solid (10 mg, 20%).1H NMR (300 MHz, DMSO-d6) δ ppm 3,91 (s, 3H) 5,64 (m, 1H) 5,77 (users, 1H) 6,80 (users, 1H) for 7.12 (m, 4H) 7,19 (users, 1H) rate of 7.54 (m, 2H) 7,66 (users, 1H) 8,49 (m, 1H) 10,38 (users, 1H) to 12.44 (users, 1H) LC-MS (ESI) m/z 366 (M+H) +.

Example 30

Receive (4-forfinal)(7-methoxy-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone

Stage A: ethyl 4-chloro-7-methoxyquinazoline-2-carboxylate (600 mg, and 2.26 mmol) in DMF (8 ml) was added DIEA (0,864 ml, 4,96 mmol), 5-methyl-1H-pyrazole-3-amine (657 mg, 6,77 mmol) and potassium iodide (374 mg, and 2.26 mmol) at room temperature. After stirring for 18 hours at 40°C the solution was concentrated, and the addition of water resulted in the formation of a precipitate, which was collected and washed with water. Drying in vacuo gave a solid (570 mg, 77%).1H NMR (300 MHz, DMSO-d6) δ ppm of 1.37 (t, 3H), and 2.27 (s, 3) 3,93 (s, 3H) 4,36 (square, 2H) 6,93 (s, 1H) 7,25 (m, 1H) 7,32 (users, 1H) to 8.62 (m, 1H) 10,53 (s, 1H) 12,18 (s, 1H); LC-MS (ESI) m/z 328 (M+H)+.

Stage B: ethyl 7-methoxy-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-carboxylate (379 mg, of 1.16 mmol) in anhydrous DMA (16 ml), cooled to -30°C bath, was added dropwise 1 n solution of 4-performancebased in THF (of 4.05 ml of 4.05 mmol). After 4 hours the reaction mixture was suppressed by the addition of saturated solution of ammonium chloride. The solution was concentrated and added H2O. the Precipitate was washed with water and diethyl ether to obtain a yellow solid (415 mg, 95%).1H NMR (300 MHz, DMSO-d6) δ ppm 2,18 (users, 3H) 3,92 (users, 3H) 6,48 (users, 1H) 7,27 (users, 2H) 7,39 (users, 2H) 8,07 (users, 2H) 8,62 (users, 1H) 10,50 (users, 1H) 12,15 (users, 1H); LC-M (ESI) m/z 378 (M+H) +.

Example 31

Receiving (R,S)-(4-forfinal)(7-methoxy-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol

To (4-forfinal)(7-methoxy-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone (150 mg, 0.40 mmol) in a solution of 2:1 MeOH/DMF (8 ml), cooled to 0°C, was added borohydride sodium (23 mg, of 0.60 mmol) in one portion. After stirring for two hours at room temperature the solution was cooled to 0°C and was suppressed by adding 1 n HCl solution. The solution was concentrated and diluted with water, which led to the formation of a white precipitate (130 mg). The precipitate was collected and purified on silica, elwira using 3-15% MeOH/DCM, to obtain white solid (20 mg, 13%).1H NMR (300 MHz, DMSO-d6) δ ppm of 2.25 (s, 3H) 3,91 (s, 3H) 5,62 (m, 1H) 5,74 (m, 1H) to 6.43 (s, 1H) of 6.96-7,19 (m, 4H) 7,51-of 7.55 (m, 2H) 8,49 (m, 1H) 10,22 (s, 1H) 12,08 (users, 1H); LC-MS (ESI) m/z 380 (M+H)+.

Example 32

Getting 2-(diftar(4-forfinal)methyl)-7-methoxy-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine

Stage A: 2,2-debtor-2-(4-forfinal)acetylchloride was obtained as described in Example 8 stage B. To a solution of 2-amino-4-methoxybenzamide (0,415 g, 2.5 mmol) and TEA (0,418 ml, 3 mmol) in DCE (15 ml) was added a solution of 2,2-debtor-2-(4-forfinal)acetylchloride (0,579 mg, 2,78 mmol) in DCE (5 ml) at room temperature and the reaction mixture was stirred during the course the e night. After addition of EtOAc (200 ml) and the mixture was washed 1 N. HCl solution, saturated aqueous NaHCO3and saturated salt solution. The organic solution was concentrated to obtain not quite white solid (371 g, 44%). LC-MS (ESI) m/z 339 (M+H)+.

Stage B: 2-(Diftar(4-forfinal)methyl)-7-methoxyquinazoline-4-ol was obtained in accordance with the procedure described in Example 20 to obtain 2-(diftar(4-forfinal)-7-florinopolis-4-ol, substituting 2-(2,2-debtor-2-(4-forfinal)acetamido)-4-perbenzoic in Example 20 2-(2,2-debtor-2-(4-forfinal)acetamido)-4-methoxybenzamido. The crude product (~100% yield) was used directly in the next stage.1H NMR (300 MHz, DMSO-d6) δ with 3.89 (s, 3H), 7,16 (m, 2H), 7,39 (t, 2H), to 7.75 (m, 2H), of 8.04 (d, 1H), 12,96 (s, 1H); LC-MS (ESI) m/z 321 (M+H)+.

Stage C: 4-Chloro-2-(diftar(4-forfinal)methyl)-7-methoxyquinazoline received in accordance with the procedure described in Example 26 synthesis of 4-chloro-2-(diftar(4-forfinal)methyl)-7-methylinosine, substituting 2-(diftar(4-forfinal)methyl)-7-methylpyrazole-4-ol in Example 26 2-(diftar(4-forfinal)methyl)-7-methoxyquinazoline-4-I. 4-Chloro-2-(diftar(4-forfinal)methyl)-7-methoxyquinazoline was isolated as a pale yellow solid (0,290 g, 89%). LC-MS (ESI) m/z 339 (M+H)+.

Stage D: 2-(Diftar(4-forfinal)methyl)-7-methoxy-N-(5-methyl-1H-pyrazole-3-yl)-hinzelin-4-amine was obtained according to the procedure of vannoy in Example 20 to obtain 2-(diftar(4-forfinal)methyl)-7-fluoro-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine, substituting 4-chloro-2-(diftar(4-forfinal)methyl)-7-florinopolis in Example 20 4-chloro-2-(diftar(4-forfinal)methyl)-7-methoxyquinazoline (36% yield).1H NMR (300 MHz, DMSO-d6) δ, and 2.27 (s, 3H), 3,93 (s, 3H), 6,28 (s, 1H), 7,37-7,20 (m, 4H), 7,71-7,66 (m, 1H), 8,58 (d, 2H), 10,53 (s, 1H); LC-MS (ESI) m/z 400 (M+H)+.

Example 33

Getting 2-(diftar(4-forfinal)methyl)-7-methoxy-N-(1H-pyrazole-3-yl)hinzelin-4-amine

2-(diftar(4-forfinal)methyl)-7-methoxy-N-(1H-pyrazole-3-yl)hinzelin-4-amine was obtained according to the procedure described in Example 20 to obtain 2-(diftar(4-forfinal)methyl)-7-fluoro-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine, substituting 4-chloro-2-(diftar(4-forfinal)methyl)-7-florinopolis in Example 20 4-chloro-2-(diftar(4-forfinal)methyl)-7-methoxyquinazoline and replacing 5-methyl-1H-pyrazole-3-amine in Example 20 1H-pyrazole-3-amine (24% yield).1H NMR (300 MHz, DMSO-d6) δ 4,17 (s, 3H), 6.75 in (s, 1H), 7,43-7,22 (m, 4H), 7,71-to 7.67 (m, 3H), at 8.60 (d, 1H), 10,70 (s, 1H), 12,50 (s, 1H); LC-MS (ESI) m/z 386 (M+H)+.

Example 34

Getting 2-(diftar(4-forfinal)methyl)-8-fluoro-N-(5-methyl-1H - pyrazole-3-yl)hinzelin-4-amine

Stage A: 2-(2,2-Debtor-2-(4-forfinal)acetamido)-3-perbenzoic received in accordance with the procedure described in Example 32 to obtain 2-(2,2-debtor-2-(4-forfinal)acetamido)-4-methoxybenzamide, replacing 2-amino-4-methoxybenzamide in Example 32 2-amine is-3-fermentation. The product was purified on a column of silica gel using DCM/MeOH as eluent (20%); LC-MS (ESI) m/z 327 (M+H)+.

Stage B: a solution of 2-(2,2-debtor-2-(4-forfinal)acetamido)-3-fermentated (0,235 g to 0.72 mmol) in acetic acid (2 ml) was heated at 120°C for 3 hours. The reaction mixture was allowed to warm to room temperature and then added water. The solid is collected by filtration and washed using H2O. 2-(Diftar(4-forfinal)methyl-8-florinopolis-4-ol was obtained in the form of not-quite-white solid (is 0.135 g, 61%).1H NMR (300 MHz, DMSO-d6) δ 7,38 (m, 2H), to 7.61 (m, 1H), 7,80-7,74 (m, 3H), of 7.97 (m, 1H), 13,43 (s, 1H); LC-MS (ESI) m/z 309 (M+H)+.

Stage C: 4-Chloro-2-(diftar(4-forfinal)methyl)-8-florinopolis received in accordance with the procedure described in Example 26 to obtain 4-chloro-2-(diftar(4-forfinal)methyl)-7-methylinosine, substituting 2-(diftar(4-forfinal)methyl)-7-methylpyrazole-4-ol in Example 26 2-(diftar(4-forfinal)methyl-8-florinopolis-4-I (94% yield). LC-MS (ESI) m/z 327 (M+H)+.

Stage D: 2-(Diftar(4-forfinal)methyl)-8-fluoro-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine was obtained according to the procedure described in Example 20 to obtain 2-(diftar(4-forfinal)methyl)-7-fluoro-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine, substituting 4-chloro-2-(diftar(4-forfinal)methyl)-7-florinopolis in Example 20 4-chloro-2-(diftar(4-forfinal)methyl)-8-ftorhinolonam. H the hundred compound was obtained after trituration in powder with MeOH (34%). 1H NMR (300 MHz, DMSO-d6) δ 2,24 (s, 3H), 6,27 (s, 1H), 7,34 (t, 2H), to 7.64 (m, 1H), 7,78-of 7.69 (m, 3H), 8,51 (d, 1H), 10,85 (s, 1H), 12,25 (s, 1H); LC-MS (ESI) m/z 388 (M+H)+.

Example 35

Obtain (4-(1H-pyrazole-3-ylamino)-8-methoxyquinazoline-2-yl)(4-forfinal)methanone

Stage A: 2-amino-3-methoxybenzoic acid (8,11 g, 48,52 mmol) in DMF (150 ml) at room temperature was added DIEA (13,2 ml, 58,22 mmol), 2 n solution of ammonia in MeOH (33,96 ml, 67,92 mmol), EDCI (11,16 g, 58,22 mmol) and 1-hydroxybenzotriazole (7,87 g, 58,22 mmol). The solution was stirred at room temperature in argon atmosphere. After 20 hours the solution was diluted with water and was extracted ten times with EtOAc. EtOAc was concentrated to reduce the volume and washed with a saturated saline solution. The EtOAc fraction was concentrated and diluted with diethyl ether. Received rusty-brown solid was collected and dried in vacuum to obtain 2-amino-3-methoxybenzamide (between 6.08 g, 76%).1H NMR (300 MHz, DMSO-d6) δ 3,79 (s, 3H), 6,26 (users, 2H), 6.48 in (m, 1H), to 6.88 (d, J=7.9 Hz, 1H), 7,12 (users, 1H), 7,19 (DD, J=8,2, 1.0 Hz, 1H), 7,70 (users, 1H); LC-MS (ESI) m/z 167 (M+H)+.

Stage B: 2-amino-3-methoxybenzamide (1 g, of 6.02 mmol) in DCM (20 ml) was added DIEA (1,37 ml, 7.82 mmol). The solution was cooled to 0°C followed by the addition of etylchlorhydrine (0,808 ml, 7.22 mmol) in DCM (5 ml) dropwise. Upon completion of this addition was added dimethylamine is iridin (10 mg) followed by removal of the cooling bath. After stirring for 20 hours at room temperature in Ar atmosphere and the mixture was washed with water and purified using chromatography on silica, elwira using EtOAc/DCM (20 to 60%) and MeOH/DCM (2 to 15%)to give a white solid (770 mg, quantities.).1H NMR (300 MHz, DMSO-d6) δ ppm of 1.30 (t, J=1,16 Hz, 3H) 3,79 (s, 3H) 4,29 (sq, J=7.03 is Hz, 2H) 7,16 (DD, J=and 17.2, 1.2 Hz, 1H) 7,21 (DD, J=17,8, 1.2 Hz, 1H) 7,27-7,39 (m, 1H) 7,44 (users, 1H) to 7.67 (users, 1H) 10,14 (users, 1H); LC-MS (ESI) m/z 250 (M-16)-.

Stage C: ethyl 2-(2-carbarnoyl-6-methoxybenzylamine)-2-oxoacetate (3.4 g, 12,77 mmol) in DCE (50 ml) at room temperature was added TEA (71 ml, 511 mmol) followed by rapid addition of tributyltinchloride (21 ml, 191 mmol) within twenty seconds. The heterogeneous solution was heated to boiling point under reflux in an atmosphere of Ar. After 18 hours the solution was cooled and poured into ice/water. The resulting mixture was acidified to pH 3-4 and the precipitated product collected by filtration. The acid layer was extracted four times with the aid of EtOAc. The aqueous layer was podslushivaet to pH 7 using saturated solution of sodium bicarbonate and was extracted using EtOAc. The organic extracts were combined, washed with saturated saline and concentrated to a volume of 50 ml was Added diethyl ether (10 ml) and the precipitate was collected. The incorporation of both precipitation gave rusty-coric Evoe solid (3,85 g, quantities.).1H NMR (300 MHz, DMSO-d6) δ ppm of 1.36 (t, J=7,06 Hz, 3H) 3,94 (s, 3H) 4,39 (sq, J=6,97 Hz, 2H) 7,44 (d, J=8,10 Hz, 1H) 7,58 (t, J=8,01 Hz, 1H) 7,72 (d, J=to $ 7.91 Hz, 1H) 12,56 (users, 1H); LC-MS (ESI) m/z 249 (M+H)+.

Stage D: phosphorus oxychloride (2 ml) was added ethyl 8-methoxy-4-oxo-3,4-dihydroquinazolin-2-carboxylate (100 mg, 0,403 mmol) followed by the addition of dimethylformamide (2 drops). The solution was heated at 80°C for 1.5 hours and then concentrated. The residue was cooled in a -20°C cooling bath and diluted with cold EtOAc. The cooled solution was washed with cold water, saturated aqueous sodium bicarbonate and saturated saline solution. Removal of solvent gave a white solid (98 mg, 91%).1H NMR (300 MHz, DMSO-d6) δ ppm to 1.38 (t, J=7,06 Hz, 3H) 4,06 (s, 3H) 4,45 (sq, J=7.03 is Hz, 2H) 7,51-7,76 (m, 1H) 7,76-to 8.12 (m, 2H).

Stage E: To ethyl 4-chloro-8-methoxyquinazoline-2-carboxylate (550 mg, 2,07 mmol) in dimethylformamide (6 ml) was added DIEA (0,468 ml, 2,69 mmol), 3-aminopyrazole (221 mg, 2,69 mmol) and potassium iodide (343 mg, 2,07 mmol) at room temperature. After stirring for 18 hours was added an additional amount of 3-aminopyrazole (100 mg) and stirring continued for 5 hours. The solution was poured into water and filtered and the solid is washed with diethyl ether to obtain a yellow solid (510 mg, 79% yield).1H NMR (300 MHz, DMSO-d6) δ ppm 137 (t, 3H) 3,7 (s, 3H) to 4.38 (sq, J=I,16 Hz, 2H) 7.18 in (users, 1H) 7,38 (d, J=7,72 Hz, 1H) 7,60 (m, 1H) 7,75 (users, 1H) of 8.25 (d, J=8,29 Hz, 1H) 10,65 (s, 1H) 12,53 (users, 1H); LC-MS (ESI) m/z 314 (M+H)+.

Stage F: To ethyl 4-(1H-pyrazole-3-ylamino)-8-methoxyquinazoline-2-carboxylate (200 mg, 0.64 mmol) in anhydrous THF (8 ml), cooled to -40°C, was added dropwise over 2 minutes in 4-performancebased in THF (2,17 ml, 2,17 mmol). After 1.5 hours the reaction mixture was suppressed by adding a saturated aqueous solution of ammonium chloride. The solution was concentrated and added H2O. the Precipitate was washed with water and diethyl ether to obtain(4-(1H-pyrazole-3-ylamino)-8-methoxyquinazoline-2-yl)(4-forfinal)methanone in the form of a yellow solid (74 mg, 87% purity according to LC/MS).1H NMR (300 MHz, DMSO-d6) δ ppm of 3.94 (s, 3H) 6,75 (s, 1H) 7,35-7,41 (m, 3H) 7,58-the 7.65 (m, 2H) 8.07-a to 8.12 (m, 2H) 8,2 (d, J=8,48 Hz, 1H) at 10.64 (users, 1H) 12,51 (users, 1H); LC-MS (ESI) m/z 364 (M+H)+.

Example 36

Receiving (R,S)-2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-ol

Stage A: 2-amino-4-methoxybenzamide (7.0 g, 42 mmol) in 1,2-dichloroethane (100 ml) was added tribromide boron (25 g, 100 mmol) at room temperature. After heating at 40°C for 20 hours was added 1 n solution of tribromide boron in THF (40 ml) and the reaction mixture was heated to 50°C for 20 hours. The mixture was cooled and extinguished by adding water is astora sodium bicarbonate. The precipitate was collected by filtration to obtain 2-amino-4-hydroxybenzamide in the form of a white solid (2.0 g). The mother solution was concentrated, diluted with the aid of MeOH, filtered and concentrated. The residue was again diluted using MeOH, filtered and concentrated and the obtained residue was purified by chromatography on silica gel, elwira using 5-15% MeOH/DCM, to obtain 2-amino-4-hydroxybenzamide in the form of a white solid (4.7 g). The solids were combined to obtain total yield 6.7 g (quantitative).1H NMR (300 MHz, DMSO-d6) δ ppm 5,91 (DD, J=8,67, and 2.26 Hz, 1H) 6,03 (d, J=2,45 Hz, 1H) 6,62 (users, 2H) 7,38 (d, J=8,67 Hz, 1H) of 9.45 (s, 1H), LC-MS (ESI) m/z 153 (M+H)+.

Stage B: To a solution of 95% NaH (1,82 g, 72,30 mmol) in DMF (100 ml) at 10°C was added 2-amino-4-hydroxybenzamide (10.0 g, 66,72 mmol) in portions, maintaining the internal temperature at about 15°C. the Cooling bath was removed and the solution was allowed to warm to 40°C for 25 minutes. The mixture was cooled to 10°C was added dropwise a solution of benzylbromide (7.8 ml, 66,72 mmol) in DMF (20 ml) and the mixture was allowed to warm to room temperature. After stirring for 20 hours at room temperature the mixture was cooled in an ice bath, and was suppressed by adding an aqueous solution of ammonium chloride. The solution was concentrated and diluted with water. The precipitate was collected by filtration and the filtrate was AKST who was agarawala using EtOAc. The precipitate mentioned above, and an ethyl acetate extracts were combined and purified using chromatography on silica gel, elwira using 20-80% EtOAc/DCM, to obtain 2-amino-4-(benzyloxy)benzamide as a solid (6.8 g, 43%).1H NMR (300 MHz, DMSO-d6) δ ppm 5,04 (s, 2H) 6,14 (DD, J=8,76, of 2.54 Hz, 1H) 6,27 (d, J=2,64 Hz, 1H) of 6.71 (users, 2H) 7,26-7,58 (m, 6H); LC-MS (ESI) m/z 243 (M+H)+.

Stage C: To a solution of 2-amino-4-(benzyloxy)benzamide (4.0 g, 16.5 mmol) in THF (60 ml) was added a solution of 5-(4-forfinal)-1,3-dioxolane-2,4-dione (3,65 g of 18.6 mmol) from Example 16 in THF (20 ml) in portions at room temperature. After heating to 63°C for 18 hours the solution was cooled and concentrated. After adding H2O the solution was extracted twice using DCM. The combined organic phase was washed with saturated saline solution and dried over sodium sulfate. Chromatography on silica gel with elution using 10 to 80% EtOAc/DCM gave 4-(benzyloxy)-2-(2-(4-forfinal)-2-hydroxyacetamido)benzamide in the form of a foamy solid (4.1 g, 64%).1H NMR (300 MHz, DMSO-d6) δ ppm of 5.06 (m, 1H), 5,12 (s, 2H) 6,68-6,74 (m, 1H) 7,14-7,20 (m, 2H) 7,32-7,51 (m, 6H) to 7.77 (d, J=cent to 8.85 Hz, 1H) 8,05 (users, 1H) 8,30 (d, J=2,64 Hz, 1H) of 12.73 (s, 1H), LC-MS (ESI) m/z 392 (M-2).

Stage D: 4-(benzyloxy)-2-(2-(4-forfinal)-2-hydroxyacetamido)benzamide (4.1 g, 10.4 mmol) in absolute EtOH (50 ml) was added 20% aqueous potassium carbonate solution (5 ml). After heating and is remesiana at 80°C for 20 hours the solution was cooled and concentrated to obtain a solid substance. The solid is washed with water and dried under vacuum to obtain 7-(benzyloxy)-2-((4-forfinal)(hydroxy)methyl)hinzelin-4(3H)-it is in the form of a white solid (3.51 g, 90%).1H NMR (300 MHz, DMSO-d6) δ ppm a 5.25 (s, 2H) of 5.55 (s, 1H) 7,10-7,21 (m, 4H) was 7.36-of 7.48 (m, 5H) 7,56-to 7.61 (m, 2H) of 7.97 (d, J=8,67 Hz, 1H), LC-MS (ESI) m/z 377 (M+H)+.

Stage E: 4-(benzyloxy)-2-((4-forfinal)(hydroxy)methyl)hinzelin-4(3H)-ONU (3.5 g, 9.3 mmol) in DMSO (15 ml) and CHCl3(30 ml) at 0°C was added in portions periodinane Dess-Martin (5,52 g, 13,02 mmol). After stirring for 6 hours was added a 1:1 mixture of 10% aqueous solution of sodium thiosulfate pentahydrate and saturated aqueous sodium bicarbonate solution. After shaking with DCM formed precipitate, which was collected by filtration. The filtrate was extracted three times using DCM and the combined organic fractions were washed with saturated saline and dried over magnesium sulfate. Concentration and unification of the initially formed precipitate gave 7-(benzyloxy)-2-(4-perbenzoic)hinzelin-4(3H)-it is in the form of a white solid (3.0 g, 86%). LC-MS (ESI) m/z 375 (M+H)+.

Stage F: phosphorus oxychloride (10 ml), cooled to 5°C, was added in portions 7-(benzyloxy)-2-(4-perbenzoic)hinzelin-4(3H)-he (500 mg, of 1.34 mmol) followed by addition of DMF (4 drops). The mixture was heated to 56°C for 10 minutes and kept at this temperature the e in for 2 minutes, then the heating bath was removed. The mixture was concentrated and the residue was diluted using EtOAc, then the solution was washed with cold water, saturated sodium bicarbonate solution (aq.), saturated saline solution and dried over sodium sulfate. The solution was concentrated to obtain (7-(benzyloxy)-4-chlorination-2-yl)(4-forfinal)methanone as not quite white solid (380 mg, 72%).1H NMR (300 MHz, DMSO-d6) δ ppm of 5.40 (s, 2H) 7,37 was 7.45 (m, 5H) 7,52-of 7.55 (m, 2H) 7,66-7,71 (m, 2H) 8,09-to 8.14 (m, 2H) 8,31 (d, J=9,04 Hz, 1H), LC-MS (ESI) m/z 393 (M+H)+.

Stage G: (7-(benzyloxy)-4-chlorination-2-yl)(4-forfinal)methanone (380 mg, 0.97 mmol) in DMF (10 ml) at room temperature was added DIEA (500 μl, 2,90 mmol), 5-methyl-1H-pyrazole-3-amine (280 mg, 2,90 mmol) and KI (161 mg, 0.97 mmol). After stirring at 40°C for 18 hours the solution was cooled and diluted with water. After maturation at 0°C for 1 hour the precipitate was collected by filtration and dried under reduced pressure to obtain (7-(benzyloxy)-4-(5-methyl-1H - pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone in the form of a yellow solid (365 mg, 83%).1H NMR (300 MHz, DMSO-d6) δ ppm to 2.18 (s, 3H) and 5.30 (s, 2H) 6.48 in (s, 1H) 7,33-7,44 (m, 8H) 7,50-7,52 (m, 2H) 8,07 (m, 2H) 8,65 (m, 1H) 10,53 (s, 1H) 12,18 (s, 1H), LC-MS (ESI) m/z 454 (M+H)+.

Stage H: 10% Pd/C (200 mg) was added to a solution of (7-(benzyloxy)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone (390 mg, 0,99 IMO the ü) in DMF (30 ml). After stirring in an atmosphere of H2at 1 ATM for 18 hours the mixture was filtered and the filtrate was concentrated. The residue was passed through a short column with silica gel, elwira first using 10-30% EtOAc/DCM, then 1-5% AcOH/9-5% MeOH/90% DCM. The fractions containing the product were combined and washed with sodium bicarbonate solution followed by evaporation to obtain (R,S)-2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-ol as a white solid (130 mg, 36%).1H NMR (300 MHz, DMSO-d6) δ ppm 2,24 (s, 3H) 5,59 (users, 1H) 5,73 (m, 1H) 6,38 (m, 1H) 6,99 (users, 2H) 7,14 (m, 2H) 7,53 (m, 2H) 8,39 (users, 1H) 10,11 (users, 1H) 12,06 (users, 1H), LC-MS (ESI) m/z 366 (M+H)+.

Example 37

Receive (4-forfinal)(7-hydroxy-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone

To 2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-Olu (50 mg, 0.14 mmol) in 1:3 DMSO/DCM was added periodinane Dess-Martin (81 mg, 0,19 mmol) in one portion. After stirring for 1 hour at room temperature the solution was cooled to 0°C and was suppressed by adding a 1:1 mixture of 10% solution of sodium thiosulfate pentahydrate and saturated sodium bicarbonate solution. The obtained dark precipitate was collected and purified using chromatography on silica, elwira mixture of 2-10% MeOH/DCM. Rubbing in powder painted firmly what about the substances with MeOH gave (4-forfinal)(7-hydroxy-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon in the form of a white solid (7 mg, 14%).1H NMR (300 MHz, DMSO-d6) δ ppm, and 2.27 (s, 3H), 6,47 (users, 1H), 7,06 (m, 2H), 7,13 (m, 1H), 7,38 (m, 2H), of 8.06 (m, 2H), to 8.57 (m, 2H), 10,41 (users, 1H), or 10.60 (users, 1H), 12,15 (users, 1H), LC-MS (ESI) m/z 364 (M+H)+.

Example 38

Receiving (R,S)-(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(2-morpholinoethoxy)hinzelin-2-yl)methanol

K (R,S)-2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-Olu (50 mg, 0.14 mmol) in DMF (2 ml) was added 4-(2-chloroethyl)morpholine (51 mg, 0.27 mmol) and cesium carbonate (134 mg, 0.41 mmol) at room temperature. After heating at 40°C for 18 hours the solution was diluted with the aid of EtOAc and washed with water and saturated saline and dried over sodium sulfate. Chromatography on silica gel with elution with a mixture of 2-10% MeOH/DCM gave (R,S)-(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(2-morpholinoethoxy)hinzelin-2-yl)methanol as a solid (26 mg, 40%).1H NMR (300 MHz, DMSO-d6) δ ppm 2,25 (users, 3H) 2,75 (m, 3H) 3,59 (m, 6H) 4.26 deaths (m, 3H) 5,63 (m, 1H) 5,75 (m, 1H) to 6.43 (users, 1H) 7,10-7,20 (m, 4H) 7,53 (m, 2H) of 8.47 (m, 1H) 10,23 (users, 1H) 12,09 (users, 1H), LC-MS (ESI) m/z 479 (M+H)+.

Example 39

Receiving (R,S)-2-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)ethanol

(R,S)-(7-(2-(tert-butyldimethylsilyloxy)ethoxy)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-ftoh the Nile)methanol was obtained, following the procedure described in Example 38 for the synthesis of (R,S)-(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(2-morpholinoethoxy)hinzelin-2-yl)methanol, substituting 4-(2-chloroethyl)morpholine in Example 38 (2 bromoethoxy)(tert - butyl)dimethylsilane, to obtain 150 mg of the crude containing impurities solids. To this crude solid substance (150 mg) in THF (1 ml) was added tetrabutylammonium (1.0 ml) dropwise at room temperature. After 18 hours the solution was concentrated, diluted with the aid of EtOAc and washed with water. Chromatography of the residue on silica gel with elution with a mixture of 2-8% 1%NH4OH.9%MeOH)/DCM gave (R,S)-2-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)ethanol as a solid (31 mg, 18%).1H NMR (300 MHz, DMSO-d6) δ ppm 2,31 (s, 3H) 3,84 (sq, J=5,09 Hz, 2H) 4,22 (t, 7=4,71 Hz, 2H) 5,01 (t, J=5,46 Hz, 1H) 5,69 (m, 1H) of 5.83 (users, 1H) 6,47 (users, 1H) 7,17-7,25 (m, 4H) to 7.59 (m, 2H) 8,54 (d, J=9,04 Hz, 1H) 10,30 (users, 1H) 12,15 (users, 1H), LC-MS (ESI) m/z 410 (M+H)+.

Example 40

Receiving (R,S)-3-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)propan-1-ol

(R,S)-3-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)propan-1-ol was obtained by following the procedure described in Example 38 for the synthesis of (R,S)-(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(2-morpholino the XI)hinzelin-2-yl)methanol substituting 4-(2-chloroethyl)morpholine in Example 38 3-chloropropane-1-I (35 mg, 30%).1H NMR (300 MHz, DMSO-d6) δ ppm a 1.96 (m, 2H) 2,24 (s, 3H) of 3.60 (m, 2H) 4.26 deaths (t, J=6,41 Hz, 2H) 5,97 (s, 1H) x 6.15 (s, 1H) 7.24 to 7,41 (m, 4H) 7,60 (m, 2H) 7,70 (users, 1H) 8,73 (d, J=9,42 Hz, 4H) 11.87 per (users, 1H) 12,56 (users, 1H) 14,21 (users, 1H); LC-MS (ESI) m/z 424 (M+H)+.

Example 41

Receive (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(piperidin-4-yloxy)hinzelin-2-yl)methanol

The intermediate compound (R,S)-tert-butyl 4-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)piperidine-1-carboxylate was obtained (105 mg)following the procedure described in Example 38 for the synthesis of (R,S)-(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(2 morpholinoethoxy)hinzelin-2-yl)methanol, substituting 4-(2-chloroethyl)morpholine in Example 38 tert-butyl 4-(methylsulfonylamino)piperidine-1-carboxylate. To the crude tert-butyl 4-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)piperidine-1-carboxylate (100 mg, 18.2 mmol) in a flask at 0°C was added 4 n HCl/dioxane (5 ml). After stirring for 20 hours the solvent was removed and the residue was which with DCM and aqueous sodium bicarbonate solution. The solvents were removed and the remaining residue was extracted using MeOH/DCM. The extracts were concentrated and the residue was purified using reverse-phase HPLC with on the doctrine (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(piperidine-4-yloxy)hinzelin-2-yl)methanol as a white solid (32 mg, 21%).1H NMR (300 MHz, DMSO-d6) δ ppm and 1.54 (m, 2H) 1,89 (C, 13H) 1,89 (s, 3H) to 1.98 (m, 2H) 2,68 (m, 2H) 2,99 (m, 2H) 4,66 (m, 4H) 5,62 (s, 1H) USD 5.76 (s, 1H) 6,36 (user., 1H) 7,08-to 7.18 (m, 4H) 7,52 (m, 2H) to 8.45 (m, 1H), 10,29 (users, 1H), LC-MS (ESI) m/z 449 (M+H)+.

Example 42

Receiving (R,S)-(4-forfinal)(7-(2-methoxyethoxy)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol

(R,S)-(4-forfinal)(7-(2-methoxyethoxy)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol was obtained (35 mg, 25%), following the procedure described in Example 38 for the synthesis of (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(2-morpholinoethoxy)hinzelin-2-yl)methanol, substituting 4-(2-chloroethyl)morpholine in Example 38 1-bromo-2-methoxyethane.1H NMR (300 MHz, DMSO-d6) δ ppm 2,24 (s, 3H), 3,71 (m, 2H), 4.26 deaths (m, 2H), 5,63 (users, 1H), 5,77 (users, 1H), 6,40 (users, 1H), 7,14 (m, 4H), 7,53 (m, 2H), of 8.47 (m, 1H), of 10.25 (users, 1H), 12,09 (users, 1H), LC-MS (ESI) m/z 424 (M+H)+.

Example 43

Receiving (R,S)-tert-butyl 2-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)acetate

(R,S)-Tert-butyl 2-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)acetate was obtained (70 mg, 30%), following the procedure described in Example 38 for the synthesis of (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(2-morpholinoethoxy)hinzelin-2-yl)methanol, substituting 4-(2-chloroethyl)morpholine in Example 38 tert-butyl 2-bromac what tatom. 1H NMR (300 MHz, DMSO-d6) δ ppm was 1.43 (s, 9H), of 2.25 (s, 3H), a 4.86 (s, 2H), 5,62 (m, 1H), 5,77 (m, 1H), 7,09-7,16 (m, 4H), 7,52 (m, 2H), and 8.50 (m, 1H), 10,26 (users, 1H), 12,09 (users, 1H), LC-MS (ESI) m/z 424 (M+H)+.

Example 44

Receiving (R,S)-2-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)acetic acid

K (R,S)-tert-butyl 2-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)acetate (26 mg, 0.05 mmol) from Example 43 in DCM (1 ml) at 0°C was added TFA (1 ml). After stirring for 18 hours at 0°C the solvent was removed and the residue was ground into powder with DCM to obtain (R,S)-2-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)acetic acid as a solid (20 mg, 87%).1H NMR (300 MHz, DMSO-d6) δ ppm, and 2.27 (s, 3H), to 5.93 (s, 1H), x 6.15 (s, 1H), 7,22-the 7.43 (m, 4H), to 7.59 (m, 3H), 8,71 (m, 1H); LC-MS (ESI) m/z 424 (M+H)+.

Example 45

Receiving (R,S)-methyl (4-forfinal)(4-(5-methyl-4H-pyrazole-3-ylamino)hinzelin-2-yl)methylcarbamate

Stage A: (4-forfinal)(4-(5-methyl-4H-pyrazole-3-ylamino)hinzelin-2-yl)methanone from Example 3 (0,700 g of 2.15 mmol) in EtOH (10 ml) were added hydrochloride methoxylamine (0,336 g, 4.02 mmol) and the mixture was heated to 60°C for 30 minutes. Added water and the yellow precipitate was collected by filtration and washed using MeOH to obtain (4-torfin the l)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon O-methyloxime (0.88 g). LC-MS (ESI) m/z 377 (M+H)+.

Stage B: To a solution of (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon O-methyloxime (0.88 g, of 2.33 mmol) in acetic acid (25 ml) was added zinc dust (3.0 g, 46 mmol) and the mixture was stirred at room temperature overnight then filtered through Celite. The filtrate was concentrated and the residue was purified using reverse-phase preparative HPLC, elwira a mixture of 30-50% CH3CN/H2O, containing 0.05% HOAc, to obtain the (R,S)-2-(amino(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine as a pale yellow solid (105 mg, 40%). LC-MS (ESI) m/z 349 (M+H)+.

Stage C: To a solution of (R,S)-2-(amino(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine (0,105 g, 0.3 mmol) in anhydrous THF (3 ml) was added dropwise methylchloroform (0,02 ml, 0.3 mmol). Added DIEA (0.06 ml, 0.36 mmol) and the mixture was stirred at 0°C for 10 minutes. The mixture was allowed to warm to room temperature and was stirred for 5 minutes. The mixture was distributed between water and EtOAc and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified using reverse-phase preparative HPLC, elwira a mixture of CH3CN/H2O, containing 0.05% HOAc, to obtain the (R,S)-methyl (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methylcarbamate in the form of a white powder (35 mg, 29% yield).1 H NMR (300 MHz, DMSO-d6) δ 2,2 (s, 3H) 3,57(s, 3H) and 5.8 (s, 1H) 6,4 (s, 1H) 7,1-7,2 (m, 2H) and 7.4-7.5 (m, 3H) of 7.7 to 7.9 (m, 3H) and 8.5 (s, 1H) 10,42 (s, 1H) 12,25 (s, 1H); LC-MS (ESI) m/z 407 (M+H)+.

Example 46

Receiving (R,S)-(4-forfinal)(8-methyl-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol

Stage A: To a solution of 2-amino-3-methylbenzoic acid (4.0 g, of 26.5 mmol) in degassed DMF (40 ml) was added HOBt (4,28 g, and 31.7 mmol), DIEA (5,52 ml, and 31.7 mmol) and 2 n solution of NH3/MeOH (19 ml, 37,1 mmol). The solution was stirred at room temperature for 16 hours, then the mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel, elwira mixture of 10-60% EtOAc/hexane, to obtain 2-amino-3-methylbenzamide in the form of solids (2,52 g, 63%).1H NMR (300 MHz, DMSO-d6) δ 2,07 (s, 3H), 6,40-6,47 (m, 3H), 7,06 (m, 2H), 7,42 (d, 1H), 7,72 (userd, 1H).

Stage B: To a solution of 2-amino-3-methylbenzamide (1.50 g, 10.0 mmol) and DIEA (2,61 ml, 15 mmol) in THF (50 ml) at 0°C was added utilisateur (1.23 ml, 11.0 mmol). The solution was allowed to warm to room temperature and was stirred for 16 hours, then concentrated under reduced pressure. The residue was purified by chromatography on silica gel, elwira mixture 20-100% EtOAc/hexane, to obtain ethyl 2-(2-carbarnoyl-6-methylphenylimino)-2-oxoacetate in the form of a solid (490 mg, 20%).1H NMR (300 MHz, DMSO-d6) δ is 1.31 (t, J=7,1 Hz, 3H), 217 (C, 3H), 4,30 (sq, J=7,1 Hz, 2H), 7,28 (m, 1H), 7,33-EUR 7.57 (m, 3H), of 7.82 (s, 1H), 10,67 (s, 1H).

Stage C: To a solution of ethyl 2-(2-carbarnoyl-6-methylphenylimino)-2-oxoacetate (490 mg, a 1.96 mmol) and TEA (10.4 ml, 75 mmol) in DCE (20 ml) was added TMS-Cl (3.6 ml, 29 mmol) and the solution was stirred at 80°C for 16 hours. The mixture was concentrated under reduced pressure and the residue was distributed between DCM (100 ml) and saturated aqueous NaHCO3. The separated aqueous phase was extracted using DCM (2×100 ml) and the combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel, elwira blend 10-40% EtOAc/hexane, to obtain ethyl 4-hydroxy-8-methylpyrazole-2-carboxylate as a solid (330 mg, 72%).1H NMR (300 MHz, DMSO-d6) δ of 1.36 (t, J=7.2 Hz, 3H), 2,58 (s, 3H), 4,39 (sq, J=7.2 Hz, 2H), 7,46-to 7.64 (m, 1H), to 7.64 (m, 1H), 8,02 (m, 1H), br12.62 (users, 1H).

Stage D: a Mixture of ethyl 4-hydroxy-8-methylpyrazole-2-carboxylate (330 mg, of 1.39 mmol), POCl3(20 ml) and DMF (3 drops) was stirred at 80°C for 48 hours. The mixture was concentrated under reduced pressure and the solid residue was distributed between DCM (100 ml) and cold H2O (100 ml). The separated aqueous phase was extracted using DCM (2×100 ml) and the combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by chromatography on silica gel, elwira a mixture of EtOAc/hexane, with policenauts 4-chloro-8-methylpyrazole-2-carboxylate as a solid (320 mg, 90%).1H NMR (300 MHz, DMSO-d6) δ of 1.39 (t, J=7,1 Hz, 3H), was 2.76 (s, 3H), 4,45 (sq, J=7,1 Hz, 2H), of 7.90 (m, 1H), 8,1 (m, 1H), and 8.2 (m, 1H).

Stage E: To a solution of ethyl 4-chloro-8-methylpyrazole-2-carboxylate (320 mg, 0.43 mmol) in THF (10 ml) at -40°C was added a 1M solution of 4-performancebased (of 1.55 ml, 1.55 mmol) and the mixture was stirred at -40°C for 1 hour. The reaction extinguished saturated aqueous NH4Cl and the mixture was concentrated under reduced pressure and the residue was distributed between DCM (100 ml) and H2O (100 ml). The separated aqueous phase was extracted using DCM (2×100 ml) and the combined organic layers were dried over MgSO4, filtered and concentrated to obtain a solid (370 mg). A solution of the obtained solid (370 mg, 1,22 mmol) and KI (224 mg, 1.35 mmol) in DMF (10 ml) was stirred at room temperature for 30 minutes and then was added 5-methyl-1H-pyrazole-3-amine (257 mg, 2,63 mmol) and DIEA (275 μl, to 1.60 mmol) and the mixture was stirred at 50°C for 24 hours. Added water and the precipitated solid substance was collected by filtration and washed several times with water. The crude product was purified using HPLC, elwira a mixture of 10-80% ACN/H2O, containing 0.05% HOAc, obtaining (4-forfinal)(8-methyl-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone in the form of a solid (64 mg, 14%).1H NMR (300 MHz, DMSO-d6) δ of 2.20 (s, 3H), at 2.59 (s, 3H), 6,56 (users, 1H), 7,40 (t, J=8.7 Hz, 2H), 7,56 t, J=7,6 Hz, 1H), to 7.77 (d, J=6,8 Hz, 1H), 8,16 (t, J=6.3 Hz, 2H), 8,56 (d, J=7.7 Hz, 1H), 10,59 (users, 1H), 12,20 (users, 1H).

Stage F: a Mixture of (4-forfinal)(8-methyl-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone (64 mg, 0,177 mmol) and NaBH4(15 mg, 0,355 mmol) in MeOH (3 ml) was stirred at room temperature for 24 hours. Added 1M HCl dropwise until a homogeneous mixture and the mixture was stirred for 5 minutes. Then was added a saturated aqueous solution of NaHCO3until then, until there was no formation of a solid precipitate. The solid is collected by filtration washing with the help of H2O obtaining (R,S)-(4-forfinal)(8-methyl-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol as a solid (42 mg, 66%).1H NMR (300 MHz, DMSO-d6) δ of 2.25 (s, 3H), 2,65 (s, 3H), of 5.68 (s, 1H), 5,78 (s, 1H), 6,41 (s, 1H), 7,15 (m, 2H), 7,41 (m, 1H), 7,56 (m, 2H), 7,68 (m, 1H), 8,42 (m, 1H), 10,31 (users, 1H), 12,11 (users, 1H); LC-MS (ESI) m/z 364 (M+H)+.

Example 47

Receiving (R,S)-(7-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol

Stage A: To a solution of 2-amino-4-fermenting acid (4.0 g, from 25.8 mmol) in degassed DMF (50 ml) was added HOBt (4,19 g, 31 mmol), DIEA (5.4 ml, 31 mmol), EDCI (5,94 g, 31 mmol) and 2 n solution of NH3/MeOH (18 ml, at 36.1 mmol). The solution was stirred at room temperature for 48 hours and then concentrated under reduced pressure. OST is OK purified using chromatography on silica gel to obtain 2-amino-4-fermentated in the form of solids (2,89 g, 66%).1H NMR (300 MHz, DMSO-d6) δ 6,28 (m, 1H), 6,44 (m, 1H), 6.90 to (users, 2H), was 7.08 (m, 1H), 7,58 (m, 1H), 7,71 (userd, 1H).

Stage B: a Solution of 2-amino-4-fermentated (750 mg, 4.40 mmol), diethyloxalate (20 ml) and AcOH (8 ml) was stirred at 140°C for 16 hours. The solid is collected by filtration and dried under reduced pressure to obtain ethyl 7-fluoro-4-hydroxyquinazoline-2-carboxylate as a solid (235 mg, 22%).1H NMR (300 MHz, DMSO-d6) δ of 1.36 (t, J=7,08 Hz, 2H), 4,39 (sq, J=7,08 Hz, 2H), 7,52 (m, 1H), to 7.67 (m, 1H), 8,25 (m, 1H), of $ 11.97 (users, 1H), 12,77 (users, 1H).

Stage C: a Mixture of ethyl 7-fluoro-4-hydroxyquinazoline-2-carboxylate (235 mg, 1.38 mmol), POCl3(15 ml) and DMF (3 drops) was stirred at 80°C for 24 hours. The mixture was concentrated under reduced pressure and the residue was distributed between cold H2O (100 ml) and DCM (50 ml). The separated aqueous phase was extracted using DCM (2×50 ml) and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, elwira a mixture of 20-80% EtOAc/hexane, to obtain ethyl 4-chloro-7-florinopolis-2-carboxylate as a solid (128 mg, 37%).1H NMR (300 MHz, DMSO-d6) δ to 1.38 (t, 7=7,10 Hz, 3H), 4,45 (sq, J=7,10 Hz, 2H), 7,92 (m, 1H), 8,15 (m, 1H), of 8.37-8,65 (m, 1H).

Stage D: To a solution of ethyl 4-chloro-7-florinopolis-2-carboxylate (122 mg, 0,479 mmol) in 5 ml THF at -40°C was added RA is creative 1M 4-performancebased/THF (of 0.58 ml, of 0.58 mmol) and the mixture was stirred at -40°C for 2 hours. Was added a saturated aqueous solution of NH4Cl and the mixture was concentrated under reduced pressure. The residue was distributed between the H2O (100 ml) and DCM (50 ml). The separated aqueous phase was extracted using DCM (2×50 ml) and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to obtain a solid (130 mg), containing (4-chloro-7-florinopolis-2-yl)(4-forfinal)methanon. The solution of this solid (130 mg, 0.43 mmol) and KI (78 mg, 0.47 mmol) in DMF (6 ml) was stirred at room temperature for 30 minutes and then was added 5-methyl-1H-pyrazole-3-amine (88 mg, 0.88 mmol) and DIEA (96 μl, of 0.56 mmol). The mixture was stirred at room temperature for 24 hours and then added water. The precipitated solid was collected by filtration washing with water. The solid was purified using preparative reverse-phase HPLC, elwira a mixture of 10-80% ACN/H2O, containing 0.05% HOAC, obtaining (7-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone in the form of a solid (96 mg, 45%).1H NMR (300 MHz, DMSO-d6) δ ppm to 2.18 (s, 3H), 6.48 in (s, 1H), 7,39 (m, 2H), 7,63 (m, 2H), 8,13 (m, 2H), 8,84 (m, 1H), 10,80 (s, 1H), 12,08 (users, 1H).

Stage E: a solution of (7-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone (96 mg, 0.26 mmol) and NaBH4 (21 mg, of 0.53 mmol) in MeOH (3 ml) was stirred at room temperature for 24 hours and then was added 1M HCl dropwise until a homogeneous mixture. The mixture was stirred for 5 minutes and then was added a saturated aqueous solution of NaHCO3up to the formation of sludge. The solid is collected by filtration and washed using H2O obtaining (R,S)-(7-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol as a solid (62 mg, 64%).1H NMR (300 MHz, DMSO-d6) (represented by one or more impurities) δ 2,25 (C)to 5.66 (1H), of 5.84 (1H), 6,44 (users, 1H), 7,14 (m), 7,37-7,50 (m), 7,47-to 7.68 (m), 8,56-8,91 (m, 1H), 10,50 (users, 1H), 12,15 (users, 1H); LC-MS (ESI) m/z 368 (M+H)+.

Example 48

Obtain (4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)bis(4-forfinal)methanol

Stage A: Stir a mixture of ethyl 4-chlorination-2-carboxylate (709 mg, 3 mmol), 3-aminopyrazole (274 mg, 3.3 mmol), potassium iodide (498 mg, 3 mmol) and DIEA (574 μl, 3.3 mmol) in N,N-dimethylformamide (5 ml) was heated at 50°C for 2 hours and then stirred at room temperature overnight. To the mixture was added water and the precipitated solid was filtered, washed with water and dried under high vacuum at 50°C for 3 hours to obtain ethyl 4-(1H-pyrazole-3-ylamino)hinzelin-2-carboxylate (595 mg, 70%). LC-MS (ESI) m/z 284 (M+H)+.

Stage B: To a stirred solution of ethyl 4-(1H-pyrazole-3-ylamino)hinzelin-2-carboxylate (595 mg, 2.1 mmol) in THF (15 ml) at -40°C was added dropwise a 2 M solution of 4-performancebased in THF (of 4.2 ml, 8.4 mmol). The mixture was stirred at -40°C for 2 hours and then kept at -30°C for 18 hours. The reaction was suppressed by addition of 0.5 n HCl solution at 0°C and the mixture was extracted using EtOAc (2×20 ml). The solid precipitate their combined organic layers were removed by filtration and the resulting filtrate was washed with saturated saline solution. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel, elwira mixture of 0-5% MeOH/DCM, to obtain (4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)bis(4-forfinal)methanol as a solid (75 mg, 8%).1H NMR (300 MHz, DMSO-d6) δ 12,50 (s, 1H), 10,66 (s, 1H), 8,67 (d, J=8,1, 1H), 7,81-7,87 (m, 2H), 7,60 to 7.62 (m, 2H), 7,42-7,47 (m, 4H), 7,07-7,13 (m, 4H), of 6.66 (s, 1H), of 6.26 (s, 1H); LC-MS (ESI) m/z 430 (M+H)+.

Example 49

Receive (2-(diftar(4-forfinal)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yl)methanol

Phase A: a Mixture of 4-(methoxycarbonyl)-3-nitrobenzoic acid (200 mg) and concentrated NH4OH (30 ml) in a sealed tube was heated at 105°C during the night. After cooling to room temperature the market and the mixture was concentrated under reduced pressure and then added 2 N. HCl (5 ml). The mixture was extracted using EtOAc (3×50 ml) and the combined organic extracts were washed with saturated brine (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. To the residue in MeOH (20 ml) was added dropwise thionyl chloride (0.2 ml) and the mixture was heated at the boiling point under reflux for 6 hours. The mixture was concentrated under reduced pressure and the residue was distributed between saturated aqueous NaHCO3(50 ml) and EtOAc (50 ml), the separated aqueous phase was extracted using EtOAc (2×50 ml). The combined organic layers were washed with saturated brine (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. To the residue in EtOH (30 ml) was added 10% Pd/C (10 mg) and the mixture was stirred at room temperature in an atmosphere of H2(1 ATM) for 4 hours. The mixture was filtered through Celite washing with the aid of MeOH. The filtrate was concentrated under reduced pressure and the residue was purified by chromatography on silica gel, elwira a mixture of 5% MeOH/DCM, to obtain methyl 3-amino-4-carbamoylmethyl in the form of a white solid (142 mg, 82.5 per cent).1H NMR (300 MHz, DMSO-d6) δ is 3.82 (s, 3H), 6.75 in (s, 2H), 7,01 (d, 1H), 7,28 (s, 1H), 7,34 (s, 1H), 7.62mm (d, 1H) 7,89 (s, 1H); LC-MS (ESI) m/z 211 (M+H)+.

Stage B: To a solution of methyl 4-carbarnoyl-3-(2,2-debtor-2-(4-Fortini is)acetamido)benzoate (1.3 g, 3.5 mmol) in DCE (20 ml) was added triethylamine (20 ml, 142 mmol) and trimethylsilane (6,7 ml, 53.2 mmol) and the mixture was heated at 85°C during the night. The mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was distributed between EtOAc (150 ml) and H2O (100 ml) and the separated aqueous phase was extracted using EtOAc (3×150 ml). The combined organic layers were washed with saturated salt solution (100 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was processed using MeOH using ultrasonic treatment and a solid substance was collected by filtration to obtain methyl 2-(diftar(4-forfinal)methyl)-4-hydroxyquinazoline-7-carboxylate (1.1 g, 89%).1H NMR (300 MHz, DMSO-d6) δ 3,91 (s, 3H), 7,39 (t, 2H), 7,78 (t, 2H), of 8.06 (d, 1H), 8,16 (s, 1H), 8,27 (d, 1H), 13,34 (s, 1H); LC-MS (ESI) m/z 349 (M+H)+.

Stage C: a Mixture of methyl 2-(diftar(4-forfinal)methyl)-4-hydroxyquinazoline-7-carboxylate (1.1 g, 3.2 mmol) and phosphorus oxychloride (15 ml) was heated at the boiling point under reflux overnight. The mixture was concentrated under reduced pressure and then added toluene (20 ml) and evaporated under reduced pressure (2×). The residue in DCM, filtered through a layer of silica gel, elwira using DCM. The filtrate was concentrated under reduced pressure to obtain methyl 4-chloro-2-(iftar(4-forfinal)methyl)hinzelin-7-carboxylate (1 g, 86%).1H NMR (300 MHz, DMSO-d6) δ 3,98 (s, 3H), 7,37 (t, 2H), of 7.75 (t, 2H), 8,39 (d, 1H), 8,49 (s, 1H), 8,64 (d, 1H).

Stage D: a Mixture of methyl 4-chloro-2-(diftar(4-forfinal)methyl)hinzelin-7-carboxylate (1 g, 2.7 mmol), 5-methyl-1H-pyrazole-3-amine (0.32 g, with 3.27 mmol), DIEA (of 0.62 ml, 3.5 mmol) and KI (0.5 g, 3 mmol) in DMF (20 ml) was stirred at room temperature for 20 hours. The mixture was diluted using H2O and stirred for 1 hour and then precipitated solid substance was collected by filtration, washed using H2O and dried to obtain methyl 2-(diftar(4-forfinal)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-carboxylate (1,17 g, 100%).1H NMR (300 MHz, DMSO-d6) δ 2,24 (s, 3H), of 3.97 (s, 3H), of 6.31 (s, 1H), 7,15-to 7.50 (m, 2H), 7,62-of 7.90 (m, 2H), 7,99-8,13 (m, 1H), 8,20-8,55 (m, 1H), 8,69-9,04 (m, 1H), 10,96 (s, 1H), to 12.28 (s, 1H); LC-MS (ESI) m/z 428 (M+H)+.

Stage E: To a suspension of LAH (0.26 g, at 6.84 mmol) in THF (50 ml) at 0°C was slowly added a suspension of methyl 2-(diftar(4-forfinal)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-carboxylate (1,17 g, is 2.74 mmol) in THF (30 ml). The mixture was stirred at 0°C for 0.5 hours and then at room temperature for 4 hours. The mixture was cooled to 0°C and added dropwise water (0,26 ml) and the mixture was stirred for 30 minutes. Then added a 15% NaOH solution (to 0.39 ml) and the mixture was stirred for 1 hour. Then added water (1.3 ml) and the mixture was stirred at room temperature overnight. With the ect was filtered through Celite washing using 20% MeOH/DCM (500 ml) and the filtrate was concentrated under reduced pressure. The residue was distributed between water (200 ml) and EtOAc (150 ml) and the separated aqueous phase was extracted using EtOAc (2×150 ml). The combined organic layers were washed with saturated brine (200 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified using preparative reverse-phase HPLC to obtain (2-(diftar(4-forfinal)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yl)methanol as a white solid (901 mg, 82%).1H NMR (300 MHz, DMSO-d6) δ 2,24 (s, 3H), 4,70 (s, 2H), 5,49 (s, 1H), of 6.31 (s, 1H), 7,35 (m, 2H), 7,56 (d, 2H), of 7.70 (t, 2H), to 7.77 (s, 1H), 8,63 (d, 1H), at 10.64 (s, 1H), 12,18 (s, 1H); LC-MS (ESI) m/z 400 (M+H)+.

Example 50

Getting 2-(diftar(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3-yl)-7-(methylsulfonylmethyl)hinzelin-4-amine

To a suspension of (2-(diftar(4-forfinal)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yl)methanol from Example 49 (150 mg, 0.38 mmol) in DCM (20 ml) was added PBr3(203 mg, 0.75 mmol) by heating the mixture at 60°C. the resulting mixture was stirred at 60°C for 30 minutes, then cooled to room temperature and concentrated under reduced pressure. Then add thiamethoxam sodium (133 mg, 1,90 mmol) and DMF (10 ml) and the mixture was stirred at room temperature for 2 days. Was added a saturated aqueous solution of NaHCO3(50 ml) and the mixture which was xtraceroute using EtOAc (3×50 ml). The combined organic layers were washed with saturated brine (3×80 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. To the residue in DCM (50 ml) was added 4-chloroperbenzoic acid (655 mg, of 3.80 mmol) and the mixture was stirred at room temperature for 4 hours. Was added a saturated aqueous solution of NaHCO3(50 ml) and the mixture was extracted using DCM (3×50 ml). The combined organic layers were washed with saturated brine (60 ml), dried over Na2SO4, filtered and concentrated. The residue was purified using preparative reverse-phase HPLC to obtain 2-(diftar(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3-yl)-7-(methylsulfonylmethyl)hinzelin-4-amine as a white solid (11.3 mg, 6.5 per cent).1H NMR (300 MHz, DMSO-d6) δ 2,24 (s, 3H), 2,96 (s, 3H), to 4.73 (s, 2H), 6,32 (s, 1H), 7,35 (m, 2H), 7,63-7,73 (m, 3H), 7,92 (s, 1H), to 8.70 (d, 1H), 10,79 (s, 1H), 12,23 (s, 1H); LC-MS (ESI) m/z 462 (M+H)+.

Example 51

Getting 2-(diftar(4-forfinal)methyl)-7-(ethoxymethyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine

To a suspension of (2-(diftar(4-forfinal)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yl)methanol from Example 49 (150 mg, 0.38 mmol) in DCM (20 ml) was added PBr3(203 mg, 0.75 mmol) by heating the mixture at 60°C. the Mixture was stirred at 60°C for 30 minutes, allowed to cool prior to matnog temperature and concentrated under reduced pressure. To the residue was added EtOH (20 ml) and 21% solution of NaOEt/EtOH (3 ml) and the mixture was heated at the boiling point under reflux for 15 hours. The mixture was allowed to cool to room temperature and then the mixture was concentrated under reduced pressure. Was added water (50 ml) and then was added slowly 1 HCl solution to bring the pH to <4, and then was added a saturated aqueous solution of NaHCO3(50 ml). The mixture was extracted using EtOAc (3×80 ml) and the combined organic layers were washed with saturated brine (80 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified using preparative reverse-phase HPLC to obtain 2-(diftar(4-forfinal)methyl)-7-(ethoxymethyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine as a white solid (11.3 mg, 6.5 per cent).1H NMR (300 MHz, DMSO-d6) δ to 1.21 (t, 3H), of 2.23 (s, 3H), 3,56 (Qut, 2H), of 4.66 (s, 2H), of 6.31 (s, 1H), 7,38 (m, 2H), 7,56 (d, 1H), 7,70 (Qut, 2H), 7,76 (s, 1H), 8,65 (d, 1H), 10,69 (s, 1H), 12,20 (s, 1H); LC-MS (ESI) m/z 428 (M+H)+.

Example 52

Receiving (R,S)(7-chloro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol

Stage A: To a solution of 2-amino-4-chlorbenzoyl acid (4.4 g, from 25.8 mmol) in degassed DMF (75 ml) were added successively HOBt (4,19 g, 31 mmol), DIEA (5.4 ml, 31 mmol), EDCI (lower than the 5.37 g, 28 mmol) and 2 n solution of NH3/MeOH (18 ml, 36 m is ol) and the solution was stirred at room temperature for 4 days. The mixture was concentrated under reduced pressure and the residue was distributed between the H2O (200 ml) and DCM (200 ml). The separated aqueous phase was extracted using DCM (2×200 ml) and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, elwira a mixture of 10-50% EtOAc/hexane, to obtain 2-amino-4-chlorobenzamide in the form of a solid (2.91 in g, 66%).1H NMR (300 MHz, DMSO-d6) δ 6,50 (DD, J=8,48, and 2.26 Hz, 1H), 6.75 in (d, J=2.26 and Hz, 1H), 6,84 (users, 2H), 7,18 (users, 1H), of 7.48-7,63 (m, 1H), 7,80 (users, 1H).

Stage B: To a solution of 2-amino-4-chlorobenzamide (393 mg, 2,30 mmol) and DIEA (0,60 ml of 3.45 mmol) in THF (15 ml) at 0°C was added ethyl chlorocatechol (0,28 ml of 2.53 mmol). The solution was allowed to warm to room temperature and was stirred for 2 hours. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on silica gel, elwira a mixture of 10-50% EtOAc/hexane, to obtain ethyl 2-(2-carbarnoyl-5-chlorpheniramine)-2-oxoacetate in the form of a solid (545 mg, 88%).1H NMR (300 MHz, DMSO-d6) δ of 1.32 (t, J=6,97 Hz, 3H), or 4.31 (sq, J=6,97 Hz, 2H), 7,34 (d, J=8,48 Hz, 1H), 7,86-8,03 (m, 2H), 8,44 (users, 1H), to 8.62 (s, 1H), 13,24 (s, 1H).

Stage C: To a solution of ethyl 2-(2-carbarnoyl-5-chlorpheniramine)-2-oxoacetate (545 mg, 2.02 mmol) and TEA (11 ml, 80 mmol) in DCE (20 ml) was added trimethylsilane (3.8 ml, 30 mmol) and the solution was stirred at 80°C in t is an increase of 16 hours. The mixture was concentrated under reduced pressure and the residue was distributed between saturated aqueous NaHCO3and DCM (100 ml). The separated aqueous phase was extracted using DCM (2×100 ml) and the combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, elwira mixture of 10-60% EtOAc/hexane, to obtain ethyl 7-chloro-4-hydroxyquinazoline-2-carboxylate as a solid (321 mg, 63%).1H NMR (300 MHz, DMSO-d6) δ of 1.36 (t, J=7,06 Hz, 3H), 4,39 (sq, J=7,10 Hz, 2H), 7,60-7,74 (m, 1H), 7,85-7,98 (m, 1H), 8,11-8,23 (m, 1H), 12,82 (users, 1H).

Stage D: (R,S)-(7-Chloro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol was obtained in the form of a solid using procedures analogous to those described in Example 46 Stage D-F using ethyl 7-chloro-4-hydroxyquinazoline-2-carboxylate instead of ethyl 4-hydroxy-8-methylpyrazole-2-carboxylate used in Example 46 stage D.1H NMR (300 MHz, DMSO-d6) δ of 2.25 (s, 3H), 5,69 (d, J=1,00 Hz, 1H), of 5.82 (d, J=1,00 Hz, 1H), gold 6.43 (s, 1H), 7,07-of 7.23 (m, 2H), 7,46 to 7.62 (m, 3H), 7,81 (s, 1H), 8,57-8,69 (m, 1H), 10,53 (users, 1H), 12,18 (users, 1H), LC-MS (ESI) m/z 384 (M+H)+.

Example 53

Obtain (6-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone

Stage A: Stir a mixture of methyl 2-amino-5-perbenzoate (1 g, of 5.92 mm is l) and ethylcarbodiimide (1,17 g, to 11.8 mmol) in HOAc (8 ml) was treated with 12 n aqueous solution of hydrochloric acid (0.8 ml). The resulting mixture was heated at 70°C for 3 hours. After cooling to room temperature the solvent was removed under reduced pressure. The residue is suspended in water and treated with saturated aqueous NaHCO3to achieve pH=7. The solid was filtered, washed with water/diethyl ether and dried under reduced pressure to obtain ethyl 6-fluoro-4-oxo-3,4-dihydroquinazolin-2-carboxylate (1.2 g, 86%).1H NMR (300 MHz, DMSO-d6) δ 12,79 (s, 1H), 7,76-to 7.95 (m, 3H), 4,39 (sq, J=7,0 Hz, 2H), 1,36 (t, J=7.0 Hz, 3H); LC-MS (ESI) m/z 237 (M+H)+.

Phase B: Mix a solution of ethyl 6-fluoro-4-oxo-3,4-dihydroquinazolin-2-carboxylate (1.2 g, 5.08 mmol) in phosphorus oxychloride (15 ml) was heated at 105°C for 6 hours. After cooling to room temperature the reaction mixture was concentrated to dryness under reduced pressure and the residue was dissolved in anhydrous toluene. The toluene was concentrated under reduced pressure. The residue was dissolved in a small volume of DCM and passed through a short plug of silica gel, elwira using DCM. Ethyl 4-chloro-6-florinopolis-2-carboxylate was obtained as a solid (1.3 g, 100%). LC-MS (ESI) m/z 255 (M+H)+.

Stage C: To a stirred solution of ethyl 4-chloro-6-florinopolis-2-carboxylate (1.06 g, 4.5 mmol) in THF (15 ml) at -40°Dobavlyali dropwise a 1 M solution of 4-performancebased/THF (5,85 ml, to 5.85 mmol). The mixture was stirred at -40°C for 2 hours. The reaction was suppressed by addition of 0.5 n HCl solution at 0°C and then the mixture was extracted using EtOAc (2×20 ml). The solid which has precipitated from the combined organic layers were removed by filtration and the filtrate was washed with saturated saline solution. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica gel to obtain (4-chloro-6-florinopolis-2-yl)(4-forfinal)methanone in the form of a solid (950 mg, 69%).1H NMR (300 MHz, DMSO-d6) δ 8,32-at 8.36 (m, 1H), 8,13-8,21 (m, 4H), 7,43 (t, J=8,2 Hz, 2H); LC-MS (ESI) m/z 305 (M+H)+.

Stage D: (6-Fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanon was obtained from (4-chloro-6-florinopolis-2-yl)(4-forfinal)methanone (306 mg, 1 mmol) and 5-methyl-1H-pyrazole-3-amine (194 mg, 2 mmol) using a procedure similar to that described in Example 48 stage A. the Crude product was ground into powder with MeOH to obtain (6-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone (310 mg, 85%).1H NMR (300 MHz, DMSO-d6) δ 12,24 (s, 1H), 10,71 (s, 1H), 8,64 (d, J=9.6 Hz, 1H), 7.95 is-of 8.09 (m, 2H), 7,93-to 7.95 (m, 1H), 7,80-7,86 (m, 1H), 7,39 (t, J=8.6 Hz, 2H), 6,53 (s, 1H), 1.91 a (s, 3H); LC-MS (ESI) m/z 366 (M+H)+.

Example 54

Receiving (R,S)-(6-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol

To a stirred suspension of (6-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone from Example 53 stage D (200 mg, 0.55 mmol) in a mixture of 4:1 MeOH/THF (10 ml) was added borohydride sodium (33 mg, 0.88 mmol) and the mixture was stirred at room temperature for 2 hours. Was added water (8 ml) and the precipitated solid substance was collected by filtration, washed using MeOH and was purified twice using preparative reverse-phase HPLC to obtain (R,S)-(6-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol as a solid (72,5 mg, 36%).1H NMR (300 MHz, DMSO-d6) δ 12,15 (s, 1H), 10,41 (s, 1H), 8,49 (d, J=9.8 Hz, 1H), 7,84-7,88 (m, 1H), 7,70-7,76 (m, 1H), 7,52-7,56 (m, 2H), 7,14 (t, J=8.5 Hz, 2H), 6,45 (s, 1H), of 5.84 (users, 1H), 5,68 (users, 1H, in), 2.25 (s, 3H); LC-MS (ESI) m/z 368 (M+H)+.

Example 55

Receiving (R,S)-(4-(1H-pyrazole-3-ylamino)-6-florinopolis-2-yl)(4-forfinal)methanol

Stage A: (4-(1H-Pyrazole-3-ylamino)-6-florinopolis-2-yl)(4-forfinal)methanon was obtained from (4-chloro-6-florinopolis-2-yl)(4-forfinal)methanone from Example 53 stage C (304 mg, 1 mmol) and 1H-pyrazole-3-amine (166 mg, 2 mmol) using a procedure similar to that described in Example 48 stage A. the Crude product was ground into powder with MeOH to obtain (4-(1H-pyrazole-3-ylamino)-6-florinopolis-2-yl)(4-forfinal)methanone in the form of a solid (275 mg, 78%).1NAMR (300 MHz, DMSO-d6) δ 12,56 (s, 1H), 10,84 (s, 1H), 8,67 (d, J=9.9 Hz, 1H), 8,08-8,13 (m, 2H), 7.95 is-to 7.99 (m, 1H), 7,82-7,87 (m, 1H), to 7.67 (s, 1H), was 7.36-7,41 (m, 2H), 6,78 (s, 1H); LC-MS (ESI) m/z 352 (M+H)+.

Stage B: (4-(1H-Pyrazole-3-ylamino)-6-florinopolis-2-yl)(4-forfinal)methanol was obtained from (4-(1H-pyrazole-3-ylamino)-6-florinopolis-2-yl)(4-forfinal)methanone (200 mg, or 0.57 mmol) using a procedure similar to that described in Example 54, to obtain the (R,S)-(4-(1H-pyrazole-3-ylamino)-6-florinopolis-2-yl)(4-forfinal)methanol as a solid (59 mg, 29%).1H NMR (300 MHz, DMSO-d6) δ 12,50 (s, 1H), 10,53 (s, 1H), 8,53 (d, J=9.8 Hz, 1H), 7,85-7,89 (m, 1H), 7,71-to 7.77 (m, 2H), 7,52-EUR 7.57 (m, 2H), 7,12 (t, J=8.5 Hz, 2H), to 6.88 (s, 1H), of 5.84 (users, 1H), 5,69 (users, 1H); LC-MS (ESI) m/z 354 (M+H)+.

Example 56

Obtaining (7-bromo-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone

Stage A: Methyl 2-amino-4-bromobenzoate received from the corresponding acid by esterification according to the method of Fischer. A mixture of methyl 2-amino-4-bromobenzoate (1.1 g, 4.8 mmol) and ethylcarbodiimide (0.95 g, to 9.66 mmol) in HOAc (4 ml) was treated with 2 N. a solution of HCl (0.4 ml) and the resulting mixture was stirred at 70°C for 3 hours. After cooling to room temperature was added water, followed by addition of an aqueous solution of sodium bicarbonate to achieve a pH of~5. The precipitated solid was filtered and washed thoroughly with water and diethyl e is Il to obtain ethyl 7-bromo-4-oxo-3,4-dihydroquinazolin-2-carboxylate (825 mg, 58%).1H NMR (300 MHz, DMSO-d6) δ 12,82 (s, 1H), 8,06-of 8.09 (m, 2H), 7,81 (d, J=8,4 Hz, 1H), to 4.38 (sq, J=7,0 Hz, 2H), 1,35 (t, J=7.0 Hz, 3H); LC-MS (ESI) m/z 296 (M+H)+.

Stage B: Ethyl 7-bromo-4-chlorination-2-carboxylate was obtained from 69% yield using a procedure similar to that described in Example 53 stage B, using ethyl 7-bromo-4-oxo-3,4-dihydroquinazolin-2-carboxylate (825 mg, 2,78 mmol) instead of ethyl 6-fluoro-4-oxo-3,4-dihydroquinazolin-2-carboxylate used in Example 53. LC-MS (ESI) m/z 315 and 317 (M+H)+.

Stage C: (7-Bromo-4-chlorination-2-yl)(4-forfinal)methanon received from 43% yield using a procedure similar to that described in Example 53 stage C using ethyl 7-bromo-4-oxo-3,4-dihydroquinazolin-2-carboxylate (605 mg, 1.92 mmol) instead of ethyl 4-chloro-6-florinopolis-2-carboxylate used in Example 53. LC-MS (ESI) m/z 387 (M+Na)+.

Stage D: (7-Bromo-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanon was obtained using a procedure similar to that described in Example 48 stage A, using (7-bromo-4-chlorination-2-yl)(4-forfinal)methanon (300 mg, 0.82 mmol) instead of ethyl 4-chlorination-2-carboxylate used in Example 48. Part of the crude product (90 mg) was purified using preparative reverse-phase HPLC to obtain (7-bromo-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone in the form of a solid (12 mg, 11%).1H I Is R (300 MHz, DMSO-d6) δ 12,23 (s, 1H), 10,85 (s, 1H), 8,69 (d, J=8.0 Hz, 1H), 8.07-a 8,11 (m, 3H), to 7.84 (d, J=9.0 Hz, 1H), was 7.36-7,42 (m, 2H), of 6.49 (s, 1H), 2,18 (s, 3H); LC-MS (ESI) m/z 426 (M+H)+.

Example 57

Obtaining (7-bromo-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol

(7-Bromo-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol was obtained using a procedure similar to that described in Example 54 using (7-bromo-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanon from Example 56 (240 mg, 0,56 mmol) instead of (6-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone used in Example 54 (31 mg, 13%).1H NMR (300 MHz, DMSO-d6) δ 12,17 (s, 1H), 10,55 (s, 1H), 8,54 (users, 1H), 7,97 (users, 1H), to 7.67 (d, J=8,4 Hz, 1H), 7,52-7,56 (m, 2H), 7,12-7,17 (m, 2H), 6,44 (s, 1H), of 5.84 (s, 1H), to 5.66 (s, 1H, in), 2.25 (s, 3H); LC-MS (ESI) m/z 428 (M+H)+.

Example 58

Receiving (R,S)-(4-(1H-pyrazole-3-ylamino)-7-bromination-2-yl)(4-forfinal)methanol

Stage A: (4-(1H-Pyrazole-3-ylamino)-7-bromination-2-yl)(4-forfinal)methanon (270 mg, 80%) was obtained using a procedure similar to that described in Example 48 stage A, using (7-bromo-4-chlorination-2-yl)(4-forfinal)methanon from Example 56 (300 mg, 0.82 mmol) instead of ethyl 4-chlorination-2-carboxylate used in Example 48.1H NMR (300 MHz, DMSO-d6) δ 12,57 (s, 1H), 10,97 (s, 1H), 8,72 (d, J=8,3 Hz, 1H), 8,10 (t, J=8,3 Hz, 3H), 7,86 (d, J=8.5 Hz, 1H), to 7.67 (users, 1H), was 7.36 (t, J=8.0 Hz, 2H), 6.75 in (users, 1H); LC-MS (ESI) m/z 412 (M+H)+.

Stage B: (R,S)-(4-(1H-Pyrazole-3-ylamino)-7-bromination-2-yl)(4-forfinal)methanol (37 mg, 18%) was obtained using a procedure similar to that described in Example 54, using (4-(1H-pyrazole-3-ylamino)-7-bromination-2-yl)(4-forfinal)methanon (200 mg, 0.49 mmol) in place of (6-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone used in Example 54.1H NMR (300 MHz, DMSO-d6) δ 12,47 (s, 1H), 10,70 (s, 1H), to 8.57 (d, J=8,9 Hz, 1H), to 7.99 (s, 1H), 7,69-7,72 (m, 2H), 7,54 (t, J=6.4 Hz, 2H), 7,12 (t, J=8,2 Hz, 2H), PC 6.82 (s, 1H), 5,86 (users, 1H), 5,68 (users, 1H); LC-MS (ESI) m/z 414 and 416 (M+H)+.

Example 59

Obtaining 2-(2-(4-forfinal)-1,3-dioxolane-2-yl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine

To (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone from Example 3 (0.20 g, of 0.58 mmol) in toluene (20 ml) was added ethylene glycol (0.2 ml) and the monohydrate p-toluensulfonate acid (catalytic amount). The mixture was heated at the boiling point under reflux during the night, while collecting water using traps Dean-stark. Added additional amount of ethylene glycol (1.5 ml) and monohydrate p-toluensulfonate acid (50 mg) and the mixture was heated at the boiling point under reflux during the night, Sobir the I water. After cooling, the mixture was evaporated to dryness and then dissolved in DMSO (8 ml). 5-ml aliquot of this solution was purified using preparative reverse-phase HPLC (column Varian diphenyl reversed-phase chromatography using a gradient of solvent B=0.05% OF HOAC/ACN and solvent A=0.05% Of HOAc/H2O), and then further purified using a preparative reversed-phase HPLC (column Phenomenex C-18 reversed-phase chromatography using a gradient of solvent B=0.05% OF HOAC/ACN and solvent A=0.05% Of HOAc/H2O) to give 2-(2-(4-forfinal)-1,3-dioxolane-2-yl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine (2 mg, 1%).1H NMR (300 MHz, DMSO-d6) δ of 2.20 (s, 3H) 4,05-4,22 (m, 4H) 6,2 (s,lH) 7,19 (t, 2H) 7.5 to the 7.65 (m, 3H) 7,81 (m, 2H) 8,59 (d, 1H) 10,38 (s, 1H) 12,08 (s, 1H); LC-MS (ESI) m/z 392 (M+H)+.

Example 60

Obtaining (8-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone

Stage A: Ethyl 2-(2-carbarnoyl-6-forgenerating)-2-oxoacetate received with reference to procedures similar to those described in Example 46 Stages a and B, where you can use 2-amino-3-fermenting acid instead of 2-amino-3-methylbenzoic acid used in Example 46.

Phase B: a Mixture of ethyl 2-(2-carbarnoyl-6-forgenerating)-2-oxoacetate (600 mg, 2.4 mmol) and tert-butoxide potassium (300 mg, 6.7 mmol) in EtOH (10 ml) was stirred at room themes is the temperature value for 5 hours. Was added a saturated aqueous NaCl solution (50 ml) and HOAc (0.5 ml) and the mixture was extracted using EtOAc (3×80 ml). The combined organic layers were washed with saturated brine (80 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain ethyl 8-fluoro-4-hydroxyquinazoline-2-carboxylate (530 mg, 93%).1H NMR (300 MHz, DMSO-d6) δ of 1.39 (t, J=7.2 Hz, 3H), 4,40 (sq, J=7.2 Hz, 2H), EUR 7.57-of 7.70 (m, 1H), 7,78 (t, J=9,2 Hz, 1H), 7,99 (d, 7=8.1 Hz, 1H), 12,86 (s, 1H); LC-MS (ESI) m/z 237 (M+H)+.

Stage C: a Mixture of ethyl 8-fluoro-4-hydroxyquinazoline-2-carboxylate (530 mg, 2.2 mmol) and POCl3(3 ml) was heated at the boiling point under reflux for 5 hours. The mixture was concentrated under reduced pressure and then added toluene twice and concentrated under reduced pressure. The residue was purified by chromatography on silica gel, elwira mixture 0-25% EtOAc/hexane, to obtain ethyl 4-chloro-8-florinopolis-2-carboxylate (365 mg, 65%).1H NMR (300 MHz, DMSO-d6) δ of 1.39 (t, J=7,1 Hz, 3H), 4,46 (sq, J=7,1 Hz, 2H), 7,97-of 8.06 (m, 1H), 8.07-a is 8.16 (m, 1H), 8,18-8,24 (m, 1H).

Stage D: To a solution of ethyl 4-chloro-8-florinopolis-2-carboxylate (360 mg, of 1.42 mmol) in THF (20 ml) at -40°C was added a 1M solution of 4-performancebased/THF (1.7 ml, 1.7 mmol) and the mixture was stirred at -40°C for 3 hours. After this time, added an additional portion of a 1M solution of 4-performancepro the d/THF (0.3 ml, 0.3 mmol) and the mixture was stirred at -40°C for 2 hours. To the mixture was added with 0.5 n HCl to achieve pH~2 and then added saturated aqueous NaCl solution (50 ml) and the mixture was extracted using EtOAc (3×50 ml). The combined organic layers were washed with saturated brine (80 ml), dried over Na2SO4, filtered and concentrated under reduced pressure to obtain (4-chloro-8-florinopolis-2-yl)(4-forfinal)methanone (0.4 g, 93%).1H NMR (300 MHz, DMSO-d6) δ? 7.04 baby mortality-7,25 (m, 1H), 7,31-7,58 (m, 2H), 7,70-at 8.36 (m, 4H); LC-MS (ESI) m/z 305 (M+H)+, 327 (M+Na)+.

Stage E: a Mixture of (4-chloro-8-florinopolis-2-yl)(4-forfinal)methanone (0.4 g, of 1.32 mmol), 5-methyl-1H-pyrazole-3-amine (0.15 g, was 1.58 mmol), DIEA (to 0.69 ml, 4.0 mmol) and KI (0.24 g, 1,45 mmol) in DMF (8 ml) was stirred at room temperature for 20 hours. The mixture was diluted using H2O (35 ml) and the precipitated solid substance was collected by filtration, washed using H2O and was ground into powder with MeOH at 0°C. part of the obtained solid substance was purified using preparative reverse-phase HPLC to obtain (8-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone1H NMR (300 MHz, DMSO-d6) δ are 2.19 (s, 3H), of 6.52 (s, 1H), 7,41 (t, 2H), of 7.64-7,80 (m, 2H), 8,11 (t, 2H), to 8.57 (d, 1H), 10,84 (s, 1H), 12,27 (users, 1H); LC-MS (ESI) m/z 366 (M+H)+.

Example 61

Receiving (R,S)-(8-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hin the Zolin-2-yl)(4-forfinal)methanol

To a suspension of (8-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone (233 mg, 0.64 mmol) in a mixture of 2:1 MeOH/THF (15 ml) at 0°C was added borohydride sodium (36 mg, 0.96 mmol) and the mixture was stirred at 0°C for 1 hour and at room temperature over night. The mixture was cooled to 0°C was added 1 n HCl to achieve a pH<2, and then was added a saturated aqueous solution of NaHCO3and saturated salt solution. The precipitated solid was collected by filtration, washed using H2O and purified using preparative reverse-phase HPLC to obtain (R,S)-(8-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol (141 mg, 60%).1H NMR (300 MHz, DMSO-d6) δ 2,24 (s, 3H), 5,69 (s, 1H), 5,86 (users, 1H), 6,41 (users, 1H), 7,15 (t, 2H), 7,47-the 7.65 (m, 4H), 8.34 per (users, 1H), 10,53 (users, 1H), 12,18 (users, 1H); LC-MS (ESI) m/z 368 (M+H)+.

Example 62

Receive (2-methoxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone

To a solution of ethyl 4-chlorination-2-carboxylate (500 mg, 2,11 mmol) in THF (20 ml) at -40°C was added dropwise 1M solution of 2-methoxyphenylacetamide (2.6 ml, 2.5 mmol) and the mixture was stirred at -40°C for 4 hours. To the mixture was added 1 n HCl to bring to pH<2 and saturated aqueous NaCl solution (50 ml) and the mixture was extracted using tOAc (3×80 ml). The combined organic layers were washed with saturated brine (50 ml), dried over Na2SO4, filtered and concentrated under reduced pressure. To the residue (673 mg) was added a solution of 5-methyl-1H-pyrazole-3-amine (247 mg, 2,84 mmol) in DMF (8 ml), potassium iodide (387 mg, of 2.33 mmol) and DIEA (822 mg, 6,36 mmol) and the mixture was stirred at room temperature overnight and then at 50°C for 5 hours and then at 80°C for 2 hours. The mixture was allowed to cool to room temperature and then added H2O (30 ml). The mixture was stirred and cooled to 0°C and the precipitated solid substance was collected by filtration and washed using MeOH. Part of a solid substance was purified using preparative reverse-phase HPLC to obtain (2-methoxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone.1H NMR (300 MHz, DMSO-d6) δ 2,11 (s, 3H), of 3.48 (s, 3H), x 6.15 (s, 1H), 7,11-to 7.18 (m, 2H), 7,56-to 7.64 (m, 3H), 7,56 (users, 2H), to 8.70 (d, 1H), of 10.58 (s, 1H), 12,11 (s, 1H); LC-MS (ESI) m/z 360 (M+H)+.

Example 63

Receiving (R,S)-(2-methoxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol

To a suspension of (2-methoxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone (420 mg, 1,17 mmol) in a mixture of 2:1 MeOH/THF (15 ml) at 0°C was added NaBH4(53 mg, of 1.40 mmol) and the mixture was stirred at 0°C for 1 hour and at room temperature during the course the e night. The mixture was cooled to 0°C was added 1 n HCl to bring to pH<2. Then was added a saturated aqueous solution of NaHCO3(50 ml) and the mixture was extracted using EtOAc (3×80 ml). The combined organic layers were washed with saturated brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified using preparative reverse-phase HPLC to obtain (R,S)-(2-methoxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol (55,3 mg, 15%).1H NMR (300 MHz, DMSO-d6) δ are 2.19 (s, 3H), 3,76 (s, 3H), 5,65 (s, 1H), 6,00 (s, 1H), 6,24 (s, 1H), 6,92-7,01 (m, 3H), 7,25 (m, 1H), 7,45-7,52 (m, 2H), 7,80 (s, 2H), to 8.57 (d, 1H), 10,36 (s, 1H), 12,05 (s, 1H); LC-MS (ESI) m/z 362 (M+H)+.

Example 64

Receive (3-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol

To (3-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone Example 1 (0.15 g, 0.43 mmol) in a mixture of 1:1 THF/MeOH (4 ml) at 0°C was added borohydride sodium (0.02 g, of 0.58 mmol) and the mixture was stirred at 0°C for 30 minutes. To the mixture was added 6 n HCl solution and DMSO (3 ml) and the mixture was purified using preparative HPLC (column Varian diphenyl reversed-phase, suirable with a gradient of solvent B=0.05% OF HOAC/MeOH and solvent A=0.05% Of HOAc/H2O) to obtain (3-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol (50 mg, 32%).sup> 1H NMR (300 MHz, DMSO-d6) δ and 2.26 (s, 3H) 5,7 (s, 1H) to 5.93 (s,lH) 6,44 (s, 1H) 7,07 (m, 1H) 7,34-7,39 (m, 3H) rate of 7.54 (m, 1H) 7,81 (s, 2H) 8,59 (d, 1H) 10,42 (s, 1H) 12,15 (s, 1H); LC-MS (ESI) m/z 350 (M+H)+.

Example 65

Obtaining N-((4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methyl)formamide

To 2-(amino(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine from Example 45 phase B (0.1 g, 0.28 mmol) in ethyl formate (4 ml) was added TEA (0.2 ml) and EtOH (0.5 ml) and the mixture was heated to 120°C for 30 minutes in a Biotage microwave reactor and then concentrated under reduced pressure. The residue was diluted using DMSO (5 ml) and was purified using reverse-phase preparative HPLC (column Varian diphenyl reversed-phase, suirable with a gradient of solvent B=0.05% OF HOAC/MeOH and solvent A=0.05% Of HOAc/H2O) to give N-((4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methyl)formamide (8 mg, 8%).1H NMR (300 MHz, DMSO-d6) δ and 2.26 (s, 3H) 6,07 (d, 1H) 6,44 (s, 1H) 7,16 (t, 2H) 7,4-7,6 (m, 3H) and 7.8 (m, 2H) 8,21 (s, 1H) to 8.62 (d, 1H) 9,06 (d, 1H) 10,48 (users, 1H) 12,17 (users, 1H); LC-MS (ESI) m/z 377 (M+H)+.

Example 66

Receiving (R,S)-(3,4-differenl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol

Phase A: a Mixture of ethyl 4-chlorination-2-carboxylate (1 g, 4.2 mmol) in THF (50 ml) was filtered and to the filtrate at -30°C in an atmosphere of Ar doba is Lyali solution 0,5M (3,4-differenl)minibrain/THF (10.4 ml, 5.2 mmol). The mixture was stirred at -30°C for 1.5 hours, and then added an additional quantity of a solution of 0,5M (3,4-differenl)minibrain/THF (3 ml). After another 1.5 hours was added an additional amount of solution 0,5M (3,4-differenl)minibrain/THF (3 ml). To the mixture was added saturated aqueous solution of ammonium chloride and the mixture was allowed to warm to room temperature. The mixture was extracted using EtOAc (2×) and the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain (4-chlorination-2-yl)(3,4-differenl)methanone (330 mg, 26%)which was used directly in the next stage.

Stage B: To a mixture of 5-methyl-1H-pyrazole-3-amine (0.18 g, 1.8 mmol), potassium iodide (0.18 g, 1.1 mmol) and TEA (0.16 ml, 1.1 mmol) in DMF (5 ml) was added a solution of (4-chlorination-2-yl)(3,4-differenl)methanone (0.33 g, 1.1 mmol) in DMF (5 ml) and the mixture was stirred at room temperature overnight. Added water and the precipitated solid substance was collected by filtration. Yellow solid (553 mg)containing (3,4-differenl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon, used directly in the next stage. LC-MS (ESI) m/z 366 (M+H)+.

Stage C: untreated (3,4-differenl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone (553 mg, 1.5 mmol) in a mixture of 1:1 MeOH/THF (40 ml) at 0°C is obavljale borohydride sodium (0.09 g, 2.4 mmol) and the solution was stirred for 30 minutes, after which was added 6 n HCl solution. The mixture was concentrated to dryness and about 2/3 the residue was purified by chromatography on silica gel, elwira mixture 0-15% MeOH/DCM, to obtain (3,4-differenl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol (34 mg).1H NMR (300 MHz, DMSO-d6) δ and 2.26 (s, 3H) 6,03 (s, 1H) 6,22 (s, 1H) 7,45-of 7.55 (m, 2H) 7,66 (t, 1H) 7,78 (t, 1H) 8,07 (t, 1H) 8,19 (t, 1H) 8,82 (d, 1H) 12,09 (users, 1H) 12,67 (users, 1H); LC-MS (ESI) m/z 368 (M+H)+.

Example 67

Receive (3-chloro-4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol

Phase A: a Mixture of ethyl 4-chlorination-2-carboxylate (1 g, 4.2 mmol) in THF (50 ml) was filtered and to the filtrate at -30°C in an atmosphere of Ar was added a 0.5 M solution of (3-chloro-4-forfinal)minibrain/THF (10.4 ml, 5.2 mmol). After stirring at -30°C in a period of 0.75 hours was added an additional amount of 0.5 M solution of (3-chloro-4-forfinal)minibrain/THF (4,2 ml). After 1 hour the reaction was suppressed by the addition of saturated aqueous ammonium chloride and allowed to warm to room temperature. The mixture was extracted using EtOAc and the extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain (3-chloro-4-forfinal)(4-chlorination-2-yl)methanone (495 mg, 37%)which was used directly in the next .LC-MS (ESI) m/z 321 (M+H) +.

Stage B: To a mixture of 5-methyl-1H-pyrazole-3-amine (0.26 g, 2.68 mmol), potassium iodide (0.26 g, 1.57 mmol) and TEA (0.45 ml, of 3.23 mmol) in DMF (30 ml) was added (3-chloro-4-forfinal)(4-chlorination-2-yl)methanon (0,495 g, 1.54 mmol) and the mixture was stirred at room temperature overnight. Added water and the precipitated solid substance was collected by filtration to obtain crude (3-chloro-4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone (458 mg)which was used directly in the next stage. LC-MS (ESI) m/z 382 (M+H)+.

Stage C: the crude (3-chloro-4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone (458 mg, 1.2 mmol) in a mixture of 1:1 MeOH/THF (60 ml) at 0°C was added borohydride sodium (0,048 g, 1.3 mmol) and the solution was stirred for 30 minutes. The reaction was suppressed by addition of 6 n HCl solution and the mixture was concentrated to dryness. The residue was purified by chromatography on silica gel, elwira mixture 0-15% MeOH/DCM. The obtained solid was ground into powder with methanol to obtain (3-chloro-4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol (42 mg).1H NMR (300 MHz, DMSO-d6) δ, and 2.27 (s, 3H) 5,70 (s, 1H) 6,01 (s, 1H) 6,41(s, 1H) of 7.36 (t, 1H) 7,47-7,52 (m, 2H) 7,79-of 7.82 (m, 3H) 8,59 (d, 1H) 10,42 (users, 1H) 12,16 (users, 1H); LC-MS (ESI) m/z 384 (M+H)+.

Example 68

Obtaining 3-(4-forfinal)-3-(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)propanenitrile

To a suspension of 60% sodium hydride/mineral oil (173 mg, 4,32 mmol) in THF (10 ml) at 0°C in an atmosphere of Ar was added dieticiansupervised (0.68 ml, 4,32 mmol) and the mixture was stirred for 10 minutes. Then was added a suspension of (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone of Example 3 (500 mg, 1.44 mmol) in THF (20 ml) and the mixture was stirred at room temperature for 30 minutes. Then was added AcOH (0.5 ml) and Celite, and the mixture was concentrated under reduced pressure. The mixture was suirable on a column of silica gel and then suirable using EtOAc/hexane. To the selected substance was added EtOH (100 ml) and 10% Pd-C (180 mg) and the mixture was heated at 70°C overnight in a hydrogen atmosphere. The mixture was concentrated and subjected to chromatography on silica gel, elwira a mixture of EtOAc/hexane, to obtain 360 mg of the crude substance. Half of this substance was subjected to additional purification using preparative HPLC (column Varian diphenyl reversed-phase, suirable with a gradient of solvent B=0.05% Of HOAc/MeOH and solvent A=0.05% Of HOAc/H2O) to give 3-(4-forfinal)-3-(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)propanenitrile (65 mg, 24%).1H NMR (300 MHz, DMSO-d6) δ of 2.25 (s, 3H) 3,24-of 3.48 (m, 2H) 4,57 (m, 1H) 6,36 (s, 1H) 7,17 (m, 2H) 7,46-of 7.55 (m, 3H) to 7.77-7,81 (m, 2H) at 8.60 (d, 1H) 10,41 (s, 1H) 12,13 (s, 1H); LC-MS (ESI) m/z 373 (M+H)+.

Example 69

Getting 2-((cyclepro is ylamino)(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine

To (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone from Example 3 (100 mg, 0.28 mmol) in 2-propanol (3 ml) was added cyclopropylamine (0.1 ml) and 3 Å (8-12 mesh) molecular sieves and the mixture was heated at 140°C in a Biotage microwave reactor. Added more cyclopropylamine (0.15 ml) and the mixture in a tightly closed vial was heated in the usual way at 90°C for 4 days. Then was added dropwise a suspension of sodium borohydride (140 mg) in 2-propanol and the mixture was stirred at room temperature for 1 hour. Then was added MeOH (0.1 ml), borohydride sodium (100 mg) and then MeOH (2 ml) and the mixture was filtered and the filtrate was concentrated. To the residue was added THF (5 ml), MeOH (2 ml) and borohydride sodium (100 mg) and the mixture was stirred for 1 hour at room temperature. Then was added AcOH (0.4 ml) and the mixture was concentrated. Added DMSO (3 ml) and the mixture was purified using preparative HPLC (column Varian diphenyl reversed-phase, suirable with a gradient of solvent B=0.05% Of HOAc/MeOH and solvent A=0.05% Of HOAc/H2O), followed by additional purification using preparative HPLC (column Phenomonex C-18 reversed-phase, suirable with a gradient of solvent B=0.05% Of HOAc/MeOH and solvent A=0.05% Of HOAc/H2O) to give 2-((cyclopropylamino)(4-forfinal)methyl)-N-(5-what ethyl-1H-pyrazole-3-yl)hinzelin-4-amine (5.5 mg, 9%).1H NMR (300 MHz, DMSO-d6) δ 0,34 (m, 4H) 1,24 (m, 1H) 2,03 (m, 1H) and 2.26 (s, 3H) 4,91 (s, 1H) 6,41 (m, 1H) 7,11 (t, 2H) 7,4-7,6 (m, 3H) 7,76 (m, 2H) 8,56 (d, 1H) 10,38 (users, 1H) 12,15 (users, 1H); LC-MS (ESI) m/z 389 (M+H)+.

Example 70

Getting 2-(1-(4-forfinal)-2-(methylsulphonyl)ethyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine

Stage A: 3-chlorobenzotriazole (77%, 11,21 g, 50 mmol) in DCM (150 ml) was added diethyl methylthiophosphonate (4.4 ml, 25 mmol) and the mixture was left to stir at room temperature overnight. Then add an additional amount of 3-chlorobenzotriazole (5.6 g) and stirring continued for 4 hours at room temperature. The solution was washed with a saturated aqueous solution of potassium carbonate and concentrated. The residue was dissolved in DCM and washed again with a saturated solution of potassium carbonate. The organic layer was concentrated to obtain diethyl methylsulfonylmethane (4,51 g, 39%).1H NMR (300 MHz, DMSO-d6) δ of 1.25 (t, 6H) of 3.13 (s, 3H) 4.09 to (m, 4H) 4,20 (d, 2H); LC-MS (ESI) m/z 231 (M+H)+.

Stage B: diethylaminocarbonylmethyl-phosphonate (746 mg, 3,24 mmol) in THF (20 ml) at 0°C was added tert-piperonyl potassium (1,0 M in THF at 3.25 ml, 3.25 mmol) and the mixture was stirred for 5 minutes. Then was added (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon from Example 3 (375 mg, of 1.08 mmol) and the mixture premesis is whether at room temperature for 4 hours. The mixture was treated with 1 N. HCl solution and the resulting mixture was extracted using EtOAc. The organic layer was washed with saturated saline solution and then concentrated to obtain a residue (700 mg), which was subjected to chromatography on silica gel, elwira using 1-10% MeOH/DCM, to obtain the crude material. Part of this substance (166 mg) in EtOAc (5 ml) was added 10% Pd-C (166 mg) and the mixture was stirred in hydrogen atmosphere at room temperature overnight. The mixture was filtered and to the filtrate was added palladium on carbon (10%). The mixture was stirred in hydrogen atmosphere for several hours and then filtered. The filtrate was concentrated to obtain a solid substance, which was ground into powder with simple ether to obtain 2-(1-(4-forfinal)-2-(methylsulphonyl)ethyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine (22 mg).1H NMR (300 MHz, DMSO-d6) δ of 2.28 (s, 3H) 2,87 (s, 3H) 3,85 (m, 1H) 4,34 (m, 1H) 4,68 (users, 1H) 6,45 (s, 1H) 7.15m (t, 2H) 7,49 (m, 3H) 7,76 (m, 2H) 8,56 (d, 1H) 10,36 (s, 1H) 12,17 (s, 1H); LC-MS (ESI) m/z 426 (M+H)+.

Example 71

Getting 2-(3-amino-1-(4-forfinal)propyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine

To 3-(4-forfinal)-3-(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)propanenitrile from Example 68 (80 mg, 0.21 mmol) in THF (3 ml) at 0°C was added sociallyengaged (20 mg) and the mixture was stirred for 5 minutes Zutendaal to warm to room temperature and was stirred for 2-3 hours. Then added more sociallyengaged (40 mg) and stirring was continued for 45 minutes. To the solution was slowly added 1 n NaOH solution (0.5 ml) followed by addition of MeOH (2 ml). The mixture was stirred for 5 minutes and then was added AcOH (0.5 ml) followed by addition of DMSO (2 ml). The resulting solution was purified using preparative HPLC (column Varian Diphenyl reversed-phase, suirable with a gradient of solvent B=0.05% Of HOAc/ACN and solvent A=0.05% Of HOAc/H2O) to give 2-(3-amino-1-(4-forfinal)propyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine in the form of the acetate salt (21 mg, 25%).1H NMR (300 MHz, DMSO-d6) δ is 1.81 (s, 3H) 2,2-2,6 (m, 7H) 4.26 deaths (t, 1H) 6,46 (s, 1H) for 7.12 (t, 2H) 7,46-7,51 (m, 3H) 7,73 for 7.78 (m, 2H) to 8.57 (d, 1H); LC-MS (ESI) m/z 377 (M+H)+.

Example 72

Receiving (R,S)(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol-1-d

To (4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone from Example 3 (200 mg, or 0.57 mmol) in THF (5 ml) and MeOH-d4(2 ml) at 0°C was added barometeric sodium (50 mg, 98%). The solution was stirred at 0°C for 1 hour and then allowed to warm to room temperature for 30 minutes. Then added 2 n HCl (0.4 ml) and the solution was concentrated. The residue was purified using preparative HPLC (column Varian diphenyl reversed-phase, e is Aravali with a gradient of solvent B=0.05% Of HOAc/ACN and solvent A=0.05% Of HOAc/H 2O) to obtain (R,S)(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol-1-d (60 mg, 30%).1H NMR (300 MHz, DMSO-d6) δ of 2.25 (s, 3H) 5,80 (s, 1H) 6,41 (s, 1H) 7,14 (t, 2H) 7,53-of 7.55 (m, 3H) 7,79 (m, 2H) 8,58 (d, 1H) 10,41 (users, 1H) 12,15 (users, 1H); LC-MS (ESI) m/z 351 (M+H)+.

Example 73

Receive (4-forfinal)(4-(5-methoxy-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone

Stage A: 3,5-dinitro-1H-pyrazole (517 mg, of 3.27 mmol) in DMF (15 ml) was added potassium carbonate (903 mg, is 6.54 mmol) and 2-(chloromethoxy)ethyl)trimethylsilane (0,64 ml and 3.59 mmol) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the residue was purified by chromatography on silica gel, elwira mixture of 0-20% ethyl acetate/hexane, obtaining oil (840 mg). To the obtained oil in MeOH (20 ml) was added a 25% solution of NaOMe/MeOH (1.25 ml, 5.83 mmol) and the mixture was heated to 60°C for 3-4 hours. Then was added AcOH (0.3 ml) and the mixture was purified using chromatography on silica gel (ethyl acetate/hexane 0-30%) with a single connection (3-methoxy-5-nitro-1-((2-trimethylsilyl)ethoxy)methyl)-1H-pyrazole or 5-methoxy-3-nitro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole)(610 mg, 68%).1H NMR (300 MHz, CDCl3) δ 0,00 (s, 9H) 0,94 (t, 2H) to 3.67 (t, 2H) was 4.02 (s, 3H) 5,41 (s, 2H), 6,23 (s, 1H); LC-MS (ESI) m/z 296 (M+H)+.

Stage B: To the product of Example 73 Stage A (150 mg, 0.55 mmol) in EtOH (10 ml) was added palladium on carbon is kind (10%, 30 mg) and the mixture was stirred in hydrogen atmosphere for 1-2 hours. The mixture was filtered and the filtrate was concentrated to obtain oil. To this oil in DMF (4 ml) was added DIEA (0,96 ml), potassium iodide (65 mg) and (4-chlorination-2-yl)(4-forfinal)methanon from Example 3 step A (112 mg, 0,39 mmol). The mixture was heated at 65°C overnight and then diluted with the aid of EtOAc and washed with water (3×), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was dissolved in THF (5 ml) and a portion (3 ml) were concentrated, were processed using TFA (3 ml) at room temperature for 45 minutes. The mixture was concentrated and then added MeOH and evaporated. The residue was dissolved in DMSO and was again combined with the second part of the sample, which was processed in the same way. The mixture was purified using preparative HPLC (column Varian diphenyl reversed-phase, suirable with a gradient of solvent B=0.05% OF HOAC/ACN and solvent A=0.05% Of HOAc/H2O) to give (4-forfinal)(4-(5-methoxy-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone (12 mg).1H NMR (300 MHz, DMSO-d6) δ of 3.73 (s, 3H) 5,78 (users, 1H) 7,40 (t, 2H) 7,78 (m, 1H) 7,94 (m, 2H) to 8.12 (m, 2H) 8,59 (users, 1H) 10,88 (users, 1H) 11,77 (users, 1H); LC-MS (ESI) m/z 364 (M+H)+.

Example 74

Receiving (R,S)-(4-(5-ethyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol

When pushing A: To a mixture of 5-ethyl-1H-pyrazole-3-amine (101 mg, of 0.91 mmol), potassium iodide (117 mg, 0.7 mmol) and DIEA (0.15 ml, 0.84 mmol) in DMF (4 ml) was added (4-chlorination-2-yl)(4-forfinal)methanon from Example 3 step A (200 mg, 0.7 mmol) and the mixture was stirred at room temperature overnight. Added water and the precipitated solid substance was collected by filtration. Yellow solid (226 mg), containing (4-(5-ethyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanon, used directly in the next stage. LC-MS (ESI) m/z 362 (M+H)+.

Stage B: To crude (4-(5-ethyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone (104 mg, 0.28 mmol) in a mixture of 1:1 MeOH/THF (4 ml) at room temperature was added borohydride sodium (22 mg, or 0.57 mmol) and the solution was stirred for 30 minutes, then was added 4 n HCl solution (0.1 ml). The mixture was concentrated to dryness and the residue was purified using preparative HPLC (column Varian diphenyl reversed-phase, suirable with a gradient of solvent B=0.05% Of HOAc/ACN and solvent A=0.05% Of HOAc/H2O) to obtain (4-(5-ethyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol (7 mg).1H NMR (300 MHz, DMSO-d6) δ of 1.24 (t, 3H) 2,62 (square, 2H) 5,67 (m, 1H) of 5.83 (s, 1H) 6,45 (s, 1H) 7,13 (t, 2H) 7,53-EUR 7.57 (m, 3H) 7,81 (s, 2H) 8,59 (d, 1H) 10,42 (users, 1H) 12,15 (users, 1H); LC-MS (ESI) m/z 364 (M+H)+.

Example 75

Receive (4-Forfinal)(4-(5-methoxy-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol

(4-Forfinal)(4-(5-methoxy-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol was obtained using a procedure similar to that described in Example 6 using (4-forfinal)(4-(5-methoxy-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon from Example 75 instead of (4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanone used in the Example 6.

Example 76

Receive (4-fluoro-3-methoxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone

Stage A: To a stirred mixture of ethyl 4-chlorination-2-carboxylate (500 mg, 2,11 mmol) in THF (17 ml) at -40°C was added dropwise a 1 M solution of 4-fluoro-3-methoxyphenylacetamide/2-methyltetrahydrofuran (2,53 ml of 2.53 mmol). The reaction mixture was stirred at a temperature in the range from - 30 to - 40°C for 3 hours. Added additional amount of 1 M solution of 4-fluoro-3-methoxyphenylacetamide/2-methyltetrahydrofuran (of 1.05 ml, 1.05 mmol) and stirring was continued at a temperature in the range from - 30 to - 40°C for 1.5 hours. To the mixture was added saturated aqueous solution of ammonium chloride (25 ml) and the mixture was allowed to warm to room temperature. The mixture was extracted using EtOAc (2×) and the combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was ground into powder with diethyl ether and extracting the Noah solid substance was collected by filtration and dried to obtain (4-chlorination-2-yl)(4-fluoro-3-methoxyphenyl)methanone in the form of a colorless solid (417 mg, 62%).1H NMR (300 MHz, DMSO-d6) δ ppm to 3.92 (s, 3H), 7,42 (DD, J=11,1, to 8.7 Hz, 1H), to 7.64 (m, 1H), a 7.85 (d, J=8,4 Hz, 1H), 8,04 (m, 1H), 8,23-of 8.25 (m, 2H), 8,43 (d, J=8,4 Hz, 1H); LC-MS (ESI) m/z 317 (M+H)+.

Phase B: a Mixture of (4-chlorination-2-yl)(4-fluoro-3-methoxyphenyl)methanone (337 mg, 1.06 mmol), 5-methyl-1H-pyrazole-3-amine (206 mg, 2,12 mmol), potassium iodide (528 mg, 3,18 mmol) and DIEA (0,37 ml, 2,13 mmol) in DMF (10 ml) was stirred at room temperature for 20 hours. To the mixture was added water (80 ml) and the obtained solid substance was collected by filtration and washed with water and then diethyl ether. The solid was dried to obtain (4-fluoro-3-methoxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone in the form of a yellow solid (300 mg, 75%).1H NMR (300 MHz, DMSO-d6) δ ppm are 2.19 (s, 3H), 3,90 (s, 3H), 6,55 (s, 1H), 7,38 (DD, J=11,1, an 8.4 Hz, 1H), to 7.59 (m, 1H), 7,68 (DD, 7=7,8, and 7.8 Hz, 1H), to 7.77-7,94 (m, 3H), up 8.75 (d, J=7.8 Hz, 1H), 10,69 (users, 1H), 12,23 (users, 1H); LC-MS (ESI) m/z 378 (M+H)+.

Example 77

Receive (4-fluoro-3-hydroxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone

To a stirred suspension of (4-fluoro-3-methoxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone from Example 76 (100 mg, 0,265 mmol) in DCM (4 ml) at 0°C was added dropwise a 1.0 M solution tribromide boron/DCM (2,12 ml, 2,12 mmol). The mixture was stirred at 0°C for 30 minutes. Added an additional amount of 1.0 M solution of three who RAID boron/DCM (1.50 ml, 1.50 mmol) and the mixture was allowed to warm to room temperature and stirred for another 2.5 hours. Was added water (10 ml) and the mixture was extracted with 25% solution of 2-propanol/DCM (2×). The combined organic layers were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was ground into powder with diethyl ether and the resulting solid was collected by filtration and dried. The solid was subjected to additional purification using reversed-phase HPLC, elwira with a mixture of water and acetonitrile, to obtain (4-fluoro-3-hydroxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone in the form of a yellow solid (20 mg, 21%).1H NMR (300 MHz, DMSO-d6) δ ppm are 2.19 (s, 3H), 6,51 (s, 1H), 7,28 (DD, J=10,8, and 8.4 Hz, 1H), 7,39 (m, 1H), 7,58 (DD, J=8,7, 1.8 Hz, 1H), to 7.67 (DDD, J=8,1, to 8.1, 1.5 Hz, 1H), 7,83-a 7.92 (m, 2H), 8,73 (d, J=8,4 Hz, 1H), 10,65 (users, 1H), 12,22 (users, 1H); LC-MS (ESI) m/z 364 (M+H)+.

Example 78

Receiving (R,S)-(2-fluoro-5-(hydroxy(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methyl)enolacetate

To a stirred solution of (4-fluoro-3-hydroxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone from Example 77 (20 mg, by 0.055 mmol) in a mixture of THF (0.3 ml) and MeOH (0.3 ml) at 0°C was added borohydride sodium (3 mg, 0,079 mmol) and the mixture was stirred at 0°C for 15 minutes. To the mixture was added kontsentrirovannymi hydrochloric acid to achieve a pH of 1. This mixture was combined with the mixture obtained in a similar way, from (4-fluoro-3-hydroxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanone (60 mg, 0,165 mmol). The resulting mixture was purified using reverse-phase HPLC, elwira a mixture of water in acetonitrile, to obtain the (R,S)-(2-fluoro-5-(hydroxy(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methyl)enolacetate in the form of a solid (26 mg, 28%).1H NMR (300 MHz, DMSO-d6) δ ppm 1,89 (s, 3H), of 2.25 (s, 3H), of 5.55 (s, 1H), 5,75 (users, 1H), gold 6.43 (users, 1H), 6,92 (m, 1H), 7,02-7,11 (m, 2H), 7,52 (m, 1H), 7,70-7,79 (osirm, 2H), 8,58 (m, 1H), 10,44 (users, 1H), 12,10 (users, 1H); LC-MS (ESI) m/z 366 (M+H)+.

Example 79

Analysis of competitive binding to determine the binding constant (Kd) compounds against JAK kinases

Analysis of competitive binding, which were used, were developed, approved and implemented, as described in Fabian et al., Nature Biotechnology 2005, 23,329-336. Kinase were obtained in the form of mergers with T7 phage (See, Fabian et al. or WO04/015142), or, alternatively, kinase expressed in HEK-293 cells and then were labeled with DNA for PCR detection (See, WO08/005310). For analyses of the binding of streptavidin coated magnetic beads were treated biotinylating affinity ligands for 30 minutes at room temperature for the formation of affinity resins. Processed ligands balls blocked excessive number is the number of Biotin and washed with blocking buffer (SeaBlock (Pierce), 1% BSA, 0.05% of Tween 20, 1 mm DTT) to remove unbound ligand and to reduce nonspecific binding. Binding assays were United by combining kinase associated with ligand affinity beads and test compounds in 1× buffer for binding (20% SeaBlock, 0,17× PBS, 0.05% of Tween 20, 6 mm DTT). Test compounds were prepared as 100× original solutions in DMSO and was quickly diluted in the aquatic environment. DMSO was added to control tests without test compounds. Interaction for the primary screening was carried out in polypropylene 384-well tablets in the final volume 34 μl, and determine the Kd was performed in polystyrene 96-well tablets in a final volume of 135 μl. Analytical plates were incubated at room temperature with shaking for 1 hour, this time was enough for the binding reaction has reached equilibrium, and the affinity beads were thoroughly washed with wash buffer (1× PBS, 0.05% of Tween 20) to remove unbound protein. The balls then resuspendable in eluting buffer (1× PBS, 0.05% of Tween 20, 2 mm nebutiniausias affinity ligand) and incubated at room temperature with shaking for 30 minutes. The kinase concentration in the eluates was measured using quantitative PCR analysis. Each kinase was tested individually against each connection. Kd identify elali using eleven serial threefold dilutions. Index selectivity, which is a quantitative measure of the selectivity of the compounds against a number of enzymes, can be calculated for connection by dividing the number of enzymes for which the connection meets the established criteria (for example, the binding constant of 100 nm or less), the total number of test enzymes. Index selectivity against kinase, S10, for example, are calculated for each compound by dividing the number of kinases for which a connection at a certain concentration (for example, 10 μm) demonstrates the inhibition of 90% or more, compared to a negative control without inhibitors (DMSO only), 321, i.e. the number of separate test kinases, with the exception of mutant variants.

In one variant embodiment of the compounds provided in the present invention, has been found to have a Kd of less than about 20 μm against JAK2. In another variant embodiment of the compounds provided in the present invention, has been found to have a Kd of less than about 10 μm against JAK2. In another variant embodiment of the compounds provided in the present invention, has been found to have a Kd of less than about 1 μm against JAK2.

In another variant embodiment of the compounds provided in the present invention, as has been discovered, which have Kd less than about 20 μm against JAK3. In another variant embodiment of the compounds provided in the present invention, has been found to have a Kd of less than about 10 μm against JAK3. In another variant embodiment of the compounds provided in the present invention, has been found to have a Kd of less than about 1 μm against JAK3.

Example 80

Analysis of reporter cell-based csTF-1

csTF-1 cells were isolated from human erythroleukemia cell lines, the growth of which is dependent on GM-CSF and which has an intact GM-CSFR/JAK2/STAT5 pathway. Cell line contains a stably integrated reporter gene beta-lactamase under the control of the responsive element of the regulatory factor 1 (irf 1), recognizable activated transcription factor STAT5. csTF-1 cells (Invitrogen K1219) washed environment for analysis (97% OPTIMEM/0,5% cialisovernight FBS/0.1 mm NEAA/1 mm Na pyr/ P/S) and were sown in the same medium at a density of 5×105cells/ml in a T150 flask. After 16 hours incubation, the cells were sown at a density of 2×105cells/well in a volume of 50 ál 96-well analytical tablets Costar with a transparent bottom. Serial dilution of the compounds were added to the tablets at the final concentration of DMSO 0.5% and GM-CSF 2 ng/ml and tablets then incubated at 30°C and 5% CO2within 4 hours. The plates were brought to room temperature before adding the Mixture to the Substrate, in accordance with duct is scrap the manufacturer (Invitrogen, Catalog # K1085). Analytical tablets containing substrate mixture, incubated in the dark at room temperature for 2 hours. Blue and green fluorescence was measured at a wavelength of excitation at 409 nm and emission at 460 nm (blue) and at the wavelength of excitation at 409 nm and emission at 530 nm (green) using devices Spectra Max Gemini EM. Compounds provided in the present invention, has been found to have IR50less than about 5 microns. In another variant embodiment of the compounds provided in the present invention, has been found to have activity at IR50less than about 500 nm.

Compounds provided in the present invention, has been found to have the following activity is shown in Table 1:

Table 1

The following illustrative compounds provided in the present invention, has been found to have the following activity is shown in Table 2:

Table 2

In Tables 1 and 2

analysis of the reporter on the basis of CSTF-1, IR50(nm):≤100, 100<B≤500<500;

JAK2 Kd (nm): A≤1, 1<B≤10, C>10; JAK3 Kd (nm): A≤10, 10<B≤100, C>100;

AuroraB Kd (nm) A≤20, 20<B≤50, 50<C≤200 D>200

Index selectivity: A≤0.3, and 0.3 to<B≤0,4, 0,4<C≤0.5, and D>0.5 and ND = no data.

In some embodiments the embodiment of the compounds provided in the present invention, are associated with JAK2 kinase with a higher specificity compared to nematandani and not related to the JAK family of kinases. For some of the compounds provided in the present invention, the binding constants in respect of less than 10 namutoni and not related to the JAK family of kinases are in the range of 100-fold values from the binding constants against JAK2 kinase for compounds provided in the present invention. For some of the compounds which, provided in the present invention, the binding constants in respect of less than 8 namutoni and not related to the JAK family of kinases are in the range of 100-fold values from the binding constants against JAK2 kinase for compounds provided in the present invention. For some of the compounds provided in the present invention, the binding constants in respect of less than 6 namutoni and not related to the JAK family of kinases are in the range of 100-fold values from the binding constants against JAK2 kinase for compounds provided in the present invention.

Example 81

Dose-response effects of compounds of the formula I in models of type II collagen-induced arthritis (CIA) in rats

On Day 0 of the experiment, female Lewis rats (Charles River) were injected by subcutaneous injection at three different sites back in 300 μl of bovine collagen type II emulsified in incomplete Freund's adjuvant, just every animal was injected with 1.2 mg of collagen. Animals received a booster dose on Day 6. Measurements with a compass (to disease) of the right and left ankle joints was performed at Day 8. Immediately after the onset of arthritis (Day 9) rats were randomly divided into processing groups, 8 animals per arthritic group (4 animals were originally reserved for the normal control of the Oh group). Starting at Day 9, the compound of formula I is diluted in Pharmatek#6 and treatment was started with oral administration of compounds of formula I with 5 mg/kg, 20 mg/kg or 60 mg/kg twice daily (BID) with a 12-hour intervals or at 60 mg/kg QD. Control arthritic groups included a control group, which entered the media control group, which entered the water, a control group not receiving any treatment, and a positive control group, which oral was administered dexamethasone at 0.03 mg/kg QD. Treatment was continued for 6 days. Measurements with a compass ankle joints was carried out every day, starting from Day 9 to Day 16. The results are shown in Fig. 1.

An illustrative compound of the formula I provided a statistically significant improvement in the thickness of the ankle joint with >5 mg/kg BID, starting even from Day 2 processing.

The most effective compounds in a rat model of CIA was observed at 60 mg/kg (QD or BID). Observed correlation between the clinical evaluation of swollen feet and histology.

The effect of treatment on body weight of rats was measured from Day 9 to Day 16 as the percentage change in body weight from baseline. The results are presented in Fig. 2.

Example 82

In vivo performance testing in mice using the murine model TELJAK

This test was carried out for definition wide-angle the effect of the selected compounds of formula I on tumor growth and survival. Mice CB17 SCID (Harlan Laboratories) were infected by grafting them 5e5 TEL-JAK cells via tail vein on Day 0. The cells were allowed to adapt in the body of the animal and Day 3 began the introduction as follows: medium (Pharmatek#6) were injected with 50 μl of BID the first group, the firm connection Ambit intended for internal use only, prepared for introduction in Pharmatek #6 and was injected with 50 mg/kg BID of the second group, and TGEN101348 prepared for introduction in Pharmatek #6 and introduced the third group at 100 mg/kg BID. Each processing group (16 animals in each group) was carried out by the introduction of two times a day for two weeks. Raw group of 10 animals served as control. Fig. 3 shows the results of survival analysis Kaplan-Meier.

A second test was performed using the same Protocol with the same controls and the following treatment groups: a firm connection Ambit intended for internal use only, prepared for introduction in Pharmatek #6 and was administered at 60 mg/kg BID, and the selected compound of formula I was prepared for introduction in Pharmatek #6 and was administered at 60 mg/kg BID. Fig. 4 shows the results of survival analysis Kaplan-Meier.

Data show that the connection is firm Ambit intended for internal use only, provides more than 70% increase in time vyziva the Oia (ILS), while TGEN101348 provides 30% ILS. It was shown that the selected compound of formula I works better than the internal joint Ambit, and therefore expect that it will do better than TGEN101348 preclinical.

Example 83

In vivo performance testing in mice using the murine model HELV617F liquid tumors

This test was carried out to determine the effect of selected compounds of formula I on tumor progression and survival. CB 17 SCID mice (Charles River Labs) was pre-treated with cyclophosphamide QD administered intraperitoneally with 150 mg/kg for two consecutive days, after which they were injected cells by injection. On Day 0, 75, the mice were infected by grafting them intravenous 5e6 HEL 92.1.7 cells, suspended in sterile saline. Animals were weighed on Day 8 and were divided into groups so that each group consisted of animals with the same average body weight and the same standard deviations from the mean. Animals were carried out introduction to Day 8 for 21-day period of administration. The processing group were as follows (10 animals in each group): the first group was injected media (Pharmatek#6), oral, BID; the second group was injected brand connection Ambit for internal use, prepared for introduction in Pharmatek#6, at 50 mg/kg, oral, BID; and the third group enter the if TGEN101348, prepared for introduction in Pharmatek#6, at 120 mg/kg orally BID. Raw group of 10 animals served as control. Fig. 5 shows the results of the analysis of Kaplan-Meier.

Another test was performed using the same Protocol with the same controls and the following treatment groups: the corporate connection Ambit for internal use, prepared for introduction in Pharmatek#6, was administered at 60 mg/kg BID, and the selected compound of formula I, prepared for introduction in Pharmatek#6, was administered at 60 mg/kg BID. Fig. 6 shows the results of the analysis of Kaplan-Meier. Fig. 5 and 6 show that the corporate connection Ambit for internal use and the selected compound of formula I provide approximately 30% increase in survival time (ILS), whereas TGEN101348 not provide any beneficial effect associated with survival time (approximately 5% ILS).

Example 84

Other cell tests

The compounds of formula I are also experienced in other cellular assays, for example, pSTAT5 electrochemiluminescent immunoassays (Meso Scale Discovery) cell lines csTF-1 and HEL, and it was found that the compounds are active in these assays. The effects of compounds of the formula I in BaF3 cell proliferation was also tested using the CellTiter-Blue® (Promega).

The inhibition of the DTH response is and ovalbumin in CD-1 mice

The test was carried out to evaluate the effect of the compounds of formula I a murine model of ovalbumin-induced allergic reactions of the delayed type (allergic reaction type IV DTH) using two schemes introduction. Allergic reaction of the delayed type is characterized by antigen-specific production of cytokines by T-cells, leading to increased vascular permeability, infiltration managername and polymorphisim cells, edema and induration. Primary exposure to antigen (sensitization phase) causes the development of antigen-specific T-cell memory, which are activated when the secondary impact (provocation).

Two-phase nature of allergic reactions type IV provides a model for differentiation immunopharmacological compounds with immunomodulatory properties. Expect that compounds that are immunosuppressants (inhibit primary immune response)will be effective when introduced in the phase of sensitization. Compounds that are anti-inflammatory, expected to be effective when introduced in the phase of re-exposure to antigen by preventing or down-regulation of antigen recognition and/or activation of T-cells memory or by interrupting secondary signaling cascades induced by produced by T-cells cyto the ins and growth factors (thus, reducing/preventing vascular permeability and mobility/recruitment of inflammatory cells). Expect that compounds that are boosting will enhance DTH response when introduced into the phase of sensitization (increased antigen presentation or expansion of T-cell memory) or in the phase of re-exposure to antigen (increased T-cell activation and production of cytokines/chemokines, and/or mobility/recruitment/activation of inflammatory cells).

Since modifications should be obvious to specialists in this field, the claimed invention should be limited only by the scope of the attached claims.

1. The compound having the formula (I):

or its pharmaceutically acceptable salt, where
R1and R2selected from (i), (ii), (iii), (iv) and (v) and have the following meanings:
(i) R1and R2together form =O;
(ii) R1and R2together with the carbon atom to which they are bound, form dioxocyclohexa;
(iii) R1represents hydrogen or halogen; and R2 represents halogen;
(iv) R1represents a C1-6alkyl, where alkyl optionally substituted by cyano, -RxS(O)qRvor-RxNRyRz; and R2represents hydrogen; and
(v) R1represents-OR12or-NR13 R14; and R2represents hydrogen, deutero or phenyl, which is optionally substituted with halogen;
R3represents hydrogen, halogen, C1-6alkyl, cyano, halogen, C1-6alkyl, C3-10cycloalkyl or C1-6alkoxy;
R4and R5represent hydrogen;
each R6independently selected from halogen, C1-6of alkyl, Halogens1-6of alkyl, RxOR18and RxS(O)qRv;
each R7independently represents halogen or-RxORw;
R12selected from hydrogen and C1-6of alkyl;
R13represents hydrogen;
R14selected from hydrogen, C3-10cycloalkyl, -C(O)Rvand-C(O)ORw;
R18represents hydrogen, C1-6alkyl or piperidinyl; where R18optionally substituted by 1-3 groups Q1every Q1independently selected from hydroxyl, C1-6alkoxy, C1-6alkoxycarbonyl, carboxyl and morpholinyl;
Rxindependently represents a C1-6alkylen or a simple bond;
Rvrepresents hydrogen or C1-6alkyl;
Rwindependently represents hydrogen or C1-6alkyl;
Ryand Rzrepresent hydrogen;
n has a value of 0-4;
p has a value of 0-5; and
each q, independently, is 0, 1 or 2.

2. Connection p., having the formula (II)

or its pharmaceutically acceptable salt, where
R1and R2selected from (i), (iii) and (v) and have the following meanings:
(i) R1and R2together form =O;
(iii) R1represents hydrogen, and R2is a halogen; and
(v) R1represents-OR12and R2represents hydrogen;
R3represents hydrogen or C1-6alkyl,
R4and R5represent hydrogen;
R6a, R6b, R6cand R6deach independently selected from halogen, C1-6of alkyl, Halogens1-6the alkyl and RxOR18;
R7is a halogen;
R12represents hydrogen;
R18represents hydrogen, C1-6alkyl or piperidinyl; where R18optionally substituted by 1-3 groups Q1where each Q1independently selected from hydroxyl, C1-6alkoxy, C1-6alkoxycarbonyl, carboxyl or morpholinyl;
each Rxindependently represents a C1-6alkylen or a simple bond; and
each q, independently, is 0, 1 or 2.

3. The compound according to claim 1 or 2, where R1and R2together form =O

4. The compound according to claim 1, where R1represents hydrogen or fluorine and R2represents fluorine.

5. The compound according to claim 1, where R represents hydroxyl, methoxy, amino or methoxycarbonylamino and R2represents hydrogen, phenyl or forfinal.

6. The compound according to claim 1, where R3represents hydrogen, C1-6alkyl or C1-6alkoxy.

7. The compound according to claim 1, where each R6independently selected from halogen, C1-6of alkyl, hydroxyl, and C1-6alkoxy.

8. The compound according to claim 1, where R7represents a halogen.

9. The compound according to claim 1, where n is 0 or 1.

10. The compound according to claim 1, where p is 1 or 2.

11. The compound according to claim 1, having the formula (III) or (IIIA)

or its pharmaceutically acceptable salt, where
R1and R2selected from (i) and (ii) and shall have the following meanings:
(i) R1and R2together form =O; and
(ii) R1represents-OR12or-NR13R14and R2represents hydrogen or phenyl;
R12selected from hydrogen and C1-6of alkyl;
R13represents hydrogen; and R14selected from hydrogen, C3-10cycloalkyl, -C(O)Rvand-C(O)ORw;
R3represents hydrogen or C1-6alkyl;
R6selected from halogen, C1-6of alkyl, Halogens1-6the alkyl and RxOR18; where R18represents hydrogen, C1-6alkyl and piperidinyl; where R18optionally substituted gr is ppoi Q 1where Q1selected from hydroxyl, Q1alkoxy, C1-6alkoxycarbonyl, carboxyl and morpholinyl;
R7represents halogen, hydroxyl or C1-6alkoxy;
Rvrepresents hydrogen or C1-6alkyl;
Rwrepresents hydrogen or C1-6alkyl;
Ryand Rzrepresent hydrogen; and
q is 0, 1 or 2.

12. The compound according to claim 1, having the formula (IV) or (IVa)

or its pharmaceutically acceptable salt.

13. The compound according to claim 1, having the formula (VI)

or its pharmaceutically acceptable salt.

14. The compound according to claim 1, having the formula (VII)

or its pharmaceutically acceptable salt.

15. The compound according to claim 1, having the formula (VIII)

or its pharmaceutically acceptable salt.

16. The compound according to claim 1, having the formula (IX)

or its pharmaceutically acceptable salt.

17. The compound according to claim 1, having the formula (X)

or its pharmaceutically acceptable salt.

18. The compound according to claim 1, selected from the following:
(3-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon;
(4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(3-forfinal)methanon;
(4-forfinal)(4-(5-methyl-1H-pyrazole-3-Ilam is but)hinzelin-2-yl)methanon;
(4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanon;
(4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(2-methoxyphenyl)methanon;
(4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol;
2-(fluoro(4-forfinal)methyl)-N-(1H-pyrazole-3-yl)hinzelin-4-amine;
2-(diftar(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3 - yl)hinzelin-4-amine;
2-(diftar(4-forfinal)methyl)-N-(1H-pyrazole-3-yl)hinzelin-4-amine;
N-(5-cyclopropyl-1H-pyrazole-3-yl)-2-(diftar(4-forfinal)methyl)hinzelin-4-amine;
3-(2-(4-perbenzoic)hinzelin-4-ylamino)-1H-pyrazole-5-carbonitrile;
(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;
2-((4-forfinal)(methoxy)methyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;
2-(amino(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;
3-(2-((4-forfinal)(hydroxy)methyl)hinzelin-4-ylamino)-1H-pyrazole-5-carbonitrile;
(5-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol;
(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(trifluoromethyl)hinzelin-2-yl)methanon;
(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(trifluoromethyl)hinzelin-2-yl);
(7-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanon;
2-(diftar(4-forfinal)methyl)-7-fluoro-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;
2-(diftar(4-forfinal)methyl)-7-fluoro-N-(1H-pyrazole-3-yl)hinzelin-4-amine;
(4-(1H-pyrazole-3-ylamino)-7-iodination-2-yl)(4-forfinal)methanon; (4-(1H-pyrazole-3-ylamino)-7-iodination-2-yl)(4-forfinal)methanol;
(4-forfinal)(7-methyl-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon;
(4-forfinal)(7-methyl-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;
2-(diftar(4-forfinal)methyl)-7-methyl-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;
2-(diftar(4-forfinal)methyl)-7-methyl-N-(1H-pyrazole-3-yl)hinzelin-4-amine;
(4-(1H-pyrazole-3-ylamino)-7-methoxyquinazoline-2-yl)(4-forfinal)methanon;
(4-(1H-pyrazole-3-ylamino)-7-methoxyquinazoline-2-yl)(4-forfinal)methanol;
(4-forfinal)(7-methoxy-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon;
(4-forfinal)(7-methoxy-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;
2-(diftar(4-forfinal)methyl)-7-methoxy-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;
2-(diftar(4-forfinal)methyl)-7-methoxy-1H-(1H-pyrazole-3-yl)hinzelin-4-amine;
2-(diftar(4-forfinal)methyl)-8-fluoro-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;
(4-(1H-pyrazole-3-ylamino)-8-methoxyquinazoline-2-yl)(4-forfinal)methanon;
2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-ol;
(4-forfinal)(7-hydroxy-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon;
(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(2-morpholinoethoxy)hinzelin-2-yl)methanol;
2-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)ethanol;
3-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyln-pyrazole-3-ylamino)hinzelin-7-yloxy)propan-1-ol;
(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)-7-(piperidin-4-yloxy)hinzelin-2-yl)methanol;
(4-forfinal)(7-(2-methoxyethoxy)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;
tert-butyl 2-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)acetate;
2-(2-((4-forfinal)(hydroxy)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yloxy)acetic acid;
methyl ester {(4-forfinal)-[4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl]methyl}carbamino acid;
bis-(4-forfinal)-[4-(5-methyl-1H-pyrazole-3-ylamino)-hinzelin-2-yl]methanol;
methyl (4-forfinal)(4-(5-methyl-4H-pyrazole-3-ylamino)hinzelin-2-yl)methylcarbamate;
(4-forfinal)(8-methyl-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;
(7-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol;
(4-(1H-pyrazole-3-ylamino)hinzelin-2-yl)bis(4-forfinal)methanol;
(2-(diftar(4-forfinal)methyl)-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-7-yl)methanol;
2-(diftar(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3-yl)-7-(methylsulfonylmethyl)hinzelin-4-amine;
2-(diftar(4-forfinal)methyl)-7-(ethoxymethyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;
(7-chloro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol;
(6-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanon;
(6-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol
(4-(1H-pyrazole-3-ylamino)-6-florinopolis-2-yl)(4-forfinal)methanol;
(7-bromo-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanon;
(7-bromo-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol;
(4-(1H-pyrazole-3-ylamino)-7-bromination-2-yl)(4-forfinal)methanol;
2-(2-(4-forfinal)-1,3-dioxolane-2-yl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;
(8-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanon;
(8-fluoro-4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol;
(2-methoxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon;
(2-methoxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;
N-((4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methyl)formamide;
(3,4-differenl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;
(3-chloro-4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;
3-(4-forfinal)-3-(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)propanenitrile;
2-((cyclopropylamino)(4-forfinal)methyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;
2-(1-(4-forfinal)-2-(methylsulphonyl)ethyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;
2-(3-amino-1-(4-forfinal)propyl)-N-(5-methyl-1H-pyrazole-3-yl)hinzelin-4-amine;
(4-forfinal)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol-1-d;
(4-forfinal)(4-(5-methoxy-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon;
(4-(5-ethyl-N-pyrazole-3-ylamino)hinzelin-2-yl)(4-forfinal)methanol;
(4-forfinal)(4-(5-methoxy-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanol;
(4-fluoro-3-methoxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon;
(4-fluoro-3-hydroxyphenyl)(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methanon; and
(2-fluoro-5-(hydroxy(4-(5-methyl-1H-pyrazole-3-ylamino)hinzelin-2-yl)methyl)enolacetate.

19. The compound according to claim 1 for use in the treatment of JAK-modulated diseases.

20. Pharmaceutical composition having inhibitory activity against JAK kinases containing a therapeutically effective amount of a compound according to any one of claims 1 to 18 and a pharmaceutically acceptable carrier, diluent or excipient.

21. A method for the treatment of JAK-modulated diseases, including the introduction of a therapeutically effective amount of a compound according to any one of claims 1 to 18.

22. A method for the treatment of JAK2-modulated diseases, including the introduction of a therapeutically effective amount of a compound according to any one of claims 1 to 18.

23. The method according to item 22, where JAK2 is a JAK2 wild-type or mutant JAK2.

24. The method according to item 21, where the disease is a cancer, myeloproliferative disorder, inflammation or autoimmune disease.

25. The method according to item 21, where the disease is selected from true polycythemia, essential of thrombocythemia, idiopathic myelofibrosis, chronic myelomonocytic leukemia, x is onechicago eosinophilic leukemia, myeloma and systemic mastocytosis.

26. The method according to paragraph 24, where the cancer is a leukemia.

27. The method according to p, where leukemia is a chronic myeloid leukemia, imatinib-resistant chronic myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia or acute megacaryoblastic leukemia.

28. The method according to paragraph 24, where the cancer is selected from cancers of the head and neck, prostate cancer, breast cancer, ovarian cancer, melanoma, lung cancer, brain cancer, pancreatic cancer, stomach cancer, thyroid cancer, carcinoma of the kidney, Kaposi's sarcoma, Castleman's disease and melanoma.

29. The method according to item 21, where the disease is selected from hypereosinophilic syndrome, disease, graft-versus-host, wound healing, kidney disease, multiple sclerosis, thyroiditis, type 1 diabetes, sarcoidosis, psoriasis, allergic rhinitis, atopic dermatitis, malignant gravis, inflammatory bowel disease, Crohn's disease, ulcerative colitis, lupus, arthritis, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma, chronic obstructive pulmonary disease, conjunctivitis, uveitis, iritis, scleritis, dry eye syndrome, dry keratoconjunctivitis, rhinitis, sinusitis, bronchitis, inflammatory myopathy, myocarditis, ischemic reperfusion what's defeats, the system inflammatory response syndrome and sepsis.

30. The method according to item 21, where the disease is selected from restenosis, fibrosis and scleroderma.

31. The method according to item 21, where the disease is selected from a virus, Epstein-Barr, hepatitis B, hepatitis C, human immunodeficiency virus human T-lymphotropic virus type 1 human, varicella zoster virus, and papilloma virus human.

32. The use of compounds according to any one of claims 1 to 18 to obtain drugs for the treatment of JAK-modulated diseases.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to isoindoline compounds, such as compounds of Formula or to their pharmaceutically acceptable salts or stereoisomers, wherein X represents CH2; Y represents O, cyanamido (N-C≡N) or amido (NH); m represents an integer of 0 or 1; R1 represents hydrogen or C1-6 alkyl; R2 represents hydrogen, C1-10 alkyl, C0-6alkyl-(5-10-merous heteroaryl containing one, two or three heteroatoms independently specified in O, S or N), C0-6alkyl-(6-merous heterocyclyl which represents morpholinyl or piperazinyl), C0-6alkyl-OH, -NHCO-C1-6alkyl, -OR21 or - (CH2-Z)-(6-merous heteroaryl which represents pyridinyl), wherein each heteroaryl and heterocyclyl is optionally substituted by one or more C1-6 alkyls; R3 represents hydrogen, halogen, -NO2, C0-6alkyl-OH, C0-4 alkyl-NH2 or -OR21; R21 represents phenyl, pyridinyl, piperidinyl or -CO(CH2)R22; R22 represents -NH2 or piperazinyl; and Z represents O; provided R1 represents hydrogen, then R2 is other than hydrogen or C1-10alkyl; provided R3 represents halogen, then R2 represents C0-6alkyl-(5-6-merous heterocyclyl). The invention also refers to pharmaceutical compositions for controlling angiogenesis or inhibiting the TNFα production on the basis of the above compounds.

EFFECT: there are prepared new compounds and compositions based thereon to be used in medicine for treating or preventing a disease or a disorder, such as cancer, pain skin diseases, lung disorders, parasitic diseases, immunodeficiency disorders, CNS disorders, CNS injuries, atherosclerosis or associated disorders, sleep disorders or associated disorders.

26 cl, 68 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a new compound of formula [I] or to its pharmaceutically acceptable salt, wherein A represents optionally substituted alkyl, wherein the substitute represents identical or different 1-3 groups specified in aryl optionally substituted by 1-3 groups specified in alkyl, halogen, alkoxy and alkanoyl; cycloalkyl optionally substituted by 1-3 groups specified in alkyl and halogen; hydroxy; alkoxy; halogen; an amino group and oxo; an optionally substituted carbocyclic group specified in a mono- and bicyclic group, wherein an aromatic ring and cycloalkyl are condensed; optionally substituted aryl, an optionally substituted completely saturated 5- or 6-merous monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, wherein the substitute of optionally substituted aryl, the optionally substituted carbocyclic group and the optionally substituted heterocyclic group for A represents identical or different 1-3 groups specified in alkyl, optionally substituted hydroxy, alkoxy, cycloalkyl or halogen; cycloalkyl optionally substituted by alkyl or alkoxy; alkoxy optionally substituted by halogen; halogen; hydroxy; oxo; heterocycle; alkyl sulphonyl; and mono- or dialkylcarbamoyl, optionally substituted amino, wherein the substitute represents identical or different 1 or 2 alkyl or aryl, or optionally substituted carbamoyl, wherein the substitute represents identical or different 1 or 2 alkyls optionally substituted by aryl, X represents optionally substituted methylene or -O-, wherein the substitute of optionally substituted methylene for X represents alkoxy or hydroxy, Q represents N or C-R4, L1 represents a single bond, methylene, -CH=CH-, -O-, -CO-, -NR11-, -NR11CO-, -CONR11- or -CH2NR11-, L2 represents a single bond, -CR6R7- or a bivalent 5- or 6-merous completely saturated monocyclic heterocyclic group each of which contains 1 heteroatom specified in nitrogen and oxygen, R1 and R2 are identical or different, and each represents hydrogen, alkyl or halogen, R3 and R4 are identical or different, and each represents hydrogen, alkyl, alkoxy, cyano or halogen, R1 and R3 are optionally bond thereby forming 5- or 6-merous cycloalkane, or a 5- or 6-merous aliphatic heterocycle containing oxygen atom, R5 represents a carboxyl group, an alkoxycarbonyl group or a bioisosteric group of the carboxyl group, R6 and R7 are identical or different, and each represents hydrogen or alkyl, or R6 and R7 are bond thereby forming cycloalkane, R8 represents hydroxy, alkanoylamino or alkyl sulphonylamino, R9 and R10 represent hydrogen or halogen, and R11 represents hydrogen or alkyl. Besides, the invention refers to specific compounds of formula [I], a drug based on the compound of formula [I], using the compound of formula [I], a method of treating based on using the compound of formula [I], and an intermediate compound of formula [II].

EFFECT: there are prepared new compounds possessing the agonist activity on thyroid hormone β receptor.

18 cl, 36 tbl, 344 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a specific list of various novel azaazulene compounds, which contain 6,5-condensed heterocycle of an indole type, benzimidazole type, purine type, 3H-imidaso[4,5-b]pyrene,3H-imidaso[4,5-c] pyridine, etc., which can be described by the general formula , where R1 is =O; R2 is H or diethylaminoalkyl; R3-R7 is H; other variables in the formula (I) are given in the specific structural formulas of the described compounds. A pharmaceutical composition which contains thereof is also described.

EFFECT: compounds possess an anti-tumour activity and can be used for treatment of cancer, such as breast cancer, lung cancer, pancreas cancer, cancer of large intestine, and acute myeloid leukemia.

5 cl, 2 dwg, 6 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula R1 is H or (1-6C alkyl); R2 represents NRbRc, (1-4C)alkyl, (1-4C)fluoroalkyl, CF3, (1-4C)hydroxyalkyl, -(1-4Calkyl)hetAr1, -(1-4Calkyl)NH2, -(1-4C alkyl)NH(1-4Calkyl), -(1-4Calkyl)N(1-4Calkyl)2, hetAr2, hetCyc1, hetCyc2, phenyl substituted where applicable by NHSO2(1-4Calkyl) or (3-6C)cycloalkyl, substituted where applicable by (1-4C alkyl), CN, OH, OMe, NH2, NHMe, N(CH3)2, F, CF3, CO2(1-4C alkyl), CO2H; C(=O)NReRf or C(=O)ORg; Rb is H or (1-6C alkyl); Rc represents H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr3 or phenyl, wherein the above phenyl is substituted where applicable by one or more substitutes independently from halogen, CN, CF3 and -O(1-4C alkyl); Re represents H or (1-4C)alkyl; Rf represents H, (1-4C)alkyl or (3-6C)cycloalkyl; Rg represents H or (1-6C)alkyl; X is absent or represents -CH2-, -CH2CH2-, -CH2O- or -CH2NRd; Rd represents H or (1-4C alkyl); R3 represents H or (1-4C alkyl); and n is equal to 0-6. The radical values NRbRc, Y, hetAr1, hetAr2, hetAr3, hetCyc1, hetCyc2, NReRf, R4 are specified in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds, to a method of treating Trk kinase mediated diseases and conditions, such as pain, cancer, inflammation, neurodegenerative disease, Typanosoma cruzi infection, osteolytic disease, and to a method of preparing the above compounds.

EFFECT: invention refers to new derivatives of pyrazolo[1,5-a]pyrimidines possessing an inhibitory activity on tropomyosin-related kinases (Trk).

42 cl, 1 tbl, 105 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: given invention refers to a compound of formula its stereoisomers, including R and S isomers, wherein: 'A' represents N; Y and Y' represent O; '---' is absent; R1 and R2 are identical or different, and independently represent hydrogen or C1-12 alkyl; R3 represents hydrogen; R4 represents heteroaryl which can be optionally substituted in any acceptable position by one or more substitutes Ra; Z represents -(CH2)n-heteroaryl which can be optionally substituted in any acceptable position by one or more substitutes Ra; T, U, V and W are identical or different, and independently represent hydrogen or halogen; Ra is independently specified in hydrogen, halogen, C1-12 alkyl, C1-12 haloalkyl, -C(=Y)OR7, -(CH2)nYR7, each of which can be optionally substituted in any acceptable position by halogen; R7 represents hydrogen or C1-12 alkyl; m represents 1; m′ represents 0; n represents 1; wherein: the above heteroaryl is specified in 1,2,3-triazolyl, pyridinyl, 1-oxypyridinyl (pyridinyl-N-oxide), pyrazinyl, isoxazolyl, imidazo[1,2-α]pyrimidinyl, imidazo[1,2-α]pyrazinyl. The compounds of the given invention are applicable to prevent, relieve and/or treat bacterial infections in an individual. The bacterial infection is caused by the drug-resistant species Staphylococcus, Streptococcus, Enterococcus, Bacterioides, Clostridia, H. influenza, Moraxella, acid-resistant species like Mycobacterium tuberculosis, as well as linezolid-resistant species Staphylococcus and Enterococcus.

EFFECT: phenyloxazolidinone compounds as antimicrobial agents.

12 cl, 8 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I) or pharmaceutically acceptable salts thereof, where Alk is an C1-C6alkyl group; G is C=O and Q is CR51R52 or NR51, where R51 and R52, being identical or different, independently denote H, C1-C6alkyl, optionally substituted with a substitute selected from a group comprising carboxy, phenoxy, benzyloxy, C1-C6alkoxy or hydroxy; C3-C6cycloalkylC1-C6alkyl; phenylC1-C6alkyl, optionally substituted with a halogen; phenylamidoC1-C6alkyl; phenylC1-C6alkylamidoC1-C6alkyl, optionally substituted with a C1-C6alkoxy group; or R51 and R52, together with a carbon atom with which they are bonded form a C=O or C2-C6alkenyl group, optionally substituted with a phenyl; M1 is CR49, where R49 is H; M2 is CR50, where R50 is H; R38 is H, C1-C6alkyl, substituted with a phenoxy group; C3-C6cycloalkylC1-C6alkyl; arylC1-C6alkyl, optionally substituted with 1 or 2 substitutes selected from a group comprising C1-C6alkyl, C1-C6alkoxy, C1-C6alkoxycarbonyl, carboxyl, N-methylamido, hydroxy, C1-C6alkoxyC1-C6alkoxy, C1-C6alkylthio, C1-C6alkylsulphanyl, cyano, halogen, perfluoroC1-C6alkyl, nitro, formyl, hydroxyC1-C6alkyl and amino, wherein the aryl moiety is a phenyl or naphthyl; and heteroarylC1-C6alkyl, where the heteroaryl moiety is pyridinyl, optionally substituted with 1 or 2 groups selected from C1-C6alkoxy or hydroxyC1-C6alkyl, pyrazolyl or isoxazolyl, substitute with 1 or 2 C1-C6alkyl groups; R47 and R48 is C1-C6alkyl. The invention also relates to specific compounds, a method of reducing or weakening bitter taste, a composition of a food/non-food product or beverage or drug for reducing or lightening bitter taste and a method of producing a compound of formula (I).

EFFECT: obtaining novel compounds which are useful as bitter taste inhibitors or taste modulators.

37 cl, 6 dwg, 12 tbl, 186 ex

Organic compounds // 2518462

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

and

,

where X represents S or O, one of X1 and X2 represents CR3' and second represents N or independently CR3', n represents integer number 1, 2 or 3; R1 represents C1-6 halogenalkyl, R2 is selected from halogen and C1-C6-halogenalkyl; R3' represents H, C1-C6-alkyl, halogen, cyanogroup, or phenyl, non-substituted or substituted with halogen, C1-C6-alcoxygroup, C1-C6-halogenalcoxygroup, C1-C6-halogenalkyl group; Z represents halogen, Q radical or group -C(O)-NR5R6; R5 represents H or C1-C4-alkyl, R6 represents H; Q', C1-C6-alkyl, non-substituted or substituted with halogen, cyanogroup, C1-C4-alcoxygroup, C1-C4-alkoxycarbonyl, C2-C4-alkanoyl, aminocarbonyl, N-mono- or N,N-di-C1-C2-alkylaminocarbonyl, C1-C4-alkylthiogroup, group -C(O)NHR7 or radical Q"; or C3-C6-cycloalkyl, substituted with group -C(O)NHR7; or C2-C4-alkinyl; Q, Q' and Q" are such as given in the invention formula; R7 represents C1-C6-alkyl, which is non-substituted or substituted with halogen, cyanogroup, pyridyl; or represents C2-C4-alkinyl. Invention also relates to composition for fighting ectoparasites, containing compound of formula (Ia) or (Ib), and to application of compounds of formula (Ia) or (Ib) for composition production.

EFFECT: compounds of formula (Ia) and (Ib), possessing activity against ectoparasites.

11 cl, 4 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel indole and benzomorpholine derivatives of a formula (I) or its pharmaceutically acceptable salt, where R1 represents C1-6-alkyl or C1-3alkyl, substituted with C3-7cycloalkyl; R2 represents halogeno; R3 represents hydrogen; n equals 2, X represents -CH2CH2-O or -CH=CH-; Y represents -O- or -CR4(OH)-; R4 represents hydrogen or C1-3 alkyl. Invention also relates to a pharmaceutical composition based on formula (I) compound and a method of treatment or prevention of the said pathological states.

EFFECT: obtained are novel compounds, which are positive allosteric modulators of matabotropic subtype 2 receptors (mGluR2), which are useful for treatment or prevention of neurological and psychiatric disorders, associated with glutamate dysfunction, and diseases, involving metabotropic subtype 2 receptors GluR2.

22 cl, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein R1 represents an alkoxy group or halogen; each U and V independently represents CH or N; "----" means a bond or is absent; W represents CH or N, or if "----" is absent, then W represents CH2 or NH, provided not all U, V and W represent N; A represents a bond or CH2; R2 represents H, or provided A means CH2, then it also can represent OH; each m and n are independently equal to 0 or 1; D represents CH2 or a bond; G represents a phenyl group that is single or double substituted in meta- and/or para-position(s) by substitutes specified in alkyl, C1-3alkoxy group and halogen, or G represents one of the groups G1 and G2: wherein each Z1, Z2 and Z3 represents CH; and X represents N or CH and Q represents O or S; it should be noted that provided each m and n are equal to 0, then A represents CH2; or a pharmaceutically acceptable salt of such compound. Besides, the invention refers to a pharmaceutical composition for treating a bacterial infection containing an active ingredient presented by a compound of formula (I) or a pharmaceutically acceptable salt thereof, and at least one therapeutically inert additive.

EFFECT: preparing the oxazolidine compounds applicable for preparing a drug for treating and preventing the bacterial infections.

14 cl, 8 dwg, 2 tbl, 33 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinazolinone compounds of formula (I) and its pharmaceutically acceptable salts, wherein n is equal to 0 to 3, and R1 is defined as stated in the patent claim. The above compounds are prolyl hydroxylase inhibitors and can be used in pharmaceutical compositions and methods of treating pathological conditions, disorders and conditions mediated by prolyl hydroxylase activity.

EFFECT: compounds can be administered into the patient for treating, eg anaemia, vascular diseases, metabolic disorders, as well as for wound healing.

22 cl, 2 tbl, 211 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to isoindoline compounds, such as compounds of Formula or to their pharmaceutically acceptable salts or stereoisomers, wherein X represents CH2; Y represents O, cyanamido (N-C≡N) or amido (NH); m represents an integer of 0 or 1; R1 represents hydrogen or C1-6 alkyl; R2 represents hydrogen, C1-10 alkyl, C0-6alkyl-(5-10-merous heteroaryl containing one, two or three heteroatoms independently specified in O, S or N), C0-6alkyl-(6-merous heterocyclyl which represents morpholinyl or piperazinyl), C0-6alkyl-OH, -NHCO-C1-6alkyl, -OR21 or - (CH2-Z)-(6-merous heteroaryl which represents pyridinyl), wherein each heteroaryl and heterocyclyl is optionally substituted by one or more C1-6 alkyls; R3 represents hydrogen, halogen, -NO2, C0-6alkyl-OH, C0-4 alkyl-NH2 or -OR21; R21 represents phenyl, pyridinyl, piperidinyl or -CO(CH2)R22; R22 represents -NH2 or piperazinyl; and Z represents O; provided R1 represents hydrogen, then R2 is other than hydrogen or C1-10alkyl; provided R3 represents halogen, then R2 represents C0-6alkyl-(5-6-merous heterocyclyl). The invention also refers to pharmaceutical compositions for controlling angiogenesis or inhibiting the TNFα production on the basis of the above compounds.

EFFECT: there are prepared new compounds and compositions based thereon to be used in medicine for treating or preventing a disease or a disorder, such as cancer, pain skin diseases, lung disorders, parasitic diseases, immunodeficiency disorders, CNS disorders, CNS injuries, atherosclerosis or associated disorders, sleep disorders or associated disorders.

26 cl, 68 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel chromenone derivatives of formula II or its pharmaceutically acceptable salts, where each R20 is hydrogen; R11 is selected from phenyl and 5-6 member saturated or aromatic heterocycle, including one or two heteroatoms, selected from N, O or S, where R11 is optionally substituted with one-two substituents, independently selected from C1-C4alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from hydrogen and -C1-C4alkyl; or two R13 together with nitrogen atom, to which they are bound, form 5-6-member saturated heterocycle, optionally including one additional O, where, when R13 is alkyl, alkyl is optionally substituted with one or more substituents, selected from -OH, fluorine, and, when two R13 together with nitrogen atom, to which they are bound, form 6-member saturated heterocycle, saturated heterocycle is optionally substituted on each carbon atom with -C1-C4alkyl; R12 is selected from phenyl and pyridyl, where R12 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen; and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, - -S(=O)2-NH-†, where † stands for place, where X1 is bound with R11; and, when R14 is H; R12is phenyl; and X1 is - C(=O)-NH-†, then R11 is not 1H-pyrazol-3-yl, possessing stimulating activity.

EFFECT: invention relates to pharmaceutical composition based on said compounds, method of treating subject, suffering from or having resistance to insulin, metabolic syndrome or diabetes, as well as to method of increasing sensitivity to insulin.

16 cl, 1 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to piridazine derivatives of formula II

,

in which radicals and symbols have determinations, given in the invention formula, or to their pharmaceutically acceptable salts.

EFFECT: compounds of formula II demonstrate inhibiting effect with respect to proteinkinases such as c-met, ron, or ALK, or chimeric proteins, and can be useful for treatment of disorders, associated with abnormal activity of proteinkinases, such as cancer.

7 cl, 1 tbl, 30 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula or their pharmaceutically acceptable salts possessing the properties of a selective inhibitor of EML4-ALK hybrid protein kinase activity.

16 cl, 201 tbl, 582 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a specific list of various novel azaazulene compounds, which contain 6,5-condensed heterocycle of an indole type, benzimidazole type, purine type, 3H-imidaso[4,5-b]pyrene,3H-imidaso[4,5-c] pyridine, etc., which can be described by the general formula , where R1 is =O; R2 is H or diethylaminoalkyl; R3-R7 is H; other variables in the formula (I) are given in the specific structural formulas of the described compounds. A pharmaceutical composition which contains thereof is also described.

EFFECT: compounds possess an anti-tumour activity and can be used for treatment of cancer, such as breast cancer, lung cancer, pancreas cancer, cancer of large intestine, and acute myeloid leukemia.

5 cl, 2 dwg, 6 tbl, 14 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel alkyl [2-(2-{5-[4-(4-{2-[1-(2-methoxycarbonylamino-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-buta-1,3-diinyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamates or their naphthalene-1,5-disulfonates, which possess properties of NS5A protein inhibitor and can be used for prevention and treatment of viral diseases, caused by viruses of hepatitis C (HCV) and hepatitis GBV-C. In claimed invention compounds, corresponding to general formula 1 R1, R2, R3 and R4 independently on each other stand for C1-C3 alkyl; R5 and R6 independently on each other stand for C1-C3alkyloxymethyl, or R3, and R5, and R4, and R6, together with carbon atoms, which they are bound with, independently on each other form tetrahydrofurane cycle.

EFFECT: improved propertied of compounds.

7 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel compound of formula (1) or its pharmaceutically acceptable salt, possessing SNS inhibiting properties. In general formula R1 represents (1) hydrogen atom, (2) halogen atom, (3) C1-6alkyl group or (4) C1-6halogenalkyl group (whereR1 can be present in any substitutable position of benzene or pyridine ring); L represents (1) simple bond, (2) -O- or (3) -CH2O- (where L can be present in position 5 or 6 of condensed cycle); R2 represents (1) C6-10aryl group (C6-10aryl group is optionally condensed with C3-6cycloalkane), optionally substituted with substituent(s), X represents carbon atom or nitrogen atom. Other values of radicals are given in the invention formula.

EFFECT: obtaining compounds which can be used to prepare medication for treatment or prevention of such diseases as neuropathic pain, nociceptive pain, dysuria, disseminated sclerosis, etc.

19 cl, 47 tbl, 237 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) , where A is a 6-member heteroaryl, having 1 nitrogen atom as a heteroatom, substituted with 2-3 substitutes such as indicated in the claim, R5 is a halogen atom, cyano or C1-C6alkyl, optionally substituted with a halogen atom; R6 is C1-C6 alkyl, optionally substituted with OH; C1-C3 alkenyl; a 5-member heteroaryl, having 2-4 heteroatoms, each independently selected from N, O or S, substituted with 0-2 substitutes such as indicated in the claim, R10 is a 5-member heteroaryl, having 2-3 heteroatoms, each selected from N, O or S, substituted with 0-2 substitutes, which are C1-C3 alkyl; R7, R8, R17 denote a hydrogen or halogen atom. The invention also relates to a pharmaceutical composition, having BK B2 receptor inhibiting activity, which contains compounds of formula (I), a method of inhibiting, a method of localising or detecting the BK B2 receptor in tissue, use of the compounds of compositions to produce a medicinal agent and methods for treatment.

EFFECT: compounds of formula (I) as BK B2 receptor inhibitors.

22 cl, 1 tbl, 54 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

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