Pyrazolpyrimidine compounds jak inhibitors and methods

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel compounds of formula Ia, their stereoisomers or pharmaceutically acceptable salts, inhibiting JAK kinase activity. Compounds can be applied in treatment of inflammatory diseases, such as rheumatoid arthritis, psoriasis, contact dermatitis, in treatment of autoimmune diseases, such as lupus, multiple sclerosis, neurodegenerative diseases, such as Alzheimer's disease, etc. In formula Ia R1 represents H; R2 represents -OR4, -NR3R4- or -NR3S(O)2R4; R3 represents H or C1-C6alkyl, where said alkyl is optionally substituted with ORa; R4 represents H, C1-C6alkyl, -(C0-C5alkyl)(C3-C6cycloalkyl), -(C0-C5alkyl)(C4-C5heteroaryl), where heteroaryl contains 1-2 nitrogen atoms as heteroatoms, or -(C0-C5alkyl)(C6aryl), where said alkyl is optionally substituted with group R8 and said aryl, cycloalkyl and heteroaryl are optionally substituted with group R9; or R3 and R4, taken together with nitrogen atom, which they are bound to, form C3heterocyclyl, containing 1 nitrogen atom as heteroatom, optionally substituted with group R13; Z represents -NR5R6; R5 represents H; R6 represents H, C1-C10alkyl, -(C0-C5alkyl)(C4-C5heterocyclyl), where heterocyclyl contains oxygen atom as heteroatom, -(C0-C5alkyl)(C3-C8cycloalkyl), -(C0-C5alkyl)(C3-C5heteroaryl), where heteroaryl contains 1 nitrogen atom or 1 oxygen atom or contains 2 atoms, selected fromoxygen, nitrogen and sulphur, as heteroatoms, -(C0-C5alkyl)(C6aryl), where said alkyl is optionally substituted with group R10, and said aryl, cycloalkyl, heteroaryl and heterocyclyl are optionally substituted with group R11; R7 represents H; R8 and R10 each independently represents halogen or ORa; R9 independently represents -CN, -CF3, halogen, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa, -(C0-C5alkyl)SRa, -O[C(Ra)2]1-3O-, C1-C3alkyl, optionally substituted with F, -(C0-C5alkyl)(C3-C6cycloalkyl), optionally substituted with group oxo or F, -(C0-C5alkyl)C3-C6heterocyclyl, where heterocyclyl contains 1-2 heteroatoms, selected from atoms of oxygen and nitrogen, and where heterocyclyl is optionally substituted with halogen or C1-C3alkyl, -(C0-C5alkyl)C6aryl, optionally substituted with halogen, or -(C0-C5alkyl)C4-C5heteroaryl, where heteroaryl contains 1 nitrogen atom or 1 oxygen atom or contains 2 atoms, selected from atom of oxygen, nitrogen and sulphur as heteroatoms, and where heteroaryl is optionally substituted with or C1-C3alkyl; R10 independently represents halogen or ORa. Other values of radicals are given in the invention formula.

EFFECT: obtaining pharmaceutically acceptable salts, inhibiting JAK kinase activity.

15 cl, 4 tbl, 452 ex

 

The technical field to which the invention relates

Pyrazolopyrimidine compounds, inhibitors of JAK kinases, as well as compositions containing such compounds, and methods of theirapplications, including, but not limited to,in vitro,in situandin vivodiagnosis or treatment of mammalian cells.

Background of the invention

Cytokine pathway mediates a wide range of biological functions, including many aspects of inflammation and immunity. Janus kinase (JAK), including JAK1, JAK2, JAK3 and TYK2, are cytoplasmic protein kinase, which is associated with cytokine receptore type I and type II and regulate signal transduction of cytokines. The binding of cytokines with cognate receptors triggers activation of related receptors, JAKs, and this leads to JAK-mediated tyrosine phosphorylation of proteins of the signal transductor and activator of transcription (STAT) and, ultimately, to the transcriptional activation of specific sets of genes (Schindler et al., 2007, J Biol. Chem. 282:20059-63). JAK1, JAK2 and TYK2 demonstrate a wide variety of gene expression, whereas the expression of JAK3 is limited to leukocytes. Receptors of cytokinesare typically functional in the form of heterodimers, and as a result, more than one type of JAK kinases is usually associated with complexes of cytokine receptors. Specific JAKs associated with different sets of cytokine receptors, have been identified in many cases through genetic studies and confirmed by other experimental data.

JAK1 was originally identified in the screening analysis for new kinase (Wilks, A. F., 1989, Proc. Natl. Acad. Sci. U. S. A. 86:1603-1607). Genetic and biochemical studies showed that JAK1 is functionally and physically associated with complexes of receptors interferon type I (for example, IFN), interferon type II (e.g., IFN), IL-2 and IL-6 cytokine(Kisseleva et al., 2002, gene 285:1-24; Levy et al., 2005, Nat. Rev. Mol. Cell Biol. 3:651-662; O'shea et al., 2002, Cell, 109 (suppl):S121-S131). Mouse JAK1-“knockout”die perinatal due to the defect signal LIF receptor (Kisseleva et al., 2002, gene 285:1-24; O'shea et al., 2002, Cell, 109 (suppl.):S121-S131). Analysis of tissues obtained from mice with JAK1-Ko”,has demonstrated the critical role of these kinases in IFN, IL-10, IL-2/IL-4 and IL-6 pathways. Humanitariannet monoclonal antibody whose target is IL-6 way (Tocilizumab), recently approved by the European Commission for the treatment of rheumatoid arthritis moderate to severe forms of(Scheinecker et al., 2009, Nat. Rev. Drug Discov. 8:273-274).

Myeloproliferative disorders (MPD) originate from hematopoietic stem cells and initially manifested in elevated levels mostly normal cells of the myeloid lineage. Can be made a basic distinction between Philadelphia chromosome-positive (Ph+) and Philadelpia chromosome-negative (Ph-) disorders. Ph+ MPD leads to chronic myelogenous leukemia and is driven by bcr-abl hybrid protein that controls proliferation of hematopoietic cells. Ph-MPD can be further divided into three distinct disorders on the appropriate varieties, namely, the true polycythemia (PV), essential trombozitemia (ET) and idiopathic myelofibrosis (IMF). Dameshek, W., Blood 6(4):372-375 (1951). Patients with PV suffer from a large number of erythrocytes, whereas patients with ET have high levels of circulating platelets. If left untreated, both diseases can lead to life-threatening thrombotic events. Patients with IMF suffer from fibrosis of the bone marrow with subsequent offset hematopoiesis in the spleen and liver. This primarily leads to splenomegaly, with subsequent anemia in the later stages of this disease, because hematomas becomes unproductive. These patients have a poor prognosis, although under certain conditions they can be cured with allogeneic bone marrow transplant. There is no known cure for Ph-MPD diseases.

Activating mutation in tyrosinemia the kinase JAK2 is associated with PV, ET, IMF and other diseases. Almost all patients with PV and approximately 50% of patients with ET and IMF have this mutation. Morgan, K. J. and Gilliland, D. G., Ann. Rev. Med. 59:213-222 (2008). This mutation is a substitution of valine FeNi is the alanine at position 617 in Mature human JAK2 protein (V617F). Additional mutations in JAK2, usually present in the exon 12 and called exon 12 mutations also have an activating effect and can lead to MPD. In addition, T875N mutation associated with megakaryoblastic leukemia. Finally, JAK2 hybrid proteins were identified in acute leukemia.

V617F mutation has functions activation of JAK2, which leads to MPD. In the non-mutated form, JAK2 is associated with cytokine receptors (i.e., EPO-R, TPO-R and others) and becomes activated only when the receptor is activated by stimulation of the related cytokine ligand. Hematomas in General then regulated through the presence of ligands. For example, the cytokine erythropoietin (EPO) stimulates hematopoietic precursor cells, leading to the formation of red blood cells. The mutation, which divides JAK2 activation from EPO, therefore, leads to increased levels of red blood cells. Similarly, thrombopoetin (TPO) regulates the growth of platelets by binding to TPO-R, which, in turn, transmits a signal through JAK2. Thus, elevated levels of platelets can also be the result of aberrant activation of JAK2.

The necessary compounds that inhibit JAK2, which could be beneficial for patients with JAK2-driven myeloproliferative disorders, and other diseases, which is responsive to inhibition of JAK2. Such diseases include diseases in which JAK2 is activated by mutation or amplification, as well as diseases in which activation of JAK2 is part of oncogenic cascade. Many different lines of tumor cells and tumor samples have high levels of phospho-STAT3, which is a gene target for JAK2.

JAK3 is associated exclusively with the gamma chain shared cytokine receptor, which is present in theIL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 complexes of cytokine receptors. JAK3 is critical for the development and proliferation of lymphoid cells, and mutations in JAK3 result in severe combined immunodeficiency (SCID) (O'shea et al, 2002, Cell, 109 (suppl):S121-S131). On the basis of its role in the regulation of lymphocytes, JAK3 and JAK3-mediated pathways are targeted in immunosuppressive conditions (e.g., graft rejection and rheumatoid arthritis) (Baslund et al., 2005, Arthritis & Rheumatism 52:2686-2692; Changelian et al., 2003, Science 302:875-878).

TYK2 is associated with complexes of cytokine receptors interferon type I (for example, IFN), IL-6, IL-10, IL-12 and IL-23 (Kisseleva et al., 2002, Gene 285:1-24; Watford, W. T. & O'shea, J. J., 2006, Immunity 25:695-697). Accordingly, primary cells isolated from human deficit TYK2, are defective in regard to the signaling of interferon type I, IL-6, IL-10, IL-12 and IL-23. Fully human monoclonal antibody targeted to the which is the common p40 subunit of IL-12 and IL-23 cytokines (Ustekinumab), it was recently approved by the European Commission for the treatment of moderate to severe plaque-like psoriasis (Krueger et al., 2007, N. Engl. J. Med. 356:580-92; Reich et al., 2009, Nat. Rev. Drug Discov. 8:355-356). In addition, the antibody attack directed at IL-12 and IL-23 pathway is under clinical trials for the treatment of Crohn's disease (Mannon et al., 2004, N. Engl. J. Med. 351:2069-79).

The invention

One implementation includes a compound of the formula I:

its enantiomers, diastereomers or pharmaceutically acceptable salts, where R1, R2, R7and Z have the meanings given in this application.

One implementation includes a compound of the formula I:

its enantiomers, diastereomers or pharmaceutically acceptable salts, where R1, R2and Z have the meanings given in this application.

Another variant implementation includes a pharmaceutical composition that includes a compound of formula Ia and a pharmaceutically acceptable carrier, adjuvant or excipient.

Another variant implementation includes a pharmaceutical composition that includes a compound of formula I and pharmaceutically acceptable carrier, adjuvant or excipient.

Another variant implementation includes a method of treating or reducing the severity of the disease or SOS is sustainability, responsive to the inhibition of the activity of the JAK kinase in a patient, comprising the administration to a patient a therapeutically effectivethe amount of compounds of formula Ia.

Another variant implementation includes a method of treating or reducing the severity of the disease or condition responsive to the inhibition of the activity of the JAK kinase activity in a patient. The method comprises the administration to a patient a therapeutically effectivethe amount of compounds of formula I.

Another variant implementation includes a kit for treatment of a disease or disorder responsive to inhibition of JAK kinases. The kit includes a first pharmaceutical composition comprising a compound of formula I, and instructions for use. In another embodiment, the kit includes a first pharmaceutical composition comprising a compound of formula Ia, and instructions for use.

Detailed description of the invention

Next is the detailed reference to some embodiments of, and examples of which are illustrated in the accompanying structures and formulas. Although the present invention will be described in connection with various types of exercise, it is assumed that the present invention covers all alternatives, modifications and equivalents that may be included in the scope of the present invention defined by the claims. When ecialists in this area should be well-known methods and substances similar or equivalent to those described in the present application, which could be used in the practical implementation of the present invention.

The term "alkyl" refers to saturated linear or branched monovalent hydrocarbon radical, this alkyl radical optionally may be substituted independently by one or more substituents described in this application. In one example, the alkyl radical comprises from one to eighteen carbon atoms (C1-C18). In other examples, the alkyl radical is a C0-C6C0-C5C0-C3C1-C12C1-C1OC1-C8C1-C6C1-C5C1-C4or C1-C3. Examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, isopropyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, isobutyl, -CH2CH(CH3)2), 2-butyl (s-Bu, sec-butyl, -CH(CH3)CH2CH3), 2-methyl-2-propyl (t-Bu, tert-butyl, -C(CH3)3), 1 pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), Methyl-2-butyl (-C(CH 3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH(CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3, 1-heptyl and 1-octyl.

The term "alkenyl" refers to a linear or branched monovalent hydrocarbon radical, at least one site of unsaturation, i.e. a carbon-carbon double bond, with alkanniny radical optionally may be substituted independently by one or more substituents described in this application, and includes radicals having "CIS" and "TRANS" orientations, or alternatively, "E" and "Z" orientations. In one example, alkanniny radical contains from two to eighteen carbon atoms (C2-C18). the other examples alkanniny radical represents a C2-C12C2-C1OC2-C8C2-C6or C2-C3. Examples include, but are not limited to, ethynyl or vinyl (-CH=CH2), prop-1-enyl (-CH=CHCH3), prop-2-enyl (-CH2CH=CH2), 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, buta-1,3-dienyl, 2-methylbuta-1,3-diene, Gex-1-enyl, Gex-2-enyl, Gex-3-enyl, Gex-4-enyl and Gex-1,3-dienyl.

The term "quinil" refers to a linear or branched monovalent hydrocarbon radical, at least one site of unsaturation, i.e. a carbon-carbon triple bond, while alkynylaryl radical optionally may be substituted independently by one or more substituents described in this application. In one example, alkynylaryl radical contains from two to eighteen carbon atoms (C2-C18). In other examples, alkynylaryl radical represents a C2-C12C2-C10C2-C8C2-C6or C2-C3. Examples include, but are not limited to, ethinyl (-C≡CH), prop-1-inyl (-C≡CCH3), prop-2-inyl (propargyl, -CH2C≡CH), buta-1-inyl, but-2-inyl and but-3-inyl.

"Cycloalkyl" refers to non-aromatic saturated or partially unsaturated hydrocarbon ring group, while cycloalkyl group is a, optional, may be substituted independently by one or more substituents described in this application. In one example cycloalkyl group contains from 3 to 12 carbon atoms (C3-C12). In other examples, cycloalkyl represents a C3-C8C3-C1Oor C5-C10. In other examples, cycloalkyl group, as a monocycle, represents a C3-C9C3-C6or C5-C6. In another example, cycloalkyl group, as Bicycle represents a C7-C12. In another example, cycloalkyl group, as spinosissima represents a C5-C12. Examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cycloneii, cyclodecyl, cyclodecyl and cyclododecyl. Illustrative structure of a bicyclic cycloalkyl containing from 7 to 12 ring atoms include, but are not limited to, [4,4], [4,5], [5,5], [5,6] or [6,6] ring system. Illustrative examples of related bridge connection bicyclic cycloalkyl include, but are not limited to, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonan. Por the measures of spirocyclohexane include, Spiro[2.2]pentane, Spiro[2.3]hexane, Spiro[2.4]heptane, Spiro[2.5]octane, Spiro[4.5]decane.

"Aryl" refers to cyclic aromatic hydrocarbon group, optionally substituted independently by one or more substituents described in this application. In one example, the aryl group includes6-20 carbon atoms (C6-C20). In another example, the aryl group represents a C6-C10. In another example, the aryl group represents a C6-C9. In another example, the aryl group represents a C6aryl group. Aryl includes bicyclic groups containing an aromatic ring condensed non-aromatic or partially saturated ring. Bicyclic aryl group may be attached via an aromatic, non-aromatic or partially saturated ring, for example, as shown below:

Examples of aryl groups include, but are not limited to, phenyl, naphthalenyl, anthracene, indenyl, indanyl, 1,2-dihydronaphthalene and 1,2,3,4-tetrahydronaphthyl. In one example, aryl includes phenyl.

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

"Heterocyclyl" refers to a saturated, partially unsaturated (i.e., containing one or more double and/or triple bonds in the ring) or aromatic (heteroaryl) cyclic GRU is PHE, in which at least one ring atom is a heteroatom independently selected from nitrogen, oxygen, phosphorus and sulfur, the remaining ring atoms are carbon atoms. Heterocyclyl group optionally may be substituted by one or more substituents described below. In one embodiment, heterocyclyl includes monocyclic or Bicycle containing from 1 to 9 carbon ring atoms (C1-C9), with the remaining ring atoms are heteroatoms selected from N, O, S and P. In other examples heterocyclyl includes monocyclic or Bicycle containing C1-C5C3-C5C3-C9or C4-C5, with the remaining ring atoms are heteroatoms selected from N, O, S and P. In another embodiment, heterocyclyl includes monocyclic 3-, 4-, 5-, 6- and 7-membered rings containing one or more heteroatoms, independently selected from N, O and S, with remaining ring atoms are carbon atoms. In another embodiment, heterocyclyl includes monocyclic 5-, 6 - and 7-membered rings, containingone or more heteroatoms, independently selected from N, O, S or P. Examples of bicyclic systems include, but are not limited to, [3,5], [4,5], [5,5], [3,6], [4,6], [5,6], Il is [6,6] system. In another embodiment, heterocyclyl includes the associated bridge connection ring system having[2.2.1], [2.2.2], [3.2.2] and [4.1.0] structure and containing from 1 to 3 heteroatoms selected from N, O, S and P. In another embodiment, heterocyclyl includes spirography containing from 1 to 3 heteroatoms selected from N, O, S and P. Heterocyclyl group may be related to carbon group or linked by a heteroatom group. "Heterocyclyl includes heterocyclyl group condensed with cycloalkyl. "Heterocyclyl also includes heterocyclyl group condensed with aryl or heteroaryl group. Additional examples heterocyclyl groups include 2,3-dihydrobenzofuranyl, octahydrophenanthrene, 1,3-dihydroisobenzofuran, bromanil, isopropanol, thiochroman, istikrari, 2,3-dihydrobenzo[b]thiophene, 2,3-dihydrobenzo[b]thiophene 1,1-dioxide, 1,3-dihydrobenzo[c]thiophene, 1,3-dihydrobenzo[c]thiophene 2,2-dioxide, isoindolines, indolinyl and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.

Illustrative heterocyclyl groups include, but are not limited to, oxiranyl, aziridinyl, thiiranes, azetidine, oxetane, titanyl, 1,2-dithietane, 1,3-dithietane, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholine, dioxane, piperazinil, homopiperazine, homopiperazine, oxetanyl, tepanil, oxazepines, dia is Epinal, thiazepines, dehydration, dihydropyran, dihydrofuran, tetrahydrofuranyl, tetrahydrothieno, tetrahydrothieno 1,1-dioxide, tetrahydrothieno 1-oxide, tetrahydropyranyl, tetrahydropyranyl, 1-pyrrolidyl, 2-pyrrolyl, 3-pyrrolyl, indolyl, 2H-pyranyl, 4H-pyranyl, dioxanes, 1,3-DIOXOLANYL, pyrazolines, pyrazolidine, dithienyl, dithiolane, pyrazolopyrimidines, imidazolidinyl, 3-azabicyclo[3.1.0]hexenyl, 3-azabicyclo[4.1.0]heptanes and azabicyclo[2.2.2]hexanal. Examples heterocyclyl group, where the ring atom is substituted by an oxo (=O) are pyrimidinones and 1,1-dioxo-thiomorpholine. Heterocyclyl group in the present application is optionally substituted independently by one or more substituents described in this application. Heterocyclesdescribed in Paquette, Leo A.; "Principles of Modern Heterocyclic Chemistry" (W. A. Benjamin, New York, 1968), particularly chapters 1, 3, 4, 6, 7, and 9; "The Chemistry of Heterocyclic Compounds, A series of Monographs" (John Wiley & Sons, New York, 1950 to present), in particular volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82:5566.

The term "heteroaryl" refers to an aromatic carbocyclic the radical, in which at least one ring atom is a heteroatom independently selected from nitrogen, oxygen and sulfur, the remaining ring atoms are carbon atoms. Heteroaryl group optionally can be substituted one or bore alkemi substituents, described in this application. In one example, the heteroaryl group contains 1 to 9 carbon ring atoms (C1-C9). In other examples, the heteroaryl group represents a C1-C5C3-C5or C4-C5. In one embodiment, illustrative heteroaryl groups include monocyclic aromatic 5-, 6 - and 7-membered rings, containingone or more heteroatoms independently selected from nitrogen, oxygen and sulfur. In another illustrative embodiment, the heteroaryl group include a condensed ring system comprising up to 9 carbon atoms, where at least one aromatic ring contains one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. "Heteroaryl" includes heteroaryl group is fused with aryl, cycloalkyl or other heterocyclyl group. Examples of heteroaryl groups include, but are not limited to, pyridinyl, imidazolyl, imidazopyridines, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolin, pyrrolyl, chinoline, ethenolysis, indolyl, benzimidazolyl, benzofuranyl, indolinyl, indazoles, indolizinyl, phthalazine, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinol, OK is diazoles, triazolyl, thiadiazolyl, furutani, benzofurazanyl, benzothiophene, benzothiazole, benzoxazole, hintline, honokalani, naphthyridines and properidine.

In some embodiments, implementation, heterocyclyl or heteroaryl group is C-connected. As an example, and not limitations on carbon heterocyclyl include communicating patternsin position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5 or 6 pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2, 3, 5 or 6 pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4 or 5 oxazole, imidazole or thiazole, position 3, 4 or 5 isoxazol, pyrazole or isothiazole, position 2 or 3 of aziridine, position 2, 3 or 4 azetidine, position 2, 3, 4, 5, 6, 7 or 8 of a quinoline or position 1, 3, 4, 5, 6, 7 or 8 of isoquinoline. (2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl).

In some embodiments, implementation, heterocyclyl or heteroaryl group is N-connected. As an example, and not limitation, associated nitrogen heterocyclyl or heteroaryl group includes communicating patternsin position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-piraso the ina, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of a isoindole, or isoindoline, position 4 of the research and position 9 carbazole or β-carboline.

"Treat" and "treatment" includes both therapeutic treatment and prophylactic or preventative measures, where the aim is to prevent or slow down (decrease undesired physiological change or disorder, such as the development or spread of cancer. For the purposes of this invention, beneficial or desired clinical results include, but are not limited to, alleviating symptoms, reducing the extent of disease, stabilized (i.e. not worsening) state of disease, delay or slowing of disease progression, relief or temporary relief of painful conditions and remission (partial or complete), regardless of whether they are defined or undefined. "Treatment" can also mean prolonging survival period compared with the expected survival period, if you do not take treatment. Those in need of treatment include those who already have the condition or disorder, as well as those who are predisposed to the development of this condition or disorder (for example, through genetic mutation), or those which should prevent this condition or Rastro the STV.

The phrase "therapeutically effective amount" means such amount of the compounds of the present invention that (i) treats or prevents the particular disease, condition, or disorder, (ii) makes, reduces, or eliminates one or more symptoms of the particular disease, condition or disorder, or (iii) prevents or slows down the occurrence of one or more symptoms of the particular disease, condition or disorder described in the present application. In one embodiment, therapeutically effective amount is an amount sufficient to reduce or alleviate symptoms of the disorders that respond to modulation of JAK2 kinase. In the case of cancer, a therapeutically effective quantity of a drug can reduce the number of cancer cells; reduce the tumor size; inhibit (i.e., slow to some extent and preferably stop) infiltration of cancer cells into peripheral organs; inhibit (i.e., slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, tumor growth; and/or relieve to some extent one or more symptoms associated with cancer. To the extent that the drug can prevent ro is t and/or kill existing cancer cells, it may be cytostatic and/or cytotoxic. For cancer therapy, efficacy can be measured, for example, by determining the time to disease progression (TTP) and/or determine the speed of response (RR). In one embodiment, therapeutically effective amount is an amount sufficient to reduce or alleviate symptoms of the disorders that respond to modulation of TYK2 JAK1 or JAK3 kinase. In the case of immunological disorders, a therapeutically effective amount is an amount sufficient to reduce or alleviate allergic disorders, symptoms of autoimmune and/or inflammatory diseases or symptoms of acute inflammatory responses (e.g., asthma). In some embodiments, implementation, therapeutically effectivethe number represents the number of chemical structures described in this application, sufficient to substantially reduce the activity or the number of B-cells.

The term "inhibition" indicates a significant decrease in baseline biological activity or process. "Inhibition of the activity of the JAK kinase" refers to the reduction in the activity of JAK1, JAK2, JAK3 or TYK2 kinase in response to the presence of at least one chemical structure described in this application, compared with the activity of JAK1, JAK2, JAK3 or TYK2 kinase in the absence of at least one chemical structure. The inhibition activity of the JAK kinase also refers to the observed inhibition of the activity of the JAK kinase in the biochemical analysis determination of activity of JAK kinases, such as the assays described in this application.

The term "bioavailability" refers to the system availability (i.e., levels in the blood/plasma) given the number of drugs introduced to the patient. Bioavailability is an absolute term that specifies the dimension of time (speed), and the total number (level) of the drug that reaches the General flow of the injected dosage forms.

The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals thattypically characterized by unregulated cell growth. "Tumor" includes one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid tumors. More particular examples of such cancers include this form may cell cancer (e.g. epithelial this form may cell cancer), lung cancer including small cell lung cancer, non-small cell lung cancer (“NSCLC”), adenocarcinoma of the lung and squamous carcinoma of the lung, cancer of the abdominal Palast is, hepatocellular cancer, gastric cancer, or stomach cancer including gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, rectal cancer, colorectal cancer, carcinoma of the endometrium or uterine carcinoma of the salivary gland, kidney cancer or renal cancer, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, anal carcinoma, carcinoma of the penis and head and neck cancer.

"Chemotherapeutic agent" is a chemical compound useful for the treatment of cancer. Examples of chemotherapeutic agents include Erlotinib (TARCEVA®, Genentech, Inc/OSI Pharm.), Trastuzumab (HERCEPTIN®, Genentech, Inc.); bevacizumab (AVASTIN®, Genentech, Inc.); Rituximab (RITUXAN®, Genentech, Inc./Biogen Idee, Inc.), Bortezomib (VELCADE®Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novartis), Imatinib mesilate (GLEEVEC®, Novartis), PTK787/ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fu), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (GSK572016, Glaxo Smith Kline), Lonafarnib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs) and Gefitinib (IRESSA®, AstraZeneca), AG1478 effect, AG1571 (SU 5271; Sugen), alkylating agents such as thiotepa and CYTOXAN®cyclosphosphamide; alkyl sulphonates such as b is Sultan, improsulfan and piposulfan; aziridines, such as benzodepa, carboquone, matureup and uredepa; ethylenimines and methylmelamine, including altretamin, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide and trimethylaniline; acetogenin (in particular, bullatacin, bullatacin);camptothecin (including the synthetic analogue topotecan); bryostatin; callistemon; CC-1065 (including its synthetic analogues of adozelesin, carzelesin and bizelesin); cryptophycin (in particular, cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including the synthetic analogues, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyin; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, halophosphate, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novemberin, finestein, prednimustine, trofosfamide, braziliera; micromachine, such as carmustine, chlorozotocin, fotemustine, lomustin, nimustine and ranimustine; antibiotics such as enediyne antibiotics (for example, calicheamicin, in particular, calicheamicin gamma and calicheamicin omegaI1 (Angew Chem. Intl. Ed. Engl. (1994) 33:183-186); dynemicin, including dynemicin A; bisphosphonates, such as clodronate; spiramycin; and neocarzinostatin chromophore and related chromoprotein-enediyne antibiotic chromophores), aclacinomycin, actinomycin, autralian, AZ is serine, bleomycin, actinomycin, carubicin, karminomitsin, calcination, chromomycosis, dactinomycin, daunorubicin, demoralizing, 6-diazo-5-oxo-1-norleucine, ADRIAMYCIN®(doxorubicin), morpholino doxorubicin, cyanomethane doxorubicin, 2-pyrroline doxorubicin and deoxidation), epirubicin, zorubicin, idarubitsin, marsellaise, mitomycin, such as mitomycin C, mycophenolate acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, colomycin, radiobeacon, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such as methotrexate and 5-fluorouracil (5-FU); analogs of folic acid, such as deeperin, methotrexate, peripherin, trimetrexate; purine analogues, such as fludarabine, 6-mercaptopurine, timipre, tioguanin; pyrimidine analogs, such as ancitabine, azacytidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenal tools such as aminoglutetimid, mitotane, trilostane; means supplying the deficiency of folic acid, such as Malinova acid; Eagleton; aldophosphamide glycoside; aminolevulinic acid; eniluracil; amsacrine; astroball; bisantrene; edatrexate; Def is Famin; demecolcine; diazinon; alternity; elliptinium acetate; epothilone; etoposide; gallium nitrate; hydroxyurea; lentinan; londini; maytansinoid, such as maytansine and ansamitocins; mitoguazone; mitoxantrone; mopidamol; nitrean; pentostatin; penomet; pirarubicin; losoxantrone; podophyllin acid; 2-acylhydrazides; procarbazine; PSK®polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofiran; spirogermanium; tenuazonic acid; triaziquone; 2,2',2"-trihlortrietilamin; trichothecenes (in particular, T-2 toxin, verrucarin a, roridin a and unguided); urethane; vindesine; dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; Galitsin; arabinoside ("Ara-C"); cyclophosphamide; thiotepa; taxoid, for example, TAXOL®(paclitaxel; Bristol-Myers Squibb Oncology, Princeton, N. J.), ABRAXANE®(without Cremophor), obtained by engineering means, based on the albumin composition of nanoparticles of paclitaxel (American Pharmaceutical Partners, Schaumberg, Illinois), and TAXOTERE®(docetaxel; Rhόne-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR®(gemcitabine); 6-tioguanin; mercaptopurine; methotrexate; platinum analogues, such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINE®(vinorelbine); Novantrone; teniposide; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; CPT-11; topoisomerase inhibitor RFS 200; deformational (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids and derivatives of any of the above.

Also included in the definition of "chemotherapeutic agent" are:(i) anti-hormonal drugs that act as regulate or inhibit hormone action on tumors such as anti-estrogens and selective modulators of estrogen receptors (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone and FARESTON®(toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulates the production of estrogen in the adrenal glands, such as, for example, 4(5)-imidazoles, aminoglutetimid, MEGASE®(megestrol acetate), AROMASIN®(exemestane; Pfizer), formestane, fadrozole, RIVISOR®(vorozole), FEMARA®(letrozole; Novartis), and ARIMIDEX®(anastrozole; AstraZeneca); (iii) anti-adrogen, such as flutamide, nilutamide, bicalutamide, leuprolide, goserelin; and troxacitabine (1,3-dioxolane nucleoside analogue of cytosine); (iv) inhibitors of protein kinases; (v) inhibitors of the lipid kinase; (vi) antisense oligonucleotides, particularly those which inhibit expression of genes in the signal path is, involved in aberrant cell proliferation, such as, for example, PKC-alpha, Raf and H-Ras; (vii) ribozymes such as VEGF inhibitors (e.g., ANGIOZYME®), and (viii) vaccines such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®and WAXED®; PROLEUKIN®rIL-2; topoisomerase inhibitor 1, such as LURTOTECAN®; ABARELIX®rmRH; (ix) anti-angiogenic funds; and (x) pharmaceutically acceptable salts, acids and derivatives of any of the above.

Additional chemotherapeutic agents include therapeutic antibodies, such as alemtuzumab (Campath), cetuximab (ERBITUX®, Imclone), panitumumab (VECTIBIX®, Amgen), pertuzumab (OMNITARG®, 2C4, Genentech), tositumomab (Bexxar, Corixia) and conjugate antibodies and drugs, gemtuzumab ozogamicin (MYLOTARG®, Wyeth). Additional humanized monoclonal antibody with therapeutic potential as tools in combination with the compounds of the present invention include: apolizumab, utilityman, talisuna, bapineuzumab, belarusemb martensen, cantuzumab mertansine, adeliza, certolizumab pegol, cefoperazone, cytosomes, daclizumab, eculizumab, efalizumab, epratuzumab, arizuma, felizola, fontolizumab, gemtuzumab ozogamicin, inotuzumab ozogamicin, ipilimumab is, labetuzumab, lintuzumab, matuzumab, mapalitan is b, motavizumab, motavizumab, natalizumab, nimotuzumab, nolasisana, numvisuals, ocrelizumab, omalizumab, palivizumab, pascolizumab, pectusinum, pertuzumab, pexelizumab, palivizumab, ranibizumab, religiosum, reslizumab, reisevisum, rovelizumab, replisome, subrotunda, siplizumab, lintuzumab, tigatuzumab tetraxetan, ladiesman, talisman, tefibazumab, tocilizumab, torulosum, tokotoukan celmoleukin, tukuitonga, omalizumab, uroxatral, ustekinumab, visilizumab and anti-interleukin-12 (ABT-874/J695, Wyeth Research and Abbott Laboratories), which is a recombinant, with exclusively human sequence, the full-size IgG1λ antibody, a genetically modified to recognize the protein interleukin-12 p40.

The term "prodrug", as used in this application refers to the form of a precursor or derivative pharmaceutically active substance that is less effective for the patient or cytotoxic to tumor cells compared to the original drug and are capable of enzymatically or hydrolytically activated or converted into the more active its original form. See, for example, Wilman, "Prodrugs in Cancer Therapy" Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast (1986) and Stella et al., "Prodrugs:A Chemical Approach to Targeted Drug Delivery," Directed Drug Delivery, Borchardt et al., (ed.), pp. 247-267, Humana Press (1985) Prodrugs of the present invention include, but not limited to, phosphate-containing prodrugs, thiophosphate-containing prodrugs, sulfate-containing prodrugs, peptide-containing prodrugs, D-amino acid-modified prodrugs, glycosylated prodrugs, β-lactam-containing prodrugs, optionally substituted phenoxyacetamide-containing prodrugs or optionally substituted phenylacetamide-containing prodrugs, 5-fortitudinous and other 5-ptoluidine prodrugs that can be converted into the more active cytotoxic drug. Examples of cytotoxic drugs that can be derivatization in the form of prodrugs for use in the present invention include, but are not limited to, chemotherapeutic agents described above.

"Liposome" refers to vesicles consisting of one or more lipids, phospholipids and/or surfactant which is useful for delivery of a drug (such as the compound of the present invention and, optionally, a chemotherapeutic drug) to a mammal. The components of the liposomes can be in the form of a bilayer, similar to the structure of the lipids of biological membranes.

The term "liner in the package" is used as referring to the instructions that are traditionally included in to marcheskie packing therapeutic products, which contain information about the indications, usage, dosage, introduction, contraindications and/or warnings concerning the use of such therapeutic products.

The term "chiral" refers to molecules that are nesovmestimymi with its mirror image, while the term "achiral" refers to molecules that are shared with its mirror image.

The term "stereoisomers" refers to compounds that have the same chemical composition, but different arrangement of atoms or groups in space.

"Diastereoisomer" refers to a stereoisomer with two or more centers of chirality, and such molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics and reactivity. A mixture of diastereoisomers can be separated by the use of analytical procedures high resolution, such as electrophoresis and chromatography.

"Enantiomers" refers to two stereoisomers of compounds that are nesovmestimymi with its mirror image.

Stereochemical definitions and conversion, ippolzuemye in this application, mainly located in accordance with S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-HillBook Company, New York; and Eliel, E. and Wilen, S., "Stereochemistry of Organic Compounds", John Wiley & Sons, Inc., New York, 1994. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. When describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(centers). The prefixes d and l or (+) and (-) used to indicate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levogyrate. Connection, preceded by the prefix (+) or d is Pervouralsk. For any particular chemical structure of these stereoisomers are identical, except that they are mirror images of each other. A specific stereoisomer may also be specified as an enantiomer, and a mixture of such isomers is often called an enantiomeric mixture. A mixture of 50:50enantiomers is called a racemic mixture or a racemate, which may be formed in the absence of stereoselectivity or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refers to an equimolar mixture of two enantiomeric types deprived Opticheskie activity.

The phrase "pharmaceutically acceptable salt", and is used in this application, refers to pharmaceutically acceptable organic or inorganic salts of the compounds of the present invention. Illustrative salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannat, Pantothenate, bitartrate, ascorbate, succinate, maleate, getitemat, fumarate, gluconate, glucuronate, saharat, formate, benzoate, glutamate, methanesulfonate, aconsultant, bansilalpet, p-toluensulfonate, pamoate (i.e., 1,1'-methylene-bis-(2-hydroxy-3-aftout)). Pharmaceutically acceptable salt may include another molecule, such as acetate ion, succinate ion or other counterion. The counterion may be any organic or inorganic group which stabilizes the charge of the original connection. In addition, pharmaceutically acceptable salt may contain more than one charged atom in its structure. Cases where where a few of charged atoms are part pharmaceutically acceptable salts can include multiple counterions. Consequently, the pharmaceutically acceptable salt may contain one or more charged atoms and/or one or more counterions.

"MES" refers to an Association or complex of one or bore the channels at the solvent molecules and compounds of the present invention. Examples of solvents that form the solvate include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid and ethanolamine. The term "hydrate" refers to the complex, where the solvent molecule is a water.

The term "protective group" or "Pg" refers to the Deputy, which is traditionally used to block or protect certain functional groups in the reaction of other functional groups in the compound. For example, "amino-protective group" is a Deputy, attached to the amino group that blocks or protects the functional amino group in the compound. Suitable amino-protective groups include acetyl, TRIFLUOROACETYL, phthalimido, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethoxycarbonyl (Fmoc). Similarly, the "hydroxy-protective group" refers to the Deputy hydroxy-group that blocks or protects the functional hydroxy-group. Suitable hydroxy protecting groups include acetyl, trialkylsilyl, dialkylanilines, benzoyl, benzyl, benzoyloxymethyl, methyl, methoxymethyl, triarylmethyl and tetrahydropyranyl. "Carboxy-protective group" refers to the Deputy carboxypropyl that blocks or protects the functional carboxypropyl. Traditionally used carboxy-for ethnie groups include-CH 2CH2SO2Ph, cyanoethyl, 2-(trimethylsilyl)ethyl, 2-(trimethylsilyl)ethoxymethyl, 2-(p-toluensulfonyl)ethyl, 2-(p-nitrobenzylidene)ethyl, 2-(diphenylphosphino)ethyl, nitroethyl and the like. General description of the protective groups and their use, see T. W. Greene and P. Wuts, Protective Groups in Organic Synthesis, Third Ed., John Wiley & Sons, New York, 1999; and P. Kocienski, Protecting Groups, Third Ed., Verlag, 2003.

The term "patient" includes patient men and patient animals. The term "animal" includes domestic animals (e.g. dogs, cats and horses), animal meat breeds, zoo animals, marine animals, birds and other such animals.

The phrase "pharmaceutically acceptable" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients that make up the composition, and/or mammals, which receives such treatment.

The terms "connection(connection) according to the invention, and the connection(connection) according to the present invention, unless otherwise indicated, include compounds of formula I and Ia and their stereoisomers, tautomers, solvate, metabolites, salts (e.g., pharmaceutically acceptable salts, polymorphs and prodrugs. Unless otherwise noted, the patterns presented in this application, also include compounds that differ only in the presence of one or more isotopically enriched atoms. Example is, compounds of formulas I and Ia and formula 1a-11, where one or more hydrogen atoms replaced by deuterium or tritium, or one or more carbon atoms replaced by13C - or14C-enriched carbon are included in the scope of the present invention.

PYRAZOLOPYRIMIDINONE CONNECTION INHIBITORS JAK

In one embodiment, is provided a compound of formula Ia and pharmaceutical compositions comprising such compound, which are useful for treating diseases, conditions and/or disorders responsive to the inhibition of JAK kinases.

In one embodiment, is provided a compound of formula I and pharmaceutical compositions comprising such compound, which are useful for treating diseases, conditions and/or disorders responsive to the inhibition of JAK kinases.

Another variant implementation includes compounds of formula Ia:

their enantiomers, diastereomers or pharmaceutically acceptable salts, where:

R1represents H;

R2represents-OR4, -NR3R4, -NR3N12R4, -NR3S(O)R4or-NR3S(O)2R4;

R3represents H or C1-C6alkyl, C2-C6alkenyl, C2-C6quinil, where these alkyl, alkenyl and quinil not battelino substituted by oxo, F, ORaor NRaRb;

R4represents H, C1-C6alkyl, C2-C6alkenyl, C2-C6quinil, -(C0-C5alkyl)(C1-C9heterocyclyl), -(C0-C5alkyl)(C3-C6cycloalkyl), -(C0-C5alkyl)(C1-C9heteroaryl), -(C0-C5alkyl)(C6-C10aryl), where these alkyl, alkenyl and quinil optionally substituted by a group R8and these aryl, cycloalkyl, heteroaryl and heterocyclyl optionally substituted by a group R9; or

R3and R4taken together with the nitrogen atom to which they are attached, form a C1-C9heterocyclyl, optionally substituted by a group R13;

Z represents-OR6or-NR5R6;

R5represents H or C1-C3alkyl;

R6represents H, C1-C10alkyl, C2-C10alkenyl, C2-C10quinil, -(C0-C5alkyl)(C1-C9heterocyclyl), -(C0-C5alkyl)(C3-C8cycloalkyl), -(C0-C5alkyl)(C1-C9heteroaryl), -(C0-C5alkyl)(C6-C9aryl), where these alkyl, alkenyl and quinil optionally substituted by a group R10and these aryl, cycloalkyl, heteroaryl and heterocyclyl need not gamestypes R 11;

R7represents H, halogen, C1-C3alkyl, C2-C3alkenyl, C2-C3quinil or-O(C1-C3alkyl);

R8independently represents oxo, F, ORaor NRaRb;

R9independently represents oxo, -CN, -CF3, halogen, -C(O)C1-C6alkyl, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa, -(C0-C5alkyl)SRa, -O[C(Ra)2]1-3O-, C1-C3alkyl, optionally substituted by oxo group or F, -(C0-C5alkyl)C1-C9heterocyclyl, optionally substituted with halogen, oxo, C1-C3the alkyl or C(O)C1-C3by alkyl, -(C0-C5alkyl)C6aryl, optionally substituted with halogenor group C1-C3alkyl-O(C1-C3alkyl), or -(C0-C5alkyl)C1-C9heteroaryl, optionally substituted with halogenor C1-C3by alkyl;

R10independently represents oxo, F, ORaor NRaRb;

R11independently represents oxo, -CN, -CF3, halogen, -O[C(Ra)2]1-3O-, -C(O)C1-C6alkyl, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C alkyl)ORaC1-C6alkyl, optionally substituted by oxo group or F, -(C0-C5alkyl)C1-C9heterocyclyl, optionally substituted with halogen, oxo, C1-C3the alkyl or C(O)C1-C3by alkyl, -(C0-C5alkyl)C1-C9heteroaryl, optionally substituted with halogenor C1-C3by alkyl, -(C0-C5alkyl)phenyl, optionally substituted C1-C3by alkyl, -CF3, halogen, -CN, -ORaor-NRaRbor -(C0-C5alkyl)C3-C6cycloalkyl, optionally substituted by oxo, -NRcRdC1-C3the alkyl or F;

R12represents H or C1-C3alkyl;

R13represents oxo, halogen, C1-C3alkyl, -C(O)C1-C6alkyl, -C(O)ORaC6aryl, C3-C6cycloalkyl, C1-C5heteroaryl or C4-C5heterocyclyl; where these aryl, cycloalkyl, heteroaryl and heterocyclyl optionally substituted C1-C4by alkyl, -(C0-C3alkyl)ORc, oxo, halogenor NRcRd;

Raand Rbindependently represent H, -CF3, -CHF2, -CH2F, C1-C6alkyl, C6aryl, C3-C6cycloalkyl or C4-C5heterocyclyl; where indicated the data alkyl, aryl and cycloalkyl optionally substituted C1-C4by alkyl, -(C0-C3alkyl)ORc, oxo, halogen, NRcRdor C4-C5heterocyclyl; or

Raand Rbtogether with the nitrogen atom to which they are attached, form a C1-C5heterocyclyl, optionally substituted by oxo, F, C1-C3by alkyl, -C(O)C1-C6the alkyl or-C(O)ORa; and

Rcand Rdindependently represent H, C1-C3alkyl, C3-C6cycloalkyl or phenyl, where these alkyl, cycloalkyl and phenyl optionally substituted with halogen, CH3, OH, NH2C(O)O(C1-C6alkyl), or C(O)NH(C1-C6alkyl).

Another variant of implementation includes the compounds of formula I:

their enantiomers, diastereomers or pharmaceutically acceptable salts, where:

R1represents H;

R2represents-OR4or-NR3R4;.

R3represents H or C1-C6alkyl, C2-C6alkenyl, C2-C6quinil, where these alkyl, alkenyl and quinil optionally substituted by oxo, F, ORaor NRaRb;

R4represents H, C1-C6alkyl, C2-C6alkenyl, C2-C6quinil, -(C0-C5alkyl)(C1-C9 heterocyclyl), -(C0-C5alkyl)(C3-C6cycloalkyl), -(C0-C5alkyl)(C1-C9heteroaryl), (C0-C5alkyl)(C6-C9aryl), where these alkyl, alkenyl and quinil optionally substituted by oxo, F, ORaor NRaRband these aryl, cycloalkyl, heteroaryl and heterocyclyl optionally substituted

oxo, -CN, -CF3, halogen, -C(O)C1-C6by alkyl, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa, -O[C(Ra)2]1-3O-,

C1-C3the alkyl, optionally substituted by oxo group or F,

-(C0-C5alkyl)C1-C9heterocyclyl, which is optionally substituted by halogen, oxo, C1-C3the alkyl or C(O)C1-C3the alkyl, or

-(C0-C5alkyl)C1-C9heteroaryl, which is optionally substituted with halogenor C1-C3by alkyl;

R3and R4taken together with the nitrogen atom to which they are attached, form a C1-C5heterocyclyl, optionally substituted byoxo, F, C1-C3by alkyl, -C(O)C1-C6the alkyl or-C(O)ORa;

R3and R4taken together with the nitrogen atom to which they are attached, form a C1-C5heterocyclyl, optionally substituted byoxo, F, C1 -C3by alkyl, -C(O)C1-C6the alkyl or-C(O)ORa;

Z represents-OR6or-NR5R6;

R5represents H or C1-C3alkyl;

R6represents H, C1-C10alkyl, C2-C10alkenyl, C2-C10quinil, -(C0-C5alkyl)(C1-C9heterocyclyl), -(C0-C5alkyl)(C3-C8cycloalkyl), -(C0-C5alkyl)(C1-C9heteroaryl), -(C0-C5alkyl)(C6-C9aryl), where these alkyl, alkenyl and quinil optionally substituted by oxo, F, ORaor NRaRband these aryl, cycloalkyl, heteroaryl and heterocyclyl optionally substituted

oxo, -CN, -CF3, halogen, -O[C(Ra)2]1-3O-, -C(O)C1-C6by alkyl, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa,

C1-C6the alkyl, optionally substituted by oxo group or F,

-(C0-C5alkyl)C1-C9heterocyclyl, which is optionally substituted by halogen, oxo, C1-C3the alkyl or C(O)C1-C3the alkyl,

-(C0-C5alkyl)C1-C9heteroaryl, which is optionally substituted with halogenor C1-C3the alkyl,

-(C0-C5alkyl)FeNi is om, which is optionally substituted C1-C3by alkyl, -CF3, halogen, -CN, -ORaor-NRaRbor

-(C0-C5alkyl)C3-C6cycloalkyl, which is optionally substituted by oxo, -NRcRdC1-C3the alkyl or F;

Raand Rbindependently represent H, -CF3, -CHF2, -CH2F, C1-C6alkyl, C6aryl, C3-C6cycloalkyl or C4-C5heterocyclyl; where these alkyl, aryl and cycloalkyl optionally substituted C1-C4the alkyl, (C0-C3alkyl)ORc, oxo, halogen, NRcRdor C4-C5heterocyclyl; or

Raand Rbtogether with the nitrogen atom to which they are attached, form a C1-C5heterocyclyl, optionally substituted by oxo, F, C1-C3by alkyl, -C(O)C1-C6the alkyl or-C(O)ORa; and

Rcand Rdindependently represent H, C1-C3alkyl, C3-C6cycloalkyl or phenyl, where these alkyl, cycloalkyl and phenyl optionally substituted with halogen, CH3, OH or NH2C(O)O(C1-C6alkyl), or C(O)NH(C1-C6alkyl).

In one embodiment, R2represents-NR3R4, -NR3N12R4, -NR3S(O)R4or-NR3S(O)2R4. the another embodiment, R 2represents-NR3R4, -NR3N12R4or-NR3S(O)2R4. In another embodiment, R2represents-NR3S(O)2R4. In another embodiment, R2represents-NR3N12R4. In one embodiment, R2represents-NR3R4. In one embodiment, R2is an-other4.

In one embodiment of formula I, R2represents-NR3R4.

In one embodiment of formula I, R2is an-other4.

In one embodiment of formula I, R2represents-OR4.

In one embodiment of formula I, R2represents-NR3R4and R3represents H or C1-C4alkyl, optionally substituted by an OH group.

In one embodiment of formula I, R4represents H or C1-C4alkyl, optionally substituted by an OH group.

In one embodiment of formula I, R4represents H, methyl, ethyl, isopropylor-CH2CH2OH.

In one embodiment of formula I, R2represents-NR3R4and R3and R4represent H.

In one embodiment, the implementation is of formula I, R4represents a C1-C6alkyl, -(C0-C3alkyl)phenyl, (C0-C3alkyl)(C3-C5heterocyclyl), -(C0-C3alkyl)(C6-C7cycloalkyl), -(C0-C3alkyl)(C3-C5heteroaryl) where the specified alkyl optionally substituted by oxo group, F, ORaor NRaRband these phenyl, cycloalkyl, heteroaryl and heterocyclyl optionally substituted

C1-C3the alkyl, optionally substituted by a group F,

-O[C(Ra)2]1-3O-, -CF3, -OCF3, -OCHF2, halogen, -C(O)C1-C6by alkyl, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa,

-(C0-C3alkyl)C3-C5heterocyclyl, which is optionally substituted by halogen, oxo, C1-C3the alkyl or C(O)C1-C6the alkyl,

or -(C0-C3alkyl)C3-C5heteroaryl, which is optionally substituted with halogenor C1-C3the alkyl.

In one embodiment, R4represents a C1-C6alkyl, -(C0-C5alkyl)(C1-C9heterocyclyl), -(C0-C5alkyl)(C3-C6cycloalkyl), -(C0-C5alkyl)(C1-C9heteroaryl), -(C0-C5alkyl)(C6-C10 aryl), where the specified alkyl optionally substituted by a group R8and these aryl, cycloalkyl, heteroaryl and heterocyclyl optionally substituted by a group R9.

In another embodiment, R3and R4taken together with the nitrogen atom to which they are attached, form a C1-C5heterocyclyl, optionally substituted by a group R13.

In one embodiment of formula I, R3and R4taken together with the nitrogen atom to which they are attached, form a C4-C5heterocyclyl, optionally substituted by oxo, F, C1-C3by alkyl, -C(O)C1-C6the alkyl or-C(O)ORa.

In one embodiment of formula I, R4represents phenyl, -(CH2)phenyl, - (CH2CH2)phenyl, -CH(CH3)phenyl, -C(CH3)2phenyl, -(C0-C3alkyl)C4-C5heterocyclyl or -(C0-C3alkyl)C3-C5heteroaryl where specified phenyl optionally substituted by 1 or 2 substituents, independently selected from methyl, ethyl, isopropyl, F, Cl, -OCH2O-, -OCH2CH2O-, -OCH2CH2CH2O-, -OCH2CH2NH2, -OCH2CH2NMe2, -OCH2(C4-C5heterocyclyl), -OH, -OCH3, -OCH2CH3, -CF3, -OCF3and-OCHF2specified heterocyclyl selected from tetrahydropyranyl, tet is hydroporinae, pyrrolidinyl, morpholinyl, piperazinil and piperidinyl specified heterocyclyl optionally substituted with halogen, stands, or C(O)O(tert-butyl), specified heteroarylselected from pyrazolyl, imidazolyl, furanyl and tanila, and the specified heteroaryl optionally substituted with halogenor stands.

In one embodiment, R4represents -(C0-C5alkyl)(C6-C10aryl), optionally substituted by a group R9. In one example, R4represents -(C0-C5alkyl)(C6-C10aryl), optionally substituted (C1-C3alkyl)om or halogen,and the aryl is a phenyl, naphthalenyl, indenyl, indanyl, 1,2-dihydronaphthalene and 1,2,3,4-tetrahydronaphthyl. In another example, R4chosen from:

where the wavy lines represent the attachment point for R4in the joint according to the present invention.

In one embodiment, R4represents phenyl, -(CH2)phenyl, -(CH2CH2)phenyl, -CH(CH3)phenyl, -CH(CH2CH3)phenyl, -(R)-CH(CH3)phenyl, -(S)-CH(CH3)phenyl, -(R)-CH(CH2CH3)phenyl, -(S)-CH(CH2CH3)phenyl or-C(CH3)2phenyl, where the specified phenyl optionally substituted by a group R9. In one example, the specified phenyl optionally C is substituted 1 or 2 groups R 9where R9independently selected from methyl, ethyl, isopropyl, cyclopropyl, F, Cl, -OCH2O-, -OCH2CH2O-, -OCH2CH2CH2O-, -OCH2CH2NH2, -OCH2CH2NMe2, -O(CH2)1-3(C4-C5heterocyclyl), C3-C5heteroaryl, -(CH2)0-3C3-C5heterocyclyl, optionally substituted C1-C3the alkyl or by halogen, -OH, -OCH3, -OCH2CH3, -SH, -SCH3, -SCH2CH3, -N(CH3)2-N(CH2CH3)2, -CN, -CF3, -OCF3, -OCHF2and C(O)O(C1-C3alkyl). In another example, R4chosen from:

where the wavy lines represent the attachment point for R4.

In another embodiment, R4represents -(C0-C5alkyl)(C1-C9heterocyclyl) or(C0-C5alkyl)(C1-C9heteroaryl), where these heteroaryl and heterocyclyl optionally substituted by a group R9. In one example, R4represents pyridinyl, -(CH2)pyridinyl, -(CH2CH2)pyridinyl, -CH(CH3)pyridinyl, pyrimidinyl, -(CH2)pyrimidinyl, imidazolyl, -(CH2)imidazolyl, PI is azolyl, -(CH2)pyrazolyl, tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinil or piperidinyl, optionally substituted by a group R9. In one example, R9represents methyl, ethyl, isopropyl, F, Cl, -NH2, -NMe2, -OCH3, -OH, -OCH2CH3, -CF3, -OCF3-OCHF2C(O)O(tert-butyl) or phenyl. In another example, R4chosen from:

where the wavy lines represent the attachment point for R4.

In one embodiment of formula I, R4represents a C4-C5heterocyclyl or -(CH2)C4-C5heterocyclyl where specified heterocyclyl is tetrahydropyranyl, tetrahydrofuranyl, pyrrolidinyl, piperazinil, piperidinyl or morpholinyl, optionally substituted by a methyl group, or C(O)O(tert-butyl).

In one embodiment of formula I, R3and R4taken together with the nitrogen atom to which they are bound, form pyrrolidinyl, piperazinil, piperidinyl or morpholinyl, optionally substituted stands.

In one embodiment, R3and R4taken together with the nitrogen atom to which they are bound, form azetidine, optionally substituted by a group R13. In another embodiment, R3and R4taken together with the atom and the PTA, with which they are linked, form azetidine, optionally substituted phenyl.

In one embodiment of formula I, R4represents pyridinyl, or -(CH2)pyridinyl, where the specified pyridinyl optionally substituted with stands, F or Cl.

In one embodiment, R4is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, -(CH2)cyclopropyl, -(CH2)cyclobutyl, -(CH2)cyclopentyl, -(CH2)cyclohexyl, -(CH2)cycloheptyl, indanyl or tetrahydronaphthyl, and specified R4independently optionally substituted by a group R9. In one example, R9represents F, oxo, methyl or CH2NH2.

In one embodiment of formula I, R4represents cyclohexyl, cycloheptyl, -(CH2)cyclohexyl, or -(CH2)cycloheptyl, and these cyclohexyl and cycloheptyl independently optionally substituted by oxo, stands or CH2NH2.

In one embodiment, Z represents-NR5R6.

In one embodiment, Z represents-NR5R6and R5represents H.

In one embodiment, Z represents-NR5R6, R5represents H, and R6represents H.

In one embodiment, formula I represents a-NR 5R6.

In one embodiment of formula I, Z represents-OR6.

In one embodiment of formula I, Z represents-NR5R6and R5represents H.

In one embodiment, R6represents a C1-C10alkyl, -(C0-C5alkyl)(C1-C9heterocyclyl), -(C0-C5alkyl)(C3-C8cycloalkyl), -(C0-C5alkyl)(C1-C9heteroaryl), -(C0-C5alkyl)(C6-C9aryl, where alkyl optionally substituted by a group R10and where the aryl, cycloalkyl, heteroaryl and heterocyclyl optionally substituted by a group R11.

In one embodiment of formula I, R6represents a C1-C8alkyl, -(C0-C3alkyl)(C3-C5heterocyclyl), -(C0-C3alkyl)(C3-C8cycloalkyl), -(C0-C3alkyl)(C3-C5heteroaryl) or(C0-C1alkyl)(phenyl), where the specified alkyl optionally substituted by oxo group, F, ORaor NRaRband these phenyl, cycloalkyl, heteroaryl and heterocyclyl optionally substituted

oxo, -CN, -CF3, halogen, -C(O)C1-C6by alkyl, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa,

C1 -C6the alkyl, optionally substituted by oxo group or F,

-(C0-C2alkyl)C3-C5heterocyclyl, which is optionally substituted by halogen, oxo, C1-C3the alkyl or C(O)C1-C3the alkyl,

-(C0-C2alkyl)C3-C5heteroaryl, which is optionally substituted with halogenor C1-C3the alkyl,

-(C0-C2alkyl)phenyl, which is optionally substituted C1-C3by alkyl, -CF3, halogen, -CN, -ORaor-NRaRbor

-(C0-C2alkyl)C6-C8cycloalkyl, which is optionally substituted by oxo, -NRcRdC1-C3the alkyl or F.

In one embodiment, R6represents a C1-C8alkyl, optionally substituted by a group R10. In one embodiment, R6represents methyl, ethyl, isopropyl, n-butyl, sec-butyl, tert-butyl, 3,3-dimethylbutan-1-yl, Penta-3-yl, octyl, -C(CH2)2CH2OH, -CH2CH2OH or-CH2CH2OCH3.

In one embodiment of formula I, R6represents a C1-C8alkyl, optionally substituted by oxo group, F, ORaor NRaRb.

In one embodiment of formula I, R6represents methyl, ethyl, isopropyl, n-butyl, WTO the-butyl, tert-butyl, 3,3-dimethylbutan-1-yl, Penta-3-yl, octyl, -C(CH2)2CH2OH, -CH2CH2OH or-CH2CH2OCH3.

In one embodiment, R6represents a C3-C5heterocyclyl or -(CH2)C3-C5heterocyclyl, optionally substituted by a group R11. In another embodiment, R6represents a C3-C5heterocyclyl or -(CH2)C3-C5heterocyclyl, optionally substituted by a group R11where specified heterocyclyl is tetrahydrofuranyl, tetrahydropyranyl, piperazinil, piperidinyl, morpholinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, pyridinyl, and where specified R11independently represents oxo, -CN, -CF3, halogen, -C(O)C1-C6alkyl, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORaC1-C6alkyl, optionally substituted by oxo group or F, -(C0-C5alkyl)C1-C9heterocyclyl, optionally substituted with halogen, oxo, C1-C3the alkyl or C(O)C1-C3by alkyl, -(C0-C5alkyl)C1-C9heteroaryl, optionally substituted with halogenor C1-C3by alkyl, -(C0-C5alkyl)phenyl, optional the nutrient substituted C 1-C3by alkyl, -CF3, halogen, -CN, -ORaor-NRaRbor -(C0-C5alkyl)C3-C6cycloalkyl, optionally substituted by oxo, -NRcRdC1-C3the alkyl or F. In one example, R6represents a C3-C5heteroaryl, optionally substituted by1-4 groups R11. In another example, R6represents a C3-C5heteroaryl where specified heteroaryl substituted by phenyl, which is optionally substituted C1-C3by alkyl, -CF3, halogen, -CN, -ORaor-NRaRband where specified heteroaryl optionally additionally substituted by 1-2 groups R11independently selected from halogen, -CF3or C1-C6the alkyl, optionally substituted by oxo group, or F.

In one embodiment of Formula I, R6represents a C3-C5heterocyclyl or -(CH2)C3-C5heterocyclyl where specified heterocyclyl is tetrahydrofuranyl, piperazinil, piperidinyl or morpholinyl, optionally substituted stands, ethyl or C(O)Wipe-bootrom.

In one embodiment of formula I, R6represents -(C0-C2alkyl)C3-C8cycloalkyl where specified cycloalkyl optionally substituted C1-C6the alkyl, C(O)OH 3C(O)OH, OH, CN, C(O) - cyclohexyl, C(O)(C4-C5heterocyclyl) or-CH2- cyclohexyl, optionally substituted by a group NH2and where specified heterocyclyl selected from piperazinil, piperidinyl or morpholinyl, and the specified heterocyclyl optionally substituted bythe stands or CH2NH2.

In one embodiment, R6is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -(CH2)cyclohexyl, -(CH2CH2)cyclohexyl, -(CH2)cycloheptyl, bicyclo[2.2.1]heptyl or -(CH2)bicyclo[2.2.1]heptyl, and where R6optionally substituted by 1-3 substituents selected from oxo, halogen, C1-C6of alkyl, C(O)OCH3C(O)OH, OH, CN, C(O)cyclohexyl, C(O)(C4-C5heterocyclyl) and-CH2of cyclohexyl, optionally substituted by a group NH2and where specified heterocyclyl selected from piperazinil, piperidinyl or morpholinyl, and the specified heterocyclyl optionally substituted stands or CH2NH2.

In one embodiment of formula I, R6is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, -(CH2)cyclohexyl, -(CH2CH2)cyclohexyl, -(CH2)cycloheptyl, bicyclo[2.2.1]heptyl or -(CH2)bicyclo[2.2.1]heptyl, and where R6optional samewe is 1-3 substituents, selected from C1-C6of alkyl, C(O)OCH3C(O)OH, OH, CN, C(O)cyclohexyl, C(O)(C4-C5heterocyclyl) or-CH2of cyclohexyl, optionally substituted NH2and where specified heterocyclyl selected from piperazinil, piperidinyl or morpholinyl, and the specified heterocyclyl optionally substituted stands or CH2NH2.

In one embodiment, R6represents a C3-C5heteroaryl or -(CH2)C3-C5heteroaryl, and where R6optionally substituted by a group R11.

In one embodiment of formula I, R6represents a C3-C5heteroaryl or -(CH2)C3-C5heteroaryl, and where R6optionally substituted by one or more substituents selected from oxo, -CN, -CF3, halogen, -C(O)C1-C6of alkyl, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa,

C1-C6the alkyl, optionally substituted by oxo group or F,

-(C0-C2alkyl)C4-C5heterocyclyl, optionally substituted with halogen, oxo, C1-C3the alkyl or C(O)C1-C3the alkyl,

-(C0-C2alkyl)C3-C5heteroaryl, optionally substituted with halogenor C1-C3the alkyl,

-(C 0-C2alkyl)phenyl, optionally substituted C1-C3by alkyl, -CF3, halogen, -CN, -ORaor-NRaRband

-(C0-C2alkyl)C6-C7cycloalkyl, optionally substituted by oxo, C1-C3the alkyl or F.

In one embodiment, R6represents isoxazolyl, oxazolyl, isothiazolin, thiazolyl, imidazolyl, pyrazolyl or pyridinyl, and where R6optionally substituted by 1-3 substituents chosen from-CF3, halogen, C1-C6the alkyl, optionally substituted by oxo group or F, -(C1-C6alkyl)ORa, phenyl, optionally substituted stands, ethyl, isopropyl, -CF3, -CN, ORa, Cl, F, Br or I, and pyridinyl, optionally substituted stands, ethyl, isopropyl, -CF3, -CN, ORa, Cl, F, Br or I.

In one embodiment of formula I, R6represents pyrazolyl or pyridinyl, and where R6optionally substituted by 1-3 substituents selected from C1-C6the alkyl, optionally substituted by oxo group or F, halogen freeand phenyl, and where specified phenyl optionally substituted with stands, ethyl, isopropyl, -CF3, -CN, ORa, Cl or F.

In one embodiment of formula I, R6represents phenyl or-CH2phenyl, and where specified phenyl optionally amesen F, Cl, -OH, -OCH3, -OCH2CH3-Fenelon, -C(O)NH2, -C(O)OH, -C(O)OCH3, cyclohexyl, stands, ethyl or isopropyl.

In one embodiment, R7represents a halogen. In one embodiment, R7represents Cl. In one embodiment, R7represents H.

In one embodiment, R8independently represents oxo, halogen, ORaor NRaRb. In one embodiment, R8independently represents a halogen. In one embodiment, R8is a F.

In one embodiment, R9independently represents-CF3, halogen, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa, -(C0-C5alkyl)SRa, -O[C(Ra)2]1-3O-, C1-C3alkyl, optionally substituted by oxo group or F, -(C0-C5alkyl)(C3-C6cycloalkyl), optionally substituted by oxo group or F, -(C0-C5alkyl)C1-C9heterocyclyl, optionally substituted with halogen, oxo, C1-C3the alkyl or C(O)C1-C3by alkyl, -(C0-C5alkyl)C6aryl, optionally substituted with halogenor group C1-C3alkyl-O(C1-C3alkyl), or -(C0-C5 alkyl)C 1-C9heteroaryl, optionally substituted with halogenor C1-C3the alkyl. In one embodiment, R9independently represents Cl, F, -CF3, -CH3, -OH, -OCH3, -OCH2CH3, -O(CH2)2O-, -O(CH2)3O-, -OCHF2, -OCF3,-N(CH3)2, -NH2morpholinyl, pyrrolidinyl, pyrazolyl, -OCH2(pyrazolyl), N-methyl-piperidinyl or-O(CH2)2(morpholinyl).

In one embodiment, R10independently represents oxo, halogen, ORaor NRaRb. In one embodiment, R10independently represents a halogen. In one embodiment, R10is a F.

In one embodiment, R11independently represents oxo, -CF3, halogen, -C(O)C1-C6alkyl, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORaC1-C6alkyl, optionally substituted by oxo group or F, -(C0-C5alkyl)C1-C9heterocyclyl, optionally substituted with halogen, oxo, C1-C3the alkyl or C(O)C1-C3by alkyl, -(C0-C5alkyl)C1-C9heteroaryl, optionally substituted with halogenor C1-C3by alkyl, -(C0-C5alkylphenyl, optionally substituted C1-C4the alkyl, C1-C4alkenyl, C1-C4the quinil, C3-C6cycloalkyl, -CF3, halogen, -CN, -ORaor-NRaRbor -(C0-C5alkyl)C3-C6cycloalkyl, optionally substituted by oxo, -NRcRdC1-C3the alkyl or F. In one embodiment, R11independently represents Cl, F, -CF3, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, 2-methyl-5-chlorophenyl, 2,5-dichlorophenyl, 2,5-differenl, 2,5-dimetilfenil, gem-debtor, gem-dimethyl, 2-hydroxyethyl, 2-methoxyethyl, 3, 5dimethylphenyl, 3,5-dichlorophenyl, 3,5-differenl, 2,4-differenl, 2-chloro-5-were, 2nd were 2-triptoreline, 2-chlorophenyl, 2-forfinal, 3-were 3-forfinal, 3-chlorophenyl, 3-cyanophenyl, 2-itfeel, 2-bromophenyl, phenyl, pyridyl, -C(O)OCH3, -CH2(4-aminocyclopent-1-yl), 2-chloro-6-itfeel, 2,6-dichlorophenyl, 2,6-dimetilfenil, 2,6-dibromophenyl, 2-chloro-6-were, 2-chloro-6-forfinal, 2-bromo-6-forfinal, 2-bromo-6-were, 2-fluoro-6-were, 2-chloro-6-triptoreline, 2-dimethylphenyl, 2-ethylphenyl, 2-ethinyl-6-were, 2-ethinyl-6-forfinal, 2-chloro-5-cyanophenyl, 2-methoxyphenyl, 2-cyclopropylethyl, 2-methoxy-6-were-2-ethynylphenyl, 2-chloro-4-cyanophenyl, 2-isopropylphenyl or 2-trifloromethyl.

In one embodiment, the implementation is of formula I, R6represents:

-(C0-C1alkyl)(C6-C9cycloalkyl), optionally substituted by oxo, -CN, -CF3, halogen, -C(O)C1-C6by alkyl, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORaor C1-C6the alkyl, optionally substituted by oxo group or F,

-(C0-C2alkyl)C4-C5heterocyclyl, optionally substituted with halogen, oxo, C1-C3the alkyl or C(O)C1-C3the alkyl,

-(C0-C2alkyl)C3-C5heteroaryl, optionally substituted with halogen, C1-C3the alkyl or phenyl, where the specified phenyl optionally substituted C1-C3by alkyl, -CF3, halogen, -CN, -ORaor-NRaRb,

-(C0-C2alkyl)phenyl, optionally substituted with halogen, -CN, -ORaor-NRaRbor -(C0-C2alkyl)C6-C7cycloalkyl, optionally substituted by oxo group, a C1-C3alkyl, or F; and

R4represents H or -(C0-C3alkyl)phenyl, where specified phenyl optionally substituted:

C1-C3the alkyl, optionally substituted by a group F,

-OCH2O-, -OCH2CH2O-, -OCH2CH2CH2O-, -CF3, -OCF3, -OCHF2, halogen, -C(O)C -C6by alkyl, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa,

-(C0-C3alkyl)C4-C4heterocyclyl, which is optionally substituted by halogen, oxo, C1-C3the alkyl or C(O)C1-C3the alkyl, or

-(C0-C3alkyl)C3-C5heteroaryl, which is optionally substituted with halogenor C1-C3the alkyl.

In another embodiment, R6represents cyclohexyl, optionally substituted by 1 or 2 substituents, independently selected from methyl, ethyl, penttila, C(O)OCH3C(O)OH, OH, CN, C(O)cyclohexyl, and C(O)(C4-C5heterocyclyl) where the specified heterocyclyl is a piperazinil, piperidinyl or morpholinyl, optionally substituted stands, CH2NH2,or CH2of cyclohexyl, optionally substituted by a group NH2; and R4represents -(CH2)phenyl, where specified phenyl optionally substituted by 1 or 2 substituents, independently selected from methyl, F, Cl, -OCH2O-, -OCH2CH2O-, -OCH2CH2CH2O-, -OCH2CH2NMe2, -OCH2(C4-C5heterocyclyl), -OH, -CF3, -OCF3, -OCH3, -OCH2CH3, -OCHF2, -(C0-C1alkyl)C4-C5heterocyclyl, where is shown heterocyclyl selected from pyrrolidinyl, morpholinyl, piperazinil or piperidinyl and optionally substituted stands, and -(C0-C1alkyl)C4-C5heteroaryl where specified heteroaryl selected from pyrazolyl, imidazolyl, furanyl and tanila and optionally substituted stands. In one example implementation of this option, R2represents-NR3R4and R1and R3represent H.

In one embodiment of formula I, R6represents -(C0-C1alkyl)(C6-C7cycloalkyl), where the specified cycloalkyl optionally substituted by oxo, -CN, -CF3, halogen, -C(O)C1-C6by alkyl, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa,

C1-C6the alkyl, optionally substituted by oxo group or F,

-(C0-C2alkyl)C4-C5heterocyclyl, which is optionally substituted by halogen, oxo, C1-C3the alkyl or C(O)C1-C3the alkyl,

-(C0-C2alkyl)C3-C5heteroaryl, which is optionally substituted with halogenor C1-C3the alkyl,

-(C0-C2alkyl)phenyl, which is optionally substituted with halogen, -CN, -ORaor-NRaRbor

-(C0-C2alkyl)C6-C7cycloalkyl, which is optional is about substituted by oxo, C1-C3the alkyl or F; and

R4represents -(C0-C2alkyl)pyridinyl, where the specified pyridinyl optionally substituted-OCH2O-, -OCH2CH2O-, -OCH2CH2CH2O-, -CF3, -OCF3, -OCHF2, halogen, -C(O)C1-C6by alkyl, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa,

C1-C3the alkyl, optionally substituted by a group F,

-(C0-C3alkyl)C4-C4heterocyclyl, optionally substituted with halogen, oxo, C1-C3the alkyl or C(O)C1-C3the alkyl, or

-(C0-C3alkyl)C3-C5heteroaryl, optionally substituted with halogenor C1-C3the alkyl.

In one embodiment of formula I, R6represents cyclohexyl, optionally substituted by 1 or 2 substituents, independently selected from methyl, ethyl, penttila, C(O)OCH3C(O)OH, OH, CN, C(O)cyclohexyl, C(O)(C4-C5heterocyclyl) where the specified heterocyclyl is a piperazinil, piperidinyl or morpholinyl, optionally substituted stands, CH2NH2or CH2of cyclohexyl, optionally substituted by a group NH2; and R4represents pyridinyl, or -(CH2)pyridinyl, where specified shall original optionally substituted stands, F or Cl. In another example of this variant implementation, R2represents-NR3R4and R1and R3represent H.

In one embodiment, R6represents a C1-C4alkyl, optionally substituted by a group R10C3-C5heterocyclyl, C3-C5heteroaryl or C3-C7cycloalkyl where specified heterocyclyl, heteroaryl and cycloalkyl optionally substituted by a group R11; and R4represents H, -(C0-C5alkyl)(C1-C9heterocyclyl), -(C0-C5alkyl)(C3-C6cycloalkyl), -(C0-C5alkyl)(C1-C9heteroaryl), -(C0-C5alkyl)(C6-C10aryl), where the specified alkyl optionally substituted by a group R8,and these aryl, cycloalkyl, heteroaryl and heterocyclyl optionally substituted by a group R9.

In one embodiment of formula I, R1represents H; R2represents-NR3R4; R3represents H; and R6represents a C3-C5heteroaryl, optionally substituted by one or more substituents selected from oxo, -CF3, halogen, -C(O)C1-C6of alkyl,

C1-C6the alkyl, optionally substituted by oxo group or F,

-(C0-C 2alkyl)C4-C5heterocyclyl, optionally substituted with halogen, oxo, C1-C3the alkyl or C(O)C1-C3the alkyl,

-(C0-C2alkyl)C3-C5heteroaryl, optionally substituted with halogenor C1-C3the alkyl,

-(C0-C2alkyl)phenyl, optionally substituted C1-C3by alkyl, -CF3, halogen, -CN, -ORaor-NRaRband

-(C0-C2alkyl)C6-C7cycloalkyl, optionally substituted by oxo, C1-C3the alkyl or F. in one example implementation of this option, R4represents H.

In one embodiment of formula I, when R4represents -(C0-C5alkyl)(C1-C5heterocyclyl), -(C0-C5alkyl)(C3-C6cycloalkyl), -(C0-C5alkyl)(C1-C9heteroaryl), -(C0-C5alkyl)(C6-C9aryl, aryl, cycloalkyl, heteroaryl and heterocyclyl optionally substituted by 1-3 substituents, independently selected from oxo, C1-C3the alkyl, optionally substituted by1-3 substituents, independently selected from oxo and F, -CN, -CF3, halogen, -C(O)C1-C6of alkyl, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa , -(C0-C5alkyl)C1-C9heterocyclyl, optionally substituted by 1-3 substituents, independently selected from halogen, oxo, C1-C3the alkyl and C(O)C1-C3of alkyl, -(C0-C5alkyl)C1-C9heteroaryl, optionally substituted by 1-3 substituents, independently selected from halogen freeand C1-C3of alkyl, -OCH2O-, -OCH2CH2O-, -OCH2CH2CH2O -, and-OCH2(C4-C5heterocyclyl). When R4represents alkyl, alkenyl or quinil, then the alkyl, alkenyl and quinil optionally substituted by 1-3 substituents, independently selected from oxo, F, ORaand NRaRb.

In one embodiment of formula I, when R3and R4taken together with the nitrogen atom to which they are attached, form a C1-C5heterocyclyl, then heterocyclyl optionally substituted by 1-3 substituents, independently selected from oxo, F, C1-C3of alkyl, -C(O)C1-C6the alkyl and-C(O)ORa.

In one embodiment of formula I, when R6represents a C6aryl, C3-C8cycloalkyl, C3-C5heteroaryl and C3-C5heterocyclyl, then aryl, cycloalkyl, heteroaryl and heterocyclyl optionally substituted by 1-3 substituents, independently selected from oxo, C1-C the alkyl, optionally substituted by 1-3 substituents, independently selected from oxo and F, -CN, -CF3, halogen, -OCH2O-, -OCH2CH2O-, -OCH2CH2CH2O-, -C(O)C1-C6of alkyl, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa, -(C0-C5alkyl)C1-C9heterocyclyl, optionally substituted by 1-3 substituents, independently selected from halogen, oxo, C1-C3the alkyl and C(O)C1-C3of alkyl, -(C0-C5alkyl)C1-C9heteroaryl, optionally substituted by 1-3 substituents, independently selected from halogen freeand C1-C3of alkyl, -(C0-C5alkyl)phenyl, optionally substituted by 1-3 substituents, independently selected from halogen, -CN, -CF3, -ORaand-NRaRband -(C0-C5alkyl)C3-C6cycloalkyl, optionally substituted by 1-3 substituents, independently selected from oxo, C1-C3the alkyl and F. When R6represents alkyl, alkenyl or quinil, then the alkyl, alkenyl and quinil optionally substituted by 1-3 substituents, independently selected from oxo, F, ORaand NRaRb.

In one embodiment of formula I, when Raand Rbrepresents a C1-C6alkyl, C6and the sludge C3-C6cycloalkyl or C4-C5heterocyclyl, then the alkyl, aryl, cycloalkyl and heterocyclyl optionally substituted by 1-3 substituents, independently selected from C1-C4of alkyl, (C0-C3alkyl)ORc, oxo, halogen, NRcRdand C4-C5heterocyclyl. When Raand Rbtogether with the nitrogen atom to which they are attached, form a C1-C5heterocyclyl, then heterocyclyl optionally substituted by 1-3 substituents, independently selected from oxo, F, C1-C3of alkyl, -C(O)C1-C6the alkyl and-C(O)ORa.

In one embodiment of formula I, when Rcand Rdrepresents a C1-C3alkyl, C3-C6cycloalkyl or phenyl, then the alkyl, cycloalkyl and phenyl optionally substituted by 1-3 substituents, independently selected from halogen, CH3, OH, NH2C(O)O(C1-C6alkyl), and C(O)NH(C1-C6alkyl).

In one embodiment, Raand Rbindependently represent H, -CF3, -CHF2, -CH2F, C1-C6alkyl, phenyl, C3-C6cycloalkyl or C4-C5heterocyclyl; where these alkyl, aryl and cycloalkyl optionally substituted C1-C4by alkyl, -(C0-C3alkyl)ORc, oxo, halogen, NRcRdor C4-C5GE is eroticism. In one embodiment, Raand Rbtogether with the nitrogen atom to which they are attached, form a C1-C5heterocyclyl, optionally substituted by oxo, F, C1-C3by alkyl, -C(O)C1-C6the alkyl or-C(O)ORa. In one embodiment, Raand Rbindependently represent H or C1-C3alkyl.

In one embodiment, Rcand Rdindependently represent H, C1-C3alkyl, C3-C6cycloalkyl or phenyl, where these alkyl, cycloalkyl and phenyl optionally substituted with halogen, CH3, OH, NH2C(O)O(C1-C6alkyl), or C(O)NH(C1-C6alkyl). In one embodiment, Rcand Rdindependently represent H or C1-C3alkyl.

In one embodiment, R7represents H; R2represents-NR3S(O)2R4; R3represents H; and R4represents phenyl, optionally substituted by1 to 3 groups of R9. In one embodiment, R2represents-NR3S(O)2R4; R3represents H; R4represents phenyl, optionally substituted by 1-3 substituents selected from C1-C3of alkyl, -CF3and halogen; Z represents-NR5R6; R represents H; and R6is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and where R6optionally substituted by 1-3 substituents selected from oxo, halogen freeand C1-C6the alkyl.

In one embodiment, R7represents H; R2represents-NR3R4; R3represents H; R5represents H; R6represents pyrazolyl, optionally substituted stands and substituted phenyl, where the specified phenyl optionally substituted by one or two groups selected from methyl, halogen, methoxy, cyano, trifloromethyl, hydroxy or triptoreline.

In one embodiment, the compound of formula I is at least 10 or more times more selective for inhibition of JAK2 kinase activity compared with the inhibition activity of each of JAK1, JAK3 and Tyk-2.

In one embodiment, the compound of the present invention is about 5 or more times more selective for inhibition of the activity of JAK3 kinase compared with inhibition of JAK2 kinase activity. In another embodiment, the compound of the present invention is about 10 or more times more selective for inhibition of the activity of JAK3 kinase compared with inhibition Akti the particular JAK2 kinase.

Compounds of the present invention may contain asymmetric or chiral centers and therefore may exist in different stereoisomeric forms. It is assumed that all stereoisomeric forms of the compounds of the present invention, including but not limited to: the diastereomers, the enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, form part of the present invention. In addition, the present invention encompasses all geometric isomers and isomers position. For example, if the connection of the present invention includes a double bond or a condensed ring, both the CIS-and TRANS-forms, as well as mixtures thereof are encompassed as included in the scope of the present invention. As a separate position isomers and mixture of isomers, for example, in the N-oxidationpyrimidinamine and parasailing rings, or E and Z forms of the compounds of the present invention (for example, Aksinya group), also included in the scope of the present invention.

In the structures shown in this application, where the stereochemistry of a particular chiral atom is not specified, provides all stereoisomers, and they are included as compounds of the present invention. When the stereochemistry is indicated by dashed cone or a dashed line represents a specific conference is the tenant, in this case, stereoisomer thus specified and defined.

Compounds of the present invention may exist in resolutional, as well as in solvated form with pharmaceutically acceptable solvents such as water, ethanol and the like, and it is assumed that the present invention as defined by the claims, includes both solvated and nonsolvated forms.

In one embodiment, compounds of the present invention may exist in different tautomeric forms, and all such forms are covered as included in the scope of the present invention defined by the claims. The term "tautomer or tautomeric form" refers to the structural isomers with different energy, which are vzaimoporozhdeniya via a low energy barrier. For example, the tautomers by proton (also known as prototroph the tautomers) include vzaimoprevrascheny via migration of a proton, such as keto-enol and Imin-Eminova isomerization. the valence tautomers include vzaimoprevrascheny by reorganizing some of the bonding electrons.

The present invention also embraces isotopically-labeled compounds of the present invention, which are identical to the compounds specified in the present application, but the ex is different, however, that one or more atoms replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. All isotopes of any particular specified atom or element are contemplated as falling in the scope of the present invention. Illustrative isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C,13N15N15O,17O,18Oh,32P,33P,35S18F,36Cl123I and125I, respectively. Certain isotopically-labeled compounds of the present invention (e.g., compound labeled with3H and14C) are useful in the analysis of the distribution connection and/or fabric substrate. The isotope tritium (i.e.3H) and carbon-14 (i.e.14C) are useful, due to the simplicity of their production and detection. In addition, the substitution of heavier isotopes such as deuterium (i.e.2H), may provide some therapeutic benefits in the form of better metabolic stability (e.g., increased half-life ofin vivoor need lower doses) and, hence, may be preferred is some circumstances. Positron-emitting isotopes, such as15O,13N11C and18F, are useful for studies using positron-emission tomography (PET) to study the level of employment substrate receptor. Stopno-labeled compounds of the present invention receives, basically following the procedures similar to those disclosed in the schemes and/or in the examples presented in this application below, by substitution not labeled isotope reagent isotope-labeled reagent.

SYNTHESIS PYRAZOLOPYRIMIDINE COMPOUNDS are inhibitors of JAK

Compounds of the present invention can be synthesized using the ways of synthesis described in this application. In some embodiments, the implementation, you can use methods that are well known in chemistry, in addition to the description contained in this application or in the light of this description. Source substances, as a rule, are available from commercial sources such as Aldrich Chemicals (Milwaukee, Wis.), or they can easily be obtained using methods well known to specialists in this field (for example, can be obtained by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v. 1-19, Wiley, N. Y. (1967-1999 ed.), Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available through the Beilstein online database) or Comprehensive HeterocyclicChemistry, Editors Katrizky and Rees, Pergamon Press, 1984.

Compounds of the present invention can be obtained separately or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds of the present invention. Libraries of compounds of the present invention can be obtained using a combinatorial 'split and mix' approach or by multiple parallel synthesis using either phase of a solution or solid-phase chemistry and procedures, well-known experts in this field. Thus, in accordance with the following aspect of the present invention, is provided a compound library comprising at least 2 compounds of the present invention, their enantiomers, diastereomers or pharmaceutically acceptable salt.

For purposes of illustration, reaction scheme 1, below, represents the way of receipt for the synthesis of compounds of the present invention, as well as key intermediates. For a more detailed description of the individual reaction stages, see the “Examples” section below. Professionals in this field should be clear that for the synthesis of compounds of the present invention can be used other ways of synthesis. Although the specific source materials and reagents shown in the diagrams and discussed below, their legkovye replace the original substances and reagents to obtain various derivatives and/or reaction conditions. In addition, many of the compounds obtained by the methods described below can be further modified in light of the present disclosure using conventional chemical techniques well-known to specialists in this field.

Compounds of the present invention can be obtained from commercially available starting compounds using the General methods illustrated in this application.

The scheme of reactions 1

The compounds of formula 1 can be synthesized as shown in reaction Scheme 1. For example, a commercially available compound 3-aminopyrazole and 1,3-dimethyluracil can interact together in solution ethoxide sodium obtaining compounds 2a, which can be converted from the form of sodium salt of compound 2b by treatment with dilute acid. Compound 2b can be jodirovannuju usingN-iodosuccinimide (NIS) in DMF to obtain compound 3. The carbonyl compound 3 under alkaline conditions (such as triethylamine (TEA) using carbon monoxide and a palladium catalyst in methanol gives methyl ester compounds 4, which can hydrolyze in an aqueous solution of lithium hydroxide to obtain compound 5. Heating of compound 5 in a mixture of phosphorus oxychloride and Diisopropylamine the ina (DIPEA) gives deklarirovannoe connection 6, which is a common intermediate compound for the final synthesis of compounds Ia, Ib and Ic. Thus, compound 6 can be subjected to interaction with primary or secondary amine under mild conditions to obtain amide 7, then more stringent conditions with a second amine or alkoxide with obtaining compounds Ic or Ib, respectively. Alternatively, compound 6 can be subjected to interaction in alkaline conditions with alcohol with the production of esters of formula 8, which can be subjected to further interaction with primary or secondary amine to obtain compounds of formula Ia.

The scheme of reactions 2

Compounds of the present invention can be synthesized as shown in Scheme 2. For example, commercially available benzoic acid can be subjected to interaction with 3-ethoxy-3-oxopropanoic potassium in the presence of carbonyldiimidazole (CDI) and magnesium chloride with obtaining β-keto-ester 9 (where R represents alkyl, e.g., ethyl). Compound 9 can be heated with 1,1-dimethoxy-N,N-dimethylethanamine (N,N-DMA) to obtain compound 10. Cyclization of compound 10 using hydrazine in ethanol provides the receiving pyrazol connection 11. Alkylation of compound (11) by alkylhalogenide in the presence of a base, that the CSOs as cesium carbonate, allows to obtain a mixture of regioisomers 12a and 12b (where R11represents aoptionally substituted alkyl). Hydrolysis of ethyl ether, followed by rearrangement of kurzius usingazide diphenylphosphonic acid (dppa) and tert-butanol provides obtaining of tert-BUTYLCARBAMATE-protected amino-pyrazole, which removes the protection using HCl, to obtain the amino-pyrazol compounds 13a and 13b. The regioisomers 13a and 13b can be separated using chromatography on silica. The acylation each regioisomer separately by5-chloropyrazole[1,5-a]pyrimidine-3-carbonylchloride (compound 6) in the presence of triethylamine, followed by aminating with the use of microwave irradiation provides obtaining compounds of formula 1d and 1e.

The reaction scheme 3

An alternative method of synthesis of compounds of the present invention is illustrated in the reaction Scheme 3. Alkylation of di-tert-butylenediamine using sodium hydride and various α-bromoketones 14 network connection 15. Compound 15 can be heated with N,N-DMA getting connection 16. Cyclization of compound 16 using hydrazine in ethanol provides the receiving pyrazol connection 17. The acylation each regioisomer CTD is the super connection 6 in the presence of triethylamine, subsequent alkylation of pyrazole-alkylhalogenide provides the connection 18a and 18b (where R11represents an optionally substituted alkyl). With the use of microwave irradiation amination gives the compounds of formula 1d and 1e.

The reaction scheme 4

The reaction scheme 4 illustrates the synthesis of compounds of formula 1f. Commercially available anilines subjected to diazotization and mediated chloride tinrestoration that provides the connection 19. Condensation of compound 19 with 3-aminocrotononitrile in the ethanol solution of hydrochloric acid gives amino-pyrazol connection 20. The acylation with the help of compound 6 in the presence of triethylamine, followed by aminating with the use of microwave irradiation provides obtaining compounds of formula 1f.

The reaction scheme 5

An alternative method of synthesis of compounds of formula 1 described in the reaction Scheme 5. Alkylation of phthalimide potassium using α-bromoketones network connection 21. Condensation with N,N-DMA network connection 22. The compounds of formula 22 can be cyklinowanie using N-methylhydrazine with getting the alkylated pyrazole 23. The acylation of compound 23 with the aid of compound 6 in the presence of triethylamine,followed by aminating with the use of microwave irradiation and substituted amines provide compounds of formula 1d.

The scheme of reactions 6

The compounds of formula 1g can be synthesized as shown in Scheme 6. Attaching primary sulfonamides to 5-chloropyrazole[1,5-a]pyrimidine intermediate compound 7, mediated by a base, such as cesium carbonate, in a polar aprotic solvent such as 1,2-dimethoxyethane, allows to obtain the compounds of formula 1g.

The scheme of reactions 7

The compounds of formula 1f can be synthesized as shown in Scheme 7. The combination of amino-substituted R45-chloropyrazole[1,5-a]pyrimidine intermediate compound 8 mediated by palladiumconditions using a ligand such as Xantphos, leads to the connection 24. Ester hydrolysis under alkaline conditions allows to obtain acid 25. The formation of amide to yield the compounds of formula 1f can be done by adding the amine to the acid chloride acid 25.

The scheme of reactions 8

The compounds of formula 1i can be synthesized as shown in Scheme 8. Bromination of kilcatherine 9 (where R represents alkyl, e.g. ethyl) gives the bromide 26. Alkylation bromide 26 using thioacetamide with subsequent cyclodehydration at elevated temperatures allows to obtain enous the l 27. Hydrolysis of ester 27 in alkaline conditions, followed by rearrangement of kurzius using diphenylphosphinite ensures carbamate 28, after trapping with the use of alcohol, such as tert-butanol. Removal of the carbamate compound 28 in acidic conditions leads to 5-aminothiazolo 29, which when combined with the acid chloride of the acid 6 provides obtaining amide 30. Amination of chloride 30 with the use of microwave irradiation allows to obtain the compounds of formula 1i.

The reaction scheme 9

The compounds of formula 1j can be synthesized as shown in Scheme 9. Condensation of kilcatherine 9 (where R represents aalkyl, e.g. ethyl) with 1,1-dimethoxy-N,N-dimethylethanamine gives aminoether 31, which upon treatment with hydroxylamine and heating allows to obtain isoxazol 32. Hydrolysis of ester 32 in acidic conditions, followed by rearrangement of kurzius gives the carbamate 33, after trapping with the use of alcohol, such as tert-butanol. Removal of the carbamate compound 33 in acidic conditions leads to the 4-aminoethoxy 34, which, when combined with the acid chloride of the acid 6 provides the amide 35. Amination of chloride 35 the use of microwave irradiation allows to obtain the compounds of formula 1j.

The scheme is of aacci 10

The compounds of formula 1k can be synthesized according to Scheme 10. Chlorination aryloxy 36 using N-chlorosuccinimide provides obtaining α-chlorobenzaldehyde 37. Treatment of α-chlorobenzaldehyde 37 tertiary aminoven base, such as triethylamine, gives benzonitrile N-oxide, which is involved in the dipolar cyclopentadiene with ether 3-pyrrolidin-1-yl-acrylic acid, obtaining isoxazol 38 (where R represents aalkyl, e.g., ethyl). Hydrolysis of ester 38 in acidic conditions and subsequent rearrangement of kurzius using diphenylphosphinite ensures carbamate 39, after trapping with the use of alcohol, such as tert-butanol. Removal of the carbamate compound 39 in acidic conditions leads to the 4-aminoethoxy 40, which when combined with the acid chloride of the acid 6 provides obtaining amide 41. Amination of chloride 41 using microwave irradiation allows to obtain the compounds of formula 1k.

The reaction scheme 11

The compounds of formula 11 can be synthesized according to Scheme 11. Join arylhydrazines 42 to ethyl 2-cyano-3-ethoxyacrylate provides obtaining 5-amino-1-arylpyrazole 43. Hydrolysis of ester 43 with subsequent decarboxylation of the acid obtained is carried out in acidic conditions to obtain 5-amino-1-arylpyrazole 44, which when combined with the acid chloride of the acid 6 provides obtaining amide 45. Amination of chloride 45 using microwave irradiation allows to obtain the compounds of formula 11.

Upon receipt of the compounds of the present invention, it may be necessary to protect a remote functional group (for example, primary or secondary amine) in the intermediate compounds. The need for such protection depends on the nature of remote functional groups and methods of obtaining. Suitable amino-protective group (NH-Pg) include acetyl, TRIFLUOROACETYL, tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBz) and 9-fluorenylmethoxycarbonyl (Fmoc). The need for such protection can easily identify the person skilled in the art. General description of the protective groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

Compounds of the present invention can be obtained from readily available starting compounds using the General methods illustrated in this application.

METHODS of SEPARATION

In each of the illustrative Schemes can be advantageous separation of the reaction products, separating them from one another and/or from ishodnih substances. The desired products of each stage or series of stages separated and/or purified (hereinafter - share) until the desired degree of homogeneity of the methods traditionally used in the art. Typically such separation include multiphase extraction, crystallization from a solvent or mixture of solvents, distillation, sublimation or chromatography. Chromatography may include any number of ways, including, for example: reversed-phase and normal phase; pressure depending on size; ion-exchange; methods and equipment for liquid chromatography high, medium and low pressure; analytical on a small scale; in the fluidized bed (SMB) and preparative thin - or thick-layer chromatography, as well as large-scale thin-layer chromatography, flash chromatography.

Another class of methods razdeleniya includes processing the mixture with a reagent selected to bind (or to any other way of obespechit the possibility of separation of unreacted educt, a by-product of the reaction or similar substances. Such reagents include adsorbents or absorbents, such as activated carbon, molecular sieves, ion-exchange environment or similar. Alternatively, the reagents can imaginean acid in the case of the basic substance, the base case of acid substances, binding reagents, such as antibodies, binding proteins, selective chelating agents, such as crown-ethers, reagents for liquid/liquid ion extraction (IX) or similar.

The selection of the suitable methods of separation depends on the nature of substances subject to division. For example, boiling point and molecular weight in distillation and sublimation, the presence or absence of polar functional groups in chromatography, stability substances in acid and alkaline environment in multiphase extraction, etc., the person skilled in the art can use the methods that are most likely to achieve the desired separation.

Diastereomer mixture can be divided into their individual diastereoisomers on the basis of their physical chemical differencesways well-known to specialists in this field, such as chromatography and/or fractional crystallization. The enantiomers can be divided by converting the enantiomeric mixture into diastereomer mixture by reacting with an appropriate optically active compound (e.g., chiral auxiliary substance, such as a chiral alcohol or the acid chloride of the acid of Mosera), division of diastereoisomers and by converting (e.g., hydrolysis) of individual diastereoisomers in the corresponding pure enantiomers. Some compounds of the present invention can be atropisomers (for example, substituted biaryl), and consider them as part of this image is the shadow. Enantiomers can also be separated using chiral HPLC column.

Single stereoisomer, e.g., enantiomer, essentially, does not contain its stereoisomer, can be obtained by separation of the racemic mixture using a method such as formation of diastereomers using optically active agents split (Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994; Lochmuller, C. H., J. Chromatogr., 113(3):283-302 (1975)). Racemic mixturechiral compounds of the present invention can be divided and highlight any suitable means, including: (1) formation of ionic diastereomeric salt with the use of chiral compounds and separation by the method of fractional crystallization or other methods, (2) formation of diastereomeric compounds using chiral agents derivatization, separation of the diastereomers, and conversion to the pure stereoisomers and (3) separating essentially pure or enriched stereoisomers directly in the chiral conditions. See: Drug Stereochemistry, Analytical Methods and Pharmacology, Irving W. Wainer, Ed., Marcel Dekker, Inc., New York (1993).

Diastereomeric salt can be formed by interaction of enantiomerically pure chiral bases such as brucine, quinine, ephedrine, strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like with asymmetric compounds that contain asimi acid functional group, such as carboxylic acid and sulfonic acid. Diastereomeric salt can be divided using fractionated crystallization or ion chromatography. For the separation of optical isomers of amino compounds, the addition of chiral carboxylic or sulfonic acids, such as camphorsulfonic acid, tartaric acid, mandelic acid or lactic acid, can lead to the formation of diastereomeric salt.

Alternatively, the substrate to be split, is subjected to the interaction with one enantiomer of chiral compounds with the formation of diastereomeric pair (Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds, John Wiley & Sons, Inc., New York, 1994, p. 322). Diastereomers connection can be formed by the interaction of asymmetric compounds with enantiomerically pure chiral derivatization agents, such as mantilini derivative, followed by separation of the diastereomers and hydrolysis of obtaining pure or enriched enantiomers. The method of determining optical purity involves obtaining chiral esters, such as metalowy ether, for example, (-) methylchloroform, in the presence of a base, or a complex ester Moser, α-methoxy-α-(trifluoromethyl)phenylacetate (Jacob, J. Org. Chem. 47:4165 (1982)), the racemic mixture and the analysis of the NMR spectrum in the presence of two atropisomers enantiomers or diastereomer the ditch. Stable diastereomers atropisomers compounds can be separated and identified with the use of chromatography with normal and reversed phase,following the methods of separation atropisomers naphthyl-isoquinolines (WO 96/15111). In accordance with the method (3), a racemic mixture of two enantiomers can be divided bychromatography using a chiral stationary phase (Chiral Liquid Chromatography W. J. Lough, Ed., Chapman and Hall, New York, (1989); Okamoto, J. of Chromatogr. 513:375-378 (1990)). Enriched or purified enantiomers can be separated by methods used for separation of other chiral molecules with asymmetric carbon atoms, such as optical rotation and circular dichroism.

Isomers, for example, E and Z forms, compounds of the present invention and intermediate compounds for their synthesis can be observed using the methods of analysis, such as NMR and analytical HPLC. For some compounds, where the energy barrier for vzaimoprevrascheny is high enough, the E and Z isomers can be separated, for example by preparative HPLC.

BIOLOGICAL ASSESSMENT

Previous studies have shown that the isolated kinase domain of human JAK2 phosphorylates a peptide substrates in kinase assaysin vitro. Salzman et al., Biochem. Biophys. Res. Commun. 246:627-633 (2004). Catalytically active kinase domain che is avechicago JAK2 was purified from extracts of insect cells SF9, infected with recombinant baculovirus - expressing vector coding for human JAK2 kinase domain (amino acid residues D812-G1132 in accordance with the numbering of GenBank sequence accession number NP_004963.1). The activity of the JAK2 kinase domain, you can measure various direct and indirect ways, including quantification of phosphorylation of peptide substrates derived from human JAK3 protein, Salzman et al., Biochem. Biophys. Res. Commun. 246:627-633 (2004). The activity of the JAK2 kinase domain was measured byin vitroby monitoring phosphorylation originating from JAK3 peptides using the method of Caliper LabChip (see Examples).

INTRODUCTION PYRAZOLOPYRIMIDINONE CONNECTIONS

Another variant implementation includes a method of treating or reducing the severity of the disease or condition responsive to the inhibition of JAK2 kinase activity in a patient. The method involves the step of introducing the patient a therapeutically effectivethe number of compounds of the present invention.

Another variant implementation includes a method of treating or reducing the severity of the disease or condition responsive to the inhibition of the activity of JAK3 kinase in a patient. The method includes the introduction phase the patient a therapeutically effectivethe number of compounds of the present invention.

In one embodiment, the compound present is ademu the invention is administered to the patient in therapeutically effective the amount for treating or reducing the severity of the disease or condition responsive to the inhibition of the activity of the JAK kinase, and the specified connection is at least 10 or more times more selective for inhibition of activity ofJAK2 kinase in comparison with the inhibition activity of each of JAK1, JAK3 and Tyk-2.

In one embodiment, the disease or condition is a cancer, stroke, diabetes, gepatomegalia, cardiovascular disease, multiple sclerosis, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, neurological disorders, a hormone-related disease, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver disease, pathological immune status with T-cell activation, and CNS disorders or myeloproliferative disorder.

In one embodiment, the disease or condition is acancer.

In one embodiment, the disease is amyeloproliferative RA is a device.

In one embodiment, the myeloproliferative disorder is a true polycythemia, essential thrombocytosis, myelofibrosis or chronic myelogenous leukemia (CML).

In one embodiment, the cancer is a cancer of the breast, ovary, cervix, prostate, testicles, penis, urinary tract, seminoma, cancer of the esophagus, larynx, stomach cancer, gastric cancer, gastrointestinal tract, skin, keratoakantoma, follicular carcinoma, melanoma, lung cancer, small cell carcinoma of the lung, non-small cell carcinoma of the lung (NSCLC), adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the colon, pancreas, thyroid, papillary, bladder, liver, bile ducts, kidneys, bones, myeloid disorders, lymphoid disorders, hairy cell cancer, cancer of the buccal cavity and pharynx (oral), lip, tongue, mouth, salivary glands, pharynx, small intestine, colon, rectum, anal, renal, prostate cancer, vulval, thyroid, colon, endometrium, uterus, brain, Central nervous system, cancer of the abdominal cavity, hepatocellular cancer, head neck cancer, Hodgkin's disease or leukemia.

In one embodiment, the cardiovascular disease presented yet a restenosis, cardiomegaly, atherosclerosis, myocardial infarction or congestive heart failure.

In one embodiment, the neurodegenerative disease is a disease of Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, Huntington's disease and cerebral ischemia and neurodegenerative disease caused by traumatic lesions, glutamate neurotoxicity or hypoxia.

In one embodiment, the inflammatory disease is a rheumatoid arthritis, psoriasis, contact dermatitis or allergic reactions of the delayed type.

In one embodiment, the autoimmune disease is a lupus or multiple sclerosis.

The compound of the present invention can be entered by any means appropriate for the disease or condition to be treated. Appropriate ways include oral, parenteral (including subcutaneous, intramuscular, intravenous, procreatively, protricity, intrathecal and epidural), percutaneous, rectal, nasal, local (including buccal and sublingual), vaginal, intraperitoneally, intra-lungs and intranasal. For local immunosuppressive treatment, the compounds can be entered into the lesion, including perfusion or exercise of any other about what atom contact of the graft with the inhibitor before transplantation. It should be clear that the preferred path may vary depending on, for example, from the state of the recipient. When the compound of the present invention is administered orally, it can be formulated in the form ofpills, capsules, tablets, etc. with a pharmaceutically acceptable carrier or excipient. When the compound of the present invention is administered parenterally, it may be formulated with a pharmaceutically acceptable parenteral carrier in a standard dosage form for injection, as described in detail below.

Dose for the treatment of a person who is a patient, may be in the range of from about 10 mg to about 1000 mg of the compounds of the present invention. A typical dose may be about 100 mg to about 300 mg of the compound of the present invention. Dose can be administered once daily (QD), twice a day (BID) or more often, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism and rate of excretion of the specific compound. In addition, the toxicity factors can affect the dose and mode of administration. When ingested by a pill, capsule or tablet can be administered daily or less frequently during a certain period of time. The scheme can be repeated in multiple cycles of therapy.

Another in the version of the implementation includes a method of treating or preventing cancer in a mammal, in need of such treatment, the method includes the introduction of the specified mammal a therapeutically effectivethe amount of compounds of formula I-Ia, its stereoisomer, tautomers, prodrugs or pharmaceutically acceptable salts.

Another variant implementation includes compounds of formula I-Ia, stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt of such compounds for use in therapy.

Another variant of implementation includes the use of compounds of formula I-Ia, its stereoisomer, tautomers, prodrugs or pharmaceutically acceptable salts to obtain drugs for the treatment of diseases described in this application (for example, cancer or inflammatory diseases).

PHARMACEUTICAL COMPOSITIONS PYRAZOLOPYRIMIDINONE CONNECTIONS

Another variant implementation includes a pharmaceutical composition that includes a compound of the present invention and a pharmaceutically acceptable carrier, adjuvant or excipient.

In one embodiment, the pharmaceutical composition also includes an additional therapeutic agent selected from anti-proliferative tools, anti-inflammatories, immune-modulating means, a neurotropic factor, a treatment for cardiovascular disease, the tion for the treatment of liver disease, antiviral agents, agents for the treatment of hematological disorders, a treatment for diabetes or means for treating immunodeficiency disorders.

In one embodiment, the compound of the present invention is present in the pharmaceutical composition in amounts that detektivami way inhibits the activity ofJAK2 kinase, together with a pharmaceutically acceptable carrier, adjuvant or excipient.

In one embodiment, the compound of the present invention is present in the pharmaceutical composition in amounts that detektivami way inhibits the activity of JAK3 kinase, together with a pharmaceutically acceptable carrier, adjuvant or excipient.

In one embodiment, the compound of the present invention is present in the pharmaceutical composition in amounts that detektivami way inhibits the activity of the JAK2 kinase, and is at least 10or more times more selective for inhibition of activity ofJAK2 kinase in comparison with the inhibition activity of each of JAK1, JAK3 and Tyk-2.

A typical composition is prepared by mixing the compounds of the present invention and a carrier, diluent or excipient. Suitable carriers, diluents and excipientswell-known specialists in this the region and include substances such as carbohydrates, waxes, water-soluble and/or vodosnabzhenie polymers, hydrophilic or hydrophobic substances, gelatin, oils, solvents, water, and similar substances. Specific carrier, diluent or excipient depends on the manner and purpose for which connection is used according to the present invention. Solvents are generally selected on the basis of the solvents that are specialist in this field considers safe (GRAS) for administration to a mammal. Generally safe solvents arenon-toxic aqueous solvents such as water and other non-toxic solvents that are soluble in water or miscible with water. Suitable aqueous solvents include water, ethanol, propylene glycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixtures thereof. The composition can also include one or more buffers, stabilizers, surfactants, wetting substances, lubricants, emulsifiers, suspendida substances, preservatives, antioxidants, substances that make the composition opaque, slip agents, processing AIDS, colorants, sweeteners, flavorings, perfumes, and other known additives to obtain drugs (i.e., compounds of the present invention or its containing f is rmaceuticals composition) in a nice looking form or to facilitate the receipt of the pharmaceutical product (i.e., medications).

The composition can be obtained using conventional procedures dissolving and mixing. For example, the bulk drug substance (i.e., the compound of the present invention or stabilized form of connection, such as a complex with cyclodextrins derivative or other known complexing substance) dissolved in a suitable solvent in the presence of one or more of the excipients described above. The compound of the present invention is typically formulated into pharmaceutical dosage forms to provide an easily controllable dosage of the medicinal product and to ensure adherence to the patient's prescribed treatment regimen.

The pharmaceutical composition (or composition) for use may be Packed in various ways depending on the method used for injection of a medicinal product. Typically, a commercial product includes a container placed in a pharmaceutical composition in suitable form. Suitable containers are well known to specialists in this field and include materials such as bottles (plastic and glass), sachets, ampoules, plastic bags, metal cylinders, etc., the Container may also include a device that protects against invasion, obstructing the existing access to the contents of the packaging, when it is not needed. In addition, the container is placed in it a label that describes the contents of the container. The label may also include appropriate warnings.

The pharmaceutical compositions of the compounds of the present invention can be obtained for various routes and types of administration. The compound of the present invention, having the desired degree of purity which is optional, is mixed with pharmaceutically acceptable diluents, carriers, excipients or stabilizers (Remington''s Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.) in the form of a lyophilized composition, fine powder or aqueous solution. The composition can be obtained by mixing, at ambient temperature under suitable pH and when the desired degree of purity with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the used doses and concentrations.the pH of the composition mainly depends on the specific application and concentration of the compound, but may be in the range of from about 3 to about 8. Composition in acetate buffer at pH 5 is a suitable option implementation.

In one embodiment, the compound of the present invention for use in the pharmaceutical composition is essentially sterile. Obedinenie is usually stored in the form of a solid composition, although acceptable, are also freeze-dried composition or aqueous solutions.

The pharmaceutical compositions of the present invention formulated, dosed, and administered way, i.e. with regard to quantity, concentration, schemes introduction, of course, carriers and routes of administration, which is consistent with traditional medical practices. Factors that should be taken into consideration in this context include the particular disorder to be treated, the particular mammal, which is being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery agent, the method of introduction, the scheme of administration and other factors known to the doctors. "Therapeutically effective amount" of a compound that must be entered depends on such factors and represents athe minimum quantity necessary for the prevention, mitigation or treatment of disorders. Such quantities of preferably below the amount that is toxic to the recipient.

As a General proposal, the initial pharmaceutically effective amount of the inhibitor, administered parenterally, per dose, ranges from about 0.01-100 mg/kg, for example, from about 0.1 to 20 mg/kg of body weight of the patient per day, with the typical initial limits the use of connections from 0.3 to 15 mg/khder.

Acceptable diluents, carriers, excipients and stabilizers is non-toxic to recipients at the used doses and concentrations, and include buffers such as phosphate, citrate and other organic acids; antioxidant, including ascorbic acid and methionine; preservatives (such as octadecyltrimethylammonium; hexamethylene; benzylaniline, benzenehexachloride; phenol, butyl or benzyl alcohol; alkylarene, such as methyl or propyl paraben; catechin; resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecular weight (less than about 10 residues) polypeptides; proteins, such as serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, histidine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; hepatoblastoma agents such as EDTA; sugars such as sucrose, mannitol, trehalose or sorbitol; soleobrazutaya counterions, such as ion sodium; metal complexes (e.g., Zn-protein complexes); and/or nonionic surfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Active pharmaceutical ingredients may also be captured in the microcapsules obtained, for example, the methods of the AMI koatservatsii or interfacial polymerization, for example, microcapsules from hydroxymethylcellulose or gelatin and microcapsules of poly-(methyl methacrylate)and, respectively, in colloidal drug-delivery systems (e.g. liposomes, albumen microspheres, microemulsions, nanoparticles and nanocapsules) or in microemulsion. Such technologies are disclosed in Remington''s Pharmaceutical Sciences 16th edition, Osol, A. Ed. (1980).

You can get drugs slow release. Suitable examples of drugs slow release include semi-permeable matrices of solid hydrophobic polymers containing a compound of the present invention, however, such matrices have the form of shaped articles, e.g. films, or microcapsules. Examples of slow release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate) or poly(vinyl alcohol)), polylactide, copolymers ofL-glutamic acid and gamma ethyl-L-glutamate, non-biodegradable ethylene-vinyl acetate, degradable copolymerslactic acid-glycolic acid such as the LUPRON DEPOT™ (microspheres for injection, consisting of a copolymer of lactic acid-glycolic acid and leuprolide) and poly-D-(-)-3-hydroxipropionic acid.

Compositions intended forin vivothe introduction must be sterile, which is easily achieved by means of filtration through erased the global membrane filters.

The compositions include compositions that are suitable for administration ways, described in detail in this application. Songs the easy way can be presented in a standard dosage form, and may be obtained by any method well known in the pharmaceutical field.The methods and compositions can mainly be found in Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA). These include the stage of bringing the active ingredient into Association with a carrier which constitutes one or more accessory ingredients. Typically, the composition is produced by homogeneous and close of bringing into Association the active ingredient with liquid carriers or finely ground solid carriers or both and then, if necessary, shaping the product.

Compositions of the compounds of the present invention suitable for oral administration, can be obtained in the form of discrete units such as pills, capsules, sachets or tablets each containing a predetermined quantity of compounds of the present invention.

Molded tablets can be obtained by molding in a suitable machine the active ingredient in a free flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert what Abbeville, preservative, surface active or dispersing agent. Molded tablets can be obtained by molding in a suitable machine a mixture of the powdered active ingredient, moistened with an inert liquid diluent. Tablets, optionally, may have a coating or a notch and, optionally, may beformulated in such a way as to provide slow or controlled release of the active ingredient.

Tablets, pills, pellets, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, for example, gelatin capsules, syrups or elixirs can be obtained for oral administration. Compositions of the compounds of the present invention, intended for oral administration, can be obtained according to any method known from the prior art to obtain pharmaceutical compositions, and such compositions can contain one or several substances, including sweeteners, flavors, colors and preservatives, to obtain a palatable preparation. Tablets containing the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients, which is suitable for receiving tablets, areacceptable. Such excipients may constitute, for example, inert is thinner, such as calcium carbonate or sodium, lactose, calcium phosphate or sodium; granulating agents or disintegrating agents such as corn starch or alginic acid, binders, such as starch, gelatin or the Arabian gum; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may have a coating applied by known methods, including microencapsulation to slow decomposition and adsorption in the gastrointestinal tract and provide, therefore, a delayed action over a longer period of time. For example, you can use providing the slow action of substances, such as glycerylmonostearate or glycerylmonostearate, alone or with a wax.

In the case of infections of the eye or other external tissues e.g. mouth and skin, the compositions are preferably applied in the form of ointment or cream for topical application containing an active ingredient(the ingredient) in an amount of, for example, of 0.075 to 20% mass/mass. When you get a song in the form of an ointment, the active ingredients can be used with either paraffin or mixed with water as a base for ointments. Alternatively, the active ingredients can be formulated in the form of a cream using a Foundation cream oil-in-water.

If desired, the aqueous phase basis is s for the cream may include a polyhydric alcohol, i.e. alcohol containing two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. Preferably, when the composition for local usecan include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such amplifiers percutaneous penetration include dimethyl sulfoxide and related analogues.

The oil phase of the emulsions according to the present invention may be constituted from known ingredients in a known manner. Although this phase may include only the emulsifier (otherwise known as “emergent”), preferably, when it includes a mixture of at least one emulsifier with a fat or oil or a fat and oil. Preferably, the hydrophilic emulsifierinclude together with a lipophilic emulsifier, which acts as a stabilizer. Also preferably, the inclusion of both oils and grease. Together, the emulsifier(emulsifying agents) anti-roll(stabilizer) or without forming a so-called emulsifying wax, and the wax together with the oil and fat form the so-called emulsifying base for ointments, which forms the oily dispersed phase of the compositions of the cream. Emulsifiers and emulsion stabilizers suitable for use in the notizie of the present invention, include Tween® 60, Span® 80, cetosteatil alcohol, benzyl alcohol, ministerului alcohol, glycerylmonostearate and sodium lauryl sulfate.

Aqueous suspensions of the present invention contain the active substance in a mixture with excipients suitable for receiving water suspensions. Such excipients include suspendisse substance, such as sodium carboxymethyl cellulose, crosscarmellose, povidone, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, gum tragakant and Arabian gum, and dispersing or wetting agents such as natural phosphatic (e.g., lecithin),the product of condensation of alkylated (for example, ethylene oxide, propylene oxide) with fatty acid (for example, polyoxyethylenated), condensation products ofof ethylene oxide and long-chain aliphatic alcohol (for example, heptadecafluorooctyl), condensation products ofof ethylene oxide partial complex ester derived fatty acid and lexicalized (for example, polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxybenzoate, one or more dyes, one or more fragrances, and one or more sweeteners, such as sucrose or saccharin.

Pharmaceutical HDMI is tion of the compounds of the present invention may be in the form of a sterile preparation for injection, such as a sterile aqueous or oily suspension for injection. This suspension can be formulated in accordance with the method known from the prior art, using suitable dispersing or wetting agents and suspendida substances that have been described above. A sterile preparation for injection may also be in the form of a sterile solution or suspension for injection in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diole, or can be obtained in the form of lyophilized powder. Acceptable vehicles and solvents that can be used, you can specify the water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils traditionally used as a solvent or medium for suspension. For these purposes you can use any light non-volatile oils, including synthetic mono - or diglycerides. In addition, fatty acids such as oleic acid, can also be used in preparations for injection.

The amount of active ingredient which can be combined substance-carrier to obtain a single unit dosage form varies depending on the host, the host treated and the particular route of administration. For example, the composition with the release on the straps, intended for oral administration to humans may contain from about 1 to 1000 mg of active substance, combined with an appropriate and convenient amount ofsubstance carrier, which may vary from about 5 to about 95% of the total amount of the composition (mass.:mass.). The pharmaceutical composition can be obtained to provide easily measured quantities for injection. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of the active ingredient per milliliter of solution for administration by infusion of a suitable volume at a rate of about 30 ml/hour.

Compositions suitable for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostatic substances and dissolved substances, which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that can include suspendresume substances and thickeners.

Compositions suitable for local injection into the eye also include eye drops, where the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such com is Aziziyah in a concentration of from 0.5 to 20%, more preferably from 0.5 to 10%, in particular about 1.5% mass/mass.

Compositions suitable for local injection in the mouth include pellet comprising the active ingredient in having a pleasant taste, usually such as sucrose and the Arabian gum or tragakant; lozenges comprising the active ingredient ininert basis such as gelatin and glycerin or sucrose and Arabian gum; and gargle for the mouth including the active ingredient in a suitable liquid carrier.

Compositions for rectal injection can be presented in the form of a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.

Composition suitable for intra-lungs or nasal administration, have a particle size, for example, in the range from 0.1 to 500 microns (including particle sizes in the range from 0.1 to 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth to reach the goal. Suitable compositions include aqueous or oily solutions of the active ingredient. Compositions suitable for administration in the form of an aerosol or dry powder, can be obtained in accordance with the traditional methods, and they can be delivered with other therapeutic means, such as compounds that BC is now used for the treatment or prevention of HIV infections, as is described below.

Compositions suitable for vaginal administration, can be presented as pessaries, tampons, creams, gels, pastes, foams or spray compositions containing, in addition to the active ingredient such carriers, which are known from the prior art as suitable.

The composition can be packaged in a single dose or mnogorazovye containers, for example sealed ampoules and vials, and can be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, for example water for injections, immediately prior to use. Improvised solutions and suspensions for injection is obtained from sterile powders, granules and tablets, such as described above. Preferred compositions of standard dosage forms referred to are those containing a daily dose or subunit daily dose, as indicated in this application above, or an appropriate part of the dose of the active ingredient.

The present invention also provides a receiving veterinary compositions comprising at least one active ingredient, as defined above, together with used in veterinary carrier. Used in veterinary carriers are substances that are useful for administering the composition and may be the Wallpaper solid, liquid or gaseous substances which are inert or acceptable in the veterinary medicine and arecompatible with the active ingredient. These veterinary compositions can be entered parenteral, oral or in any other desirable way.

COMBINATION THERAPY

The compound of the present invention can be combined, inpharmaceutical joint composition or mode of administration as combination therapy, with a second compound that has anti-hyperproliferative or chemotherapeutic properties, which is useful for the treatment of diseases or disorders responsive to the inhibition of JAK kinases, for example, hyperproliferative disorders (e.g., cancer), or which is useful in treating other disorders, specified in this application. The second compound of the pharmaceutical combination composition or mode of administration preferably has activity complement activity of the compounds of the present invention, which is part of this combination, therefore, they do not have any adverse effect on each other. Such molecules are suitably present in combination in amounts that are effective for the purposes intended.

So another option exercise included the t method of treating or reducing the severity of the disease or condition, responsive to inhibition of JAK2 kinase activity in a patient, including the introduction of the indicated patient a therapeutically effectivethe number of compounds according to the present invention and, in addition, including the introduction of a second chemotherapeutic agents.

Another variant implementation, therefore, includes a method of treating or reducing the severity of the disease or condition responsive to the inhibition of the activity of JAK3 kinase in a patient, including the introduction of the indicated patient a therapeutically effectivethe number of compounds according to the present invention and, in addition, including the introduction of a second chemotherapeutic agents.

Combination therapy can be entered using the simultaneous or sequential administration. The sequential introduction, this combination can be entered using two or more injections. The combined introduction includes co-administration, using separate compositions or in a single pharmaceutical composition, as well as the consistent introduction in any order, but preferably there is a time period during which both (or all) active funds simultaneously exert their biological activity.

Suitable dosages for any of the above in conjunction input means are such that sportsouth currently, and can be reduced, due to the combined action (synergy) of the new identified tools and other chemotherapeutic agents or treatments.

Combination therapy may provide "synergy" and to be “synergistic”, i.e., the effect achieved by the joint use of active ingredients is greater than the sum of the effects that come with the separate use of such compounds. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined composition, representing a standard dosage form; (2) delivered serially or in parallel as separate compositions; or (3) using any other mode of administration. When delivered in the form of alternating therapy, a synergistic effect can be obtained when the compound is administered or delivered sequentially, for example, by separate injections in separate syringes. Typically, when alternating therapythe effective dose of each active ingredient is administered sequentially, i.e., serially, whereas in the combination therapy effective dose of two or more active ingredients are administered together.

METABOLITES PYRAZOLOPYRIMIDINONE CONNECTIONS

Another variant implementation includesin vivothe Metabo is practical products of the introduced compound of the present invention. Such products can be formed, for example, oxidation, recovery, hydrolysis, amidation, deliciouse, esterification, deesterification, enzymatic degradation, etc. of the input connections.

Metabolic productstypically identified by obtaining radiochango (for example,14With or3H) isotope compounds of the present invention, the introduction of its parenteral dose, which makes possible its detection (e.g., greater than about 0.5 mg/kg) to an animal such as rat, mouse, Guinea pig, monkey, or to man, allowing sufficient time for metabolism (typically from about 30 seconds to 30 hours) and highlighting its transformation products from the urine, blood or other biological samples. These products can be easily isolated, as they are labeled (other products secrete antibody, is able to connect with epitopes of surviving metabolite). Patterns of metabolites determined in the traditional way, for example, by analysis of MS, LC/MS or NMR. Typically, the analysis of metabolites carried out in the same way as the commonly used methods for studying metabolism of drugs that are well known to specialists in this field. The transformation products, if they are not found in any other about what atom in vivoare useful for diagnostic assays for determining therapeutic doses of the compounds of the present invention.

INDUSTRIAL PRODUCTS

Another variant implementation includesset for treatment of diseases or disorders responsive to the inhibition of JAK kinases. The set includes:

(a) a first pharmaceutical composition comprising a compound of the present invention; and

(b) instructions for use.

In another embodiment, the kit additionally includes:

(c) a second pharmaceutical composition, which comprises a chemotherapeutic agent.

In one embodiment, thethe instructions include instructions for simultaneous, sequential or separate introduction of these first and second pharmaceutical compositions to a patient in need of it.

In one embodiment, the first and second compositions are contained in separate containers.

In one embodiment, the first and second compositions are contained in the same container.

Containers for use include, for example, bottles, vials, syringes, blister packaging, etc., Containers can be made of various materials, such as glass or plastic. The container includes a compound of the present invention or its containing composition, which is s are effective for treating the condition, and may have a sterile access hole (for example, the container may contain a package with intravenous solution or vial having a stopper which can be pierced by hypodermic needle for injection). The container includes a composition including at least one compound of the present invention. Label or an insert in the packaging indicates that the composition is used to treat a certain condition, such as cancer. In one embodiment, the label or inserts in the packaging indicates that the composition comprising the compound of the present invention, can be used for treatment of a particular disorder. In addition, the label or the liner in the package may indicate that the patient to be treated, this is a patient whosethere is a disorder characterized by excessive or abnormal kinase activity. The label or the liner in the package can alsoto indicate that the composition can be used to treat other disorders.

Industrial product may include (a) a first container with a compound of the present invention contained therein; and (b) a second container with a second pharmaceutical composition contained therein, while the second pharmaceutical composition comprises a chemotherapeutic agent. Industrial product which this embodiment of the present invention, in addition, may include an insert in the packaging indicating that the first and second connections can be used to treat patients at risk of disorders such as stroke, blood clots or thrombosis. Alternative or additionally, industrial product, in addition, may include thethe second (or third) container comprising a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate-buffered saline,the ringer's solution and dextrose. It may also include other substances which are desirable from a commercial point of view or from the point of view of the consumer, including other buffers, diluents, filters, needles and syringes.

In one embodiment, compounds of the present invention can be used for control of JAK kinases, tyrosine kinases, additional serine/treoninove kinases and/or protein kinases with dual specificity. Thus, they are useful as pharmacological standards for use in the development of new biological tests and analyses in the search for new pharmacological agents.

Compounds of the present invention can be tested for their ability to modulate the activity of JAK kinases, tyrosine kinases, additional serine/treoninove kinases and/or to the nae with dual specificity in vitroandin vivo.In vitrotests include biochemical and cellular assays that determine inhibition of kinase activity. Otherin vitrothe tests are designed to quantify the ability of the compound of the present invention to contact kinases, and this can be measured either by radioactive labeling of the compounds of the present invention to binding, separation of the complex compound of the present invention/the kinase and determine the amount of bound radioactive label, or by conduct competitive analysis, where the compound of the present invention is incubated with a known radiocanada ligands. These and other usefulin vitroassays well known to specialists in this field.

To illustrate the present invention the following examples are included. However, it should be clear that these examples do not limit the present invention only and are intended to suggest ways of implementation in practice of the present invention. Professionals in this field should be clear that the described chemical reaction can be easily adapted to obtain other compounds of the present invention, and alternative methods of producing compounds of the present invention is included in the scope of the present invention. For example, the synthesis connect the developments of the present invention, which are not illustrated with examples, can be successfully carried out using modifications, obvious to a person skilled in this field, for example, by protecting interfering reaction groups as appropriate, through the use of other suitable reagents known in the prior art, other than those described in the present invention, and/or through the implementation of routine modifications of reaction conditions. Alternatively, other reactions disclosed in this application or known from the prior art, will be recognized as suitable to obtain other compounds of the present invention.

BIOLOGICAL EXAMPLES

Activity of selected kinase domain of JAK2 can be measured by monitoring the phosphorylation of peptide substrates derived from human JAK3 kinase,in vitro(Saltzman et al, Biochem. Biophys. Res. Commun. 246:627-633 (2004). Human JAK2 kinase domain expressed using N-terminal His6 tag, and then the cleavage site of thrombin using baculovirus expressing vector. Expressed kinase domain were identified as amino acid residues D812-G1132, in accordance with the numbering of GenBank access number sequence NP_004963.1. Recombinant vectors for DNA transfer to-transfusional using BakPAK6 linearized DNA (Clontech Laboratories, Inc., Mountain View, CA) and p is obtained initial viral products amplified using standard protocols. Protein was produced in SF9 cells, which were grown to a density of 2E6 cells/ml in ESF921 medium (Expression Systems LLC, Woodland, CA) and were infected with M. O. I=1 in Wave bioreactors. Cells were collected 72 hours after infection and active JAK2 enzyme was purified from lysates of infected cells using Ni-NTA (Qiagen, Valencia, CA) column chromatography, followed Sephacryl S-200 (GE Healthcare, Piscataway, NJ) column chromatography.

Previous studies have shown that the isolated kinase domains of human JAK1, JAK2, JAK3 or TYK2 phosphorylate a peptide substrate in thein vitrokinase assays (Saltzman et al., Biochem. Biophys. Res. Commun. 246:627-633 (2004)). Catalytically active kinase domain of human JAK1, JAK2, JAK3 or TYK2 was purified from extracts of SF9 insect cells infected with recombinant baculovirus expressing vector coding for human JAK1, JAK2, JAK3 or TYK2 kinase domains (JAK1 amino acid residues N852-D1154 in accordance with the numbering of GenBank access number sequence P23458, JAK2 amino acid residues D812-G1132 in accordance with the numbering of GenBank access number sequence NP_004963.1; JAK3 amino acid residues S783-S1124 in accordance with the numbering of GenBank access number sequence P52333, and TYK2 amino acid residues N873-C 1187 in accordance with the numbering of GenBank access number sequence P29597). The activity of JAK1, JAK2, JAK3 or TYK2 kinase domain mo is to measure various direct and indirect ways, including quantification of phosphorylation of peptide substrates derived from human JAK3 protein (Saltzman et al., Biochem. Biophys. Res. Commun. 246:627-633 (2004)). The activity of JAK1, JAK2, JAK3 or TYK2 kinase domain was measured byin vitroby monitoring phosphorylation originating from JAK3 peptides using the method of Caliper LabChip.

Example a

Protocol analysisinhibition of JAK2

The activity highlighted the JAK2 kinase domain was measured by monitoring phosphorylation of a peptide derived from JAK3 (Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr), fluorescently labeled N-end 5-carboxyfluorescein using the Caliper LabChip (Caliper Life Sciences, Hopkinton, MA). To determine the inhibition constants (Ki), was carried out by serial dilution of compounds in DMSO and added to 50 μl of the mixtures for kinase reactions containing 0.2 nm purified JAK2 enzyme, 100 mm Hepes pH7,2, of 0.015% Brij-35, 1.5 μm peptide substrate, 25 μm ATP, 10 mm MgCl2, 4 mm DTT at a final concentration of DMSO 2%. Reactions were incubated at 22°C in 384-well polypropylene microtiter tablets for 30 minutes and then stopped by adding 25 µl containing EDTA solution (100 mm Hepes pH of 7.2, of 0.015% Brij-35, 150 mm EDTA), obtaining a final concentration of 50 mm EDTA. After the termination of the kinase reaction, the relative amount of phosphorylated product was determined ka is the fraction of the total peptide substrate using the Caliper LabChip 3000, in accordance with the manufacturer's instructions. Then determine the values of Kiusing the model of Morrison durable binding. Morrison, J. F., Biochim. Biophys. Acta. 185:269-296 (1969); William, J. W. and Morrison, J. F., Meth. Enzymol, 63:437-467 (1979).

Example B

Protocol analysis of inhibition of JAK1 and TYK2

The activity highlighted JAK1 or TYK2 kinase domain was measured by monitoring phosphorylation of a peptide derived from JAK3 (Val-Ala-Leu-Val-Asp-Gly-Tyr-Phe-Arg-Leu-Thr-Thr), fluorescently labeled N-end 5-carboxyfluorescein using the Caliper LabChip (Caliper Life Sciences, Hopkinton, MA). To determine the inhibition constants (Ki) was carried out by serial dilution of compounds in DMSO and added to 50 μl of the mixtures for kinase reactions containing 1.5 nm JAK1, 0.2 nm purified JAK2 or 1 nm purified TYK2 enzyme, 100 mm Hepes pH7,2, of 0.015% Brij-35, 1.5 μm peptide substrate, 25 μm ATP, 10 mm MgCl2, 4 mm DTT at a final concentration of DMSO 2%. Reactions were incubated at 22°C in 384-well polypropylene microtiter tablets for 30 minutes and then stopped by adding 25 µl containing EDTA solution (100 mm Hepes pH of 7.2, of 0.015% Brij-35, 150 mm EDTA) to obtain a final concentration of 50 mm EDTA. After the termination of the kinase reaction the relative amount of phosphorylated product was defined as the proportion of the total number of peptide substrate using the Caliper LabChip 3000,in accordance with the manufacturer's instructions. Then determine the values of Kiusing the model of Morrison strong binding (Morrison, J. F., Biochim. Biophys. Acta. 185:269-296 (1969); William, J. W. and Morrison, J. F., Meth. Enzymol, 63:437-467 (1979)).

Example C

Protocol analysis of inhibition of JAK3

The activity highlighted JAK3 kinase domain was measured by monitoring phosphorylation of a peptide derived from JAK3 (Leu-Pro-Leu-Asp-Lys-Asp-Tyr-Tyr-Val-Val-Arg), a fluorescently labeled N-end 5-carboxyfluorescein using the Caliper LabChip (Caliper Life Sciences, Hopkinton, MA). To determine the inhibition constants (Ki), was carried out by serial dilution of compounds in DMSO and added to 50 μl of the mixtures for kinase reactions containing 5 nm purified JAK3 enzyme, 100 mm Hepes pH7,2, of 0.015% Brij-35, 1.5 μm peptide substrate, 5 μm ATP, 10 mm MgCl2, 4 mm DTT at a final concentration of DMSO 2%. Reactions were incubated at 22°C in 384-well polypropylene microtiter tablets for 30 minutes and then stopped by adding 25 µl containing EDTA solution (100 mm Hepes pH of 7.2, of 0.015% Brij-35, 150 mm EDTA) to obtain a final concentration of 50 mm EDTA. After the termination of the kinase reaction the relative amount of phosphorylated product was defined as the proportion of the total number of peptide substrate using the Caliper LabChip 3000, in accordance with the manufacturer's instructions. Then determine the values of Kithe BL is reattaching the model of Morrison strong binding (Morrison, J. F., Biochim. Biophys. Acta. 185:269-296 (1969); William, J. W. and Morrison, J. F., Meth. Enzymol, 63:437-467 (1979)).

Example D

Cellular pharmacological tests

Activity of compounds was determined in cellular assays, which are designed to measure JAK2-dependent signal or proliferation. Was carried out by serial dilution of compounds in DMSO and incubated with Set-2 cells (German Collection of Microorganisms and Cell Cultures (DSMZ); Braunschweig, Germany), which Express JAK2V617F mutant protein in 96-well microtiter tablets for 1 hour at 37°C in RPMI medium at finite density of 100,000 cells per well and a final DMSO concentration of 0.57%. Indirect connections effects onphosphorylation of STAT5 then measured in the lysates incubated cells using the method of Meso Scale Discovery (MSD) (Gaithersburg, Maryland), in accordance with the Protocol of the manufacturer, and determine the values of EC50. Alternatively, serially diluted compounds were added to 384-well microtiter plates in RPMI medium with 10% fetal bovine serum (Invitrogen Corp.; Carlsbad, CA), at finite density of 2500 cells per well and a final DMSO concentration of 0.3%, and incubated at 37°C for 72 hours. Then determined the cell viability using the test kit CellTiter-Glo® Luminescent Cell Viability Assay according to the Protocol of the manufacturer (Promega; Madison, WI), and determined the EC50 values.

Activity is connected to the th was determined in cellular assays, which are designed to measure TYK2-dependent signal. Was carried out by serial dilution of compounds in DMSO and incubated with NK92 cells (American Type Culture Collection (ATCC); Manassas, VA) in 96-well microtiter tablets for 1 hour at 37°C in RPMI medium at finite density of 100,000 cells per well and a final DMSO concentration of 0.57%. Then in microtiter plates, containing NK92 cells and connection, added human recombinant IL-12 (R&D systems; Minneapolis, MN) at a final concentration of 10 ng/mland the plates were incubated for 1 hour at 37°C. Indirect connections effects onphosphorylation of STAT4 then measured in the lysates incubated cells using the method of Meso Scale Discovery (MSD) (Gaithersburg, Maryland), in accordance with the manufacturer's Protocol, and was determined EC50 values.

Activity of compounds was determined in cellular assays, which are designed to measure JAK1 or JAK2-dependent signal. Was carried out by serial dilution of compounds in DMSO and incubated with TF-1 cells (American Type Culture Collection (ATCC); Manassas, VA) in 384-well microtiter tablets in OptiMEM medium without phenol red, 1% FBS, which was preliminarily subjected to a desorption treatment with charcoal/dextran, 0.1 mm NEAA, 1 mm sodium pyruvate (Invitrogen Corp.; Carlsbad, CA), at finite density of 100,000 cells per well and a final DMSO concentration of 0.2%. Then in microtitre the performance communications tablets, containing TF-I cells and connection, added human recombinant IL-6 (R&D systems; Minneapolis, MN) or EPO (Invitrogen Corp.; Carlsbad, CA) at a final concentration of 30 ng/ml or 10 Units/ml, respectively, and the plates were incubated for 30 minutes at 37°C. Indirect connections effects onphosphorylation of STAT3 or STAT5 then measured in the lysates incubated cells in the presence of IL-6 or EPO, respectively, using the methodMeso Scale Discovery (MSD)(Gaithersburg, Maryland), in accordance with the manufacturer's Protocol, and was determined EC50 values.

PREPARATIVE EXAMPLES

In the examples described below, unless otherwise indicated, all temperatures are in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge, and used without further purification unless otherwise stated.

The reactions described below were carried out mainly under positive pressure of dry nitrogen, unless otherwise stated), in anhydrous solvents.

Column chromatography was performed on a Combiflash system (Manufacturer: Teledyne Isco) that includes a column with silica gel, the traditional method flash chromatography on silica gel or by using reverse-phase HPLC on C-18 column using as eluent acetonitrile/water containing either 0.1% of triperoxonane acid (TFA) or 0.1% of formic key is lots. 1H NMR spectra were recorded on a device Bruker, operating at 400 MHz or 500 MHz.1H NMR spectra were obtained as solutions in CDCl3or d6-DMSO (indicated at M. D.), using tetramethylsilane as standard (0,00 memorial plaques). When specifying the multiplicity of peaks used the following abbreviations: s (singlet), d (doublet), t (triplet), m (multiplet), user. (broadened), DD (doublet of doublets), dt (doublet of triplets). Constant interaction (J), when they are presented, specified in Hertz (Hz).

Example 1

5-(3-chlorobenzylamino)-N-cyclohexylphenol[1,5-α]pyrimidine-3-carboxamide

pyrazolo[1,5-α]pyrimidine-5-Olathe sodium

A mechanically stirred mixture of 3-aminopyrazole (9,38 g 0,11 mm, 1.0 EQ.), 1,3-dimethyluracil (14,7 g 0,11 mm, 1.0 EQ.) and 21% of ethoxide sodium in ethanol (170 ml, 5.0 EQ.) they were heated to the boiling temperature under reflux. Within a few minutes there was a formation of a heavy precipitate. After boiling under reflux for 1 hour, 1,3-dimethyluracil no longer determined by thin-layer chromatography (TLC) (92:8 dichloromethane (dichloromethane):MeOH). The reaction mixture was cooled, filtered, washed with cold ethanol and dried in vacuum to obtain 13,47 g (95%) pyrazolo[1,5-α]pyrimidine-5-olate sodium. LCMS (ESI) m+H=136,0;1H NMR (40 MHz, DMSO-d6) δ: 8.0 a (d, 1H), 7,43 (d, 1H), 5,65 (d, 1H), lower than the 5.37 (d, 1H).

pyrazolo[1,5-α]pyrimidine-5(4H)-he

Pyrazolo[1,5-α]pyrimidine-5-Olathe sodium (13,47 g) was dissolved in 500 ml of acetic acid and 100 ml of water, was stirred for 15 minutes, then evaporated to dryness in vacuum. The residue is suspended in 300 ml of a mixture of 9:1 dichloromethane:methanol and filtered under vacuum through silica gel to remove sodium acetate. The layer of silica gel was washed using 700 ml of additional solution of dichloromethane:methanol. The combined solution of dichloromethane:methanolconcentrated to dryness. The solid product is suspended in a mixture of 1:1 hexane:dichloromethane and filtered to obtain 9,9 g (85%) pyrazolo[1,5-α]pyrimidine-5(4H)-she. LCMS (ESI) m+H=136,0;1H NMR (400 MHz, DMSO-d6) δ: 12,1 (with a wide exchanged, 1H), of 8.47 (d, 1H, J=7,9), of 7.75 (d, 1H, J=1,9), 5,94 (d, 1H, J=7,5), of 5.81 (d, 1H, J=1,7).

3-Moderato [1,5-α]pyrimidine-5(4H)-he

Pyrazolo[1,5-α]pyrimidine-5(4H)-he (1.0 g, 7.4 mm, 1.0 EQ.) and N-iodosuccinimide (1,67 g, 7.4 mm, 1.0 EQ.) combined with 20 ml of DMF and slightly heated. Within minutes formed a heavy precipitate. The reaction mixture was stirred for 1 hour at ambient temperature, then cooled on ball of ice-water and filtered. The collected solid was washed using 20 ml of dichloromethane and dried in air to obtain 1.66 g (86%) 3-and pyrazolo[1,5-α]pyrimidine-5(4H)-she. LCMS (ESI) m+H=262,2;1H NMR (400 MHz, DMSO-d6) δ: 12,1 (s, 1H), and 8.5 (d, 1H, J=7,6), to 7.84 (s, 1H), 6,01 (d, 1H, J=7,1).

methyl 5-oxo-4,5-dihydropyrazolo[1,5-α]pyrimidine-3-carboxylate

A mixture of 3-Moderato[1,5-α]pyrimidine-5(4H)-she (1.5 g, 5,7 mm, 1.0 EQ.), of palladium acetate, or 0.27 g, 1.2 mm, 0.2 equiv.) triethylamine (2.3 ml, 17 mm, 3.0 EQ.) and 75 ml of methanol was stirred, was degirolami twice under vacuum with nitrogen purge), then created a shell of carbon monoxide using a cylinder. The reaction mixture was heated to 55°C for 5 hours. Analysis TLC (95:5 dichloromethane:methanol) showed complete reaction. The reaction mixture was filtered through celite and concentrated in vacuum. The residue was recrystallized from water and filtered to obtain 0,81 g (73%) of methyl 5-oxo-4,5-dihydropyrazolo[1,5-α]pyrimidine-3-carboxylate, which had a purity of 97.6% according to HPLC.1H NMR (400 MHz, DMSO-d6) δ: 11,0 (user.s, 1H), 8,58 (d, 1H), 8,19 (s, 1H), to 6.19 (d, 1H), 3,80 (s, 3H).

5-oxo-4,5-dihydropyrazolo[1,5-α]pyrimidine-3-carboxylic acid

A solution of methyl 5-oxo-4,5-dihydropyrazolo[1,5-α]pyrimidine-3-carboxylate (0.75 g, to 3.89 mm, 1.0 EQ.), of lithium hydroxide (0,466 g of 19.4 mm, 5.0 equiv.) and 20 ml of water was stirred at ambient temperature for 3 hours. The HPLC analysis showed complete reaction. Was added acetic acid (5 ml) and the precipitated solid prophetic the TWT was collected by filtration under vacuum to obtain 0.65 g (93%) of 5-oxo-4,5-dihydropyrazolo[1,5-α]pyrimidine-3-carboxylic acid. 1H NMR (400 MHz, DMSO-d6) δ: 12,5 (user.s, 1H), 11,3 (user.s, 1H), to 8.57 (d, 1H), 8,08 (d, 1H), x 6.15 (d, 1H).

5-chloropyrazole[1,5-α]pyrimidine-3-carbonylchloride

A mixture of 5-oxo-4,5-dihydropyrazolo[1,5-α]pyrimidine-3-carboxylic acid (371 mg, 2.1 mm, 1.0 EQ.), the phosphorus oxychloride (20 ml) and N,N-diisopropylethylamine (1,2 mo, 6.9 mm, 3.3 EQ.) boiled under reflux for 2 hours. The reaction mixture was cooled and concentrated under reduced pressure. Was carried out by absorption of the residue in dichloromethane and concentrated again 3 times. The residue was distributed between water and dichloromethane. The dichloromethane layer was dried with sodium sulfate, was filtered under vacuum through a layer of silica gel and concentrated to obtain 390 mg (87%) 5-chloropyrazole[1,5-α]pyrimidine-3-carbonylchloride in the form of a yellow solid, which was used directly without further purification.

5-chloro-N-cyclohexylphenol[1,5-α]pyrimidine-3-carboxamide

To a stirred solution of the crude 5-chloropyrazole[1,5-α]pyrimidine-3-carbonylchloride (200 mg, 0.9 mm, 1.0 EQ.) in 15 ml of dichloromethane was added cyclohexylamine (400 μl, 4.0 mm, 4 EQ.). The reaction mixture was stirred for 15 minutes then extinguished using 0.4 ml of acetic acid. The reaction mixture was concentrated under reduced pressure and the residue is especilaly between water and dichloromethane. The dichloromethane phase was concentrated and the crude product was purified flash chromatography on silica gel (97:3 dichloromethane methanol) to give 310 mg (100%) 5-chloro-N-cyclohexylphenol[1,5-α]pyrimidine-3-carboxamide. LCMS (ESI) m+H=279,1;1H NMR (400 MHz, CDCl3) δ: 8,66 (s, 1H), 8,65 (d, 1H), 7,47 (d (wide exchanged) 1H), 6,93 (d, 1H), 4,08 (m, 1H), 2,02 (m, 2H), 1,80 (m, 2H), 1,62 (m, 1H), 1,40 (m, 5H).

5-(3-chlorobenzylamino)-N-cyclohexylphenol[1,5-α]pyrimidine-3-carboxamide

A solution of 5-chloro-N-cyclohexylphenol[1,5-α]pyrimidine-3-carboxamide (28 mg, 0.09 mm, 1.0 EQ.), 3-chlorobenzylamino (28 mg, 0.18 mm, 2.0 equiv.) N,N-diisopropylethylamine (26 mg, 0.18 mm, 2.0 EQ.) and 2 ml of ethanol was heated using microwave irradiation at 120°C for 10 minutes. Analysis TLC (95:5 dichloromethane:methanol) showed complete reaction. The reaction mixture was cooled, the crystalline product was collected by filtration, washed with cold ethanol and dried in the air to receive to 29.7 mg (77%) of 5-(3-chlorobenzylamino)-N-cyclohexylphenol[1,5-α]pyrimidine-3-carboxamide. LCMS (ESI) m+H=384,2;1H NMR (400 MHz, DMSO-d6) δ: 8,61 (overlapping d and t, 2H), of 8.06 (s, 1H), 7,60 (d, 1H), 7,4-7,25 (m, 4H), of 6.49 (d, 1H), 3,70 (m, 1H), about 1.75 to 1.5 (m, 5H), 1,4-0,8 (m, 5H).

Example 2

5-amino-N-(1-(3-chlorophenyl)-3-methyl-1H-pyrazole-5-yl)pyrazolo-[1,5-α]pyrimidine-3-carboxamide

5 the PRS-N-(l-(3-chlorophenyl)-3-methyl-1H-pyrazole-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide

A solution of 5-chloropyrazole[1,5-α]pyrimidine-3-carbonylchloride (150 mg, 0,69 mm, 1.0 EQ.), 1-(3-chlorophenyl)-3-methyl-1H-pyrazole-5-amine (140 mg, 0,69 mm, 1.0 EQ., available from Enamine Ltd., Cincinnati, OH Cat# EN300-02447), N,N-diisopropylethylamine (of 0.18 ml, 1.0 mm, 1.0 EQ.) and 15 ml of dichloromethane was stirred at ambient temperature for 3 days. The reaction mixture was distributed between dichloromethane and water. The dichloromethane phase was dried over sodium sulfate and filtered under vacuum over silica gel. The layer of silica gel was washed with a mixture of 95:5 dichloromethane:methanol. The combined filtrates were concentrated to obtain 250 mg (93%) of 5-chloro-N-(l-(3-chlorophenyl)-3-methyl-1H-pyrazole-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide which had a purity of 74% according to HPLC, and it was used without additional purification. IHMS (ESI) m+H=387,2, (two isotopes of chlorine).

A mixture of 74% pure 5-chloro-N-(l-(3-chlorophenyl)-3-methyl-1H-pyrazole-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide (55 mg, 0.14 mm, 1.0 EQ.) and 3 ml of concentrated ammonium hydroxide was tightly closed and heated in a microwave reactor at 105°C for 30 minutes. The reaction mixture was cooled and the precipitated product was collected by filtration to obtain 25 mg (48%) of 5-amino-N-(1-(3-chlorophenyl)-3-methyl-1H-pyrazole-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide, which was purified by reversed-phase chromatography on C-18 using a mixture of acetonitrile/water (gradi is NT 0→60, 0.1% of TFA) and liofilizirovanny. IHMS (ESI) m+H=368,3 (one isotope of chlorine),1H NMR (400 MHz, DMSO-d6) δ: 9,94 (s, 1H), 8,66 (d, 1H), to 8.20 (s, 1H) to 7.67 (s, 1H), EUR 7.57 (d, 1H), 7,49 (DD, 1H), 7,44 (d, 1H), 6.89 in (user.s, 1H), 6,40 (overlapping d and s, 2H), and 2.26 (s, 3H).

Example 3

N-isopropyl-5-(pyridine-3-ylethoxy)pyrazolo[1,5-α]pyrimidine-3-carboxamide

5-chloro-N-isopropylpyrazole[1, 5-α]pyrimidine-3-carboxamide

A mixture of 5-oxo-4,5-dihydropyrazolo[1,5-α]pyrimidine-3-carboxylic acid (2.0 g, 10 mm, 1.0 EQ.), 30 ml of phosphorus oxychloride (300 mm, 30 EQ.) and N,N-diisopropylethylamine (8 ml, 40 mm, 4 EQ.) was heated with stirring to the boiling temperature under reflux for 2 hours. The reaction mixture was cooled and concentrated in vacuum. The brown oil was absorbed in dichloromethane and was added Isopropylamine (3 ml, 30 mm, 3 EQ.). The reaction mixture was stirred for 5 minutes, and then was distributed between ethyl acetate and water. The organic phase was washed with saturated saline solution, dried over sodium sulfate and filtered under vacuum through a layer of silica gel. The filtrate was concentrated and cooled and the crystallized product was collected by filtration to obtain 2,31 g (90%) of 5-chloro-N-isopropylpyrazole[1,5-α]pyrimidine-3-carboxamide. IHMS (ESI) m+H=239,1 (mono-chlorinated isotope)1H NMR (400 MHz, DMSO-d6) δ: was 9.33 (d, 1H), and 60 (C, 1H), 7,47 (d, 1H), was 7.36 (d, 1H), 4.09 to (m, 1H), 1,20 (d, 6H).

To a degassed solution of 3-pyridylcarbinol (17.6 mg, 0.16 mm, 1.5 equiv.) in 0.8 ml DMFadded odnokolernyh solution hexamethyldisilazide lithium (215 μl, 0.22 mm, 2.0 EQ.). This mixture was stirred for 10 minutes, then added dropwise to a stirred solution of 5-chloro-N-isopropylpyrazole[1,5-α]pyrimidine-3-carboxamide (of 25.7 mg, 0,11 mm, 1.0 EQ.) one ml of DMF. The reaction mixture was purified using reverse-phase HPLC (5→30% acetonitrile/water with 0.1% formic acid) and the product liofilizirovanny with getting to 22.7 mg (68%) of N-isopropyl-5-(pyridine-3-ylethoxy)pyrazolo[1,5-α]pyrimidine-3-carboxamide. IHMS (ESI) m+H=312,2,1H NMR (400 MHz, DMSO-d6) δ: a 9.09 (d, 1H), 8,76 (d, 1H), 8,59 (DD, 1H), scored 8.38 (s, 1H), 7,95 (d, 1H), 7,45 (DD 2H), for 6.81 (d, 1H), 5,61 (s, 1H), 4,08 (m, 1H), 1,19 (d, 6H).

Example 4

methyl 5-(3-forbindelsen)pyrazolo[1,5-α]pyrimidine-3-carboxylate

methyl 5-chloropyrazole[1,5-α]pyrimidine-3-carboxylate

A mixture of 5-oxo-4,5-dihydropyrazolo[1,5-α]pyrimidine-3-carboxylic acid (151 mg, 0.84 mm, 1.0 EQ.), the phosphorus oxychloride (20 ml) and N,N-diisopropylethylamine (440 μl, 2.5 mm, 3.0 EQ.), was heated at the boiling point under reflux for 2 hours. The reaction mixture was cooled to ambient temperature overnight, then concentrated under reduced on the no. The residue was dissolved in 20 ml of methanol was stirred for 30 minutes and concentrated in vacuum. The residue was distributed between ethyl acetate and water. The organic phase was washed with saturated saline solution, dried over sodium sulfate, filtered through a layer of silica gel and concentrated to obtain 160 mg (90%) of methyl 5-chloropyrazole[1,5-α]pyrimidine-3-carboxylate IHMS (ESI) m+H=212,2,1H NMR (400 MHz, DMSO-d6) δ: 9,34 (d, 1H), 8,68 (s, 1H), 7,42 (d, 1H), 3,83 (s, 3H).

A solution of methyl 5-chloropyrazole[1,5-α]pyrimidine-3-carboxylate (240 mg, 1.1 mm, 1.0 EQ.), 3-forbindelsen (200 μl, 2.0 mm, 2.0 equiv.) 30 ml of ethanol and 400 μl of N,N-diisopropylethylamine (2.0 mm, 2 EQ.) were combined and heated at the boiling point under reflux for 4 hours. The mixture was concentrated and the product was collected by filtration and washed with cold ethanol to obtain 271 mg (80%) of methyl 5-(3-forbindelsen)pyrazolo[1,5-α]pyrimidine-3-carboxylate IHMS (ESI) m+H=301,2,1H NMR (400 MHz, DMSO-d6) δ: 8,56 (d, 1H), to 8.41 (m, 1H), 8,17 (s, 1H), 7,35 (m, 3H), was 7.08 (TD, 1H), 6,44 (d, 1H), br4.61 (d, 2H), 3,74 (s, 3H)

Examples 5-221 presented in Table 1, was obtained in accordance withthe above-described methods.

Table 1
Ave. No.StructureName CMS M+H/1
5benzyl 5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxylate360,2
6N-(2-ethoxyphenyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide389,2
7N-(2-methoxyphenyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide375,1
8N-(2-phenoxyphenyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide437,1

9N-cyclopropyl-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide309,2
10N-cyclohexyl-5-(pyridine-3-ylmethyl the Mino)pyrazolo[1,5-α]pyrimidine-3-carboxamide 351,2
11N-isobutyl-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide325,2
12N-(2-methoxyethyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide327,2
13N-tert-butyl-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide325,2

14N-(3,3-dimethylbutyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide353,5
15N-isopropyl-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide311,2
165-(pyridine-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide 269,1
17N-butyl-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide325,2
18N-(4-methylcyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide365,3

19N-(4-methylcyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide365,3
20N-(4-methylcyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide365,3
21N-(cyclohexylmethyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide365,3
22 N-(2,3-dimethylcyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide379,3
23N-cyclobutyl-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide323,2

24N-cyclopentyl-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide337,2
25N-(pentane-3-yl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide339,2
26N-(1-hydroxymethyl)cyclopentyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide367,2
27N-phenyl-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide345,2
285-(pyridine-3-ylmethylamino)-N-p-tollerate[1,5-α]pyrimidine-3-carboxamide359,2

29N-(4-tert-butylcyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide407,3
30N-octyl-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide381,3
31N-cyclopentyl-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide365,3
32N-(4-ethylcyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide379,3

335-(pyridine-ylmethylamino-N-(3,3,5-trimethylcyclohexyl)-pyrazolo[1,5-α]pyrimidine-3-carboxamide to 393.3
34N-(1-1-hydroxy-2-methylpropan-2-yl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide341,2
35N-(2-hydroxyethyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide313,2
365-(pyridine-3-ylmethylamino)-N-((tetrahydrofuran-2-yl)methyl)-pyrazolo[1,5-α]pyrimidine-3-carboxamide353,2
37N-(2-hydroxycyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide367,3

38N-(pyridine-2-yl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide346,2
39 N-(pyridine-3-yl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide346,3
40N-((1S,2S,4R)-bicyclo[2.2.1]heptane-2-yl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide363,2
41N-(bicyclo[2.2.1]heptane-2-yl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide363,2
42N-cyclohexyl-5-methoxypyrazine[1,5-α]pyrimidine-3-carboxamide275,2

43N-cyclooctyl-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide379,3
44benzyl 5-(benzyloxy)pyrazolo[1,5-α]pyrimidine-3-carboxylate360,2
455-(pyridine-3-ylmethylamino-N-(1,3 .3m-trimethylbicyclo[2.2.1]heptane-2-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide405,4
46N-cyclohexyl-5-(pyridine-3-ylethoxy)pyrazolo[1,5-α]pyrimidine-3-carboxamide352,2
47N-(4-ethylcyclohexyl)-5-(pyridine-3-ylethoxy)pyrazolo[1,5-α]pyrimidine-3-carboxamide380,4

485-(pyridine-3-ylmethylamino-N-((1R,2R,4R)-1,7,7-trimethylbicyclo[2.2.1]heptane-2-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide405,3
49N-(4-ethylcyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide379,4
50(R)-N-(1-cyclohe salatil)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide 379,3
51(S)-N-(1-cyclohexylethyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide379,4

52N-(4-ethylcyclohexyl)-5-methoxypyrazine[1,5-α]pyrimidine-3-carboxamide303,2
53N-(piperidine-1-yl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide352,2
54N-(4-ethylphenyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide373,2
55N-(4-cyclohexylphenol)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide427,2

56 N-((1R,4R)-4-hydroxycyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide367,2
57methyl 4-(5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamido)benzoate403,2
58(1R,4R)-4-(5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamido)cyclohexanecarbonyl acid395,2
59(1R,4R)-4-(5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamido)cyclohexanecarbonyl acid395,2

60N-(4-carbamoylmethyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide388,2
61N-(cycloheptylmethyl)-5-(pyridine-3-ylmethylamino)pyrazole is[1,5-a]pyrimidine-3-carboxamide 379,3
62N-((1S)-3-methylcyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide365,3
63N-((1S)-3-methylcyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide365,3

645-(2-chlorobenzylamino)-N-cyclohexylphenol[1,5-a]pyrimidine-3-carboxamide384,2
655-(3-chlorobenzylamino)-N-cyclohexylphenol[1,5-α]pyrimidine-3-carboxamide384,2
665-(4-chlorobenzylamino)-N-cyclohexylphenol[1,5-α]pyrimidine-3-carboxamide384,2
674-(5-(is iridin-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamido)benzoic acid 389,2

685-(benzylamino)-N-cyclohexylphenol[1,5-α]pyrimidine-3-carboxamide350,2
69N-cyclohexyl-5-(2-hydroxyethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide304,2
70N-cyclohexyl-5-(phenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide336,2
71N-(3-carbamoylmethyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide388,2

N-(4-methylbenzyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide
72N-(4-forfinal)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide363,2
73373,2
74N-benzyl-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide359,2
75N-(4-chlorophenyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamideto 379.2

76N-cyclohexyl-5-(ethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide288,2
77N-(3-hydroxyphenyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide361,2
78N-(4-hydroxyphenyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide361,2
79 N-(4-methoxyphenyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide375,2

80N-((1R,4R)-4-((4-aminocyclohexane)methyl)cyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide462,3
81(1S,4S)-4-((5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamido)methyl)cyclohexanecarbonyl acid409,2
82N-(3-methoxyphenyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide375,2
83N-(2-ethoxyphenyl)-5-methoxypyrazine[1,5-a]pyrimidine-3-carboxamide313,2

84 N-(4-tert-pentylcyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide421,3
85N-(4,4-dimethylcyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide379,3
86(1R,4R)-methyl 4-(5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclohexanecarboxylate409,2
87(1S,4S)-methyl 4-(5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamido)cyclohexanecarboxylate409,4

88N-((3-aminomethyl)cyclohexyl)methyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide394,3
89N-((4-aminomethyl)cyclohexyl)methyl)-5-(pyridine-3-ylmethylamino)PI is azolo[1,5-a]pyrimidine-3-carboxamide 394,0
90N-(3-forfinal)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide363,2
91N-((1R,4R)-4-(morpholine-4-carbonyl)cyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide464,2

92N-((1R,4R)-4-(cyclohexylcarbonyl)cyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide476,3
93N-(1-(3-chlorophenyl)-3-methyl-1H-pyrazole-5-yl)-5-(ethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide396,2
94tert-butyl 4-(5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamido)piperidine-1-carboxylate452,3
95 N-(1-(3-chlorophenyl)-3-methyl-1H-pyrazole-5-yl)-5-methoxypyrazine[1,5-a]pyrimidine-3-carboxamide383,2

96N-(1-(3-chlorophenyl)-3-methyl-1H-pyrazole-5-yl)-5-(methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide382,2
975-amino-N-(1-(3-chlorophenyl)-3-methyl-1H-pyrazole-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide368,2
98N-(piperidine-4-yl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide352,2
99(R)-N-(piperidine-3-yl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide352,2
100N-cyclohexyl-5-(cyclohexylamino)pyrazolo[1,-α]pyrimidine-3-carboxamide 342,3

101N-cyclohexyl-5-(phenethylamine)pyrazolo[1,5-α]pyrimidine-3-carboxamide364,3
102N-(4-pentylcyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide421,3
103N-(4-pentylcyclohexyl)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide421,3
104N-cyclohexyl-5-(cyclohexylethylamine)pyrazolo[1,5-α]pyrimidine-3-carboxamide356,3

105N-cyclohexyl-5-(4-methylbenzylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide364,3
106 N-cyclohexyl-5-(4-forbindelsen)pyrazolo[1,5-α]pyrimidine-3-carboxamide368,2
107N-cyclohexyl-5-(2-forbindelsen)pyrazolo[1,5-α]pyrimidine-3-carboxamide368,2
108N-cyclohexyl-5-(3-forbindelsen)pyrazolo[1,5-α]pyrimidine-3-carboxamide368,2

109tert-butyl 4-((3-(cyclohexylcarbonyl)pyrazolo[1,5-a]pyrimidine-5-ylamino)methyl)piperidine-1-carboxylate457,3
110N-cyclohexyl-5-(2,4-diferentiating)pyrazolo[1,5-a]pyrimidine-3-carboxamide386,2
111N-cyclohexyl-5-(3-methoxybenzylamine)pyrazolo[1,5-a]pyrimidine-3-carboxamide380,3
112N-cyclohexyl-5-(3-(trifluoromethyl)benzylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide418,2

113N-cyclohexyl-5-(piperidine-4-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide357,3
114N-cyclohexyl-5-(hydroxymethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide366,2
115N-cyclohexyl-5-(2,5-diferentiating)pyrazolo[1,5-α]pyrimidine-3-carboxamide386,2
116N-cyclohexyl-5-(3,4-diferentiating)pyrazolo[1,5-α]pyrimidine-3-carboxamide386,2

1175-(3-Chlorobenzyl the Mino)-N-isopropylpyrazole[1,5-α]pyrimidine-3-carboxamide 344,2
118N-cyclohexyl-5-(3,4-dichloraniline)pyrazolo[1,5-α]pyrimidine-3-carboxamide418,1
119N-cyclohexyl-5-(2,3-dichloroaniline)pyrazolo[1,5-α]pyrimidine-3-carboxamide418,1
120N-cyclohexyl-5-(2,3-dimethoxyaniline)pyrazolo[1,5-α]pyrimidine-3-carboxamide410,2

121N-cyclohexyl-5-(3,4-dimethoxyphenethylamine)pyrazolo[1,5-α]pyrimidine-3-carboxamide410,2
122N-cyclohexyl-5-(4-hydroxy-3-methoxybenzylamine)pyrazolo[1,5-α]pyrimidine-3-carboxamide396,2
123 N-cyclohexyl-5-(2-hydroxyethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide366,2
1245-(benzylamino)-N-isopropylpyrazole[1,5-α]pyrimidine-3-carboxamide310,2
125N-cyclohexyl-5-(2-methoxybenzylamine)pyrazolo[1,5-α]pyrimidine-3-carboxamide366,2

126N-cyclohexyl-5-(3,5-dimethoxyphenethylamine)pyrazolo[1,5-α]pyrimidine-3-carboxamide410,2
127N-cyclohexyl-5-(2-(deformedarse)benzylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide416,2
128N-cyclohexyl-5-(3-(4-methylpiperazin-1-yl)benzylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide448,3
129 N-cyclohexyl-5-(3-(morpholinomethyl)benzylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide449,3

1305-(benzo[d][1,3]dioxol-5-ylmethylamino)-N-cyclohexylphenol[1,5-a]pyrimidine-3-carboxamide394,2
131N-cyclohexyl-5-(3-(pyrrolidin-1-yl)benzylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide419,3
1325-(2-chlorobenzylamino)-N-isopropylpyrazole[1,5-a]pyrimidine-3-carboxamide344,2
1335-(4-chlorobenzylamino)-N-isopropylpyrazole[1,5-a]pyrimidine-3-carboxamide344,2

134N-cyclohexyl-5-(3-(furan-2-yl)benzylamine is)pyrazolo[1,5-a]pyrimidine-3-carboxamide 416,2
135N-cyclohexyl-5-(3,5-diferentiating)pyrazolo[1,5-α]pyrimidine-3-carboxamide386,2
136N-cyclohexyl-5-(2-(triptoreline)benzylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide434,2
137N-cyclohexyl-5-(3,5-dichloraniline)pyrazolo[1,5-α]pyrimidine-3-carboxamide418,1

138N-cyclohexyl-5-(2,6-diferentiating)pyrazolo[1,5-α]pyrimidine-3-carboxamide386,2
139N-cyclohexyl-5-(2,3-diferentiating)pyrazolo[1,5-α]pyrimidine-3-carboxamide386,2
140N-isop the sawdust-5-(phenylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide 296,2
1415-(3-forbindelsen)-N-isopropylpyrazole[1,5-α]pyrimidine-3-carboxamide328,2
142N-cyclohexyl-5-(2-ethoxybenzylidene)pyrazolo[1,5-a]pyrimidine-3-carboxamide394,3

143N-cyclohexyl-5-((tetrahydro-2H-Piran-4-yl)methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide358,3
144N-cyclohexyl-5-((3,4-dihydro-2H-benzo[b][1,4]doxepin-6-yl)methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide422,2
145N-cyclohexyl-5-(2-(2-morpholinoethoxy)benzylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide479,3
146 N-cyclohexyl-5-(2-morpholinoethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide435,3

147N-cyclohexyl-5-(2-(4-methylpiperazin-1-yl)benzylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide448,3
1485-(3,5-diferentiating)-N-isopropylpyrazole[1,5-a]pyrimidine-3-carboxamide346,2
1495-(3-((1H-pyrazole-1-yl)methyl)benzylamino)-N-cyclohexylphenol[1,5-a]pyrimidine-3-carboxamide430,2
1505-((3-(aminoethyl)cyclohexyl)methylamino)-N-cyclohexylphenol[1,5-a]pyrimidine-3-carboxamide385,2

1515-(2-(1H-pyrazole-1-yl)benzylamino)-N-cyclog xelerate[1,5-a]pyrimidine-3-carboxamide 416,2
152N-(4,4-diverticulosis)-5-(pyridine-3-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide387,1
153N-cyclohexyl-5-(2,5-dimethoxyaniline)pyrazolo[1,5-a]pyrimidine-3-carboxamide410,2
154N-cyclohexyl-5-(3-(dimethylamino)benzylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide393,2
1555-(cycloheptylmethyl)-N-cyclohexylphenol[1,5-a]pyrimidine-3-carboxamide370,2

156N-cyclohexyl-5-(3-((4-methylpiperidin-1-yl)methyl)benzylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide461,3
157 5-(2,5-diferentiating)-N-isopropylpyrazole[1,5-a]pyrimidine-3-carboxamide346,1
158N-isopropyl-5-(2-methoxybenzylamine)pyrazolo[1,5-a]pyrimidine-3-carboxamide340,2
159N-cyclohexyl-5-(2-(2-methyl-1H-imidazol-1-yl)benzylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide430,2

160N-cyclohexyl-5-((tetrahydrofuran-2-yl)methylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide344,2
161N-isopropyl-5-(3-(morpholinomethyl)benzylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide409,2
162N-isopropyl-5-(3-(4-methylpiperazin-1-yl)benzylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 408,3
1635-(3-(furan-2-yl)benzylamino)-N-isopropylpyrazole[1,5-a]pyrimidine-3-carboxamide376,2

1645-(3-aminobenzoylamino)-N-cyclohexylphenol[1,5-a]pyrimidine-3-carboxamide365,2
165N-isopropyl-5-(3-(pyrrolidin-1-yl)benzylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamideto 379.2
166N-isopropyl-5-(2-(4-methylpiperazin-1-yl)benzylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide408,2
167N-isopropyl-5-((1-methylpiperidin-2-yl)methylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide331,2

168 N-isopropyl-5-(3-methoxybenzylamine)pyrazolo[1,5-α]pyrimidine-3-carboxamide340,1
169N-isopropyl-5-(pyridine-2-ylmethylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide311,1
170methyl 5-(3-forbindelsen)pyrazolo[1,5-α]pyrimidine-3-carboxylate301,1
1715-(1H-pyrazole-5-ylamino)-N-isopropylpyrazole[1,5-α]pyrimidine-3-carboxamide286,1
1725-(3-forbindelsen)pyrazolo[1,5-α]pyrimidine-3-carboxamide286,1

1735-(3,5-diferentiating)-N-(4,4-diverticulosis)pyrazolo[1,5-α]pyrimidine-3-carboxamide422,2
174 N-tert-butyl-5-(3,5-diferentiating)pyrazolo[1,5-α]pyrimidine-3-carboxamide360,2
175N-tert-butyl-5-(3,5-diferentiating)pyrazolo[1,5-α]pyrimidine-3-carboxamide356,2
1765-(benzylamino)-N-(1-tert-butyl-3-methyl-1H-pyrazole-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide404,2

1775-(2-forbindelsen)-N-isopropylpyrazole[1,5-α]pyrimidine-3-carboxamide328,1
1785-(2,6-dimethoxyaniline)-N-isopropylpyrazole[1,5-α]pyrimidine-3-carboxamide370,2
1795-(2,5-dimethoxyaniline)-N-isopropylpyrazole[1,5-α]pyrimidine-3-carboxamide 370,2
1805-(2,3-dimethoxyaniline)-N-isopropylpyrazole[1,5-α]pyrimidine-3-carboxamide370,2

1815-(2,3-diferentiating)-N-isopropylpyrazole[1,5-α]pyrimidine-3-carboxamide346,1
1825-(3,5-dichloraniline)-N-isopropylpyrazole[1,5-α]pyrimidine-3-carboxamide378,1
1835-(2-ethoxybenzylidene)-N-isopropylpyrazole[1,5-α]pyrimidine-3-carboxamide354,2
184N-isopropyl-5-(2-morpholinoethyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide395,2

185 5-(3-forgenerating)-N-isopropylpyrazole[1,5-a]pyrimidine-3-carboxamide314,1
186N-isopropyl-5-(2-methoxybenzylamine)pyrazolo[1,5-a]pyrimidine-3-carboxamideto 326.1
1875-(2-(2-(dimethylamino)ethoxy)benzylamino)-N-isopropylpyrazole[1,5-a]pyrimidine-3-carboxamide397,2
188N-isopropyl-5-(3-((4-methylpiperidin-1-yl)methyl)benzylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamideUAH 421,2

1895-(3-((1H-pyrazole-1-yl)methyl)benzylamino)-N-isopropylpyrazole[1,5-a]pyrimidine-3-carboxamide390,2
190N-isopropyl-5-(2-(triptoreline)benzylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide394,1
1915-(2-(dimethylamino)benzylamino)-N-isopropylpyrazole[1,5-a]pyrimidine-3-carboxamide353,2
1925-((3,4-dihydro-2H-benzo[b][1,4]doxepin-6-yl)methylamino)-N-isopropylpyrazole[1,5-a]pyrimidine-3-carboxamide382,2

193methyl 3-((3-(isopropylcarbamate)pyrazolo[1,5-a]pyrimidine-5-ylamino)methyl)benzoate368,2
1945-(2,3-dihydrobenzo[b][1,4]dioxin-5-yl)methylamino)-N-isopropylpyrazole[1,5-a]pyrimidine-3-carboxamide368,2
195N-isopropyl-5-(3-(piperidine-1-yl)benzylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide393,2
196N-isopropyl-5-(3-Mor is aminobenzoylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide 395,2

197N-isopropyl-5-(pyridine-3-ylethoxy)pyrazolo[1,5-a]pyrimidine-3-carboxamide312,2
1985-(3-(dimethylamino)benzylamino)-N-isopropylpyrazole[1,5-a]pyrimidine-3-carboxamide353,2
199N-isopropyl-5-(pyridine-2-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide311,2
200N-isopropyl-5-(pyridine-4-ylmethylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide311,2
2015-(4-chlorpheniramine)-N-isopropylpyrazole[1,5-a]pyrimidine-3-carboxamide330,2

202 5-(1-(3-forfinal)ethylamino)-N-isopropylpyrazole[1,5-a]pyrimidine-3-carboxamide342,2
2035-(1-(3,5-differenl)ethylamino)-N-isopropylpyrazole[1,5-a]pyrimidine-3-carboxamide360,2
204N-isopropyl-5-(3-(trifluoromethyl)phenylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide364,2
205N-(4,4-diverticulosis)-5-(2-methoxybenzylamine)pyrazolo[1,5-a]pyrimidine-3-carboxamide416,2

2065-(2,5-diferentiating)-N-(4,4-diverticulosis)pyrazolo[1,5-a]pyrimidine-3-carboxamide422,2
207N-(1,3-dimethyl-1H-pyrazole-5-yl)-5-(isopropylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide 314,1
2085-(benzylamino)-N-(1,3-dimethyl-1H-pyrazole-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide362,2
209N-(1,3-dimethyl-1H-pyrazole-5-yl)-5-(methylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide286,1
210N-(1,3-dimethyl-1H-pyrazole-5-yl)-5-(phenylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide348,2

2115-amino-N-(1,3-dimethyl-1H-pyrazole-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide272,1
2125-(isopropylamino)-N-(3-methyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide444,2
213N-of the propyl-5-(2-phenylpropane-2-ylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide 338,2
214(R)-N-isopropyl-5-(1-phenylethylamine)pyrazolo[1,5-α]pyrimidine-3-carboxamide324,2

2155-amino-N-(3-methyl-1-(2-(trifluoromethyl)phenyl)-1H-pyrazole-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide402,1
2165-amino-N-(3-methyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide402,1
217(S)-N-isopropyl-5-(1-phenylethylamine)pyrazolo[1,5-α]pyrimidine-3-carboxamide324,2
2185-(isopropylamino)-N-(3-methyl-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole-5-yl)pyrazolo[1,5-α]pyrimidine-3-carboxamide444,2

219N-isopropyl-5-(2-phenylpropane-2-ylamino)pyrazolo[1,5-α]pyrimidine-3-carboxamide338,2
220(R)-N-isopropyl-5-(1-phenylethylamine)pyrazolo[1,5-α]pyrimidine-3-carboxamide324,2
2215-amino-N-(1-(2-forfinal)-3-methyl)-1H-pyrazole-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide353,1

Example 222

5-Amino-N-(3-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Ethyl 3-(5-chloro-2-were)-3-oxopropanoic

To a stirred solution of 5-chloro-2-methylbenzoic acid (4,85 g, 28.4 mmol) in tetrahydrofuran (30 ml) was added N,N-carbonyldiimidazole (4,87 g, 30.0 mmol, 1.06 EQ.). After 30 minutes the reaction mixture was added to a suspension of ethylmalonate potassium (to 11.61 g, 68,22 mmol, 2,40 EQ.) and magnesium chloride (3,27 g, to 34.3 mmol, 1,21 EQ.) in tetrahydrofuran (50 ml). The resulting suspension was heated at 50°C. After 10 hours, the reaction mixture was distributed between ethyl acetate and water. Organicheskoyj was dried over magnesium sulfate, was filtered and concentrated to obtain 8,07 g (118%) ethyl 3-(5-chloro-2-methoxyphenyl)-3-oxopropanoic, which was used without purification. IHMS (ESI) m+H=241,2

Ethyl 2-(5-chloro-2-methylbenzoyl)-3-(dimethylamino)acrylate

A solution of ethyl 3-(5-chloro-2-were)-3-oxopropanoic (28.4 mmol) in 1,1-dimethoxy-N,N-dimethylethanamine (10.0 ml, 75,3 mmol, 2.6 EQ.) was heated at 90°C. After 3 hours the reaction mixture was concentrated in vacuum and the obtained residue was column purified flash chromatography on silica gel (0→80% ethyl acetate in dichloromethane) to give the 2,87 g (34%) of ethyl 2-(5-chloro-2-methylbenzoyl)-3-(dimethylamino)acrylate. IHMS (ESI) m+H=296,3.

Ethyl 5-(5-chloro-2-were)-1H-pyrazole-4-carboxylate

A solution of ethyl 2-(5-chloro-2-methylbenzoyl)-3-(dimethylamino)acrylate (2,87 g to 9.70 mmol) and hydrazine (0,50 ml, 16.0 mmol, 1.6 EQ.) in 30 ml of ethanol was heated at 70°C for 2 hours. The solvent and excess hydrazine is then evaporated with getting to 2.57 g (100%) of ethyl 5-(5-chloro-2-methoxyphenyl)-1H-pyrazole-4-carboxylate, which was used without further purification. IHMS (ESI) m+H=265,2.

A solution of ethyl 5-(5-chloro-2-were)-1H-pyrazole-4-carboxylate (9,70 mmol), cesium carbonate (3,83 g of 11.8 mmol, 1.2 EQ.) and iodomethane (0,90 ml, 14.0 mmol, 1.5 EQ.) in N,N-dimethylformamide (35 ml) was heated at 40°C. After 7 hours the PE clonney the mixture was distributed between ethyl acetate and water. The organic portion was dried over magnesium sulfate, filtered and concentrated. The crude product was purified column flash chromatography on silica gel (0→40% ethyl acetate in dichloromethane) to give to 2.18 g (81%) 1:1 mixture of regioisomeric products, ethyl 3-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-carboxylate and ethyl 5-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-carboxylate. IHMS (ESI) m+H=279,2.

A solution of ethyl 3-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-carboxylate and ethyl 5-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-carboxylate (1:1 mixture of regioisomers, 2,179 g 7,818 mmol) and 1.0 M aqueous sodium hydroxide solution (14 ml, 20 mmol, 4 equiv.) in ethanol (10 ml) was heated at 50°C for 16 hours. After evaporation of the ethanol, the residue was diluted with water. The resulting aqueous solution was acidified to about pH 2 bya 1.0 M aqueous solution of phosphoric acid. This solution was extracted with dichlormethane (3×). The combined organic extracts were dried over MgSO4, filtered and concentrated to obtain 1,936 g (99%) of the corresponding carboxylic acid, which was used immediately without further purification. IHMS (ESI) m+H=251,1.

To a solution of intermediate carboxylic acid in dioxane (15 ml) was added triethylamine (2.2 ml, 15.8 mmol, 4.1 EQ.) and azide diphenylphosphonic acid (1.9 ml, 8,82 mmol, 2.3 EQ.). After 1 hour the reaction mixture is heated to 90°C was added tert-butyl alcohol (15 ml). After 2 hours the reaction mixture was concentrated in vacuo and the resulting residue was distributed between ethyl acetate and water. The organic portion was washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified column flash chromatography on silica gel (0→50% ethyl acetate in dichloromethane) to give 1.64 g (66%) 1:1 mixture of regioisomeric products. IHMS (ESI) m+H=322,2.

To a solution of tert-butyl 3-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-ylcarbamate and tert-butyl 5-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-ylcarbamate (1:1 mixture of regioisomers, 1.64 g, 5,09 mmol) in dichloromethane (10 ml) was added hydrogen chloride (10.0 ml, 40 mmol, 16 equiv., 4.0m in 1,4-dioxane). After 16 hours the reaction mixture was concentrated in vacuum. The obtained solid residue was distributed between dichloromethane and saturated aqueous sodium bicarbonate. The aqueous portion was extracted againdichloromethane and the combined organic extracts were dried over magnesium sulfate and concentrated. The crude product was purified and the regioisomers were separated column flash chromatography on silica gel (0→100% ethyl acetatein dichloromethane) to obtain: 429,7 mg3-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-amine. IHMS (ESI) m+H=222,1;1H NMR (400 MHz, CDCl3) δ: to 7.35 (d, J1,8, 1H), 7.24 to 7,17 (m, 2H),? 7.04 baby mortality (s, 1H), 3,84 (s, 3H), was 2.76 (s, 2H), 2,30 (s, 3H) and 420,2 mg of 5-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-amine. IHMS (ESI) m+H=to 222.2;1H NMR (400 MHz, CDCl3) δ: 7,33 (DD, J=8,3, 2,1, 1H), 7,28 (s, 1H), 7.24 to 7,19 (m, 2H), only 3.57 (s, 3H), 2,71 (s, 2H), of 2.15 (s, 3H).

5-Chloro-N-(3-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 3-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-amine (182,9 mg, 0,4826 mmol, 1.2 EQ.) in dichloromethane (5 ml) was added 5-chloropyrazole[1,5-a]pyrimidine-3-carbonylchloride (91,2 mg, 0,411 mmol, 1.0 EQ.) and triethylamine (of 0.30 ml, 2.2 mmol, 5.2 EQ.) at room temperature. After 16 hours the reaction mixture was distributed between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was dried over magnesium sulfate, filtered and concentrated to obtain 143,1 mg (87%) of 5-chloro-N-(3-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was used without further purification. IHMS (ESI) m+H=401,0.

5-amino-N-(3-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Gaseous ammonia was barbotirovany through ice a suspension of 5-chloro-N-(3-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (143,1 mg, 0,3566 mmol) in 3.0 ml of isopropanol for 20 minutes. The reaction vessel was closed with cover the koi and heated using microwave irradiation at 110°C for 30 minutes. The reaction mixture was concentrated to dryness. The crude product was purified using reverse-phase HPLC and liofilizirovanny with getting to 76.4 mg (56%) of 5-amino-N-(3-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. IHMS (ESI) m+H=382,1;1H NMR (400 MHz, DMSO) δ 9,34 (s, 1H), 8,63 (d, J=7,6, 1H), 8,16 (d, J=9,6, 2H), 7,41 (m, 3H), 6,37 (d, J=7,6, 1H), with 3.89 (s, 3H), and 2.26 (s, 3H).

Example 223

5-Amino-N-(5-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Using 5-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-amine and following the procedures described in Example 222, got mentioned in the title compound 5-amino-N-(5-(5-chloro-2-were)-1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. IHMS (ESI) m+H=382,1;1H NMR (400 MHz, DMSO) δ 9,16 (s, 1H), 8,61 (d,J=7,6, 1H), 8,13 (s, 1H), 7,83 (s, 1H), 7,50 (m, 3H), 6.35mm (d, J=7,6, 1H), 3,60 (s, 3H), 2.13 and (s, 3H).

Example 224

5-Amino-N-(3-(5-chloro-2-were)-1-(2-methoxyethyl)-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Ethyl 3-(5-chloro-2-were)-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylate

A solution of ethyl 5-(5-chloro-2-were)-1H-pyrazole-4-carboxylate (0,2286 g, 0,8636 mmol), cesium carbonate (359,1 mg, 1,102 mmol, 1,276 EQ.) and 1-bromo-2-methoxyethane in N,N-dimethylformamide (6 ml) was heated at 50°C. After 2.5 hours, the reaction to the offer was distributed between ethyl acetate and water. The organic layer was dried over magnesium sulfate, filtered and concentrated to obtain 257,7 mg (92%) of ethyl 3-(5-chloro-2-were)-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylate, which was used without further purification. IHMS (ESI) m+H=323,2.

5-Amino-N-(3-(5-chloro-2-were)-1-(2-methoxyethyl)-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Specified in the title compound was obtained using ethyl 3-(5-chloro-2-were)-1-(2-methoxyethyl)-1H-pyrazole-4-carboxylate and following the procedures described in Example 222. IHMS (ESI) m+H=to 426.2;1H NMR (400 MHz, DMSO) δ 9,34 (s, 1H), 8,63 (d, J=7,5, 1H), 8,16 (d, J=1,6, 2H), 7,41 (m, 3H), 6,37 (d, J=7,6, 1H), or 4.31 (t, J=5,2, 2H), 3,74 (t, J=5,2, 2H), 3.27 to (s, 3H), and 2.26 (s, 3H).

Example 225

5-Amino-N-(3-(2,5-dimetilfenil)-1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Di-tert-butyl 2-(2,5-dimetilfenil)-2-oxoethylidene

In kiln dried flask was loaded di-tert-butylimidazolium (2,566 g, 11,81 mmol, 1,10 EQ.) in N,N-dimethylformamide (30 ml) was added sodium hydride (0,586 g, 14.6 mmol, 1,37 EQ., 60% in mineral oil) at room temperature. After 1.5 hours the reaction mixture was added 2-bromo-1-(2,5-dimetilfenil)alanon (UAH 2.432 g, 10,71 mmol, 1.00 equiv.) at room temperature. After 1.5 hours the reaction mixture was distributed between utilize the atom and water. The organic portion was washed with water and saturated aqueousa solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified column flash chromatography on silica gel (0→40% ethyl acetatein heptane) to obtain a 3.01 g (77%) of di-tert-butyl 2-(2,5-dimetilfenil)-2-oxoethylidene. IHMS (ESI) m+Na = 386,2.

Di-tert-butyl l-(dimethylamino)-3-(2,5-dimetilfenil)-3-oxoprop-1-EN-2-eliminationof

A solution of di-tert-butyl 2-(2,5-dimetilfenil)-2-oxoethylidene (3,0076 g, 8,2752 mmol, 1 EQ.) and 1,1-dimethoxy-N,N-dimethylethanamine (6,0 ml, 45 mmol, 5.4 EQ.) was heated at 70°C for 17 hours and then at 100°C for 24 hours. After evaporation of the excess of 1,1-dimethoxy-N,N-dimethylethanamine the crude product was purified column flash chromatography on silica gel (0→50% ethyl acetatein heptane) to obtain 1,305 g (38%)di-tert-butyl 1-(dimethylamino)-3-(2,5-dimetilfenil)-3-oxoprop-1-EN-2-eliminationof. IHMS (ESI) m+H=419,3.

3-(2,5-Dimetilfenil)-1H-pyrazole-4-amine

Di-tert-butyl 1-(dimethylamino)-3-(2,5-dimetilfenil)-3-oxoprop-1-EN-2-eliminationof (1,305 g, 3,118 mmol, 1.0 EQ.) and hydrazine (0,20 ml, 6.4 mmol, 2.0 EQ.) dissolved together in ethanol (15 ml). The reaction mixture was heated at 70°C for 1 hour and then evaporated to dryness. TBE is every the residue was dissolved in dichloromethane (8 ml) and hydrogen chloride (8.0 ml, 100 mmol, 40 EQ., 4.0m in 1,4-dioxane) and stirred at room temperature for 3.5 hours. The solvent and excess hydrogen chloride is evaporated and the crude product was distributed between saturated aqueous sodium bicarbonate and dichloromethane. The aqueous layer was extracted once with dichloromethane and the combined organic extracts were dried over magnesium sulfate and concentrated to obtain 605,4 mg (104%) of 3-(2,5-dimetilfenil)-1H-pyrazole-4-amine, which was used without further purification. IHMS (ESI) m+H=of 188.3.

5-Chloro-N-(3-(2,5-dimetilfenil)-1-methyl-1H-pyrazole-4-yl)pyrazolo [1,5-a]pyrimidine-3-carboxamide

To a solution of 5-chloropyrazole[1,5-a]pyrimidine-3-carbonylchloride (400,4 mg, 1,853 mmol, 1.16 EQ.) in dichloromethane (6 ml) was added 3-(2,5-dimetilfenil)-1H-pyrazole-4-amine (300,0 mg, 1,602 mmol, 1.0 EQ.) and triethylamine (to 0.70 ml, 5.0 mmol, 3.1 EQ.) at room temperature. After 14 hours the reaction mixture was distributed between dichloromethane and polysystem aqueous solution of sodium bicarbonate. The aqueous layer was extracted once with dichloromethane. The combined organic part was dried over magnesium sulfate, filtered and concentrated to obtain 5-chloro-N-(3-(2,5-dimetilfenil)-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was used without further purification. IHMS (ESI) m+H=367,1.

To the solution obtained to enter the crude substance in N,N-dimethylformamide (12 ml) was added cesium carbonate (0,890 g, by 2.73 mmol, 2.0 EQ.) and methyliodide (is 0.135 ml, 2,17 mmol, 1,61 EQ.). The reaction mixture then was heated at 40°C. After 5 hours the reaction mixture was distributed between ethyl acetate and water. The organic portion was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude product was purified column flash chromatography on silica gel (20→90% ethyl acetatein dichloromethane) to give to 45.5 mg (9%) 5-chloro-N-(3-(2,5-dimetilfenil)-1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. IHMS (ESI) m+H=381,2.

5-Amino-N-(3-(2,5-dimetilfenil)-1-methyl-1H-pyrazole-4-yl)pyrazolo [1,5-a]pyrimidine-3-carboxamide

Gaseous ammonia was barbotirovany through ice a suspension of 5-chloro-N-(3-(2,5-dimetilfenil)-1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (to 45.5 mg, 0,119 mmol) in ethanol (3.0 ml) for 20 minutes. The reaction vessel was closed with a lid and heated at 100°C using microwave irradiation for 30 minutes. The reaction mixture was concentrated to dryness and the crude product was purified by reversed-phase HPLC and liofilizirovanny with getting 4.0 mg (9.3 per cent)5-amino-N-(3-(2,5-dimetilfenil)-1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. IHMS (ESI) m+H=362,1;1H NMR (400 MHz, DMSO) δ for 9.47 (s, 1H), to 8.62 (d, J=7,5, 1H), 8,16 (d, J=7,1, 2H), 7,30 (d, J=8,2, 1H), 7,19 (d, J=6,2,2 H), 6,36 (d, J=7,6, 1H), of 5.75 (s, 2H), 3,88 (s, 3H), to 2.29 (s, 3H), of 2.21 (s, 3H).

Example 226

5-Amino-N-(1-(5-chloro-2-were)-3-methyl-1H-pyrazole-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

(5-Chloro-2-were)hydrazine hydrochloride

To ice the suspension of 5-chloro-2-methylaniline (equal to 1.4362 g, 10,143 mmol, 1.00 equiv.) in water (10 ml) was added concentrated hydrochloric acid (10 ml). To this reaction mixture was added dropwise a solution of sodium nitrite(0,791 g, 11.5 mmol, 1,13 EQ.) in water (5 ml) at 0°C. After 2 hours the reaction mixture was slowly added to a stirred cooled with ice to a solution of tin chloride dihydrate (5,88 g for 25.8 mmol, 2.55 equiv.) in concentrated hydrochloric acid (8 ml). Water was added as needed to maintain agitation in the process of formation of solid particles. The reaction was maintained at 0°C for 45 minutes. The white solids were filtered and washed with diethyl ether (2×50 ml). The solids were dried in vacuum to obtain 1,49 g (76%)hydrochloride (5-chloro-2-were)of hydrazine.1H NMR (400 MHz, DMSO-d6) δ: 10,08 (s, 3H), 7,98 (s, 1H), 7,13 (d, 1H), 6,97 (s, 1H), 6,91 (d, 1H), and 2.14 (s, 3H).

1-(5-Chloro-2-were)-3-methyl-1H-pyrazole-5-amine

To a solution of hydrochloride (5-chloro-2-were)hydrazine (1,49 g, 7,72 mmol, 1.00 equiv.) e is anole (8 ml) was added hydrogen chloride (4.0 ml, 20 mmol, 2 EQ., 5 M aqueous solution) and 3-aminocrotonate (0,664 g of 8.09 mmol, of 1.05 EQ.). The reaction mixture was stirred at 80°C for 16 hours and then brought to neutral pH by means of a saturated aqueous solution of sodium bicarbonate. The resulting solution was extracted twice with dichloromethane and the combined extracts were dried over magnesium sulfate, filtered and concentrated to obtain 1,41 g (82%)1-(5-chloro-2-were)-3-methyl-1H-pyrazole-5-amine, which was used further without additional purification. IHMS (ESI) m+H=to 222.2;1H NMR (400 MHz, DMSO-d6) δ: 7,39 (d, 1H), 7,37 (d, 1H), 7,25 (s, 1H), 5,22 (s, 1H), 5,00 (s, 2H), 2,04 (overlapping s and s, 6H).

5-Amino-N-(1-(5-chloro-2-were)-3-methyl-1H-pyrazole-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

Specified in the title compound was obtained using l-(5-chloro-2-were)-3-methyl-1H-pyrazole-5-amine and following the procedures described in Example 222. IHMS (ESI) m+H=382,1;1H NMR (400 MHz, DMSO) δ 9,73 (s, 1H), 8,63 (d, J=7,5, 1H), 8,18 (s, 1H), 7,58 was 7.45 (m, 3H), 6,41 (s, 1H), 6,37 (d, J=7,6, 1H), 2,22 (s, 3H), 2,04 (s, 3H).

Example 227

N-(3-(3-Chlorophenyl)-1-methyl-1H-pyrazole-4-yl)-5-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

2-(2-(3-Chlorophenyl)-2-oxoethyl)isoindoline-1,3-dione

A solution of 2-bromo-3'-chloroacetophenone (0,9271 g 3,971 mmol,1,0 EQ.) and phthalimide potassium (0,8129 g, 4,389 mmol, 1.1 EQ.) in N,N-dimethylformamide (15 ml) was heated at 50°C. After 1 hour the solvent was removed using a rotary evaporator. The obtained solids were ground into powder with ethyl acetate and filtered. The collected solids were dried in vacuum to obtain 1.19 g (117%)2-(2-(3-chlorophenyl)-2-oxoethyl)isoindoline-1,3-dione, which was used without further purification.1H NMR (400 MHz, DMSO-d6) δ: 8,13 (s, 1H), with 8.05 (d, 1H), of 7.96 (m, 2H), to 7.93 (m, 2H), 7,83 (d, 1H), 7,65 (t, 1H), from 5.29 (s, 2H).

2-(3-(3-Chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-EN-2-yl)isoindoline-1,3-dione

Stir a mixture of 2-(2-(3-chlorophenyl)-2-oxoethyl)isoindoline-1,3-dione (782,2 mg, 2,610 mmol, 1 EQ.) and 1,1-dimethoxy-N,N-dimethylethanamine (1.5 ml, 11 mmol, 4.3 EQ.) was heated at 100°C for 18 hours. An excess of 1,1-dimethoxy-N,N-dimethylethanamine was removed using a rotary evaporator. The crude product was purified column flash chromatography on silica gel (50→100% ethyl acetatein heptane) to give 740 mg (80%)2-(3-(3-chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-EN-2-yl)isoindoline-1,3-dione. IHMS (ESI) m+H=355,2;1H NMR (400 MHz, CDCl3) δ: of 7.90 (d of d, 2H), to 7.77 (d of d, 2H), EUR 7.57 (s, 1H), 7,44 (d, 1H), 7,37 (overlapping d and s, 2H), 7,31 (m, 1H), 3.00 and (s, 6H).

3-(3-Chlorophenyl)-1-methyl-1H-pyrazole-4-amine

A solution of 2-(3-(3-chlorophenyl)-1-(dimethylamino)-3-oxoprop-1-EN-2-yl)isoindoline-1,3-d is it (2.30 g, 6,48 mmol, 1.0 EQ.) and N-methylhydrazine (1,4 ml, 26 mmol, 4.0 EQ.) in ethanol (50 ml) was heated at 80°C. After 2 hours the reaction mixture was concentrated and the crude mixture of the regioisomers were separated and purified flash column-chromatography on silica gel (0→80% ethyl acetatein dichloromethane) to obtain: 715,0 mg (53%)3-(3-chlorophenyl)-1-methyl-1H-pyrazole-4-amine. IHMS (ESI) m+H=208,2;1H NMR (400 MHz, CDCl3) δ: for 7.78 (s, 1H), 7,63 (d, 1H), 7,33 (t, 1H), 7,25 (overlapping CDCl3, 1H),? 7.04 baby mortality (s, 1H), 3,84 (s, 3H) and 274,6 mg (20%)5-(3-chlorophenyl)-1-methyl-1H-pyrazole-4-amine. IHMS (ESI) m+H=208,2;1H NMR (400 MHz, CDCl3) δ: the 7.43 (t, 1H), 7,38 (overlapping d and s, 2H), 7,27 (d, 1H), 7.23 percent (s, 1H), 3,76 (s, 3H).

N-(3-(3-Chlorophenyl)-1-methyl-1H-pyrazole-4-yl)-5-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a solution of 5-chloropyrazole[1,5-a]pyrimidine-3-carbonylchloride (0,166 g, 0,768 mmol) in dichloromethane (8 ml) was added 3-(3-chlorophenyl)-1-methyl-1H-pyrazole-4-amine (73,6 mg, 0,354 mmol) and triethylamine (of 0.20 ml, 1.4 mmol) at room temperature. After 1 hour the reaction mixture was distributed between dichloromethane and polysystem aqueous solution of sodium bicarbonate. The organic layer was dried over magnesium sulfate and concentrated to obtain 5-chloro-N-(3-(3-chlorophenyl)-1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, which was used without further purification. IHMS(ESI) m+H=387,1.

The solution obtained above crude 5-chloro-N-(3-(3-chlorophenyl)-1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide, cyclopropanemethylamine (0.1 ml, 1.0 mmol) and N,N-diisopropylethylamine (0,20 ml, 1.1 mmol) in ethanol (5 ml) was heated at 120°C using microwave irradiation. After 30 minutes the reaction mixture was concentrated to dryness and the crude product was purified by reversed-phase HPLC and liofilizirovanny with getting to 95.7 mg (64%)N-(3-(3-chlorophenyl)-1-methyl-1H-pyrazole-4-yl)-5-(cyclopropylamino)pyrazolo[1,5-a]pyrimidine-3-carboxamide. IHMS (ESI) m+H=422,1;1H NMR (400 MHz, DMSO) δ 9,62 (s, 1H), 8,58 (d, J=7,6, 1H), to 8.20 (s, 1H), 8,14 (s, 2H), 7,75-to 7.59 (m, 2H), 7,46 (t, J=7,8, 1H), 7,42-7,34 (m, 1H), 6,41 (d, J=7,6, 1H), 3,90 (s, 3H), 2,62-of 2.54 (m, 2H), 0,76 (s, 1H), 0,38-0,24 (m, 2H), -0,14 (m, 2H).

Example 228

[3-(2,5-Dichlorophenyl)-1-methyl-1H-pyrazole-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid

To a stirred solution of 5-amino-1H-pyrazole-4-carboxylic acid (10.0 g, and 71.4 mmol) in ethanol (100 ml) was added ethoxide sodium (17.0 g, 245 mmol) followed by addition of 1,3-dimethyluracil (11,0 g of 78.6 mmol). The reaction mixture was then stirred at the boiling point under reflux overnight in an argon atmosphere. The mixture was poured into ice water, the resulting solution was acidified to about pH=3-4 using concentrated HCl. The suspension was stirred for 2 hours and then filtered to obtain an intermediate compound which was used without further purification (10.0 g, 58% yield).1H NMR (400 MHz, DMSO-d6): 8,54 (d, J=9,2 Hz, 1H), of 8.06 (s, 1H), 6,11 (d, J=12 Hz, 1H).

5-Chloropyrazole[1,5-a]pyrimidine-3-carbonylchloride

A suspension of 5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carboxylic acid (9.5 g, 53,1 mmol) and diisopropylethylamine (17.1 g, to 132.6 mmol) in phosphorus oxychloride(V) (250 ml) was heated at 130°C in argon atmosphere for 3.5 hours. The mixture was concentrated in vacuo and passed through a column of silica gel (dichloromethane) to give 5-chloropyrazole[1,5-a]pyrimidine-3-carbonylchloride in the form of a solid (8.0 g, 70% yield).1H NMR (400 MHz, CDCl3) δ: 8,72 (d, J=7.2 Hz, 1H), 8,65 (s, 1H), 7,17 (d, J=7,6 Hz, 1H).

2-Bromo-1-(2,5-dichlorophenyl)alanon

It chilled with ice to a solution of 2',5'-dichloroacetophenone (1.0 g, 5.0 mmol) in acetic acid (10 ml) was added HBr (~ 1%) with the subsequent addition of a solution of bromine (0,80 g, 5.0 mmol) in acetic acid (3 ml). The resulting mixture was heated to room temperature and was stirred overnight. The mixture was poured into ice water and then neutralized with a saturated aqueous solution of sodium carbonate. Then to the mixture was added saturated aqueous solution of thiosulfateof sodium. According to the scientists, the mixture was extracted with ethyl acetate. The organic phase is washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated. Purification column flash chromatography gave 2-bromo-1-(2,5-dichlorophenyl)Etalon in the form of oil (0,70 g, 50% yield).1H NMR (400 MHz, CDCl3) δ: rate of 7.54 (d, J=2.4 Hz, 1H), 7,43 (m, 1H), 7,40 (m, 1H), and 4.68 (s, 2H).

2-(2-(2,5-Dichlorophenyl)-2-oxoethyl)isoindoline-1,3-dione

It chilled with ice to a solution of 2-bromo-1-(2,5-dichlorophenyl)alanon (0.10 g, of 0.37 mmol) in N,N-dimethylformamide (8 ml) was added phthalimide potassium (76 mg, 0.41 mmol). The mixture was heated to room temperature within 2 hours. The resulting mixture was then poured into water and was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. Recrystallization using diethyl ether gave 2-(2-(2,5-dichlorophenyl)-2-oxoethyl)isoindoline-1,3-dione as a white solid. (110 mg, 88% yield).1H NMR (400 MHz, CDCl3) δ: 7,92-7,94 (m, 2H), 7,78-7,80 (m, 2H), 7,72 (m, 1H), 7,45-7,46 (m, 2H), to 5.08 (s, 2H).

2-(3-(2,5-Dichlorophenyl)-1-(dimethylamino)-3-oxoprop-1-EN-2-yl)isoindoline-1,3-dione

A solution of 2-(2-(2,5-dichlorophenyl)-2-oxoethyl)isoindoline-1,3-dione (0.10 g, 0.30 mmol) in 1,1-dimethoxy-N,N-dimethylethanamine (8 ml) was heated at the boiling point under reflux for 2 hours the century The resulting mixture was then concentrated. Purification column flash chromatography gave 2-(3-(2,5-dichlorophenyl)-1-(dimethylamino)-3-oxoprop-1-EN-2-yl)isoindoline-1,3-dione as a solid (0,90 g, 77% yield).

3-(2,5-Dichlorophenyl)-1-methyl-1H-pyrazole-4-amine

It chilled with ice to a solution of 2-(3-(2,5-dichlorophenyl)-1-(dimethylamino)-3-oxoprop-1-EN-2-yl)isoindoline-1,3-dione (0,050 g, 0.13 mmol) in ethanol (6 ml) was added 40% aqueous solution of methylhydrazine (45 mg, 0,39 mmol). The mixture then was heated at the boiling point under reflux for 3 hours. The reaction mixture was then concentrated and purified flash column-chromatography to obtain 3-(2,5-dichlorophenyl)-1-methyl-1H-pyrazole-4-amine as a solid (12 mg, 38% yield).1H NMR (400 MHz, CDCl3) δ: 7,50 (d, J=3.6 Hz, 1H), 7,38 (d, J=8,8 Hz, 1H), 7,28 (m, 1H), 7,06 (s, 1H), 3,86 (s, 3H), 2,98 (s, 2H).

5-Chloro-N-(3-(2,5-dichlorophenyl)-1-methyl-1H-pyrazole-4-yl)pyrazolo-[1,5-a]pyrimidine-3-carboxamide

It chilled with ice to a solution of 3-(2,5-dichlorophenyl)-1-methyl-1H-pyrazole-4-amine (121 mg, 0.50 mmol) and triethylamine (101 mg, 1.00 mmol) in dichloromethane (15 ml) was added 5-chloropyrazole[1,5-a]pyrimidine-3-carbonylchloride (162 mg, 1.5 mmol). The reaction mixture was heated to room temperature within 3 hours. The mixture was then washed with a saturated aqueous solution of sodium chloride. Own the data organic layers were dried over anhydrous sodium sulfate, was filtered and concentrated. Purification bypreparative HPLC gave 5-chloro-N-(3-(2,5-dichlorophenyl)-1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide in the form of a solid (110 mg, 52% yield).1H NMR (400 MHz, DMSO-d6) δ: 9,34 (d, J=7,6 Hz, 1H), of 9.21 (s, 1H), 8,69 (s, 1H), with 8.33 (s, 1H), 7,71 (d, J=9,2 Hz, 1H), 7,60 (d, J=9,2 Hz, 1H), 7,54 (s, 1H), was 7.36 (d, J=6,8 Hz, 1H), 3,93 (s, 3H).

[3-(2,5-Dichloro-phenyl)-1-methyl-1H-pyrazole-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A solution of 5-chloro-N-(3-(2,5-dichlorophenyl)-1-methyl-1H-pyrazole-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (110 mg, 0.26 mmol) in ethanol saturated with ammonia (4 ml) was heated at 95°C for 30 minutes using microwave irradiation. The mixture was concentrated. Purification column flash chromatography gave [3-(2,5-dichloro-phenyl)-1-methyl-1H-pyrazole-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid as a solid (80 mg, 77% yield).1H NMR (400 MHz, DMSO-d6) δ: 9,37 (s, 1H), 8,63 (d,J=7,6 Hz, 1H), 8,14-8,16 (m, 2H), of 7.70 (m, 1H), 7,52-of 7.55 (m, 2H), to 6.39 (d, J=8.0 Hz, 1H), 3,91 (s, 3H).

Example 229

Isopropylated 5-benzosulfimide-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A mixture of 5-chloro-N-isopropylpyrazole[1,5-a]pyrimidine-3-carboxamide (95,5 mg, 0.40 mmol, 1.0 EQ.), benzosulfimide (62,0 mg, 0.40 mmol, 1.0 EQ.) and cesium carbonate (312 mg, 0.6 mmol, 2.4 EQ.) in 1,2-dimethoxyethane (8 ml) was heated to 85°C for 72 hours. The solvent was removed in vacuo and the resulting residue was dissolved in water. the pH of the solution is then brought up to about 5 by addition of aqueous 1M HCl and was extracted with dichloromethane (2×30 ml). The organic extracts were concentrated in vacuum and the residue was purified column flash chromatography on silica gel (gradient: 0→10% methanol in dichloromethane) to give to 57.0 mg (40%)Isopropylamine 5-benzosulfimide-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in the form of solids. IHMS (ESI) m+H=360,3;1H NMR (400 MHz, DMSO-d6) δ: 12,2 (s, 1H), 8,97 (d, 1H), 8.30 to (s, 1H), 8,01 (d, 2H), to 7.64 (m, 4H), only 6.64 (m, 1H), 4,13 (m, 1H), 1,21 (d, 6H).

Example 230

(5-Methyl-isoxazol-3-yl)-amide 5-(6-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

Ethyl 5-Chloropyrazole[1,5-a]pyrimidine-3-carboxylate

To a suspension of ethyl ester 5-oxo-4,5-dihydro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (obtained in accordance with Gavrin, L. K. et al, J. Org. Chem. 2007, 72, 1043-1046) (3.00 g, 14.5 mmol, 1 EQ.) in phosphorus oxychloride (30 ml) was added diisopropylethylamine (2.00 ml, 11.6 mmol, 0.8 EQ.). The mixture was heated to 90°C for 4.5 hours. After cooling, the mixture carefully extinguished ice water and was extracted with dichloromethane. The organic extract prom the Wali saturated aqueous sodium bicarbonate, was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to obtain a solid substance. Rubbing the powder (diethyl ether) gave 2.38 g (73%)ethyl 5-chloropyrazole[1,5-a]pyrimidine-3-carboxylate in the form of solids. IHMS (ESI) m+H=226,2 (monochlorobiphenyl isotope);1H NMR (400 MHz, CDCl3) δ: 8,63 (d, 1H), 8,56 (s, 1H), 6,99 (d, 1H), 4,43 (kV, 2H), of 1.42 (t, 3H).

Ethyl 5-(6-(trifluoromethyl)pyridine-2-ylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate

A 20-ml microwave reaction vessel were loaded ethyl 5-chloropyrazole[1,5-a]pyrimidine-3-carboxylate (1.28 g, 5,67 mmol, 1 EQ.), 2-amino-6-(trifluoromethyl)pyridine (1.10 g, for 6.81 mmol, 1.2 equiv.) 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (132 mg, 0.22 mmol, 4 mol%), Tris(dibenzylideneacetone) dipalladium(0) (104 mg, 0.11 mmol, 2 mol%), tert-piperonyl sodium (652 mg, for 6.81 mmol, 1.2 EQ.) and toluene (12 ml). The vessel was tightly closed and the contents were degirolami was purged with argon and then heated in a microwave reactor at 140°C for 20 minutes. After cooling, the mixture was diluted with ethyl acetate and filtered through a layer of Celite®. The filtrate was washed with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The obtained residue was column purified flash chromatography on silica gel (gradient: 0→20% ethylacetate> in dichloromethane) to obtain 344 mg (17%)ethyl 5-(6-(trifluoromethyl)pyridine-2-ylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate as an orange solid. IHMS (ESI) m+H=352,1;1H NMR (300 MHz, DMSO-d6) δ: 11,06 (s, 1H), 9,16 (d, 1H), to 8.94 (d, 1H), 8,39 (s, 1H), 8,10 (t, 1H), EUR 7.57 (d, 1H), 7,05 (d, 1H), or 4.31 (q, 2H), 1,40 (t, 3H).

5-(6-Trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A mixture of ethyl 5-(6-(trifluoromethyl)pyridine-2-ylamino)pyrazolo[1,5-a]pyrimidine-3-carboxylate (344 mg, 0.98 mmol, 1.0 EQ.), 2M aqueous sodium hydroxide solution (1.50 ml, 3.0 EQ.) and ethanol (15 ml) was heated to boiling point under reflux for 5 hours. After cooling, the precipitate was collected by filtration, washed with ethanol and dried in the air. The obtained solid is suspended in a solution of 1.25 M HCl in methanol (16 ml) and then concentrated in vacuum. The residue was ground into a powder (diethyl ether) to obtain 355 mg (quantitative yield)5-(6-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid, which was used without further purification. IHMS (ESI) m+H=324,2;1H NMR (300 MHz, DMSO-d6) δ: 11,03 (s, 1H), 9,01 (d, 1H), 8,95 (d, 1H), 8,35 (s, 1H), 8,10-8,02 (m, 1H), 7,54 (d,lH), 7,16 (d, 1H).

(5-Methyl-isoxazol-3-yl)-amide 5-(6-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carb is new acid

Diisopropylethylamine (101 mg, 0.78 mmol, 0.8 EQ.) was added to a suspension of 5-(6-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.98 mmol, 1.0 EQ.) in phosphorus oxychloride (6 ml) at 0°C. the Mixture was then heated to 90°C for 20 hours. After cooling, the solvent was removed in vacuum and the residue was subjected to azeotropic distillation with dichloromethane and then concentrated to obtain the crude carboxylic acid in the form of solids. Half of the crude substance (about 0,49 mmol) was used directly in the next stage.

A mixture of carboxylic acid (0.49 mmol, 1.0 EQ.) and 5-amino-3,4-dimethyl-1,2-isoxazol (66,0 mg, 0.59 mmol, 1.2 EQ.) in pyridine (4 ml) was heated to 60°C for 90 minutes. After cooling, the solvent was removed in vacuum and the selected residue was ground into a powder (water) and again was ground into powder (methanol) and the resulting solid was dried in vacuum to obtain 56,3 mg (28%) (5-methyl-isoxazol-3-yl)-amide5-(6-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. IHMS (ESI) m+H=418,1;1H NMR (400 MHz, DMSO-d6) δ: 11,12 (s, 1H), 10,04 (s, 1H), 9,04 (d, 1H), and 8.50 (s, 1H), to 8.41 (d, 1H), 8,02 (t, 1H), 7,58 (d, 1H), 7,30 (d, 1H), 2,19 (s, 3H), of 1.88 (s, 3H).

Example 231

(2-methyl-4-o-tolyl-thiazol-5-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

Ethyl ester of 3-oxo-3-o-tolyl-propionic acid

To a stirred suspension of sodium hydride (60% dispersion in mineral oil, 7.20 g, 180 mmol, 3.6 EQ.) in toluene (300 ml) was slowly added diethylmalonate (23,6 g, 200 mmol, 4.0 EQ.) when the ambient temperature. After stirring for 15 minutes was added 2-methylacetophenone (6,70 g, 50.0 mmol, 1.0 EQ.) and the resulting mixture was heated to boiling point under reflux for 18 hours. Then added dropwise glacial acetic acid (15 ml) for 10 minutes, followed by careful addition of ice water (150 ml). The resulting mixture was extracted with ethyl acetate and the combined organic extracts were dried over magnesium sulfate and concentrated in vacuum. The obtained residue was column purified flash chromatography on silica gel (gradient: 0→5% ethyl acetatein pentane) to give the 7,94 g (77%)ethyl ester of 3-oxo-3-o-tolyl-propionic acid in the form of oil (4:1 mixture of keto/enol tautomers).1H NMR (Keto tautomer) (400 MHz, CDCl3) δ: 7,66 (s, 1H), 7,41 (s, 1H), 7,30-7,25 (m, 2H), 4,22-to 4.15 (m, 2H), 3.96 points-of 3.94 (m, 2H), by 2.55 (s, 3H), 1,28-1,22 (m, 3H).

Ethyl ester of 2-bromo-3-oxo-3-o-tolyl-propionic acid

Bromine (1.65 g, or 10.3 mmol, 1.03 EQ.) was added dropwise to a stirred solution of ethyl ester of 3-oxo-3-o-tolyl-propionic acid (to 2.06 g, 100 mmol, 1.0 EQ.) in 1,4-dioxane (25 ml) at ambient temperature. The mixture was stirred for 1 hour and then was dilutedtert-butylmethylamine ether (50 ml). The resulting solution was washed successively with water, aqueous potassium carbonate solution and saturated aqueous sodium chloride. The collected organic layers were dried over magnesium sulfate, filtered and concentrated in vacuum to obtain 2,74 g (96%)ethyl ester of 2-bromo-3-oxo-3-o-tolyl-propionic acid as a dark brown residue.1H NMR (400 MHz, CDCl3) δ: 7,66 (d, 1H), 7,46-7,37 (m, 1H), 7,28 (m, 2H), 5,62 (s, 1H), 4,29-4,22 (kV, 2H), 2,52 (s, 3H), 1,28-to 1.19 (t, 3H).

Ethyl ester of 2-methyl-4-o-tolyl-thiazole-5-carboxylic acid

Stir a mixture of ethyl ester of 2-bromo-3-oxo-3-o-tolyl-propionic acid (2,74 g, 9,60 mmol, 1.0 EQ.) and thioacetamide (0,76 g, 10.1 mmol, of 1.05 equiv.) in ethanol (30 ml) was heated to boiling point under reflux for 4 hours. The cooled mixture was filtered and concentrated in vacuum. The residue was distributed between ethyl acetate and water and the organic phase was separated and then washed with a saturated aqueous solution of sodium chloride. Collected organics were dried over magnesium sulfate, filtered and concentrated in vacuum. The obtained residue was column purified flash chromatography on silica gel (radiant: 0→20% ethyl acetate in pentane) to give 0.84 g (34%)ethyl ester of 2-methyl-4-o-tolyl-thiazole-5-carboxylic acid in the form of oil. IHMS (ESI) m+H=USD 261.9 bn;1H NMR (400 MHz, CDCl3) δ: 7,31-to 7.18 (m, 4H), to 4.16 (q, 2H), was 2.76 (s, 3H), of 2.18 (s, 3H), 1.14 in (t, 3H).

2-Methyl-4-o-tolyl-thiazole-5-carboxylic acid

A mixture of ethyl ester of 2-methyl-4-o-tolyl-thiazole-5-carboxylic acid (0.84 g, 3,20 mmol, 1.0 EQ.) and potassium hydroxide (0.36 g, 6,40 mmol, 2.0 EQ.) 50% aqueous solution of methanol (10 ml) was heated to 50°C for 5 hours. The mixture was concentrated and the residue was diluted with water and acidified to about pH 1 by adding 6N HCl solution. The resulting solution was extracted with ethyl acetate (3×). The combined extracts were dried over magnesium sulfate, filtered and concentrated in vacuum to obtain and 0.61 g (81 %)2-methyl-4-o-tolyl-thiazole-5-carboxylic acid in the form of solids. IHMS (ESI) m+H=234,0;1H NMR (400 MHz, CDCl3) δ: 7,32-7,17 (m, 4H), to 2.75 (s, 3H), 2,17 (s, 3H).

tert-Butyl ether (2-methyl-4-o-tolyl-thiazol-5-yl)-carbamino acid

A mixture of 2-methyl-4-o-tolyl-thiazole-5-carboxylic acid (300 mg, 1,29 mmol, 1.0 EQ.), diphenylphosphinite (DPPA) (354 mg, 1,29 mmol, 1.0 EQ.) triethylamine (130 mg, 1,29 mmol, 1.0 EQ.) in tert-butanol (10 ml) was heated to 85°C for 4 hours. After cooling, the mixture was diluted with water and extracted with ethyl acetate (3×). Joint the United organic extracts were dried over magnesium sulfate, was filtered and concentrated in vacuum. The residue was purified column flash chromatography on silica gel (gradient: 2→25% ethyl acetatein pentane) to give 352 mg (90%)tert-butyl ether (2-methyl-4-o-tolyl-thiazol-5-yl)-carbamino acid in the form of oil. IHMS (ESI) m+H=305,1;1H NMR (400 MHz, CDCl3) δ: 7,33-7,24 (m, 4H), to 6.58 (s, 1H), 2,64 (s, 3H), 2,24 (s, 3H), of 1.48 (s, 9H).

2-Methyl-4-o-tolyl-thiazol-5-ylamine

A solution of tert-butyl methyl ether (2-methyl-4-o-tolyl-thiazol-5-yl)-carbamino acid (340 mg, 1.12 mmol, 1.0 EQ.) in dichloromethane (10 ml) was treated triperoxonane acid (0.7 ml, of 9.00 mmol, 8.0 EQ.) within 24 hours at ambient temperature. The mixture was concentrated in vacuo and the resulting residue was dissolved in dichloromethane and washed successively with 10% aqueous potassium carbonate solution and saturated aqueous sodium chloride. The collected organic phase was dried over magnesium sulfate and filtered. The filtrate was passed through catridge Isolute® SCX-2 (suirable dichloromethane, a mixture of dichloromethane/methanol (1:1) and 2M ammonia in methanol) to obtain the 62,0 mg (27%)2-methyl-4-o-tolyl-thiazole-5-ylamine in the form of a brown residue. IHMS (ESI) m+H=205,0;1H NMR (400 MHz, CDCl3) δ: 7,33-to 7.18 (m, 4H), 3,54 is-3.45 (user, 2H), 2,58 (s, 3H), to 2.29 (s, 3H).

(2-Methyl-4-o-tolyl-thiazol-5-yl)-amide 5-chloro-pyrazolo[1,5-a]Piri is one-3-carboxylic acid

It chilled with ice to a solution of 2-methyl-4-o-tolyl-thiazole-5-ylamine (55,0 mg, 0.27 mmol, 1.0 EQ.) and diisopropylethylamine (52,0 mg, 0.41 mmol, 1.5 EQ.) in dichloromethane (10 ml) was added a solution of 5-chloropyrazole[1,5-α]pyrimidine-3-carbonylchloride (58,0 mg, 0.27 mmol, 1.0 EQ.) in dichloromethane (5 ml). The reaction mixture was heated to ambient temperature and was stirred overnight. The mixture was washed with water and saturated aqueous sodium chloride, dried over magnesium sulfate, filtered and concentrated in vacuum. Purification column flash chromatography on silica gel (gradient: 0→3% methanol in dichloromethane) gave 74,0 mg (73%)(2-methyl-4-o-tolyl-thiazol-5-yl)-amide 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in the form of solids. IHMS (ESI) m+H=384,0 (monochlorobiphenyl isotope);1H NMR (400 MHz, CDCl3) δ: 9,73 (s, 1H), to 8.70 (s, 1H), 8,63 (d, 1H), 7,44-7,30 (m, 4H), 6,93 (d, 1H), 2,72 (s, 3H), 2,31 (s, 3H).

(2-Methyl-4-o-tolyl-thiazol-5-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A mixture of (2-methyl-4-o-tolyl-thiazol-5-yl)-amide 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (74,0 mg, 0,19 mmol, 1.0 EQ.) and a solution of 2M ammonia in propan-2-OLE (3 ml) was tightly closed and heated in a microwave reactor at 120°C for 1 hour. The solvent was removed in vacuum and the obtained residue was column purified flash chromatography on forces is the Kagel (gradient: 0→5% methanol in dichloromethane) to give 11.0 mg (16%) (2-methyl-4-o-tolyl-thiazol-5-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. IHMS (ESI) m+H=365,1;1H NMR (400 MHz, DMSO-d6) δ: 10,35 (s, 1H), 8,66 (d, 1H), 8,23 (s, 1H), 7,47-7,37 (m, 4H), 6,38 (d, 1H), 2,61 (s, 3H), of 2.20 (s, 3H).

Example 232

[5-(2-Trifluoromethyl-phenyl)-isoxazol-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

Ethyl ester of 3-dimethylamino-2-(2-trifluoromethyl-benzoyl)-acrylic acid

A solution of ethyl ester of 3-oxo-3-(2-trifluoromethyl-phenyl)-propionic acid obtained in accordance with the procedure similar to that described in Example 231, (3,14 g, 12.1 mmol, 1.0 EQ.), and 1,1-dimethoxy-N,N-dimethylethanamine (the ceiling of 5.60 ml, 42.2 per mmol, 3.5 EQ.) in N,N-dimethylformamide was heated to boiling point under reflux for 5 hours. After cooling, the mixture was distributed between ethyl acetate and water. The organic phase was separated and washed successively with water (4×) and saturated aqueous sodium chloride. Collected organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to obtain 3,20 g (83%)ethyl ester of 3-dimethylamino-2-(2-trifluoromethyl-benzoyl)-acrylic acid as an orange waxy solid.1H NMR (400 MHz, CDCl3) δ: 7,86 (s, 1H), to 7.67-to 7.64 (m, 1H), 7,51-7,41 (m, 2H), 7,35 (d, 1H), 3,81 (kV, 2H), 3,42-3,17 (m, 3H), 3,11-of 2.93 (m, 3H), 0,78-0.69 (t, 3H).

Ethyl EPE is 5-(2-trifluoromethyl-phenyl)-isoxazol-4-carboxylic acid

A mixture of ethyl ester of 3-dimethylamino-2-(2-trifluoromethyl-benzoyl)-acrylic acid (3,10 g of 9.80 mmol, 1.0 EQ.) and hydroxylaminopurine (683 mg, 9,80 mmol, 1.0 EQ.) in methanol (25 ml) was heated to boiling point under reflux for 90 minutes. After cooling, the mixture was distributed between water and ethyl acetate and separated. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. Purification column flash chromatography on silica gel (gradient: 0→30% ethyl acetatein cyclohexane) gave 1,43 g (51%)ethyl ester 5-(2-trifluoromethyl-phenyl)-isoxazol-4-carboxylic acid.1H NMR (300 MHz, CDCl3) δ: scored 8.38 (s, 1H), 7,69 (d, 1H), to 7.61-7,47 (m, 2H), 7,27 (d, 1H), 3,93 (user, 2H), 0,87 (user, 3H).

tert-Butyl ester of [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-carbamino acid

A mixture of ethyl ester 5-(2-trifluoromethyl-phenyl)-isoxazol-4-carboxylic acid (1,43 g, 5,01 mmol, 1.0 EQ.), aqueous 6M HCl (34 ml) and acetic acid (20 ml) was heated to boiling point under reflux for 5.5 hours. After cooling, the mixture was distributed between water and ethyl acetate and separated. The organic phase was washed successively with water and us is placed in an aqueous solution of sodium chloride, was dried over anhydrous sodium sulfate and concentrated in vacuum to obtain 745 mg (58%)the crude 5-(2-trifluoromethyl-phenyl)-isoxazol-4-carboxylic acid, which was used without purification.

A mixture of 5-(2-trifluoromethyl-phenyl)-isoxazol-4-carboxylic acid (745 mg, 2,90 mmol, 1.0 EQ.) and thionyl chloride (8 ml) was heated to boiling point under reflux for 3 hours. The mixture was cooled to room temperature and concentrated in vacuum. The residue was dissolved in acetone (8 ml), cooled in an ice bath was added sodium azide (339 mg, 5,20 mmol, 1.8 EQ.). The mixture was stirred for 1 hour at the same temperature, then for 1 hour at ambient temperature. The reaction mixture was diluted with ethyl acetate and the resulting solution was washed successively with water and saturated aqueous sodium chloride. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The obtained residue was dissolved in tert-butanol (8 ml) and heated to boiling point under reflux for 16 hours. The reaction mixture was concentrated in vacuum. Purification using flash column-chromatography on silica gel (gradient: 0→20% ethyl acetatein cyclohexane) to give 345 mg (36%)tert-butyl ester [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-carbs the OIC acid. 1H NMR (300 MHz, CDCl3) δ: 8,89 (s, 1H), 7,88-to 7.84 (m, 1H), 7,72-7,66 (m, 2H), 7,54-7,49 (m, 1H), 5,98 (s, 1H), to 1.48 (s, 9H).

[5-(2-Trifluoromethyl-phenyl)-isoxazol-4-yl]-amide 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A mixture of tert-butyl ester [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-carbamino acid (345 mg, 1.05 mmol, 1.0 EQ.), 4M HCl in dioxane (2 ml) in 1,4-dioxane (3 ml) was heated to 40°C for 20 hours. The mixture was concentrated in vacuo to obtain a residue, which was dissolved in dichloromethane (12 ml) and treated with diisopropylethylamine (271 mg, 2.10 mmol, 2.0 EQ.). The mixture was cooled in an ice bath was added dropwise a solution of 5-chloropyrazole[1,5-α]pyrimidine-3-carbonylchloride (1.05 mmol, 1.0 EQ.) in dichloromethane (6 ml). The resulting mixture was stirred at ambient temperature for 18 hours. The solution was washed successively with an aqueous solution of 1M HCl, saturated aqueous sodium bicarbonate and water. The collected organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was ground into a powder (methanol) and the selected solid is washed with methanol and diethyl ether, then dried in vacuum to obtain 367 mg(86%) [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-amide 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. IHMS (ESI) m+H=408,0 (mono Cl);1H NMR (400 MHz, DMSO-d 6) δ: 9,50 (s, 1H), 9,35 (d, 1H), which 9.22 (s, 1H), 8,71 (s, 1H), 8,03 (d, 1H), 7,97-of 7.82 (m, 3H), 7,38 (d, 1H).

[5-(2-Trifluoromethyl-phenyl)-isoxazol-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A mixture of [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-amide 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (200 mg, 0.49 mmol, 1.0 EQ.) and 2M ammonia in propan-2-OLE (4 ml) was tightly closed and heated in a microwave reactor at 120°C for 40 minutes. The solvent was removed in vacuum and the obtained residue was column purified flash chromatography on silica gel (gradient: 0→5% methanol in dichloromethane) to give to 58.6 mg(31%) [5-(2-trifluoromethyl-phenyl)-isoxazol-4-yl]-amide5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. IHMS (ESI) m+H=389,1;1H NMR (400 MHz, DMSO-d6) δ: a 9.60 (s, 1H), 9,07 (s, 1H), 8,63 (d, 1H), 8,18 (s, 1H), to 7.99 (d, 1H), 7.95 is-to 7.77 (m, 3H), 7,70-6,60 (user, 2H), to 6.39 (d, 1H).

Example 233

(3-o-Tolyl-isoxazol-4-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

2-Methyl-benzaldehyde

A mixture of o-tolualdehyde (5,00 g of 41.6 mmol, 1.0 EQ.), hydroxylaminopurine (3,18 g, with 45.8 mmol, 1.1 EQ.) and pyridine (3,29 g of 41.6 mmol, 1.0 EQ.) in ethanol (100 ml) was stirred at ambient temperature for 2 hours. the pH of the mixture was brought to about 1 by the addition of an aqueous solution of 1M HCl. According to the scientists, the solution was extracted with dichloromethane. The collected organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain an oil (6,30 g) which was used directly in the next stage. IHMS (ESI) m+H+MeOH = 168,0;1H NMR (400 MHz, CDCl3) δ: 8,42 (s, 1H), 7,70-7,63 (d, 1H), 7,29-7,16 (m, 3H), 2,43 (s, 3H).

N-Hydroxy-2-methylbenzyloxycarbonyl

N-Chlorosuccinimide (2,22 g of 16.6 mmol, 1.0 EQ.) was added to a stirred solution of 2-methyl-benzaldehyde (2.25 g, of 16.6 mmol, 1.0 EQ.) in N,N-dimethylformamide (30 ml) at ambient temperature. Stirring was continued for 2 hours and the reaction was suppressed (ice-water). The resulting mixture was extracted with ethyl acetate. The combined organic extracts were washed successively with water (6×) and saturated aqueous sodium chloride (2×). The organic phase is then dried over anhydrous sodium sulfate, filtered and concentrated in vacuum to obtain 2,07 g (74%)N-hydroxy-2-methylbenzyloxycarbonyl in the form of a green oil.1H NMR (300 MHz, CDCl3) δ: 8,14 (s, 1H), of 7.48-7,44 (m, 1H), 7,37-7,20 (m, 3H), 2,43 (s, 3H).

Ethyl ester of 3-o-tolyl-isoxazol-4-carboxylic acid

To a stirred solution of N-hydroxy-2-methylbenzyloxycarbonyl (2,07 g, 12.2 mmol, 1.0 EQ.) in diethyl ether (15 ml) was added a solution of e is silt ester 3-pyrrolidin-1-yl-acrylic acid (obtained in accordance with the procedure described in U.S. Patent No. 4187099) from 2.06 g, 12.2 mmol, 1.0 EQ.) triethylamine (1.48 g, 12.2 mmol, 1.0 EQ.) in diethyl ether (30 ml) dropwise within 15 minutes. The resulting mixture was stirred at ambient temperature for 16 hours, distributed between water and diethyl ether and separated. The aqueous phase was extracted with diethyl ether (2×) and the combined ethereal extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. Purification column flash chromatography on silica gel (gradient: 0→20% ethyl acetatein cyclohexane) gave 1,32 g (47%)ethyl ester of 3-o-tolyl-isoxazol-4-carboxylic acid.1H NMR (400 MHz, CDCl3) δ: 9,02 (s, 1H), 7,39-7,34 (m, 1H), 7,32-7,24 (m, 3H), 4,19 (kV, 2H), of 2.23 (s, 3H), of 1.17 (t, 3H).

tert-Butyl methyl ether (3-o-tolyl-isoxazol-4-yl)-carbamino acid

A solution of ethyl ester of 3-o-tolyl-isoxazol-4-carboxylic acid (1,32 g, 5,71 mmol, 1.0 EQ.), aqueous 6M HCl (40 ml) and acetic acid (24 ml) was heated to boiling point under reflux for 5 hours. After cooling, the mixture was distributed between water and ethyl acetate and separated. The organic phase is then washed with water and saturated aqueous sodium chloride. Collected organics were then dried over anhydrous sodium sulfate, filtered and concentrate which has demonstrated in vacuum to obtain 930 mg (80%) the crude 3-o-tolyl-isoxazol-4-carboxylic acid, which was used without purification.

A mixture of 3-o-tolyl-isoxazol-4-carboxylic acid (930 mg, 4,58 mmol, 1.0 EQ.), azide diphenylphosphonic acid (1.26 g, 4,58 mmol, 1.0 EQ.) triethylamine (463 mg, 4,58 mmol, 1.0 EQ.) in tert-butanol (40 ml) was heated to 85°C for 16 hours. The mixture was concentrated in vacuo and the residue was swallowed up in ethyl acetate and sequentially washed with an aqueous solution of 1M HCl, saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. Collected organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was purified column flash chromatography on silica gel (gradient: 0→15% ethyl acetatein cyclohexane) to give 943 mg (75%)tert-butyl methyl ether (3-o-tolyl-isoxazol-4-yl)-carbamino acid. IHMS (ESI) m+H=275,0;1H NMR (300 MHz, CDCl3) δ: of 8.92 (s, 1H), 7,47-7,29 (m, 4H), by 5.87 (s, 1H), to 2.29 (s, 3H), of 1.48 (s, 9H).

(3-o-Tolyl-isoxazol-4-yl)-amide 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A mixture of tert-butyl methyl ether (3-o-tolyl-isoxazol-4-yl)-carbamino acid (500 mg, 1.82 mmol, 1.0 EQ.), 4M HCl in dioxane (4 ml) in 1,4-dioxane (5 ml) was stirred at ambient temperature for 22 hours and at 40°C for 1 hour. The mixture was concentrated in Vacu the IU obtaining balance, which was dissolved in dichloromethane (15 ml) and treated with diisopropylethylamine (523 mg, of 4.05 mmol, 2.2 EQ.). The mixture was cooled in an ice bath was added dropwise a solution of 5-chloropyrazole[1,5-α]pyrimidine-3-carbonylchloride (1.82 mmol, 1.0 EQ.) in dichloromethane (10 ml). After the addition the reaction mixture was heated to room temperature. After 65 hours the solution was sequentially washed with an aqueous solution of 1M HCl, saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was ground into a powder (methanol) to give 444 mg (70%) (3-o-tolyl-isoxazol-4-yl)-amide5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid. IHMS (ESI) m+H=354,2 (mono Cl);1H NMR (300 MHz, DMSO-d6) δ: for 9.47 (s, 1H), 9,36 (d, 1H), 9,11 (s, 1H), 8,72 (s, 1H), 7,53-7,40 (m, 4H), 7,37 (d, 1H), 2,31 (s, 3H).

(3-o-Tolyl-isoxazol-4-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A mixture of (3-o-tolyl-isoxazol-4-yl)-amide 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (200 mg, or 0.57 mmol, 1.0 EQ.) and 2M ammonia in propan-2-OLE (3 ml) was heated in a tightly closed vessel at 65°C for 18 hours and then in a microwave reactor at 100°C for 30 minutes. After cooling, the precipitate was isolated by filtration. Hard part is s then washed with propan-2-I and diethyl ether and dried in vacuum at 55°C to obtain 153 mg (80%) (3-o-tolyl-isoxazol-4-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid in the form of solids. IHMS (ESI) m+H=335,1;1H NMR (400 MHz, DMSO-d6) δ: of 9.51 (s, 1H), 9,34 (s, 1H), 8,65 (d, 1H), 8,21 (s, 1H), 7,58-7,44 (m, 4H), 7,01 (user, 1H), to 6.39 (d, 1H), and 2.27 (s, 3H).

Example 234

[2-(3-Trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

Ethyl 5-amino-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylate

To a solution of ethyl 2-cyano-3-ethoxyacrylate (0,81 g, 4.8 mmol) in ethanol (50 ml) was added 3-(trifluoromethyl)phenylhydrazine of 0.85 g, 4.8 mmol). The reaction mixture is boiled under reflux for 24 hours under nitrogen atmosphere. The mixture was cooled to room temperature and concentrated under reduced pressure to get to 0.94 g (yield: 66%) of the substance, which was used without further purification. MS (ESI) m/z:300,3.

1-(3-(Trifluoromethyl)phenyl)-1H-pyrazole-5-amine

A solution of ethyl 5-amino-1-(3-(trifluoromethyl)phenyl)-1H-pyrazole-4-carboxylate (0.9 g, 3 mmol) in dioxane (20 ml) saturated with HCl was heated to 150°C for 5 hours in a sealed tube. The reaction mixture was then cooled and concentrated in vacuum. The residue was diluted with water and the aqueous solution was extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried over with what LifeCam magnesium, was filtered and concentrated. The obtained residue was column purified flash chromatography (5:1 ethyl acetate/petroleum ether) to give the product (430 mg, 63%). MS (ESI) m/z:to 228.1.

5-Chloro-N-(1-(3-(trifluoromethyl)phenyl)-1H-pyrazole-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide

To a stirred solution of 1-(3-(trifluoromethyl)phenyl)-1H-pyrazole-5-amine (200 mg, 0.88 mmol) in dichloromethane (30 ml) was added 5-chloropyrazole[1,5-a]pyrimidine-3-carbonylchloride (215 mg, 1.0 mmol) and diisopropylethylamine (130 mg, 1.0 mmol). The mixture was heated to 50°C during the night. After cooling to room temperature the mixture was concentrated to obtain crude 5-chloro-N-(l-(3-(trifluoromethyl)phenyl)-1H-pyrazole-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (210 mg, yield 58%) which was used in the next stage without additional purification. MS (ESI) m/z 407,2

[2-(3-Trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid

A solution of 5-chloro-N-(l-(3-(trifluoromethyl)phenyl)-1H-pyrazole-5-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (210 mg, 0.52 mmol) in ethanol (20 ml) saturated with ammonia was heated to 100°C overnight in a sealed tube. After cooling to room temperature the solvent was removed under reduced pressure and the obtained residue was purified preparative HPLC to obtain [2-(3-Tr is formetal-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (8 mg, yield: 4%).1H NMR (400 MHz, DMSO-d6) δ: 9,94 (s, 1H), to 8.62 (d, J=7,6 Hz, 1H), 8,16 (s, 1H), 7,49-of 7.69 (m, 8H), 6,53 (s, 1H), 6,37 (d, J=7,6 Hz, 1H), MS (ESI) m/z : 388,1.

Examples 235-452 presented in Table 2, was obtained in accordance with the above described methods.

Table 2
Ave. No.StructureNameIHMS
(ESI) m/z
235[3-(5-chloro-2-methyl-phenyl)-1-(2-hydroxy-ethyl)-1H-pyrazole-4-yl]-amide
5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
412,2
236(1-methyl-3-o-tolyl-1H-pyrazole-4-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid348,1
237[5-(2,5-dichlorophenyl)-1-methyl-1H-pyrazole-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid402,0

238 (5-methyl-isoxazol-3-yl)-amide 5-(6-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid404,0
239isoxazol-3-alamid 5-(6-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid390,0
240(3-methyl-isoxazol-5-yl)-amide 5-(3-trifluoromethyl-phenylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid403,0
241(3-methyl-isoxazol-5-yl)-amide 5-(3-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid404,0

242(3-methyl-isoxazol-5-yl)-amide 5-(4-methoxy-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid366,1
243 [5-(3-chloro-phenyl)-isoxazol-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid355,1
244(3-methyl-isoxazol-5-yl)-amide 5-(pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid336,2
245(5-o-tolyl-isoxazol-4-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid335,2

246[2-(2-chloro-5-methyl-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid382,1
247[3-(2,5-dimethyl-phenyl)-1H-pyrazole-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid348,1
248[3-(2,5-dichloro-phenyl)-1H-pyrazole-4-yl]-amide 5-amino-pyrazole is[1,5-a]pyrimidine-3-carboxylic acid 388,0
249tert-butylamide 5-(2,5-differentialtopologie)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid410,1

250[3-(3-chloro-phenyl)-isoxazol-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid355,1
251(tetrahydro-Piran-4-yl)-amide 6-chloro-5-(2,5-debtor-benzylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid422,1
252(tetrahydro-Piran-4-yl)-amide 5-amino-6-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid296,1
253[3-(2-Cryptor-methyl-phenyl)-isoxazol-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid389,1

254(3-methyl-isoxazol-5-yl)-amide 5-(4-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid404,1
255[4-(3-chloro-phenyl)-2-methyl-thiazol-5-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid385,1
256isopropylated 5-(toluene-2-sulfonylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid374,1
257[2-(3,5-dichloro-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid388,1

258[2-(2,5-debtor-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-6-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid
259 (5-methyl-2-o-tolyl-2H-pyrazole-3-yl)-amide 5-amino-6-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid382,0
260tert-butylamide 5-(2-methyl-2H-pyrazole-3-sulfonylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid378,1
261cyclohexylamin 5-(toluene-2-sulfonylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid414,1

262cyclohexylamin 5-benzosulfimide-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid400,1
263[2-(2-iodine-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid446,0
264[2-(2,4-debtor-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo [5-a]pyrimidine-3-carboxylic acid 355,7
265[2-(2-fluoro-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid338,2

266[2-(2,4-debtor-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid369,9
267[2-(2,5-dichloro-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid402,2
268[2-(3,5-dimethyl-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid347,9
269(2-m-tolyl-2H-pyrazole-3-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid333,9

270(2-o-tolyl-2H-pyrazole-3-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid334,0
271[2-(3-chloro-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid354,0
272cyclohexylamin 5-(4-methoxy-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid367,2
273cyclohexylamin 5-(6-methyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid351,2

274[2-(3,5-debtor-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid356,6
275 [3-(3-cyano-phenyl)-1H-pyrazole-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid345,1
276cyclohexylamin 5-(pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid337,2
277[2-(2,5-dichloro-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid388,0

278[2-(2-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid388,0
279tert-butylamide 5-(toluene-2-sulfonylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid388,2
280tert-butylamide 5-benzosulfimide-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 347,2
281[2-(2,5-dimethyl-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid348,0

282[2-(2-chloro-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid353,9
283(3-methyl-isoxazol-5-yl)-amide 5-(6-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid404,2
284(2,5-dimethyl-2H-pyrazole-3-yl)-amide 5-(6-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid417,2
285pyridine-3-yl-amide 5-(6-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid400,2

286(tetrahydro-Piran-4-yl)-amide 5-(4-trifluoromethyl-pyrimidine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid408,2
287[3-(3-chloro-phenyl)-1-methyl-1H-pyrazole-4-yl]-amide 5-tert-butylamino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid424,1
288(tetrahydro-Piran-4-yl)-amide 5-(4,7-debtor-indan-1-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid414,1
289(4,4-debtor-cyclohexyl)-amide 5-(4,7-debtor-indan-1-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid448,1

290tert-butylamide 5-(2-trifluoromethyl-pyridine-4-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acidto 379.2
(4,4-debtor-cyclohexyl)-amide 5-(4-trifluoromethyl-pyrimidine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid442,1
292(4,4-debtor-cyclohexyl)-amide 5-(6-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid441,1
293(tetrahydro-Piran-yl)-amide 5-(6-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid407,2

294isopropylated 5-(6-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid365,1
295cyclohexylamin 5-(6-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid405,2
296 tert-butylamide 5-(6-trifluoromethyl-pyridine-3-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acidto 379.2
297(tetrahydro-Piran-4-yl)-amide 5-(indan-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid378,2
298(tetrahydro-Piran-4-yl)-amide 5-cyclopentylamine)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid330,1

299(4-hydroxy-cyclohexyl)-amide 5-(indan-1-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid392,2
300(4,4-debtor-cyclohexyl)-amide 5-(2,3-dihydro-benzofuran-3-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid414,1
301(those who rehydro-Piran-4-yl)-amide 5-(2,3-dihydro-benzofuran-3-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 380,1
302(4,4-diverticulosis)-amide 5-cyclohexylamino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid378,2

303(4,4-diverticulosis)-amide 5-cyclopentylamine-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid364,1
304(4,4-diverticulosis)-amide 5-(indan-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid412,1
305(4,4-diverticulosis)-amide 5-(4-hydroxy-cyclohexylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid394,2
306pyridine-3-alamid 5-(indan-1-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid371,1

307[2-(2-chloro-5-trifluoromethyl-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acidkm 436.0
308[2-(2,5-debtor-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid356,0
309tert-butylamide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid234,3
310tert-butylamide 5-(6-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acidto 379.2

311tert-butylamide 5-(4-trifluoromethyl-pyridine-2-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acidto 379.2
312 (4,4-debtor-cyclohexyl)-amide 5-(tetrahydro-Piran-4-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid380,1
313[2-(3-cyano-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid359,1
314[2-(4-chloro-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid368,0

315(tetrahydro-Piran-4-yl)-amide 5-(6-ferroman-4-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid412,1
316(4,4-diverticulosis)-amide 5-(1,2,3,4-tetrahydro-naphthalene-1-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acidto 426.2
317(4,4-ditto the cyclohexyl)-amide 5-(6-ferroman-4-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 446,1
318(tetrahydro-Piran-4-yl)-amide 5-[(S)-1-(2,5-differenl)ethyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid402,1

319(tetrahydro-Piran-4-yl)-amide 5-(indan-1-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid378,1
320(4,4-diverticulosis)-amide 5-(indan-1-ylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid412,2
321(tetrahydro-Piran-4-yl)-amide 5-[(R)-1-(2,5-differenl)ethyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid402,1
322[2-(1,1-dioxo-tetrahydro-1$%6&-thiophene-3-yl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid36,1

323tert-butylamide 5-(methylsulfanyl-phenylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid356,1
324(4-hydroxy-cyclohexyl)-amide 5-(3-trifluoromethyl-phenylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid420,1
325tert-butylamide 5-[1-(2,5-differenl)ethylamino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid374,1
326[2-(4-cyano-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid359,0

327[2-(2-cyano-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid359,0
328[5-(3-fluoro-phenyl)-1H-pyrazole-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid338,1
329[5-(3-fluoro-phenyl)-1-methyl-1H-pyrazole-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid352,1
330[3-(3-fluoro-phenyl)-1-methyl-1H-pyrazole-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid352,0

331(4-hydroxy-cyclohexyl)-amide 5-[1-(2,5-differenl)ethyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid416,2
332pyridine-3-alamid 5-[1-(2,5-differenl)ethylamino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid395,1
333 (tetrahydro-Piran-4-yl)-amide 5-(3-trifluoromethyl-phenylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid406,2
334(5-methyl-2-phenyl-2H-pyrazole-3-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid334,2

335[2-(4-fluoro-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid352,2
336[2-(3-fluoro-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid352,2
337[2-(2-chloro-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid368,2
338(2-phenyl-2H-pyrazole-3-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carb is new acid 320,1

339(4,4-diverticulosis)-amide 5-(4-methylsulfanyl-phenylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid418,1
340(4,4-diverticulosis)-amide 5-[(R)-1-(2,5-differenl)ethyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid436,1
341(tetrahydro-Piran-4-yl)-amide 5-[1-(2,5-differenl)ethyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid402,1
342(5-methyl-2-m-tolyl-2H-pyrazole-3-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid348,1

343(5-methyl-2-o-tolyl-2H-pyrazole-3-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic sour is s 348,1
344(5-phenyl-2H-pyrazole-3-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid320,1
345[3-(3-chloro-phenyl)-1H-pyrazole-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid354,0
346[5-(3-chloro-phenyl)-1-methyl-1H-pyrazole-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid348,1

347[3-(3-chloro-phenyl)-1-methyl-1H-pyrazole-4-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid368,1
348tert-butylamide 5-[N'-(2,5-differenl)hydrazino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid361,1
349 tert-butylamide 5-(N'-pyridin-2-yl-hydrazino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acidto 326.1
350tert-butylamide 5-(1-pyridin-3-yl-ethylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid339,2
351tert-butylamide 5-(1-pyridin-2-yl-ethylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid339,1

352cyclohexylamin 5-[(2-methyl-5-phenyl-2H-pyrazole-3-ylmethyl)-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid430,2
353cyclohexylamin 5-[(2-methyl-2H-pyrazole-3-ylmethyl)-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid354,2
354cyclohexylamin 5-[(3-methyl-3H-imidazol-4-ILM is Teal)-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 354,2
355cyclohexylamin 5-[(2,5-dimethyl-2H-pyrazole-3-ylmethyl)-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid368,2
356pyridine-3-alamid 5-[(R)-1-(3,5-differenl)ethyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid395,1

357(4,4-diverticulosis)-amide 5-[(S)-1-(3,5-differenl)propyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid450,2
358(4,4-diverticulosis)-amide 5-[(R)-1-(3,5-differenl)propyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid450,2
359(4,4-diverticulosis)-amide 5-[1-(3,5-differenl)propyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 450,2
360(4-hydroxycyclohexyl)-amide 5-[(R)-1-(3,5-differenl)ethyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid416,2

361(tetrahydro-Piran-4-yl)-amide 5-[(R)-1-(3,5-differenl)ethyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid402,2
362(5-methyl-2-pyridin-2-yl-2H-pyrazole-3-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid335,1
363tert-butylamide 5-[(2-dimethylamino-pyridine-3-ylmethyl)-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid368,2
364tert-butylamide 5-[(R)-1-(3,5-differenl)ethyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid374,2

365(4,4-diverticulosis)-amide 5-[(S)-1-(3,5-differenl)ethyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid436,1
366(4,4-diverticulosis)-amide 5-[(R)-1-(3,5-differenl)ethyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid436,1
367(4,4-diverticulosis)-amide 5-(2-methyl-benzylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid400,1
368(4,4-diverticulosis)-amide 5-[(pyridine-2-ylmethyl)-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid386,9

369tert-butylamide 5-[(pyridine-2-ylmethyl)-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid224,9
370 (4-hydroxy-cyclohexyl)-amide 5-[1-(3,5-differenl)ethyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid416,2
371(4,4-diverticulosis)-amide 5-[1-(3,5-differenl)ethyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acidkm 436.0
372cyclopropylamino 5-[1-(3,5-differenl)ethyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid358,0

373tert-butylamide 5-[1-(3,5-differenl)ethyl-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid373,9
374pyridine-2-alamid 5-(3,5-debtor-benzylamino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid381,1
375the cycle is propelled 5-(3,5-debtor-benzylamino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 343,9
376amide 5-(3,5-debtor-benzylamino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acidthe volume reached 303.9
377isopropylated 5-[(3-methyl-pyridine-2-ylmethyl)-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid325,1

378(4,4-diverticulosis)-amide 5-(2-trifluoromethyl-benzylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid454,1
379isopropylated 5-(2-fluoro-6-methoxy-benzylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid358,1
380tert-butylamide 5-(2-dimethylamino-benzylamino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid376,2
381 tert-butylamide 5-(2,5-debtor-benzylamino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid360,1
382tert-butylamide 5-(2-methoxy-benzylamino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid354,2

383tert-butylamide 5-(2-hydroxy-benzylamino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid340,1
384(4-hydroxy-cyclohexyl)-amide 5-[(pyridine-2-ylmethyl)-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid367,1
385pyridine-3-alamid 5-[(pyridine-2-ylmethyl)-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid346,0
386pyridine-2-alamid 5-[(pyridine-2-elmet the l)-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 346,0

387pyridine-3-alamid 5-[1-(3,5-differenl)ethylamino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid395,0
388pyridine-2-alamid 5-[1-(3,5-differenl)ethylamino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid395,1
389isopropylated 5-(3,5-dipertanyakan]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid332,0
390isopropylated 5-[(3-chloropyridin-2-ylmethyl)-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid344,9
391isopropylated 5-[(3-herperidin-2-ylmethyl)-amino]-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid329,4

392(2-tert-butyl-5-methyl-2H-pyrazole-3-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid314,1
393(4,4-diverticulosis)-amide 5-benzosulfimide-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid436,2
394(1-methyl-piperidine-4-yl)amide 5-benzosulfimide-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid415,1
395(4-methyl-cyclohexyl)amide 5-benzosulfimide-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid414,1

396(2-methyl-cyclohexyl)amide 5-benzosulfimide-pyrazolo[1,5-a]pyrimidine-3-carboxylic acidlevel of 414.2
397 bicyclo[2.2.1]hept-2-alamid 5-benzosulfimide-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid412,2
398piperidine-4-alamid 5-benzosulfimide-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid401,0
399(2-chroman-4-yl-5-methyl-2H-pyrazole-3-yl)-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid389,8

400[2-(2-ethinyl-6-fluoro-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid376,1
401tert-butylamide 5-(pyridine-3-ylsulphonyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid375,1
402cyclopentolate 5-benzosulfimide-irazola[1,5-a]pyrimidine-3-carboxylic acid 385,8
403phenylamide 5-benzosulfimide-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid393,7

404cyclohexylamin 5-(2-fluoro-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid418,1
405[2-(2-ethinyl-6-methyl-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid372,0
406cyclohexylamin 5-(2-phenyl-azetidin-1-yl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid376,2
407[2-(2-chloro-6-iodine-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid493,7

408[2-(2-cyclopropyl-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid373,8
409cyclohexylamin 5-(3,4-debtor-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid436,1
410cyclohexylamin 5-(3,4-dichloro-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid468,0
411cyclohexylamin 5-(3,5-debtor-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid436,1

412cyclohexylamin 5-(butane-1-sulfonylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid380,1
413img src="https://img.russianpatents.com/1192/11920721-s.jpg" height="29" width="43" /> cyclohexylamin 5-(2,4-debtor-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid436,1
414cyclohexylamin 5-(2,5-dichloro-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid468,0
415cyclohexylamin 5-(2,4-dichloro-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid468,0

416cyclohexylamin 5-(2,5-debtor-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid436,1
417cyclohexylamin 5-(2,6-dichloro-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid468,0
418cyclohexylamin 5-(3,5-dihl the p-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 468,0
419cyclohexylamin 5-(2,3-dichloro-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid468,0

420cyclohexylamin 5-(2,6-debtor-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid436,1
421[2-(2-fluoro-6-methyl-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid366,1
422[5-methyl-2-(2-triptoreline-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid418,1
423cyclohexylamin 5-(3-triptoreline-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acidOzenmunaygas given KZT 484.1 ecological

424cyclohexylamin 5-(2-triptorelin-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid468,1
425cyclohexylamin 5-(3-triptorelin-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid468,1
426cyclohexylamin 5-(toluene-3-sulfonylamino)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid414,1
427tert-butylamide 5-(2-chloro-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid408,0
428tert-butylamide 5-(2-fluoro-benzosulfimide)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid392,1

429[2-(2-bromo-6-fluoro-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid429,1
430[2-(2-chloro-6-trifluoromethyl-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid436,1
431[2-(2-chloro-6-fluoro-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid386,1
432tert-butylamide 5-methanesulfonamido-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid312,1

433[2-(2,6-dibromo-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid491,7
434 [2-(2-methoxy-6-methyl-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid378,2
435[2-(2-bromo-6-methyl-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid425,8
436[2-(2,6-dichloro-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid402,1

437[2-(2-chloro-6-methyl-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid382,1
438[2-(2-methoxy-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid364,0
439[2-(2-x is or-5-cyano-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 393,2
440[2-(2-ethinyl-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid358,0

441[2-(2-ethyl-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid362,2
442[5-methyl-2-(2-methylsulfanyl-phenyl)-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid380,1
443[2-(2,6-dimethyl-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid362,2
444[2-(2-iodine-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid460,1

445[2-(2-bromo-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid412,1446[2-(2-chloro-4-cyano-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid393,0447[2-(2-isopropyl-phenyl)-5-methyl-2H-pyrazole-3-yl]-amide 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid376.3 on4485-[1-(3,5-differenl)ethylamino]-N-phenylpyrazole[1,5-a]pyrimidine-3-carboxamide394,1

4495-[1-(3,5-differenl)ethylamino]-N-(3-forfinal)pyrazolo[1,5-a]pyrimidine-3-carboxamide412,1
450 5-(3,5-diferentiating]-N-(4-hydroxycyclohexyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide402,2
4515-(3,5-diferentiating]-N-(tetrahydro-2H-Piran-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide387,9
4525-(3,5-diferentiating]-N-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide380,9

Connection Examples 1-452 were tested for their ability to inhibit the activity of the JAK kinase. Connection Examples 1-452, as was found to have Kiless than about 1 μm in the assays of the activity of the JAK kinase (for example, see Examples A-C). Compounds of the present invention are therefore useful as inhibitors of JAK kinases.

In Table 3 below presents data enzymatic activity (Kifor some compounds of the present invention tested in the above assays (Examples A-C).

Table 4 below presents some of the data cell analysis of pharmacological activity (EC50for compounds of the present invention, when is the R in the above-described cellular assays (Example D).

Although the present invention has been described and illustrated to some extent specifically, it should be clear that the present disclosure is presented only in theas an example, and that the experts in this field can make various changes in the combination and arrangement of the parts without departure from the essence and scope of the present invention defined by the claims.

Reference is made to Provisional application U.S. serial No. 61/110497, filed October 31, 2008, which is incorporated into the present application by reference in its entirety for all purposes.

1. The compound of formula Ia

its stereoisomers, or a pharmaceutically acceptable salt,
where:
R1represents H;
R2represents-OR4, -NR3R4- or-NR3S(O)2R4;
R3represents N or C1-C6alkyl, where the specified alkyl optional substituted ORa;
R4represents H, C1-C6alkyl, -(C0-C5alkyl)(C3-C6cycloalkyl), -(C0-C5alkyl)(C4-C5heteroaryl), where heteroaryl contains 1-2 nitrogen atom as the heteroatoms, or(C0-C5alkyl)(C6aryl), where the specified alkyl optionally substituted by a group R8and these ar the l, cycloalkyl and heteroaryl optionally substituted by a group R9; or
R3and R4taken together with the nitrogen atom to which they are attached, form a C3heterocyclyl containing 1 nitrogen atom as heteroatoms, optionally substituted by a group R13;
Z represents a-NR5R6;
R5represents H;
R6represents H, C1-C10alkyl, -(C0-C5alkyl)(C4-C5heterocyclyl), where heterocyclyl contains an oxygen atom as a heteroatom, -(C0-C5alkyl)(C3-C8cycloalkyl), -(C0-C5alkyl)(C3-C5heteroaryl), where heteroaryl contains 1 nitrogen atom or 1 oxygen atom, or contains 2 atoms selected from oxygen, nitrogen and sulfur as heteroatoms, -(C0-C5alkyl)(C6aryl), where the specified alkyl optionally substituted by a group R10and these aryl, cycloalkyl, heteroaryl and heterocyclyl optionally substituted by a group R11;
R7represents H;
R8independently represents halogen or ora;
R9independently represents-CN, -CF3, halogen, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa, -(C0-C5alkyl)SRa,- [C(Ra)2]1-3the-, C1-C3alkyl, optionally substituted by F, -(C0-C5alkyl)(C3-C6cycloalkyl), optionally substituted by oxo group or F, -(C0-C5alkyl)3-C6heterocyclyl where heterocyclyl contains 1-2 heteroatoms selected from oxygen atoms and nitrogen, and where heterocyclyl optionally substituted with halogen or C1-C3by alkyl, -(C0-C5alkyl)C6aryl, optionally substituted with halogen, or -(C0-C5alkyl)C4-C5heteroaryl where heteroaryl contains 1 nitrogen atom or 1 oxygen atom, or contains 2 atoms selected from atoms of oxygen, nitrogen and sulfur as heteroatoms, and where heteroaryl optionally substituted with halogen or C1-C3by alkyl;
R10independently represents halogen or ora;
R11independently represents-CN, -CF3, halogen, -O[C(Ra)2]1-3O-, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)ORaC1-C6alkyl, optionally substituted by oxo group or F, -(C0-C5alkyl)C4-C5heterocyclyl where heterocyclyl contains 1 nitrogen atom or 1 sulfur atom as heteroatoms and where heterocyclyl optionally substituted with halogen, oxo, or C1-C3by alkyl, -(C0-C5alkyl)C4-C5heteroaryl, where courtesans the aryl contains 1 nitrogen atom or 1 oxygen atom, or contains 2 atoms, selected from atoms of oxygen, nitrogen and sulfur as heteroatoms, and where heteroaryl optionally substituted with halogen or C1-C3by alkyl, -(C0-C5alkyl)phenyl, optionally substituted C1-C4the alkyl, C2-C4the quinil,3-C6cycloalkyl, -CF3, halogen, -CN, -ORaor-NRaRbor -(C0-C5alkyl)3-C6cycloalkyl, optionally substituted C1-C3by alkyl;
R13represents a C6aryl;
Raand Rbindependently represent H, -CF3C1-C6alkyl, C6aryl, C3-C6cycloalkyl or C4-C5heterocyclyl where heterocyclyl contains 1-2 heteroatoms selected from oxygen atoms and nitrogen; where these alkyl, aryl and cycloalkyl optionally substituted C1-C4by alkyl, -(C0-C3alkyl)ORc, halogen or NRcRd; or
Raand Rbtogether with the nitrogen atom to which they are bound, form a4-C5heterocyclyl where heterocyclyl contains 1-2 heteroatoms selected from oxygen atoms and nitrogen, and where heterocyclyl optionally substituted C1-C3the alkyl or-C(O)ORa;
Rcand Rdindependently represent N or C1-C3alkyl.

2. Connection on p. 1, selected from the Fort the uly I

its stereoisomers, or a pharmaceutically acceptable salt,
where:
R1represents H;
R2represents-OR4or-NR3R4;
R3represents N or C1-C6alkyl, where the specified alkyl optional substituted ORa;
R4represents H, C1-C6alkyl, -(C0-C5alkyl)(C3-C6cycloalkyl), -(C0-C5alkyl)(C4-C5heteroaryl), where heteroaryl contains 1-2 nitrogen atom as the heteroatoms, or (C0-C5alkyl)(C6aryl), where the specified alkyl optionally substituted by F or oraand these aryl, cycloalkyl and heteroaryl optionally substituted
-CN, -CF3, halogen, -C(O)ORa, -C(O)NRaRb, -(C0-C5alkyl)NRaRb, -(C0-C5alkyl)ORa,- [C(Ra)2]1-3Oh,
C1-C3the alkyl, optionally substituted by F,
-(C0-C5alkyl)3-C6heterocyclyl where heterocyclyl contains 1-2 heteroatoms selected from oxygen atoms and nitrogen, and where heterocyclyl optionally substituted with halogen or C1-C3the alkyl, or
-(C0-C5alkyl)C4-C5heteroaryl where heteroaryl contains 1 nitrogen atom or 1 oxygen atom, or contains 2 atoms selected from atomistilor, nitrogen and sulfur as heteroatoms, and where heteroaryl optionally substituted with halogen or C1-C3by alkyl; or
R3and R4taken together with the nitrogen atom to which they are bound, form a3heterocyclyl containing 1 nitrogen atom as a heteroatom;
Z represents a-NR5R6;
R5represents H;
R6represents H, C1-C10alkyl, -(C0-C5alkyl)(C4-C5heterocyclyl), where heterocyclyl contains an oxygen atom as a heteroatom, -(C0-C5alkyl)(C3-C8cycloalkyl), -(C0-C5alkyl)(C3-C5heteroaryl), where heteroaryl contains 1 nitrogen atom or 1 oxygen atom, or contains 2 atoms selected from atoms of oxygen, nitrogen and sulfur as heteroatoms, or(C0-C5alkyl)(C6aryl), where the specified alkyl optionally substituted by F or oraand these aryl, cycloalkyl, heteroaryl and heterocyclyl optionally substituted
-CN, -CF3, halogen, -O[C(Ra)2]1-3O-, -C(O)ORa-C(O)NRaRb, -(C0-C5alkyl)ORa,
C1-C6the alkyl, optionally substituted by oxo group or F,
-(C0-C5alkyl)C4-C5heterocyclyl where heterocyclyl contains 1 nitrogen atom or 1 sulfur atom as heteroatoms and g the e heterocyclyl optionally substituted with halogen, oxo or C1-C3the alkyl,
-(C0-C5alkyl)C4-C5heteroaryl where heteroaryl contains 1 nitrogen atom or 1 oxygen atom, or contains 2 atoms selected from atoms of oxygen, nitrogen and sulfur as heteroatoms, and where heteroaryl optionally substituted with halogen or C1-C3the alkyl,
-(C0-C5alkyl)phenyl, which is optionally substituted C1-C3by alkyl, -CF3, halogen, -CN, -ORaor-NRaRbor
-(C0-C5alkyl)3-C6cycloalkyl, which is optionally substituted C1-C3by alkyl;
Raand Rbindependently represent H, -CF3C1-C6alkyl, C6aryl, C3-C6cycloalkyl or4-C5heterocyclyl where heterocyclyl contains 1-2 heteroatoms selected from oxygen atoms and nitrogen; where these alkyl, aryl and cycloalkyl optionally substituted C1-C4the alkyl, (C0-C3alkyl)ORc, halogen or NRcRd; or
Raand Rbtogether with the nitrogen atom to which they are attached, form a C4-C5heterocyclyl where heterocyclyl contains 1-2 heteroatoms selected from oxygen atoms and nitrogen, and where heterocyclyl optionally substituted C1-C3the alkyl or-C(O)ORa;
Rcand Rdindependently depict ablaut a N or C 1-C3alkyl.

3. Connection PP.1, 2, where R2is an-other4.

4. Connection on p. 1, where R2represents-NH2.

5. Connection on p. 1, where R4represents a C1-C6alkyl, -(C0-C5alkyl)(C3-C6cycloalkyl), -(C0-C5alkyl)(C4-C5heteroaryl), where heteroaryl contains 1-2 nitrogen atom as heteroatoms, -(C0-C5alkyl)(C6aryl), where the specified alkyl optionally substituted by a group R8and these aryl, cycloalkyl and heteroaryl optionally substituted by a group R9.

6. Connection on p. 1, where R3and R4taken together with the nitrogen atom to which they are bound, form a3heterocyclyl containing 1 nitrogen atom as heteroatoms, optionally substituted by a group R13.

7. Connection on p. 1, where R2represents-NHS(O)2R4.

8. Connection PP.1 and 7, where R4represents -(C6aryl), optionally substituted by a group R9.

9. Connection on p. 1, where Z is an-other6.

10. Connection on p. 1, where R6represents a C1-C10alkyl, -(C0-C5alkyl)(C4-C5heterocyclyl), where heterocyclyl contains an oxygen atom as a heteroatom, -(C0-C5alkyl)(C3-C8 cycloalkyl), -(C0-C5alkyl)(C3-C5heteroaryl), where heteroaryl contains 1 nitrogen atom or 1 oxygen atom, or contains 2 atoms selected from atoms of oxygen, nitrogen and sulfur as heteroatoms, -(C0-C5alkyl)(C6aryl), where the specified alkyl optionally substituted by a group R10and these aryl, cycloalkyl, heteroaryl and heterocyclyl optionally substituted by a group R11.

11. Connection on p. 1, where R2represents-NR3S(O)2R4; R3represents H; and R4represents phenyl, optionally substituted by 1-3 substituents selected from C1-C3of alkyl, -CF3and halogen; and R6is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl and where R6optionally substituted by 1-3 substituents selected from halogen and C1-C6the alkyl.

12. Connection on p. 1, where R2represents-NR3R4; R3represents H; R6represents pyrazolyl, substituted phenyl and optionally additionally substituted by stands, and where specified phenyl optionally substituted by one or two substituents selected from methyl, halogen, methoxy, cyano, trifloromethyl, hydroxy, triptoreline.

13. Pharmaceutical composition, obladaushi the ability of inhibiting JAK kinase, comprising a therapeutically effective amount of a compound according to any one of paragraphs.1-12 and a pharmaceutically acceptable carrier, adjuvant or excipient.

14. A method of treating or reducing the severity of the disease or condition responsive to the inhibition of the activity of a JAK kinase, comprising introducing a therapeutically effective amount of compound on the PP.1-12.

15. Connection on p. 1, capable of inhibiting JAK kinase, to obtain drugs for the treatment of diseases mediated by the activity of the JAK kinase.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compounds of formula , where R1 represents hydroxyadamantyl, methoxycarbonyladamantyl, carboxyadamantyl, aminocarbonyladamantyl or aminocarbonylbicyclo[2.2.2]octanyl and where A represents CR5R6; or phenyl, chlorobenzyl, benzyl, chlorophenylethyl, phenylethyl, difluorobenzyl, dichlorophenyl, trifluoromethylphenyl or difluorophenylethyl and where A represents CR5R6; R2 and R3 together with nitrogen atom N* and carbon atom C*, which they are bount to, form group or ; R4 represents hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, alkoxyalkyl, arylalkyl, arylalkoxygroup, arylalkoxyalkyl, hydroxyalkyl, aryl, heteroarylalkyl, heteroaryloxyalkyl, substituted aryl, substituted heteroarylalkyl or substituted heteroaryloxyalkyl, where substituted aryl, substituted heteroarylalkyl and substituted heteroaryloxyalkyl are substituted with 1-3 substituents, independently selected from alkyl, cycloalkyl, cyanogroup, halogen, halogenalkyl, hydroxygroup and alkoxygroup; R5 represents hydrogen; R6represents hydrogen; as well as to their pharmaceutically acceptable salts and esters, which can be used as 11b-HSD1 inhibitors.

EFFECT: obtaining compounds which can be used as 11b-HSD1 inhibitors.

9 cl, 1 tbl, 103 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula or its therapeutically acceptable salts, wherein A1 represents furyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, piperidinyl, morpholinyl, dihydro-1,3,4-thiadiazol-2-yl, benzothien-2-yl, banzothiazol-2-yl, tetrahydrothien-3-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl or imidazo[2,1-b][1,3]-thiazol-5-yl; wherein A1 is unsubstituted or substituted by one, or two, or three, or four, or five substitutes independently specified in R1, OR1, C(O)OR1, NHR1, N(R1)2, C(N)C(O)R1, C(O)NHR1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br and CF3; R1 represents R2, R3, R4 or R5; R2 represents phenyl; R3 represents pyrazolyl or isoxazolyl; R4 represents piperidinyl; R5 represents C1-C10alkyl or C2-C10alkenyl each of which is not specified or specified by substitutes specified in R7, SR7, N(R7)2, NHC(O)R7, F and Cl; R7 represents R8, R9, R10 or R11; R8 represents phenyl; R9 represents oxadiazolyl; R10 represents morpholinyl, pyrrolidinyl or tetrahydropyranyl; R11 represents C1-C10alkyl; Z1 represents phenylene; Z2 represents piperidine unsubstituted or substituted by OCH3, or piperazine; both Z1A and Z2A are absent; L1 represents C1-C10alkyl or C2-C10alkenyl each of which is unsubstituted or substituted by R37B; R37B represents phenyl; Z3 represents R38 or R40; R38 represents phenyl; R40 represents cyclohexyl or cyclohexenyl; wherein phenylene presented by Z1 is unsubstituted or substituted by the group OR41; R41 represents R42 or R43; R42 represents phenyl, which is uncondensed or condensed with pyrrolyl, imidazolyl or pyrazole; R43 represents pyridinyl, which is uncondensed or condensed with pyrrolyl; wherein each cyclic fragment presented by R2, R3, R4, R8, R9, R10, R38, R40, R42 and R43 is independently unsubstituted or substituted by one or more substitutes independently specified in R57, OR57, C(O)OR57, F, Cl CF3 and Br; R57 represents R58 or R61; R58 represents phenyl; R61 represents C1-C10alkyl; and wherein phenyl presented by the group R58 is unsubstituted or substituted by one or more substitutes independently specified in F and Cl.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, and to a method of treating diseases involving the expression of anti-apoptotic Bcl-2 proteins.

7 cl, 2 tbl, 48 ex

Jak inhibitors // 2538204

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I wherein R means C1-6alkyl, C1-6halogenalkyl, hydroxy-C1-6alkyl, hydroxygroup or halogen; m, n is equal to 0 or 1; Z1 means CH or NH; Z2 means CH or N; Z3 means CR1, N or NR2; R1 means H, C1-6alkyl, C3-7cycloalkyl, cyanogroup, cyano-C1-6alkyl or halogen; R2 means H or C1-6alkyl; X means CH, CR' or N; X' means CH, CR' or N; r is equal to 1; Y means CH or CR'; R' means R'a or R'b; R'a means a halogen or cyanogroup; R'b means C1-6alkyl, heterocycloalkyl specified in piperazinyl, morpholinyl, piperidinyl, thiomorpholinyl, azetidinyl, pyrrolidinyl, OR", SR", S(=O)2R" or NR"R", optionally substituted by one or more R'c; R'c means a hydroxygroup, oxogroup, cyanogroup, C1-6alkyl, pyridinyl, carboxy-C1-6alkyl, aminocarbonyl-C1-6alkylaminogroup, C1-6alkylaminogroup, C1-6dialkylaminogroup or C1-6alkoxygroup; R" means H, C1-6alkyl, hydroxy-C1-6alkyl, piperidinyl, C3-7cycloalkyl or pyridinyl; Q means S(=O)2Q1, C(=O)Q2, C(=O)OQ3 or Q4; Q1 means C1-6alkyl, C3-7cycloalkyl-C1-6alkyl, C1-6alkylaminogroup or C1-6dialkylaminogroup optionally substituted by one or more Q1'; each Q1' independently means C1-6alkyl or cyanogroup; Q2 means C1-6alkyl optionally substituted by one or more Q2'; each Q2' independently means a cyanogroup; Q3 means C1-6alkyl; Q4 means C1-6alkyl, oxetanyl optionally substituted by one or more Q4'; each Q4' independently means a halogen, cyanogroup, cyano-C1-6alkyl; p is equal to 0, 1 or 2; q is equal to 1 or 2; each means a single bond or a double bond; provided one of Z1 and Z2, and Z3 and Z3 bonds are double and single.

EFFECT: compounds of formula I as JAK inhibitors.

23 cl, 2 tbl, 121 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula IV, VIII-A and X, and to their pharmaceutical acceptable salts possessing the inhibitory activity on PI3-kinase (phosphoinositide-3-kinase). In compounds of formula IV and IX and Wd is specified in a group consisting of, , , and each of which can be substituted. In formula VIII-A, the group Wd represents the group or , wherein Ra is hydrogen, R11 is amino; in compound IV, Wa2 represents CR5; Wa3 represents CR6; Wa4 represents N or CR7; in compound IX, Wa1 and Wa2 independently represent CR5, N or NR4, and Wa4 independently represents CR7 or S, wherein no more than two neighbouring atoms in a ring represent atom or sulphur; Wb5 represents N; B represents a grouping of formula II, as well as in case of compound IV, B means C1-C10alkyl, C3-C10cycloalkyl, C3-C10heterocycloalkyl having one to six ring heteroatoms specified in N, O and S; in case of compound IX, B also means C1-C10alkyl, C3-C10cycloalkyl or 6-merous heterocycloalkyl having nitrogen atom; Wc represents C6-C10aryl or 5-18-merous heteroaryl having one or more ring heteroatoms specified in N, O and S, or phenyl or 6-merous heteroaryl respectively is equal to an integer of 0, 1, 2, 3 or 4; X is absent or represents -(CH(R9))z-, respectively; z is equal to 1; Y is absent. The other radical values are specified in the patent claim.

EFFECT: compounds can be used for treating such diseases, as cancer, bone disorders, an inflammatory or immune disease, diseases of the nervous system, metabolic disorders, respiratory diseases, thrombosis or cardiac diseases mediated by PI3-kinase.

68 cl, 11 dwg, 7 tbl, 55 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically 4-((2-hydroxyethoxy)methyl)-5-methyl-2-methylmercapto-1,2,4-triazolo[1,5-a]pyrimidin-7(4H)-one of formula (I) . The invention also relates to a method of producing and using said compound to treat West Nile fever.

EFFECT: obtaining a novel compound with useful biological activity.

3 cl, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: described is novel biologically active compound 2-methylsulphanyl-6-nitro-7-oxo-1,2,4-triazolo[5,1-c][1,2,4]triazinide L-argininium dehydrate of formula , which has antiviral action, method of its obtaining and application for prevention and treatment of West Nile fever.

EFFECT: increased efficiency of compound application.

3 cl, 2 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula

possessing inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases. In formula (I-b), ring A and ring B represents phenyl; Ry represents -CN, -CF3, C1-4 aliphatic group, C1-4 halogenaliphatic group, -OR, -C(O)R or -C(O)N(R)2; each group R independently represents hydrogen or a group specified in C1-6 aliphatic group optionally containing a substitute presented by halogen, -(CH2)0-4R°, -(CH2)0-4OR°, -(CH2)0-4N(R°)2, -(CH2)0-4N(R°)C(O)OR°, -(CH2)0-4C(O)R°, -(CH2)0-4S(O)2R°, or 5-6-merous substituted or aryl ring containing 1-2 heteroatoms independently specified in nitrogen or oxygen optionally substituted by group =O, -(CH2)0-4R°, -(CH2)0-4N(R°)2 or -(CH2)0-4OR°; phenyl; 5-6-merous heterocyclic ring containing 1-2 heteroatoms independently specified in nitrogen, oxygen or sulphur optionally substituted by group -(CH2)0-4R°, -(CH2)0-4OR° or =O; or 6-merous monocyclic heteroaryl ring containing 1 nitrogen atom; W1 and W2 represent -NR2-; R2 represents hydrogen, C1-6aliphatic group or -C(O)R; m and p are independently equal to 0, 1, 2, 3 or 4; Rx is independently specified in -R, -OR, -O(CH2)qOR or halogen, wherein q=2; Rv is independently specified in -R or halogen; R1 and R° radical values are presented in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds.

EFFECT: preparing the compounds possessing the inhibitory activity on BTK, TEC, BMX, ITK, ErbB1, ErbB4 and/or JAK3 kinases.

17 cl, 25 dwg, 20 tbl, 286 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new compounds of formula I or their pharmaceutically acceptable salts, wherein R1 means phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen or 5-6-merous heteroaryl; R2 is phenyl once or twice substituted by C1-6 alkyl, C1-6 alkoxy, halogen, halogen-C1-6alkyl, halogen-C1-6alkoxy, C1-6 alkylsulphonyl, nitrile, etc. R3 means H or C1-6 alkyl; X - -O-, -NRa-,-S(O)m- or CRbRc, wherein Ra - H, C1-6 alkyl or C1-6 alkylcarbonyl; Rb and Rc mean H or together with the atom to which they are attached, form 5-merous cycle additionally containing 2 oxygen atoms; m is equal to 0-2; Y means -NRc-, wherein Rc - H or C1-6 alkyl.

EFFECT: compounds can find application in medicine for treating autoimmune and inflammatory diseases related to P2X7 purinoceptor.

15 cl, 1 tbl, 10 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula I, possessing a modulating action with respect to the CC chemokine receptor 3 (CCR3), a based on them pharmaceutical composition, versions of treatment methods and a method of controlling the CCR3 activity. In the general formula I R1 and R2 represent halogen or C1-6alkyl; R3 represents cyano or nitro; R4 represents or ; R5 represents oxo; C1-6alkyl, optionally substituted with halogen atoms; or C(O)OR1a; X represents O or S; Y represents -O-, -S-, -N(R1a)-, -C(R1a)(R1d)- or -C(R1a)(NR1bR1c)-; m represents an integer number from 0 to 2; n represents 1; p represents an integer number from 0 to 2; r represents 1 or 2; and each R1a, R1b, R1c and R1d represents (a) hydrogen; (b) C3-7cycloalkyl; or (c) C1-6alkyl, optionally substituted with hydroxyl, or each pair R1b and R1c together with a N atom, which they are bound to, form imidazoimidazolyl, substituted with oxo, butyl or chlorine, or heterocycle, containing 5 or 6 atoms in a cycle.

EFFECT: improvement of the composition properties.

41 cl, 2 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to benzoimidazole derivatives of formula (I), as well as to their enantiomers, diastereoisomers, racemates and pharmaceutically acceptable salts, where n equals from 2 to 4, each of R1 substituents is independently selected from H, halogen, -C1-4alkyl, -C1-4pergaloalkyl, trifluoro-C1-4alkoxy, -NO2, -CN, CO2H, -OC1-4alkyl, -SC1-4alkyl, -S(C1-4alkyl)-Rc, -S(O)2(C1-4alkyl)-Rc, -S(O)-C1-4alkyl, -SO2-C1-4alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -SO2-NH-Rc, -O-Rc, -CH2-O-Rc, -C(O)NH-Rc, -NRaRb, benzyloxy, phenyl, optionally substituted with one-two Rd, cyanobiphenyl-4-ylmethylsulpfanyl, cyanobiphenyl-4-ylmethanesulphonyl, or -S-(CH2)2-morpholine and two adjacent groups R1 can bind with formation of an aromatic 5-6-membered ring, optionally substituted with one methyl group or two atoms of halogen, optionally containing one or two S or N; Ra and Rb each independently represents C1-4alkyl, -C(O)C1-4alkyl, -C(O)-Rc, -C(O)CH2-Re, C1-4alkyl-Re, -SO2-Rc, -SO2-C1-4alkyl, phenyl, benzyl; or Ra and Rb together with a nitrogen atom, which they are bound with, form a monocyclic 5-6- membered heterocycloalkyl ring, optionally containing one heteroatom, selected from O; Rc represents -C3-8cycloalkyl, phenyl, optionally substituted with one-two Rd, benzyl, optionally substituted with one-three Rd; morpholine; Rd independently represents halogen, -OH, -C1-4alkyl or -C1-4perhalogenalkyl, trifluorine C1-4alcoxy, -OC1-4alkyl, or -O-benzyl optionally substituted with halogen, Re represents -C6heterocycloalkyl, optionally containing one or two of O or N atoms, optionally substituted with a methyl group; R2 and R3 both represent H, -CF3 or C1-3alkyl; each of Z represents a C or N atom, on condition that simultaneously not more than two Z represent N. The invention also relates to particular compounds, a pharmaceutical composition, based on formula (I) compound or a particular said compound, a method of treating diseases, mediated by propyl hydroxylase activity.

EFFECT: novel derivatives of benzimidazole, possessing an inhibiting activity with respect to PHD are obtained.

11 cl, 1 tbl, 186 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula I , II or IV , wherein the radical values W, V, Ra, Rb, X, L, Rt, A are presented in the patent claim.

EFFECT: declared compounds identify and bind the CA-IX protein; they can contain a radioactive element for radionuclide imaging or therapeutic application.

27 cl, 1 tbl, 5 dwg, 25 ex

FIELD: medicine.

SUBSTANCE: treating locally advanced oropharyngeal cancer is ensured by a radiation therapy in the mode of dynamic dose fractionation. The radiation therapy is started by supplying a fraction dose of 2.4 Gy. After 2 days of treatment gap, the patient is exposed to total fractions at a fraction dose of 3.6Gy for three days. Each session is precede by placing high-structure hydrogel matrix of sodium alginate under a patient's tongue with metronidazole 150mg and bilberry 20-35mg pre-introduced into the matrix, for 4-5 hours twice every 1-2 hours. The two following sessions of the exposure at a fraction dose of 2.4 Gy are preceded by placing the matrix once under the tongue for 4-5 hours. After 2 days of treatment gap, the following 5 sessions of the radiation therapy are performed at a fraction dose of 2.4 Gy to a cumulative dose of 30Gy. Colegel-DNA-Ch high-structure disk is preliminary placed under the tongue for 4-5 hours.

EFFECT: method enables avoiding the compulsory gaps of the radiation therapy by reducing a rate of severe local radiation reactions, and provides the target delivery and accurate dosage of metronidazole administered into the patient's body leading to the partial death of well-oxygenated cells and re-oxygenation of hypoxic tumour cells.

2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula or its therapeutically acceptable salts, wherein A1 represents furyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, piperidinyl, morpholinyl, dihydro-1,3,4-thiadiazol-2-yl, benzothien-2-yl, banzothiazol-2-yl, tetrahydrothien-3-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl or imidazo[2,1-b][1,3]-thiazol-5-yl; wherein A1 is unsubstituted or substituted by one, or two, or three, or four, or five substitutes independently specified in R1, OR1, C(O)OR1, NHR1, N(R1)2, C(N)C(O)R1, C(O)NHR1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br and CF3; R1 represents R2, R3, R4 or R5; R2 represents phenyl; R3 represents pyrazolyl or isoxazolyl; R4 represents piperidinyl; R5 represents C1-C10alkyl or C2-C10alkenyl each of which is not specified or specified by substitutes specified in R7, SR7, N(R7)2, NHC(O)R7, F and Cl; R7 represents R8, R9, R10 or R11; R8 represents phenyl; R9 represents oxadiazolyl; R10 represents morpholinyl, pyrrolidinyl or tetrahydropyranyl; R11 represents C1-C10alkyl; Z1 represents phenylene; Z2 represents piperidine unsubstituted or substituted by OCH3, or piperazine; both Z1A and Z2A are absent; L1 represents C1-C10alkyl or C2-C10alkenyl each of which is unsubstituted or substituted by R37B; R37B represents phenyl; Z3 represents R38 or R40; R38 represents phenyl; R40 represents cyclohexyl or cyclohexenyl; wherein phenylene presented by Z1 is unsubstituted or substituted by the group OR41; R41 represents R42 or R43; R42 represents phenyl, which is uncondensed or condensed with pyrrolyl, imidazolyl or pyrazole; R43 represents pyridinyl, which is uncondensed or condensed with pyrrolyl; wherein each cyclic fragment presented by R2, R3, R4, R8, R9, R10, R38, R40, R42 and R43 is independently unsubstituted or substituted by one or more substitutes independently specified in R57, OR57, C(O)OR57, F, Cl CF3 and Br; R57 represents R58 or R61; R58 represents phenyl; R61 represents C1-C10alkyl; and wherein phenyl presented by the group R58 is unsubstituted or substituted by one or more substitutes independently specified in F and Cl.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, and to a method of treating diseases involving the expression of anti-apoptotic Bcl-2 proteins.

7 cl, 2 tbl, 48 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmacology and oncology, particularly to a new antitumour agent. Beta-ethyldiphacyl is presented to be used as an agent of an epithelial tumour (carcinoma) inhibition. There is provided to administer Ethyldiphacyl in doses of 15-50 mg/kg both before, and after the tumour grafting; the therapeutic course is up to 2 months after the tumour grafting with administrations following every 6-7 days; or preventive administration is performed 2-24 hours before the tumour grafting.

EFFECT: technical effect consists in prolonging the life of mammals suffering the from the tumour by 30%; the life is not burdened with the disease progression.

4 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: what is presented is a group of inventions concerning treating and preventing a disease dependent on mTOR (mammalian target of rapamycin) kinase and representing cancer or malignant growth. The group involves a pharmaceutical combination for the above application containing 5-(2,6-dimorpholin-4-ylpyrimidin-4-yl)-4 trifluoromethylpyridin-2-ylamine or its salt and the mTOR inhibitor everolimus; using it for preparing a drug preparation for the same application and a pharmaceutical composition containing the above combination.

EFFECT: synergetic effect of the antitumour action of 5-(2,6-dimorpholin-4-ylpyrimidin-4-yl)-4 trifluoromethylpyridin-2-ylamine and everolimus.

7 cl, 2 dwg

FIELD: medicine.

SUBSTANCE: oxaliplatin 100 mg in 0.9% NaCl 200 ml is introduced into a nutrient artery of the tumour at 200 ml/h. That is followed by a chemoembolisation of the nutrient artery of the tumour with using a composition of the preparation oxaliplatin. For this purpose the preparation oxaliplatin 1 mg and 1 bottle of HepaSphere embolisation material is dissolved in water for injections 5 ml. That is followed by a bolus administration of the prepared composition. A curative operation is performed not earlier than 24 hours later.

EFFECT: method provides reducing the oncogenic activity of the tumour tissue, and as a consequence preventing tumour metastases, recurrent tumour growth and lymph node metastases, shortening considerably the length of the combination treatment of rectal cancer.

2 ex

FIELD: medicine.

SUBSTANCE: group of inventions relates to medicine and deals with application of antibody to HER2 and/or antibody to VEGF for preparation of medication intended for reduction of metastases in treatment of breast cancer, characterised by super-expression of HER2 receptor protein in patient, unsusceptible to preceding therapy with application of antibody to VEGF, in which treatment includes introduction to patient of therapeutically effective amount of antibody to HER2 and antibody to VEGF, with antibody to VEGF representing bevacizumab, and antibody to HER2 representing trastuzumab. Group of inventions also deals with application of antibody to HER2 for reduction of metastases in method of breast cancer treatment and application of antibodies to VEGF for reduction of methastases in method of breast cancer treatment.

EFFECT: combination of bevacizumab and trastuzumab makes it possible to achieve prevention of metastases formation.

12 cl, 1 ex, 2 dwg, 4 tbl

FIELD: chemistry.

SUBSTANCE: claimed invention relates to novel crystals of type I of 1-(2'-cyano-2'-desoxy-β-D-arabinofuranosyl)cytosine monohydrochloride, which have characteristic peaks at 13.7°, 15.7°, 16.0°, 18.6°, 20.3° and 22.7° in form of diffraction angles (2θ±0.1°), measured in powder X-ray crystallography, and melting temperature 192-197°C, as well as to novel crystals of type II of 1-(2'-cyano-2'-desoxy-β-D-arabinofuranosyl)cytosine monohydrochloride, which have characteristic peaks at 6.4°; 12.6°; 17.3° and 21.7° in form of diffraction angles (2θ±0.1°), measured in powder X-ray crystallography, and melting temperature 192-196°C, possessing anti-tumour properties.

EFFECT: invention relates to anti-tumour medication, containing claimed crystals, and to methods of obtaining crystals of type I and crystals of type II of 1-(2'-cyano-2'-desoxy-β-D-arabinofuranosyl)cytosine monohydrochloride.

7 cl, 3 dwg, 1 tbl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new pyrimidine compounds of general formula (I) or their pharmaceutically acceptable salts, which can be used in treating the diseases related to mTOR kinase or PI3K kinase, such as cancer, immune diseases, viral infections, inflammations, neurological and other disorders. In general formula (I) , R1 means a group (A), wherein P represents C6aryl optionally substituted by a halogen, -OH, -NH2, -OC1-C6alkyl, unsubstituted 6-merous heteroaryl containing 1-2 heteroatoms N, unsubstituted indolyl, unsubstituted indazolyl, Q is specified in -H, -OR, -SR, -halo, -NR3R4, -OS(O)mR, -OC(O)NHR, -S(O)mNR3R4, -NRC(O)R, -NRS(O)mR, -NRC(O)NR3R4 and -NRC(S)NR3R4, wherein each R, R3 and R4 are independently specified in H, C1-C6 alkyl optionally substituted by a halogen, -N(C1-C3alkyl)2, 5-, 6-merous heterocyclic group containing 1-2 heteroatoms specified in N and O, 6-merous heterocyclic group containing 1-2 heteroatoms specified in N and O, optionally substituted by C1-C6alkyl, C6aryl group optionally substituted by one or two substitutes specified in a halogen, -OC1-C3alkyl, -CF3, -NH2, -C(O)NH2, -NHC(O)C1-C3alkyl, -N(C1-C3alkyl)2, -COOH, -SO2NH2, -SO2C1-C3alkyl, -NHSO2C1-C3alkyl, -CO2C1-C6alkyl, dioximethylene group, -NHC(O)CF3, -C(O)NH(CH2)2÷3N(C1-C3alkyl)2, -O(CH2)2N(C1-C3alkyl)2, 6-merous heterocyclyl containing 1-2 heteroatoms specified in N, O and S optionally substituted by oxo, C1-C3alkyl, -SO2C1-C3alkyl, -C(O)-6-merous heterocyclyl optionally substituted by C1-C3alkyl, 6-merous heteroaryl containing 1-2 heteroatoms N optionally substituted by one or two substitutes presenting a 6-merous heterocyclyl or -SC1-C3alkyl, or a 5-, 6-merous heteroaryl group containing 1-2 heteroatoms specified in N, O and S, optionally condensed with a benzene ring and optionally substituted by a halogen, -CO2C1-C3alkyl, oxo, -NHC(O)C1-C3alkyl, C1-C3alkyl, 6-merous heterocyclyl containing 2 heteroatoms specified in N and O optionally substituted by C1-C3alkyl, m means 1 or 2, or R3 and R4 together with a nitrogen atom to which they are attached, form a saturated 5-, 6-merous N-containing heterocyclic group, which is unsubstituted or substituted by C1-C3alkyl, -SO2C1-C3alkyl, oxo, Y is specified in -O-(CH2)n-, -S-(CH2)n- and -S(O)m(CH2)n-, wherein m means 1, n means 0 or an integer from 1 to 2, R2 is specified in H or a group -NR3R4, wherein R3 and R4 are those as specified above, Z is specified in halo, -(CH2)s-COOR, -(CH2)sCONR3R4, -(CH2)sCH2NR3R4, wherein s means 0 or an integer from 1 to 2 and wherein R, R3 and R4 are those as specified above, unsubstituted 6-merous heteroaryl containing one heteroatom N, substituted or unsubstituted heterocyclyl containing two heteroatoms specified in N and O; the substitute is specified in C1-C3alkyl and C1-C3alkylsulphonyl, and W is specified in a morpholine cycle and pyridine cycle. The invention also refers to a method for preparing the compounds of formula (I).

EFFECT: preparing the new pyrimidine compounds.

12 cl, 5 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bio-compatible conjugated polymer nanoparticle, dicarbonyl-lipid compound, compound in form of vesicles, micelles or liposomes, containing multitude of nanoparticles, including said dicarbonyl-lipid compound, method of treating cancer or metastases, biocompatible polymer, as well as to conjugate. Biocompatible conjugated polymer nanoparticle includes main chain of copolymer, with at least one polymer monomer containing two side chains, selected from the group, consisting of carboxylic acid, amide and ester, and sad side chains are separated from each other by 1-1- carbon atoms, oxygen atoms or sulphur atoms, or their any combinations. Said nanoparticle further contains multitude of side chains, covalently bound with said main chain, with said side chains being selected from the group, consisting of monosaccharides, dicarboxylic acids, polyethyleneglycol and their combinations; and multitude of platinum compounds, dissociatedly bound with said main chain. Multiple platinum compounds are connected with said main chain via at least one coordination bond between carbonyl oxygen of carbonyl or amide group of main chain and platinum atom of platinum compound. Said platinum compound is selected from Pt(II) compounds, Pt(IV) compounds and any their combinations. Invention is also aimed at dicarbonyl-lipid compounds, in which platinum compound is dissociatedly bound with dicarbonyl compound. Invention is also aimed at method of treating cancer and metastases. Methods include selection of subject, requiring treatment of cancer or metastases, and introduction to subject of effective amount of nanoparticles, compounds or compositions of the invention.

EFFECT: obtaining biocompatible conjugated polymer nanoparticles for chemotherapeutic platinum-based preparation.

40 cl, 1 tbl, 29 dwg, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula or its therapeutically acceptable salts, wherein A1 represents furyl, imidazolyl, isothiazolyl, isoxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, thienyl, triazolyl, piperidinyl, morpholinyl, dihydro-1,3,4-thiadiazol-2-yl, benzothien-2-yl, banzothiazol-2-yl, tetrahydrothien-3-yl, [1,2,4]triazolo[1,5-a]pyrimidin-2-yl or imidazo[2,1-b][1,3]-thiazol-5-yl; wherein A1 is unsubstituted or substituted by one, or two, or three, or four, or five substitutes independently specified in R1, OR1, C(O)OR1, NHR1, N(R1)2, C(N)C(O)R1, C(O)NHR1, NHC(O)R1, NR1C(O)R1, (O), NO2, F, Cl, Br and CF3; R1 represents R2, R3, R4 or R5; R2 represents phenyl; R3 represents pyrazolyl or isoxazolyl; R4 represents piperidinyl; R5 represents C1-C10alkyl or C2-C10alkenyl each of which is not specified or specified by substitutes specified in R7, SR7, N(R7)2, NHC(O)R7, F and Cl; R7 represents R8, R9, R10 or R11; R8 represents phenyl; R9 represents oxadiazolyl; R10 represents morpholinyl, pyrrolidinyl or tetrahydropyranyl; R11 represents C1-C10alkyl; Z1 represents phenylene; Z2 represents piperidine unsubstituted or substituted by OCH3, or piperazine; both Z1A and Z2A are absent; L1 represents C1-C10alkyl or C2-C10alkenyl each of which is unsubstituted or substituted by R37B; R37B represents phenyl; Z3 represents R38 or R40; R38 represents phenyl; R40 represents cyclohexyl or cyclohexenyl; wherein phenylene presented by Z1 is unsubstituted or substituted by the group OR41; R41 represents R42 or R43; R42 represents phenyl, which is uncondensed or condensed with pyrrolyl, imidazolyl or pyrazole; R43 represents pyridinyl, which is uncondensed or condensed with pyrrolyl; wherein each cyclic fragment presented by R2, R3, R4, R8, R9, R10, R38, R40, R42 and R43 is independently unsubstituted or substituted by one or more substitutes independently specified in R57, OR57, C(O)OR57, F, Cl CF3 and Br; R57 represents R58 or R61; R58 represents phenyl; R61 represents C1-C10alkyl; and wherein phenyl presented by the group R58 is unsubstituted or substituted by one or more substitutes independently specified in F and Cl.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, and to a method of treating diseases involving the expression of anti-apoptotic Bcl-2 proteins.

7 cl, 2 tbl, 48 ex

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