P38 inhibitors and application methods

FIELD: chemistry.

SUBSTANCE: invention can be applied in medicine and concerns inhibitors of MaR-kinase p38 of formula where W represents N or O, when Y represents C, and W represents C, when Y represents N; U represents CH or N; V represents C-E or N; X represents O, S, SO, SO2, NH, C=O,-C=NOR1 or CHOR1; B represents H or NH2; R1, E and A stands for H or various alkyl, heteroalkyl, aromatic and heteroaromatic substitutes.

EFFECT: production of new biologically active compounds.

48 cl, 138 ex, 54 dwg

 

This application claims priority to application U.S. No. 10/688849, filed October 15, 2003, and application U.S. No. 10/378164, filed March 3, 2003, which are both incorporated in their entirety in this document by reference.

BACKGROUND of the INVENTION

The scope of the invention

This invention relates to new inhibitors MAR-kinase R and related kinase, pharmaceutical compositions containing these inhibitors, and methods for producing these inhibitors. They are useful for the treatment of inflammation, osteoarthritis, rheumatoid arthritis, psoriasis, Crohn's disease, inflammatory bowel disease, cancer, autoimmune diseases and for the treatment of other cytokine-mediated diseases.

Description of the prior art,

A number of chronic and acute inflammatory conditions associated with overproductive proinflammatory cytokines. Such cytokines include, but are not limited to, tumor necrosis factor alpha (TNF-α),

interleukin-1 beta (IL-1β), interleukin-8 (IL-8) and interleukin-6 (IL-6). Rheumatoid arthritis (RA) is a chronic disease in which TNF-α and IL-β are involved in the appearance of disease symptoms and progression of the destruction of bones and joints observed in this state, debilitating. Recently approved therapeutic methods for the treatment of RA include actuarily receptor TNF-α (etanercept) and the receptor antagonist IL-1 (anakinra). These treatments work by blocking the ability of their respective cytokines contact with their natural receptors. Currently being explored alternative methods of treatment of cytokine-mediated diseases. One such method involves the inhibition of the signaling pathway that regulates the synthesis and the production of proinflammatory cytokines, such R.

R (also CSBP or RK) is a serine/threonine mitogen-activated protein kinase (MARK), which, as shown, regulates proinflammatory cytokines. First R was identified as a kinase, which after treatment with lipopolysaccharide (LPS) becomes phosphorylated on tyrosine in the murine monocytes. The relationship between R and the response of cells to cytokines was first installed Saklatvala J. et al. (Cell, 78: 1039-1049 (1994)), which showed that IL-1 activates proteinkinase cascade that leads to phosphorylation of the small heat shock protein Hsp27, probably via the mitogen-activated protein-activated protein kinase 2 (MARGAR kinase-2). Analysis of the peptide sequences derived from purified kinase, showed that it belongs to MARK R, activated LPS in murine monocytes (Han, J., et al., Science, 265: 808-811 (1994)). Simultaneously, it was shown that MARK R itself is activated kinase, located in the cascade is use, in response to a variety of cellular stresses, including exposure to ultraviolet radiation and osmotic shock, and was confirmed the identity of the kinase that directly phosphorylates Hsp27, as MARGAR kinase-2 (Rouse, J., et al., Cell 78: 1027-1037 (1994)). Subsequently, the staff SmithKline Beecham showed that MARK R was a molecular target for a number of pyridinedimethanol compounds that inhibited the production of TNF LPS-stimulated human monocytes (Lee, J., et al., Nature, 372: 739-746). This was a key discovery led to the development of a number of selective inhibitors MARK R and elucidation of their role in cytokine signaling.

It is now known that many forms MARK R (α, β, γ, δ), each encoded by separate genes form part of a kinase cascade involved in the response of cells to various stimuli, including osmotic stress, UV light and cytokine-mediated events. Consider these four isoforms R regulate various aspects of intracellular signaling. Its activation is part of a cascade of signaling events that lead to the synthesis and production of proinflammatory cytokines, like TNF-α. R acts through phosphorylation of substrates located in the cascade below, which include other kinases and transcription factors. The model is x in vitro and in vivo was shown to agents that inhibit the kinase R, blocking the production of cytokines, including, but not limited to, TNF-α, IL-6, IL-8 and IL-1β (Adams, J. L., et al., Progress in Medicinal Chemistry, 38: 1-60 (2001)).

It was shown that peripheral blood monocytes (IPC), during stimulation with lipopolysaccharide (LPS) in vitro, Express and secrete proinflammatory cytokines. Inhibitors R effectively block this action, when the IPC pre-treated with these compounds before to stimulate using FSC (Lee, J. C., et al., Int. J. Immunopharmacol., 10: 835-843 (1988)). The effectiveness of inhibitors R in animal models of inflammatory diseases has accelerated the study of lying(they are) the basis of the mechanism(s)that(e) can(Lee) would explain the action of these inhibitors. Role R in the response of cells to IL-1 and TNF was investigated in different cell systems related to inflammatory response, using pyridinedimethanol inhibitor: endothelial cells and IL-8 (Hashimoto, S., et al., J. Pharmacol. Exp. Ther., 293: 370-375 (2001)), fibroblasts and IL-6/GM-CSF/PGE2 (Beyaert, R., et al., EMBO J. 15: 1914-1923 (1996)), neutrophils and IL-8 (Albanyan, E. A., et al., Infect. Immun., 68: 2053-2060 (2000)), macrophages and IL-1 (Caivano, M. and Cohen, P., J. Immunol., 164: 3018-3025 (2000)) and smooth muscle cells and RANTES (Maruoka, S., et al., Am. J. Respir. Crit. Care Med., 161: 659-668 (1999)). The devastating effects of many painful conditions caused by overproductive proinflammatory cytokines. The ability inhibit the ditch R to regulate this overproduction makes them excellent candidates for agents altering disease.

Inhibitors R are active against many recognized disease models and demonstrate positive effects in a number of standard animal models of inflammation, including collagen-induced arthritis in rats (Jackson, J.R., et al., J.Pharmacol. Exp. Ther., 284: 687-692 (1998)); adjuvant-induced arthritis rats (Badger, A.M., et al., Arthritis Rheum., 43: 175-183 (2000); Badger, A.M., et al., J. Pharmacol. Exp. Ther., 279: 1453-1461 (1996)) and carrageenan-induced swelling of the paws of mice (Nishikori, T., et al., Eur. J. Pharm., 451: 327-333 (2002)). In these animal models, it was shown that molecules that block the action R, effective in the inhibition of bone resorption, inflammation and other immune abnormalities and inflammatory pathologies. Thus, safe and effective inhibitor R provide a method of treatment of diseases, debilitating, which can be adjusted by modulating the signaling pathways R such as but not limited to these, RA.

Inhibitors R well known to specialists in this field of technology. Reviews of early inhibitors contributed to the establishment of the dependence of activity on the structure, is important for improving activity both in vitro and in vivo (Salituro, E.G., et al., Current Medicinal Chemistry, 6: 807-823 (1999) and Foster, M.L, et al., Drug News Perspect., 13: 488-497 (2000)). More modern surveys concentrated on the structural diversity of new inhibitors studied as is inhibitorof R (Boehm, J.D. and Adams, J.L., Exp. Opin. Ther. Patents, 10: 25-37 (2000)). This invention describes a new group substituted 2-Aza[4.3.0]bicyclic heteroaromatic compounds as inhibitors R, which are useful for the treatment of inflammation, osteoarthritis, rheumatoid arthritis, autoimmune diseases and for the treatment of other cytokine-mediated diseases.

SUMMARY of the INVENTION

In the proposed invention the compounds, methods of obtaining these compounds and the pharmaceutical compositions which inhibit R alpha and associated R-mediated events, such as the inhibition of cytokine production. Such compounds, commonly called 2-Aza[4.3.0]bicyclic heteroaromatic rings which are useful as therapeutic agents against diseases that can be treated by inhibiting signaling pathways R. In General terms, the invention relates to inhibitors R General Formula I

where Y represents S, N;

W represents C, N, S or O, provided that W represents N, S or O, Y represents S, and W represents C or N when Y is N;

U represents CH or N;

V is a S-S or N;

X represents O, S, SO, SO2, NR7, C=O, CHR7, -C=NOR1, -C=CHR1and the and CHOR 1;

R1represents H, RHO3H2, SO3H2, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci or Zn-Ar1may be substituted or unsubstituted;

Z represents alkylene having from 1 to 4 carbon atoms, or albaniles or akinyan, each of which has 2 to 4 carbon atoms, where the specified alkylen, albaniles or akinyan may be substituted or unsubstituted;

R7represents H or substituted or unsubstituted methyl;

Ar1represents a substituted or unsubstituted aryl or heteroaryl;

And represents H, HE, a protective group for amino, Zn-NR2R3,

Zn-NR2(C=O)R2, Zn-SO2R2, Zn-SOR2, Zn-SR2, Zn-OR2, Zn-(C=O)R2, Zn-(C=O)OR2, Zn-O-(C=O)R2, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci Il is Z n-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci or

Zn-Ar1may be substituted or unsubstituted;

R2and R3independently represent H, HE, the protective group for the amino protective group for an alcohol protective group for the acid, the protective group for thio, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci or

Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci or Zn-Ar1may be substituted or unsubstituted, or R2together with R3and N forms a saturated or partially unsaturated heterocycle, containing one or more heteroatoms, where the heterocycle may be substituted or unsubstituted, and where the heterocycle may be condensed with an aromatic ring;

In represents N, NH2or substituted or unsubstituted methyl;

E represents N, Zn-NR2R3, Zn-(C=O)R4, Zn-(C=O)R5, Zn-NR5(C=O)R 5,

Zn-O(C=O)R5, Zn-OR5, Zn-SOR5, Zn-SOR5, Zn-SR5, Zn-NH(C=O)other5or R5;

R4represents a substituted or unsubstituted natural or unnatural amino acid, a protected natural or unnatural amino acid, NH(CHR6) (CH2)mOR5where m denotes an integer from 1 to 4, or NR2R3;

R5represents H, HE, the protective group for the amino protective group for an alcohol protective group for the acid, the protective group for thio, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci or Zn-Ar1may be substituted or unsubstituted;

R6is a natural amino acid side chain, Zn-NR2R3,

Zn-OR5, Zn-SO2R5, Zn-SOR5or Zn-SR5and

n means 0 or 1,

provided that when a represents N and a represents CH=CH-R8where R8represents a substituted or asamese the hydrated alkyl, alkenyl, cycloalkyl, heteroseksualci, aryl or heteroaryl, then X-Ar1is a Deputy, where Ar1is other than substituted or unsubstituted aryl, heteroaryl, NH-alkyl, NH-cycloalkyl, NH-heteroseksualci, NH-aryl, NH-heteroaryl, NH-alkoxy, or NH-dialkylamide, when X represents O, S, C=O, S=O, C=CH2, CO2, NH or N(C1-C8-alkyl).

The invention is also directed to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of the compounds of Formula I. Also describes methods of preparing compounds of Formula I.

In another embodiment of this invention relates to compounds of General Formula II

where a, b, X and Ar1are as defined above.

In another embodiment of this invention relates to compounds of General Formula III

where a, b, X, E and Ar1are as defined above.

In another embodiment of this invention relates to compounds of General formula IV

where a, b, X, E and Ar1are as defined above, provided that when a represents N and a represents CH=CH-R8where R8represents a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocyclyl, aryl or heteroaryl, then X-Ar1is a Deputy, where Ar1is other than substituted or unsubstituted aryl, heteroaryl, NH-alkyl, NH-cycloalkyl, NH-heteroseksualci, NH-aryl, NH-heteroaryl, NH-alkoxy, or NH-dialkylamide, when X represents O, S, C=O, S=O, C=CH2, CO2, NH or

N(C1-C8-alkyl).

In another embodiment of this invention relates to compounds of General Formula V

where A, X, E and Ar1are as defined above.

In another embodiment of this invention relates to compounds of General Formula VI

where a, b, E and Ar1are as defined above.

In another embodiment of this invention relates to compounds of General Formula VII

where a, b, E and Ar1are as defined above.

In another embodiment of this invention relates to compounds of General Formula VIII

where a, b, E and Ar1are as defined above.

In another embodiment of this invention relates to compounds of General Formula IX

where a, b, E and Ar1are as defined above.

In another embodiment of this invention relates to compounds of General is ormula X

where a, b, E and Ar1are as defined above.

In another embodiment of this invention relates to compounds of General Formula XI

where a, b, E and Ar1are as defined above.

In another embodiment of this invention relates to compounds of General Formula XII

where a, b, E, R1and Ar1are as defined above.

In another embodiment of this invention relates to compounds of General Formula XIII

where a, b, E and Ar1are as defined above.

In another embodiment of this invention relates to ether compounds of General Formula XIV

where a, b, X, Ar1, R2and R3are as defined above.

In another embodiment of this invention relates to compounds of General Formula XV

where a, b, X and Ar1are as defined above, and R12and R13independently represent an alkyl, allyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl or heteroaryl where the specified alkyl, allyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl or heteroaryl may be substituted or unsubstituted.

In another the embodiment of this invention relates to compounds of General Formula XVI

where a, b, X, R2, R3and Ar1are as defined above.

In another embodiment of this invention relates to compounds of General Formula XVII

where Y represents CR1, O, S or NR2;

W represents CR3, N, NR4, S or O, provided that W represents NR4, S or O, Y represents CR1and W represents CR3or N, Y represents NR2;

R3represents N, NH2, F, Cl, methyl or substituted methyl;

R4represents H, or methyl or substituted methyl;

R1and R2independently represent H, HE, a protective group for amino, Zn-NRaRb, Zn-NRa(C=O)Rb, Zn-SO2Ra, Zn-SORa, Zn-SRa, Zn-ORa, Zn-(C=O)Ra, Zn-(C=O)OR3, Zn-O-(C=O)Ra, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl where specified cycloalkyl is saturated or partially unsaturated, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, or Zn-Ar1where the specified alkyl, allyl, alkenyl, Ala the Nile, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci and Zn-Ar1may be substituted or unsubstituted;

Ar1represents aryl or heteroaryl, each of which may be substituted or unsubstituted;

Raand Rbindependently represent H, HE, the protective group for the amino protective group for an alcohol protective group for the acid, the protective group for sulfur, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl where specified cycloalkyl is saturated or partially unsaturated, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci and Zn-Ar1may be substituted or unsubstituted,

or Raand Rbtogether with the atoms to which they are both attached, form a saturated or partially unsaturated heterocyclic ring having one or more heteroatoms in the specified ring, where the heterocycle may be substituted or nezameshchenny is and where the heterocycle may be condensed with an aromatic ring;

Z represents alkylene having from 1 to 4 carbon atoms, or albaniles or akinyan, each of which has 2 to 4 carbon atoms, where the specified alkylen, albaniles or akinyan may be substituted or unsubstituted;

n means 0 or 1;

U represents CRcor N;

V represents CRcor N;

Rcrepresents H, F, Cl, methyl or substituted methyl;

X represents O, S, SO, SO2, NR5, C=O, CH2CH2Zn-OH or=NORb;

R5represents H, methyl or substituted methyl;

Rdrepresents H, RHO3H2, SO3H2, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl where specified cycloalkyl is saturated or partially unsaturated, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci and Zn-Ar1may be substituted or unsubstituted;

G, H, J and T independently represent N or CRzprovided that when any such G, H, J and which are N, then the total number of G, H, J or T, which are N, does not exceed 2;

Rzrepresents H, F, Cl, Br, CF3, OR6, SR6lowest (1-C4)alkyl, CN or

NR6R7;

R6and R7independently represent H, CF3lowest (1-C4)alkyl, or

low (1-C4)heteroalkyl;

Q represents-NR8CONH-, -NHCO-, -NR8SO2NH-, -NHSO2-, -CONR11-;

R8represents H or lower (1-C4)alkyl;

R11represents H or lower (1-C4)alkyl;

Rxrepresents -(CR9R10)m-, -O(CR9R10)m-, NH(CR9R10)m- or-S(CR9R10)mprovided that Q is a-CONR11-when Rxrepresents-O(CR9R10)m-, -NH(CR9R10)m- or-S(SR9R10)m-;

R9and R10independently represent H or lower alkyl, or R9and R10together with the atoms to which they are both attached, form cycloalkyl ring which may be saturated or partially unsaturated;

m means 1-3;

Ryrepresents H, RHO3H, a protective group for the amino protective group for oxygen, alkyl, allyl, alkenyl, quinil, heteroa the keel, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl where specified cycloalkyl is saturated or partially unsaturated, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, or Zn-Ar2where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-Ar2and Zn-heteroseksualci may be substituted or unsubstituted;

Ar2represents aryl or heteroaryl, each of which may be substituted or unsubstituted, where the specified substitution can be performed 1-3 substituents, independently selected from F, Cl, Br, CF3, CN, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl,

-OR12, -SR12, -SO2R12, -SO2NR13R12, NR13SO2R12, Zn-cycloalkyl where specified cycloalkyl is saturated or partially unsaturated, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-recloak is l, Zn-heteroseksualci and Zn-Ar1may be substituted or unsubstituted;

R12and R13independently represent H, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, Zn-cycloalkyl where specified cycloalkyl is saturated or partially unsaturated, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci and Zn-Ar1may be substituted or unsubstituted;

where Ar2replaced-SO2NR13R12then R12and R13can form cycloalkyl ring or geteroseksualnoe ring which may be substituted or unsubstituted, where the specified substitution can be carried out by substituents selected from alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl where specified cycloalkyl is saturated or partially unsaturated, -COR12, -SO2R12, Zn-heteroseksualci where specified heteroseksualci is saturated or frequent is a rule unsaturated, or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci and Zn-Ar1may be substituted or unsubstituted;

where Q is a-CONR11-, then Rytogether with R11additionally represent cycloalkyl ring or geteroseksualnoe ring which may be substituted or unsubstituted groups selected from alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl where specified cycloalkyl is saturated or partially unsaturated, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, Zn-Ar1, -COR14or-SO2R14where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci, Zn-Ar1, -COR14and-SO2R14may be substituted or unsubstituted, and

R14represents alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, Zn-cycloalkyl where specified cycloalkyl is the tsya saturated or partially unsaturated, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci and Zn-Ar1may be substituted or unsubstituted.

In another aspect of the present invention proposed compounds that inhibit the production of cytokines, such as TNF-α, IL-1, IL-6 and IL-8, including compounds of Formulas I-XVII.

In another aspect of the present invention, a method of treating diseases or medical conditions mediated by cytokines, in which a warm-blooded animal is administered an effective amount of the compounds of Formula I-XVII, or its pharmaceutically acceptable salt, or prodrug that is cleaved in vivo.

In another aspect of the present invention, a method for inhibiting the production of cytokines, such as TNF-α, IL-1, IL-6 and IL-8, in which a warm-blooded animal is administered an effective amount of the compounds of Formula I-XVII, or its pharmaceutically acceptable salt, or prodrug that is cleaved in vivo.

In another aspect of the present invention, a method for ensuring the effect of inhibition of kinase R, in which a warm-blooded animal enter the effective the effective amount of the compounds of Formula I-XVII, or its pharmaceutically acceptable salt, or prodrug that is cleaved in vivo.

In another aspect of the present invention proposed treatment or prevention of a condition mediated R in which a person or an animal in need this, enter the amount of compound effective to treat or prevent this condition, mediated R, or a pharmaceutical composition containing the join, where the join is a compound of Formulas I-XVII, or its pharmaceutically acceptable salt, or prodrug that is cleaved in vivo. Condition mediated R, which can be treated by the methods of the present invention, includes an inflammatory disease, autoimmune disease, destructive bone violation, proliferative violation, infectious disease, viral disease, or neurodegenerative disease.

The compounds of this invention are also useful in methods of preventing cell death and hyperplasia and, therefore, they can be used for treating or preventing reperfusion/ischemia in stroke, heart attacks and hypoxia bodies. The compounds of this invention are also useful in methods of preventing thrombin-induced platelet aggregation.

Compounds according to the invention the advantage is the natural enemy can be used in combination with other known therapeutic agents.

The invention also relates to pharmaceutical compositions containing an effective amount of an agent selected from compounds of Formulas I-XVII, or their pharmaceutically acceptable prodrugs, pharmaceutically active metabolite, or pharmaceutically acceptable salt.

Additional advantages and novel features of this invention will be partially set forth in the description which follows, and in part will be obvious to a person skilled in the art after studying the following description of the invention, or may become known during implementation of the invention. Advantages of the invention can be understood and implemented with the help of agents, combinations, compositions and methods specified in the attached claims.

A BRIEF DESCRIPTION of GRAPHIC MATERIALS

The accompanying diagrams, which are included in this document and form part of the specification, illustrate a non-limiting embodiment of the present invention and together with the description serve to explain the principles of the invention.

Figure 1 shows the reaction scheme for the synthesis of compounds having the General structure 7a.

Figure 2 shows the reaction scheme for the synthesis of compound 14a.

Figure 3 shows the reaction scheme for the synthesis of compound 15A.

Figure 4 shows the reaction scheme for the synthesis of the compounds 16A.

Figure 5 shows the reaction scheme for the synthesis of compound 17A.

Figure 6 shows the reaction scheme for the synthesis of compound 18a.

7 shows the reaction scheme for the synthesis of compounds having the General structure 7b.

On Fig shows the reaction scheme for the synthesis of compound 8b.

On Figa-9B shows the reaction scheme for the synthesis of compound 10C.

Figure 10 shows the reaction scheme for the synthesis of compound 14C.

Figure 11 shows the reaction scheme for the synthesis of compound 17c.

On Fig shows the reaction scheme for the synthesis of compounds having the General structure 18C.

On Fig shows the reaction scheme for the synthesis of compound 26C.

On Figa-14C shows the reaction scheme for the synthesis of compound 34C.

On Fig shows the reaction scheme for the synthesis of compound 38C-1.

On Fig shows the reaction scheme for the synthesis of compound 39C.

On Fig shows the reaction scheme for the synthesis of compound 40C.

On Fig shows the reaction scheme for the synthesis of compound 4d.

On Fig shows the reaction scheme for the synthesis of compounds having the General structure 5d.

On Fig shows the reaction scheme for the synthesis of compound 8d.

On Fig shows the reaction scheme for the synthesis of compound 10d-1.

On Fig shows the reaction scheme for the synthesis of compound 11d-1.

On Fig shows the reaction scheme for the synthesis of compound 13d.

On Figa-24V shows the reactions is fair scheme of the synthesis of compounds 8E-1.

On Fig shows the reaction scheme for the synthesis of compound 9F.

On Fig shows the reaction scheme for the synthesis of compound 10E-1.

On Fig shows the reaction scheme for the synthesis of compounds having the General structure 7f.

On Fig shows an alternative reaction scheme for the synthesis of compounds having the General structure 7f.

On Fig shows the reaction scheme for the synthesis of intermediate carboxamide used in the synthesis of compound 7f-5 and 7f-6.

On Figa-30C shows the reaction scheme for the synthesis of compounds having the General structure 1g.

On Fig shows the reaction scheme for the synthesis of compounds having the General structure 4f.

On Fig shows the reaction scheme for the synthesis of compounds having the General structure 5f.

On Fig shows an alternative reaction scheme for the synthesis of compounds having the General structure 5f.

On Fig shows the reaction scheme for the synthesis of compounds having the General structure of 2h.

On Fig shows the reaction scheme for the synthesis of compounds having the General structure 1j.

On Fig shows the reaction scheme for the synthesis of compounds having the General structure 1k.

On Fig shows the reaction scheme for the synthesis of compounds having the General structure 1m.

On Fig shows the reaction scheme for the synthesis of compound 6n.

On Fig shows the reaction scheme for the synthesis of compounds R.

On Fig shown reacts the pension scheme of the synthesis of compounds 16R.

On Figa Is shown In reaction scheme for the synthesis of compounds 9q-1 and 9q-2.

On Fig shows the reaction scheme for the synthesis of compounds 6r-2.

On Figa Is shown In reaction scheme for the synthesis of compounds 8s-2.

On Fig shows the reaction scheme for the synthesis of compounds 7t-2.

On Fig shows the reaction scheme for the synthesis of compounds 26t.

On Fig shows the reaction scheme for the synthesis of compounds 28t.

On Fig shows the reaction scheme for the synthesis of compounds 32t.

On Fig shows the reaction scheme for the synthesis of compounds 4u.

On Fig shows the reaction scheme for the synthesis of compounds 7v and 8v.

On Fig shows the reaction scheme for the synthesis of compounds 10v.

On Fig shows the reaction scheme for the synthesis of compound 17d.

On Fig shows the reaction scheme for the synthesis of compound 20d.

On Fig shows the reaction scheme for the synthesis of compound 26d.

On Fig shows the reaction scheme for the synthesis of compound 47d.

DETAILED description of the INVENTION

Compounds of Formulas I-XVII according to the invention are useful for inhibiting R alpha and associated R-mediated events such as cytokine production. Such compounds are effective as therapeutic agents against diseases that can be treated by inhibiting signaling pathways R. In General terms, the invention relates to compounds of General Fo the mules I

where Y represents S, N;

W represents C, N, S or O, provided that W represents N, S or O, Y represents S, and W represents C or N when Y is N;

U represents CH or N;

V is a S-S or N;

X represents O, S, SO, SO2, NR7, C=O, CHR7, -C=NOR1, -C=CHR1or CHOR1;

R1represents H, RHO3H2, SO3H2, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci or Zn-Ar1may be substituted or unsubstituted;

Z represents alkylene having from 1 to 4 carbon atoms, or albaniles or akinyan, each of which has 2 to 4 carbon atoms, where the specified alkylen, albaniles or akinyan may be substituted or unsubstituted;

R7represents H or substituted or unsubstituted methyl;

Ar1represents a substituted or unsubstituted aryl or heteroaryl;

And represents H, HE, the safety group for amino, Zn-NR2R3,

Zn-NR2(C=O)R2, Zn-SO2R2, Zn-SOR2, Zn-SR2, Zn-OR2, Zn-(C=O)R2, Zn-(C=O)OR2, Zn-O-(C=O)R2, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci or

Zn-Ar1may be substituted or unsubstituted;

R2and R3independently represent H, HE, the protective group for the amino protective group for an alcohol protective group for the acid, the protective group for thio, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci or

Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci or Zn-Ar1may be substituted or unsubstituted, or R2together with R3and N forms a saturated or partially unsaturated heterocycle, which within one or more heteroatoms, where the heterocycle may be substituted or unsubstituted, and where the heterocycle may be condensed with an aromatic ring;

In represents N, NH2or substituted or unsubstituted methyl;

E represents N, Zn-NR2R3, Zn-(C=O)R4, Zn-(C=O)R5, Zn-NR5(C=O)R5, Zn-O(C=O)R5, Zn-OR5, Zn-SO2R5, Zn-SOR5, Zn-SR5, Zn-NH(C=O)other5or R5;

R4represents a substituted or unsubstituted natural or unnatural amino acid, a protected natural or unnatural amino acid, NH(CHR6) (CH2)mOR5where m denotes an integer from 1 to 4, or NR2R3;

R5represents H, HE, the protective group for the amino protective group for an alcohol protective group for the acid, the protective group for thio, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci or Zn-Ar1may be substituted or unsubstituted;

R6 represents a natural amino acid side chain, Zn-NR2R3,

Zn-OR5, Zn-SO2R5, Zn-SOR5or Zn-SR5and

n means 0 or 1,

provided that when a represents N and a represents CH=CH-R8where R8represents a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heteroseksualci, aryl or heteroaryl, then X-Ar1is a Deputy, where Ar1is other than substituted or unsubstituted aryl, heteroaryl, NH-alkyl, NH-cycloalkyl, NH-heteroseksualci, NH-aryl, NH-heteroaryl, NH-alkoxy, or NH-dialkylamide, when X represents O, S,

C=O, S=O, C=CH2, CO2, NH or N(C1-C8-alkyl).

Used herein, the term "alkyl" refers to saturated linear or branched monovalent hydrocarbon radical of length from one to twelve carbon atoms, where the alkyl moiety may be independently substituted one or more than one Deputy described below. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, tert-pentyl, hexyl, isohexyl and the like.

"Alkylene" means a linear or branched saturated divalent hydrocarbon radical of length from one to twelve at the MOU carbon for example, methylene, ethylene, propylene, 2-methylpropene, pentile and the like.

The term "alkenyl" refers to linear, branched monovalent hydrocarbon radical ranging in length from two to twelve carbon atoms containing at least one double bond, for example, to Attila, propenyl and the like, where alkanniny radical may be independently substituted one or more than one Deputy described herein, and includes radicals having CIS - and TRANS - orientation or, alternatively, E - and Z - orientation.

The term "albaniles" refers to a linear or branched divalent hydrocarbon radical ranging in length from two to twelve carbon atoms containing at least one double bond, where alkenylamine radical may be independently substituted one or more than one Deputy described here. Examples include, but are not limited to, ethenylene, propylen and the like.

The term "quinil" refers to a linear or branched monovalent hydrocarbon radical ranging in length from two to twelve carbon atoms containing at least one triple bond. Examples include, but are not limited to, ethinyl, PROPYNYL, and the like, where alkynylaryl radical may be independently substituted one or bol is e than one Deputy, are described here.

The term "akinyan" refers to a linear or branched divalent hydrocarbon radical ranging in length from two to twelve carbon atoms containing at least one triple bond, where alkynylaryl radical may be independently substituted one or more than one Deputy described here.

The term "allyl" refers to the radical having the formula RC=CHCHR, where R represents alkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, heteroaryl or any Deputy, as defined here, where the allyl may be independently substituted one or more than one Deputy described here.

The term "cycloalkyl" refers to saturated or partially unsaturated cyclic hydrocarbon radical, having from three to twelve carbon atoms, where cycloalkyl may be independently substituted one or more than one Deputy described here. Moreover, the term "cycloalkyl includes bicyclic and tricyclic cycloalkyl patterns, where the bicyclic and tricyclic structures may include saturated or partially unsaturated cycloalkyl condensed with a saturated or partially unsaturated cycloalkyl or heteroseksualnymi ring, or aryl or heteroaryl ring. An example is cycloalkyl groups include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

The term "heteroalkyl" refers to saturated linear or branched monovalent, hydrocarbon radical in length from one to twelve carbon atoms, where at least one carbon atom is replaced by a heteroatom selected from N, O or S, and where the radical may be a carbon radical or heteroatomic radical (i.e., the heteroatom may be in the middle or at the end of this radical). Heteroalkyl radical may be independently substituted one or more than one Deputy described here. The term "heteroalkyl" embraces alkoxy - and heteroassociation.

The term "heteroseksualci" refers to saturated or partially unsaturated cyclic radical in length from 3 to 8 ring atoms in which at least one atom of the ring is a heteroatom selected from nitrogen, oxygen and sulfur, the remaining ring atoms are C, where one or more ring atoms may be independently substituted one or more than one Deputy described below, and where geteroseksualnoe ring may be saturated or partially unsaturated. The radical may be a carbon radical or heteroatomic radical. "Heteros is cycloalkyl" also includes radicals, where heterocyclic radicals are fused with an aromatic or heteroaromatic rings. Examples geterotsiklicheskikh rings include, but are not limited to, pyrrolidine, piperidine, piperazine, tetrahydropyran, morpholine, thiomorpholine, homopiperazine, phthalimide and their derivatives.

The term "heteroalkyl" refers to a linear or branched monovalent hydrocarbon radical ranging in length from two to twelve carbon atoms containing at least one double bond, such as Attila, propenyl and the like, where at least one of the carbon atoms replaced by a heteroatom selected from N, O or S, and where the radical may be a carbon radical or heteroatomic radical (i.e., the heteroatom may be in the middle or at the end of this radical). Heteroalkyl radical may be independently substituted one or more than one Deputy described herein, and includes radicals having CIS - and TRANS - orientation or, alternatively, E - and Z - orientation.

The term "heteroalkyl" refers to a linear or branched monovalent hydrocarbon radical ranging in length from two to twelve carbon atoms containing at least one triple bond. Examples include, but are not limited to, ethinyl, PROPYNYL, and the like, where the about at least one carbon atom is replaced by a heteroatom, selected from N, O or S, and where the radical may be a carbon radical or heteroatomic radical (i.e., the heteroatom may be in the middle or at the end of this radical). Heteroalkyl radical may be independently substituted one or more than one Deputy described here.

The term "heteroaryl" refers to radicals having the formula RC=CHCHR, where R represents alkyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl, heteroaryl or any Deputy, as defined here, where at least one carbon atom is replaced by a heteroatom selected from N, O or S and where the radical may be a carbon radical or heteroatomic radical (i.e., the heteroatom may be in the middle or at the end of this radical). Heteroaryl may be independently substituted one or more than one Deputy described here.

"Aryl" means a monovalent aromatic monocyclic hydrocarbon radical of 6-10 ring atoms or a polycyclic aromatic hydrocarbon may independently substituted by one or more than one Deputy described here. More specifically, the term "aryl" includes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl and derivatives thereof.

"Heteroaryl" means a monovalent monocyclic aromatic radical and the 5-10 ring atoms, or a polycyclic aromatic radical, containing one or more than one heteroatom in the ring, selected from N, O or S, with remaining ring atoms are C. the Aromatic moiety may independently substituted by one or more than one Deputy described here. Examples include, but are not limited to, furyl, thienyl, pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, pyrazinyl, indolyl, thiophene-2-yl, hinely, benzopyranyl, thiazolyl and their derivatives.

The term "halogen" is a fluorescent, chloro, bromo or iodine.

The term "protective group for the amine" refers to organic groups intended to protect nitrogen atoms against undesirable reactions in the synthesis process, and includes, but is not limited to, benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (New), TRIFLUOROACETYL, and the like.

The term "protective group of the alcohol" refers to organic groups intended to protect an alcohol groups or substituents from unwanted reactions in the synthesis process, and includes, but is not limited to, (trimethylsilyl)ethoxymethyl (SEM), tert-butyl, methoxymethyl (MOM) and the like.

The term "protective group of sulfur" refers to organic groups intended to protect the sulfur-containing groups or substituents from unwanted reactions in the synthesis process, and includes, but is not ogranichivaetsya this, benzyl, (trimethylsilyl)ethoxymethyl (SEM), tert-butyl, trityl and the like.

The term "protective group acid" refers to organic groups intended to protect the acid groups or substituents from unwanted reactions in the synthesis process, and includes, but is not limited to, benzyl, (trimethylsilyl)ethoxymethyl (SEM), methylethyl and tert-butyl esters and the like.

In General, different groups or functional groups of the compounds of Formulas I-XVII can be possibly substituted by one or more than one Deputy. Examples of substituents suitable for purposes of this invention, include, but are not limited to, halogen, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci, Zn-OR, Zn-NO2, Zn-CN, Zn-CO2R, Zn-(C=O)R, Zn-O(C=O)R, Zn-O-alkyl, Zn-OAr, Zn-SH, Zn-SR, Zn-SOR, Zn-SO2R, Zn-S-Ar, Zn-SOAr, Zn-SOzAr, aryl, heteroaryl, Zn-Ar, Zn-(C=O)NR2R3, Zn-NR2R3, Zn-NR(C=O)R, Zn-SO2NR2R3, RHO3H2, SO3H2protective group for the amine protective group for an alcohol protective group for sulfur or a protective group for whom islote, where

Z represents alkylene having from 1 to 4 carbon atoms, or albaniles or akinyan, each of which has 2 to 4 carbon atoms, where the specified alkylen, albaniles or akinyan may be substituted or unsubstituted;

n means 0 or 1,

R1, R2and R3represent alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl or Zn-heteroseksualci and

Ar represents aryl or heteroaryl where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci, Ar, R1, R2and R3can optionally be substituted or unsubstituted.

Compounds according to this invention may possess one or more asymmetric center; therefore, such compounds can be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. If not stated otherwise, we assume that the description or title of a specific connection in the description and claims includes both individual enantiomers and mixtures, racemic or otherwise. Accordingly, this invention also includes the racemates and separated enantiomers and Diaz is arameri compounds of Formulas I-XVII. Methods of determination of stereochemistry and the separation of stereoisomers are well known in the prior art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4 th edition, J. March, John Wiley and Sons, New York, 1992).

In addition to the compounds of Formulas I-XVII invention also includes a solvate, pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts of such compounds.

The term "MES" refers to the aggregation of the molecules with one or more molecules of solvent.

"Pharmaceutically acceptable prodrug" is a compound that may be converted under physiological conditions or by solvolysis to the specified compound or pharmaceutically acceptable salt of such compounds.

"Pharmaceutically active metabolite" is a pharmacologically active product produced as a result of metabolism in the organism a compound or its salt. Metabolites of compounds can be identified using conventional methods known from the prior art, and their activity can be determined using tests such as the tests described here.

Prodrugs and active metabolites of compounds can be identified using conventional methods known from the prior art. Various forms of prodrugs are known the s from the prior art. Examples of derivatives of such prodrugs are described, for example, in a) Design of Prodrugs, edited by H.Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol.42, p.309-396, edited by K.Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H.Bundgaard p.113-191 (1991); C) H.Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988), and e) N. Kakeya, et al., Chem. Pharm Bull., 32: 692 (1984), each of which is incorporated herein by reference.

"Pharmaceutically acceptable salt" is a salt that retains the biological effectiveness of the free acids and bases of the specified compound and that is not biologically or otherwise undesirable. The connection according to the invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly to interact with any number of inorganic or organic bases, and inorganic and organic acids with the formation of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include salts obtained by the interaction of the compounds according to the present invention with a mineral or organic acid or inorganic base, such salts include the sulfates, pyrosulfite, bisulfate, sulfites, bisulfite, phosphates, monohydrogenphosphate, dihydrophosphate, metafora is s, pyrophosphates, chlorides, bromides, iodides, acetates, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalates, malonate, succinate, suberate, sebacate, fumarate, maleate, Butin-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalates, sulfonates, cellsurface, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartratami, methansulfonate, propanesulfonate, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelate.

If the connection according to the invention is a base, the desired pharmaceutically acceptable salt may be obtained by any suitable method available in the prior art, for example by treatment of the free base of an inorganic acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, or organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, paranoidly (pyranosidyl acid, such as glucuronic acid or galacturonic acid, alpha-hydroxic the slot, such as citric acid or tartaric acid, an amino acid such as aspartic acid or glutamic acid, aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid such as p-toluensulfonate acid or econsultancy acid, or the like.

If the connection according to the invention is an acid, the desired pharmaceutically acceptable salt may be obtained in any suitable way, for example by treatment of the free acid with an inorganic or organic base such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide or alkali earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts of sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

Compounds according to the invention can be obtained using the reaction routes and synthesis schemes as described below, using the techniques available in the prior art using starting compounds, which are easily available.

In addition to joint the General Formula I, this invention additionally encompasses compounds of General Formula II

where a, b, X and Ar1are as defined above.

Figure 1-6 presents examples of the synthesis of specific compounds having the General Formula II. In one General method for the synthesis of pyrazol the compounds of Formula II was prepared as follows. 2-Chloro-4-methyl-5-nitropyridine in a suitable anhydrous solvent is treated with an aryl - or heteroarylboronic or thiophenols and a base such as NaH. After an appropriate period of time, the reaction mixture is partitioned between an organic solvent and water and the organic layer give 2-O-aryl -, or 8-aryl-substituted-4-methyl-5-nitropyridine intermediate connection. Deputy NO2then restore, for example, by treatment with iron powder in acetic acid when heated over a period of time followed by treatment with a suitable base, such as NaOH. The obtained aniline intermediate connection allocate by extraction of the reaction mixture with an organic solvent. Then the intermediate aniline compound combine with tetrafluoroborate ammonium followed by the addition of bases, such as COAs, and catalyst phase transfer (for example, 18-crown-6) and get bicyclic pyrazol connection Formula, where a represents hydrogen. To obtain 1-N-substituted pyrazol compounds of Formula II where a is a non-hydrogen pyrazol connection is subjected to interaction with a suitable base and a compound of formula RX, where X is a halogen and R represents an alkyl, allyl, alkenyl, quinil, allyl, cycloalkyl, heteroseksualci, benzyl or CH2-heteroaryl, as defined above.

In another embodiment of this invention relates to compounds of General Formula III

where a, b, X, E and Ar1are as defined above.

7-8 presents examples of the synthesis of specific compounds having the General Formula III. In one General method of synthesis of compounds of Formula III was prepared as follows. Aristophanes or arilena add to a strong base in an anhydrous solvent, and then subjected to interaction with 5-chloro-3-methyl-2-nitropyridine, getting 6-S-aryl - or 6-O-aryl-substituted 2-methyl-C-nitropyridine intermediate connection. NO2Deputy restore, for example, by treatment with iron powder in acetic acid when heated over a period of time followed by treatment with a suitable base, such as NaOH. The obtained aniline intermediate connection allocate by extraction of the reaction mixture org the organic solvent. Intermediate aniline compound is then treated with tetrafluoroborate ammonium followed by the addition of bases, such as COAs, and catalyst phase transfer (for example, 18-crown-6) and get bicyclic azaindole compound of Formula III, where a is a hydrogen. To obtain 1-N-substituted azaindole compounds of Formula III, where a is other than hydrogen, azaindole connection is subjected to interaction with a suitable base and a compound of formula RX, where X is a halogen, and R represents an alkyl, allyl, alkenyl, quinil, cycloalkyl, heteroseksualci, benzyl or CH2-heteroaryl, as defined above.

In another embodiment of this invention relates to compounds of General Formula IV

where a, b, X, E and Ar1are as defined above, provided that when a represents N and a represents CH=CH-R8where R8represents a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heteroseksualci, aryl or heteroaryl, then X-Ar1is a Deputy, where Ar1is other than substituted or unsubstituted aryl, heteroaryl, NH-alkyl, NH-cycloalkyl, NH-heteroseksualci, NH-aryl, NH-heteroaryl, NH-alkoxy, or NH-dialkylamide, when X represents O, S, C=, S=O, C=CH2, CO2, NH or

N(C1-C8-alkyl).

Figure 9-13 presents examples of the synthesis of specific compounds having the General Formula IV. In one General method of synthesis of compounds of Formula IV obtained as follows. 6-Nitroindole handle base and iodine and the resulting 3-iodine-6-nitroindole is treated with a base and an agent with a protective group for amino, such as trimethylsilylamodimethicone (SEM-Cl). Processing of protected 6-nitroindoline compounds TRANS-2-vanilinovoi acid and a suitable catalyst, such as Pd(PPh3)4gives 1-N-fineliner-6-nitroindoline intermediate connection. Restore 6-NO2Deputy regenerating agent such as hydrazine, and a suitable catalyst (e.g. palladium on coal) gives l-N-substituted 6-aminoindole derived. Treatment of this derivative with sodium nitrite followed by the addition of sodium iodide and iodine gives 1-N-substituted-3-phenylphenyl-6-iodination derived. Treatment of this derivative oxidizing(s) agent(s), such as osmium tetroxide and periodate sodium, gives 1-N-protected 3-carbaldehyde-6-iodination derived. This derivative can then be used in some synthesis methods to produce different indazol compounds according to this invention, such as described in point is imarah.

In an alternative method for the synthesis of 6-OAr-substituted compounds of Formula IV obtained as follows. Treatment 2-fluoro-4-hydroxyacetophenone appropriate reagent with a protective group for a phenol followed by the addition of hydrazine when heated to induce cyclization gives indazol connection. Indazol connection protects in position 1-N with a suitable reagent with a protective group for amino. The removal of the protective group for the phenol and processing arylboronic acid with the subsequent removal of the protective group for amino give 6-OAr-substituted compound of Formula IV.

In an alternative method for the synthesis of 6-SAr-substituted compounds of Formula IV obtained as follows. 4-Portifino treated with a strong base such as tert-piperonyl potassium, and received phenoxide add 2,4-diplocraterion. Adding hydrazine to the obtained intermediate compound followed by heating to induce cyclization gives 6-SAr-substituted compound of Formula IV.

In an alternative method for the synthesis of 5-OAr - and 5-SAr-substituted compounds of Formula IV obtained as follows. Etherification of 5-fluoro-2-nitrobenzoic acid with subsequent processing of the received complex ether mixture or ArOH, or ArSH and strong base gives a 5-XAr-substituted methyl ether 2-nitrobenzoic acid, where X represents O or S. Omielaniets complex ether followed by the addition of ammonium hydroxide gives 2-nitrobenzamide intermediate connection. 2-Nitrobenzamide turn 2-nitrobenzonitrile intermediate compound by treatment with oxalylamino. Recovery of microsatellites followed by the addition of sodium nitrite gives 3-amino-5-XAr-substituted indazol compound of Formula IV, where X represents O or S.

In an alternative method for the synthesis of 6-OAr-substituted compounds of Formula IV obtained as follows. 2-Fluoro-4-hydroxybenzonitrile unite with arylboronic acid, copper acetate and a base receiving 2-fluoro-4-aryloxypropanolamine intermediate connection.

The stirred solution of this intermediate compound with hydrazine is heated under reflux, getting 3-amino-6-aryloxazolo connection. This connection can be used as the starting material for the synthesis of 3-amendatory derived using standard chemistry for the synthesis of amides, well-known specialists in this field of technology.

In another embodiment of this invention relates to compounds of General Formula V

where A, X, E and Ar are as defined above.

On Fig-26 presents examples of the synthesis of specific compounds having the General Formula V. In one General method of synthesis of compounds of Formula V obtained as follows. 4-fluoro-2-hydroxybenzoic acid is subjected to these is eficacia and 2-hydroxy-group protects a suitable protecting group for the alcohol. The substitution of phorography group O-Ar or S-Ar carried out by treatment with base and ArOH or ArSH, where Ar represents aryl or heteroaryl, as defined above. The removal of the protective group for alcohol and saponification of ester followed by treatment of the carbonyl diimidazol to implement cyclization gives 6-OAr - or 6-SAr-3-hydroxybenzotriazole connection. 3-Hydroxybenzenesulfonate connection turn 3-chlorobenzotriazole derived by processing POCl3and the ground. This product can then be used to obtain 3-O-Ar -, or 3-NH-Ar-substituted benzisoxazole compounds according to this invention. For example, a 6-substituted-3-chlorobenzotriazole the connection can be added to the mixture ArOH and strong base (such as NaH) to obtain 6-substituted-3-O-Ar-benzisoxazole derived. In an alternative method for the synthesis of 6-substituted-3-chlorobenzotriazole the connection can be added to the mixture ArNH2and a strong Foundation with obtaining 6-substituted-3-NHAr-benzisoxazole derived.

In another embodiment of this invention relates to compounds of General Formulas VI and VII

where a, b, E and Ar1are as defined above.

On Fig-15 presents examples of the synthesis of specific compounds having the General Faure the Ulu VI, and Fig, 19 and 23 are examples of the synthesis of specific compounds having the General Formula VII. In one General method for the synthesis of compounds of Formulas VI and VII was obtained as follows. 5-Iodine-1H-indazol obtained by treatment of 5-amino-1H-indazole solution NaNO2in water followed by the addition of KI. After separation of the product by extraction of the reaction mixture with an organic solvent, this product can then be used in various synthesis methods to obtain indazol compounds according to this invention. In the same way 1-amino group of 5-iodine-1 N-indazole protects a suitable protecting group for amino and protected 5-logindata is treated with a base, a copper powder and kilfenora or aristotelem, receiving 5-O-arylsubstituted indazol (Formula VI) or 5-3-arylsubstituted indazol (Formula VII). The removal of the protective group for amino network connection according to this invention, having the Formula VI or VII.

In an alternate method 5-iodine-1 N-indazol handle base and RX or Ar1CH2X, where R is an alkyl or allyl and Ar1represents an aryl or heteroaryl group, as defined above, and X represents a halogen or other suitable leaving group. 1-N-Substituted 5-logindata is then treated with base, copper powder and aristotelem or kilfenora, receiving-O-aryl-substituted indazol (Formula VI) or 5-S-aryl-1-N-substituted indazol (Formula VII) the compound according to this invention.

In another embodiment of this invention relates to compounds of General Formula VIII

where a, b, E and Ar1are as defined above.

On Fig presents an example of the synthesis of specific compounds having the General Formula VIII. In one General method of synthesis of compounds of Formula VIII is obtained by oxidation of compounds of Formula VII is an oxidizing agent that will oxidize allsolid to the appropriate arylsulfonyl derived.

In another embodiment of this invention relates to compounds of General Formula IX

where a, b, E and Ar1are as defined above.

On Fig presents an example of the synthesis of specific compounds having the General Formula IX. In one General method of synthesis of compounds of Formula IX are obtained by oxidation of compounds of Formula VII is an oxidizing agent that will oxidize allsolid to the appropriate arylsulfonyl derived.

In another embodiment of this invention relates to compounds of General Formula X

where a, b, E and Ar1are as defined above.

On Fig presents an example of the synthesis of specific compounds having the General Formula X. In one General method of synthesis of compounds of Formula X obtained as follows. The MCA is and tetrafluoroborate ammonium and acetic acid added 4-bromo-2-methylaniline. Some time later to this mixture is added sodium nitrite, and then a base, such as potassium acetate and a catalyst phase transfer, such as 18-crown-6, receiving 5-brominator. Brominator RBr process in the presence of a base, getting 1-N-substituted 5-bromination derivative, where R is as defined above for Formula X, with the exception of hydrogen. Treatment of 1-N-substituted derivative with Ar1SNO in the presence of a strong base, such as utility, where Ar1is the same as defined above, gives the alcohol compound of Formula X.

In another embodiment of this invention relates to compounds of General Formula XI

where a, b, E and Ar1are as defined above.

On Fig presents an example of the synthesis of specific compounds having the General Formula XI. In one General method of synthesis of compounds of Formula XI obtained as follows. To a mixture of tetrafluoroborate ammonium and acetic acid added 4-bromo-2-methylaniline. Some time later to this mixture is added sodium nitrite, and then a base, such as potassium acetate and a catalyst phase transfer, such as 18-crown-6, receiving 5-brominator. Brominator RBr process in the presence of a base, getting 1-N-substituted 5-bromination intermediate compound, where R is predstavljaet a While, as defined above for Formula XI, with the exception of hydrogen. Treatment of 1-N-substituted intermediate compound with Ar1SNO in the presence of a strong base, such as utility, where Ar1is the same as defined above, followed by treatment with a suitable oxidizing agent to give 1-N-substituted compound of Formula XI. An alternative method of synthesis of compounds of Formula XI are shown in Fig.

In another embodiment of this invention relates to compounds of General Formula XII

where a, b, E, R1and Ar1are as defined above.

On Fig presents an example of the synthesis of specific compounds having the General Formula XII. In one General method of synthesis of compounds of Formula XII obtained as follows. To a mixture of tetrafluoroborate ammonium and acetic acid added 4-bromo-2-methylaniline. Some time later to this mixture is added sodium nitrite, and then a base, such as potassium acetate and a catalyst phase transfer, such as 18-crown-6, receiving 5-brominator. Brominator RBr process in the presence of a base, getting 1-N-substituted 5-bromination derivative, where R represents an alkyl, allyl, ArCH2or heteroaryl-CH2as defined above. Treatment of 1-N-substituted derivative with Ar1SNO in the presence of the SIL is wow grounds such as utility, where Ar1is the same as defined above, followed by treatment with a suitable oxidizing agent to give 1-N-substituted 5-C=OR-derived. The addition of NH2OR1to this derivative in pyridine, where R6is the same as defined above, gives the oxime of Formula XII. An alternative method of synthesis of compounds of Formula XII are shown in Fig.

In another embodiment of this invention relates to compounds of General Formula XIII

where a, b, E and Ar1are as defined above.

On Fig presents an example of the synthesis of specific compounds having the General Formula XIII. In one General method of synthesis of compounds of Formula XIII prepared as follows. To a mixture of tetrafluoroborate ammonium and acetic acid added 4-bromo-2-methylaniline. Some time later, to the mixture sodium nitrite, and then a base, such as potassium acetate and a catalyst phase transfer, such as 18-crown-6, receiving 5-brominator. Brominator RBr process in the presence of a base, getting 1-N-substituted 5-bromination intermediate compound, where R is as defined above for Formula XIII with the exception of hydrogen. Treatment of 1-N-substituted intermediate compound is a strong base, such as tert-utility, and then adding the relativedate gives indazol intermediate compound 5-Bronevoy acid. The addition of copper(II) catalyst followed by the addition of substituted or unsubstituted aniline gives compound of Formula XIII.

In another embodiment of this invention relates to compounds of General Formula XIV

where a, b, X, Ar1, R2and R3are as defined above.

On Figa-30C shows an example of the synthesis of specific compounds having the General Formula XIV. In one General method of synthesis of compounds of Formula XIV is obtained as follows. 1-Fluoro-3-methylbenzo subjected to the reactions proceed with the formation of 2-fluoro-4-methylbenzoic acid, and then to nitration to obtain 2-fluoro-4-methyl-5-nitrobenzoic acid. Acid group etherification, and then floragraph replaces ArO - after processing ArOH and a strong base. The restoration of the nitro group followed by diazotization and cyclization of 5-OAr-6-CO2IU indazol derivative, which is then treated with RBr in the presence of a base, getting 1-N-substituted derivative. Hydrolysis of the ester group, followed by amidation gives 6-amide indazol derivative having the Formula XIV.

In another embodiment of this invention relates to compounds of General Formula XV

where a, b, X and Ar1are as defined above, and R12and R13nez is performance represent alkyl, allyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl or heteroaryl where the specified alkyl, allyl, alkenyl, quinil, cycloalkyl, heteroseksualci, aryl or heteroaryl may be substituted or unsubstituted.

On Fig presents an example of the synthesis of specific compounds having the General Formula XV. In one General method of synthesis of compounds of Formula XV obtained as follows. 5-OAr-6-CO2IU indazol get derived, as described above for the synthesis of compounds of Formula XIV, and then treated with RBr in the presence of a base, getting 1-N-substituted derivative. Hydrolysis of the ester group followed by treatment of the carbonyl diimidazol and amino acid gives 6-substituted indazol derivative having the Formula XV.

In another embodiment of this invention relates to compounds of General Formula XVI

where a, b, X, R2, R3and Ar1are as defined above.

In one General method of synthesis of compounds of Formula XVI is obtained as follows. 5-OAr-6-CO2IU indazol get derived as described above for the synthesis of Formula XIV, and then restore, for example, processing NR3in THF. Cleaning gives compound of Formula XVI.

In another embodiment of this invention relates to compounds of General Formula XVII

where Y represents CR1, O, S or NR2;

W represents CR3, N, NR4, S or O, provided that W represents NR4, S or O, Y represents CR1and W represents CR3or N, Y represents NR2;

R3represents N, NH2, F, Cl, methyl or substituted methyl;

R4represents H or methyl or substituted methyl;

R1and R2independently represent H, HE, a protective group for amino, Zn-NRaRb, Zn-NRa(C=O)Rb, Zn-SO2Ra, Zn-SORa, Zn-SRa, Zn-ORa, Zn-(C=O)Ra, Zn-(C=O)ORa, Zn-O-(C=O)Ra, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl where specified cycloalkyl is saturated or partially unsaturated, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci and Zn-Ar1may be substituted or unsubstituted;

Ar1represents ar is l or heteroaryl, each of which may be substituted or unsubstituted;

R3and R13independently represent H, HE, the protective group for the amino protective group for an alcohol protective group for the acid, the protective group for sulfur, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl where specified cycloalkyl is saturated or partially unsaturated, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci and Zn-Ar1may be substituted or unsubstituted,

or Raand Rbtogether with the atoms to which they are both attached, form a saturated or partially unsaturated heterocyclic ring having one or more heteroatoms in the specified ring, where the heterocycle may be substituted or unsubstituted, and where the heterocycle may be condensed with an aromatic ring;

Z represents alkylene having from 1 to 4 carbon atoms, or albaniles or akinyan, each of which has 2 to 4 carbon atoms, where the specified Alki the Yong, albaniles or akinyan may be substituted or unsubstituted;

n means 0 or 1;

U represents CRcor N;

V represents CRcor N;

Rcrepresents H, F, Cl, methyl or substituted methyl;

X represents O, S, SO, SO2, NR5, C=O, CH2CH2Zn-OH or=NORd;

R5represents H, methyl or substituted methyl;

Rdrepresents H, RHO3H2, SO3H2, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl where specified cycloalkyl is saturated or partially unsaturated, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci and Zn-Ar1may be substituted or unsubstituted;

G, H, J and T independently represent N or CRzprovided that when any such G, H, J and T are N, then the total number of G, H, J or T, which are N, does not exceed 2;

Rzrepresents H, F, Cl, Br, CF3, OR6, SR6 lowest (1-C4)alkyl, CN or

NR6R7;

R6and R7independently represent H, CF3lowest (1-C4)alkyl, or

low (1-C4)heteroalkyl;

Q represents-NR8ONH-, -NHCO-, -NR8SO2NH-, -NHSO2-, -CONR11-;

R8represents H or lower (1-C4)alkyl;

R11represents H or lower (1-C4)alkyl;

Rxrepresents -(CR9R10)m-, -O(CR9R10)m-, NH(CR9R10)m- or-S(CR9R10)mprovided that Q is a-CONR11-when Rxrepresents a

O(CR9R10)m-, -NH(CR9R10)m- or-S(CR9R10)m-;

R9and R10independently represent H or lower alkyl, or R9and R10together with the atoms to which they are both attached, form cycloalkyl ring which may be saturated or partially unsaturated;

m means 1-3;

Ryrepresents H, RHO3H, a protective group for the amino protective group for oxygen, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl where specified cycloalkyl is saturated or h is partially unsaturated, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, or Zn-Ar2where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-Ar2and Zn-heteroseksualci may be substituted or unsubstituted;

Ar2represents aryl or heteroaryl, each of which may be substituted or unsubstituted, where the specified substitution can be performed 1-3 substituents, independently selected from F, Cl, Br, CF3, CN, alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl,

-OR12, -SR12, -SO2R12, -SO2NR13R12, NR13SO2R12, Zn-cycloalkyl where specified cycloalkyl is saturated or partially unsaturated, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci and Zn-Ar1may be substituted or unsubstituted;

R12and R13independently represent H, alkyl, allyl, and canil, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, Zn-cycloalkyl where specified cycloalkyl is saturated or partially unsaturated, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci and Zn-Ar1may be substituted or unsubstituted;

where Ar2replaced-SO2NR13R12then R12and R13can form cycloalkyl ring or geteroseksualnoe ring which may be substituted or unsubstituted, where the specified substitution can be carried out by substituents selected from alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl where specified cycloalkyl is saturated or partially unsaturated, -COR12, -SO2R12, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, or Zn-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic,Z n-cycloalkyl, Zn-heteroseksualci and Zn-Ar1may be substituted or unsubstituted;

where Q is a-CONR11-, then Rytogether with R11additionally represent cycloalkyl ring or geteroseksualnoe ring which may be substituted or unsubstituted groups selected from alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl where specified cycloalkyl is saturated or partially unsaturated, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, Zn-Ar1, -COR14or-SO2R14where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci, Zn-Ar1, -COR14and-SO2R14may be substituted or unsubstituted, and

R14represents alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, Zn-cycloalkyl where specified cycloalkyl is saturated or partially unsaturated, Zn-heteroseksualci where specified heteroseksualci is saturated or partially unsaturated, and which and Z n-Ar1where the specified alkyl, allyl, alkenyl, quinil, heteroalkyl, heteroallyl, heteroalkyl, heteroalkyl, alkoxy, heteroatomic, Zn-cycloalkyl, Zn-heteroseksualci and Zn-Ar1may be substituted or unsubstituted.

On Fig-50 presents examples of the synthesis of specific compounds having the General Formula XVII.

Therapeutically effective amounts of compounds according to the invention can be used for the treatment of diseases mediated by modulation or regulation of protein kinases. "Effective amount" is intended to indicate the quantity of a compound that when administered to a mammal in need of such treatment, is sufficient to effect the treatment of a disease mediated by the activity of one or more than one protein kinase, such as R alpha, and associated R-mediated events such as cytokine production. For example, a therapeutically effective amount of a compound selected from Formulas I-XVII, or its salt, active metabolite or prodrug, is a quantity sufficient to modulate, regulate, or inhibiting the activity of one or more than one protein kinase in such a way that a painful condition which is mediated by that activity is eliminated or alleviated.

<> The number of times a given agent that will correspond to such an amount will vary depending on factors such as the particular compound, disease state and its severity, characteristics (e.g., weight) of the mammal in need of treatment, but nevertheless can be normally determined by a person skilled in the art. "Treatment" is intended to refer to at least mitigate the painful condition in a mammal, such as man, which is influenced, at least partially, the activity of one or more than one protein kinase, such as R, and includes, but is not limited to, the prevention of occurrence of a pathological state in a mammal, particularly when detected that the mammal is predisposed to have this painful condition, but which he had not revealed; modulating and/or inhibiting the disease condition; and/or alleviating the disease condition.

To apply the compounds of Formula I-XVII , or its pharmaceutically acceptable salt, or prodrug that is cleaved in vivo, for therapeutic treatment (including prophylactic treatment) of mammals including humans, it is usually prepared in the form of pharmaceutical compositions in accordance with standard pharmaceutical what ractical. According to this aspect of the invention proposed pharmaceutical composition which contains a compound of Formulas I-XVII , or its pharmaceutically acceptable salt, or prodrug that is cleaved in vivo, as defined above, together with a pharmaceutically acceptable diluent or carrier.

The composition of the invention can be in a form suitable for oral use (for example, in the form of tablets, pellets, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example, in the form of creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example, in the form of finely ground powder or a liquid aerosol), for administration by insufflation (for example, in the form of finely ground powder) or for parenteral administration (for example, in the form of a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular dosing or as a suppository for rectal dosing). For example, compositions intended for oral use may contain, for example, one or more than one dye, sweetener, corrigent and/or preservative.

Suitable pharmaceutically acceptable excipients for the preparation of tablets include is in itself, for example, inert diluents, such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating and loosening agents such as corn starch or alginic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl - or propyl-p-hydroxybenzoate, and antioxidants, such as ascorbic acid. Preparations in the form of tablets can be uncoated or coated or to modify their disintegration and the subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve their stability and/or appearance, in any case, using traditional covering agents and techniques well known in the prior art.

Compositions for oral administration can be in the form of hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules in which the active ingredient is mixed with water or oil, such as peanut is small, liquid paraffin or olive oil.

Aqueous suspensions generally contain the active ingredient in the form of fine powder together with one or more than one suspendium agent such as on dicarboximides, methylcellulose, hydroxypropylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum Arabic; dispersing or wetting agent such as lecithin, or condensation products of accelerated with fatty acids (for example, polyoxyethylenated), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with partial esters derived from fatty acids and exit, such as polyoxyethylenesorbitan monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides of exit, such as polietilensorbit monooleate. Aqueous suspensions can also contain one or more than one preservative (such as ethyl - or propyl-p-hydroxybenzoate), antioxidants (such as ascorbic acid), colouring agents, corrigent and/or sweetening agents (such as sucrose, saccharin or aspartame).

Oil suspensions can be prepared by suspension of the active ingredient in a vegetable oil (such as peanut butter, olive oil, sesame oil or coconut oil) or mineral oil such as liquid paraffin). Oily suspensions may contain a thickening agent, such as beeswax, hard couple is in or cetyl alcohol. To ensure a pleasant taste oral drug can be added sweeteners, such as described above, and corrigentov. These compositions may be preserved by adding an antioxidant such as ascorbic acid.

Dispersible powders and granules suitable for obtaining aqueous slurry by adding water, usually contain the active ingredient together with a dispersing or wetting agent, suspenders agent and one or more than one preservative. Examples of suitable dispersing or wetting agents and suspendida agents are those which are already mentioned above. There may be additional excipients, such as sweeteners, corrigentov or dyes.

The pharmaceutical compositions according to the invention can also be in the form of emulsions of oil-in-water. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or mineral oil, such as, for example, liquid paraffin, or a mixture of any of these oils. Suitable emulsifying agents may represent, for example, natural resins such as gum Arabic or tragacanth gum, natural phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and anhydrides of exit (such as sorbitol monooleate), and condensation products of these partial esters with ethylene oxide, such as polyoxyethylenesorbitan monooleate. The emulsion may contain sweeteners, corrigentov and preservatives.

Syrups and elixirs can be prepared with a sweetener, such as glycerin, propylene glycol, sorbitol, aspartame or sucrose and can also contain yspokaitelnoe agent, preservative, corrigent and/or dye.

Pharmaceutical compositions can also be in the form of sterile injectisome aqueous or oil suspensions, which can be prepared according to known procedures using one or more than one suitable dispersing or wetting agent and a suspending agent, as mentioned above. A sterile preparation for injection may also be a sterile solution or suspension for injection in a non-toxic acceptable for parenteral use diluent or solvent, for example a solution in 1,3-butanediol.

Suppozitornyj preparations can be prepared by mixing the active ingredient with a suitable non-irritating by excipients, which is solid at normal temperature but becomes liquid at rectal temperature and therefore will melt in the rectum with vysvobozhdenijah. Suitable excipients include, for example, cocoa butter and polyethylene glycols.

Local preparations, such as creams, ointments, gels, and aqueous or oil solutions or suspensions can usually be obtained by preparation of the active ingredient from traditional, acceptable for local use solvent or diluent by conventional methods, well known in this technical field.

Compositions for administration by insufflation may be in the form of finely ground powder containing particles with an average diameter of, for example, 30 μm or much less, the powder includes either the active ingredient or active ingredient diluted with one or more physiologically acceptable carrier such as lactose. Powder for insufflation convenient to store in a capsule containing, for example, from 1 to 50 mg of active ingredient, for use with turbomaschinen device, therefore, which is used for insufflation known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of a traditional aerosol under pressure, adapted to release the active ingredient, either in the form of an aerosol containing finely dispersed solids or liquid droplets. Can be used cent is as aerosol propellants, such as volatile fluorinated hydrocarbon or hydrocarbons, or aerosol device is conveniently adapted to release a metered amount of the active ingredient.

For more information about pharmaceutical drugs, see Chapter 25.2 in Comprehensive Medicinal Chemistry, Volume 5, Corwin Hansch; Chairman of Editorial Board, Pergamon Press, 1990, which is specifically incorporated herein by reference.

The number of compounds according to this invention, which combine with one or more than one excipient to obtain a uniform dosage form will necessarily vary depending on the body's "master", which is treated and the particular route of administration. For example, a drug intended for oral administration to man, will contain, for example, from 0.5 mg to 2 g of active ingredient with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 wt.% the overall composition. Dosage forms will generally contain from about 1 mg to about 50 mg of the active ingredient. For more information on routes of administration and dose modes, see Chapter 25.3 in Comprehensive Medicinal Chemistry, Volume 5, Corwin Hansch; Chairman of Editorial Board, Pergamon Press, 1990, which is specifically incorporated herein by reference.

The size of the dose of the compounds of Formula I-XVII for therapeutic or prophylactic purposes is going to be naturally vary depending on the nature and severity of the conditions, age and sex of the animal or patient and the route of administration, in accordance with the rules, well known in medicine.

In one aspect of this invention, the compounds of this invention or their pharmaceutically acceptable salts or prodrugs can be prepared in the form of pharmaceutical compositions for administration to animals or humans for the treatment or prevention of a condition mediated R. The term "condition mediated R", used herein, means any disease or other dangerous condition in which R, as you know, plays a role. It includes state, which, as is known, caused by overproduce IL-1, TNF, IL-6 or IL-8. Such conditions include, without limitation, inflammatory diseases, autoimmune diseases, destructive bone disorders, proliferative disorders, infectious disease, viral disease, and neurodegenerative diseases.

Inflammatory diseases that can be treated or prevented include, but are not limited to, acute pancreatitis, chronic pancreatitis, asthma, allergies and respiratory distress syndrome in adults.

Autoimmune diseases that can be treated or prevented include, but are not limited to, glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus, skirter is, chronic thyroiditis, graves ' disease, autoimmune gastritis, insulin-dependent diabetes mellitus (type I), autoimmune hemolytic anemia, autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronic active hepatitis, asthenic bulbar palsy, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, psoriasis or disease graft-versus-host.

Destructive bone disorders that can be treated or prevented include, but are not limited to, osteoporosis, osteoarthritis and bone abnormalities associated with multiple myeloma.

Proliferative disease that can be treated or prevented include, but are not limited to, acute myeloid leukemia, chronic myeloid leukemia, metastatic melanoma, sarcoma Galoshes and multiple myeloma.

Infectious diseases that can be treated or prevented include, but are not limited to, sepsis, septic shock, and shigellosis.

Viral diseases that can be treated or prevented include, but are not limited to, acute infectious hepatitis (including hepatitis a, hepatitis b and hepatitis C), HIV infection and CMV (cytomegalovirus) retinitis.

Degenerative conditions or diseases that can be treated or pre order to avert the compounds according to this invention, include, but are not limited to, Alzheimer's disease, Parkinson's disease, cerebral ischemia and other neurodegenerative diseases.

"State-mediated R also include ischemia/reperfusion in stroke, heart attacks, myocardial ischemia, hypoxia bodies, vascular hyperplasia, cardiac hypertrophy, and thrombin-induced platelet aggregation.

In addition, inhibitors R according to this invention is also able to inhibit the expression of inducible Pro-inflammatory proteins such as prostaglandin-endoperoxide-synthase-2 (PGHS-2), also known as cyclooxygenase-2 (SOH-2). Therefore, other state, mediated R"represent edema, analgesia, fever and pain, such as neuromuscular pain, headache, cancer pain, dental pain and arthritic pain.

Conditions and diseases that can be treated or prevented by inhibitors R according to this invention can also be conveniently grouped in accordance with the cytokine (such as IL-1, TNF, IL-6, IL-8), which are believed to be responsible for this disease.

Thus, a disease or condition mediated(th) IL-1, includes rheumatoid arthritis, osteoarthritis, stroke, groove toxins and/or toxic shock syndrome, inflammatory reaction induced by endotoxin, inflammatory bowel disease, tuberculosis, atherosclerosis, muscle is know dystrophy, cachexia, psoriatic arthritis, Reiter syndrome, gout, traumatic arthritis, arthritis, caused by the rubella virus, acute synovitis, diabetes, disease of the pancreatic β-cells and Alzheimer's disease.

A disease or condition mediated(th) TNF, includes rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, respiratory distress syndrome of adults, cerebral malaria, chronic obstructive pulmonary disease, silicosis, pulmonary sarcoidosis, bone resorption, reperfusion injury, graft vs. host rejection, allograft, fever and myalgia due to infection, cachexia secondary to infection, AIDS, AIDS-associated complex or malignancy, keloid formation, scar tissue, Crohn's disease, ulcerative colitis or hyperthermia. Diseases mediated by TNF, also include viral infections such as HIV, CMV, influenza and herpes, and viral infections in veterinary medicine, such as lentivirinae infection, including, but not limited to, virus equine infectious anemia virus arthritis goats, virus visna or virus maedi (maedi), or retroviral infection, including virus immune the deficit cats, human immunodeficiency virus cows or human immunodeficiency virus dogs.

A disease or condition mediated(th) IL-8, includes diseases characterized by massive infiltration of neutrophils, such as psoriasis, inflammatory bowel disease, asthma, reperfusion injury of the heart and kidneys, respiratory distress syndrome of adults, thrombosis and glomerulonephritis.

In addition, the compounds of this invention can be used topically for the treatment or prevention of conditions caused or aggravated by IL-1 or TNF. Such conditions include inflamed joints, eczema, psoriasis, inflammatory skin conditions such as sunburn, inflammatory condition of the eye such as conjunctivitis, hyperthermia, pain and other conditions associated with inflammation.

Compounds according to this invention can be used in combination with other drugs and therapies used to treat painful conditions for which it would be useful for the inhibition of cytokines, in particular IL-1, TNF, 1L-6 or IL-8.

For example, due to its ability to inhibit cytokines, the compounds of Formula I-XVII are of great importance in the treatment of certain inflammatory and non-inflammatory diseases which are currently treated with nonsteroidal anti-inflammatory drug (NSAID), inhibiting cyclooxygenase, so the AK indomethacin, Ketorolac, acetylsalicylic acid, ibuprofen, sulindac, tolmetin and piroxicam. Co-administration of compounds of Formula I-XVII with an NSAID may cause a reduction in the number of the last agent required to achieve a therapeutic effect, and thus to reduce the likelihood of adverse side-effects from the introduction of NSAIDs, such as gastrointestinal effects. Thus, according to another characteristic of the invention the proposed pharmaceutical composition comprising a compound of Formulas I-XVII, or its pharmaceutically acceptable salt, or ester, cleaved in vivo, in combination or in a mixture with non-steroidal anti-inflammatory agent, inhibiting cyclooxygenase, and a pharmaceutically acceptable diluent or carrier.

The compounds of Formula I-XVII can also be used in the treatment of conditions such as rheumatoid arthritis, in combination with anti-arthritis agents, such as gold, methotrexate, steroids and penicillinases, and conditions such as osteoarthritis, in combination with steroids.

Compounds of the present invention also can be used to degradation diseases, such as osteoarthritis, with chondro-protective, protivoerozionnye and/or reparative agents such as diacetin (Diacerhein), hyaluronic acid, such as Gilan, Rumalon, Arteparon, the glucosamine salts, such as Antril.

The compounds of Formula I-XVII can also be used in the treatment of asthma in combination with anti-asthmatic agents such as bronchodilators and leukotriene antagonists.

Despite the fact that the compounds of Formula I-XVII mainly have great importance as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit the effects of cytokines. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.

The activity of the compounds according to this invention can be analyzed for inhibition R in vitro, in vivo or in cell lines. In vitro studies include studies that determine or inhibition of kinase activity or ATPase activity of activated R. Alternative in vitro studies quantify the ability of the inhibitor to contact R and can be measured either by radioactive labeling of the inhibitor prior to binding, secretion of complex inhibitor/R and identifying number associated with a radioisotope, or by conducting competition experiment where new inhibitors are incubated with R associated with known and the radio. These and other studies are useful in in vitro and in cell cultures and is well known to specialists in this field of technology.

Analysis of inhibitory effect of the compounds according to this invention on cell cultures can be used to determine the amounts of TNF-α, IL-1, IL-6 or IL-8 produced in whole blood or cell fractions in cells treated with inhibitor, compared to cells treated with negative control substances. The level of these cytokines can be determined by using a commercially available ELISA or, as described in Biological Examples below.

BIOLOGICAL EXAMPLES

Biological activity of compounds according to the invention were demonstrated by the following in vitro tests.

Biochemical analysis R

Activity R analyzed at room temperature in 100 μl of reaction mixture containing 5 nm of activated enzyme RA and 1 μm ATF-2 (fused protein activating transcription factor 2) as a substrate in 25 mm HEPES (pH 7.4), 100 μm Vanadate, 1 mm DTT, 10 mm MgCl2and 10 μm [□-33P]-ATP (approximately 0.1 µci R33/reaction). The reaction was interrupted after 30-40 minutes, adding 25%THU, left to stand for 5 minutes and then transferred directly to GF-B membrane filtration tablet. The filter is washed twice is if within 30 seconds with 0.5%phosphoric acid using a Tomtec Mach III Automated Harvester. After washing, the vacuum was maintained for 30 seconds to dry the filter. To each well of the filtration tablet was added about 30 μl acquired scintillation fluid and then took the readings in liquid acquired scintillation counter (Packard TopCount HTS).

Analysis RVMS

The ability of compounds of this invention inhibit the production of TNF-α was evaluated using the mononuclear cells of peripheral blood (RVMS), which synthesize and secrete TNF-α upon stimulation with lipopolysaccharide.

The solutions of the investigated compounds were prepared, making a 5-fold serial dilution in DMSO, then diluted to 5-fold mother solutions by breeding MEM, 2%V / V heat inactivated fetal calf serum (FBS), 20 mm HEPES, 2 mm L-glutamine and 1% penicillin/streptomycin.

RWMS was isolated from human blood as described below. Samples of whole blood was collected from volunteers in Vacutainer™ CPT (Becton Dickinson). The contents of the tubes were mixed and centrifuged at room temperature (18-25°C) in a horizontal rotor for at least 15 minutes at 1500-1800 RCF (relative centrifugal force). For each donor layers of cells were combined in a separate test tube and washed twice with phosphate-saline buffer (PBS). Cellular precipitate resuspendable in MEM, 2%V / V heat inactivated FET is through calf serum (FBS), 20 mm HEPES, 2 mm L-glutamine and 1% penicillin/streptomycin.

The total number of cells was determined using hemocytometer and the concentration of cell suspension was brought to 2×106cells/ml

In each well of 96-well plate to cell cultures were added 0.1 ml of cell suspension. Added 30 μl of a solution of tested compound and the cells were incubated at 37°C in CO2-incubator (5% CO2within 1 hour. Then to each well was added 20 μl of 7.5 ng/ml of lipopolysaccharide (LPS from E. coli K-235) and the cells were returned to the incubator with 5% CO2at 37°C for 16-20 hours. Cells were centrifuged for 15 minutes at 1100 RCF. Approximately 0,12 ml of supernatant was transferred into a clean 96-well polypropylene plate. The samples were analyzed either immediately, or store them at -80°C until being used for analysis. The levels of TNF-α was determined in each sample using enzyme-linked immunosorbent assay (ELISA) for TNF-α human, as described below.

The levels of TNF-α was determined using the following methodology. The tablets are coated with an antibody to TNF-α, were prepared by adding to the wells of the 96-hole tablet Immunol 4 (Immulon 4 ELISA Flat Bottom Plate; Dynex, catalog number 011-010-3855) 150 μl of 2 μg/ml purified mouse monoclonal anti-TNF-α IgG in carbonate-bicarbonate buffer (Vern™ Carbonate-bicarbonate-heat Buffer Pack) and incubated overnight at 2-8°C. Pokrywa is the overall solution was removed and added to 200 μl of blocking buffer (20 mm HEPES, pH 7.4, 150 mm NaCl, 2% BSA), the tablets were stored at 2-8°C prior to use. Destitution standard curve of recombinant human TNF-α was obtained by serial dilution (1:2) in the "diluent" (20 mm HEPES, pH 7.4, 150 mm NaCl, 2 mm MgCl2, 1% BSA) with a maximum concentration of 6000 PG/ml

The blocking solution was removed from the tablets for ELISA analysis of TNF-α by 5 times washing in 300 μl of buffer for washing" (20 mm HEPES, pH 7.4, 150 mm NaCl, 2 mm MgCl2, 0,02% Tween-20). Into each well was added 50 μl of "diluent", and then into each well was added 50 μl of a standard solution of TNF-α, or the supernatant of the investigated compounds. Tablet incubated at room temperature for 1 hour under stirring (300 rpm). The tablet was washed 5 times with 300 ál of buffer for washing." To each well was added 100 μl of 0.2 μg/ml biotinylated goat anti-TNF-α human "antibody diluent" (20 mm HEPES, pH 7.4, 150 mm NaCl, 2 mm MgCl2, 1% BSA, 0.02% of Tween-20) and the plate incubated at room temperature for 1 hour under stirring (300 rpm). The tablet was washed 5 times with 300 ál of buffer for washing" on the hole. To each well was added 100 μl of 0.02 μg/ml streptavidin-alkaline phosphatase in the diluent for antibodies, and the plate is incubated at room temperature for 1 hour under stirring (300 rpm). PLA is Shet washed 5 times with 300 ál of buffer for washing" on the hole. To each well was added 200 μl of 1 mg/ml pNPP (p-nitrophenylphosphate) in diethanolamine buffer with 0.5 mm MgCl2and the plate is incubated for 30-45 minutes at room temperature and stirring (300 rpm). The reaction course was monitored by determining the optical density (OD): when the upper standard value was reached OD values between 2.0 and 3.0, to each well was added 50 μl of 2 N. NaOH. The optical density in each well was determined within 30 minutes, using microtiter tablet reader set at 405 nm. Data were analyzed XL fit using a 4-parametric approximation of the curve.

In the above studies used the following reagents: phosphate-saline buffer, Dulbecco without calcium or magnesium (Gibco, catalog No. 14190); Minimum supportive environment Needle (MEM; Gibco, catalog No. 11090); penicillin-streptomycin (Gibco, catalog No. 15140); L-glutamine, 200 mm (Gibco, catalog No. 25030 casual); HEPES, 1 M (Gibco, catalog No. 15630); fetal calf serum (FBS; HyClone, catalog No. SH30070.03); lipopolysaccharides from Escherichia coli K-235 (LPS; Sigma, catalog No. L2018); anti-TNF-α, purified mouse monoclonal IgG (R&D Systems, catalog No. MAV); packaging Vern™ carbonate-bicarbonate buffer (Pierce, catalog No. 28382); HEPES (FW 238.3; Sigma, catalog No. N); NaCl (Sigma, catalog No. S7653); bovine serum albumin (BSA; Jackson ImmunoReseach, # the directory 001-000-162); polyoxyethylene 20 sorbitan monolaurate (Sigma, catalog No. R); uranyl magnesium chloride (Sigma, catalog No. M); recombinant human TNF-α human (R&D Systems, catalog No. TA); biotinylated, affinity purified, goat IgG against TNF-α (R&D Systems, catalog No. BAF210); streptavidin-alkaline phosphatase (Jackson ImmunoResearch, catalog No. 016-050-084); diethanolamine substrate buffer (Pierce, catalog No. 34064); p-nitrophenylphosphate (Sigma No. N2765).

Table 3 shows the results of inhibition R and inhibition of LPS-induced secretion of TNF-α from mononuclear cells of peripheral blood (RVMS). The "active" connection is defined as a connection with IC50below 500 nm.

tr>
TABLE 3
ConnectionInhibition R IC50(nm)RVMS IC50(nm)
7f-1Activeactive
7f-2Activeactive
7f-3Activeactive
7f-4The act is main not analyzed
7f-7Activenot analyzed
7f-9Activenot analyzed
7f-12Activenot analyzed
7f-13Activenot analyzed
7f-14Activenot analyzed
7f-15Activenot analyzed
7f-17Activenot analyzed
11g-1Activenot analyzed
11g-10Activeactive
11g-14Activenot analyzed
4f-1Activeactive
4f-2Activeactive
4f-7Activenot analyzed
4f-8Activenot analyzed
4f-9Activeactive
4f-10Activenot analyzed
5f-1Activeactive
5f-2Activeactive
5f-7Activeactive
5f-8Activenot analyzed
5f-9Activeactive
5f-10Activeactive
5f-11Activenot what was analizirovali
5f-12Activenot analyzed
2h-1Activeactive
2h-2Activeactive
2h-10Activeactive
1j-2Activenot analyzed
1j-4Activenot analyzed
2h-1Activeactive
28tActive-
9q-2Active-
7t-1Active-
6nActive-
16pActive-

The study of mice

a Murine model of LPS-induced production of TNF-α

TNF-α induced in mice-males breed DBA-2J (from Jackson Laboratories) injection of 2 mg/kg of lipopolysaccharide (Sigma, St. Louis) into the tail vein. After ninety minutes of mice, shot by isoflurane, were bled by cardiac puncture. Then the blood samples were left to collapse within two hours at 4°C and centrifuged. Serum was separated in a test tube type "Eppendorf" for further analysis of TNF-α. Analysis of TNF-α was performed using an ELISA kit (Quantikine, MN), in accordance with the instructions attached to the kit.

Connection AR-00112190 was obtained with 10% DMSO and 90% 20%2-hydroxyl-p-cyclodextrin (HPCD). Connection AR-00112190 is derived compounds d (see figure 3), where a represents isobutyl. Then the connection was sequentially diluted with solvent (10% DMSO, 90% 20%HPCD) to obtain the concentration required to lower dose levels. The connection is passed into the solution with the addition of DMSO, and then "released" from the solution by adding 20%HPCD. Therefore, the compounds were dosed out in the form of suspensions. 30 minutes before the injection of LPS connection AR-00112190 (10, 30 and 100 mg/kg) orally was administered seven groups of male mice breed DBA-2J (seven animals per group).

Treatment of compound AR-00112190 (10, 30 and 100 mg/kg) also significantly reduced the levels of TNF-α. AR-00112190 showed similar inhibition (42%)observed at the dose of 100 mg/kg (table 4).

Rez is ltati this analysis demonstrated significant positive effects at 10, 30 and 100 mg/kg AR-00112190 (29%, 44% and 42%).

TABLE 4
GroupProcessingAnimalThe level of TNF, PG/mlAverageSE% inhibition
ILPS + solvent1329038253900
23545
33212
45604
54978
62947
73196
IILPS + AR-00112190, 10 mg/kg13373270620629
2047
32782
42080
52365
63298
72967
IIILPS + AR-00112190, 30 mg/kg12815212629244
21826
3
41464
53135
61393
72124
IVLPS + AR-00112190, 100 mg/kg12074221622442
21783
31832
42333
53257
61553
71683

PREPARATIVE EXAMPLES

The following examples are included to illustrate the invention. However, it should be understood that these examples do not limit the invention only and are intended to offer a practical way of carrying out the invention. Specialists in the art will understand that the described chemical reaction can be easily adapted to obtain a number of other inhibitors R according to the invention, and alternative methods of producing compounds according to this invention are considered to be within the framework of the invention. For example, the synthesis of compounds according to the invention, for which no examples, can be successfully performed by modifications obvious to a person skilled in the art, for example by using the appropriate protection of interfering groups, or through other suitable reagents known in the art and may differ from those described and/or by implementing standard changes the reaction conditions. Alternative other reactions disclosed here or known from the prior art, will be considered applicable for other compounds according to the invention.

EXAMPLES

In the examples described below, unless otherwise indicated, all defined temperature in degrees Celsius. Reagents were purchased from such commercial suppliers, as Aldrich Chemical Company, Lancaster, TCI or Maybridge, and, unless otherwise stated, were used without additional purification. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dichloromethane (DHM), toluene, dioxane and 1,2-differetn were purchased from the Aldrich company in securely sealed bottles and used as they were received.

Below the reaction is usually conducted at a positive pressure of nitrogen or argon or using a drying cartridge (if not indicated otherwise) in anhydrous solvent; the reaction flask were usually fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was dried in a drying Cabinet and/or by heating.

Column chromatography was carried out on a Biotage system (manufacturer: Dyax Corporation)having a column of silica gel, or on the toner cartridge with silica gel SepPak (Waters).

Spectra1H-NMR were recorded on a Bruker instrument operating at 300 MHz or on a Varian instrument operating at 400 MHz. Spectra1H-NMR received the C

CDCl3solutions (in million-1) using chloroform as the reference standard (7,25 million-1). Other solvents for NMR were used if necessary. When informed of the multiplet peak, the following abbreviations were used: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). In those cases, when given constant interaction, they are represented in Hertz (Hz).

Example 1

Getting 5-(4-perpenicular)-1-(4-methoxybenzyl)-1H-pyrazolo[3,4-C]pyridine (7a)

Figure 1 shows the reaction scheme for the synthesis of compounds 7a, having the General Formula II. This example describes the synthesis of compounds 7a, where R is a 4-methoxybenzyl and X represents sulphur.

Stage A: 1,285 g of 2-chloro-4-methyl-5-nitropyridine (compound 1A) and 1,023 g of 4-fermentation was dissolved in 15 ml of anhydrous THF in a dry nitrogen atmosphere. To this solution was slowly added 207 mg of sodium hydride (95% oil). Then the reaction mixture was distributed between EtOAc and 0.1 G. of aqueous NaOH (to remove any quantity of unreacted thiol), and then the organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified on a Biotage column, elwira gradient from 1: 1 hexane/CH2Cl2up to 100% CH2Cl2and p is the best 1,90 g of compound 2A.

Stage: Approx 1,90 g of compound 2A and 1.88 g of iron powder was added to 20 ml of acetic acid in a dry nitrogen atmosphere. Then the reaction mixture was heated to 90°C for approximately 45 minutes to obtain an intermediate product 3A. About 1,90 g of the intermediate product 3A and 1,160 g of NaOH was dissolved in 20 ml of methanol in a dry nitrogen atmosphere for about 3.5 hours, then the reaction mixture was cooled to ambient temperature and was stirred at ambient temperature for 12 hours. The reaction mixture was concentrated under vacuum and then distributed between CH2Cl2and water. Then a layer of CH2Cl2washed with brine, dried over Na2SO4, was filtered and was concentrated under vacuum, obtaining the connection 4A.

Stage C: 1.54 g of compound 4A (without further purification) and 896 mg tetrafluoroborate ammonium was transferred into a 10 ml solution of acetone and water (1:1). Then the reaction mixture was placed in an ice bath (0°C)to which was added 600 μl of concentrated HCl, and then 514 mg of sodium nitrite. Then the reaction mixture was stirred for approximately 45 minutes, after which the precipitate was formed intermediate compounds 5A. The precipitate was collected, air-dried and then further dried by azeotropic distillation of ethanol and toluene, getting about 800 mg of compound 5A. About 800 mg of the compounds is of 5A (without further purification), 312 mg of potassium acetate and 190 mg of 18-crown-6 were dissolved/suspended in 5 ml of chloroform in a dry nitrogen atmosphere. Then the reaction mixture was distributed between CH2Cl2and water. Layer CH2Cl2washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified on a Biotage column, getting 388 mg of compound 6A.

Stage D: to 173.3 mg of compound 6A, 195 mg of potassium carbonate, 110 μl of 4-methoxybenzylamine and 10.5 mg of sodium iodide were dissolved/suspended in 1 ml of anhydrous DMF in a dry nitrogen atmosphere. The reaction mixture was heated to 85°C. for about 1.5 hours and then was cooled to ambient temperature. The reaction mixture was distributed between CH2Cl2and water, a layer of CH2Cl2washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified on a Biotage column, getting about 100 mg of compound 7a.

Example 2

Obtain 1-allyl-5-(4-pertenece)-1H-pyrazolo[3,4-C]pyridine (14a)

Figure 2 shows the reaction scheme for the synthesis of compound 14a having the General Formula II.

Stage A: In a round bottom flask 4-terfenol (compound 8A; 1.3 ml, 2.0 mmol) was diluted in 25 ml of anhydrous THF and the reaction mixture was cooled in an ice bath while slowly added tert-piperonyl potassium (12.0 ml, 12,0 the mol). Then added 2-chloro-4-methyl-5-nitropyridine (compound 1A; of 2.23 g, 12.5 mmol), the reaction mixture was heated to room temperature and was stirred for 12 hours. The reaction mixture was concentrated and the residue was diluted with CH2Cl2. The organic layer was washed 1 N. NaOH solution and brine, dried over Na2SO4and filtered. The filtrate was concentrated to a dark residue, which was purified on a column of silica Biotage 40 M, elwira a mixture of CH2Cl2/hexane (50:50) and receiving 2,84 g of compound 10A as a white solid.

Stage: In a round bottom flask compound 10A (2.6 g, 11 mmol) was diluted in 40 ml of EtOH, and then was added Pd(OH)2(230 mg, 2 mmol) followed by the addition of ammonium formate (3,3 g, 53 mmol). The reaction mixture was heated up to 80°C until the starting material 10A will not be spent that was determined by HPLC. The reaction mixture was filtered through paper, glass fiber and the filtrate was concentrated. The residue was diluted with CH2Cl2, the organic layer was washed with saturated NaHCOCand brine, dried over Na2SO4was filtered and concentrated, obtaining 1.92 g of compound 11a as a white solid.

Stage C: Compound 11a was made in connection 13A according to the method described in stage With Example 1. Compound 11a and tetrafluoroborate ammonium n is reasily in a solution of acetone and water (1:1). Then the reaction mixture was placed in an ice bath (0°C), was added concentrated HCl, then sodium nitrite, and a precipitate was formed. The precipitate was collected, air-dried and then further dried by azeotropic distillation of ethanol and toluene, obtaining an intermediate compound 12A. Connection 12A, potassium acetate and 18-crown-6 were dissolved/suspended in chloroform in a dry nitrogen atmosphere. Then the reaction mixture was distributed between CH2Cl2and water. Layer CH2Cl2washed with water and brine, dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified on a Biotage column, receiving the connection 13A.

Stage D: In a round bottom flask compound 13A was diluted in 4 ml of DMF, was then added 22 mg of NaH, and started bubbling. After stabilization was added 0.8 ml of allylbromide and the mixture was stirred in nitrogen atmosphere at room temperature. The reaction mixture was extinguished with water and then concentrated. The residue was diluted with CH2Cl2, the organic layer was washed with saturated sodium bicarbonate and brine, concentrated to film and dried. The resulting residue was purified on column (Biotage 12 M with silicon dioxide, elwira a mixture of 4% EtOAc:CH2Cl2and receiving the connection 14a.

Example 3

Obtain 3-[5-(4-torpedolike)pyrazolo[3,4-C]pyridin-1-yl]propane-1,2-diol is (15A)

Figure 3 shows the reaction scheme for the synthesis of compound 15A having the General Formula II. In a round bottom flask 79 mg (0.3 mmol) of compound 14a, obtained according to Example 2, was diluted in 2 ml of anhydrous CH2Cl2. In an atmosphere of nitrogen was added trimethylamine-N-oxide (27 mg, 0.35 mmol). After all solids were dissolved, was added OsO4(11 mg, 0.04 mmol) and the reaction mixture was stirred at room temperature. Then the reaction mixture was distributed between CH2Cl2and water. The organic layer was dried over Na2SO4, filtered and then concentrated to film. The film was purified on column (Biotage 12 M with silicon dioxide, elwira EtOAc and getting 82 mg of compound 15A.

Example 4

Obtain [5-(4-torpedolike)pyrazolo[3,4-C]pyridin-1-yl]acetaldehyde (16A)

Figure 4 shows the reaction scheme for the synthesis of compound 16A. 0.3 M solution NaIO4(2 ml) was combined with 1 g of silica gel to obtain the suspension. The suspension was diluted with 3 ml of CH2Cl2and added 82 mg (0.3 mmol) of compound 15A, obtained according to Example 3, in suspension with 1 ml of CH2Cl2and this suspension was stirred for 2 hours. After 3 hours the reaction mixture was filtered and the filler washed CH2Cl2. The filtrate was concentrated, receiving 35 mg of compound 16A as a brown film.

Example 5

Getting 5-(4-perfe is yloxy)-1-oxazol-5-ylmethyl-1H-pyrazolo[3,4-C]pyridine (17A)

Figure 5 shows the reaction scheme for the synthesis of compounds 17A having the General Formula II. In a round bottom flask compound 16A (32 mg, 0.11 mmol), obtained according to Example 4 was combined with the Meon (2 ml) and K2CO3(32 mg, 0.2 mmol)was then added dosimetrician (25 mg, 0.13 mmol) and the reaction mixture was heated to the temperature of reflux distilled. Then the reaction mixture was concentrated, the residue was diluted with CH2Cl2. CH2Cl2washed with water and 1 N. HCl, separated and concentrated. The resulting residue was purified on a column of silica, elwira a mixture of 80% EtOAc/CH2Cl2and receiving the connection 17A.

Example 6

Obtain 1-allyl-5-(4-perpenicular)-1H-pyrazolo[3,4-C]pyridine (18a)

Figure 6 shows the reaction scheme for the synthesis of compounds 18a having the General Formula II. In a round bottom flask with an inlet for nitrogen compound 6A, obtained according to Example 1, was diluted in 4 ml of DMF, was then added 22 mg of NaH, and started bubbling. After stabilization was added allylbromide (0.8 ml) and the reaction was stirred under nitrogen atmosphere at room temperature. The reaction mixture was extinguished with water and then concentrated. The residue was transferred into a CH2Cl2and washed with saturated sodium bicarbonate solution and brine, then dried up orange film. The film was purified on column (Biotage 12 M with what Maxidom silicon, elwira a mixture of 4% EtOAc/CH2Cl2and receiving the connection 18a.

Example 7

Obtain 1-N-substituted 7-azaindole (7b)

7 shows the reaction scheme for the synthesis of compound 7b having the General Formula III.

Stage A: In a round bottom flask 4-fermentation was diluted with anhydrous THF. The reaction mixture was cooled to 0°C in an ice bath and then the reaction mixture was slowly added 1.0 M of tert-piperonyl potassium in THF. The reaction mixture was stirred at 0°C for 10 minutes, then was added 5-chloro-3-methyl-2-nitropyridine (compound 1b), the reaction mixture was stirred at 0°C for 10 minutes and then heated to room temperature. The reaction mixture was concentrated, the residue was diluted with CH2Cl2. CH2Cl2washed with 1 N. NaOH solution and brine, dried over Na2SO4was filtered and the filtrate was concentrated to a yellow oil. The resulting residue was purified on column (Biotage 40 M, elwira a mixture of hexane/CH2Cl2(50:50) and receiving connection 3b.

Stage b: Compound 3b was reduced by iron powder and acetic acid as described in Example 1, stage b, when receiving the connection 4b.

Stage C: Compound 4b was then treated with tetrafluoroborate ammonia followed by treatment with concentrated HCl and sodium nitrite as described in Example 1, stage C receives the intermediate compound 5. Without purification, compound 5b was combined with potassium acetate and 18-crown-6 as described in Example 1, stage C receives the connection 6b.

Stage D: Each of the compounds 7b-1, 7b-2 and 7b-3 was obtained from compound 6b as shown in Fig.7. To obtain compounds 7b-1 compound 6b was treated with NaH and allylbromide as described in Example 6.

Example 8

Obtain 3-[5-(4-perpenicular)pyrazolo[4,3-b]pyridine-1-yl]Propylamine (8b)

On Fig shows the reaction scheme for the synthesis of compound 8b having the General Formula III. In a round bottom flask compound 7b-3, obtained according to Example 7 was diluted with CH2Cl2and triperoxonane acid. The reaction mixture was stirred until then, until the starting material used, which was determined by TLC, and then concentrated, the obtained residue was diluted with CH2Cl2. CH2Cl2washed with 1 N. NaOH and brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified on column (Biotage 12 M with silicon dioxide, elwira a mixture of 10% MeOH/CH2Cl2/NH4OH and getting the connection 8b.

Example 9

Getting 6-(4-perpenicular)-3-(4-methoxybenzyl)-1H-indazole (10C)

Figure 9 shows the reaction scheme for the synthesis of compound 10C having the General Formula IV.

Stage A: In a round bottom flask 6-nitroindole (compound 1C; 15.5 g, 95 mmol who) was dissolved in 1,4-dioxane (400 ml). Was added NaOH (3.8 g, 95 mmol) and the reaction mixture was stirred for 10 minut.zatem to the reaction mixture were added 266 ml 2 N. NaOH followed by the addition of iodine crystals (two servings, of 54.4 g for General add 214 mmol) and the reaction mixture was stirred for 12 hours. The reaction mixture was extinguished 10%citric acid and diluted with EtOAc. The organic layer is washed with 10%NaHSO3, NaHCO3and brine, dried over Na2SO4was filtered and concentrated, obtaining of 27.5 mg of compound 2C in the form of an orange solid.

Stage b: Compound 2C (5,18 g) was dissolved in 50 ml of anhydrous THF in a dry nitrogen atmosphere. To this solution was added 18.8 ml of 1.0 M solution of tert-butoxide potassium in THF. The reaction mixture was stirred for about 15 minutes, after which was added 3,20 ml of chlorotrimethylsilane. Then the reaction mixture was distributed between EtOAc and saturated aqueous NaHCO3. The organic phase was dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified on a Biotage column, receiving of 3.85 g of compound 3C as a yellow solid.

Stage C: Compound 3C (3,85 g), 7,66 g of TRANS-2-vanilinovoi acid, 531 mg of Pd(PPh3)4and 14,20 ml of 2.0 M Na2CO3was dissolved/suspended in 50 ml of dioxane in a dry nitrogen atmosphere. The reaction mixture was heated to pace atory reflux distilled during the night, then was cooled to ambient temperature and concentrated under vacuum. The obtained residue was distributed between CH2Cl2and water. Layer CH2Cl2dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified on a Biotage column, receiving the connection 4C.

Stage D: Compound 4C (573 mg) and 103 mg of 10% Pd/C was dissolved/suspended in 10 ml of EtOH/THF (3:1) in a dry nitrogen atmosphere. To this solution was added 500 μl of hydrazine and the reaction mixture was stirred for 2 hours at ambient temperature. Then the reaction mixture was filtered through celite, the celite washed with EtOH and CH2Cl2the filtrate was concentrated under vacuum. The obtained residue was distributed between CH2Cl2and water. Layer CH2Cl2washed with water and brine, dried over Na2SO4, was filtered and was concentrated under vacuum, obtaining the compound 5C.

Stage E: Compound 5C (of 2.51 g) was dissolved in a solution of 30 ml of acetic acid and 6 ml of water in a dry nitrogen atmosphere. To this reaction mixture was added 3.2 ml of concentrated HCl. The reaction mixture then was cooled to 0°C and added 535 mg sodium nitrite. Then the reaction mixture was stirred for about 30 minutes, after which the reaction mixture was added to 4.0 ml of an aqueous solution of 1.23 mg of sodium iodide and 885 mg yo is and. After about 4 hours the reaction mixture was extinguished aqueous saturated NaHCO3(slow addition) and then distributed among

CH2Cl2and water. Layer CH2Cl2dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified on a Biotage column, receiving 1,90 g of compound 6C.

Stage F: Compound 6C (1,90 g) and 509 mg dihydrate trimethylamine-N-oxide was dissolved in 30 ml of CH2Cl2in a dry nitrogen atmosphere. To this reaction mixture was added 51 mg of osmium tetroxide. The reaction mixture was stirred for 12 hours at room temperature. Added periodate sodium (1,71 g)dissolved in approximately 30 ml of water, and the reaction mixture was stirred for 1 hour. Then the reaction mixture was distributed between EtOAc and water. The EtOAc layer was washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified on a Biotage column, getting 889 mg of compound 7C.

Stage G: Compound 7C (460 mg) was added to 10 ml of anhydrous THF in a dry nitrogen atmosphere. The mixture was cooled to -78°C and then added 2,80 ml 4-methoxyphenylacetamide in THF (0.5 M). The reaction mixture was slowly heated to room temperature, reduce water and was distributed between EtOAc and saturated aqueous NaHCO3. The organic layer was dried over Na2SO4that filter is concentrated under vacuum. The resulting residue was purified on a Biotage column, receiving 320 mg of the intermediate product. The intermediate product (151 mg) was dissolved in 1 ml of CH2Cl2and 60 μl of triethylsilane in dry nitrogen atmosphere. To this reaction mixture was added 1 ml triperoxonane acid. Then the reaction mixture was concentrated under vacuum and the residue was distributed between CH2Cl2and aqueous saturated NaHCO3. Layer CH2Cl2dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified on a Biotage column, elwira gradient: from 10:1 hexane/CH2Cl2up to 100% CH2Cl2and getting to 76.6 mg of compound 8C.

Stage H: Compound 8C (151 mg), 80 μl of 4-florfenicol, 12.0 mg of copper powder and 300 μl of 5.0 M aqueous NaOH was added to 1 ml of anhydrous DMF in a sealed tube and then heated to 90°C for 16 hours. The reaction mixture was distributed between CH2Cl2and 1.0 M aqueous NaOH. The layer of CH2Cl2washed with 1.0 M aqueous NaOH, 3,0 N. water NH4OH and brine, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified on a Biotage column, getting to 76.6 mg of compound 9c.

Stage I: Compound 9c (76,6 mg) and 100 μl of Ethylenediamine was dissolved in 1.6 ml of 1.0 M solution of tetrabutylammonium fluoride in THF in an atmosphere of dry nitrogen. The reaction mixture was heated up to the temperature is elegnace for about 12 hours. Then the reaction mixture was cooled to room temperature and distributed between CH2Cl2and water. The layer of CH2Cl2washed with 10%aqueous citric acid and saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under vacuum. The residue was purified on a Biotage column, elwira gradient: from 5:1 hexane/CH2Cl2up to 100% of CH2Cl2receiving 25 mg of compound 10C.

Example 10

Obtaining [6-(4-perpenicular)-1H-indazol-3-yl]methanol (14C)

Figure 10 shows the reaction scheme for the synthesis of compound 14C having the General Formula IV.

Stage A: Compound 7C (520 mg)obtained according to Example 9, was dissolved in 5 ml of methanol in a dry nitrogen atmosphere. To this solution was added 98.3 mg of sodium borohydride. After about 30 minutes the reaction mixture was concentrated under vacuum and then distributed between CH2Cl2and water. Layer CH2Cl2dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified on a Biotage column, receiving the connection 12C.

Stage b: Compound 12C (151 mg), methanol, 100 μl of 4-florfenicol, 6.0 mg of copper powder and 250 μl of 5.0 M aqueous NaOH was added to 1 ml of anhydrous DMF in a sealed tube and then heated to 90°C for about 30 hours, after which the reaction mixture was cooled to temperatureincrease environment and distributed between CH 2Cl2and 1.0 M aqueous NaOH. Layer CH2Cl2washed with 1.0 M aqueous NaOH, 3,0 N. water NH4OH and brine, dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified on a Biotage column, elwira mixture of CH2Cl2/EtOAc (5:1) and getting to 67.9 mg of compound 13C.

Stage C: Compound 13C (67,9 mg) and 100 μl of Ethylenediamine was dissolved in 1.5 ml of tetrabutylammonium fluoride in THF (1.0 M) in a dry nitrogen atmosphere. The reaction mixture was heated to the temperature of reflux distilled for about 12 hours, then cooled to room temperature and distributed between CH2Cl2and water. Layer

CH2Cl2washed with 10%aqueous citric acid and saturated aqueous NaHCO3, dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified on a Biotage column, receiving 18 mg of compound 14C.

Example 11

Getting 6-(4-perpenicular)-3-methoxymethyl-1H-indazole (17c)

Figure 11 shows the reaction scheme for the connection 17c having the General Formula IV.

Stage A: Compound 12C (186 mg)obtained according to Example 10, step A, was dissolved in 5 ml of anhydrous THF in a dry nitrogen atmosphere. To this solution was added to 36.8 mg of sodium hydride (60% in oil), the reaction mixture was stirred for about 15 minutes and then the reaction mixture on balali 60 μl of methyliodide. After about 1 hour the reaction mixture was extinguished with water and distributed between CH2Cl2and aqueous saturated NaHCO3. Layer CH2Cl2dried over Na2SO4, filtered and concentrated under vacuum. The resulting residue was purified on a Biotage column, elwira mixture of CH2Cl2/EtOAc (100:1) and receiving 76,1 mg of compound 15C.

Stage b: Compound 15 was subjected to interaction with 4-portifino, copper powder and aqueous NaOH at Dempatem same way as described in stage b of Example 10, when receiving the connection 16C with the release of 22%.

Stage C: Compound 16C was subjected to interaction with tetrabutylammonium fluoride and Ethylenediamine in THF in the same way, which is described in the stage With Example 10, when receiving the connection 17c with the release of 53%.

Example 12

Getting 6-(4-pertenece)-3-methyl-1H-indazole (18C-2)

On Fig shows the reaction scheme for the synthesis of compounds having the General structure 18C and the General Formula IV. This example describes the synthesis of compound 18C-2, where Ar is a 4-forfinal.

Stage A: 2-Fluoro-4-hydroxyacetophenone (compound 19 (C); 1.42 g) and 1.40 g of potassium carbonate was dissolved/suspended in 30 ml of anhydrous DMF in a dry nitrogen atmosphere. To this reaction mixture was added 1.20 ml benzylbromide. After about 90 minutes the reaction mixture was heated to 65°C for about 45 minutes and then was cooled to on the th temperature. The reaction mixture was concentrated under vacuum, the residue was distributed between CH2Cl2and water. Layer CH2Cl2washed with water and brine, dried over Na2SO4, was filtered and was concentrated under vacuum, obtaining the connection 20s.

Stage b: Compound 20C (1,87 g) was added to 20 ml of ethylene glycol in an atmosphere of dry nitrogen. To this reaction mixture was added 250 μl of anhydrous hydrazine. The mixture was stirred for 1 hour at room temperature and then was heated up to 160°C for about 7 hours. Then the reaction mixture was cooled to room temperature and extinguished with water. Precipitated precipitated salt was collected and dried in the air and then further dried by azeotropic distillation of ethanol and toluene. Precipitated precipitated salt was diluted with anhydrous acetonitrile and then added 500 mg of dimethylaminopyridine and 311 mg of di-tert-BUTYLCARBAMATE (BOC-anhydride). After dissolution of all solids, the reaction mixture was concentrated under vacuum and the resulting residue was purified on a Biotage column, receiving 710 mg of the compound s.

Stage C: the Connection s (710 mg), 662 mg of ammonium formate and 223 mg of the catalyst Perlman (Pearlman, Pd(OH)2/C) was dissolved/suspended in 20 ml of ethanol in a dry nitrogen atmosphere. The reaction was heated to 85°C. for about 30 minutes and then filtered through celite. Celite prom is Wali EtOH and the combined filtrates were concentrated under vacuum. The obtained residue was distributed between CH2Cl2and saturated aqueous NaHCO3, dried over Na2SO4, was filtered and was concentrated under vacuum, obtaining the connection 22p.

Stage D: Compound 22 ° C (103 mg), 174 mg of 4-ftorhinolonovy acid, 75 mg of copper acetate (II) and 300 μl of triethylamine were dissolved/suspended in 2 ml of anhydrous CH2Cl2and to this solution was added 4Å molecular sieves. The reaction mixture was subjected to air for about 5 hours and then filtered and concentrated under vacuum. The resulting residue was purified on a Biotage column, elwira CH2Cl2and getting 85 mg of compound 23C.

Stage E: Compound 23C (85 mg) was dissolved in 2 ml of CH2Cl2/TFU (1:1) in a dry nitrogen atmosphere. The reaction mixture was stirred for about 30 minutes, after which it was concentrated under vacuum. The obtained residue was distributed between CH2Cl2and aqueous saturated NaHCO3. Layer CH2Cl2dried over Na2SO4, was filtered and was concentrated under vacuum, obtaining 18C-2.

For other compounds, having the General structure 18C, the connection 22s were subjected to interaction with phenylboron or appropriately substituted phenylboron, as described in stage D, and then treated as described in stage E.

Example 13/p>

Obtain 3-ethyl-6-(4-perpenicular)-1H-indazole (26C)

On Fig shows the reaction scheme for the synthesis of compound 26C having the General Formula IV.

Stage A: 4-Portifino (compound 24C; 900 μl) was dissolved in 40 ml of anhydrous THF in a dry nitrogen atmosphere. To this solution was added to 8.40 ml of tert-butoxide potassium in THF (1.0 M), and then 10 ml of anhydrous DMF. The reaction mixture was stirred at ambient temperature for 10 minutes, after which was added 1,43 g of 2,4-diplocraterion and the mixture was left to react for about 12 hours at room temperature. Then the reaction mixture was distributed between Et2O and water. Layer Et2O was washed with saturated aqueous

NaHCO3, dried over Na2SO4, was filtered and was concentrated under vacuum, obtaining the connection 25s.

Stage b: Compound 25C (2,34 g) and 260 μl of anhydrous hydrazine suspended/dissolved in ethylene glycol in an atmosphere of dry nitrogen. Then the reaction mixture was heated to about 70°C for about an hour, and then to about 160°C for about 12 hours. The reaction mixture was cooled to room temperature and put about 100 ml of water, then distributed between CH2Cl2and water. Layer CH2Cl2washed with water and aqueous saturated NaHCO3, dried over Na2SO4, filtered and concentrated the od vacuum. The resulting residue was purified on a Biotage column, receiving 770 mg of compound 26C.

Example 14

Getting 5-(4-pertenece)-1H-indazol-3-ylamine (34C)

On Fig shows the reaction scheme for the synthesis of compound 34C having the General Formula VI.

Stage A: In a round bottom flask to 5-fluoro-2-nitrobenzoic acid (compound 27C; 10.0 g, 54.0 per mmol) was added to 50 ml of the Meon and 200 ml of toluene. Added about 41 ml trimethylsilyldiazomethane (2.0 M) slowly with stirring. After the termination of allocation of bubbles reaction extinguished 1 ml of acetic acid. The reaction mixture was concentrated in vacuum, obtaining the compound 28C.

Stage: In a round bottom flask 4-terfenol (4.0 g, 35 mmol) was diluted in 100 ml of anhydrous THF. The reaction mixture was cooled to 0°C in an ice bath and then was slowly added 1.0 M of tert-piperonyl potassium in THF (35 ml, 35 mmol). The reaction mixture was stirred for 10 minutes and then was added the compound 28C (7,4 g, 37 mmol) in 50 ml of THF. The reaction mixture was stirred at 0°C for 10 minutes and then heated to room temperature and was stirred for approximately 12 hours. The reaction mixture was concentrated, the residue was diluted with CH2Cl2. CH2Cl2washed with 1 N. NaOH and brine, dried over Na2SO4, filtered and concentrated to oil. The oil was purified on column (Biotage 40 M, elwira a mixture of hexane/CH2Cl2 (50:50) and receiving connection 29s in the form of oil.

Stage C: In a round bottom flask connection 29s (40 g, 13 mmol) was added to 60 ml of the Meon and then adding 6 N. NaOH (4.3 ml, 26 mmol). The reaction mixture was stirred at room temperature for 4 hours, then concentrated and the resulting residue was diluted with 50 ml water. Added about 5 ml of 2 n HCl solution (pH is 2.0), and the solution was precipitated solid. The solid was dissolved in CH2Cl2, the organic layer was washed with brine, dried over Na2SO4, filtered and then concentrated in toluene, receiving the connection 30C in the form of a white solid.

Stage D: In a round bottom flask compound 30C was dissolved in 40 ml of thionyl chloride and heated to 90°C for 2 hours. The reaction mixture was cooled and then concentrated to a yellowish solid. The solid was dissolved in 20 ml of acetone and cooled to 0°C in an ice bath, then very slowly added 10 ml of NH4OH. The reaction mixture was extinguished with water and then concentrated. The obtained residue was extracted with CH2Cl2CH2Cl2dried over Na2SO4and concentrated, obtaining the connection s.

Stage E: In a round bottom flask connection s (3.4 g, 12.3 mmol) was dissolved in 100 ml of dichloroethane, and then added oxalicacid (5,4 ml, 62 mmol) and reaction the second mixture was heated to 55°C for 2 hours. The reaction mixture was concentrated, the resulting oil was stirred in water (50 ml) and then cooled to about 0°C in an ice bath (as was slowly added NH4OH to absorb excess oxalylamino). The reaction mixture was extracted with CH2Cl2, the organic layer was dried over Na2SO4was filtered and concentrated, obtaining the connection 32C in the form of a dark oil.

Stage F: In a round bottom flask compound 32C (2,21 g, 8.5 mmol) was diluted in 100 ml of EtOH and then added Pd(OH)2(300 mg) followed by the addition of ammonium formate (2.7 g, 43 mmol). The reaction mixture was heated to the temperature of reflux distilled for 18 hours, filtered through paper, glass fiber to remove Pd and the paper washed with EtOH. The filtrate was concentrated, the obtained residue was transferred into a CH2Cl2and washed with saturated sodium bicarbonate and brine, dried over Na2SO4was filtered and concentrated, obtaining compound 33 as a yellow solid.

Stage G: Compound 33C (280 mg, 1.3 mmol) were placed in a round bottom flask in a bath of ice water, and was added to 5 ml of the SPLA and 2.5 ml of N2O. the Reaction mixture is maintained at a temperature of 0°C, was added HCl (0.35 ml, 6 mmol) and after 5 minutes was added NaNO2(93 mg, 1.3 mmol). Approximately 1 hour was added chloride dihydrate tin (II) (554 mg, 2.5 mmol) and Rea is operating and the mixture was stirred for 30 minutes. Then the reaction mixture was heated to room temperature, concentrated and the residue was transferred into a CH2Cl2. The organic layer was washed with water and brine, filtered, dried over Na2SO4, filtered and concentrated to film. The film was rubbed with CH2Cl2and the solids collected. These solids were then heated in 1-butanol (120°C) in the tube under pressure for 12 hours to induce cyclization, and then the reaction was cooled and the solid collected by filtration to obtain compound 34C.

Example 15

Obtaining N-[6-(4-pertenece)-1H-indazol-3-yl]ndimethylacetamide (38C-1)

On Fig shows the reaction scheme for the synthesis of compounds 38, having the General Formula IV. This example describes the synthesis of compound 38C-1, where X represents the oxygen.

Stage A: 2-Fluoro-4-hydroxybenzonitrile (compound 35C-1; 1.40 g), 2.86 g of 4-ftorhinolonovy acid, 1.86 g of copper acetate (II) and 7,20 ml of triethylamine were dissolved/suspended in 100 ml of anhydrous CH2CI2to this reaction mixture was added 4Å molecular sieves. The reaction mixture was subjected to air through the drying cartridge and stirred at ambient temperature for 16 hours. The reaction mixture was filtered, the filtrate washed with 10%aqueous NaHSO4, 1 N. aqueous NaOH and brine, dried over Na2SO4, Phi is trevali and concentrated under vacuum, getting 530 mg of the compound 36C-1.

Stage: Connection 36C-1 (208 mg) and 150 μl of anhydrous hydrazine was dissolved in 5 ml of butanol. The reaction mixture was heated to the temperature of reflux distilled in an atmosphere of dry nitrogen for 15 hours, then was cooled to ambient temperature, concentrated under vacuum and triturated with ethyl ether. Received a pink solid (connection s-1) was collected by filtration, washed with ethyl ether and then dried in the air.

Stage C: the Connection s-1 (97 mg) and 40 μl of acetic anhydride suspended/dissolved in dichloromethane in a dry nitrogen atmosphere. The reaction mixture was heated to 60°C for about 1 hour, then cooled to room temperature and was stirred for 12 hours. A white precipitate (compound 38C-1) was collected by filtration under vacuum and then dried in the air.

Example 16

Getting 2-[6-(4-pertenece)-1H-indazol-3-yl]isoindole-1,3-dione (39C)

On Fig shows the reaction scheme for the synthesis of compound 39C having the General Formula VI.

Connection s-1 (660 mg) and 654 mg N-carbomethoxyamino suspended/dissolved in 15 ml of dichloroethane in a dry nitrogen atmosphere at room temperature for about 13 hours. After about 20 minutes the reaction mixture was heated to 65°C. for about 5.5 hours, after which it was cooled to room temperature and filter the I. A white precipitate (compound 39C) was washed with dichloromethane and then dried in the air.

Example 17

Obtaining 3-(1,3-dihydroindol-2-yl)-6-(4-pertenece)-1H-indazole (40s)

On Fig shows the reaction scheme for the synthesis of compound 40C having the General Formula VI. Compound 39C (25 mg)obtained according to Example 16, suspended in 1 ml of anhydrous THF in a dry nitrogen atmosphere. To this solution was added 1.0 ml of 1.0 M solution NR3in THF. The reaction mixture was stirred at room temperature for about 1 hour and then heated to the temperature of reflux distilled for 2 hours. Then the reaction mixture was cooled to room temperature and carefully added to 2.0 ml of methanol. The mixture was stirred for about 10 minutes and then concentrated under vacuum. The resulting residue was purified on a Biotage column, receiving 5 mg of compound 40C.

Example 18

Getting 5-(4-perpenicular)-1H-indazole (4d)

On Fig shows the reaction scheme for the synthesis of compounds 4d, having the General Formula VII.

Phase A: a Mixture of 6-iodine-1H-indazole (compound 1d) in CH3CN (11 ml) was treated with triethylamine and dimethylaminopyridine. After cooling to 0°C was added dropwise a solution of di-tert-BUTYLCARBAMATE (BOC-anhydride) in CH3CN (10 ml). After stirring at room temperature for 3 hours the reaction mixture koncentrira is whether in vacuum, the obtained residue was distributed between H2O and ether. the pH was brought to 1 N. HCl to 2, the organic phase was separated, dried (Na2SO4), filtered and concentrated in vacuum, obtaining the compound 2d in the form of oil.

Stage b: a Mixture of compound 2d in DMF (25 ml) was treated with 5 n KOH, Cu powder and ArSH. In this example, ArSH was a 4-portifino. The reaction mixture was heated at 110°C for 48 hours, then cooled to room temperature, concentrated in vacuo, acidified 1 N. HCl and was extracted into CH2Cl2. The organic layer was filtered through 1PS paper, concentrated in vacuo, the resulting residue was purified on a Biotage column, elwira 100% CH2Cl2, 5% Et2O/CH2Cl2and then 10% Et2O/CH2Cl2receiving a connection 4d.

Example 19

Getting 5-(4-perpenicular)-1-isopropyl-1H-indazole (5d-1)

On Fig shows the reaction scheme for the synthesis of compounds having the General structure 5d and having the General Formula VII. This example describes the synthesis of compounds 5d-1, where R represents isopropyl.

A solution of compound 4d was obtained according to Example 18, in THF (1 ml) was treated with powdered KOH followed by the addition of 18-crown-6 and RX. In this example, the RX was isopropylated. The reaction mixture was stirred at room temperature for 18 hours in the atmosphere is ore of nitrogen. Then the reaction mixture was diluted with CH2Cl2and filtered, the filtrate was concentrated in vacuo and the residue was diluted with CH2Cl2. The organic layer was washed with saturated aqueous NaHCO3, filtered through 1PS paper and concentrated in vacuum. The resulting residue was purified on a Biotage column, elwira a mixture of hexane/Et2O (4:1) and receiving the connection 5d-1 as a yellow oil.

Example 20

Getting 5-iodine-1-(4-methoxybenzyl)-1H-indazole (8d-1)

On Fig shows the reaction scheme for the synthesis of compounds 8d. This example describes the synthesis of compound 8d-1, where Ar1represents a 4-methoxyphenyl.

Stage A: a Suspension of 5-aminoindazole (compound 6d) in 6 M HCl solution (150 ml) was cooled to 0°C and treated dropwise with a solution of NaNO2in water (15 ml). After stirring at 0°C for 30 minutes the reaction mixture was added to a cold solution of KI in water (105 ml). The mixture was left to warm to room temperature, and stirring was continued at room temperature for 18 hours. The mixture was suppressed to 10%Na2S2O3and was extracted with Et2O. two-phase mixture was filtered, the insoluble solids were washed with water and dried in vacuum over night. The organic phase was separated and optionally washed with aqueous saturated NaHCO3, water, filtered through 1PS paper, evaporated vacuume to pink residue.

Stage b: a Solution of compound 1d in DMF was treated To a2CO3with the subsequent addition of substituted or unsubstituted benzylchloride at room temperature in a nitrogen atmosphere. In this example, benzylchloride was a 4-methoxybenzylidene. The mixture was heated at 100°C for 48 hours under nitrogen atmosphere. The mixture was treated with 0.2 EQ. NaI (123 mg) and heating was continued for 18 hours. The solvent is evaporated in vacuum and the residue was transferred into a CH2Cl21 N. HCl. The organic layer was separated, washed with aqueous saturated NaHCOCand concentrated to obtain oil. The oil was purified on Biotage column, elwira gradient hexane/Et2About (from 3:1 to 3:2), and receiving a connection 8d-1.

Example 21

Getting 5-(4-permentantly)-1-(4-methoxybenzyl)-1H-indazole (10d-1)

On Fig shows the reaction scheme for the synthesis of compounds 10d having the General Formula IX. This example describes the synthesis of compound 10d-1, where Ar1represents a 4-methoxyphenyl and Ar2is a 4-forfinal.

Phase A: a Mixture of compound 8d, 5 N. COHN, copper powder and Ar2SH in a solution of water and DMF was heated under reflux for about 18 hours. In this example, Ar2SH was a 4-portifino. Then the mixture was cooled to room temperature, acidified 1 N. HCl and was extracted with CH2Cl2 . The organic layer was filtered through 1PS paper, concentrated in vacuo, the resulting residue was purified on a cartridge with silica gel SepPak, elwira a mixture of hexane/Et2O (4:1) and receiving the connection 9d.

Stage b: a Solution of compound 9d in acetone (0.2 ml)containing MgSO4, was treated with a solution of NaIO4and KMnO4in water (0.2 ml) and the reaction mixture was stirred at room temperature for 18 hours. Then the reaction mixture was treated with aqueous sodium bisulfite and extracted with CH2Cl2. The organic layer was filtered through 1PS paper and concentrated in vacuum, obtaining 2.1 mg of compound 10d in the form of a yellow oil.

Example 22

Getting 5-(4-ferbedollwine)-1-(4-methoxybenzyl)-1H-indazole

On Fig shows the reaction scheme for the synthesis of compound 11d-1, having the General Formula VIII. A solution of compound 9d-1, obtained according to Example 21, in a mixture of water/acetonitrile (1:1) was treated with NaIO4and the reaction mixture was stirred at room temperature for 18 hours. Then the reaction mixture was filtered and the filtrate was concentrated in vacuum. The obtained residue was distributed between water and CH2Cl2. The organic layer was separated, filtered through 1PS paper, concentrated in vacuo and purified on a cartridge with silica gel SepPak, elwira gradient hexane/Et2O (4:1, 2:1 and 1:1) and produces the connection 11d-1.

Example 23

Getting 1-benzazolyl-5-(4-perpenicular)-1H-indazole (13d)

On Fig shows the reaction scheme for obtaining compounds 13d having the General Formula VII.

Stage A: a Solution of 5-iodinate (compound 1d) in pyridine was treated with benzosulphochloride at room temperature in a nitrogen atmosphere for 18 hours. The reaction mixture was concentrated in vacuo, the residue was transferred into a CH2Cl21 N. HCl. The organic layer was separated, filtered through 1PS filter paper and concentrated in vacuum. The resulting residue was purified on a Biotage column, elwira a mixture of hexane/Et2O (5:1) and receiving the connection 12d.

Stage b: a Mixture of compound 12d, 5 N. COHN, copper powder and 4-portifino in a solution of water and DMF was heated under reflux for about 18 hours. Then the mixture was cooled to room temperature, acidified 1 N. HCl and was extracted with CH2Cl2. The organic layer was filtered through 1PS paper, concentrated in vacuo, the resulting residue was purified on a cartridge with silica gel SepPak, elwira a mixture of hexane/Et2O (4:1) and receiving the connection 13d.

Example 24

Obtain 3-chloro-6-phenoxybenzyl[d]isoxazol (8E-1)

On Fig shows the reaction scheme for the synthesis of compounds 8E having the General Formula V. this example describes the synthesis of compounds 8E-1, where Ar2is the battle phenyl.

Stage A: a Solution of 4-fluoro-2-hydroxybenzoic acid (compound 1E) in the Meon was slowly treated with concentrated H2SO4and then was heated under reflux for 12 days. Then the reaction mixture was concentrated in vacuo to a yellow oil and oil carried in CH2Cl2. The organic layer was washed with saturated aqueous NaHCO3brine and water, dried over Na2SO4, filtered and concentrated in vacuum, obtaining 12.7 g of compound 2E in the form of oil of amber.

Stage b: a Solution of compound 2E, K2CO3and benzylchloride in DMF (200 ml) was heated at 95°C for 18 hours. The mixture was filtered and the filtrate was concentrated in vacuo to a yellow oil. The oil was purified on Biotage column, elwira a mixture of hexane/EtOAc (7:2), and receiving and 19.4 g of compound 3E as a clear oil.

Stage C: a Solution of compound 3 in DMSO (2 ml) was treated with K2CO3then add Ar2HE at room temperature in a nitrogen atmosphere. In this example, Ar2HE was a phenol. The mixture was heated at 90°C for 3 days under nitrogen atmosphere. Was slowly added water (1 ml) and the product was extracted with EtOAc. The aqueous layer was separated and was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated in in the cosmology vacuum to a dark oil. The oil was purified on Biotage column, elwira a mixture of hexane/Et2About (6:1) and receiving the connection 4E-1 in the form of a clear oil.

Stage D: 1.0 M solution of compound 4E-1 in the Meon (30 ml) was purged with nitrogen and was treated with 20% Pd(OH)2/C (15 wt.% equal to 297 mg). After the reaction mixture was passed additional amount of nitrogen and then stirred at room temperature for 2 days in an atmosphere of hydrogen. The catalyst was filtered and washed Meon. The filtrate was evaporated in vacuo to a clear oil which was purified on a Biotage column, elwira a mixture of 5% Et2O/hexane and receiving connection 5e-1 in the form of a clear oil.

Stage E: 3 M NaOH (9 ml) was added to a solution of NH2OH·HCl in water (14 ml) followed by a solution of compounds 5e-1 in dioxane (10 ml). The cloudy mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. The obtained transparent mixture was cooled in an ice bath, acidified with 2 M HCl and was extracted with EtOAc. The combined organic layers were washed with brine, filtered through 1PS paper and evaporated in a vacuum, getting 235 mg of beige solid. This solid is triturated in a mixture of hexane/EtOAc (4:1) and the resulting white solid (compound 6E-1) was collected by filtering.

Stage F: the Solution carbonyldiimidazole in THF was added to a solution of compound 6E-1 in THF, which was heated with about ATiM fridge and this heating was continued for 18 hours. Then the mixture was concentrated in vacuum, diluted with water, acidified 1 N. HCl and was extracted with CH2Cl2. The organic layer was filtered through 1PS paper and evaporated in vacuum, obtaining the compound 7E-1 in the form of a pale yellow solid or foam.

Stage G: a Suspension of compound 7E-1 in POCl3was treated with triethylamine at room temperature and the mixture was heated at 110°C for 6 hours. The mixture was cooled to room temperature and was poured into a beaker containing ice water. The product was extracted with CH2Cl2, filtered through 1PS paper and evaporated in vacuo to give 10 mg of the compounds 8E-1 in the form of oil of amber.

Example 25

Getting 3,6-diphenoxybenzene[d]isoxazol (9F-1)

On Fig shows the reaction scheme for the synthesis of compounds 9F, having the General Formula V. this example describes the synthesis of compound 9F-1, where Ar1represents phenyl and Ar2represents phenyl. A solution of compounds 8E-1, obtained according to Example 24, in DMF (1 ml) was added to a mixture of NaH and phenol (1 ml) in DMF. The reaction mixture was heated at 110°C for 18 hours. The solvent is evaporated in vacuum and the residue was distributed between 1 N. HCl and CH2Cl2. The organic layer was separated and filtered through 1PS paper. Evaporation of solvent gave a brown oil, which was purified on a cartridge with silica the LEM Sep Pak, elwira a mixture of hexane/Et2O (4:1) and receiving the connection 9F-1 in the form of a clear oil, which was hardened with the formation of long white needles.

Example 26

Receive (4-methoxyphenyl)-(6 phenoxybenzyl[d]isoxazol-3-yl)amine (10E-1)

On Fig shows the reaction scheme for the synthesis of compounds 10E having the General Formula V. this example describes the synthesis of compound 10E-1, where Ar1represents a 4-methoxyphenyl and Ar2represents phenyl. The solution Ar1NH2in THF was cooled to -78°C and treated with n-butyllithium in nitrogen atmosphere. In this example, Ar1NH2represented aniline. After stirring at -78°C for 20 minutes was added a solution of compounds 8E-1, obtained according to Example 25, in THF under nitrogen atmosphere. The mixture was slowly heated to room temperature, then extinguished aqueous saturated NH4Cl and was extracted with NH4Cl. The organic layer is washed with 1 N. hydrochloric acid and water, filtered through 1PS paper, concentrated in vacuum and purified on the cartridge Sep-Pak, elwira a mixture of hexane/Et2Oh (4:1) and receiving the connection 10E-1 as a yellow oil.

Example 27

Getting oxime (2,4-differenl)-(1-isobutyl-1H-indazol-5-yl)methanone (7f-1)

On Fig shows the reaction scheme for the synthesis of compounds 4f, having the General formula X, and compounds 7f, having the General Formula XII. This example describes sintezavana 7f-1, where R1represents isobutyl, R2represents H, and Ar is a 2,4-differenl.

Stage a: Tetrafluoroborate ammonium (20,97 g, 200 mmol) was dissolved in an aqueous solution of acetic acid (500 ml Asón/250 ml water) and cooled to 0°C. was Sequentially added 4-bromo-2-methylaniline (compound 1f, 18,61 g, 100 mmol) and 42 ml of concentrated aqueous HCl (36% (wt./wt.), 12 N., 500 mmol). The mixture was stirred for 20 minutes at 0°C and then added NaNO2(to 7.59 g, 110 mmol). The reaction was stirred for 1 hour at 0°C and warmed up to room temperature. After 16 hours at room temperature the mixture was concentrated under reduced pressure, the residue was subjected to azeotropic distillation with toluene and dried under high vacuum. The solid is suspended in 500 ml of CHCl3and added COAs (of 12.76 g, 130 mmol) and 18-crown-6 (of 7.93 g, 30 mmol). The reaction mixture was stirred for 1.5 hours at room temperature. The mixture was washed with water, dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure, obtaining 30 g of 5-bromo-1H-indazole (2f) as a yellow-brown solid. The crude substance was used without further purification.

Stage b: the Crude compound 2f (100 mmol) was dissolved in 250 ml of DMF. Added To2CO3(20.7 g, 150 mmol) and 1-bromo-2-methylpropan (163 ml, 150 mmol). The mixture was heated to 120°C. in a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. To the residue was added water (200 ml) and CH2Cl2(200 ml) and was intensively stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure, getting about 30 grams of the crude substance. The crude substance was purified by chromatography (ether/hexane: from 1:9 to 1:4), receiving 12,87 g of compound 3f-1 in the form of a dark red oil output 50,8% for stages a and B. MS IER (+), found: m/z 253 and 255 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.87 (m, 1H), 7.43 (m, 1H), 7.29 (m, 1H), 7.29 (m, 1H), 4.15 (m, 2H), 2.33 (m, 1H), 0.92 (m, 6N).

Stage C: Compound 3f-1 (to 121.0 mg, 0,478 mmol) was dissolved in 2 ml of ether and cooled to -78°C. To this solution was added tert-BuLi (1.70 M in pentane, of 0.59 ml, 1,004 mmol). The reaction mixture was additionally stirred for one hour at -78°C. was Added 2,6-differentally (58 μl, 0,526 mmol) at -78°C. the cooling bath was removed and the reaction mixture was slowly heated to room temperature. The reaction extinguished 10 ml of water. The layers were separated and the aqueous layer was extracted several times CH2Cl2. The combined extracts were dried over anhydrous MgS 4was filtered through celite, concentrated under reduced pressure and purified by chromatography using a mixture of ether/hexane (1:1) and receiving the connection 4f-1 in the form of a pale yellow crystalline solid (104,5 mg, yield 69,1%). MS IER (+), found: m/z 317 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.73 (s, 1H), 7.56 (m, 1H), 7.40~7.35 (m, 2H), 6.91 (m, 2H), 6.78 (m, 1H), 6.22 (m, 1H), 4.15 (m, 2H), 2.39~2.26 (m, 2H, overlap with IT), 0.92 (m, 6N).

Stage D: Compound 4f-1 (316,3 mg, 1.00 mmol), triacetonediamine (445,3 mg, 1.05 mmol) and 10 ml of CH2Cl2was stirred for 2 hours at room temperature. The reaction mixture was extinguished 10 ml of a saturated solution of K2CO3and the layers were separated. The aqueous layer was extracted with CH2Cl2the combined extracts were dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure. The crude product was purified by chromatography using a mixture of ether/hexane (1:2), and receiving 237,6 mg of compound 5f-1 in the form of a viscous light brown oil (yield of 75.6%). MS IER (+), found: m/z 315 (M+1).1H-NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 8.11 (s, 1H), 7.99 (m, 1H), 7.60 (m, 1H), 7.47 (m, 1H), 7.03 (m, 1H), 6.94 (m, 1H), 4.21 (m, 2H), 2.37 (m, 1H), 0.95 (m, 6N).

Stage E: a Mixture of compound 5f-1 (96,7 mg, 0,308 mmol), hydroxylamine-HCl (compound 6f-1; 213,8 mg, 3,076 mmol) and 5 ml of pyridine was stirred at room temperature for 65 hours. Excess the pyridine was removed under reduced pressure. The residue was dissolved in 20 ml of CH2Cl2. White solid precipitated, the mixture was transferred into a separating funnel and washed with 1 N. HCl. The organic layer was dried over anhydrous MgSO4was filtered through celite, concentrated under reduced pressure and purified by chromatography using a mixture of ether/hexane (1:2) and getting to 66.5 mg of compound 7f-1 in the form of a pale yellow foamy solid (yield 65,5%), which was a mixture of isomers (1:4). MS IER (+), found: m/z 330 (M+1).

Example 28

Obtaining On-atylosia (2,4-differenl)-1-isobutyl-1H-indazol-5-yl)methanone (7f-3)

This example describes the synthesis of compound 7f-3, having the General Formula XII, as shown in Fig, where R1represents isobutyl, R2represents ethyl and Ar is a 2,4-differenl. Compound 5f, where R1represents isobutyl and Ar is a 2,4-differenl received in accordance with the stages A-D of Example 27. A mixture of compound 5f (43,3 mg, was 0.138 mmol), hydrochloric salt of O-ethylhydroxylamine (53,8 mg, 0,551 mmol) and 2 ml of dry pyridine was stirred at room temperature. The mixture was stirred for 90 hours at room temperature. The excess pyridine was removed under reduced pressure. To the residue was added 2 ml of water and 2 ml of CH2Cl2. The layers were separated and the aqueous layer was extracted with C 2Cl2. The combined extracts washed with 1 N. HCl (20 ml), dried over MgSO4was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (1:4), and receiving of 21.2 mg of compound 7f-3 as an oil (yield of 43.1%), which was a mixture of isomers (1:9).

Example 29

Obtain tert-butyl ether {2-[(2,4-differenl)-(1-isobutyl-1H-indazol-5-yl)methylenedioxy]ethyl}carbamino acid (7f-5)

This example describes the synthesis of compound 7f-5, having the General Formula XII, as shown in Fig, where R1represents isobutyl, R2represents a

CH2CH2NHBoc and Ar is a 2,4-differenl. Compound 5f, where R1represents isobutyl and Ar is a 2,4-differenl received in accordance with the stages A-D of Example 27. A mixture of compound 5f (50 mg, strength of 0.159 mmol), tert-butyl methyl ether (2-aminoacetyl)carbamino acid, obtained as described in Example 30 (112 mg, 0,636 mmol), pyridine (1.5 ml) and a drop of 6 N. HCl-MeOH (mixture of concentrated HCl and the Meon (1:1 by volume)) was stirred at room temperature for 64 hours. The excess pyridine was removed under reduced pressure, the residue was purified by chromatography using a mixture of ether/hexane (1:2), and receiving a connection 7f-5 with the release of 63.9%.

Example 30

Obtain tert-butile the CSOs ether (2-aminoacetyl)carbamino acid

The reaction scheme for the synthesis of tert-butyl methyl ether (2-aminoacetyl)carbamino acid shown in Fig.

Phase A: a Mixture of tert-butyl methyl ether (2-bromacil)carbamino acid (2,77 g, KZT 12.39 mmol), N-hydroxyphthalimide (2,02 g, KZT 12.39 mmol), tea (5,18 ml, 37,16 mmol) and 25 ml of DMF was stirred at room temperature for 64 hours. The mixture was diluted with 100 ml of water. White solid precipitated and was collected by filtration. The solid was dissolved in CH2Cl2(50 ml) and the solution washed with 1 N. HCl (20 ml), saturated NaHCO3(20 ml), water (20 ml) and brine (20 ml). The solution was dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure, getting 0,842 g white solids (yield 22%).

Stage b: tert-Butyl ether [2-(1,3-dioxo-1,3-dihydroindol-2-yloxy)ethyl]carbamino acid (0,842 g, 2,749 mmol) was dissolved in 20 ml of CH2Cl2and added methylhydrazine (150 μl, at 2,776 mmol) at room temperature. Once added methylhydrazine, white precipitate was formed. The reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure, getting 0,496 g viscous oil (exit 102%). The crude substance was used without further purification.

Example 31

Getting oxime (4-ft is henyl)-(1-isobutyl-1H-indazol-5-yl)methanone (7f-2)

This example describes the synthesis of compound 7f-2, having the General Formula XII, as shown in Fig, where R1represents isobutyl, R2represents h, and Ar is a 4-forfinal.

Stages a and b: Compound 3f was obtained as described in stages a and b of Example 27.

Stage C: Compound 3f-2 (616,3 mg, 2,436 mmol) was dissolved in 20 ml of ether and cooled to -78°C. To the solution was added dropwise t-BuLi (1.70 M in pentane, 2,94 ml). After adding tert-BuLi and the mixture was stirred for 30 minutes at -78°C. was added dropwise 4-forbindelse (290 μl, 2,678 mmol) at -78°C. the Mixture was slowly heated to room temperature. The reaction extinguished CH2Cl2the combined extracts were washed with brine (20 ml), dried over anhydrous MgSO4was filtered through celite and concentrated, receiving 750 mg of compound 4f-2 as a yellow-brown solid. The solid was purified by chromatography using a mixture of ether/hexane (1:1) and receiving 554 mg of compound 4f-2 as a light brown solid (yield of 76.3%).

Stage D: Compound 4f-2 (100,6 mg of 0.337 mmol) was dissolved in 10 ml of CH2Cl2to the solution was added a reagent dess-Martin (Dess Martin periodinane) (triacetoxyborohydride; to 150.2 mg, 0,354 mmol). After 25 minutes at room temperature the mixture became turbid. The reaction mixture was stirred for another 30 minutes in to the room temperature and transferred into a separating funnel. The mixture was diluted with 30 ml of CH2Cl2and washed with saturated NaHCO3. Yellow insoluble solid is formed between the organic and aqueous layers were removed. The organic layer was dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (1:1) and receiving compound 5f-2 in the form of an oil with a yield of 85.4%.

Stage E: a Mixture of compound 5f-2 (to 41.6 mg, 0,140 mmol) and hydroxylamine hydrochloride (20.0 mg, 0,281 mmol) in 1 ml of pyridine was stirred overnight at room temperature. After one day study by HPLC showed about 50%conversion. Was added 5 equivalents of NH2OH-HCl and the reaction was stirred for 72 hours. The excess pyridine was removed under reduced pressure, the residue was purified by chromatography using a mixture of ether/hexane (1:2), and receiving of 31.4 mg of compound 7f-2 (output 71,8%) as a mixture of isomers (1:2). MS IER (+), found: m/z 312 (M+1).

Example 32

Obtaining On-atylosia (4-forfinal)-(1-isobutyl-1H-indazol-5-yl)methanone (7f-4)

This example describes the synthesis of compound 7f-4, having the General Formula XII, as shown in Fig, where R1represents isobutyl, R2represents ethyl and Ar is a 4-forfinal.

Stage A-D: Compound 5f-2 was obtained as described in adiah A-D of Example 31.

Stage E: a Mixture of compound 5f-2 (a 51.2 mg, 0,173 mmol), O-ethylhydroxylamine-HCl (67,4 mg, 0,691 mmol) and 2 ml of dry pyridine was stirred at room temperature. The mixture was stirred for 90 hours at room temperature. The excess pyridine was removed under reduced pressure. To the residue was added 2 ml of water and 2 ml of CH2Cl2. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined extracts washed with 1 N. HCl (20 ml), dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (1:4), and receiving of 47.1 mg of compound 7f-4 in the form of an oil (yield of 80.3%), which was a mixture of isomers (1:2). MS IER (+), found: m/z 340 (M+1).

Example 33

Obtain tert-butyl ether {2-[(4-forfinal)-(1-isobutyl-1H-indazol-5-yl)methylenedioxy]ethyl}carbamino acid (7f-6)

This example describes the synthesis of compound 7f-6, having the General Formula XII, as shown in Fig, where R1represents isobutyl, R2represents a

CH2CH2NHBoc and Ar represents 4-forfinal.

Stage A-D: Compound 5f-2 was obtained as described in stages A-D of Example 31.

Stage E: a Mixture of compound 5f-2, tert-butyl methyl ether (2-aminoacetyl)carbamino acid, obtained as described in Example 30 (120 mg, 0,675 mmol),pyridine (1.5 ml) and a drop of 6 N. HCl/MeOH (mixture of concentrated HCl and the Meon (1:1 by volume)) was stirred at room temperature for 39 hours. The excess pyridine was removed under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (1:1) and receiving 65,6 mg (yield of 85.5%) of compound 7f-6 in the form of a pale yellow oil.1H-NMR analysis showed that the compound 7f-6 was a mixture of isomers in a ratio of 1:1,8.

Example 34

Obtaining On-benzyloxy (2,4-differenl)-(1-isobutyl-1H-indazol-5-yl)methanone (7f-7)

The synthesis of compound 7f-7, having the General Formula XII, shown in Fig.

Stage A: Compound 5f was obtained as described in Example 27.

Stage b: Compound 5f (76,9 mg, 0,244 mmol) was dissolved in 2 ml of pyridine was added the hydrochloride of O-benzylhydroxylamine (of € 0.195 g, 1,22 mmol). The mixture was stirred at room temperature for 2 days and then concentrated under reduced pressure. The residue is suspended in CH2Cl2the suspension was filtered through a cotton plug, and purified by chromatography using a mixture of ether/hexane (1:4) and receiving 0,069 g of compound 7f-7 as a mixture of E - and Z-isomers (1:4, output 67.2 per cent). MS IER (+), found: m/z 420 (M+H).

Example 35

Receiving O-(2-amino-ethyl)oxime (2,4-differenl)-(1-isobutyl-1H-indazol-5-yl)methanone (7f-8)

The synthesis of compound 7f-8, having the General Formula XII, shown in Fig.

Stage A: Compound 7f-5 a which were given, as described in Example 29.

Stage b: Compound 7f-5 (32,3 mg, 0,0656 mmol) was dissolved in 2 ml of a mixture of CH2Cl2:TFU (1:1) and the mixture was stirred for 0.5 hour at room temperature. The whole mixture was concentrated under reduced pressure and dried under high vacuum over night. The residue was dissolved in 5 ml of CH2Cl2and washed with saturated K2CO3. The organic layer was dried over MgSO4was filtered through celite and concentrated under reduced pressure, getting to 18.6 mg of compound 7f-8 in the form of an oil (yield 76,1%). MS IER (+), found: m/z 373 (M+H).

Example 36

Obtaining Q-methyloxime (4-forfinal)-(1-isobutyl-1H-indazol-5-yl)methanone (7f-9)

The synthesis of compound 7f-9, having the General Formula XII, shown in Fig.

Stage A: Compound 5f-2 was obtained as described in Example 31.

Stage b: Compound 5f-2 was dissolved in tert-butyl methyl ether ethyl) - carbamino acid (120 mg, 0,675 mmol), pyridine (1.5 ml) was added one drop in 2 ml of pyridine and MeONH2-HCl. The mixture was stirred at room temperature for 2 days and then concentrated under reduced pressure. The residue is suspended in CH2Cl2the suspension was filtered through a cotton plug, and purified by chromatography using a mixture of ether/hexane (1:4), and receiving of 33.5 mg of fraction 1, 1.0 mg fraction 2 and 17.7 mg of a mixed fraction, comprising in total of 52.2 mg preprogram the Oia 7f-9 (yield 58%). MS IER (+), found: m/z 344 (M+H).

Example 37

Receiving O-(2-amino-ethyl)oxime (4-forfinal)-(1-isobutyl-1H-indazol-5-yl)methanone (7f-10)

The synthesis of compound 7f-10, having the General Formula XII, shown in Fig.

Stage A: Compound 7f-6 was obtained as described in Example 33.

Stage b: Compound 7f-6 (50.5 mg, 0,107 mmol) was dissolved in 4 ml of CH2Cl2to the solution was added triperoxonane acid (4 ml). After 0.5 hours at room temperature the mixture was concentrated under reduced pressure and dried under high vacuum over night. The oil was dissolved in 10 ml of CH2Cl2and washed with saturated solution of K2CO3. The organic layer was dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure, getting to 34.9 mg of compound 7f-10 in the form of oil, containing a mixture of isomers (1:2, the yield of 88.6%). MS IER (+), found: m/z 355 (M+H).

Example 38

Obtaining On-methyloxime (2,4-differenl)-(1-methyl-1H-indazol-5-yl)methanone (7f-11)

The synthesis of compound 7f-11, having the General Formula XII, shown in Fig.

Stage A: Compound 9f-1 was obtained as described in Example 74.

Stage b: Compound 9f-1 (622 mg, 2,409 mmol), K2CO3(499 mg, 1.50 equiv.) and DMF (10 ml) were placed in a test tube Slinka (Schlenk). Added logmean (225 μl, 1.50 EQ.) and the tube tightly closed. The tube was heated to 100°C. After 23 hours the ri 100°C. the mixture was cooled to room temperature and opened the tube. The mixture was transferred into a round bottom flask and concentrated under reduced pressure. The remainder extinguished with water and CH2Cl2the layers were separated. The aqueous layer was extracted with CH2Cl2. The combined organic extracts were dried over MgSO4was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (1:1) and getting 176 mg of compound 5f-13 as a yellow solid (yield 26.9 percent). MS IER (+), found: m/z 273 (M+H).

Stage C: Compound 5f-13 (0,040 g, 0.147 mmol) and hydrochloric salt of methoxylamine (0,123 g of 1.47 mmol) were placed in the reaction vessel 5 ml) was added 1 ml of pyridine. The reaction vessel was tightly closed and heated to 50°C. After 18 hours the excess pyridine was removed under reduced pressure and to the residue was added water. The aqueous mixture was extracted with CH2Cl2. The combined extracts washed with 1 N. HCl and saturated NaHCO3, dried over MgSO4was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (1:1) and receiving 0,033 g of compound 7f-11 (exit 74,6%) as a viscous oil containing a mixture of isomers (1:9).

MS IER (+), found: m/z 302 (M+H).

Example 39

Getting oxime (2,4-differenl)-[1-(2,2,2-triptorelin)-1H-indazol-5-yl]methanone (7f-12)

Synthesis connected to the I 7f-12, having the General Formula XII, shown in Fig.

Stage A: Compound 5f-11 was obtained as described in Example 74.

Stage b: Compound 5f-11, hydroxylamine-HCl (0,051 g, 0,735 mmol) and 1 ml of pyridine was placed in a vessel and the mixture was heated to 50°C. Through a 14.5 hours, the pyridine was removed under reduced pressure, the residue was diluted with CH2Cl2and water. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined extracts washed with 1 N. HCl and saturated NaHCO3, dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (1:1) and getting to 22.9 mg (yield 87,7%) of compound 7f-12 as a white foam containing a mixture of isomers (1:4).

MS IER (+), found: m/z 356 (M+H).

Example 40

Obtaining On-methyloxime (2,4-differenl)-[1-(2,2,2-triptorelin)-1H-indazol-5-yl]methanone (7f-13)

The synthesis of compound 7f-13, having the General Formula XII, shown in Fig.

Stage A: Compound 5f-11 was obtained as described in Example 74.

Stage b: Compound 5f-11 (0,023 g 0,067 mmol), hydroxylamine-HCl (0,056 g, 0,676 mmol) and 1 ml of pyridine was placed in a vessel and the mixture was heated to 50°C. Through a 14.5 hours, the pyridine was removed under reduced pressure and the residue was diluted with CH2Cl2and water. The layers were separated and the aqueous layer was extracted with CH2Cl2. United extrac the s washed with 1 N. HCl and saturated NaHCO3, dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (1:1) and receiving a 19.6 mg of compound 7f-13 (yield of 78.5%) as a white foam containing a mixture of isomers (1:4). MS IER (+), found: m/z 370 (M+H).

Example 41

Getting oxime (2,4-differenl)-(1-methanesulfonyl-1H-indazol-5-yl)methanone (7f-14)

The synthesis of compound 7f-14, having the General Formula XII, shown in Fig.

Stage A: Compound 9f-1 was obtained as described in Example 74.

Stage b: Compound 9f-1 (258 mg, 1.00 mmol) was dissolved in 5 ml of pyridine was added methanesulfonamide (81 μl, 1.05 mmol). After 15 hours the excess pyridine was removed under reduced pressure and to the residue was added water. The aqueous mixture was extracted with CH2Cl2. The combined extracts washed with 1 N. HCl and saturated NaHCOC, dried over MgSO4was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (1:1) and receiving 238,1 mg of compound 5f-14 as a white solid (total yield of 70.8%).1H-NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 8.23 (s, 1H), 8.18 (d, 1H), 8.07 (d, 1H), 7.66 (q, 1H), 7.06 (t, 1H), 6.95 (t, 1H), 3.36 (s, 3H).

Stage C: Compound 5f-14 (to 0.060 g, 0,177 mmol), hydroxylamine-HCl (0,123 g, 1.77 mmol) and 1 ml of pyridine was placed in a vessel and the mixture n is gravely to 50°C. After 26 hours the excess pyridine was removed under reduced pressure and the residue was diluted with CH2Cl2and water. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined extracts washed with 1 N. HCl and saturated NaHCO3, dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (2:1). The compound was dissolved in a mixture of Meon-CH2Cl2and was applied on the column, receiving or 37.4 mg of compound 7f-14 (exit 60,0%) as a white powder containing a mixture of isomers (1:2). MS IER (+), found: m/z 352 (M+H).

Example 42

Obtaining On-methyloxime (2,4-differenl)-(1-methanesulfonyl-1H-indazol-5-yl)methanone (7f-15)

The synthesis of compound 7f-15, having the General Formula XII, shown in Fig.

Stage A: Compound 5f-14 was obtained as described in Example 41.

Stage b: Compound 5f-14 (to 0.060 g of 0.250 mmol), methoxylamine-HCl (0,209 g of 2.50 mmol) and 1 ml of pyridine was placed in a vessel, and the mixture was heated to 50°C. After 26.5 hours the excess pyridine was removed under reduced pressure and the residue was diluted with CH2Cl2and water. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined extracts washed with 1 N. HCl and saturated NaHCO3, dried over anhydrous MgSO4was filtered through celite and concentrated under reduced on the no. The residue was purified by chromatography using a mixture of ether/hexane (1:1) and getting to 44.8 mg of compound 7f-15 in the form of a white solid containing a mixture of isomers (1:4, yield 49%). MS IER (+), found: m/z 366 (M+H).

Example 43

Obtaining On-methyloxime (2,4-differenl)-(1H-indazol-5-yl)methanone (7f-16)

The synthesis of compound 7f-16, having the General Formula XII, shown in Fig.

Stage A: Compound 9f-1 was obtained as described in Example 74.

Stage b: Compound 9f-1 and hydrochloric salt of methoxylamine were placed in a 5 ml reaction vessel was added 1 ml of pyridine. The reaction vessel was tightly closed and heated to 50°C. After 18 hours the excess pyridine was removed under reduced pressure and to the residue was added water (10 ml). The aqueous mixture was extracted with CH2Cl2. The combined extracts washed with 1 N. HCl (20 ml) and saturated NaHCO3(20 ml), dried over MgSO4was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (1:1) and receiving of 33.0 mg of compound 7f-16 (exit 74,6%) as a viscous oil containing a mixture of isomers (1:4). MS IER (+), found: m/z 288 (M+H).

Example 44

Getting oxime (1-allyl-1H-indazol-5-yl)-(2,4-differenl)methanone (7f-17)

The synthesis of compound 7f-17, having the General Formula XII, shown in Fig.

Stage A: Compound 9f-1 was obtained as described is Example 74.

Stage b: Compound 9f-1 (0,516 g, 2.00 mmol), K2CO3(0,0415 g, 3.00 mmol), DMF (10 ml) and allylbromide (0,363, 3.00 mmol) was added in a test tube Slinka. The tube was tightly closed and heated to 100°C. After 19 hours, the supernatant solution decantation and the salt washed with DMF (5 ml × 3). The combined supernatant solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2and washed with water. The aqueous layer was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (1:1) and getting to 142.1 mg of compound 5f-12 (exit 23,8%). MS IER (+), found: m/z 299 (M+H).

Stage C: Compound 5f-12 (0,027 g 0,090 mmol), hydroxylamine-HCl (0,063 g, 0.90 mmol) and pyridine (1 ml) were placed in the reaction vessel and the mixture was heated to 50°C. After 21.5 hours, the reaction mixture was transferred into a separating funnel and was added water (10 ml). The mixture was extracted with CH2Cl2. The combined extracts washed with 1 N. HCl (20 ml) and saturated NaHCO3, dried over MgSO4was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (1:1) and receiving of 23.1 mg (yield of 81.6%) of compound 7f-17 in the form of a foamy solid, containing the his mixture of isomers (1:3). MS IER (+), found: m/z 356 (M+H).

Example 45

Obtaining On-methyloxime (1-allyl-1H-indazol-5-yl)-2,4-differenl)methanone (7f-18)

The synthesis of compound 7f-18, having the General Formula XII, shown in Fig.

Stage A: Compound 5f-12 was obtained as described in Example 44.

Stage b: Compound 5f-12 (0,027 g 0,090 mmol), methoxylamine-HCl (0,063 g, 0.90 mmol) and pyridine (1 ml) were placed in the reaction vessel and the mixture was heated to 50°C. After 21.5 hours, the reaction mixture was transferred into a separating funnel and was added water (10 ml). The mixture was extracted with CH2Cl2. The combined extracts washed with 1 N. HCl and saturated NaHCO3, dried over MgSO4was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (1:1) and getting to 24.7 mg of compound 7f-18 (exit 83,1%) in the form of oil, containing a mixture of isomers (1:3). MS IER (+), found: m/z 328 (M+H).

Examples 46-61 describe the synthesis of amide compounds of this invention having the General Formula XIII. On Figa-30C shows the reaction scheme for the synthesis of compounds having the General structure 11g.

Example 46

Getting amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (11g-1)

Stage A: 1-Fluoro-3-methylbenzo (compound 1g; 18.7 g, 170 mmol) were placed in a three-neck flask with a volume of 500 ml and cooled to -78°C. Then slowly with a syringe is obavljale a solution of tert-butoxide potassium (11,0 g, 170 mmol) in THF. After 10 minutes the reaction was slowly added tert-BuLi (19,0 g, 170 mmol) in pentane via cannula under nitrogen atmosphere. After stirring for 2.5 hours the reaction was suppressed by a large number of crushed dry ice, cleaned the bath to -78°C and manually stirred with a metal spatula until then, until dark brown substance turns into a very light yellow suspension. After 20 minutes of hand mixing was added about 500 ml of water and this reaction mixture was stirred. Then the reaction mixture was washed with Et2O and then acidified 6 N. HCl to pH less than 3 and was extracted with Et2O. the Organic layer was washed with brine, dried over MgSO4, filtered and concentrated to obtain 10 mg of compound 2g (yield 45%).1H-NMR (400 MHz, CDCl3) δ 7.90 (t, 1H), 7.04 (d, 1H), 6.97 (d, 1H), 2.39 (s, 3H).

Stage b: Compound 2g (8.0 g, 52 mmol) was added in a 500 ml flask and cooled to a temperature salt baths with ice. Added H2SO4(150 ml) and the mixture was stirred. Then the reaction mixture for 10 minutes bury a mixture of freshly prepared H2SO4(6.11 g, of 62.3 mmol) and HNO3(5,2 g, 83 mmol). After 3 hours at 0°C. the reaction was completed, the mixture was added to 1500 ml of a mixture of ice/ice water and was stirred for 1 hour. The reaction was filtered, washed several times with cold water and dried on the high vacuum, receiving 8 g of compound 3g (yield 80%).1H-NMR (400 MHz, CDCl3) δ 8.74 (d, 1H), 7.20 (d, 1H), 2.69 (s, 3H).

Stage C: the 3g Connection (8 g, 40.0 mmol) was dissolved in Meon and slowly added H2SO4(20,0 g, 201 mmol). The reaction mixture was heated to 65°C for 20 hours. The reaction mixture was concentrated, diluted with ice and water, and treated with ultrasound, was filtered, washed several times with cold water and dried under high vacuum for 2 days. The crude substance (compound 4g) was used directly in the next stage.1H-NMR (400 MHz, CDCl3) δ 8.66 (d, 1H), 7.01 (d, 1H), 3.95 (s, 3H), 2.68 (s, 3H).

Stage D: a 4g Connection (5,4 g, 41 mmol) was added to THF and cooled to 0°C. was Added 4-terfenol (5,1 g, 45 mmol). Then portions was added NaH (60% in oil, 1.8 g, 45 mmol). After 1 hour the reaction mixture was heated to room temperature and was stirred for about 2 hours. The reaction mixture was concentrated and extinguished a large excess of 0.5 N. Na2CO3to pH 7.0. The reaction mixture was treated with ultrasound for 30 minutes, filtered and optionally washed with buffer and N2O. the Reaction mixture was dried under high vacuum for 1 hour, then added to THF and MgSO4for drying, was filtered and was evaporated to obtain approximately 8 g of compound 5g (yield 75%).1H-NMR (400 MHz, DMSO-d6) δ 8.66 (d, 1H), 7.01 (d, 1H), 3.95 (s, 3H), 2.68(s, 3H).

Stage E: Compound 5g (10.0 g, 33.0 mmol) and zinc (11,0 g, 164 mmol) was added to methanol and stirred. Was slowly added acetic acid (4.0 g, 66 mmol). The reaction mixture was stirred overnight, treated with ultrasound and was passed through celista concentrated to obtain about 14 g of compound 6g and by-products of zinc. At the next stage, used a crude substance.

Stage F: Compound 6g (9.0 g, 33.0 mmol), tetrafluoroborate ammonium (6.0 g, 65 mmol) and HCl (17.0 g, 163 mmol) was added to 200 ml of Asón/N2About (2:1) and treated with ultrasound. The substance scraped from the walls round-bottom flask was added NaNO2(2.7 g, 3 mmol). The reaction was treated with ultrasound for 10 minutes, turning dark brown mixture until it formed a new precipitate (salt of the product). The reaction mixture was left to mix for 4 hours. The reaction mixture was concentrated in quick vacuum at 65°C, then transferred in toluene and evaporated to dryness. The crude substance (compound 7g) directly used in the next stage without any processing.

Stage G: Compound 7g (11,0 g, 31 mmol), potassium acetate (5.2 g, 53 mmol) and 18-crown-6 (0.1 EQ.) was added to the chloroform and treated with ultrasound for 10 minutiae proceeded overnight at room temperature. The column was placed in a filter the social flask 1000 ml, consisting of approximately 2 inches (5 cm) of silica gel, 2 inches (5 cm) of celite located on top of the silica gel, a sheet of filter paper on top of celite and 0.5 inch (1.3 cm) of sand on top of the filter paper. The column was washed CHCl3. The crude substance was applied on the column directly in CHCl3that column was suirable CHCl3until then, not yet identified a large number of yellow substances. Then the product was suirable from the column with an ethyl acetate ethyl acetate and eluate were combined and concentrated to obtain about 7 g of compound 8g (yield 95%). MS IER (+), found: m/z 287 (M+H).

Stage H: Compound 8g (0,250 g, 0.87 mmol) was added to dry DMF and to this mixture was added isobutyramide (0.15 ml, 1.2 mmol) and K2CO3(0.5 g, 3.6 mmol). Then this reaction mixture was placed in a vessel covered with a membrane, and stirred at 95°C during the night. The substance was purified column chromatography using a mixture of diethyl ether/hexane (1:1) and receiving of 0.1 g of compound 9g-1 (yield 33%). MS IER (+), found: m/z 343 (M+H).

Stage I: the Connection 9g-1 (0,100 g, 0,292 mmol) were placed in a mixture of 1 N. LiOH/THF (1:1) and stirred at 55°C. After 4 hours, THF evaporated and added 1 N. HCl. The reaction mixture was treated with ultrasound and filtered, allocating approximately 0.075 g of compound 10g (yield 78%) as a pure substance. MS IER (+), found: m/z 329 (M+H).

Stage : a Solution of compound 10g (20 mg, 0.061 mmol) in THF (1 ml) was treated with CBI (1.2 EQ.) at room temperature in a nitrogen atmosphere. After stirring for 18 hours the reaction mixture was treated with 0.5 M NH4in dioxane (of 0.11 ml, 0.67 mmol). After 18 hours the solvent was left to slowly evaporate and the mixture was purified on a cartridge Sep-Pak, elwira CH2Cl2- 5% MeOH/CH2Cl2and getting 2.2 mg of compound 11g-1 in the form of an oil with a yield of 12%.1H-NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1H), 7.99 (s, 1H), 7.73 (s, 1H), 7.57 (s, 1H), 7.26 (s, 1H), 7.20 (m, 2H), 7.05 (m, 2H), 4.27 (d, 2H), 2.24 (m, 1H), 0.86 (d, 6H).

Example 47

Obtain [5-(4-pertenece)-1-isobutyl-1H-indazol-6-yl]morpholine-4-ylmethanone (11g-2)

A solution of 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (compound 10g, obtained as described in Example 46) in THF was treated with carbonyl diimidazol (1.2 EQ.) at room temperature in a nitrogen atmosphere. After stirring for 18 hours the reaction mixture was treated with morpholine (1 EQ.). After 18 hours the solvent was left to slowly evaporate, and the residue was purified on a cartridge Sep-Pak, elwira gradient: from 100% CH2Cl2to MeOH/CH2Cl2and receiving the connection 11g-2 in the form of an oil with a yield of 93%.

Example 48

Obtain [5-(4-pertenece)-1-isobutyl-1H-indazol-6-yl]-4-methylpiperazin-1-yl)methanone (11g-3)

A solution of 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (link is 10g, obtained as described in Example 46) in THF was treated with carbonyl diimidazol (1.2 EQ.) at room temperature in a nitrogen atmosphere. After stirring for 18 hours the reaction mixture was treated with 1-methylpiperazine (1 EQ.). After 18 hours the solvent was left to slowly evaporate, the residue was purified on a cartridge Sep Cancer, elwira gradient: from 100% CH2Cl2to 5% MeOH/CH2Cl2and receiving the connection 11g-3 in the form of an oil with a yield of 95%.

Example 49

Obtain (1-benzylpiperidine-4-yl)amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (11g-4)

A solution of 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (compound 10g, obtained as described in Example 46) in THF was treated with carbonyl diimidazol (1.2 EQ.) at room temperature in a nitrogen atmosphere. After stirring for 18 hours the reaction mixture was treated with 1-benzylpiperidine-4-aluminum (1 EQ.). After 18 hours the solvent was left to slowly evaporate, the residue was purified on a cartridge Sep Cancer, elwira gradient: from 100% CH2Cl2to 5% MeOH/CH2Cl2and receiving the connection 11g-4 in the form of an oil with a yield of 97%.

Example 50

Receive (2-benzylamino)amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (11g-5)

A solution of 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (compound 10g received the CSOs, as described in Example 46) in THF was treated with carbonyl diimidazol (1.2 EQ.) at room temperature in a nitrogen atmosphere. After stirring for 18 hours the reaction mixture was treated with N1-benzyliden-1,2-diamine (1 equiv.). After 18 hours the solvent was left to slowly evaporate, the residue was purified on a cartridge Sep Cancer, elwira gradient: from 100% CH2Cl2to MeOH/CH2Cl2and receiving the connection 11g-5 in the form of an oil with a yield of 100%.

Example 51

Receive (2-piperidinoethyl)amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (11g-6)

A solution of 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (compound 10g, obtained as described in Example 46) in THF was treated with carbonyl diimidazol (1.2 EQ.) at room temperature in a nitrogen atmosphere. After stirring for 18 hours the reaction mixture was treated with 2-piperidine-1-ylethylamine (1 EQ.). After 18 hours the solvent was left to slowly evaporate and the residue was purified on a cartridge Sep Cancer, elwira gradient: from 100% CH2Cl2to 5% MeOH/CH2Cl2and receiving the connection 11g-6 in the form of an oil with a yield of 100%.

Example 52

Receive (2-pyrrolidin-1-retil)amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (11g-7)

A solution of 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (compound 10g obtained, as is isano in Example 46) in THF was treated with carbonyl diimidazol (1.2 EQ.) at room temperature in a nitrogen atmosphere. After stirring for 18 hours the reaction mixture was treated with 2-pyrrolidin-1-ylethylamine (1 EQ.). After 18 hours the solvent was left to slowly evaporate, the residue was purified on a cartridge Sep Cancer, elwira gradient: from 100% CH2Cl2to 5% MeOH/CH2Cl2and receiving the connection 11g-7 in the form of an oil with a yield of 63%.

Example 53

Receive (3-morpholine-4-ylpropyl)amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (11g-8)

A solution of 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (compound 10g, obtained as described in Example 46) in THF was treated with carbonyl diimidazol (1.2 EQ.) at room temperature in a nitrogen atmosphere. After stirring for 18 hours the reaction mixture was treated with 3-morpholine-4-iproplatin (1 EQ.). After 18 hours the solvent was left to slowly evaporate, the residue was purified on a cartridge Sep-Pak, elwira gradient: from 100% CH2Cl2to 5% MeOH/CH2Cl2and receiving the connection 11g-8 in the form of an oil with a yield of 70%.

Example 54

Receive (3-dimethylaminopropyl)amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (11g-9)

A solution of 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (compound 10g, obtained as described in Example 46) in THF was treated with carbonyl diimidazol (1.2 EQ.) at room temperature in a nitrogen atmosphere. the donkey stirring for 18 hours the reaction mixture was treated with N-1 DIMETHYLPROPANE-1,3-diamine (1 equiv.). After an additional 18 hours, the solvent was left to slowly evaporate, the residue was purified on a cartridge Sep-Pak, elwira gradient: from 100% CH2Cl2to 5% MeOH/CH2Cl2and receiving the connection 11g-9 in the form of an oil with a yield of 44%.

Example 55

Receive (2-dimethylaminoethyl)amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (11g-10)

A solution of 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (compound 10g, obtained as described in Example 46) in THF was treated with carbonyl diimidazol (1.2 EQ.) at room temperature in a nitrogen atmosphere. After stirring for 18 hours the reaction mixture was treated with N1-dimethylated-1,2-diamine (1 equiv.). After an additional 18 hours, the solvent was left to slowly evaporate, the residue was purified on a cartridge Sep-Pak, elwira gradient: from 100% CH2Cl2up to 5% of the Meon/CH2Cl2and receiving the connection 11g-10 in the form of an oil with a yield of 58%.

Example 56

Obtaining methyl-(1-methylpiperidin-4-yl)amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (11g-11)

A solution of 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (compound 10g, obtained as described in Example 46) in THF was treated with carbonyl diimidazol (1.2 EQ.) at room temperature in a nitrogen atmosphere. After stirring for 18 hours the reaction mixture was treated metal-methylpiperidin-4-yl) - amine (1 EQ.). After an additional 18 hours, the solvent was left to slowly evaporate, the residue was purified on a cartridge Sep-Pak, elwira gradient: from 100% CH2Cl2to 5% MeOH/CH2Cl2and receiving the connection 11g-11 in the form of an oil with a yield of 3%.

Example 57

Obtain [3-(methylpentylamino)propyl]amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (11g-12)

A solution of 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (compound 10g, obtained as described in Example 46) in THF was treated with carbonyl diimidazol (1.2 EQ.) at room temperature in a nitrogen atmosphere. After stirring for 18 hours the reaction mixture was treated with N1-methyl-N1-phenylpropane-1,3-diamine (1 equiv.). After an additional 18 hours, the solvent was left to slowly evaporate, the residue was purified on a cartridge Sep-Pak, elwira gradient: from 100% CH2Cl2up to 5% of the Meon/CH2Cl2and receiving the connection 11g-12 in the form of an oil with a yield of 78%.

Example 58

Obtain tert-butyl ester 3-{[5-(4-pertenece)-1-isobutyl-1H-indazol-6-carbonyl]amino}pyrrolidin-1-carboxylic acid (11g-13)

A solution of 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid (compound 10g, obtained as described in Example 46) in THF was treated with carbonyl diimidazol (1.2 EQ.) at room temperature in a nitrogen atmosphere. After stirring for 18 hours the reaction is ionic mixture was treated with tert-butyl ether 3-aminopyrrolidine-1-carboxylic acid (1 EQ.). After an additional 18 hours, the solvent was left to slowly evaporate, the residue was purified on a cartridge Sep-Pak, elwira gradient: from 100% CH2Cl2up to 5%

Meon/CH2Cl2and receiving the connection 11g-13 in the form of an oil with a yield of 94%.

Example 59

Receive (2-dimethylaminoethyl)amide 5-(4-pertenece)-1-(2,2,2-triptorelin)-1H-indazol-6-carboxylic acid (11g-14)

Stage A: Compound 8g was obtained as described in Example 46.

Stage b: Compound 8g, 2-bromo-1,1,1-trifluoroethane, K2CO3and DMF were combined and the reaction mixture was stirred overnight at 75°C. was Added 2 additional equivalent of 2-bromo-1,1,1-triptorelin and the reaction mixture was stirred at 90°C. was Added a few equivalents of 2-bromo-1,1,1-triptorelin and the reaction mixture was stirred at 50°C for 72 hours. The reaction mixture was concentrated, transferred in toluene and purified column chromatography (elwira a mixture of hexane/Et2A)receiving 80 mg of compound 9g-2 (yield 24%). MS IER (+), found: m/z 369 (M+H).

Stage C: the Connection 9g-2 (0.075 g, 0.20 mmol) were placed in a mixture of 1 N. LiOH/THF (1:1) and was stirred for 18 hours at room temperature. THF is evaporated and 1 N. HCl was added to the reaction mixture, which was then treated with ultrasound and filtered, allocating approximately 0,070 g of compound 10g-2 (yield 97%) as a pure substance. MS IER (+), about arozena: m/z 355 (M+H).

Stage D: Compound 10g-2 (0.03 g, 0,847 mmol), benzotriazol-1,3-diol (0,022 g, 0.25 mmol) and (3-dimethylaminopropyl)ethylcarbodiimide (0,011 g, 0.10 mmol) were added to dichloroethane and stirred for 5 minutes. Then was added N1-dimethylated-1,2-diamine is 0.019 g, 0.10 mmol) and the reaction mixture was stirred for 3 hours. The reaction mixture was concentrated, transferred in dichloromethane, was dried under high vacuum and purified by reversed-phase HPLC according to the method (see below), receiving 25 mg of compound 11g-14 (yield 56%) as a salt TFU.1H-NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.10 (s, 1H), 7.90 (s, 1H), 7.12 (m, 4H), 5.02 (q, 2H), 3.93 (br, 2H), 3.34 (br, 6H), 2.72 (s, 6H).

Example 60

Receive (2-dimethylaminoethyl)amide 5-(4-pertenece)-1-methyl-1H-indazol-6-carboxylic acid (11g-15)

Stage A: Compound 8g was obtained as described in Example 46.

Stage b: Compound 8g, logmean and K2CO3added to DMF and heated to approximately 75°C. After 48 hours the reaction mixture was filtered to remove

To2CO3concentrated, transferred in toluene and purified column chromatography (elwira mix Et2O/hexane (1:1))to give 70 mg of compound 9g-3 (output 36,7%). MS IER (+), found: m/z 301 (M+H).

Stage C: the Connection 9g-3 (0.075 g, 0.25 mmol) were placed in a mixture of 1 N. LiOH/THF (1:1) and was stirred for 18 hours at room temperature. THF is evaporated and 1 N. HCl was added reaktsionnoi mixture, which was then treated with ultrasound and filtered, getting about to 0.060 g of compound 10g-3 (yield 84%) as a pure substance. MS IER (+), found: m/z 287 (M+H).

Stage D: Compound 10g-3 (0,030 g, 0,105 mmol), benzotriazol-1,3-diol (0,028 g, 0.31 mmol) and (3-dimethylaminopropyl)ethylcarbodiimide is 0.019 g, 0.13 mmol) were added to dichloroethane and stirred for 5 minutes.

Then was added N1-dimethylated-1,2-diamine (0,024 g, 0.13 mmol) and the reaction mixture was stirred for 3 hours. The reaction mixture was then concentrated, transferred in dichloromethane, was dried under high vacuum and purified by reversed-phase HPLC according to the method of Example 86, receiving 25 mg of compound 11g-15 (yield 52%) as a salt TFU.1H-NMR (400 MHz, CDCl3) δ 8.44 (br, 1H), 8.21 (s, 1H), 7.85 (s, 1H), 7.05 (m, 4H), 4.15 (s, 3H), 3.90 (br, 2H), 3.30 (br, 2H), 2.92 (s, 6H).

Example 61

Receive (2-dimethylaminoethyl)amide 5-(4-pertenece)-1H-indazol-6-carboxylic acid (11g-16)

Stage A: Compound 8g was obtained as described in Example 46.

Stage b: Compound 8g was stirred in THF, was added one volume equivalent of 1 N. LiOH and the reaction mixture was stirred at 60°C for 6 hours. The reaction mixture was concentrated, extinguished 1 N. HCl, cooled, treated with ultrasound, filtered and dried, obtaining and 0.40 g of compound 10g-4 (84% pure substance). MS IER (+), found: m/z 287 (M+H).

Stage C: the Connection 10g-4 (0,030 is, 0,110 mmol), benzotriazol-1,3-diol (0,029 g, 0.33 mmol) and (3-dimethylaminopropyl)ethylcarbodiimide (at 0.020 g, 0.13 mmol) were added to dichloroethane and stirred for 5 minutes. Then was added N1-dimethylated-1,2-diamine (0.025 g, 0.13 mmol) and the reaction mixture was stirred for 3 hours. The reaction mixture was evaporated, transferred in dichloromethane, was dried under high vacuum and purified by reversed-phase HPLC according to the method of Example 86, receiving 25 mg of compound 11g-16 (51%yield) as a salt TFU.1H-NMR (400 MHz, CDCl3) δ 8.45 (br, 1H), 8.22 (s, 1H), 7.91 (s, 1H), 7.09 (s, 1H), 7.06 (m, 3H), 3.85 (br, 2H), 3.20 (br, 2H), 2.90 (s, 6H).

Examples 62-67 describe the synthesis of the alcohol compounds having the General Formula IX. On Fig shows the reaction scheme of the synthesis of shared connections 4f.

Example 62

Receiving (2,4-differenl)-(1-isobutyl-1H-indazol-5-yl)methanol (4f-1)

This example describes the synthesis of compounds 4f-1, as shown in Fig, where R1represents isobutyl and Ar is a 2,4-differenl.

Stage a: Tetrafluoroborate ammonium (20,97 g, 200 mmol) was dissolved in an aqueous solution of acetic acid (500 ml Asón/250 ml water) and cooled to 0°C. was Sequentially added 2-methyl-4-bromaniline (compound 1f; 18,61 g, 100 mmol) and 42 ml of concentrated aqueous HCl (36% (wt./wt.), 12 N., 500 mmol). The mixture was stirred for 20 minutes at 0°C was added NaNO2(to 7.59 g, 110 mmol). Reaction the second mixture was stirred for 1 hour at 0°C and warmed up to room temperature. After 16 hours at room temperature the mixture was concentrated under reduced pressure, the residue was subjected to azeotropic distillation with toluene and dried under high vacuum. The solid is suspended in 500 ml of CHCl3and added COAs (of 12.76 g, 130 mmol) and 18-crown-6 (of 7.93 g, 30 mmol). The reaction mixture was stirred for 1.5 hours at room temperature. The mixture was washed with water, dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure, obtaining 30 g of 5-bromo-1H-indazole (compound 2f) as a yellow-brown solid. The crude substance was used without further purification.

Stage b: the Crude 5-bromo-1H-indazole (compound 2f; 100 mmol) was dissolved in 250 ml of DMF. Added To2CO3(20.7 g, 150 mmol) and 1-bromo-2-methylpropan (16,3 ml, 150 mmol). The mixture was heated to 120°C. in a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. To the residue was added water (200 ml) and CH2Cl2(200 ml) and was intensively stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure, getting about 30 grams of the crude substance. The crude substance was purified in pore the STV chromatography (ether/hexane: from 1:9 to 1:4), getting 12,870 g of compound 3f as dark red oil with a yield of 50.8 per cent in the stages a and B. MS IER (+), found: m/z 253 and 255 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.87 (m, 1H), 7.43 (m, 1H), 7.29 (m, 1H), 7.29 (m, 1H), 4.15 (m, 2H), 2.33 (m, 1H), 0.92 (m, 6N).

Stage C: Compound 3f (to 121.0 mg, 0,478 mmol) was dissolved in 2 ml of ether and cooled to -78°C. To the solution was added tert-BuLi (1.70 M in pentane, of 0.59 ml, 1,004 mmol). The reaction mixture was stirred for another hour at -78°C. was Added 2,4-differentally (58 μl, 0,526 mmol) at -78°C. the cooling bath was removed, the reaction mixture was slowly warmed to room temperature. The reaction extinguished 10 ml of water. The layers were separated, and the aqueous layer was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4was filtered through celite, concentrated under reduced pressure and purified by chromatography using a mixture of ether/hexane (1:1) and receiving of 104.5 mg of compound 4f-1 (output 69,1%) as a pale yellow crystalline solid. MS IER (+), found: m/z 317 (M+1).1H-NMR (400 MHz, CDCI3) δ 7.96 (s, 1H), 7.73 (s, 1H), 7.56 (m, 1H), 7.40~7.35 (m, 2H), 6.91 (m, 2H), 6.78 (m, 1H), 6.22 (m, 1H), 4.15 (m, 2H), 2.39~2.26 (m, 2H, overlap with IT), 0.92 (m, 6H).

Example 63

Receive (4-chloro-2-forfinal)-(1-isobutyl-1H-indazol-5-yl)methanol (4f 7)

This example describes the synthesis of compounds 4f-7, as shown in Fig, where R1represents isobutyl and Ar is predstavljaet a 4-chloro-2-forfinal.

Stage a: 5-Bromo-1-isobutyl-1H-indazole (compound 3f) were obtained as described in Example 62, stages a-C.

Stage C: Compound 3f (132 mg, 0,521 mmol) in 1 ml of ether was cooled to -78°C. To the solution was added tert-BuLi (1.70 M in pentane, of 0.64 ml, 1.10 mmol). After 1 hour at -78°C was added a solution of 4-chloro-2-forventelige (and 86.8 mg, 0,548 mmol) in 1 ml of ether and the mixture was slowly heated to room temperature. The mixture is extinguished with water (5 ml) and the layers were separated. The aqueous layer was extracted with CH2Cl2the combined extracts were dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure. The crude substance was purified by chromatography using a mixture of ether/hexane (1:2), and receiving 43,7 mg of compound 4f-7 as a pale yellow solid (yield 25.2 percent). MS IER (+), found: m/z 333 and 335 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.72 (s, 1H), 7.56 (m, 1H), 7.39~7.35 (m, 2H), 7.18 (m, 1H), 7.05 (m, 1H), 6.21 (m, 1H), 4.15 (m, 2H), 2.37~2.27 (m, 2H, overlap with IT), 0.91 (m, 6H).

Example 64

Receive (2-chloro-4-forfinal)-(1-isobutyl-1H-indazol-5-yl)methanol (4f-8)

This example describes the synthesis of compounds 4f-8, as shown in Fig, where R1represents isobutyl and Ar represents 2-chloro-4-forfinal.

Stage a: 5-Bromo-1-isobutyl-1H-indazole (compound 3f) were obtained as described in Example 62, stages a-C.

Stage C: a Solution of compound 3f (for 116.2 mg, 0,459 IMO the ü) in 1 ml of ether was cooled to -78°C. To the solution at -78°C was added tert-BuLi (1.70 M in pentane, or 0.57 ml). After 1 hour at -78°C was added a solution of 2-chloro-4-forventelige (76,4 mg, 0,482 mmol) in 1 ml of ether and the mixture was slowly heated to room temperature. The mixture is extinguished with water (5 ml) and the layers were separated. The aqueous layer was extracted with CH2Cl2the combined extracts were dried over MgSO4was filtered through celite and concentrated under reduced pressure. The crude substance was purified by chromatography using a mixture of ether/hexane (1:2), and receiving 47,6 mg of compound 4f-8 as a pale yellow solid (yield of 31.2%). MS IER (+), found: m/z 333 and 335 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.72~7.66 (m, 2H), 7.39~7.34 (m, 2H), 7.13~7.03 (m, 2H), 6.29 (m, 1H), 4.15 (m, 2H), 2.38~2.27 (m, 2H, overlap with IT), 0.92 (m, 6H).

Example 65

Receive (4-forfinal)-(1-isobutyl-1H-indazol-5-yl)methanol (4f-2)

This example describes the synthesis of compounds 4f-2, as shown in Fig, where R1represents isobutyl and Ar is a 4-forfinal.

Stage a: 5-Bromo-1-isobutyl-1H-indazole (compound 3f) were obtained as described in Example 62, stages a-C.

Stage C: Compound 3f (1,49 g of 5.89 mmol) was dissolved in 50 ml of ether and the solution was cooled to -78°C. To the solution was added dropwise t-BuLi (1.70 M in pentane, 7.01 ml, 12,07 mmol). Adding tert-BuLi was formed brown solid and the mixture was turned into su is pensiju. After adding tert-BuLi was completed, the mixture was stirred for 30 minutes at -78°C. was Added dropwise 4-forbindelse (700 μl, 6,475 mmol) at -78°C, after which the cooling bath was removed and the reaction mixture was slowly heated to room temperature. The reaction was suppressed 20 ml of water and the layers were separated. The aqueous layer was extracted with CH2Cl2the combined extracts were washed with brine (20 ml), dried over MgSO4was filtered through celite and concentrated, obtaining 1.70 g of a yellow-brown solid. Then the solid was purified by chromatography using a mixture of ether/hexane (1:1) and receiving 1,233 g of compound 4f-2 as a light brown solid (yield of 70.2%). MS IER (+), found: m/z 299 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.72 (s, 1H), 7.40~7.31 (m, 4H), 7.07~7.00 (m, 2H), 5.96 (m, 1H), 4.15 (m, 2H), 2.38~2.27 (m, 2H, overlap with IT), 0.92 (m, 6H).

Example 66

Receiving (2,4-dichlorophenyl)-(1-isobutyl-1H-indazol-5-yl)methanol (4f-9)

This example describes the synthesis of compounds 4f-9, as shown in Fig, where R1represents isobutyl and Ar is a 2,4-dichlorophenyl.

Stage a: 5-Bromo-1-isobutyl-1H-indazole (compound 3f) were obtained as described in Example 62, stages a-C.

Stage C: Compound 3f (106.8 mg, 0,422 mmol) was dissolved in 2 ml of ether. The solution was cooled to -78°C and was stirred for 15 minutes.The this mixture is antenna was added tert-BuLi (1.70 M in pentane, of 0.52 ml, 0,886 mmol). The mixture was turned into the red suspension and it was stirred for another hour at -78°C. 2,4-Dichlorobenzaldehyde them (81.2 mg, 0,464 mmol) was dissolved in 1 ml of ether and the solution was transferred into a slurry using a needle with two ends. The cooling bath was removed allowing the reaction mixture to slowly warm to room temperature. The reaction was suppressed with 10 ml water and the layers were separated. The aqueous layer was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4was filtered through celite, concentrated under reduced pressure and purified by chromatography using a mixture of ether/hexane (1:1) and receiving the connection 4f-9 as a yellow foam (99,6 mg, yield 67.6 per cent). MS IER (+), found: m/z 349 and 351 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.70 (s, 1H), 7.68 (m, 1H), 7.38~7.36 (m, 3H), 7.33 (m, 1H), 6.27 (m, 1H), 4.15 (m, 2H), 2.39 (m, 1H, -OH), 2.37~2.26 (m, 1H), 0.92 (m, 6N).

Example 67

Obtain (1-isobutyl-1H-indazol-5-yl)-O-trimethanol (4f-10)

This example describes the synthesis of compounds 4f-10, as shown in Fig, where R1represents isobutyl and Ar is a 2-were.

Stage a: 5-Bromo-1-isobutyl-1H-indazole (compound 3f) were obtained as described in Example 62, stages a-C.

Stage C: Compound 3f (123,3 mg, 0,487 mmol) was dissolved in 2 ml of ether. The solution was cooled to -78°C and was stirred for 15 minutes. To the mixture was slowly added tert-BuLi (1.70 M in the Penta is not, of 0.62 ml, 1,023 mmol). The mixture was turned into the red suspension and it was stirred for another hour at -78°C. was Added O-tolualdehyde (62 μl, 0,536 mmol) at -78°C. the Cooling bath was removed allowing the reaction mixture to slowly warm to room temperature. The reaction extinguished 10 ml of water, the layers were separated and the aqueous layer was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4was filtered through celite, concentrated under reduced pressure and purified by chromatography using a mixture of ether/hexane (1:1) and receiving the connection 4f-10 in the form of a very viscous pale yellow oil (96,4 mg, yield 67.2 per cent). MS IER (+), found: m/z 295 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 7.64~7.61 (m, 2H), 7.38~7.33 (m, 2H), 7.29 (m, 1H), 7.23 (m, 1H), 7.17~7.13 (m, 1H), 6.13 (m, 1H), 4.15 (m, 2H), 2.32 (m, 1H), 2.24 (s, 3H), 2.18 (m, 1H, HE), 0.91 (m, 6N).

Examples 68-75 describe the synthesis of compounds of General Formula X. In Fig and 33 shows the reaction scheme for the synthesis of compounds having the General structure 5f.

Example 68

Receiving (2,4-differenl)-(1-isobutyl-1H-indazol-5-yl)methanone (5f-1)

This example describes the synthesis of compound 5f-1, as shown in Fig, where R1represents isobutyl and Ar is a 2,4-differenl.

Stage a: Tetrafluoroborate ammonium (20,97 g, 200 mmol) was dissolved in an aqueous solution of acetic acid (500 ml Asón/250 ml water) and cooled to 0°C. sequence is correctly added 2-methyl-4-bromaniline (18,61 g, 100 mmol) and 42 ml of concentrated aqueous HCl (36% (wt./wt.), 12 N., 500 mmol). The mixture was stirred for 20 minutes at 0°C was added NaNO2(to 7.59 g, 110 mmol). The reaction mixture was stirred for 1 hour at 0°C and warmed up to room temperature. After 16 hours at room temperature the mixture was concentrated under reduced pressure, the residue was subjected to azeotropic distillation with toluene and dried under high vacuum. The solid is suspended in 500 ml of CHCl3and added COAs (of 12.76 g, 130 mmol) and 18-crown-6 (of 7.93 g, 30 mmol). The reaction mixture was stirred for 1.5 hours at room temperature. The mixture was washed with water, dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure, obtaining 30 g of 5-bromo-1H-indazole (compound 2f) as a yellow-brown solid. The crude substance was used without further purification.

Stage b: the Crude 5-bromo-1H-indazole (compound 2f; 100 mmol) was dissolved in 250 ml of DMF. Added To2CO3(20.7 g, 150 mmol) and 1-bromo-2-methylpropan (16,3 ml, 150 mmol). The mixture was heated to 120°C. in a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. To the residue was added water (200 ml) and CH2Cl2(200 ml) and was intensively stirred for 30 minutes. The layers were separated and the command layer was extracted with CH 2Cl2. The combined extracts were dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure, getting about 30 grams of the crude substance. The crude substance was purified by chromatography (ether/hexane: from 1:9 to 1:4), receiving 12,870 g of compound 3f as dark red oil with a yield of 50.8 per cent in the stages a and B. MS IER (+), found: m/z 253 and 255 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.87 (m, 1H), 7.43 (m, 1H), 7.29 (m, 1H), 7.29 (m, 1H), 4.15 (m, 2H), 2.33 (m, 1H), 0.92 (m, 6H).

Stage C: Compound 3f (to 121.0 mg, 0,478 mmol) was dissolved in 2 ml of ether and cooled to -78°C. To the solution was added tert-BuLi (1.70 M in pentane, of 0.59 ml, 1,004 mmol). The reaction mixture was stirred for another hour at -78°C. was Added 2,4-differentally (58 μl, 0,526 mmol) at -78°C. the cooling bath was removed and the reaction mixture was slowly heated to room temperature. The reaction extinguished 10 ml of water. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4was filtered through celite, concentrated under reduced pressure and purified by chromatography using a mixture of ether/hexane (1:1) and receiving the connection 4f-1 in the form of a pale yellow crystalline solid (104,5 mg, yield 69,1%). MS IER (+), found: m/z 317 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.73 (s, 1H), 7.56 (m, 1H), 7.40~7.35 (m, 2H), 6.91 (m, 2H), 6.78(m, 1H), 6.22 (m, 1H), 4.15 (m, 2H), 2.39~2.26 (m, 2H, overlap with IT), 0.92 (m, 6H).

Stage D: Compound 4f-1 (316,3 mg, 1.00 mmol), Reagent dess-Martin" (triacetoxyborohydride; 445,3 mg, 1.05 mmol) and 10 ml of CH2Cl2was stirred for 2 hours at room temperature. The reaction mixture was extinguished 10 ml of a saturated solution of K2CO3and the layers were separated. The aqueous layer was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure. The crude substance was purified by chromatography using a mixture of ether/hexane (1:2), and receiving 237,6 mg of compound 5f-1 in the form of a viscous light brown oil (yield of 75.6%). MS IER (+), found: m/z 315 (M+1).1H-NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 8.11 (s, 1H), 7.99 (m, 1H), 7.60 (m, 1H), 7.47 (m, 1H), 7.03 (m, 1H), 6.94 (m, 1H), 4.21 (m, 2H), 2.37 (m, 1H), 0.95 (m, 6N).

Example 69

Receive (4-forfinal)-(1-isobutyl-1H-indazol-5-yl)methanone (5f-2)

This example describes the synthesis of compound 5f-2, as shown in Fig, where R1represents isobutyl and Ar is a 4-forfinal.

Stage a-C: (4-Forfinal)-(1-isobutyl-1H-indazol-5-yl)methanol (compound

4f-2) was obtained as described in Example 27, stages a-C, except that instead of 2,4-diferentialglea used 4-forbindelse.

Stage D: a Mixture of (4-forfinal)-(1-isobutyl-1H-indazol-5-yl)methane is La (compound 4f-2; 745,9 mg of 2.50 mmol), Reagent dess-Martin (triacetoxyborohydride; 1,166 g, a 2.75 mmol) and 50 ml of CH2Cl2was stirred at room temperature for 2 hours. The reaction was suppressed 20 ml of a saturated solution of K2CO3. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (1:4) and receiving 599 mg of compound 5f-2 as a light brown solid (yield of 80.9%). MS IER (+), found: m/z 297 (M+1).1H-NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 8.11 (s, 1H), 7.94 (m, 1H), 7.87 (m, 1H), 7.85 (m, 1H), 7.49 (m, 1H), 7.22~7.16 (m, 2H), 4.23 (m, 2H), 2.38 (m, 1H), 0.96 (m, 6N).

Example 70

Receiving (2,4-dichlorophenyl)-(1-isobutyl-1H-indazol-5-yl)methanone (5f-9)

This example describes the synthesis of compound 5f-9, as shown in Fig, where R1represents isobutyl and Ar is a 2,4-dichlorophenyl.

Stage a-C: (2,4-Dichlorophenyl)-(1-isobutyl-1H-indazol-5-yl)methanol (compound 4f-9) was obtained as described in Example 27, stages a-C, except that instead of 2,4-diferentialglea used 2,4-dichlorobenzaldehyde.

Stage D: a Mixture of compound 4f-9, Reagent dess-Martin (triacetoxyborohydride; 20 mg, 0.046 mmol) and 1 ml of CH2Cl2was stirred at room tempera is ur for 2 hours. The mixture was applied on a Biotage system and suirable a mixture of ether/hexane (1:2)to give 12.9 mg of compound 5f-9 (yield 85%). MS IER (+), found: m/z 347 and 349 (M+1).1H-NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 8.06 (m, 1H), 7.53 (m, 1H), 7.47 (m, 1H), 7.41~7.34 (m, 2H), 4.21 (m, 2H), 2.36 (m, 1H), 0.95 (m, 6N).

Example 71

Obtain (1-isobutyl-1H-indazol-5-yl)-O-tailltean (5f-10)

This example describes the synthesis of compound 5f-10, as shown in Fig, where R1represents isobutyl and Ar is a 2-were.

Stage a-C: (1-Isobutyl-1H-indazol-5-yl)-O-trimethanol (compound 4f-10) were obtained as described in Example 27, stages a-C, except that instead of 2,4-diferentialglea used On-Truelove aldehyde.

Stage D: Compound 4f-10 (21 mg, 0,070 mmol), Reagent dess-Martin (triacetoxyborohydride; 31 mg, 0,0735 mmol) and 1 ml of CH2Cl2was stirred at room temperature for 2 hours. The mixture was applied on a Biotage system and suirable a mixture of ether/hexane (1:2), getting to 18.7 mg of compound 5f-10 (exit 91,4%). MS IER (+), found: m/z 293 (M+1).1H-NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 8.06 (s, 1H), 8.04 (m, 1H), 7.46 (m, 1H), 7.41 (m, 1H), 7.35~7.30 (m, 2H), 7.30~7.25 (m, 1H), 4.21 (m, 2H), 2.36 (m, 1H), 2.33 (s, 3H), 0.95 (m, 6H).

Example 72

Receive (2-chloro-4-forfinal)-(1-isobutyl-1H-indazol-5-yl)methanone (5f-8)

This example describes the synthesis of compound 5f-8, as shown in Fig, where R1is isobut the l and Ar represents 2-chloro-4-forfinal.

Stage a-C: (2-Chloro-4-forfinal)-(1-isobutyl-1H-indazol-5-yl)methanol (compound 4f-8) was obtained as described in Example 27, stages a-C, except that instead of 2,4-diferentialglea used 2-chloro-4-forbindelse.

Stage D: (2-Chloro-4-forfinal)-(1-isobutyl-1H-indazol-5-yl)-methanol (compound 4f-8; 16,2 mg, 0,0487 mmol), Reagent dess-Martin" (triacetoxyborohydride; 21,7 mg, 0,0511 mmol) and 1 ml of CH2Cl2was stirred for 2 hours at room temperature. The reaction mixture was applied to a Biotage system and suirable a mixture of ether/hexane (1:2), receiving 13,0 mg of compound 5f-8 in the form of an oil (yield 80,7%). MS IER (+) m/z.

Example 73

Receive (4-chloro-2-forfinal)-(1-isobutyl-1H-indazol-5-yl)methanone (5f-7)

This example describes the synthesis of compound 5f-7, as shown in Fig, where R1represents isobutyl and Ar represents 4-chloro-2-forfinal.

Stage a-C: (4-Chloro-2-forfinal-(1-isobutyl-1H-indazol-5-yl)methanol (compound 4f-7) were obtained as described in Example 27, stages a-C, except that instead of 2,4-diferentialglea used 4-chloro-2-perfumevintage.

Stage D: (4-Chloro-2-forfinal)-(1-isobutyl-1H-indazol-5-yl)methanol (compound 4f-7; of 20.4 mg, 0,0613 mmol), Reagent dess-Martin (triacetoxyborohydride; 27.3 mg, 0,0644 mmol) and 1 ml of CH2Cl2was stirred for 2 hours at room temperaturereading mixture was applied on a Biotage system. Elution with a mixture of ether/hexane (1:2) gave to 12.0 mg of compound 5f-7 in the form of a solid substance (yield 59,2%). MS IER (+) m/z.1H-NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 8.11 (s, 1H), 7.99 (m, 1H), 7.53 (m, 1H), 7.47 (m, 1H), 7.30 (m, 1H), 7.24 (m, 1H), 4.21 (m, 1H), 2.37 (m, 1H), 0.95 (m, 6H).

Example 74

Receiving (2,4-differenl)-[1-(2,2,2-triptorelin)-1H-indazol-5-yl]methanone (5f-11)

Stage A: 5-Brominator (compound 2f; 9,852 g, 50.0 mmol) was dissolved in 150 ml of ether and the solution was cooled to -78°C. was Slowly added tert-BuLi (1.70 M solution in pentane, 88,2 ml, 150 mmol) at -78°C. After 0.5 h at -78°C the reaction was suppressed 2,4-diferentialglea (10.9 ml, 100.0 mmol) and slowly heated to room temperature. The mixture was stirred for 72 hours at room temperature in a nitrogen atmosphere and extinguished 100 ml of water. The layers were separated and the aqueous layer was extracted with CH2Cl2(6×50 ml). The combined organic extracts were washed with saturated NaCl solution (100 ml), dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure, obtaining a yellow solid. The reaction mixture was purified by chromatography elwira a mixture of 5% Meon in CH2Cl2. During processing of the sample for chromatography, it was found that the target faction have a low solubility in CH2Cl2. Mixed fractions were combined and concentrated under reduced pressure. Received the th resulting oil was treated with CH 2Cl2(about 50 ml)and the formed solid substance. The solid is collected by filtration.1H-NMR spectra for "flash" and the filtered sample were identical. Because the samples had poor solubility in CHCl3to1H-NMR samples were added two drops of DMSO-d6, got 6,034 g 8f-1 in the form of a pale yellow solid (yield 46.4 per cent). MS IER (+), found: m/z 261 (M+H).

Stage b: Compound 8f-1 (4,954 g, 19,04 mmol) suspended in 150 ml of CH2Cl2and portions were added reagent dess-Martin (9,156 g of 1.10 EQ.) at room temperature. After 3 hours at room temperature the mixture was concentrated under reduced pressure to put on Samplet and suirable 2% Meon in CH2Cl2getting solid. The solid is suspended in 300 ml of CH2Cl2and 100 ml of a saturated solution of K2CO3and was intensively stirred for 2 hours. The mixture was filtered and the filtrate was extracted with CH2Cl2(3×100 ml). To the aqueous layer was added a saturated solution of NaCl and the layer was extracted with CH2Cl2(3×100 ml). The combined extracts were dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure, getting 9f-1 as a pale brown solid (3,407 g, yield of 69.3%). MS IER (+), found: m/z 259 (M+H).

Stage C: Compound 9f-1 (0,258 g, 1,0 shall mol), To2CO3(0,207, 1.5 mmol) and DMF (5 ml) were placed in a small test tube, Slinka designed for multiple sealing. From the tube was pumped out the air and pre-cooled her in the bath with dry ice (without acetone). The syringe and triptoreline (0,244 g, 1.5 mmol) is also pre-cooled in a bath of dry ice. The tube was opened and introduced triptoreline until the entire system was cold. The tube was tightly closed and heated to 100°C. After 18 hours the excess DMF was removed under reduced pressure. The residue was treated with water (20 ml) and CH2Cl2(20 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2(4×10 ml). The combined extracts were washed with brine, dried over MgSO4was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (1:1) and receiving 64,7 mg of compound 5f-11 (yield 19%). MS IER (+), found: m/z 341 (M+H).1H-NMR (400 MHz, CDCl3) δ 8.20 (s, 2H), 8.05 (d, 2H), 7.62 (q, 1H), 7.52 (d, 1H), 7.04, (t, 1H), 6.95 (t, 1H), 5.00 (q, 2H).

Example 75

Obtain (1-allyl-1H-indazol-5-yl)-(2,4-differenl)methanone (5f-12)

Stage A: Compound 9f-1 was obtained as described in Example 74.

Stage: In a test tube Slinka were placed compound 9f-1 (0,516 g, 1.0 mmol), K2CO3(0,415 g, 1.5 mmol), DMF (10 ml) and allylbromide (0,363 g, 1.5 mmol). The tube is hermetically closing the Lee and was heated to 100°C. After 19 hours the supernatant solution decantation and the salt washed with DMF (5 ml × 3). The combined supernatant solution was concentrated under reduced pressure. The residue was dissolved in CH2Cl2(20 ml) and washed with water. The aqueous layer was extracted with CH2Cl2(10 ml × 2). The combined extracts were dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure. The residue was purified by chromatography using a mixture of ether/hexane (1:1) and getting to 142.1 mg of compound 5f-12 (exit 23,8%). MS IER (+), found: m/z 299 (M+H).1H-NMR (400 MHz, CDCl3) δ 8.17 (s, 1H), 8.12 (s, 1H), 7.98 (d, 1H), 7.60 (m, 1H), 7.48, (d, 1H), 7.04 (td, 1H), 6.95 (td, 1H), 6.05 (m, 1H), 5.28 (d, 1H), 5.17 (d, 1H), 5.06 (dt, 2H).

Examples 76-79 describe the synthesis of aniline compounds of General Formula XI. On Fig shows the reaction scheme for the synthesis of compounds having the General structure of 2h.

Example 76

Receiving (2,4-differenl)-(1-isobutyl-1H-indazol-5-yl)amine (2h-1)

This example describes the synthesis of compound 2h-1, as shown in Fig, where R1represents isobutyl and Ar is a 2,4-differenl.

Stage a: Tetrafluoroborate ammonium (20,97 g, 200 mmol) was dissolved in an aqueous solution of acetic acid (500 ml Asón/250 ml water) and cooled to 0°C. was Sequentially added 2-methyl-4-bromaniline (18,61 g, 100 mmol) and 42 ml of concentrated aqueous HCI (36% (wt./wt.), 12 N., 500 mmol). A mixture of p is remedial for 20 minutes at 0°C was added NaNO 2(to 7.59 g, 110 mmol). The reaction mixture was stirred for 1 hour at 0°C and warmed up to room temperature. After 16 hours at room temperature the mixture was concentrated under reduced pressure, the residue was subjected to azeotropic distillation with toluene and dried under high vacuum. The solid is suspended in 500 ml of CHCl3and added COAs (of 12.76 g, 130 mmol) and 18-crown-6 (of 7.93 g, 30 mmol). The reaction mixture was stirred for 1.5 hours at room temperature. The mixture was washed with water, dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure, obtaining 30 g of 5-bromo-1H-indazole (compound 2f) as a yellow-brown solid. The crude substance was used without further purification.

Stage b: the Crude 5-bromo-1H-indazole (compound 2f; 100 mmol) was dissolved in 250 ml of DMF. Added To2CO3(20.7 g, 150 mmol) and 1-bromo-2-methylpropan (16,3 ml, 150 mmol). The mixture was heated to 120°C. in a nitrogen atmosphere for 16 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. To the residue was added water (200 ml) and CH2Cl2(200 ml) and was intensively stirred for 30 minutes. The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4was filtered through celite and concentration of Aravali under reduced pressure, getting about 30 grams of the crude substance. The crude substance was purified by chromatography (ether/hexane from 1:9 to 1:4), receiving 12,870 g of compound 3f as dark red oil with a yield of 50.8 per cent in the stages a and B. MS IER (+), found: m/z 253 and 255 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.87 (m, 1H), 7.43 (m, 1H), 7.29 (m, 1H), 7.29 (m, 1H), 4.15 (m, 2H), 2.33 (m, 1H), 0.92 (m, 6H).

Stage C: Compound 3f (2,53 g, 10.0 mmol) was dissolved in 50 ml of ether and the solution was cooled to -78°C. was Added dropwise and 12.4 ml of tert-BuLi (1.7 M, or 21.0 mmol) and the mixture was stirred another 30 minutes at -78°C. the Reaction was suppressed In(OMe)3(2.4 ml, or 21.0 mmol) and the mixture was slowly heated to room temperature. After 15 minutes the reaction was suppressed 6 N. HCl (10 ml, 60 mmol). The reaction mixture was transferred into a separating funnel and was added water (100 ml) and CH2Cl2(100 ml). The layers were separated and the aqueous layer was extracted with CH2Cl2. The combined extracts were dried over anhydrous MgSO4was filtered through celite and concentrated under reduced pressure and was purified by chromatography: ether/hexane (2:1) up to 5% of the Meon in CH2Cl2receiving compound 1h in the form of a pale yellow solid (1,41 g, yield 64,7%). MS IER (+), found: m/z 219 (M+1).

Stage D: Compound 1h (109 mg, 0.50 mmol), copper acetate (II) (50,3 mg, 0.10 mmol), myristic acid (46 mg, 0.20 mmol) and 2 ml of dry toluene were placed in a flask. Added 2,6-Lucy is in (58 μl, 0.50 mmol) and the mixture was stirred for several minutes. Added 2,4-diptiranjan (0.75 mmol, 76 μl) and the mixture was intensively stirred in air for 90 hours. The mixture was diluted with 10 ml of ether, filtered through celite and concentrated under reduced pressure, obtaining a viscous dark green oil. The crude substance was purified by chromatography using a mixture of ether/hexane (1:4) and receiving 59 mg of compound 2h-1 as a yellow-brown oil (yield 39%). MS IER (+), found: m/z 302 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.39 (m, 1H), 7.36 (m, 1H), 7.16 (m, 1H), 7.07 (m, 1H), 6.89 (m, 1H), 6.75 (m, 1H), 5.59 (br s, 1H, NH), 4.16 (m, 2H), 2.35 (m, 1H), 0.95 (m, 6H).

Example 77

Receive (4-forfinal)-(1-isobutyl-1H-indazol-5-yl)amine (2h-2)

This example describes the synthesis of compound 2h-2, as shown in Fig, where R1represents isobutyl and Ar is a 4-forfinal.

Stage a-C: Compound 1h was obtained as described in Example 76, stages a-C.

Stage D: Compound 1h (109 mg, 0.50 mmol), copper acetate (II) of 25.2 mg, 0.05 mmol), myristic acid (23 mg, 0.10 mmol) and 2 ml of dry toluene were placed in a flask. To the mixture was added 2,6-lutidine (58 μl, 0.50 mmol, 1.0 EQ.) and stirred it for a few minutes. Added 4-ftoranila (71 μl, 0.75 mmol, 1.5 equiv.) and the mixture was intensively mixed in the air (in the air for oxidation of the copper catalyst) within 21 the Asa. The mixture was diluted with 10 ml of ether, filtered through celite and concentrated under reduced pressure, getting a very viscous, dark-green oil. The crude substance was purified by chromatography using a mixture of ether/hexane (1:1) and receiving 41 mg of compound 2h-2 (output 28,9%) as a yellow-brown oil. MS IER (+), found: m/z 284 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.34 (s, 1H), 7.33 (m, 1H), 7.13 (m, 1H), 6.98~6.91 (m, 4H), 4.15 (m, 2H), 2.35 (m, 1H), 0.94 (6N).

Example 78

Receiving (2,4-dichlorophenyl)-(1-isobutyl-1H-indazol-5-yl)amine (2h-9)

This example describes the synthesis of compound 2h-9, as shown in Fig, where R1represents isobutyl and Ar is a 2,4-dichlorophenyl.

Stage a-C: Compound 1h was obtained as described in Example 76, stages a-C.

Stage D: Compound 1h (109 mg, 0.50 mmol), copper acetate (II) (50,3 mg, 0.10 mmol), myristic acid (46 mg, 0.20 mmol) and 2 ml of dry toluene were placed in a flask. To the mixture was added 2,6-lutidine (58 μl, 0.50 mmol, 1.0 EQ.) and was stirred for two minutes. Added 2,4-dichloraniline (122 mg, 0.75 mmol, 1.5 equiv.) and the mixture was intensively mixed in the air (in the air for oxidation of the copper catalyst) for 90 hours. The mixture was diluted with 10 ml of ether, filtered through celite and concentrated under reduced pressure, getting a very viscous, dark-green oil. The crude substance was purified by chromatography using a mixture of ether/hexane (1:4) and receiving 59 mg of compound 2h-9 as a yellow-brown oil (yield 35%). MS IER (+), found: m/z 334 and 336 (M+1).

Example 79

Obtain (1-isobutyl-1H-indazol-5-yl)-O-tolylamino (2h-10)

This example describes the synthesis of compound 2h-10, as shown in Fig, where R1represents isobutyl and Ar is a 2-were.

Stage a-C: Compound 1h was obtained as described in Example 76, stages a-C.

Stage D: Compound 1h (109 mg, 0.50 mmol), copper acetate (II) (50,3 mg, 0.10 mmol), myristic acid (46 mg, 0.20 mmol) and 2 ml of dry toluene were placed in a flask. To the mixture was added 2,6-lutidine (58 μl, 0.50 mmol, 1.0 EQ.) and was stirred for two minutes. Added 80 μl of O-toluidine (0.75 mmol, 1.5 equiv.) and the mixture was intensively mixed in the air (in the air for oxidation of the copper catalyst) for 90 hours. The mixture was diluted with 10 ml of ether, filtered through celite and concentrated under reduced pressure, getting a very viscous, dark-green oil. The crude substance was purified by chromatography using a mixture of ether/hexane (1:4) and getting 77 mg of compound 2h-10 as a yellow-brown oil (yield 55%). MS IER (+), found: m/z 280 (M+1).

Examples 80-82 describe the synthesis of amino acid compounds of General Formula XV. On Fig shows the reaction scheme for the synthesis of compounds having the General structure 1j.

Example 80

Obtain methyl ester of 4-amino-2-{[5-(4-pertenece)-1-isobutyl-1H-indazol-6-carbonyl]the Mino}butyric acid (1j-2)

Stage A: Connection 10g-1 was obtained as described in Example 46.

Stage b: a Solution of compound 10g-1 (50 mg, 0.15 mmol) in THF (0.5 ml) was treated with CBI (1.1 EQ.) at room temperature in a nitrogen atmosphere. After stirring for 18 hours was added methyl ether 2-amino-4-tert-butoxycarbonylmethylene acid (36 mg, 0,165 mmol) followed by addition of N,N-diisopropylethylamine (29 mg, 0,225 mmol). After stirring for 18 hours the reaction mixture was concentrated, the residue was transferred into a CH2Cl2and washed with 1 N. HCl. The organic layer was filtered through 1PS paper and cleaned the cartridge Sep-Pak, elwira a mixture of CH2Cl2/Et2O (10:1). The target fraction was concentrated, receiving 72 mg of compound 1j-1 in the form of a beige foam (yield 99%).1H-NMR (400 MHz, DMSO-d6) δ 8.65 (br, 1H), 8.10 (s, 1H), 7.9 (s, 1H), 7.28 (1H, s), 4.21 (d, 2H), 4.42 (m, 1H), 3.6 (s, 3H), 2.95 (m, 2H).

Stage C: a Solution of compound 1j-1 (72 mg, 0.13 mmol) in CH2Cl2(0.2 ml) was treated with TFU (0.1 ml) at room temperature. After 18 hours the solvent was concentrated and co evaporated with ether, receiving 70 mg (yield 98%) of compound 1j-2 in the form of oil of amber.1H-NMR (400 MHz, DMSO-d6) δ 8.85 (br, 1H), 8.01 (s, 1H), 7.98 (s, 1H), 7.70 (br, 2H), 4.60 (m, 1H), 4.22 (d, 2H), 3.80 (s, 3H), 2.85 (m, 2H).

Example 81

Obtain methyl ester of 4-amino-2-{[5-(4-pertenece)-1-(2,2,2-triptorelin)-1H-indazol-6-carbonyl]amino}wt is Jana acid (1j-4)

Stage A: Connection 10g-2 was obtained as described in Example 59.

Stage b: Compound 10g-2 (0,026 g, 0,073 mmol), benzotriazol-1,3-diol (0,013 g, 0,088 mmol) and (3-dimethylaminopropyl)ethylcarbodiimide (0,017 g, 0,088 mmol) were added to dichloroethane and mixed for 10 minutes. Then was added to a heterogeneous mixture of hydrochloric salt of methyl ester of 2-amino-4-tert-butoxycarbonylmethylene acid (0,039 g, 0.147 mmol) and triethylamine (0,030, 0.29 mmol) in dichloroethane. The reaction mixture was stirred for 3 hours, concentrated and purified by reversed-phase HPLC according to method a of Example 86, getting about 30 mg of pure compound 1j-3 (output to 71.9%). MS IER (+), found: m/z 569 (M+H).

Stage C: Compound 1j-3 (0,0012 g 0,024 mmol) was added to a mixture of CH2Cl2/TFU (1:1) for 1.5 hours, then concentrated, receiving 2.3 mg (yield 100%) of compound 1j-4.1H-NMR (400 MHz, CDCl3) δ 9.21 (br, 1H), 8.40 (br, 1H), 8.04 (br, 1H), 7.44 (br, 1H), 7.18 (s, 1H), 7.03 (m, 3H), 5.05 (m, 2H), 4.80 (br, 1H), 3.75 (s, 3H), 3.36 (br, 1H), 2.97 (br, 1H), 2.51 (br, 1H), 1.92 (br, 1H).

Example 82

Obtain methyl ester of 4-amino-2-{[5-(4-pertenece)-1-methyl-1H-indazol-6-carbonyl]amino}butyric acid (1j-6)

Stage A: Connection 10g-3 were obtained as described in Example 60.

Stage b: Compound 10g-3 (0,026 g 0,090 mmol), benzotriazol-1,3-diol (0,017 g, 0.11 mmol) and (3-dimethylaminopropyl)ethylcarbodiimide (0,021 g of 0.017 mmol) was added to dichlorid the well and mixed for 10 minutes. Then was added to a heterogeneous mixture of hydrochloric salt of methyl ester of 2-amino-4-tert-butoxycarbonylmethylene acid (0.05 g, 0.20 mmol) and triethylamine (0,037, 0.36 mmol) in dichloroethane. The reaction mixture was stirred for 3 hours and then purified by reversed-phase HPLC according to method a of Example 86, receiving 30 mg (yield 66%) of compound 1j-5 in the form of pure substances. MS IER (+), found: m/z 501 (M+H).

Stage C: Compound 1j-5 (0,0012 g 0,024 mmol) was added to a mixture of CH2Cl2/TFU (1:1) for 1.5 hours, then concentrated, receiving 1.2 mg of compound 1j-6 (yield 100%).1H-NMR (400 MHz, CDCl3) δ 9.10 (br, 1H), 8.32 (br, 1H), 8.05 (br, 1H), 7.90 (s, 1H), 7.05 (s, 1H), 7.05 (m, 3H), 4.75 (br, 1H), 4.14 (s, 3H) 3.65 (s, 3H), 3.30 (br, 1H), 2.92 (br, 1H), 2.51 (br, 1H), 1.82 (br, 1H).

Examples 83-85 describe the synthesis of compounds of Formula XVI, as shown in Fig.

Example 83

Obtain [5-(4-pertenece)-1-isobutyl-1H-indazol-6-yl]methyl-(2-dimethylaminoethyl)amine (1k-1)

Connection 11g-10 (0.05 g, 0.12 mmol), obtained as described in Example 55, was treated with 6 equivalents NR3in THF (1 M solution) and stirred at 65°C for 6 hours and then at room temperature for 14 hours. The solvent was removed by evaporation and the residue was purified preparative TLC using a mixture of hexane/ethyl acetate (1:1) and 5% triethylamine, receiving of 0.014 g of product (yield 30%). Found: MN+385.

Por the measures 84

The connection is 1k-2

Compound 1k-1, obtained as described in Example 83 was treated with excess methanesulfonanilide and triethylamine in THE at room temperature for 4 hours and then concentrated, receiving 0,010 g 1k-2. Found: MH+ 427.

Example 85

The connection is 1k-3

Compound 1k-1, obtained as described in Example 83 was treated with excess acetic anhydride and triethylamine in THE at room temperature for 4 hours. The reaction mixture was concentrated, the residue was purified preparative TLC using a mixture of hexane/ethyl acetate (1:1) and 5% triethylamine, getting 0.005 g (yield 50%). Found: MH+ 463.

Example 86

Conditions for preparative reversed-stasovoi HPLC

Method:

Column: YMC ODS-AQ, int. dia. 250×20 mm, s-10/20 µm, 12 nm. Solvent A: H2About 0.1% of the TFU. Solvent b: acetonitrile with 0.05% of TFU. The collection was started with the help of a mass spectrometer.

%%Speed duct
0,03 min851510 ml/min
1,50 min8515 20 ml/min
22,5 min158520 ml/min
24,0 min59520 ml/min
32,25 min59515 ml/min
32,75 min95515 ml/min

Method:

Column: YMC ODS-AQ, int. dia. 250×20 mm, s-10/20 µm, 12 nm. Solvent A: H2About 0.1% of the TFU. Solvent b: acetonitrile with 0.05% of TFU. The collection was started with the help of a mass spectrometer.

%%Speed duct
0,03 min95510 ml/min
1,50 min95520 ml/min
22,5 min59520 ml/min
24,0 min59515 ml/min
30,5 min95515 ml/min

The method:

Column: YMC ODS-AQ, int. dia. 250×20 mm, s-10/20 µm, 12 nm. Solvent A: H2About 0.1% of the TFU. Solvent b: acetonitrile with 0.05% of TFU. The collection was started with the help of a mass spectrometer.

%%Speed duct
0,03 min95510 ml/min
1,50 min95515 ml/min
18,5 min59515 ml/min
20,0 min59515 ml/min
20,85 min95515 ml/min

Example 87

Getting connection 1m-1

p> Synthesis of compound 1m-1 shown in Fig.

Stage A: Compound 1j-7 (0.07 g, 0.13 mmol), obtained in a manner analogous to the method described for compound 1j-3, was treated with sodium borohydride (10 EQ., 0,049 g, 1.3 mmol) in a mixture of Meon/THF (1:1) and heated to 60°C for 3 hours. The reaction mixture was concentrated and then was co-evaporated with Meon, receiving the connection 1l-1.

Stage b: Compound 1l-1 was placed in a mixture of Meon/4 M HCl in dioxane (1:1) for 1.5 hours and then the reaction mixture was concentrated. The residue was transferred into chloroform, washed with 0.6 M solution of Na2CO3(pH 7.0) and aqueous saturated NaCl and dried over MgSO4. After filtration, the filtrate was evaporated, receiving the connection 1m-1 (purity 99%) in the form of free base.1H-NMR (400 MHz, CDCl3: δ 8.39 (d, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.24 (s, 1H), 6.98 (M, 4H), 4.27 (m, 1H), 4.20 (d, 2H), 3.64 (m, 2H), 2.65 (m, 1H), 2.39 (m, 1H), 2.37 (m, 1H), 2.18 (m, 1H), 1.59 (m, 1H), 0.93 (d, 6H).

Examples 88-109 describe the synthesis of aniline compounds of General Formula XVII.

Example 88

Obtaining 1-(5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl)-3-[2-(1-methyl-1H-indazol-5-yloxy)pyridine-3-ylmethyl]urea (6n)

The reaction scheme for the synthesis of compound 6n shown in Fig.

Stage A: 2-(1-Methyl-1H-indazol-5-yloxy)nicotinamide (3n). 1-Methyl-1H-indazol-5-ol (1n) (synthesized as described in Example 94) (0.10 g, of 0.68 mmol) and 2-chloronicotinamide (2n) (0.11 g, 0.81 mmol) of suspendido is whether in DMSO (2 ml). The reaction mixture was heated to 110°C for 18 hours. The reaction mixture was diluted with water and extracted into EtOAc. The combined organic substance was dried Na2SO4and concentrated under reduced pressure, obtaining the crude product. Purification column flash chromatography (20-100% EtOAc/hexane) gave the desired product (3n), (0.152 g, yield 90%).1H-NMR (400 MHz, CD3OD) δ 8.27-8.25 (m, 1H), 8.23-8.20 (m, 1H), 8.01 (s, 1H), 7.62 (d, J=8.6 Hz, 1H), 7.57 (d, J=2.3 Hz, 1H), 7.28-7.26 (m, 1H), 7.23-7.20 (m, 1H), 4.10 (s, 3H). MS IER (+), found: m/z 251 (M+H).

Stage b: S-[2-(1-Methyl-1H-indazol-5-yloxy)pyridine-3-yl]methylamine (4n). 2-(1-Methyl-1H-indazol-5-yloxy)nicotinamide (3n) (0,132 g, 0,528 mmol) suspended in the Meon (6 ml). Was added Pd(OH)2(to 0.060 mg, 0,427 mmol) under nitrogen atmosphere followed by the addition of concentrated aqueous HCl (0.6 ml). The system was purged with gaseous H2and the reaction mixture was stirred at room temperature for 3 hours in an atmosphere of H2(g). The reaction mixture was filtered through a filler of celite, washed Meon. Organic matter was concentrated under reduced pressure, obtaining the crude product, which was purified flash column-chromatography (MeOH/Et3N/EtOAc)to give the target product (4n) (0,047 g, yield 35%).1H-NMR (400 MHz, CD3OD) δ 7.96 (s, 1H), 7.90 (d, J=4.7 Hz, 1H), 7.82 (d, J=7.0 Hz, 1H), 7.56 (d, J=9.4 Hz, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.23-7.21 (m, 1H), 7.097.06 (m, 1H), 4.07 (s, 3H), 3.95 (s, 2H).

Stage C: 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-yl)-3-[2-(1-methyl-1H-indazol-5-yloxy)pyridine-3-ylmethyl]urea (6n). S-[2-(1-Methyl-1H - indazol-5-yloxy)pyridine-3-yl]methylamine (4n) (0,017 g 0,067 mmol) and 2,2,2-trichlorethylene ether (5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl)carbamino acid (5n) (0.035 g, 0,087 mmol) were placed in a 10 ml reaction vessel and dissolved in DMF (5 ml). To the reaction mixture were added DIEA (diisopropylethylamine) (0,058 ml, 0,334 mmol) and the system was heated up to 80°C for 18 hours. The reaction mixture was concentrated under reduced pressure, obtaining the crude produktneuheiten substance was purified column flash chromatography using cartridge Sep-Pak (10 g, 35 cm3with silica (50% EtOAc/hexane), obtaining the target product (6n) (0,034 g, yield 100%).1H-NMR (400 MHz, DMSO) δ 8.32 (s, 1H), 8.00 (s, 1H), 7.94 (d, J=4.7 Hz, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.60 (d, J=7.8 Hz, 1H), 7.46 (s, 1H), 7.36 (d, J=7.8 Hz, 2H), 7.29 (d, J=7.8 Hz, 2H), 7.19-7.16 (m, 1H), 7.07-7.03 (m, 2H), 6.26 (s, 1H), 4.37 (d, J=6.3 Hz, 2H), 4.06 (s, 3H), 2.36 (s, 3H), 1.25 (s, 9H). MS IER (+), found: m/z 510 (M+H).

Example 89

Obtaining 2-(4-{2-[2-(1-cyclobutylmethyl-1H-indazol-5-yloxy)-5-forfinal]acetyl}piperazine-1-yl)-N-isopropylacrylamide (R)

The reaction scheme for the synthesis of compounds R shown in Fig.

Stage A: 1-Allyloxy-4-torbenson (3P). To a solution of 4-terfenol (1R) (30 g, 268,0 mmol) in acetone (250 ml) was added To anhydrous2CO (65 g, 468,3 mmol)and then 3-bromopropene (2P) (28 ml, 321,1 mmol). The resulting mixture was heated under reflux for 16 hours, cooled to room temperature and then was poured into ice water (500 ml). The aqueous layer was extracted with ether (3×250 ml), the combined organic layers were washed with 2 M NaOH (2×150 ml) and dried over a mixture of anhydrous K2CO3and Na2SO4. The solvent was removed under vacuum, obtaining the target product (3P) (40,4 g, 99%) as a pale yellow oil.1H-NMR (400 MHz, CDCl3) δ 7.01-6.92 (m, 2H), 6.89-6.82 (m, 2H), 6.10-6.82 (m, 1H), 5.44-5.41 (m, 1H), 5.39-5.37 (m, 1H), 4.51-4.448 (m, 2H).

Stage b: 2-Allyl-4-terfenol (4P). The intermediate compound (3P) (14,7 g that 96.6 mmol) was heated to 210°C for 7 hours, cooled to room temperature and kept overnight. The reaction course was monitored by thin layer chromatography. In TLC analysis found a new spot (Rf ~0,65 in a mixture of hexane/ethyl acetate, 7:3). HPLC of the crude mixture gave a main peak with a retention time of 2,07 minutes and a minor peak at 2,36 minutes Main crude product (4P) was confirmed as the target product and sent it immediately to the next stage without purification.1H-NMR (400 MHz, CDCl3) δ 6.88-6.78 (m, 2H), 6.78-6.72 (m, 1H), 6.05-5.93 (m, 1H), 5.21-5.13 (m, 2H), 4.8 (br s, OH), 3.38 (d, J=6.26 Hz, 2H).

Stage C: 2-Allyl-4-forfinally ether acetic acid (5P). To the crude (4R) was added to kasny anhydride (to 36.5 ml, 386,4 mmol) and pyridine (37.5 ml, 463,7 mmol). The resulting mixture was stirred at room temperature for 18 hours and the next day was controlled by HPLC (reaction, apparently, was largely completed). Then the mixture was poured into a cold mixture of H2O/Et2O, and the aqueous layer was extracted with Et2O (2×), the combined organic layers are successively washed with 10%HCl solution (3×), saturated NaHCO3(2×), N2About (2×) and brine and then dried over anhydrous Na2SO4. The purity of the crude product after concentration was checked by thin-layer chromatography (hexane/ethyl acetate, 7:3) and HPLC. Mass ion not detected. The crude product (5P) was sent immediately to the next stage without further purification.1H-NMR (400 MHz, CDCl3) δ 7.04-6.91 (m, 3H), 6.09-5.65 (m, 1H), 5.19-5.06 (m, 2H), 3.27 (d, J=6.26 Hz, 2H), 2.30 (s, CH3).

Stage D: (2-Acetoxy-5-forfinal)acetic acid (6R-2). To a solution of (5P) (10 g, was 51.5 mmol) in 100 ml of a mixture of CCl4/acetonitrile (1:1) solution was added metaperiodate sodium (NaIO4, 33,6 g, 154,5 mmol) in 500 ml of N2O. After stirring for several minutes was added to hydrate trichloride ruthenium (0,93 g of 4.12 mmol). The dark mixture was stirred at room temperature for 2 hours and added DHM (600 ml). The layers were separated, the aqueous phase was extracted with DHM (3×), the combined organic layer is washed with N 2O and dried over Na2SO4. Filtration through celite 545 and evaporation gave a mixture of aldehyde (6R-1) and acid (6R-2) (9,1 g, 83%) as a brown oil, which was sent to the next stage without purification.

Stage E: (2-Acetoxy-5-forfinal)acetic acid (7đ). A solution of sodium chlorite (52,16 g, 576,7 mmol) and sodium dihydrophosphate (44,5 g, 371 mmol) in 225 ml of N2Oh was added to a solution of acid (6R-2) and aldehyde (6R-1) in 100 ml of ISO-D at 0°C. the resulting solution was stirred at 0°C for 3 hours, diluted with ether and then separated the layers. The organic phase is washed with N2Oh, 10%sodium thiosulfate (2×), N2O and brine and dried over Na2SO4. After evaporation to a small volume was added a few drops of hexane. Gradually formed crystals were collected by filtration and washed with cold mixture of ether/hexane, obtaining the target compound (7đ) (3,95 g, the output of the selected product 36%).1H-NMR (400 MHz, CDCl3) δ 7.12-6.98 (m, 3H), 3.57 (s, 2H), 2.29 (s, CH3). MC (head-) (chemical ionization at atmospheric pressure), found: m/z 422,7 (2M-N).

Stage F: (5-fluoro-2-hydroxyphenyl)acetic acid (8P). Connection (7đ) (3.5 g, 16.5 mmol) was dissolved in 65 ml Meon and added 7 ml of ammonium hydroxide (49,5 mmol). The mixture was stirred at room temperature overnight and then analyzed by TLC (DHM/Meon/AND WHAT HE (9:1:0,15)), HPLC and MS. The original substance is not found. The substance was concentrated to dryness, obtaining the target product (8P), which is directly sent to the next stage. MS (head-), found: m/z 168,9 (M-N), 338,7 (2M-N).

Stage G: [2-(1-Cyclobutylmethyl-1H-indazol-5-yloxy)-5-forfinal]acetic acid (10p). To a solution of (8P) (2.8 g, 16.5 mmol) in 6 ml of NMP (N-methylpyrrolidone) was added cesium carbonate (24.2 g, 74,24 mmol)and the reaction mixture was aterials. Was added 12 ml of NMP and cesium carbonate (6,29 g, and 19.3 mmol) and the reaction mixture was purged with nitrogen. After intensive stirring was added the compound (9R) (a 5.25 g of 19.8 mmol) and 2,2,6,6-tetramethylheptane-3,5-dione (90,86 ml of 4.12 mmol). The reaction mixture was degirolami and was purged with nitrogen. Added copper chloride (I) (0,82 g, 8,24 mmol), the reaction mixture was degirolami, was purged with nitrogen and heated to 140°C. After stirring for 18 hours the reaction mixture was cooled to room temperature (approximately 23°C), diluted with Et2O and filtered. The collected solids were washed several times with ether, was dissolved in N2Oh, acidified 6 N. HCl and was extracted with DHM (4×). The combined organic layers were washed N2O and brine and dried over Na2SO4. After concentration the residue was purified normal-phase chromatography using hexane/EtOAc/Asón (9:1:0,15), obtaining the target product (10p) (1.01 g, Ihad selected product 17%). 1H-NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.36 (d, J=at 8.62 Hz, 1H), 7.14 (d, J=2.35 Hz, 1H), 7.11 (dd, J=8.61, 2.35 Hz, 1H), 7.05 (dd, J=8.61, 3.13 Hz, 1H), 6.92 (ddd, J=8.61, 8.61, 3.13 Hz, 1H), 6.79 (dd, J=8.61, 4.70 Hz, 1H), 4.35 (d, J=7.04 Hz, 2H), 3.73 (s, 2H), 2.93-2.82 (m, 1H), 2.06-1.97 (m, 2H), 1.94-1.76 (m, 4H). MC IER (+), found: m/z 355 (M+H).

Stage H: 2-(4-{2-[2-(1-Cyclobutylmethyl-1H-indazol-5-yloxy)-5-forfinal]acetyl}piperazine-1-yl)-N-isopropylacetate (R). Connection (10p) (0,087 g, 0,247 mmol) was dissolved in CHCI3(1.6 ml), mixed with EDCI (1-ethyl-3,3-bis-(methylamino)propylbromide) (0,072 g, 0,372 mmol) and stirred at room temperature for 30 minutes. Was added N-isopropyl-2-piperazine-1-ylacetamide (R) (0,069 g, 0,372 mmol), and then addition of 0.8 ml of CHCl3. The resulting solution was stirred at room temperature for 18 hours. Added PS-isocyanate (0,850 g, 1.6 mmol/g) and the reaction mixture was shaken for 1 hour. After filtration, the filtrate is washed with N2About (2×), dried over Na2SO4and concentrated. The residue was purified by chromatography (Sep-Pak, 10 g) (DHM, EtOAc)to give the target product (R) (0.1 g, 77%).1H-NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.40 (d, J=8.61 Hz, 1H), 7.13-7.06 (m, 3H), 6.91 (ddd, J=8.61, 8.61, 3.13 Hz, 1H), 6.83-6.72 (m, 2H), 4.38 (d, J=7.04 Hz, 2H), 4.15-4.02 (m, 1H), 3.74 (s, 2H), 3.67-3.60 (m, 2H), 3.55-3.49 (m, 2H), 2.99-2.87 (m, 1H), 2.91 (s, 2H), 2.44-2.33 (m, 4H), 2.10-2.00 (m, 2H), 1.97-1.79 (m, 4H), 1.16 (s, CH3), 1.15 (s, CH3). MS (head+), found: m/z 522,2 (M+H).

Example 90

Receive their 2-[2-(1-isobutyl-1H-indazol-5-yloxy)phenyl]-N-(4-(morpholine-4-ylphenyl)ndimethylacetamide (16R)

The reaction scheme for the synthesis of compounds 16R shown in Fig.

Stage A: 5-Bromo-1-isobutyl-1H-indazole (R): To a solution of 5-brominate in DMF was added To a2CO3. The mixture was heated to 105°C. After the disappearance of 5-brominate the reaction mixture was poured into DHM/brine. Two layers were separated, the aqueous layer was extracted with DHM (2×) and were analyzed by TLC. The combined organic substances washed with N2About (2×) and brine and dried over Na2SO4. After filtration, the filtrate was concentrated, the obtained residue was purified by chromatography using hexane/EtOAc (of 9.5:0.5) and obtaining the target product (R).

Stage b: [2-(1-Isobutyl-1H-indazol-5-yloxy)phenyl]acetic acid (R). To a degassed suspension of 2-hydroxybenzoic acid (2.4 g, 15.8 mmol) and Cs2CO3(7,72 g, with 23.7 mmol) in NMP (13 ml) was added 2,2,6,6-tetramethylheptane-3,5-dione (0,41 ml, 1.97 mmol) and compound R (2.0 g, of 7.90 mmol), and then a small amount of NMP for washing. The resulting mixture was again degirolami nitrogen, then was added CuCl (0.39 g, 3.95 mmol) and the reaction mixture was again degirolami. The mixture was heated to 140-150°C. After stirring for 22 hours, the reaction mixture was poured into ether/N2O. the Two layers were separated and the aqueous layer (pH ~11) was washed with ether. The aqueous layer was acidified to pH 7 and extracted with ether (4×), the combined organic layers were dried over Na 2SO4. The solvent was removed under reduced pressure. The precipitate formed gradually in a small volume of a mixed solvent of ether/hexane/DHM and it was collected by filtration, obtaining the target compound (R) (0,93 g, the output of the selected product 36%).1H-NMR (400 MHz, CDCl3) δ 7.87 (br s, 1H), 7.38-7.28 (m, 2H), 7.25-7.17 (m, 2H), 7.13 (d, J=9.39 Hz, 1H), 7.10-7.03 (m, 1H), 6.79 (d, J=8.61 Hz, 1H), 4.15 (br s, 2H), 3.79 (s, 2H), 2.40-2.27 (m, 1H), 0.93 (s, 3H), 0.92 (s, 3H). MS (head+), found: m/z 325 (M+H), MS (head-), found: m/z 322,8 (M-N) and 646,8 (2M-N).

Stage C: 2-[2-(1-Isobutyl-1H-indazol-5-yloxy)phenyl]-N-(4-(morpholine-4-ylphenyl)ndimethylacetamide (16R). To a solution of (R) (0.04 g, 0,123 mmol), PyBOP (is 0.135 g, 0.26 mmol) and DIEA (0,02 ml, 0.12 mmol) in CHCl3(2 ml) was added 4-morpholine-4-elfenlied (0,044 g, 0,247 mmol). The mixture was stirred at room temperature for 16 hours, treated with resin AR-trisamin (0.25 g, 2.49 mmol/g) and the solvent was finally removed under reduced pressure after filtration of the resin. The obtained residue was purified by chromatography (Sep-Pak, 10 g) with ether, obtaining the target product (16R) (0,024 g, 40%).1H-NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 7.50 (br s, 1H), 7.45 (dd, J=7.83, 1.57 Hz, 1H), 7.39 (d, J=9.39 Hz, 2H), 7.31-7.26 (m, 3H), 7.23 (dd, J=7.83, 1.57 Hz, 1H), 7.15-7.09 (m, 2H), 6.86-6.79 (m, 3H), 4.17 (d, J=7.04 Hz, 2H), 3.86-3.82 (m, 4H), 3.80 (s, 2H), 3.11-3.06 (m, 4H), 2.41-2.29 (m, 1H), 0.95 (s, CH3), 0.94

(s, CH3). MS (head+), found: m/z 485,2 (M+H).

Example 91

Obtaining 1-[5-cycloprop the l-2-(4-triptoreline)-2H-pyrazole-3-yl]-3-[5-fluoro-2-(1-methyl-1H-indazol-5-ylamino)benzyl]urea (9q-1) and 1-(5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl)-3-[2-(1-cyclobutylmethyl-1H-indazol-5-ylamino)-5-Torbinskiy (9q-2)

The reaction scheme for the synthesis of compounds 9q-1 and 9q-2 shown in Figa and C.

Stage A: 2-Azido-5-perbenzoate (1q). The mixture NaN3(1,17 g, 1.8 mmol) and difterential (0.5 g, 3.6 mmol) in DMF (60 ml) was heated at 100°C for 30 minutes. Then the mixture was diluted with water (300 ml) and ether (300 ml). The organic layer was thrice washed with water and brine. The organic layer was dried (MgSO4) and concentrated. The crude product was purified column flash chromatography, using as eluent a mixture of ether:hexane (1:5) and obtaining the target product (1q) in the form of white crystals (0.3 g, the output of the selected product 53%).1H-NMR (400 MHz, CDCl3) δ 7.38-7.31 (m, 2H), 7.27-7.18 (m, 1H).

Stage b: 2-Amino-5-perbenzoate (2q). To a solution of CoBr2(15 mg, 0,068 mmol) in ethanol (3 ml) was added 2,2'-dipyridyl (10 mg, 0,068 mmol) at room temperature followed by the addition of NaBH4(40 mg, of 1.02 mmol). The reaction mixture was cooled to -10°C. and then was added dropwise intermediate compound (2q) (0,22 g, of 1.36 mmol) in ethanol (1 ml) for 10 minutes. The reaction mixture was stirred for 15 minutes and then extinguished acetic acid and methanol at -10°C. the Residue was then dissolved in ethyl acetate and washed with saturated sodium bicarbonate, brine, dried (MgSO4) and the solvents were removed under reduced pressure. The crude product was purified column flash chrome is cografya, using as eluent a mixture of ether:hexane (1:2), and receiving a connection (2q) in the form of white crystals (0.16 g, the output of the selected product 87%).1H-NMR (400 MHz, CDCl3) δ 7.12-7.08 (m, 2H), 6.7 (dd, J=10.4, 4.8 Hz, 1H), 4.3 (or s, 2H).

Stage C: tert-Butyl ether (2-cyano-4-forfinal)-bis-(carbamino acid) (3q). To a solution of (2q) (33 mg, 0.24 mmol) in THF (3 ml) was added BOC2About (200 mg, to 0.72 mmol) and DMAP (dimethylaminopyridine) (5.9 mg, 0,048 mmol) at room temperature. The reaction mixture was heated under reflux for 2.5 hours, then cooled to room temperature and the solvent evaporated under reduced pressure. The crude product was purified column flash chromatography, using as eluent a mixture of ether:hexane (1:3) and receiving the product (3q) in the form of white crystals (0.08 g, the output of the selected product 98%).1H-NMR (400 MHz, CDCl3) δ 7.4-7.26 (m, 3H), 1.45 (s, 18H).

Stage D: tert-Butyl ether (2-aminomethyl-4-forfinal)-bis-(carbamino acid) (4q). To a solution of (3q) (1 g, of 2.97 mmol) in ethanol (30 ml) was added CoBr2(27 mg, 0.12 mmol), 2,2'-dipyridyl (57 mg, 0.36 mmol) at room temperature followed by the addition of NaBH4(350 mg, 9.2 mmol). The reaction mixture was stirred at room temperature for 30 minutes and extinguished acetic acid and methanol at 0°C. Then the residue was dissolved in ethyl acetate and washed with saturated bi is arboretum sodium, brine, dried (MgSO4) and the solvents were removed under reduced pressure. The crude product (4q) was used directly in the next stage (1 g, the output of the selected product 100%).

Stage E: Hydrochloric salt of 2-aminomethyl-4-ftorhinolona (5C). The crude intermediate compound (4q) (0.95 g, 2.8 mmol) was dissolved in Meon/DHM (15 ml). Then added 4 N. HCl (10.5 ml, 42.0 mmol) in dioxane and stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the residue (5q) was sent to the next stage without additional purification or identification.

Stage F: tert-Butyl ether (2-amino-5-terbisil)carbamino acid (6q). A solution of BOC-anhydride (0,49 g, 2.5 mmol) in dioxane (5 ml) was added dropwise to cooled in an ice bath, the solution (5q) (2.8 mmol, 1 EQ.) 5.7 ml of 1 M NaHCO3(5,63 mmol) and dioxane (11.2 ml) (1:2). The reaction mixture was left to warm to room temperature and continued stirring at room temperature for 18 hours. The next day, the mixture was diluted with Et2O and washed with brine. The layers were separated. The aqueous layer (brine) was extracted with Et2O (3×), the combined organic layers were extracted with 10%KHSO4(3×), washed with H2O and brine and dried over Na2SO4. Obtained after concentration the crude product PTS is attended by chromatography (Sep-Pak) using hexane and a mixture of hexane/EtOAc (9:1), receiving the product (6q) (0.34 g, the output of the selected product 50%).1H-NMR (400 MHz, CD3OD) δ 6.85-6.75 (m, 2H), 6.6 (dd, J=7.8, 4.7 Hz, 1H), 4.82 (br s, NH), 4.21 (d, J=6.2 Hz, 2H), 4.06 (br s, NH2), 1.45 (s, 9H). LC-MS IER (+), found: m/z 241 (M+H).

Stage G: tert-Butyl ether [5-fluoro-2-(1-cyclobutylmethyl-1H-indazol-5-ylamino)benzyl]carbamino acid (7q-2). Into the flask containing Bronevoy acid (0,175 g, from 0.76 mmol), amine (6q) (0,22 g, 0,915 mmol), Cu(SLA)2(is 0.135 g, from 0.76 mmol) and 4Å sieves (0.2 g) in DHM, was slowly added Et3N (of 0.52 ml, 3.7 mmol). The mixture was stirred at room temperature for 3 days. To the reaction mixture were added DHM and filtered. The filtrate is washed with N2About (2×), brine and dried over Na2SO4. After concentration the residue was purified by chromatography (Sep-Pak; 10 g), using hexane/Et2About (3:1). The fractions containing the product were combined, receiving (7q-2) (0.12 g, yield 37%).1H-NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.34 (d, J=8.6 Hz, 1H), 7.24 (br s, 1H), 7.13 (d, J=8.6 Hz, 1H), 6.94-6.84 (m, 3H), 5.02 (br s, NH), 4.35 (d, J=7.8 Hz, 2H), 4.29 (d, J=6.2 Hz, 2H), 2.98-2.85 (m, 1H), 2.10-1.98 (m, 2H), 1.95-1.79 (m, 4H), 1.44 (s, 9H). MC (head+), found: m/z 425 (M+H).

Stage N: (2-Aminomethyl-4-forfinal)-(1-cyclobutylmethyl-1H-indazol-5-yl)amine (8q-2). The intermediate compound (7q-2) (0,076 g, 0.18 mmol) was dissolved in DHM/ISO-D (5 ml, 1:1), was added 0.5 ml of HCl (1.97 mmol) in dioxane and the reaction mixture was stirred for 3 days. The solvent issue is rivali, receiving the product (8q-2), which is sent to the next stage. LC-MS IER (+), found: m/z 308 (M-NH2). As (7q-1)and (8q-1) were sent to the final stage, using a Protocol similar to 7q-2 and 8q-2.

Stage I: 1-[5-Cyclopropyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-3-[5-fluoro-2-(1-methyl-1H-indazol-5-ylamino)benzyl]urea (9q-1). Solution (8q-1) (0.15 g, 0.54 mmol) in DMF (4.5 ml) was treated at room temperature with carbamate 10q (0.26 g, 0.6 mmol), and then DIEA (0.35 ml, 2.0 mmol). The mixture was heated at 80°C for 18 hours and then the solvent is evaporated under reduced pressure. The residue was transferred into DHM and washed with 1 N. HCl. The organic layer was filtered through 1PS paper and evaporated to dryness. Then the crude product was purified by HPLC, receiving the product (9q-1) (0,027 g, the output of the selected product 9%).1H-NMR (500 MHz, CDCl3) δ 7.88 (s, 1H), 7.59 (d, J=7.96 Hz, 2H), 7.54 (d, J=7.43 Hz, 2H), 7.57 (br s, NH), 7.37 (d, J=8.49 Hz, 1H), 7.22-7.16 (m, 2H), 7.15 (s, 1H), 6.99-6.91 (m, 2H), 6.21 (s, 1H), 4.34 (s, 2H), 4.07 (s, 3H), 2.01-1.93 (m, 1H), 1.14-0.98 (m, 2H), 0.90-0,83 (m, 2H). MS (head+), found: m/z 564 (M+H).

Stage J: 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-yl)-3-[2-(1-cyclobutylmethyl-1H-indazol-5-ylamino)-5-terbisil]urea (9q-2). Connection (8q-2) (0.18 mmol) was dissolved in DMF (2.5 ml), was added to the carbamate 10q (0.08 g, 0.20 mmol), and then DIEA (0.1 ml, or 0.57 mmol). The reaction mixture was heated up to 80°C for 18 hours. The solvent is evaporated under reduced d is the pressure, the residue was transferred into DHM and washed with 1 N. HCl. The organic layer was filtered through 1PS paper and evaporated under reduced pressure to an oil. Then the crude product was purified by HPLC, receiving the product (9q-2) (0,045 g, the output of the selected product 44%).1H-NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.7 (br s, NH), 7.32 (d, J=9.39 Hz, 1H), 7.18-7.06 (m, 7H), 6.94-6.85 (m, 2H), 6.50 (s, 1H), 4.37-4.30 (m, 6H), 2.96-2.81 (m, 1H), 2.27 (s, 3H), 2.09-1.96 (m, 2H), 1.94-1.76 (m, 4H), 1.34 (s, 9H). MS (head+), found: m/z 580 (M+H).

Example 92

Obtaining 1-(5-tert-butyl-2-p-chlorophenyl-2H-pyrazole-3-yl)-3-[2-(1-methyl-1H-indiso-5-ylsulphonyl)-5-terbisil]urea (6r-2)

The reaction scheme for the synthesis of compounds 6r-2 shown in Fig.

Stage A: 5-Bromo-1H-indazole (1r). 4-Bromo-2-methylaniline (20 g, 107 mmol), tetrafluoroborate ammonium (23 g, 215 mmol) and concentrated HCl (45 ml, 537 mmol) was added to the Asón/N2O (350 ml, 2:1) and treated with ultrasound. Then slowly added NaNO2(8,9 g, 129 mmol) and the reaction mixture was treated with ultrasound for a further 10 minutes (it was dark brown, and immediately formed precipitate). The reaction mixture was left to mix overnight. The next day the original substance was not detected. The mixture was evaporated in quick vacuum at 65°C and then subjected to azeotropic distillation with toluene to dryness. The substance was used directly in the next stage without additional purification Mentioned above crude substance, potassium acetate (42 g, 428 mmol) and 18-crown-6 (2.8 g, 11 mmol) was added to the chloroform (300 ml) and treated with ultrasound for 10 minutes. The reaction mixture was stirred over night at room temperature. The substance was passed through a filter funnel with a mixture of silica gel/celite/sand and repeatedly washed with CHCl3(the substance was not collected). Then the column was washed EtOAc, getting orange substance were collected, combined and evaporated, getting about 16 g of substance. Then the crude product was subjected to flash chromatography on silica gel using DHM:Meon (5%) as eluent and dried under high vacuum over night, receiving the target product (1 g) (8 g, 50% yield).1H-NMR (400 MHz, CDCl3) δ 11.9 (br s, 1H), 8.05 (s, 1H), 7.9 (s, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.39 (d, J=8.8 Hz, 1H). MS (EEC) m/z 197,1 (M+N)+.

Stage b: 5-Bromo-1-methyl-1H-indazol (2 g). 5-Bromo-1H-indazole (1 g) (10 g, 51 mmol) in THF was slowly added to a cold solution of NaH (2.2 g, 60 wt.% in oil, 56 mmol) in THF under nitrogen atmosphere. After 15 minutes, the dark solution was added logmean (10.8 g, 76 mmol) at 0°C. After 2 hours the mixture was poured into 1 N. HCl (30 ml), was extracted with EtOAc (2×50 ml), the combined extracts were washed with brine (50 ml), dried over Na2SO4)was filtered and concentrated. Column chromatography (silica gel)with hexane:EtOAc (10-40%) to give 8.2 g of the final product (2r). H-NMR (400 MHz, CDCl3) δ 7.9 (s, 1H), 7.84 (s, 1H), 7.43 (d, J=8.8 Hz, 1H), 7.24 (d, J=8.8 Hz, 1H), 4.04 (s, 3H). MS (EEC) m/z 213 (M+N)+.

Stage C: 5-(Triisopropylphenylsulfonyl)-1-methyl-1H-indazol (3r). KN (1.3 g, 30 wt.%, 9.8 mmol) washed with THF and then suspended in THF (10 ml) at 5°C. for 15 minutes was added triisopropylsilyl (1.8 g, 9.3 mmol) with intensive hydrogen evolution. The mixture was stirred at 5°C for one hour and then at 25°C for 1 hour. This solution was added to a solution of 1-methyl-5-brominate (2 g) (2 g, 9.5 mmol) and (Ph3P)4Pd (1.1 g, of 0.93 mmol) in THF (15 ml). The yellow suspension was stirred for 1 hour at 70°C. After cooling, was added to the ether solution was washed with brine, dried (Na2SO4) and concentrated. The residue was subjected to chromatography (silica gel, 3% EtOAc in hexane)to give 5-(triisopropylsilyl)-1-methyl-1H-indazol (3r) (1.8 g, 59%).1H-NMR (400 MHz, CDCl3) δ 7.89 (s, 1H), 7.86 (s, 1H), 7.48 (d, J=8.8 Hz, 1H), 7.25 (d, J=8.4 Hz, 1H), 4.05 (s, 3H), 1.28-1.19 (m, 3H), 1.08 (d, J=7.6 Hz, N).

Stage D: 2-(1-Methyl-1H-indazol-5-ylsulphonyl)-5-perbenzoate (4r). The compound (3r) (0.65 g, 2 mmol), potassium carbonate (0.34 g, 2.4 mmol), CsF (and 0.46 g, 3 mmol), 2,5-diferential (0.56 g, 4.1 mmol) and DMF (5 ml) were placed in a 60 ml reaction vessel and the vessel was tightly closed. The mixture was heated to 100°C for 16 hours. Excess DMF was removed under reduced pressure. This substance perenosili DHM (50 ml) and washed with water (20 ml). The aqueous layer was extracted with DHM (3×). The combined organic layers were washed with brine (2×) and dried over MgSO4that was filtered through the filler celite/silica gel and concentrated under reduced pressure. The residue was purified by chromatography on silica gel with hexane/EtOAc (20%), obtaining the final product in the form of a viscous liquid (4 g) (0,43 g, the output of the selected product 75%).1H-NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.97 (s, 1H), 7.46 (dd, J=16.8, 8.8 Hz, 2H), 7.35-7.32 (m, 1H), 7.14-7.07 (m, 1H), 7.05-7.01 (m, 1H), 4.1 (s, 3H). MS (EEC) m/z 284,2 (M+N)+.

Stage E: 2-(1-Methyl-1H-indazol-5-ylsulphonyl)-5-forbindelsen (5r). A solution of compound (4r) (0,43 g, 1.5 mmol) in Meon (30 ml) was purged with nitrogen and was treated with the catalyst Pd(OH)2/C (15 wt.%, 280 mg, 0.3 mmol), and then concentrated HCl (0,38 ml, 4.6 mmol). After purging with nitrogen in the upper part of the flask were placed a balloon filled with hydrogen. After stirring at room temperature for 18 hours analysis by LC showed the absence of starting material. Then put2CO3(0.5 g). The catalyst was filtered through a filler silica gel/celite/sand and washed with a mixture of CHCl3/Et3N, the solvent was removed under reduced pressure. The obtained pale-yellow foam (5r) (0,43 g, the output of the selected product 87%) kept under nitrogen atmosphere. MS (EEC) m/z 287,9 (M+N)+.

Stage F: 1-(5-Cyclopropyl-2-pchlorophenyl-2H-pyrazole-3-yl)-3-[2-(1-methyl-1H-indiso-5-ylsulphonyl)-5-terbisil]urea (6r-1). A solution of the compound (5r) (70 mg, 0.21 mmol) in DMF (1 ml) was treated with the corresponding carbamate (97 mg, 0.24 mmol), and then DIEA (70 μl, 0.54 mmol). The mixture was heated at 80°C for 18 hours under nitrogen atmosphere. Then the crude product was purified preparative thin-layer chromatography using hexane/EtOAc (1:1) as eluent (Rf 0,6) and getting the final product (6r-1) (80 mg, yield of the selected product 68%).1H-NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.57 (s, 1H), 7.34-7.26 (m, 5H), 7.2-7.14 (m, 2H), 6.97 (dd, J=9.2, 2.8 Hz, 1H), 6.92-6.84 (m, 2H), 5.99 (s, 1H), 5.7 (t, J=6.0 Hz, 1H), 4.4 (d, J=5.6 Hz, 2H), 1.89 (m, 1H), 0.95-0.9 (m, 2H), 0.75-0.71 (m, 2H). MS (EEC) m/z 547,1 (M+N)+.

Stage G: 1-(5-tert-Butyl-2-p-chlorophenyl-2H-pyrazole-3-yl)-3-[2-(1-methyl-1H-indiso-5-ylsulphonyl)-5-terbisil]urea (6r-2). A solution of amine (5) (70 mg, 0.21 mmol) in DMF (1 ml) was treated with the corresponding carbamate (100 mg, 0.24 mmol), and then DIEA (70 μl, 0.54 mmol). The mixture was heated at 80°C for 18 hours under nitrogen atmosphere. Then the crude product was purified preparative thin-layer chromatography using hexane/EtOAc (1:1) as eluent (Rf 0,6) and getting the final product (6r-2) (80 mg, yield of the selected product 66%).1H-NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.58 (s, 1H), 7.39-7.26 (m, 5H) 7.21-7.14 (m, 2H), 6.98 (dd, J=9.2, 2.4 Hz, 1H), 6.88 (d(t), J=8.4, 2.4 Hz, 1H), 6.68 (s, 1H), 6.24 (s, 1H), 5.64 (t, J=6.0 Hz, 1H), 4.42(d, J=6.4 Hz, 2H), 4.02 (s, 3H), 1.3 (s, 9H). MS (EEC) m/z 563,1 (M+N)+.

Example 93

Obtain 1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-3-{2-[1-(3-isopropylaminomethyl)-1H-indazol-5-ylamino]benzyl}urea (8s-2)

The reaction scheme for the synthesis of compounds 8s-2 shown in Figa-Century

Stage A: 1-Allyl-5-bromo-1H-indazole (1s). 5-Brominator (Bioorg. Med. Chem. Lett., 11: 1153-1156 (2001)) (3.94 g, 20.0 mmol), allylbromide (2.6 ml, 30 mmol) and potassium carbonate (4.15 g, 30.0 mmol) was heated in DMF (25 ml) at 100°C for 18 hours. The reaction mixture was cooled, filtered through celite and the solids washed with EtOAc. The solution was concentrated almost to dryness and then distributed between EtOAc and water. The organic phase is washed with NaHCOC, dried (MgSO4), concentrated and purified column chromatography (silica gel, 7% EtOAc/hexane), getting the N1 isomer (fast eluruumis) 1-allyl-5-bromo-1H-indazole (1s) (1.7 g, yield 36%).1H-NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.44 (dd, J=8.6, 1.6 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.06-5.97 (m, 1H), 5.24 (dd, J=10.2, 1.6 Hz, 1H), 5.12 (d, J=16.4 Hz, 1H), 5.01-5.00 (m, 2H).

MS IER (+), found: m/z 237, 239 (M+H, Br pattern). HPLC (5-95%) 2,98 minutes

Stage b: 3-(5-Brominated-1-yl)propan-1-ol (2s). 1-Allyl-5-bromo-1H-indazole (1s) (0.50 g, 2.1 mmol) was dissolved in 2 ml THF and cooled to 0°C. Then slowly via a syringe under nitrogen atmosphere and with stirring was added a solution of 9-BBN in THF (0.5 M solution of 8.9 ml, 4.4 mmol). The reaction mixture was heated to room temperature for 6.5 hours. Then to this solution was slowly added to the solution water N2About2(30 wt.%-cent solution of 1.4 ml) in 1 N. NaOH (14 ml, 14 mmol). Reactio the ing the mixture was stirred at room temperature overnight, which led to the formation of a white precipitate. The reaction mixture was diluted with H2Oh and Et2O. the Layers were separated and the organic phase was washed with brine. The aqueous phase was extracted once with Et2O. the Organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum. The crude compound (2s) sent to the next stage without identification.

Stage C: 5-Bromo-1-[3-(tert-butyldiphenylsilyl)propyl]-1H-indazol (3s). The crude 3-(5-brominated-1-yl)propan-1-ol (2s) (2.1 mmol) and imidazole (0,22 g, 3.2 mmol) was dissolved in 10 ml of CH2Cl2. To the solution was added tert-butyldiphenylsilyl (of 0.58 g, 2.1 mmol) and the reaction mixture was stirred at room temperature for 4 hours. Added additional imidazole (0.07 g, 1.0 mmol) and tert-butyldiphenylsilyl (0.16 g, to 0.63 mmol), the reaction mixture was stirred at room temperature overnight. The mixture was diluted with Et2O and sequentially washed with 3%aqueous HCl and brine. The aqueous phase was extracted once with Et2O. the Organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified on silica gel with Et2O/hexane (1:6)to give (3s) (1.0 g, yield on 2 stages 96%) as a colourless oil.1H-NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.86 (s, 1H), 7.61 (d, J=7.8 Hz, 4H), 7.44-7.42 (m, 3H), 7.36-733 (m, 5H), 4.53 (t, J=10.2 Hz, 2H), 3.63 (t, J=9.0 Hz, 2H), 2.16-10 (m, 2H), 1.08 (s, 9H). HPLC (5-95%) 4.72 in minutes

Stage D: 1-[3-(tert-Butyldiphenylsilyl)propyl]-1H-indazol-5-baronova acid (4s). 5-Bromo-1-[3-(tert-butyldiphenylsilyl)propyl]-1H-indazol (3s) (200 mg, 0.41 mmol) was dissolved in 4.0 ml THF and cooled to -78°C. was Slowly added a solution of n-utility in a mixture of hexanol (2.5 M, 0.17 ml). The yellow solution was stirred for 30 minutes. Added trimethylboron (130 mg, 1.2 mmol), the reaction mixture was heated to room temperature and was stirred for 30 minutes. The reaction extinguished 10 ml of 0.3%aqueous HCl and the resulting mixture was stirred for 30 minutes. The reaction mixture was diluted with Et2O and the layers were separated. The organic phase was washed with brine. The aqueous phase was extracted once with Et2O. the Organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum. The crude product was partially purified on silica gel with 3% MeOH/CH2Cl2receiving (4s) (97 mg, 52%). MS IER (+) m/z 459 (M+N)+. HPLC (5-95%) 3,74 minutes This mixture is sent to the next stage without additional purification.

Stage E: 1-(2-Aminobenzyl)-3-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)urea (5s). 5-tert-Butyl-2-methyl-2H-pyrazole-3-ylamine (10s) (4.8 g, 31 mmol) and carbonyldiimidazole (4.6 g, 32 mmol) was partially dissolved in EDC (100 ml) and heated at 70°C for 2 hours. The reaction mixture was cooled and obavljale 2-aminoethylethanolamine (9s) (4,2 g, 34 mmol), the reaction mixture was stirred for 14 hours. The reaction mixture was concentrated to remove solvent and then distributed between EtOAc and 0.5 N. HCl (60 ml). The organic phase is washed with NH4Cl and water and dried (MgSO4). The solution was concentrated and recrystallized from EtOAc (200 ml)to give the target product (5s) (4.6 g, yield 49%).1H-NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 6.98 (d, J=1.6 Hz, 1H), 6.96 (dt, J=7.8, 1.6 Hz, 1H), 6.63 (t, J=6.3 Hz, 1H), 6.59 (d, J=7.0 Hz, 1H), 6.48 (t, J=6.3 Hz, 1H), 5.93 (s, 1H), 5.07 (s, 2H), 4.12 (d, J=6.3 Hz, 2H), 3.51 (s, 3H), 1.16 (s, 9H).

Stage F: 1-(2-{1-[3-(tert-Butyldiphenylsilyl)propyl]-1H-indazol-5-ylamino}benzyl)-3-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)urea (6s). Bronevoy acid 4 (240 mg, 0.52 mmol), 1-(2-aminobenzyl)-3-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)urea (5s) (170 mg, of 0.58 mmol), copper acetate (II) (90 mg, 0.52 mmol) and 240 mg of 4Å molecular sieves suspended in 10 ml of CH2Cl2. Was added triethylamine (of 0.36 ml, 2.6 mmol) and the mixture was stirred at room temperature during the night, exposing the influence of air. Was added 3 ml of CH2Cl2the mixture was filtered through celite and volatiles were removed in vacuum. The crude product was purified on silica gel with 2-4% Meon/CH2Cl2receiving (6s) (170 mg, yield 45%) as a brown resin.

MS IER (+), found: m/z 714 (M+N)+. HPLC (5-95%) 4,32 minutes

Stage G: 1-(5-tert-Butyl-2-methyl-2H-pyrazole-3-yl)-3-2-[1-(3-hydroxypropyl)-1H-indazol-5-ylamino]benzyl}urea (7s). 1-(2-{1-[3-(tert-Butyldiphenylsilyl)propyl]-1H-indazol-5-ylamino}benzyl)-3-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)urea (6s) (40 mg, 0,056 mmol) was dissolved in 0.5 ml of THF and was treated with TBAF (1.0 M solution in THF, of 0.11 ml, 0.11 mmol). The reaction mixture was stirred at room temperature for 1 hour. Added additional amount of TBAF (0.3 ml, 0.3 mmol) and the reaction mixture was stirred for another 2 hours. The reaction mixture was diluted with CH2Cl2and washed with N2O. the Aqueous phase was extracted once CH2Cl2. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum. The product was purified on silica gel with 5% Meon/CH2Cl2receiving the target compound (7s) (8 mg, 30%, purity about 90%as detected1H-NMR and HPLC).1H-NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.36-7.31 (m, 2H), 7.21-7.12 (m, 4H), 6.85 (s, 1H), 6.81 (t, J=10.6 Hz, 1H), 5.93 (s, 1H), 5.41-5.38 (m, 1H), 4.49 (t, J=9.0 Hz, 2H), 4.43 (d, J=6.3 Hz, 2H), 3.57 (t, J=8.2 Hz, 3H), 3.52 (s, 3H), 2.13-2.07 (m, 2H), 1.25 (s, 9H). MS (head) m/z 476 (M+N)+. HPLC (5-95%) 2,79 minutes

Stage N: 1-(5-tert-Butyl-2-methyl-2H-pyrazole-3-yl)-3-{2-[1-(3-dimethylaminopropyl)-1H-indazol-5-ylamino]benzyl}urea (8s-1). The anhydride of methansulfonate (12 mg, 0,070 mmol) was added to a solution of alcohol (7s) (24 mg, 0,050 mmol) and diisopropylethylamine (20 mg, 0.15 mmol) at room temperature. The solution was stirred for 1 hour. Added demeti the amine (2.0 M in THF, 0.25 ml, 0.50 mmol) and the reaction mixture was stirred over night. Added additional amount of dimethylamine (2.0 M in THF, 0.25 ml, 0.50 mmol) and the reaction mixture was stirred for another 2 days. The mixture is then distributed between CHCl3and water. The aqueous phase was extracted once CHCl3. The organic phases were combined, dried (MgSO4), filtered and concentrated in vacuum. The crude product was purified on silica gel using a mixture of 5% Meon/CH2Cl2containing 1% Et3N, and obtaining the target compound (8s-1) (11 mg, yield 43%) as a dark foam.1H-NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.42 (s, 1H), 7.35-7.33 (m, 2H), 7.19-7.11 (m, 4H), 6.80-6.75 (m, 2H), 5.94 (s, 1H), 5.55 (m, 1H), 4.43 (d, J=6.6 Hz, 2H), 4.38 (t, J=10.5 Hz, 2H), 3.57 (s, 3H), 2.24 (t, J=10.5 Hz, 2H), 2.19 (s, 6N), 2.08-2.01 (m, 2H), 1.24 (s, 9H). MS IER (+), found: m/z 503 (M+N)+. HPLC (5-95%) 2,59 minutes

Stage I: 1-(5-tert-Butyl-2-methyl-2H-pyrazole-3-yl)-3-{2-[1-(3-isopropylaminomethyl)-1H-indazol-5-ylamino]benzyl}urea (8s-2). The anhydride of methansulfonate (18 mg, 0.11 mmol) was added to a solution of alcohol (7s) (36 mg, 0,076 mmol) and diisopropylethylamine (29 mg, 0.23 mmol) at room temperature. The solution was stirred for 1 hour. Added Isopropylamine (0,13 ml, 1.50 mmol) and the reaction mixture was stirred at room temperature for 60 hours. Volatiles were removed in vacuum. The crude product was purified on silica gel using the UYa mixture of 5% Meon/CH 2Cl2containing 1% Et3N, and then on silica gel With18with CH3CN/H2O, obtaining the target compound (8s-2) (8 mg, yield 20%).1H-NMR (400 MHz, MeOD) δ 7.88 (s, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.31-7.24 (m, 3H), 7.17-7.16 (m, 2H), 6.93-6.89 (m, 1H), 6.05 (s, 1H), 4.52 (t, J=10.2 Hz, 2H), 4.41 (s, 2H), 3.57 (s, 3H), 3.35-3.30 (m, 1H), 3.03 (t, J=11.7 Hz, 2H), 2.29-2.22 (m, 2H), 1.29 (d, J=6.3 Hz, 6N), 1.26 (s, 9H). MS IER (+), found: m/z 517 (M+N)+. HPLC (5-95%) 2,61 minutes

Example 94

Obtaining 1-(5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)benzyl]urea (7t-1) and 1-[5-tert-butyl-2-(4-chlorophenyl)-2H-pyrazole-3-yl]-3-[5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)benzyl]urea (7t-2)

The reaction scheme for the synthesis of compounds 7t-2 shown in Fig.

Stage A: 5-Methoxy-1-methyl-1H-indazol (2t). A solution of 5-methoxyindole (1t) (5 g, 33,75 mmol; Tet Lett., 43 (15): 2695 (2002)) in DMF (200 ml) was treated with potassium carbonate (6,06 g, 43,87 mmol) at room temperature. After stirring for 15 minutes was added methyliodide (2,33 ml, 37,12 mmol). The resulting mixture was heated at 110°C for 18 hours. Analysis by LC showed a slight remains of the original substance. Added more methyliodide (2,33 ml) and stirring continued for a further 18 hours. Analysis by LC showed the presence of a mixture of N1 and N2 alkyl isomers (1:2). The solvent is evaporated in vacuo, the residue was transferred into DHM and washed with 1 N. HCl. The body is ical layer was filtered through 1PS paper, was evaporated in vacuo and purified on Biotage, elwira a mixture of hexane/Et2About(4:3, 3:1). United target fraction (N1 isomer) was evaporated in vacuum, obtaining the target product (2t) as a yellow oil (2.57 m) g; 47%).1H-NMR (400 MHz, CDCl3) δ 7.38 (d, J=7.8 Hz, 1H), 7.17 (dd, J=7.8, 1.6 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 5.19-5.18 (m, 1H), 4.51-4.44 (m, 1H), 4.43-4.36 (m, 1H), 2.53-2.45 (m, 1H), 2.36-2.30 (m, 1H). MS IER (+), found: m/z 163 (M+H).

Stage b: 1-Methyl-1H-indazol-5-ol (3t). To a solution of (2t) (0,99 g, 6.1 mmol) in toluene (30 ml) was added AlCl3(2,44 g, and 18.3 mmol) at room temperature, after which he formed a mixture of purple. After heating under reflux for 20 minutes formed a mixture of olive color. The mixture was heated under reflux for 2 hours, left to cool to room temperature and was poured into a bath of ice water. Insoluble solids were collected by filtration (398 mg). The filtrate was extracted with DHM, filtered through 1PS paper, evaporated in vacuo and purified on Biotage, elwira mix Et2O/DHM ((1:9), then (3:7)) and finally the mixture DHM/Et2O (1:1). Fraction of the product was evaporated in vacuum, obtaining the compound (3t) as a brown foam (122 mg). Total combined output was 520 mg (58%).1H-NMR (400 MHz, CDCl3) δ 7.38 (d, J=7.8 Hz, 1H), 7.17 (dd, J=7.8, 1.6 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 5.19-5.18 (m, 1H), 4.51-4.44 (m, 1H), 4.43-4.36 (m, 1H), 2.53-2.45 (m, 1H), 2.36-2.30 (m, 1H). MS IER (+), about naruhina: m/z 149 (M+H).

Stage C: 5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)benzonitrile (4t). Solution (3t) (0,70 g, 4,74 mmol) in DMF (50 ml) was cooled to 0°C. and was treated with 60 wt.%-NYM sodium hydride (0.28 g, 7,11 mmol). After stirring at this temperature for 20 minutes was added halftoned (0,79 g, 5,69 mmol) at 0°C. the Reaction mixture was heated to room temperature and was stirred for 1 hour. Then the mixture was cooled to 0°C and treated with water (50 ml), was extracted with Et2O (3×150 ml), the combined organic layers were washed with water (2×20 ml), brine (2×20 ml), dried over MgSO4and evaporated in vacuo to an oil. This substance was purified column flash chromatography (EtOAc/hexane = 2:3; put in a warm mixture of toluene and DMF). The target fraction was evaporated in vacuum and subjected to azeotropic distillation with toluene. Received connection (4t) in the form of white crystals (1,09 g; output the selected product 86%).1H-NMR (400 MHz, CDCl3) δ 7.38 (d, J=7.8 Hz, 1H), 7.17 (dd, J=7.8, 1.6 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 5.19-5.18 (m, 1H), 4.51-4.44 (m, 1H), 4.43-4.36 (m, 1H), 2.53-2.45 (m, 1H), 2.36-2.30 (m, 1H). MS IER (+), found: m/z 268 (M+H).

Stage D: Hydrochloride 5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)benzylamine (5t). Solution (4t) (0.32 g, 1,22 mmol) in Meon (20 ml) was purged with nitrogen and was treated with the catalyst of 20% Pd(OH)2/C (15 wt.%, 180 mg), and then concentrated HCl (0.3 ml, 3.6 mmol). After purging with nitrogen in the upper part to what would have placed the container, filled with hydrogen. After stirring at room temperature for 18 hours analysis by LC showed the absence of starting material. The catalyst was filtered through a filler silica gel/celite/sand and washed Meon. The solvent is evaporated in vacuum and the residue was co-evaporated with ether. The obtained pale-yellow foam (5t) kept in an atmosphere of N2(0.34 g; output the selected product 91%).1H-NMR (400 MHz, CDCl3) δ 7.38 (d, J=7.8 Hz, 1H), 7.17 (dd, J=7.8, 1.6 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 5.19-5.18 (m, 1H), 4.51-4.44 (m, 1H), 4.43-4.36 (m, 1H), 2.53-2.45 (m, 1H), 2.36-2.30 (m, 1H). MS IER (+), found: m/z 272 (M+H).

Stage E: 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)benzyl]urea (7t-1). Solution (5t) (70 mg, 0.23 mmol) in DMF (1 ml) was treated with the corresponding carbamate (6t-1) (100 mg, 0.25 mmol), and then DIEA (99 μl, or 0.57 mmol). The mixture was heated at 80°C for 18 hours, blowing with nitrogen. The solvent is evaporated in vacuo, the residue was transferred into DHM and washed with 1 N. HCl. The organic layer was filtered through 1PS paper and evaporated in vacuo to an oil, which was purified on a cartridge with silica gel Sep Pak, elwira mixture DHM/Et2O (10:1). The target fraction was evaporated in vacuum, obtaining the target compound (7t-1) in the form of a pale yellow oil (80 mg; output the selected product 67%).1H-NMR (400 MHz, CDCl3) δ 7.38 (d, J=7.8 Hz, 1H), 7.17 (dd, J=7.8, 1.6 Hz, 1H), 7.13 (d, J=1.6 G the, 1H), 5.19-5.18 (m, 1H), 4.51-4.44 (m, 1H), 4.43-4.36 (m, 1H), 2.53-2.45 (m, 1H), 2.36-2.30 (m, 1H). MS IER (+), found: m/z 527 (M+H).

Stage F: 1-[5-tert-Butyl-2-(4-chlorophenyl)-2H-pyrazole-3-yl]-3-[5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)benzyl]urea (7t-2). Solution (5t) (74 mg, or 0.57 mmol) in DMF (1 ml) was treated with the corresponding carbamate (6t-2) (110 mg, 0.25 mmol), and then DIEA (99 ml, or 0.57 mmol). The mixture was heated at 80°C for 18 hours, blowing with nitrogen. The solvent is evaporated in vacuo, the residue was transferred into DHM and washed with 1 N. HCl. The organic layer was filtered through 1PS paper and evaporated in vacuo to an oil, which was purified on a cartridge with silica gel Sep Pak, elwira mixture DHM/Et2O (10:1). The target fraction was evaporated in vacuum, obtaining the target compound (7t-2) in the form of a pale yellow oil (80 mg; output the selected product 64%).1H-NMR (400 MHz, CDCl3) δ 7.38 (d, J=7.8 Hz, 1H), 7.17 (dd, J=7.8, 1.6 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 5.19-5.18 (m, 1H), 4.51-4.44 (m, 1H), 4.43-4.36 (m, 1H), 2.53-2.45 (m, 1H), 2.36-2.30 (m, 1H). MS IER (+), found: m/z 547 (M+H).

In a similar way were synthesized the following compounds.

Example 95

Getting 2-(1-cyclobutylmethyl-1H-indazol)-5-formanilide cyclopropanecarbonyl acid (9t)

Solution (8t) (20 mg, 0.06 mmol; obtained by the method described in Example 94, stages A-D, except for the treatment of concentrated HCl) in DHM (0.5 ml) was treated with base (13 μl, 0.09 is IMO the b) and then cyclopropanecarbonitrile (6 μl, 0.07 mmol) at room temperature and purging with nitrogen. The mixture was stirred at room temperature for 18 hours and then purified on a cartridge with silica gel Sep Pak, elwira mixture DHM-Et2About (10:1). The target fraction was evaporated in vacuum, obtaining the product (9t) as a pale yellow oil (10,2 mg; output the selected product 42%). MS IER (+), found: m/z 394 (M+H).

Example 96

Obtaining N-[5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)benzyl]-3-cryptomelane (11t)

A solution of the compound (10t) (14 mg, 0.05 mmol; obtained by the method described in Example 94, stages A-D, except for the treatment of concentrated HCl) in DHM (0.5 ml) was treated with base (11 μl, 0.06 mmol)and then 3-triftoratsetilatsetonom (12 mg, of 0.075 mmol) at room temperature and purging with nitrogen. The mixture was stirred at room temperature for 18 hours and then purified on a cartridge with silica gel Sep Pak, Eluru mixture DHM-Et2O (10:1). The target fraction was evaporated in vacuum, obtaining the product (11t) as a yellow oil (16.6 mg; output the selected product 53%).1H-NMR (400 MHz, CDCl3) δ 7.38 (d, J=7.8 Hz, 1H), 7.17 (dd, J=7.8, 1.6 Hz, 1H), 7.13 (d, J=1.6 Hz, 1H), 5.19-5.18 (m, 1H), 4.51-4.44 (m, 1H), 4.43-4.36 (m, 1H), 2.53-2.45 (m, 1H), 2.36-2.30 (m, 1H). MS IER (+), found: m/z 468 (M+H).

Example 97

Obtaining N-[2-(1-isobutyl-1H-indazol-5-yloxy)be the ZIL]-2-(3-triptoreline)ndimethylacetamide (14t)

Obtaining N-[2-(1-isobutyl-1H-indazol-5-yloxy)benzyl]-2-(3-triptoreline)ndimethylacetamide (14t)

A solution of (3-triptoreline)acetic acid (12t) (10 mg, 0,051 mmol) in THF (0.5 ml) at room temperature was treated with 1,1-carbonyl diimidazol (CBI, 9 mg, by 0.055 mmol). After stirring at room temperature and purging with nitrogen for 18 hours was added benzylamine (13t) (17 mg, 0.05 mmol; obtained by the method described in Example 94, stage A-D) at room temperature. Stirring was continued for another 18 hours. The solvent is evaporated in vacuo, the residue was transferred into DHM and was purified on a cartridge with silica gel Sep Pak, elwira mixture DHM-Et2About (10:1). The target fraction was evaporated in vacuum, obtaining the product (14t) as a pale yellow oil (10 mg; output the selected product 42%). MS IER (+), found: m/z 482 (M+H).

Example 98

Getting 5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)benzylamine 5-tert-butyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid (16t)

A solution of 5-tert-butyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid (15t) (12 mg, 0.05 mmol) in THF (0.5 ml) was treated with 1,1-carbonyl diimidazol (CBI, 9 mg, 0.05 mmol) at room temperature. After stirring at room temperature and purging with nitrogen for 18 hours was added benzylamine (13t) (15 mg, 0.05 mmol; obtained the way, described in Example 94, stage A-D) at room temperature. Stirring was continued for another 18 hours. The solvent is evaporated in vacuo, the residue was transferred into DHM and was purified on a cartridge with silica gel Sep Pak, elwira Meon (2-10%) in THM. The target fraction was evaporated in vacuum, obtaining the product (16t) as a yellow oil (5.2 mg; output the selected product 23%). MS IER (+), found: m/z 541 (M+H).

Example 99

Getting 2-cyclopropyl-N-[5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)benzyl]ndimethylacetamide (18t)

A solution of the compound (13t) (15 mg, 0.05 mmol; obtained by the method described in Example 94, stage A-D) in DHM (0.5 ml) was added to the corresponding TFP (tetracarpidium) ether complex (17T load) (1 mmol/g) at room temperature. The mixture was shaken for 18 hours. The resin was washed DHM. The combined filtrates were concentrated in vacuo and purified on a cartridge with silica gel Sep Pak, elwira mixture DHM-Et2O (10:1). The target fraction was evaporated in vacuum, obtaining the product (18t) as a yellow oil (12.6 mg; output the selected product 66%). MS IER (+), found: m/z 400 (M+H).

Example 100

Obtain 3-chloro-N-[5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)benzyl]benzamide (20t)

Solution (13t) (15 mg, 0.05 mmol; obtained by the method described in Example 94, stage A-D) in DHM (0.5 ml) was added to appropriate the TFP complex ether (19t) (1 mmol/g) at room temperature. The mixture was shaken for 18 hours. The resin was washed DHM. The combined filtrates were concentrated in vacuo and purified on a cartridge with silica gel Sep Pak, elwira mixture DHM-Et2O (10:1). The target fraction was evaporated in vacuum, obtaining the product (20t) as a yellow oil (14.4 mg; output the selected product 66%). MS IER (+), found: m/z 452 (M+H).

Example 101

Obtaining N-[5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)benzyl]-4-triftoratsetilatsetonom (21t)

A solution of the compound (13t) (15 mg, 0.04 mmol; obtained by the method described in Example 94, stage A-D) in pyridine (0.5 ml) was treated with 4-triftoratsetilatsetonom (13 mg, 0.05 mmol) at room temperature and purging with nitrogen. The mixture was stirred at room temperature for 18 hours. The solvent is evaporated in vacuum, transferred in DHM and washed with 1 N. HCI. The organic layer was filtered through 1PS paper, concentrated in vacuo and purified on a cartridge with silica gel Sep Pak, elwira mixture DHM-Et2O (10:1). The target fraction was evaporated in vacuum, obtaining the product (21t) as a yellow oil (15.6 mg; output the selected product 70%). MS IER (+), found: m/z 522 (M+H).

Example 102

Obtaining N-[5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)benzyl]methanesulfonamide (22t)

A solution of the compound (13t) (15 mg, 0,043 mmol; polucen is th way described in Example 94, stage A-D) in pyridine (0.5 ml) was treated with methanesulfonamide (4 μl, 0.05 mmol) at room temperature and purging with nitrogen. The mixture was stirred at room temperature for 18 hours. The solvent is evaporated in vacuum, transferred in DHM and washed with 1 N. HCl. The organic layer was filtered through 1PS paper, concentrated in vacuo and purified on a cartridge with silica gel Sep Pak, elwira mixture DHM-Et2O (10:1). The target fraction was evaporated in vacuo to a yellow oil (22t) (13,1 mg; output the selected product 78%). MS IER (+), found: m/z 392 (M+H).

Example 103

Getting 5-fluoro-2-(1H-indazol-5-yloxy)benzonitrile (26t)

The reaction scheme for the synthesis of compounds 26t shown in Fig.

Stage A: 5-fluoro-2-hydroxybenzonitrile (23t). 2.5-Diferential (14.9 g, 107 mmol) and benzyl alcohol (11,1 ml, 11.6 g, 107 mmol) was dissolved in DMF (330 ml) and cooled to 0°C. To this solution was added sodium hydride (60% in oil, 6,40 g, 161 mmol) at 0°C and the reaction mixture was left to warm to room temperature. After stirring for 1 hour at room temperature the reaction solution was cooled to 0°C. and to this solution was gradually added water (330 ml). The mixture was transferred into a separating funnel and three times was extracted with 500 ml of Et2O. the combined organic layer was twice washed with 100 ml water, once with brine, C is the dried over MgSO 4. After filtration the solution was concentrated under reduced pressure to get crude pale yellow solid. The crude solid was dissolved in Meon (500 ml). To the solution was added 10% palladium on charcoal in an atmosphere of nitrogen. Nitrogen gas was replaced with gaseous hydrogen, the reaction mixture was stirred at room temperature for 30 minutes, the reaction did not occur, then palladium on coal was filtered and the reaction was carried out again). After stirring for 2 hours palladium on coal was filtered and washed Meon. The solution was concentrated under reduced pressure to obtain a pale yellow solid. The solid is recrystallized from hot toluene (100 ml), adding hexane (10 ml) then cooled to 0°C. the Obtained white needles were washed with a mixture of toluene and hexane (1:1, of 7.23 g, yield 49%). The mother liquor was concentrated and purified on silica gel with Et2O/hexane (2:3-1:1)to give the target compound (23t) (6,94 g, yield 47%). Total output on 2 stages of 14.2 g (96%).1H-NMR (400 MHz, d6-DMSO) δ 11.09 (s, 1H), 7.58 (dd, J=8.4, 3.2 Hz, 1H), 7.40 (td, J=8.6, 3.2 Hz, 1H), 7.03 (dd, J=9.2, 4.4 Hz, 1H) million-1.

Stage b: 5-fluoro-2-(3-methyl-4-nitrophenoxy)benzonitrile (24t). The intermediate compound (23t) (10.0 g, with 72.9 mmol), 4-fluoro-2-methyl-1-nitrobenzene (13,6 g of 87.5 mmol) and potassium carbonate (11.1 g, 8.2 mmol) was dissolved in dimethylacetamide (DMA, 400 ml) and then the mixture was heated to 100°C under vigorous stirring. After stirring for 16 hours the reaction mixture was cooled to room temperature, and then to this mixture was added 400 ml of water. The mixture was extracted three times with 500 ml Et2O. the combined organic layer washed three times with 100 ml of water and once with brine. Then the solution was dried over MgSO4, filtered and concentrated under reduced pressure. The obtained orange crude solid is washed with 100 ml of warm (about 50°C) hexane and 400 ml of hexane (not warm)to give a pale yellow solid (16.4 g). The orange filtrate was concentrated and the residue was purified on silica gel with Et2O/hexane (1:4-1:3), getting slightly orange solid, which was washed with a mixture of Et2O and hexane (1:3) (1.2 g). Uniting the two portions of a pale yellow solid, receiving connection (24t) (17.6 g, yield 89%).

1H NMR (400 MHz, CDCl3) δ 8.08 (d, J=8.6 Hz, 1H), 7.43 (dd, J=7.6, 3.1 Hz, 1H), 7.35 (ddd, J=9.7, 3.1 Hz, 1H), 7.09 (dd, J=9.5, 4.7 Hz, 1H), 6.95-6.87 (m, 2H), 2.62 (s, 3H) million-1.

Stage C: 2-(4-Amino-3-methylphenoxy)-5-perbenzoate (25t). The intermediate compound (24t) (14.3 g, mmol) and zinc dust (17,2 g, 263 mmol) suspended in a mixed solvent Meon/THF (1:1, 125 ml) was added saturated NH4Cl (125 ml). The reaction mixture became warm. Was I the ing the change in zinc suspension. The reaction was terminated after 10 minutes. The reaction mixture was filtered through a filler made of silicon dioxide and is diluted with EtOAc and saturated NaHCO3. The layers were separated, the combined organic substances were dried over MgSO4and concentrated under reduced pressure. The crude residue (25t) was pure enough for an NMR spectrum.1H NMR (400 MHz, d6-DMSO) δ 7.83 (dd, J=8.5, 3.1 Hz, 1H), 7.47 (td, J=8.9, 3.1 Hz, 1H), 6.83-6.77 (m, 2H), 6.74 (dd, J=8.6, 2.3 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 4.88 (s, 1H), 2.06 (s, 3H) million-1.

Stage D: 5-fluoro-2-(1H-indazol-5-yloxy)benzonitrile (26t). The intermediate compound (25t) (13,2 g of 54.5 mmol) and NH4BF4was dissolved in 550 ml of a mixed solvent Asón and water (2:1) and cooled to 0°C. To the solution at 0°C was added concentrated HCl (12 N., 23 ml, 272 mmol) and NaNO2(4,14 g to 59.9 mmol), then the mixture was left to warm to room temperature and stirred. After 3 hours stirring, the solution was concentrated under reduced pressure and 4 times was subjected to azeotropic distillation with toluene to dryness, obtaining a pale yellow crude solid. The solid was dissolved in 600 ml of EtOAc and this solution was added COAs, then the mixture was stirred at room temperature. After 30 minutes, the yellow solution became orange, and it was further stirred. After stirring over night the orange suspension was filtered and n is the number of times washed with EtOAc to a total volume of 1000 ml The organic solution was transferred into a separating funnel and washed with saturated NaHCO3and brine, dried over MgSO4, was filtered and was evaporated. The crude orange solid was purified on silica gel with EtOAc /hexane (1:2-1:1)to give an orange solid (13,2 g), which was washed with toluene. Toluene solution of orange was concentrated and again washed with toluene. The repetition of the same toluene wash was given connection (26t) in the form of solid compounds slightly orange (11.7 g, yield on 2 stages 84%).1H-NMR (400 MHz, CDCl3) δ 12.12 (s, 1H), 8.03 (s, 1H), 7.58 (d, J=9.4 Hz, 1H), 7.40 (d, J=2.3 Hz, 1H), 7.37 (dd, J=7.9, 3.1 Hz, 1H), 7.18 (ddd, J=9.4, 7.9, 3.1 Hz, 1H), 7.13 (dd, J=8.5, 2.3 Hz, 1H), 6.80 (dd, J=9.3, 3.9 Hz, 1H) million-1.

Example 104

Obtain 3-(5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl)-1-[5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)benzyl]-1-metalmachine (28t)

The reaction scheme for the synthesis of compounds 28t shown in Fig.

Stage A: Hydrochloride 5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)benzylamine (5t). The intermediate compound (4t) (1.13 g, to 4.23 mmol; obtained as described in Example 94, phase a-C) was dissolved in methanol (50 ml) and to the solution was added 20%palladium hydroxide on charcoal (0.50 g, 0.71 mmol) under nitrogen atmosphere. After adding concentrated HCl (12 N., 5.0 ml, 60 mmol) and the mixture was stirred in hydrogen atmosphere overnight (18 hours) - Rev.). The mixture was filtered and palladium hydroxide was washed Meon. After evaporation the crude residue was subjected to azeotropic distillation with a mixture of toluene and EtOH (dry)to give compound (5t) in the form of a white powder (1.29 g, yield 99%).1H-NMR (400 MHz, CDCl3) δ 8.72 (br, 3H), 8.01 (s, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.57 (dd, J=9.4, 2.3 Hz, 1H), 7.38 (s, 1H), 7.19 (d, J=3.1 Hz, 1H), 7.04 (td, J=74.8, 3.1 Hz, 1H), 7.02 (dd, J=195.1,4.7 Hz, 1H), 4.07 (s, 3H) million-1.

Stage b: tert-Butyl ether [5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)benzyl]carbamino acid (26t). The intermediate compound (5t) (134 mg, 0.43 mmol) was dissolved in CH2Cl2(5 ml) and to the solution was added diisopropylethylamine (151 μl, 112 mg, 0.87 mmol) and di-tert-BUTYLCARBAMATE (94,7 mg, 0.43 mmol). After stirring overnight (12 hours) the reaction mixture was diluted with ethyl acetate (100 ml), washed with 0.2 N. HCl (5 ml), saturated NaHCO3(5 ml) and brine, dried over MgSO4and concentrated under reduced pressure, obtaining the crude yellow oil, which was purified on silica gel with EtOAc/hexane (1:2)to give the product (26t) as a colourless oil (150 mg, yield 93%).1H-NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.35 (d, J=9.4 Hz, 1H), 7.15-7.08 (m, 3H), 6.87 (t, J=9.4 Hz, 1H), 6.75 (dd, J=8.7, 4.7 Hz, 1H), 5.09 (br, 1H), 4.35 (d, J=6.3 Hz, 2H), 4.06 (s, 3H), 1.42 (s, N) million-1.

Stage C: tert-Butyl ether [5-fluorescent-2-(1-methyl-1H-indazol-5-yloxy)benzyl]methylcarbamate acid (27t). The intermediate connection of the tell (26t) (50 mg, is 0.135 mmol) was dissolved in DMF (2 ml) and cooled to 0°C. To the solution at 0°C was added sodium hydride (60%, and 8.1 mg, 0.20 mmol) and methyliodide (42 μl, with 95.5 mg, 0.67 mmol), then the mixture was left to warm to room temperature. After stirring for 1 hour the mixture was poured into a saturated solution of NH4Cl and was extracted three times with 30 ml of ether. The combined organic layer was twice washed in 5 ml of water and once with brine, dried over MgSO4and evaporated under reduced pressure. The pale yellow residue was purified on silica gel with EtOAc/hexane (1:2)to give compound (27t) as a colourless oil (52 mg, quantitative yield).1H-NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.35 (s, 0,4H), 7.33 (s, 0,6H), 7.11 (s, 0,6H), 7.08 (s, 1,4H), 6.98 (d, J=8.6 Hz, 1H), 6.92-6.81 (m, 1), 6.81-6.73 (m, 1H), 4.49 (s, 0,8H), 4.45 (s, 1,2H), 4.04 (s, 3H), 2.89 (s, 1.8H), 2.85 (s, 1,2H), 1.45 (s, 3,6H), 1.41 (s, 5,4H) million-1.

Stage D: 3-(5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-yl)-1-[5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)benzyl]-1-metalmachine (28t).

The intermediate compound (27t) (52 mg, is 0.135 mmol) was dissolved in CH2Cl2(2 ml) and to the solution at room temperature was added TFU (1 ml). After stirring for 1 hour the reaction solution was evaporated under reduced pressure. The residue was diluted with EtOAc (50 ml) and neutralized with saturated NaHCO3, washed with brine, dried over MgSO4and evaporated under reduced pressure. The crude pale yellow m the slo was dissolved in DMA (2 ml). To the solution was added to the carbamate (6t-1) and diisopropylethylamine and was heated up to 80°C in a sealed tube. After stirring for 16 hours the reaction mixture was diluted with Et2O (50 ml) and washed three times with 5 ml of water and once with brine, dried over MgSO4and evaporated under reduced pressure. The crude oil was purified flash column-chromatography (ethyl acetate/hexane, 1:1)to give compound (28t) as a white foam (to 63.8 mg, yield on 2 stages 87%).1H-NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.32 (d, J=9.4 Hz, 1H), 7.22 (d, J=7.8 Hz, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.02 (s, 1H), 6.98 (d, J=8.6 Hz, 1H), 6.89 (t, J=8.6 Hz, 1H), 6.72 (dd, J=7.7, 4.7 Hz, 1H), 6.62 (s, 1H), 6.39 (s, 1H), 4.51 (s, 2H), 4.05 (s, 3H), 2.94 (s, 2H), 2.32 (s, 3H), 1.30 (s, 9H) million-1.

Example 105

Obtaining 1-(5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)benzyl]-1-metalmachine (32t)

The reaction scheme for the synthesis of compounds 32t shown in Fig.

Stage A: [5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)benzyl]-(4-methoxybenzyl)Amin (29t). The intermediate compound (5t) (136 mg, 0,442 mmol; obtained as described in Example 106, step A) was dissolved in EtOAc (100 ml) and neutralized with saturated NaHCO3, then washed with brine, dried over MgSO4and evaporated under reduced pressure, obtaining the free amine. The free amine was dissolved in 1,2-dichloroethane (5 ml) and to this solution at room temperature was added p-anisic aldehyde. After re is eshiwani within 2 hours, the solution was evaporated under reduced pressure. The residue was dissolved in Meon (5 ml) and cooled to 0°C. To the solution was added borohydride sodium at 0°C. After stirring for 40 minutes at 0°C. the reaction mixture was extinguished with a few drops of acetic acid at 0°C., then the reaction mixture was evaporated under reduced pressure. The residue was diluted with EtOAc (50 ml) and neutralized with saturated NaHCO3and washed with brine, dried over MgSO4and evaporated, obtaining the crude oil, which was purified on silica gel with EtOAc/hexane (1:1) with 1% Et3N, receiving the connection (29t) as a colourless oil (139 mg, yield 80%).1H-NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.34 (d, J=9.4 Hz, 1H), 7.28 (d, J=7.0 Hz, 1H), 7.23-7.15 (m, 2H), 7.13-7.06 (m, 2H), 6.92-6.85 (m, 2H), 6.84-6.78 (m, 2H), 4.61 (s, 1H), 4.06 (s, 3H), 3.82 (s, 2H), 3.77 (s, 3H), 3.72 (s,, 2H) million-1.

Stage b: 3-(5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-yl)-1-[5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)benzyl]-1-(4-methoxybenzyl)urea (30t). The intermediate compound (29t) (135 mg, 0,354 mmol), trichlorethylene (6t-1) (154 mg, 0,379 mmol) and Diisopropylamine (120 μl, 89 mg, 0.69 mmol) was dissolved in DMA (5 ml) and heated to 80°C. After stirring at 80°C for 12 hours the reaction mixture was cooled to room temperature, diluted with ether (50 ml) and washed three times with 5 ml of water and once with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude oil was purified on silica gel with EtOc/hexane (2:3), receiving connection (30t) as a colourless oil (180 mg, yield 83%).1H-NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.07-6.95 (m, 8H), 6.94-6.89 (m, 1H), 6.89-6.84 (m, 1H), 7.29 (d, J=9.0 Hz, 1H), 6.75 (d, J=8.6 Hz, 2H), 6.69 (dd, J=8.9, 4.7 Hz, 1H), 6.60 (s, 1H), 6.41 (s, 1H), 4.57 (s, 2H), 4.44 (s, 2H,), 4.04 (s, 3H), 3.78 (s, 1H), 3.77 (s, 3H), 2.31 (s, 3H), 1.30 (s, 9H) million-1.

Stage With:

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)benzyl]-3-(4-methoxybenzyl)-1-metalmachine (31t). The intermediate compound (30t) (150 mg, 0.23 mmol) was dissolved in DMF (2 ml) and cooled to 0°C. To the solution at 0°C was added sodium hydride (60% in oil, 14 mg, 0.36 mmol) and methyliodide (73,8 μl, 168 mg, 1,19 mmol) and the reaction mixture was stirred at 0°C for 1 hour. The reaction mixture was suppressed by adding 5 ml of water at 0°C and then was extracted three times with 50 ml of Et2O. the combined organic layer was twice washed in 5 ml of water and once with brine, dried over MgSO4, was filtered and was evaporated under reduced pressure. The residue was purified on silica gel with EtOAc/hexane (1:2)to give compound (31t) as a pale yellow amorphous substance (134 mg, yield 87%).1H-NMR (400 MHz, CDCl3) δ 7.82 (s, 1H), 7.37 (d, J=8.6 Hz, 2H), 7.28 (d, J=9.4 Hz, 1H), 7.15-7.02 (m, 2H), 7.00-6.81 (m, 6H), 6.80-6.60 (m, 3H), 5.85 (s, 1H), 4.21 (s, 2H), 4.20 (s, 2H), 4.05 (s, 3H), 3.76 (s, 3H), 2.98 (s, 3H)), 2.29 (s, 3H), 1.23 (s, 9H) million-1.

Stage D: 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)benzyl]-1-methyl machev is on (32t). The intermediate compound (31t) (85 mg, 0,131 mmol) was dissolved in 5 ml of 2% (vol./about.) anisole in triperoxonane acid and stirred at room temperature for 1.5 hours. After evaporation the crude residue was dissolved in EtOAc (80 ml) and neutralized with saturated NaHCO3, washed with brine, dried over MgSO4, was filtered and was evaporated under reduced pressure. The crude oil was purified on silica gel with EtOAc/hexane (2:3)to give compound (32t) as a white amorphous substance (68.6 mg, yield 99%).1H-NMR (400 MHz, CDCl3) δ 7.84 (s, 1H), 7.32 (d, J=9.4 Hz, 1H), 7.25 (d, J=7.8 Hz, 2H), 7.13 (d, J=7.8 Hz, 2H), 7.07 (t, J=10.2 Hz, 1H), 7.20-6.96 (m, 1H), 6.93 (td, J=8.6, 3.1 Hz, 1H), 6.85 (td, J=8.6, 3.1 Hz, 1H), 6.68 (dd, J=8.6, 4.7 Hz, 1H), 6.11 (s, 1H), 5.31 (t, J=6.3 Hz, 0.8 H), 5.17 (t, J=6.3 Hz, 0,2H), 4.48-4.26 (m, 2H), 4.05 (s, 3H), 3.00 (s, 3H), 2.33 (s, 2,4H), 2.32 (s, 0.6H), 1.36 (s, 1,8H), 1.29 (s, 7,2H) million-1.

Example 106

Obtaining 1-(5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(1-methyl-1H-pyrazolo[3,4-C]pyridine-5-yloxy)benzyl]urea (4u)

The reaction scheme for the synthesis of compounds 4u shown in Fig.

Stage A: 5-fluoro-2-hydroxybenzonitrile (23t). 2.5-Diferential (14.9 g, 107 mmol) and benzyl alcohol (11,1 ml, 11.6 g, 107 mmol) was dissolved in DMF (330 ml) and cooled to 0°C. To the solution at 0°C was added sodium hydride (60% in oil, 6,40 g, 161 mmol) and the reaction mixture was left to warm to room temperature. After stirring in ECENA 1 hour at room temperature the reaction solution was cooled to 0°C. and to the solution was gradually added water (330 ml). The mixture was transferred into a separating funnel and was extracted three times with 500 ml Et2O. the combined organic layer was twice washed with 100 ml water, once with brine, then dried over MgSO4. After filtration the solution was concentrated under reduced pressure, obtaining the crude pale yellow solid. The crude solid was dissolved in Meon (500 ml). In the atmosphere of nitrogen to the solution was added 10% palladium on charcoal. Nitrogen gas was replaced with gaseous hydrogen and the reaction mixture was stirred at room temperature for 30 minutes, the reaction did not occur, then Pd/C was filtered and the reaction was carried out again). After stirring for 2 hours palladium on coal was filtered and washed Meon. The solution was concentrated under reduced pressure, obtaining a pale yellow solid. The solid is recrystallized from hot toluene (100 ml), adding hexane (10 ml) then cooled to 0°C. the Obtained white needles were washed with a mixture of toluene and hexane (1:1, of 7.23 g, yield 49%). The mother liquor was concentrated and purified on silica gel with Et2O/hexane (2:3-1:1)to give the target compound (23t) (6,94 g, yield 47%). Total output on 2 stages of 14.2 g (96%).1H-NMR (400 MHz, d6-DMSO) δ 11.09 (s, 1H), 7.58 (dd, J=8.4, 3.2 Hz, 1H), 7.40 (td, J=8.6, 3.2 Hz, 1H), 7.03 (dd, J=9.2, 4.4 Hz, 1H) million-1.

Stage b: 5-f the PR-2-(4-methyl-5-aminopyridine-2-yloxy)benzonitrile (1u). The intermediate compound (23t) (1.78 g, 13,0 mmol), 2-chloro-4-methyl-5-nitropyridine (2,31 g, 13,0 mmol) and potassium carbonate (1.80 g, 13,0 mmol) was dissolved in DMF (120 ml). When the mixture was heated to 60°C, colourless solution for 10 minutes, it was blue. After stirring for 16 hours at 60°C. the reaction mixture was left to cool to room temperature and then diluted with 100 ml of Et2O. Inorganic precipitate was removed by filtration and washed with Et2O. the combined organic solution (600 ml) was transferred into a separating funnel and washed three times with 60 ml of water and once with brine. The solution was dried over MgSO4and then concentrated under reduced pressure, obtaining the crude brown solid. The crude solid was dissolved in Meon (240 ml). To a solution under nitrogen atmosphere was added 10% palladium on charcoal. Nitrogen gas was replaced with gaseous hydrogen and the reaction mixture was stirred at room temperature for 30 minutes, the reaction did not occur, then Pd/C was filtered and the reaction was carried out again). After stirring for 1.5 hours palladium on coal was filtered and washed Meon. The solution was concentrated under reduced pressure, obtaining a pale yellow solid. The crude compound was purified on silica gel with EtOAc/hexane (1:1-3:2)to give (1u) in the form of a white t is ejogo substances (2,21 g, the yield on 2 stages 70%).1H-NMR (400 MHz, CDCl3) δ 7.57 (s, 1H), 7.33 (ddd, J=7.8, 3.1, 1.6 Hz, 1H), 7.29-7.22 (m, 1H), 7.23 (s, OH), 7.15 (ddd, J=9.3, 4.7, 1.6 Hz, 1H), 6.82 (s, 1H), 2.22 (s, MN)mn-1.

Stage C: 5-fluoro-2-(1H-pyrazolo[3,4-C]pyridine-5-yloxy)benzonitrile (2u): the Intermediate compound (1u) (0.25 g, of 1.03 mmol) and NH4BF4(0,22 g, of 2.06 mmol) was dissolved in 10 ml of mixed solvent Asón/water (2:1) and cooled to 0°C, then to the solution at 0°C was added concentrated HCl (0,43 ml, 5,16 mmol) and NaNO2(0,078 g, 1.13 mmol). After adding sodium nitrate color of the solution immediately became yellow. Then the reaction mixture was left to warm to room temperature. After stirring for 2 hours the solvent was removed under reduced pressure three times and subjected to azeotropic distillation with toluene for water removal, getting pale yellow crude solid. The solid was dissolved in 10 ml EtOAc and the solution was added COAs. After 30 minutes the color of the suspension became a dark orange and then it was stirred for another hour. A white inorganic salt was removed by filtration and washed with EtOAc. The combined filtrate was diluted with EtOAc to a total volume of 100 ml, was transferred into a separating funnel, washed with saturated NaHCO3(10 ml) and brine, dried over MgSO4, was filtered and was evaporated, getting a solid dark orange color. Neocidin the second solid was purified on silica gel with EtOAc/hexane (2:3), getting a solid orange-yellow (2u) (0,23 g, the yield on 2 stages 88%).1H-NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.15 (s, 1H), 7.30-7.34 (m, 2H), 7.32-7.22 (m, 2H), 7.12 (dd, J=9.4, 4.7 Hz, 1H) million-1.

Stage D: 5-fluoro-2-(1-methyl-1H-pyrazolo[3,4-C]pyridine-5-yloxy)benzonitrile (3u). The intermediate compound (2u) (0,23 g) was dissolved in DMF (9 ml) and cooled to 0°C. To the solution at 0°C was added sodium hydride (60% in oil, 0,054 g of 1.36 mmol) and methyliodide (of 0.28 ml, 642 mg, to 4.52 mmol), the reaction mixture is then stirred for one hour at 0°C. the Mixture was extinguished 10 ml of water and was extracted three times with 30 ml of ether. The combined organic layer was twice washed in 5 ml of water and once with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude oily residue was purified on silica gel with EtOAc/hexane (1:1)to give colorless oil (3u) (0.124 g, 51%yield).1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.02 (s, 1H), 7.40-7.32 (m, 2H), 7.31-7.23 (m, 2H), 7.11-7.05 (m, 1H), 4.17 (s, 3H) million-1.

Stage E:

1-(5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(1-methyl-1H-pyrazolo[3,4-C]pyridine-5-yloxy)benzyl]urea (4u). The intermediate compound (3u) was dissolved in 10 ml Meon and to the solution was then added concentrated HCl (12 N., 1.0 ml, 12 mmol) and 10% palladium on charcoal. The mixture was stirred in hydrogen atmosphere. After stirring for 24 hours palladium on activated Lu the e was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was twice subjected to azeotropic distillation with a mixture of toluene and ethanol (dry), receiving crude hydrochloric amine salt. The crude salt was dissolved in 5 ml of DMF. To the solution was added diisopropylethylamine and trichlorethylene and was heated to 80°C. After stirring for 16 hours, the DMF is evaporated under reduced pressure, the residue was diluted with 50 ml EtOAc and washed with saturated NaHCO3and brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude oil was purified preparative TLC with EtOAc/hexane (2:1)and then with 100%CH2Cl2receiving a colorless oil (4u) (9.0 mg, yield 4%).1H-NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.90 (s, 1H), 7.24 (s, 1H), 7.20 (d, J=8.2 Hz, 2H), 7.08 (d, J=8.6 Hz, 2H), 7.06-7.00 (m, 2H), 6.91 (td, J=8.3, 3.1 Hz, 1H), 6.82 (dd, J=8.9, 4.7 Hz, 1H), 6.46 (br, 1H), 6.18 (s, 1H), 5.84 (t, J=8.6 Hz, 1H), 4.36 (s, 1H), 4.34 (s, 2H), 4.05 (s, 3H), 2.28 (s, 3H), 1.28 (s, 9H) million-1.

Example 107

Obtaining 1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(3-pyrrolidin-1 ylmethylene[d]isoxazol-6-yloxy)benzyl]urea (7v) and 1-(5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(3-pyrrolidin-1 ylmethylene[d]isoxazol-6-yloxy)benzyl]urea (8v)

The reaction scheme for the synthesis of compounds 7v and 8v shown in Fig.

Stage A: 5-fluoro-2-(3-methylbenzo[d]isoxazol-6-yloxy)benzonitrile (3v). 3 Methylbenzo[d]isoxazol-6-ol (1v) (link to synthesis: Indan J. Chem. Sect. In; 19: 571-575 (1980)) (1,58 g, 10.6 mmol) and 2,5-diferential (2v) (1.47 g, 10.6 mmol) was combined with potassium carbonate (of 1.46 g, 10.6 mmol) in 15 ml of dry DMA. The reaction mixture was heated in a 100°C. bath for 6 hours. The reaction mixture was cooled and diluted with EtOAc (200 ml) and washed three times with water, NH4Cl, NaHCO3and brine. The organic solution was dried over MgSO4and concentrated. The crude residue was purified column chromatography (silica, 70-80% of CH2Cl2/hexane)to give compound (3v) (1.65 g, yield 58%).1H-NMR (400 MHz, CDCl3) δ 7.63 (d, J=8.6 Hz, 1H), 7.44-7.41 (m, 1H), 7.33-7.26 (m, 1H), 7.10-7.06 (m, 2H), 7.03 (dd, J=8.2, 4.7 Hz, 1H), 2.59 (s, 3H). MS IER (+), found: m/z 269 (M+H).

Stage b: 2-(3-Bromeilles[d]isoxazol-6-yloxy)-5-perbenzoate (4v). 5-fluoro-2-(3-methylbenzo[d]isoxazol-6-yloxy)benzonitrile (3v), (0.87 g, 3.2 mmol), N-bromosuccinimide (0,82 g, 4.6 mmol), benzoyl peroxide (0.12 g, 0.49 mmol) and o-dichlorobenzene (6 ml) were combined in 15 ml test tube for reactions under pressure. The mixture was stirred and heated at 150°C bath. After 2.5 hours, the reaction mixture was cooled and the residue was immediately purified column chromatography (silica, 70% of CH2Cl2/hexane)to give compound (4v) (0,29 g, yield 26%) and recovered starting material (3v) (0,57 g, 65%).1H-NMR (400 MHz, CDCl3) δ 7.84 (d, J=7.0 Hz, 1H), 7.45-7.43 (m, 1H), 7.35-7.31 (m, 1H), 7.16-7.13 (m, 2H), 7.08-7.05 (m, 1H), 4.72 (s, 2H).

The study is From: 5-fluoro-2-(3-pyrrolidin-1 ylmethylene[d]isoxazol-6-yloxy)benzonitrile (5v). 2-(3-Bromeilles[d]isoxazol-6-yloxy)-5-perbenzoate (4v) (0,295 g 0,850 mmol) was dissolved in dichloromethane and was added dropwise pyrrolidine (0.18 g, 2.5 mmol). After 2 hours the reaction mixture was concentrated and distributed between NaHCO3(15 ml) and EtOAc (30 ml). The aqueous layer was again extracted with EtOAc, the organic fractions were combined, washed with brine and dried (MgSO4), receiving the connection (5v) (0.27 g, 94%)which was used without further purification.1H-NMR (400 MHz, CDCl3) δ 7.90 (d, J=8.6 Hz, 1H), 7.42 (d, J=6.3 Hz, 1H), 7.30-7.26 (m, 1H), 7.11 (s, 1H), 7.07-7.02 (m, 2H), 4.02 (s, 2H), 2.62 (s, 4H), 1.82 (s, 4H). MS IER (+), found: m/z 338 (M+H).

Stage D: 5-fluoro-2-(3-pyrrolidin-1 ylmethylene[d]isoxazol-6-yloxy)benzylamine (6v). 5-fluoro-2-(3-pyrrolidin-1 ylmethylene[d]isoxazol-6-yloxy)benzonitrile (5v) (0.20 g, 0.59 mmol) was dissolved in THF (4 ml) and cooled to 0°C. was Slowly added a solution of lithium aluminum hydride in THF (1.0 ml, 1.0 mmol) and the reaction mixture was left to warm to room temperature. After 1 hour the reaction mixture was cooled to 0°C and added an additional portion of LAH in THF (0.9 ml, 0.9 mmol). The reaction mixture was left to mix for 20 minutes. Then the reaction was suppressed by adding portions decahydrate sodium sulfate at 0°C. until the gas evolution stops. Added THF, the mixture was filtered through celite and was suirable EtOAc. The solution was concentrated, receiving 5-fluoro-2-(3-feast of alidin-1 ylmethylene[d]isoxazol-6-yloxy)benzylamine (6v) (0.15 g), which is the next stage was used without additional purification. MS (head+), found: m/z 342 (M+H).

Stage E: 1-(5-tert-Butyl-2-methyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(3-pyrrolidin-1 ylmethylene[d]isoxazol-6-yloxy)benzyl]urea (7v). 5-fluoro-2-(3-pyrrolidin-1 ylmethylene[d]isoxazol-6-yloxy)benzylamine (6v) (50 mg, 0.15 mmol), 2,2,2-triptoreline ether (5-tert-butyl-2-methyl-2H-pyrazole-3-yl)carbamino acid (a) (68 mg, 0.21 mmol) and diisopropylethylamine (of 0.038 ml, 0.22 mmol) were combined in DMF (1.5 ml) and heated at 85°C for 3 hours. The reaction mixture was cooled, concentrated in vacuo and was purified column chromatography (silica, 4% MeOH/CH2Cl2/0,5% Et3N), obtaining 1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(3-pyrrolidin-1 ylmethylene[d]isoxazol-6-yloxy)benzyl]urea (7v) (30 mg, 39%).1H-NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.6 Hz, 1H), 7.16 (d, J=8.6 Hz, 1H), 7.03-6.80 (m, 4H), 6.11 (s, 1H), 5.93 (s, 1H), 5.25 (t, J=8.6 Hz, 1H), 4.38 (d, J=6.3 Hz, 2H), 3.99 (s, 2H), 3.67 (s, 3H), 2.61 (s, 4H), 1.81 (s, 4H), 1.26 (s, 9H). MS (head+), found: m/z 521 (M+H). HPLC (5-95%) 2,61 minutes

Stage F: 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(3-pyrrolidin-1 ylmethylene[d]isoxazol-6-yloxy)benzyl]urea (8v). 5-fluoro-2-(3-pyrrolidin-1 ylmethylene[d]isoxazol-6-yloxy)benzylamine (6v) (50 mg, 0.15 mmol), 2,2,2-triptoreline ether (5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl)carbamino acid (b) (75 mg, 0.18 mmol) and diisopropyl the ethylamine (0,038 ml, 0.22 mmol) were combined in DMF (1.5 ml) and heated at 85°C for 3 hours. The reaction mixture was cooled, concentrated in vacuo and was purified column chromatography (silica, 40 to 60% EtOAc/hexane/a 0.25% Et3N), obtaining 1-(5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(3-pyrrolidin-1 ylmethylene[d]isoxazol-6-yloxy)benzyl]urea (8v) (30 mg, yield 34%).1H-NMR (400 MHz, CDCl3) δ 7.78 (d, J=8.6 Hz, 1H), 7.31 (d, J=7.0 Hz, 2H), 7.20 (d, J=7.8 Hz, 2H), 7.02-6.88 (m, 5H), 6.17 (s, 1H), 6.02 (s, 1H), 5.30 (t, J=8.6 Hz, 1H), 4.36 (d, J=5.5 Hz, 2H), 3.98 (s, 2H), 2.60 (s, 4H), 2.36 (s, 3H), 1.80 (s, 4H), 1.32 (s, 9H). MS IER (+), found: m/z 597 (M+H). HPLC (5-95%) of 2.93 min

Example 108

Obtaining 1-(5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(3-methylbenzo[d]isoxazol-6-yloxy)benzyl]urea (10v)

The reaction scheme for the synthesis of compounds 10v shown in Fig.

Stage A: 5-fluoro-2-(3-methylbenzo[d]isoxazol-6-yloxy)benzylamine (9v). 5-fluoro-2-(3-methylbenzo[d]isoxazol-6-yloxy)benzonitrile (3v) (84 mg, 0.31 mmol; obtained as described in Example 108) was dissolved in THF (3 ml) and cooled to 0°C. was Slowly added a solution of lithium aluminum hydride in THF (0.35 ml, 0.35 mmol) and the reaction mixture was left to warm to room temperature. After 1 hour the reaction was suppressed by adding portions decahydrate sodium sulfate at 0°C. until the gas evolution stops. Added THF and the mixture was filtered through celite and was suirable EtOAc. The solution was concentrated, is learn the crude product (9v) (66 mg), which was used without further purification.

Stage b: 1-(5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(3-methylbenzo[d]isoxazol-6-yloxy)benzyl]urea (10v). 5-fluoro-2-(3-methylbenzo[d]isoxazol-6-yloxy)benzylamine (9v) (60 mg, 0.22 mmol), 2,2,2 - triptoreline ether (5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl)carbamino acid (12v) (89 mg, 0.22 mmol) and diisopropylethylamine (0,058 ml, 0.33 mmol) were combined in DMF (2 ml) and heated at 75°C for 3 hours. The reaction mixture was cooled, concentrated in vacuo and was purified column chromatography (silica, 30-40% EtOAc/hexane)to give compound (10v) (90 mg, yield 77%).1H-NMR (400 MHz, CDCl3) δ 7.51 (d, J=8.6 Hz, 1H), 7.30 (d, J=8.6 Hz, 2H), 7.20 (d, J=7.8 Hz, 2H), 7.02-6.88 (m, 5H), 6.15 (s, 1H), 5.99 (s, 1H), 5.28 (t, J=7.6 Hz, 1H), 4.36 (d, J=5.5 Hz, 2H), 2.53 (s, 3H), 2.36 (s, 3H), 1.31 (s, 9H). MS IER (+), found: m/z 528 (M+H). HPLC (5-95%) 3,49 minutes

Example 109

Getting 5-bromo-1-cyclopropylmethyl-1H-indazole

To a solution of 5-brominate (15 g, with 76.1 mmol) and (methyl bromide)cyclopropane (8,12 ml, 83.7 mmol) in 75 ml of DMF was added To a2CO3(16 g, 114,0 mmol). The mixture was heated to 105°C. After 24 hours was still observed the original substance. Added additional amount (methyl bromide)cyclopropane (5.7 ml, to 57.0 mmol) and the reaction mixture was heated to 105°C for another 24 hours. Again found 5-brominator, so I added additional is sustained fashion number (methyl bromide)cyclopropane (4 ml, 38 mmol) and the reaction mixture was heated at 95°C for another 48 hours. After the disappearance of 5-brominate the reaction mixture was poured into a mixture of DGM/brine. Two layers were separated, the aqueous layer was extracted with DHM (2×) and analyzed by TLC. In the water layer not found any product. The combined organic substances washed with N2About (2×) and brine and dried over Na2SO4. After filtration, the filtrate was concentrated, the obtained residue was purified by chromatography using hexane/EtOAc (of 9.5:0.5) and receiving 5-bromo-1-cyclopropylmethyl-1H-indazol (a total of 8.74 g, the output of the selected product 45%).1H-NMR (400 MHz, CDCl3) δ 7.93 (s, 1H), 7.86 (d, J=1.57 Hz, 1H), 7.43 (dd, J=8.61, 1.57 Hz, 1H), 7.31 (d, J=8.61 Hz, 1H), 4.24 (d, J=6.26 Hz, 2H), 1.37-1.26 (m, 1H), 0.62-0.55 (m, 2H), 0.43-0.37 (m, 2H). MS (head+), found: m/z 251/253 (M/M+2N, 1:1).

Example 110

Getting 5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (17d)

The reaction scheme for the synthesis of compound 17d according to this Example is shown in Fig.

Stage A: 1,2-Dibromo-4-methyl-5-nitrobenzene. 3,4-Dibromsalan (108,11 ml, 800 mmol) was added dropwise over 4 hours to nitric acid (90%, 280 ml, 6000 mmol)which was cooled to 0°C. in a nitrogen atmosphere with mechanical stirring. During the addition the internal temperature of the mixture was maintained below 10°C. after the addition the mixture was stirred for 1 hour at 0°is. To the mixture was added dropwise water (840 ml), maintaining the internal temperature below 10°C. the Crude product was collected by filtration and washed with water (5×500 ml) to remove excess nitric acid. The solids were dried under high vacuum and was purified by recrystallization from ethanol (800 ml), receiving 180,9 g of the target product (yield 77%) as a solid.1H-NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 7.64 (s, 1H), 2.55 (s, 3H).

Stage b: 1-Bromo-2-(2,4-divergence)-4-methyl-5-nitrobenzene. A mixture of 1,2-dibromo-4-methyl-5-nitrobenzene (84,3 g, 286 mmol), 2,4-differenoe (37,2 g, 286 mmol) and K2CO3(43,5 g, 315 mmol) was heated to 100°C for 45 hours. The reaction mixture was cooled to room temperature and then kept in a refrigerator at 5°C during the night. The entire reaction mixture at one time was poured into 1200 ml of ice water. The obtained wet solid was collected, partially crushed and stirred in 900 ml of N2About 45 minutes. The solid is collected by filtration and washed with 700 ml of water (portions). The obtained solid substance was dried under high vacuum over night, getting to 93.5 g of brown solid (yield 95%).1H-NMR (400 MHz, CDCl3) δ 8.38 (s, 1H), 7.18 (m, 1H), 7.03 (m, 1H), 6.97 (m, 1H), 6.52 (s, 1H), 2.50 (s, 3H).

Stage C: 5-Bromo-4-(2,4-divergence)-2-methylphenylamine. 1-Bromo-2-(2,4-divergence)-4-methyl-5-nitrobenzene (87,0 g, 253 mmol) dissolve the Yali in THF (300 ml) and was diluted Meon (900 ml). Was added zinc dust (82.7 g, 126 mol) and was slowly added to 1 l of saturated NH4Cl, so that the reaction temperature never exceeded 42°C. the Reaction mixture is intensively mechanically stirred for 16 hours. The reaction mixture was filtered through celite and the filter cake was washed with ethyl acetate. Then the filtrate was concentrated using 1.2 l of saturated NH4The OAc. After removal of THF/Meon solids were collected and washed with water. Then the solids were stirred in 1 l of water for 30 minutes, collected by filtration and washed with three portions of water (1 liter). The obtained solid substance was dried under high vacuum for 48 hours, receiving 64 g of the target product (yield 81%). MS (IER+), found: m/z 314, 316 (M+1, Br pattern).1H-NMR (400 MHz, CDCl3) δ 6.92 (m, 1H), 6.91 (s, 1H), 6.75 (m, 2H), 6.70 (s, 1H), 3.57 (br. s, 2H), 2.08 (s, 3H).

Stage D: 6-Bromo-5-(2,4-divergence)-1H-indazol (14d).

Tetrafluoroborate 5-bromo-4-(2,4-divergence)-2-methylbenzothiazole. 5-Bromo-4-(2,4-divergence)-2-methylphenylamine (30.0 g, 96 mmol) was dissolved in a mixture of Asón/N2About (2:1, 960 ml). Added NH4BF4(20,0 g, 191 mmol) and the mixture was cooled to 3°C (about 30 minutes). Then at one time was added concentrated HCl (40 ml), the mixture was heated to 6°C. the Mixture was cooled to 2°C and then added NaNO2(7,25 g, 105 mmol). The reaction mixture was stirred in an ice bath for 5 min is t and then left to mix for 1 hour at room temperature. The mixture was concentrated under reduced pressure and the residue was subjected to azeotropic distillation with toluene (3×400 ml). The crude substance (tetrafluoroborate 5-bromo-4-(2,4-divergence)-2-methylbenzothiazole) was used for the next reaction stage without further purification.

6-Bromo-5-(2,4-divergence)-1H-indazol. The crude tetrafluoroborate 5-bromo-4-(2,4-divergence)-2-methylbenzothiazole suspended in ethyl acetate (650 ml) and was treated with 10 equivalents of COAs. The mixture was intensively stirred at room temperature for 1.5 hours and then filtered and diluted with ethyl acetate to a total volume of 1 L. the Mixture was washed with a mixture of saturated NaHCO3/brine (800 ml, 1:1). The aqueous phase was extracted with ethyl acetate (400 ml). Organic substances were combined, dried (MgSO4) and concentrated to a brown solid (31 g, yield 99%).1H-NMR (400 MHz, CDCl3) δ 10.55 (br. s, 1H), 7.98 (s, 1H), 7.84 (s, 1H), 7.20 (s, 1H), 6.99 (m, 1H), 6.94 (m, 1H), 6.84 (m, 1H).

Stage E: 6-Bromo-5-(2,4-divergence)-1-isobutyl-1H-indazole (15d). 6-Bromo-5-(2,4-divergence)-1H-indazol (60,0 g, 185 mmol) was dissolved in DMF and was treated To a2CO3(76,5 g, 554 mmol) and isobutylamine (126,4 g, 923 mmol). The mixture was stirred and heated to 80°C for 16 hours. Was added 15 g

To2CO3and the mixture was intensively stirred for another 24 hours. Then reactionuses was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and was dissolved in ether (1 liter). The mixture was washed with a mixture of brine/water (1:5, 2×600 ml). The aqueous phase was extracted with ether (300 ml), the combined organic substance was dried (MgSO4) and concentrated under reduced pressure. The crude product was subjected to chromatography on a Biotage Flash 75 two servings (approximately 35 g each), elwira a mixture of 5% ethyl acetate in hexano. United purified products were given to 30.1 g of the desired product as a solid (yield 43%). MS (IER+), found: m/z 381, 383 (M+1, Br pattern).1H-NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.72 (s, 1H), 7.16 (s, 1H), 6.98 (m, 1H), 6.92 (m, 1H), 6.82 (m, 1H), 4.12 (d, 2H), 2.34 (m, 1H), 0.94 (d, 6H).

Stage F: 5-(2,4-Divergence)-1-isobutyl-1H-indazol-6-carbonitrile (16d). 6-Bromo-5-(2,4-divergence)-1-isobutyl-1H-indazole (31,2 g, 82 mmol) and Cu(I)CN (13,9 g, 156 mmol) was dissolved in DMA and degirolami nitrogen under vacuum. The reaction mixture was heated to 150°C for 16 hours. The mixture was cooled to room temperature and was diluted with ethyl acetate before the double flushing 7 M NH4OH. The organic layers were washed with brine and was degirolami nitrogen, and then was dried over MgSO4and concentrated under reduced pressure. The crude product was subjected to chromatography elwira a mixture of 10% ethyl acetate in hexano, receiving a 25.1 g of product (yield 95%).

Stage G: 5-(2,4-Divergence)-1-isobut what-1H-indazol-6-carboxylic acid (17d). 5-(2,4-Divergence)-1-isobutyl-1H-indazol-6-carbonitrile (25,1 g, 77 mmol) suspended in ethanol (620 ml) and KOH (2.5 M, 310 ml) and was heated to the temperature of reflux distilled within 24 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to remove ethanol. The resulting aqueous solution was diluted with water and washed with ether. The aqueous layer was acidified with concentrated HCl to pH 1 and was extracted several times with ethyl acetate. The organic layers were combined and concentrated under reduced pressure, obtaining of 25.5 g of product (yield 96%).1H-NMR (400 MHz, CDCl3) δ 8.37 (s, 1H), 7.91 (s, 1H), 7.20 (m, 1H), 7.07 (s, 1H), 7.04 (m, 1H), 6.95 (m, 1H), 4.24 (d, 2H), 2.36 (m, 1H), 0.94 (d, 6H).

Example 111

Obtaining {(3-[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-yloxy]propyl}dimethylamine (20d)

The reaction scheme for the synthesis of compound 20d according to this Example is shown in Fig.

Stage A: 5-(2,4-Divergence)-1-isobutyl-1H-indazol-6-ol (15d; obtained according to Example 110, stages a-E). 6-Bromo-5-(2,4-divergence)-1-isobutyl-1H-indazole (1,36 g, 3.6 mmol) was dissolved in dry ether (17.5 ml) and was cooled to -78°C. was Added dropwise n-utility (1.7 ml of 2.5 M solution in hexane) in 10 minutes and the mixture was stirred for 30 minutes. Was added dropwise trimethylboron (6 ml, of 53.5 mmol) for 10 minutes, the reaction mixture was left to warm to room the temperature and mixed for 18 hours. The mixture was cooled to -10°C was added 2 N. NaOH (3.6 ml) and water (3 ml), and then H2About2(3.6 ml) and 2 N. NaOH (3.6 ml). The reaction mixture was stirred at room temperature for 2 hours until a white precipitate was formed. Was added water (3 ml), 4 N. NaOH (4 ml) and N2About2(1 ml), the mixture was stirred for another 20 minutes. Then the mixture was diluted with ether and the layers were separated. The aqueous layer was washed with ether, acidified and then extracted with ether (2×). The combined ether extracts were washed with water and brine, dried over Na2SO4and concentrated under reduced pressure, getting 0,465 g of product (yield 41%).

Stage b: 6-(3-Chloropropoxy)-5-(2,4-divergence)-1-isobutyl-1H-indazole (19d). To a solution of 5-(2,4-divergence)-1-isobutyl-1H-indazol-6-ol (0.015 g, 0.05 mmol) in DMF (1 ml) was added Cs2CO3. The reaction mixture was stirred for 30 minutes, after which was added 1-bromo-3-chloropropane (0.01 g, 0.08 mmol) and the mixture was then heated to 80°C for 25 hours. After cooling the mixture to room temperature, the reaction mixture was diluted with water and ether, the layers were separated. The aqueous layer was extracted with ether and the combined organic layers were washed 1 N. NaOH, water and brine. The crude mixture was dried over Na2SO4and concentrated under reduced pressure, obtaining a product with a small amount of impurities. Untreated with whom ect was used in the next reaction stage without further purification.

Stage C: {3-[5-(2,4-Divergence)-1-isobutyl-1H-indazol-6-yloxy]propyl}dimethylamine (20d). To a solution of 2 N. dimethylamine in THF (1.4 ml) was added 6-(3-chloropropoxy)-5-(2,4-divergence)-1-isobutyl-1H-indazol is 0.019 g, 0.05 mmol). The mixture was stirred at room temperature for 62 hours and then was heated to 45°C for 3 hours. The solvent was removed under reduced pressure and the residue was distributed between dichloromethane and 0.1 G. of NaOH. The layers were separated and the aqueous layer was extracted with dichloromethane (3×). The combined organic layers were washed with water and brine and then dried over Na2SO4. The mixture was concentrated under reduced pressure, obtaining the crude mixture which was purified by reversed-phase HPLC. The target fraction was concentrated to salt TFU (7 mg, yield 37%). MS (IER+), found: m/z 404 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.34 (s, 1H), 6.97 (m, 1H), 6.82 (s, 1H), 6.78 (m, 2H), 4.14 (m, 2H), 4.11 (d, 2H), 2.98 (m, 2H), 2.76 (s, 6H), 2.35 (m, 1H), 2.22 (m, 2H), 0.95 (d, 6H).

Example 112

Getting 5-(2,4-divergence)-1-isobutyl-6-(piperidine-4-ylethoxy)-1H-indazole (21d)

To a solution of 5-(2,4-divergence)-1-isobutyl-1H-indazol-6-ol (0.06 g, 0,19 mmol) and tert-butyl ester 4-(toluene-4-sulfonyloxy)piperidine-1-carboxylic acid (0.08 g, 0.20 mmol) in DMF (3 ml) was added NaI (0,014 g 0,009 mmol) and K2CO3(0.08 g, 0,56 mmol). The reaction mixture was heated to 70°C for 20 hours. CME is ü was diluted with ether and water, the layers were separated. The aqueous layer was extracted with ether (2×), the combined organic layers were washed with water and brine and dried over Na2SO4. The crude mixture was concentrated under reduced pressure and was purified by reversed-phase HPLC. The target fraction was concentrated to 0.037 g, which is then treated with a solution of HCl (4 BC in dioxane) for 7 hours. The solvent was removed under reduced pressure and the final product was dried under high vacuum, receiving 0,031 g of solid substance (yield 37%). MS (head+), found: m/z 416 (M+1).

Example 113

Getting 5-(2,4-divergence)-1-isobutyl-6-(3-piperazine-1-ylpropionic)-1H-indazole (22d)

To a solution of 6-(3-chloropropoxy)-5-(2,4-divergence)-1-isobutyl-1H-indazole (0.025 g, 0,063 mmol) and NaI is 0.019 g, 0.13 mmol) in DMA (0.5 ml) and THF (5 ml) was added tert-butyl ether piperazine-1-carboxylic acid (0,059 g, 0.32 mmol). The reaction mixture was heated in a sealed reaction vessel to 65°C for 20 hours. The mixture was concentrated under reduced pressure, the residue was distributed between water, brine and ether. The layers were separated and the aqueous layer was extracted with ether (2×). The combined organic layers were washed with water and brine and dried over Na2SO4. The crude mixture was concentrated under reduced pressure and treated with a solution of HCl (4 BC in dioxane) for 3 hours. The mixture of koncentrira is whether and purified by reversed-phase HPLC, getting 0.025 g of salt TFU (51%yield). MS (head+), found: m/z 445 (M+1).1H-NMR (400 MHz, CD3OD) δ 7.88 (s, 1H), 7.32 (s, 1H), 7.17 (s, 1H), 7.14 (m, 1H), 6.89 (m, 2H), 4.23 (t, 2H), 4.18 (d, 2H), 3.52 (m, 4H), 3.41 (m, 4H), 3.14 (t, 2H), 2.31 (m, 1H), 2.19 (m, 2H), 0.92 (d, 6H).

Example 114

Getting 5-(2,4-divergence)-1-isobutyl-6-(morpholine-2-ylethoxy)-1H-indazole (23d)

Stage A: tert-Butyl ether 2-hydroxymethylpropane-4-carboxylic acid. To a solution of (4-benzylmorphine-2-yl)methanol (0.66 g, 3,18 mmol, Synth. Comm. 1980, 10, 59-73) in the Meon (20 ml) was added BOC-anhydride (0,83 g is 3.82 mmol), then Pd/C (0.66 g, of 6.20 mmol). The mixture was stirred in hydrogen atmosphere for 60 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure, obtaining the product as a colourless oil (0,69 g, yield 99%).

Stage b: tert-Butyl ether 2-bromethalin-4-carboxylic acid. To a cooled (0°C.) solution of tert-butyl methyl ether 2-hydroxymethylpropane-4-carboxylic acid (1.04 g, 4,79 mmol, see stage 1) in dichloromethane (20 ml) was added CBr4(1.98 g, 5,98 mmol). After stirring the mixture for 10 minutes portions was added triphenylphosphine (2.20 g, scored 8.38 mmol). The reaction mixture was stirred at 0°C for 6 hours, then left to warm to room temperature and was stirred for 60 hours. The mixture was concentrated under reduced pressure and then diluted with ether. Untreated, see the camping was filtered, the filtrate was concentrated, obtaining the crude product, which was subjected to chromatography on a Biotage, elwira dichloromethane. The target fractions were combined and concentrated to obtain 0.50 g of product (yield 37%).

Stage C: 5-(2,4-Divergence)-1-isobutyl-6-(morpholine-2-ylethoxy)-1H-indazol. To a solution of 5-(2,4-divergence)-1-isobutyl-1H-indazol-6-ol (0.035 g, 0.11 mmol) in DMA (3.5 ml) was added Cs2CO3(0.11 g, 0.33 mmol). The mixture was stirred at room temperature for 1 hour, after which was added tert-butyl ester 2-bromethalin-4-carboxylic acid (0,062 g, 0.22 mmol). The resulting mixture was stirred at room temperature for 14 hours. The reaction mixture was diluted with ether and water, the layers were separated. The aqueous layer was extracted with ether (3×), the combined organic layers were washed with water and brine and dried over Na2SO4. The crude mixture was concentrated under reduced pressure and was purified by reversed-phase HPLC, obtaining the target product. MS (head+), found: m/z 418 (M+1).1H-NMR (400 MHz, CD3OD) δ 7.90 (s, 1H). 7.38 (s, 1H), 7.21 (s, 1H), 7.11 (m, 1H), 6.84 (m, 2H), 4.22 (m, 2H), 4.18 (d, 2H), 4.05 (m, 2H), 3.31 (m, 3H), 3.03 (m, 2H), 2.31 (m, 1H), 0.92 (d, 6H).

Example 115

Obtaining 1-[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-yloxy]-3-pyrrolidin-1-improper-2-ol (24d)

Stage A: 5-(2,4-Divergence)-1-isobutyl-6-oxiranylmethyl-1H-indazol. To a solution of 5-(2,4-di is torproxy)-1-isobutyl-1H-indazol-6-ol (0.15 g, 0.47 mmol) in DMA (5 ml) was added Cs2CO3(0,46 g of 1.41 mmol). After stirring the mixture for 3 hours was added 2-Bromeliaceae (0,13 g of 0.94 mmol) and the resulting mixture was stirred at room temperature for 16 hours. The mixture was diluted with ether and water, the layers were separated. The aqueous layer was extracted with ether (3×), the combined organic layers were washed with water and brine and dried over Na2SO4. The crude product was concentrated under reduced pressure and used in the next reaction stage without further purification (is 0.135 g, yield 77%).

Stage b: 1-[5-(2,4-Divergence)-1-isobutyl-1H-indazol-6-yloxy]-3-pyrrolidin-1-improper-2-ol. To a solution of 5-(2,4-divergence)-1-isobutyl-6-oxiranylmethyl-1H-indazole (0.035 g, 0,093 mmol, step 1) in the Meon (3 ml) was added pyrrolidine (0,007 g, 0,093 mmol). The mixture was stirred at room temperature for 36 hours and then concentrated under reduced pressure. The crude product was purified by reversed-phase HPLC, obtaining the final product in the form of a salt TFU (0.037 g, yield 59%). MS (head+), found: m/z 446 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.92 (s, 1H), 7.33 (s, 1H), 6.96 (m, 1H), 6.88 (s, 1H), 6.79 (m, 2H), 4.34 (m, 1H), 4.25 (m, 1H), 4.14 (d, 2H), 3.95 (m, 1H), 3.82 (m, 2H), 3.17 (m, 1H), 3.08 (m, 1H), 2.88 (m, 1H), 2.78 (m, 1H), 2.33 (m, 1H), 2.12 (m, 4H), 0.94 (d, 6H).

Example 116

Receive (3-dimethylaminopropyl)amide 5-(2,4-divergence)-1-isobutyl-1H and dasol-6-sulfonic acid (26d)

The reaction scheme for the synthesis of compound 26d according to this Example is shown in Fig.

Stage A: 5-(2,4-Divergence)-1-isobutyl-1H-indazol-6-sulphonylchloride (25d). To a cooled (-78°C) solution of 6-bromo-5-(2,4-divergence)-1-isobutyl-1H-indazole (15d; obtained as described in Example 110, stages a-E) (2.0 g, 5.2 mmol) in THF (50 ml) in an atmosphere of N2was added dropwise n-utility (1.5 ml of 2.5 M solution). The resulting solution was stirred at -78°C for 5 minutes and then transferred via cannula to a cooled (-78°C.) suspension of SO2(0.34 g, a 5.25 mmol) in THF (5 ml). The mixture was stirred at -78°C for 2 hours, then was diluted with ether (20 ml) and stirred at room temperature for 1 hour. The suspension was concentrated under reduced pressure and the residue was stirred in an ice bath with saturated NaHCO3(15 ml) and NCS (0,77 g, 5.8 mmol) for 45 minutes. The reaction mixture was extracted with ethyl acetate (3×), the combined organic layers were washed with brine and dried over Na2SO4. The solution was concentrated under reduced pressure receiving fluid with high viscosity, which was used in the next reaction stage without further purification.

Stage b: (3-Dimethylaminopropyl)amide 5-(2,4-divergence)-1-isobutyl-1H-indazol-6-sulfonic acid (26d). To a cooled (0°C.) solution of 5-(2,4-divergence)-1-isobutyl-1H and dasol-6-sulphonylchloride (0.20 g, 0.50 mmol) in dichloromethane in the atmosphere N2added portions 3-(dimethylamino)Propylamine (0.05 g, 0.50 mmol) and triethylamine (0.15 g, 1.5 mmol). The reaction mixture was stirred for 4 hours, then was diluted with dichloromethane (20 ml), washed with water, saturated NaHCO3and brine and then dried over MgSO4. The mixture was concentrated under reduced pressure and subjected to preparative chromatography on TLC plates, elwira a mixture of dichloromethane/Meon/Et3N (95:4:1) and getting 93 mg of the final product (yield 40%). MS (head-), found: m/z 466.1H-NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.91 (s, 1H), 7.20 (m, 1H), 7.09 (s, 1H), 7.00 (m, 1H), 6.90 (m, 1H), 4.22 (d, 2H), 3.12 (t, 2H), 2.35 (m, 3H), 2.13 (s, 6H), 1.70 (m, 2H), 0.94 (d, 6H).

Example 117

Obtain (S)-methyl-2-(5-(2,4-divergence)-1-isobutyl-1H-indazol-6-sulphonamido)-4-(dimethylamino)butanoate (27d)

Received as described in Example 116, stages a and b, substituting 3-(dimethylamino)Propylamine dihydrochloride a methyl ester 2-amino-4-dimethylaminomethylene acid. The crude product was subjected to preparative chromatography on TLC plates, elwira a mixture hexane/ethyl acetate/Et3N (50:50:5) and obtaining a final product with a yield of 37%. MeOH/Et3N (95:4:1) to give 93 mg of the final product (yield 40%). MS (head-), found: m/z 523 (M-1).1H-NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.90 (s, 1H), 7.23 (m, 1H), 7.08 (s, 1H), 7.00 (m, 1H), 6.89 (m, 1H), 4.32 (t, 1H), 4.21 (d, 2H), 3.45 (s, 3H), 2.37 (m, 3H), 2.15 (s, 6N), 2.05 (m, 1H), 1.90 (m, 1H), 0.92 (dd, 6N).

Example 118

Obtaining [2-(1-methylpyrrolidine-2-yl)ethyl]amide 5-(2,4-divergence)-1-isobutyl-1H-indazol-6-sulfonic acid (28d)

Received as described in Example 116, stages a and b, substituting 3-(dimethylamino)Propylamine 2-(1-methylpyrrolidine-2-yl)ethylamine. The crude product was subjected to preparative chromatography on TLC plates, elwira a mixture hexane/ethyl acetate/Et3N (1:1:0,1) and obtaining a final product with a yield of 24%. MS (head+), found: m/z 493 (M+1).1H-NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.93 (s, 1H), 7.19 (m, 1H), 7.12 (s, 1H), 7.00 (m, 1H), 6.90 (m, 1H), 4.23 (d, 2H), 3.12 (m, 3H), 2.44 (m, 1H), 2.36 (m, 1H), 2.34 (s, 3H), 2.24 (m, 1H), 1.92 (m, 1H), 1.77 (m, 4H), 1.51 (m, 1H), 0.94 (d, 6H).

Example 119

Receive (2-dimethylaminoethyl)amide 5-(2,4-divergence)-1-isobutyl-1H-indazol-6-sulfonic acid (29d)

Received as described in Example 116, stages a and b, substituting 3-(dimethylamino)Propylamine by diethylaminoethylamine. The crude product was subjected to preparative chromatography on TLC plates, elwira a mixture hexane/ethyl acetate/Et3N (1:1:0,1), with the final product. MS (head+), found: m/z 453 (M+1).1H-NMR (400 MHz, CDCl3) δ 8.15 (s, 1H), 7.92 (s, 1H), 7.18 (m, 1H), 7.12 (s, 1H), 7.00 (m, 1H), 6.89 (t, 1H), 4.23 (d, 2H), 3.07 (t, 2H), 2.41 (t, 2H), 2.36 (t, 1H), 2.15 (s, 6H), 0.94 (d, 6H).

Example 120

Obtain (S)-methyl-2-(5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxamido)-4-(dimethylamino)butane is ATA (30d)

Stage A: (S)-2-(tert-Butoxycarbonyl)-4-hydroxipropionic acid. To a solution of L-homoserine (to 49.9 g, 419 mmol) in 1 N. NaOH (460 ml) and EtOH (400 ml) solution was added BOC-anhydride (100,6 g, 461 mmol) in THF (400 ml) for 15 minutes. The reaction mixture was stirred at room temperature for 16 hours. Then the mixture was washed with ether (3×500 ml), acidified 1 N. HCl to pH 2 and extracted with ethyl acetate (6×250 ml). The combined organic extracts were washed with brine (2×250 ml), dried over MgSO4was filtered through celite and concentrated under reduced pressure, getting to 72.6 g of white solid (yield 79%).

Stage b: Complex (S)-2-(tert-butoxycarbonyl)-4-hydroxybutiric acid and dicyclohexylamine. To a solution of (S)-2-(tert-butoxycarbonyl)-4-hydroxybutiric acid (to 72.6 g, 331 mmol) in EtOH (500 ml) was added dropwise dicyclohexylamine (73 ml, 364 mmol). The mixture was stirred for 2 hours at room temperature and then concentrated under reduced pressure. White solid was dried under high vacuum and then triturated with ether (1000 ml). Fine white powder was collected by filtration, washed with ether, and dried under high vacuum (125,6 g, yield 95%).

Stage C: Methyl ester of (S)-2-tert-butoxycarbonylamino-4-hydroxybutiric acid. To a suspension of the complex (S)-2-(tert-butoxycarbonyl)-4-hydrox the butyric acid and dicyclohexylamine (110 g, 275 mmol) in DMF (900 ml) was added logmean (20.5 ml, 330 mmol). The mixture was stirred at room temperature for 16 hours. The clear solution was concentrated under reduced pressure and subjected to azeotropic distillation with toluene (5×200 ml). The residue was diluted with water (500 ml) and ethyl acetate (500 ml) and was stirred for 2 hours, after which the layers were separated. The aqueous layer was extracted by ethyl acetate (9×250 ml). The combined extracts were washed with brine (250 ml), dried over MgSO4was filtered through celite and concentrated under reduced pressure, obtaining a yellow oil. The crude oil was subjected to chromatography on silica, elwira a mixture of ether/hexane (3:1) and receiving 53 g of colorless oil (yield 83%).

Stage D: Methyl ester of (S)-4-bromo-2-tert-butoxycarbonylamino acid. To a cooled (0°C.) solution of methyl ester (S)-2-tert-butoxycarbonylamino-4-hydroxybutiric acid (28,7 g, 123 mmol) in dichloromethane (500 ml) was added CBr4(51,0 g, 154 mmol). The mixture was stirred for 5 minutes, after which portions were added triphenylphosphine (48,41 g, 185 mmol). The mixture continued to stir at 0°C for 1 hour and then left to warm to room temperature. The solvent was removed under reduced pressure and then diluted with ether (500 ml) and was stirred for 30 minutes. The mixture was filtered and the filtrate to what has centriole under reduced pressure. The residue was subjected to chromatography elwira a mixture of ether/hexane (1:2), and receiving 27.5 g of white solid (yield 76%).

Stage E: Methyl ester of (S)-2-tert-butoxycarbonylamino-4-dimethylaminomethylene acid. To a solution of methyl ester (S)-4-bromo-2-tert-butoxycarbonylamino acid (27.5 g, 93 mmol) in THF (100 ml) in a vessel for reactions under pressure was added triethylamine (26 ml) and dimethylamine (93 ml of 2.0 M solution in THF). The reaction vessel was tightly closed and heated to 60°C for 16 hours and then cooled to room temperature. The reaction mixture was concentrated under reduced pressure and then dissolved in dichloromethane (500 ml). The solution was washed with water (3×200 ml) and brine (200 ml), dried over MgSO4was filtered through celite and concentrated under reduced pressure. The residue was dried under high vacuum, receiving and 23.4 g of a yellow oil (yield 97%).

Stage F: Dihydrochloride (S)-methyl-2-amino-4-(dimethylamino)butanoate. To a cooled (0°C.) solution of methyl ester (S)-2-tert-butoxycarbonylamino-4-dimethylaminomethylene acid (23,4 g, 90 mmol) in dioxane (100 ml) was added dropwise HCl (225 ml, 4 M solution in dioxane). The mixture was heated to room temperature and was stirred for 3 hours. The solid was filtered, washed with ether (3×100 ml) and dried under high vacuum, receiving a 20.2 g of product (yield 96%).

With the adiya G: (S)-Methyl-2-(5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxamido)-4-(dimethylamino)butanoate (30d). 5-(2,4-Divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (17d; obtained according to Example 110) (0,396 g to 1.14 mmol) was mixed with HOBt (N-hydroxybenzotriazole) (0,192 g of 1.26 mmol) and EDCI (0,241 g of 1.26 mmol) in dichloroethane (2 ml) for 10 minutes at room temperature. Then this mixture was added to a suspension dihydrochloride (S)-methyl-2-amino-4-(dimethylamino)butanoate (0,280 g, 1.20 mmol) and triethylamine (1 ml, 6,9 mmol) in dichloromethane (6 ml). The reaction mixture was stirred for 3 hours and then concentrated under reduced pressure. The residue was diluted with chloroform (50 ml) and washed with 1 N. HCl (2×25 ml), saturated To2CO3(2×50 ml), water (25 ml), brine (25 ml) and dried over MgSO4. The filtered solution was concentrated under reduced pressure, obtaining a yellow oil. The oil was subjected to chromatography elwira 5% Meon in dichloromethane, and received a viscous colorless oil, which after drying under high vacuum hardened (0,393 g, 71%yield). MS (IER+), found: m/z 489 (M+1).1H-NMR (400 MHz, CDCl3) δ 8.91 (d, 1H), 8.36 (s, 1H), 7.86 (s, 1H), 7.16 (m, 1H), 7.03 (m, 1H), 7.00 (s, 1H), 6.93 (m, 1H), 4.88 (m, 1H), 4.21 (d, 2H), 3.74 (s, 3H), 2.34 (m, 3H), 2.06 (s, 6H), 2.01 (m, 2H), 0.92 (d, 6H).

Example 121

Obtain (S)-5-(2,4-divergence)-N-(4-(dimethylamino)-1-hydroxybutane-2-yl)-1-isobutyl-1H-indazol-6-carboxamide (31d)

A mixture of (S)-methyl-2-(5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxamido)-4-(dimethylamino)Boo is anoeta (30d; Example 120, stage a-E) (0,370 g, from 0.76 mmol) and

NaBH4(0,114 g, 3.04 from mmol) in THF/EtOH (20 ml, 3:2) was heated to 60°C for 7 hours. The reaction mixture was concentrated under reduced pressure and diluted with dichloromethane. The suspension was subjected to chromatography on a Biotage, elwira a mixture of 10% Meon in dichloromethane with 1% triethylamine. Received of 0.337 g of the product as a viscous oil (yield 97%). MS (IER+), found: m/z 461 (M+1).1H-NMR (400 MHz, CDCl3) δ 8.34 (d, 1H), 8.31 (s, 1H), 7.86 (s, 1H), 7.13 (m, 1H), 7.02 (s, 1H), 7.00 (m, 1H), 6.90 (m, 1H), 4.33 (m, 1H), 4.22 (d, 2H), 3.64 (m, 2H) 2.37 (m, 1H), 2.17 (s, 6H), 2.10 (m, 1H), 1.82 (m, 1H), 1.07 (m,2H), 0.93 (d, 6H).

Example 122

Obtain (1-hydroxymethyl-3-isopropylaminomethyl)amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (32d)

Stage a: Isopropyl-(4-methoxybenzyl)amine. A mixture of 4-methoxybenzylamine (of 1.37 g, 10 mmol) and acetone (0,81 ml, 11 mmol) in dry dichloroethane (20 ml) was stirred at room temperature for 30 minutes. To the solution was added triacetoxyborohydride sodium (3,18 g, 15 mmol) and the resulting mixture was stirred at room temperature for 17 hours. The reaction mixture is extinguished 1 N. NaOH (50 ml) and the layers were separated. The aqueous layer was extracted with dichloromethane (2×20 ml). The combined extracts were washed with water (20 ml), brine (20 ml), dried over MgSO4was filtered through celite and concentrated under reduced pressure. The residue was subjected to chromatogra the AI, elwira a mixture of 10% Meon in dichloromethane with 1% triethylamine and receiving of 1.53 g of an oil (yield 85%).

Stage b: (S)-Methyl-4-bromo-2-(tert-butoxycarbonyl)butanoate. To a cooled (0°C.) solution of (S)-methyl-2-amino-4-bromobutyrate (1.80 g, 6.5 mmol) in THF (20 ml) was added triethylamine (4,53 g, 32.5 mmol) and BOC-anhydride (1,49 g, 6,83 mmol, solution in 20 ml THF). The mixture was stirred at 0°C for 30 minutes, then was heated to room temperature and was stirred for 18 hours. The reaction mixture is extinguished 1 N. HCl (50 ml) and the layers were separated. The aqueous layer was extracted with ether (2×20 ml), the combined organic extracts were washed with water (20 ml) and brine (20 ml), dried over MgSO4was filtered through celite and concentrated under reduced pressure, obtaining a pale yellow oil. The oil was subjected to chromatography elwira a mixture of ether/hexane (1:2), and obtained 1.45 g of colorless oil, which under high vacuum hardened (yield 75%).

Stage C: Hydrochloride (S)-methyl-4-((4-methoxybenzyl)(isopropyl)amino)-2-(tert-butoxycarbonyl)butanoate. A mixture of isopropyl-(4-methoxybenzyl)amine (0,111 g of 0.62 mmol), (S)-methyl-4-bromo-2-(tert-butoxycarbonyl)butanoate (0,150 g, 0.51 mmol) and triethylamine (0.21 in ml, of 1.52 mmol) in THF (5 ml) was heated to the temperature of reflux distilled for 65 hours. Then the mixture was cooled to room temperature and concentrated under reduced pressure. The balance of experience and chromatography elwira 5% Meon in dichloromethane and receiving was 0.026 g of colorless oil (yield 13%). Then, the compound was treated with HCl (1 ml of 4 n solution in dioxane) at room temperature for 3 hours. The mixture was concentrated under reduced pressure and dried under high vacuum.

Stage D: (S)-Methyl-4-((4-methoxybenzyl)(isopropyl)amino)-2-(5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxamido)butanoate. 5-(2,4-Divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (17d; obtained according to Example 110) (0,022 g, 0,064 mmol) was mixed with HOBt (0,011 g 0,070 mmol) and EDCI (0,014 g 0,070 mmol) in dichloroethane (1 ml) for 10 minutes at room temperature. Then to this mixture was added a suspension of the hydrochloride of (S)-methyl-4-((4-methoxybenzyl)(isopropyl)amino)-2-(tert-butoxycarbonyl)butanoate (0.025 g, 0,067 mmol) and triethylamine (0,054 ml, 0.384 mmol) in dichloromethane (2 ml). The mixture was stirred at room temperature for 16 hours. The solution was filtered through celite and concentrated under reduced pressure. The crude oil was subjected to chromatography elwira 2% Meon in dichloromethane with 1% triethylamine and receiving 0.035 g of a viscous pale yellow oil (yield 89%).

Stage E: (S)-N-(4-((4-Methoxybenzyl)(isopropyl)amino)-1-hydroxybutane-2-yl)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxamide. (S)-Methyl-4-((4-methoxybenzyl)(isopropyl)amino)-2-(5-(2,4-divergence)-1-isobutyl-1H-indazol-6-it is rocksmith)butanoate (0.035 g, 0,057 mmol) and NaBH4(0,022 g, or 0.57 mmol) was dissolved in a mixture of THF/Meon (5 ml, 3:2) and heated to 50°C for 3 hours. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was subjected to chromatography elwira 5% Meon in dichloromethane with 1% triethylamine, getting 0,020 g of gel (yield 59%).

Stage F: (1-Hydroxymethyl-3-isopropylaminomethyl)amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (32d). To a solution of (S)-N-(4-((4-methoxybenzyl)(isopropyl)amino)-1-hydroxybutane-2-yl)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxamide (0,020 g 0,033 mmol) in Meon (5 ml) was added wet Pd/C (0,020 g, 10 wt.%). The mixture was repeatedly purged with hydrogen and then stirred at room temperature in an atmosphere of H2within 5 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was subjected to chromatography elwira a mixture of 10% Meon in dichloromethane with 2% triethylamine and getting to 9.4 mg of colorless gel (yield 60%). MS (IER+), found: m/z 475 (M+1).1H-NMR (400 MHz, CDCl3) δ 8.40 (d, 1H), 8.31 (s, 1H), 7.87 (s, 1H), 7.13 (m, 1H), 7.03 (s, 1H), 7.01 (m, 1H), 6.91 (m, 1H), 4.33 (m, 1H), 4.22 (d, 2H), 3.69 (m, 2H), 2.69 (m, 2H), 2.37 (m, 2H), 1.32 (m, 2H), 1.09 (d, 3H), 1.01 (d, 3H), 0.93 (d, 6H).

Example 123

Obtain (S)-2-{[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carbonyl]amino}4-dimethylaminomethylene acid (33d)

Stage A: 2,5-Dioxopiperidin silt ester 5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid. 5-(2,4-Divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (17d; obtained according to Example 110) (25,0 g, 72.2 mmol), EDCI (18.0 g, 93,8 mmol) and 1-hydroxypyrrolidine-2,5-dione (becomes 9.97 g, 86,6 mmol) suspended in dichloromethane and stirred at room temperature for 2 hours. The mixture was diluted with dichloromethane (500 ml) and washed with saturated NH4Cl (2×200 ml), saturated NaHCO3(2×200 ml) and brine (200 ml). The organic layers were dried over MgSO4and concentrated under reduced pressure, obtaining the crude product as a yellow foam.

Stage b: Methyl ester of (S)-2-{[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carbonyl]amino}-4-dimethylaminomethylene acid. To a solution of 2,5-dioxopiperidin-1 silt ester 5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (32,0 g, 72.2 mmol) and methyl ester dihydrochloride of 2-amino-4-dimethylaminomethylene acid (19,35 g, 83.0 mmol) in dichloromethane was added triethylamine (35 ml, 253 mmol) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure and diluted with dichloromethane (400 ml). The solution was washed with saturated NH4Cl (2×200 ml), saturated NaHCO3(2×200 ml) and brine (200 ml). The organic layers were dried over MgSO4and concentrated under reduced pressure, obtaining the crude product.

Stage C: (S)-2-{[5-(2,4-Diferena the si)-1-isobutyl-1H-indazol-6-carbonyl]amino}-4-dimethylaminomethylene acid (33d). To a solution of methyl ester (S)-2-{[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carbonyl]amino}-4-dimethylaminomethylene acid (3,36 g, to 6.88 mmol) in THF (5 ml) was added triethylsilane potassium (1.77 g, of 13.8 mmol). The reaction mixture was stirred at room temperature for 4 hours. Before concentrating the mixture under reduced pressure, thereto was added a solution of HCl (17 ml of a 4 M solution in dioxane). The residue is suspended in dichloromethane and filtered. The filtrate was concentrated under reduced pressure, obtaining of 2.23 g of product (yield 68%). MS (IER+), found: m/z 475 (M+1).1H-NMR (400 MHz, DMSO-d6) δ 8.81 (d, 1H), 8.02 (s, 1H), 7.99 (s, 1H), 7.48 (m, 1H), 7.25 (m, 1H), 7.22 (s, 1H), 7.11 (m, 1H), 4.50 (m, 1H), 4.28 (d, 2H), 3.17 (m, 1H), 3.04 (m, 1H), 2.70 (s, 6N), 2.25 (m, 2H), 2.13 (m, 1H), 0.87 (d, 6H).

Example 124

Obtain (1-hydroxymethyl-3-piperidine-1-ylpropyl)amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (34d)

Stage A: Methyl ester of (S)-2-tert-butoxycarbonylamino-4-piperidine-1-ilalagay acid. Methyl ester of (S)-4-bromo-2-tert-butoxycarbonylamino acid (0.10 g, 0.34 mmol) (obtained as described in Example 120, stage A-D) and piperidine (1 ml) was heated to 50°C for 16 hours and then cooled to room temperature and concentrated under reduced pressure. The residue was subjected to azeotropic distillation with toluene (3×10 ml), and then chromatography elwira mixture Meon/dichlor the Tang (1:9) and receiving 93 mg of colorless oil (yield 97%).

Stage b: methyl ester Dihydrochloride (S)-2-amino-4-piperidine-1-ilalagay acid. To methyl ether (S)-2-tert-butoxycarbonylamino-4-piperidine-1-ilalagay acid was added HCl (0.45 ml of a 4 M solution in dioxane) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and dried under high vacuum for 16 hours, getting the product outlet 46%.

Stage C: Methyl ester of (S)-2-{[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carbonyl]amino}-4-piperidine-1-yl-butyric acid. To a solution of 5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (0,050 g, 0.14 mmol), methyl ester dihydrochloride (S)-2-amino-4-piperidine-1-ilalagay acid (0,043 g, 0.16 mmol), EDCI (0,033 g, 0,17 mmol) and HOBt (0,023 g, 0,17 mmol) in dichloromethane was added dropwise, DIEA (0,093 g to 0.72 mmol). The reaction mixture was stirred at room temperature until until HPLC analysis showed that the original substance has slashdowns, and then was diluted with dichloromethane and washed with saturated NaHCO3. The organic layer was dried over MgSO4and concentrated under reduced pressure. The residue was subjected to chromatography getting 0,051 g of product (yield 67%).

Stage D: (1-Hydroxymethyl-3-piperidine-1-ylpropyl)amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (34d). Borohydride sodium (0,g, 0.31 mmol) portions was added to a heated (50°C) solution of methyl ester (S)-2-{[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carbonyl]amino}-4-piperidine-1-ilalagay acid (0,022 g 0,042 mmol) in Meon. The reaction mixture was stirred at 50°C until HPLC analysis showed that the original substance has slashdowns. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was diluted with ethyl acetate and 1 N. HCl. Organic matter was extracted with 1 N. HCl up until the organic layer containing the product was determined by HPLC. The aqueous solution was podslushivaet NaOH to pH 14 and then was extracted several times with dichloromethane. The combined organic substances were dried over MgSO4and concentrated under reduced pressure, obtaining 9.1 mg of an oil (yield 44%). MS (head+), found: m/z 501 (M+1).

Example 125

Receive (3-dimethylamino-1-dimethylcarbamoyl)amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (35d)

To a solution of (S)-2-{[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carbonyl]amino}-4-dimethylaminomethylene acid (33d; Example 123) (0,100 g, 0.21 mmol), dimethylamine (0,095 g, 2,11 mmol), EDCI (0,053 g, 0.27 mmol), HOBt (0.037 g, 0.27 mmol)dissolved in dichloromethane was added dropwise, DIEA (0,082 g to 0.63 mmol). The reaction mixture was stirred at room temperature until pokeshade substance has not been fully expended, that was determined by HPLC. Then the reaction mixture was diluted with dichloromethane and washed with saturated NaHCO3, dried over MgSO4and concentrated under reduced pressure. The residue was subjected to chromatography on a flash column (Isolute SPE Si (5 g), elwira gradient, tea/dichloromethane (100 ml 0,3:99,7), tea/Meon/dichloromethane (100 ml 0,3:0,5:99,2), tea/Meon/dichloromethane (100 ml 0,3:2,5:97,2), tea/Meon/dichloromethane (100 ml 0,3:5:94,7). The final product was obtained with the yield of 86%. MS (IER+), found: m/z 502 (M+1).1H-NMR (400 MHz, DMSO-d6) δ 8.63 (d, 1H), 8.01 (s, 1H), 7.96 (s, 1H), 7.48 (m, 1H), 7.23 (m, 1H), 7.20 (s, 1H), 7.09 (m, 1H), 4.98 (m, 1H), 4.26 (d, 2H), 3.07 (s, 3H), 2.84 (s, 3H), 2.23 (m, 2H), 2.13 (m, 1H), 2.03 (s, 6N), 1.80 (m, 1H), 1.65 (m, 1H), 0.86 (d, 6H).

Example 126

Receive (3-dimethylamino-1-methylcarbamoylmethyl)amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (36d)

Received in accordance with the procedure described in Example 125, substituting dimethylamine with methylamine. The product was obtained with the yield of 78%. MS (IER+), found: m/z 488 (M+1).1H-NMR (400 MHz, CDCl3) δ 9.05 (d, 1H), 8.29 (s, 1H), 7.86 (s, 1H), 7.44 (m, 1H), 7.19 (m, 1H), 7.02 (m, 1H), 7.01 (s, 1H), 6.93 (m, 1H), 4.78 (m, 1H), 4.21 (d, 2H), 2.81 (d, 3H), 2.50 (m, 1H), 2.42 (m, 1H), 2.36 (m, 1H), 2.23 (s, 6N), 2.15 (m, 1H), 1.88 (m, 1H), 0.92 (d, 6H).

Example 127

Obtain (1-carbarnoyl-3-dimethylaminopropyl)amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (37d)

Received in accordance with the procedure described in Example 125, replacement is I dimethylamine ammonia. The product was obtained with the yield of 70%. MS (head+), found: m/z 474 (M+1).1H-NMR (400 MHz, DMSO-d6) δ 8.59 (d, 1H), 8.07 (s, 1H), 8.01 (s, 1H), 7.50 (m, 1H), 7.39 (s, 1H), 7.27 (m, 1H), 7.19 (s, 1H), 7.11 (m, 2H), 4.44 (m, 1H), 4.27 (d, 2H), 2.24 (m, 2H), 2.15 (m, 1H), 2.00 (s, 6H), 1.88 (m, 1H), 1.71 (m, 1H), 0.86 (d, 6H).

Example 128

Obtain [1-(2-dimethylaminoethyl)-2-hydroxy-2-methylpropyl]amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (38d)

To a cooled (0°C.) solution of methyl ester (S)-2-{[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carbonyl]amino}-4-dimethylaminomethylene acid (Example 123, stage a-b) (0,112 g, 0,229 mmol) in THF (2 ml) was added dropwise methylmagnesium (2,00 ml of 1.4 M solution). The reaction mixture was left to warm to room temperature and mixed for 16 hours in an atmosphere of N2. The mixture was distributed between ethyl acetate and saturated NH4Cl. The layers were separated and the aqueous layer was twice extracted with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was subjected to chromatography on a flash column (Isolute SPE Si (5 g), elwira gradient: tea/CH2Cl2(100 ml of 0.3:99,7), tea/Meon/CH2Cl2(100 ml of 0.3:0,5:99,2), tea/Meon/CH2Cl2(100 ml of 0.3:2,5:97,2), tea/Meon/CH2Cl2(100 ml of 0.3:5:94,7). The final product was obtained with the yield of 41%. MS (head+), found: m/z 489 (M+1).1Mr. YAM is (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.97 (d, 1H), 7.89 (s, 1H), 7.48 (m, 1H), 7.23 (m, 1H), 7.18 (s, 1H), 7.10 (m, 1H), 4.58 (m, 1H), 4.27 (d, 2H), 3.88 (m, 1H), 2.23 (m, 2H), 2.07 (s, 6N), 1.88 (m, 1H), 1.43 (m, 1H), 1.13 (s, 3H), 1.04 (s, 3H), 0.86 (dd, 6H).

Example 129

Obtain {1-hydroxymethyl-3-[(2-methoxyethyl)methylamino]-propyl}amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (39d)

Stage A: Methyl ester of (S)-2-tert-butoxycarbonylamino-4-jetmalani acid: a Mixture of methyl ester (S)-4-bromo-2-tert-butoxycarbonylamino acid (1.19 g, 4.0 mmol) (Example 120, stage A-D) and NaI (6.0 g, 40.0 mmol) in acetone (25 ml) was heated to 70°C for 2 hours. Then the mixture was cooled to room temperature, concentrated under reduced pressure and was distributed between water (10 ml) and ether (40 ml). The layers were separated, the organic layer was washed with water (10 ml), dried over MgSO4was filtered through celite and concentrated under reduced pressure, getting 1.26 g of product (yield 92%).

Stage b: Methyl ester of (S)-2-tert-butoxycarbonylamino-4-[(2-methoxyethyl)methylamino]butyric acid. A mixture of methyl ester (S)-2-tert-butoxycarbonylamino-4-jetmalani acid (0,200 g of 0.58 mmol), (2-methoxyethyl)methylamine (0,062 g, 0.70 mmol) and triethylamine (of 0.41 ml, 2.9 mmol) in dioxane (1 ml) was stirred at 70°C for 16 hours. The mixture was cooled to room temperature, concentrated under reduced pressure and dissolved in dichloromethane is (20 ml). The solution was washed with water (3×10 ml), brine (10 ml), dried over MgSO4was filtered through celite and concentrated under reduced pressure. Yellow-brown oil was subjected to chromatography elwira ether and receiving 0.87 g of pale yellow oil (yield 49%).

Stage C: the methyl ester Dihydrochloride (S)-2-amino-4-[(2-methoxyethyl)methylamino]butyric acid. Methyl ester of (S)-2-tert-butoxycarbonylamino-4-[(2-methoxyethyl)methylamino]butyric acid (0,086 g, 0.28 mmol) was treated with HCl (1 ml, 4 M solution in dioxane) and treated with ultrasound. The mixture was concentrated and dried under high vacuum, receiving the product.

Stage D: Methyl ester of (S)-2-{[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carbonyl]amino}-4-[(2-methoxyethyl)methylamino]butyric acid. To a solution of 5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (obtained as described in Example 110, stages A-G) (0,094 g, 0.27 mmol), methyl ester dihydrochloride (S)-2-amino-4-[(2-methoxyethyl)methylamino]butyric acid (0.079 in g, 0.28 mmol), EDCI (0,057 g, 0.30 mmol) and HOBt (0,045 g, 0.30 mmol) in dichloroethane (2 ml) dropwise was added triethylamine (0,23 ml of 1.62 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. The mixture was concentrated under reduced pressure and subjected to chromatography, elwira with ethyl acetate and receiving 0,100 g of product (yield 69%).

Stage E: {1-Hydroxy shall ethyl-3-[(2-methoxyethyl)methylamino]propyl}amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (39d). Methyl ester of (S)-2-{[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carbonyl]amino}-4-[(2-methoxyethyl)methylamino]butyric acid (0,023 g 0,043 mmol) and NaBH4(0,016 g, 0.43 mmol) was dissolved in THF/Meon (7 ml, 5:2) and heated to 70°C. in a sealed vessel for 5 hours. The mixture was cooled to room temperature, concentrated under reduced pressure and subjected to chromatography, elwira with a mixture of tea/ethyl acetate (1:4) and receiving 0,007 g of the product as a viscous oil (yield 31%). MS (head+), found: m/z 505 (M+1).

Example 130

Obtain [3-dimethylamino-1-(2-hydrooximethylcarbamil)propyl]amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (40d)

Received in accordance with the procedure described in Example 125, substituting dimethylamine 2-aminoethanol. The product was obtained in 51%yield. MS (head+), found: m/z 518 (M+1).1H-NMR (400 MHz, CDCl3) δ 9.00 (d, 1H), 8.29 (s, 1H), 7.86 (s, 1H), 7.81 (t, 1H), 7.18 (m, 1H), 7.02 (m, 1H), 7.00 (s, 1H), 6.92 (m, 1H), 4.82 (m, 1H), 4.21 (d, 2H), 3.42 (m, 2H), 2.86 (m, 1H), 2.49 (m, 2H), 2.35 (m, 1H), 2.23 (s, 6H), 2.17 (m, 2H), 1.94 (m, 1H), 0.92 (d, 6H).

Example 131

Obtaining N'-[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-yl]-N,N-DIMETHYLPROPANE-1,3-diamine (41d)

A mixture of 6-bromo-5-(2,4-divergence)-1-isobutyl-1H-indazole (15d; Example 110, stages a-E) (0,030 g 0,079 mmol), 3-(dimethylamino)Propylamine (0,012 g, amount of 0.118 mmol), BINAP (0,009 g to 0.016 mmol), Pd2dba3(0,007 g 0,008 mmol) and NaO-t-Bu (0,g, 0,087 mmol) in dioxane was stirred in the flask three times and was purged with nitrogen. Then the reaction mixture was heated to 100°C for 16 hours. The mixture was cooled to room temperature and distributed between ethyl acetate (20 ml) and brine (20 ml). The aqueous phase was extracted with ethyl acetate, the combined organic layers were dried over MgSO4and concentrated under reduced pressure. The residue was subjected to chromatography on silica, elwira a mixture of acetone/ether (1:1,5) with 0.2% triethylamine. The product was again subjected to chromatography elwira 5% Meon in dichloromethane and receiving of 0.022 g of the product as a colourless oil (yield 69%). MS (IER+), found: m/z 403 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 6.95 (m, 3H), 6.80 (m, 1H), 6.40 (s, 1H), 5.48 (br. s, 1H), 4.06 (d, 2H), 3.28 (m, 2H), 2.43 (m, 2H), 2.35 (m, 1H), 2.20 (s, 6N), 1.86 (m, 2H), 0.94 (d, 6H).

Example 132

Obtain [5-(2,4-divergence)-1-isobutyl-1H-indazol-6-yl]piperidine-4-ylamine (42d)

Stage A: tert-Butyl ether 4-[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-ylamino]piperidine-1-carboxylic acid.

Received as described in Example 131, substituting 3-(dimethylamino)Propylamine tert-butyl ether 4-aminopiperidin-1-carboxylic acid. The crude product was subjected to chromatography on silica, elwira a mixture of ether/hexane (1:2), and receiving 0.035 g of product as a yellow oil (yield 78%).

Stage b: [5-(2,4-Divergence)-1-isobutyl-1H and dasol-6-yl]piperidine-4-ylamine (42d). To a solution of tert-butyl ester 4-[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-ylamino]piperidine-1-carboxylic acid (0.035 g, 0,070 mmol) in Meon (2 ml) was added HCl (2 ml of 4 M solution in dioxane). The mixture was stirred at room temperature for 40 minutes and then concentrated under reduced pressure. The residue was subjected to azeotropic distillation with Meon (2×), getting to 0.032 g of a yellow solid substance in the form of a hydrochloric salt (yield 97%).1H-NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 7.26 (m, 1H), 7.20 (m, 1H), 7.04 (m, 1H), 6.93 (s, 1H), 6.89 (s, 1H), 4.27 (d, 2H), 3.95 (m, 1H), 3.52 (m, 2H), 3.28 (m, 2H), 2.34 (m, 3H), 1.83 (m, 2H), 0.95 (d, 6H).

Example 133

Obtain [5-(2,4-divergence)-1-isobutyl-1H-indazol-6-yl]piperidine-3-ylmethylamino (43d)

Stage A: tert-Butyl ether 3-{[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-ylamino]methyl}piperidine-1-carboxylic acid. Received in accordance with the procedure described in Example 131, substituting 3-(dimethylamino)Propylamine tert-butyl ester 3-aminomethylpyridine-1-carboxylic acid. The crude product was subjected to chromatography on silica, elwira a mixture of ether/hexane (1:2), and receiving 0,051 g of the product as a yellow foam (yield 94%).

Stage b: [5-(2,4-Divergence)-1-isobutyl-1H-indazol-6-yl]piperidine-3-ylmethylamino (43d). To a cooled (0°C.) solution of tert-butyl ester 3-{[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-ylamino]methyl}piperidine-1-to benovoy acid (0,051 g, 0,099 mmol) in Meon (3 ml) was added concentrated HCl (0,18 ml). The reaction mixture was heated to room temperature and was stirred for 16 hours. Added additional concentrated HCl (0.4 ml) and the mixture was stirred at room temperature for more than 24 hours. The mixture was concentrated under reduced pressure and subjected to azeotropic distillation with Meon (3×)to give 0.037 g of a yellowish solid (yield 77%). MS (IER+), found: m/z 415 (M+1).

Example 134

Getting 2-(5-{2-[3-(5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl)freedomites]-4-fervency}indazol-1-yl)-N,N-dimethylacetamide (47d)

The reaction scheme for the synthesis of compound 47d according to this invention is shown in Fig.

Stage A: 2-[5-(2-Cyano-4-pertenece)indazol-1-yl]-N,N-dimethylacetamide (45d). To a solution of 5-fluoro-2-(1H-indazol-5-yloxy)benzonitrile (44d) (0,200 g, 0,790 mmol) in DMF (6 ml) was added 2-chloro-N,N-dimethylacetamide (0,115 g, 0,948 mmol) and tetrabutylammonium iodide (0,088 g, 0,237 mmol), and then To2CO3(0,164 g, 1,19 mmol). The mixture was heated to 110°C for 48 hours in an atmosphere of N2. The reaction mixture was concentrated under reduced pressure and dissolved in dichloromethane. The solution was washed 1 N. HCl, filtered and subjected to chromatography on a Biotage, elwira a mixture of 5% Meon in dichloromethane and getting to 0.032 g of product (yield 12%).

Stage b: 2-[5-(2-Aminomethyl-4-pertenece)indazol-1-yl]-N,N (46d). To a solution of 2-[5-(2-cyano-4-pertenece)indazol-1-yl]-N,N-dimethylacetamide (0,090 g 0,266 mmol) in EtOH (0.5 ml) was added CoBr2(27 μl, of 0.005 mmol), and then [2,2']bipyridinyl (81 μl, 0.015 mmol). To the mixture was added NaBH4(0,030 g, 0,798 mmol) and stirred at room temperature for 18 hours. The mixture was treated with another portion of CoBr2, [2,2']bipyridinyl and NaBH4and was stirred for another 18 hours. The mixture was suppressed Meon, and then acetic acid and then concentrated under reduced pressure. The white residue was distributed between saturated NaHCO3and ethyl acetate. The organic layer was filtered and concentrated under reduced pressure to give 10 mg of a white solid (yield 11%).

Stage C: 5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-ylamine. A solution of the hydrochloride of p-tolylhydrazine (15,86 g, 100 mmol) and pihlajaniemi (17.9 g, 143 mmol) in Meon (65 ml) was heated to the temperature of reflux distilled for 18 hours in an atmosphere of N2. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue is triturated with ether and collected by filtration. The solid was dried under high vacuum, getting to 26.6 g of white solid (yield 99%).

Stage D: 2,2,2-Trichlorethylene ether (5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl)carbamino acid. A cooled (0°C) two-phase solution of 5-tert-butyl-2-p-tolyl-2H-pyrazole-ylamine (26,6 g, 100 mmol) in water (80 ml) and ethyl acetate (180 ml) was treated with NaOH (10 g, 250 mmol), and then trichlorethylphosphate (29,7 g, 140 mmol). The reaction mixture was heated to room temperature and was stirred for 1 hour. The layers were separated and the organic layer was washed with brine (100 ml), dried over MgSO4was filtered through celite and concentrated under reduced pressure, obtaining of 40.3 g of a pale yellow solid (yield 99%).

Stage E: 2-(5-{2-[3-(5-tert-Butyl-2-p-tolyl-2H-pyrazole-3-yl)freedomites]-4-fervency}indazol-1-yl)-N,N-dimethylacetamide (47d). To a solution of 2-[5-(2-aminomethyl-4-pertenece)indazol-1-yl]-N,N-dimethylacetamide (46d) (0,010 g 0,029 mmol) and 2,2,2-trichlorethylene ether (5-tert-butyl-2-p-tolyl-2H-pyrazole-3-yl)carbamino acid (0,013 g to 0.032 mmol) in DMF (1 ml) was added DIEA (0.01 ml, 0,058 mmol). The mixture was heated up to 80°C for 18 hours in an atmosphere of N2. The mixture was concentrated under reduced pressure and dissolved in dichloromethane. The solution was washed 1 N. HCl, filtered and concentrated under reduced pressure. The oil was subjected to chromatography elwira a mixture of dichloromethane/ether (10:1) and then 5% Meon in dichloromethane, getting to 6.3 mg of pale yellow oil (yield 36%). MS (head+), found: m/z 598 (M+1).1H-NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 7.97 (s, 1H), 7.58 (d, 1H), 7.36 (d, 2H), 7.28 (d, 2H), 7.19 (d, 1H), 7.12 (d, 1H), 7.07 (m, 2H), 6.99 (m, 1H), 6.84 (m, 1H), 6.24 (s, 1H), 5.40 (s, 2H), 4.28 (d, 2H), 3.10 (s, 3H), 2.84 (s, 3H), 2.3 (s, 3H), 1.25 (s, 9H).

Example 135

Obtaining 1-(5-tert-butylisoxazole-3-yl)-3-[5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)benzyl]urea (48d)

Stage A: 1-Isobutyl-5-methoxy-1H-indazol. A solution of 5-methoxy-1H-indazole (5,00 g, or 33.7 mmol) in DMF (100 ml) was treated with K2CO3(of 5.83 g, 42.2 per mmol) and stirred at room temperature for 15 minutes. To this solution was added 1-bromo-2-methylpropan (5,09 g, 37,1 mmol) and the resulting mixture was heated to 110°C for 18 hours. Added one equivalent of 1-bromo-2-methylpropane and continued to heat the mixture for a further 48 hours. The mixture was concentrated under reduced pressure and dissolved in dichloromethane. The solution was washed 1 N. HCl, filtered and concentrated under reduced pressure. The residue was subjected to chromatography on a Biotage, elwira a mixture hexane/ether (5:1) and receiving of 2.51 g of orange oil (yield 36%).

Stage b: 1-Isobutyl-1H-indazol-5-ol. To a cooled (-78°C) solution of 1-isobutyl-5-methoxy-1H-indazole (to 2.57 g, 12.6 mmol) in dichloromethane (100 ml) was added BBr3(25 ml of 1 M solution in dichloromethane). The mixture was stirred at -78°C for 2 hours and then heated to room temperature and was stirred for 18 hours. The reaction mixture was poured into ice water and was extracted with dichloromethane. The organic extract was filtered and concentrated under reduced pressure, obtaining 2.3 g of solid which substances (yield 96%).

Stage C: 5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)benzonitrile. To a solution of 1-isobutyl-1H-indazol-5-ol (2,33 g, 12.2 mmol) and K2CO3(2,03 g, 14.7 mmol) in DMF (75 ml) was added 2,5-diferential (of 1.87 g, 13.5 mmol). The mixture was heated to 110°C for 18 hours in an atmosphere of N2. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in dichloromethane. The solution was washed 1 N. HCl, filtered and concentrated under reduced pressure. The residue was subjected to chromatography on a Biotage, elwira a mixture hexane/ether (5:2), and receiving of 3.05 g of a pale yellow oil (yield 81%).

Stage D: 5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)benzylamine. To a solution of 5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)benzonitrile (3,05 g, 9,86 mmol) in Meon (50 ml), subjected to a nitrogen purge, was added concentrated HCL (1.6 ml) and Pd(OH)2/C (15 wt.%, 0,457 g). The mixture was stirred at room temperature for 18 hours in an atmosphere of H2. The catalyst was removed by filtration and the solution was concentrated under reduced pressure, obtaining of 3.32 g of a pale yellow foam (yield 96%).

Stage E: 1-(5-tert-Butylisoxazole-3-yl)-3-[5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)benzyl]urea. To a cooled (0°C.) solution of 5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)benzylamine (0,364 g, 1.04 mmol) and DIEA (0.5 ml, of 2.08 mmol) in dichloromethane (10 ml) was added triphosgene (0,131 g, 0,374 mmol). The mixture displaced ivali at 0°C for 1 hour and then stirred at room temperature for 18 hours in an atmosphere of N 2. The reaction mixture was concentrated under reduced pressure and suspended in dichloromethane (10 ml) to obtain the 0,123 M solution. 0.4 ml of this solution (0.015 g, 0,048 mmol) was treated with 5-tert-butylisoxazole-3-aluminum (0.008 g, 0,053 mmol). The product was obtained with the yield of 44%. MS (head+), found: m/z 480 (M+1).

Example 136

Obtain 1-(3-tert-butylisoxazole-5-yl)-3-{5-fluoro-2-[1-(2-piperazine-1-retil)-1H-indazol-5-yloxy]benzyl)urea (49d)

Stage A: 2-[1-(2,2-Dimethoxymethyl)-1H-indazol-5-yloxy]-5-perbenzoate. To a cooled (0°C.) solution of 5-fluoro-2-(1H-indazol-5-yloxy)benzonitrile (0,100 g, 0,395 mmol) and 2-bromo-1,1-dimethoxyethane (0,114 g, 0,671 mmol) in DMF (4 ml) was added NaH (0,024 g, 60%, 0.59 mmol). The reaction mixture was heated to room temperature and was stirred for 1 hour. To the mixture was added tetrabutylammonium iodide (0,029 g 0,079 mmol) and was heated to 60°C for 3 hours. The mixture was cooled to room temperature, diluted with water (4 ml) and was extracted with ether (3×30 ml). The combined extracts were washed with water (2×5 ml) and brine, dried over MgSO4and concentrated under reduced pressure. The residue was subjected to chromatography elwira a mixture of ethyl acetate/hexane (1:2), and receiving of 0.066 g of product (yield 49%).

Stage b: 5-fluoro-2-[1-(2-oxoethyl)-1H-indazol-5-yloxy]benzonitrile. To a solution of 2-[1-(2,2-dimethoxymethyl)-1H-indazol-5-yloxy]-5-perbenzoate (1.42 g, 4.6 mmol) in dichloromethane (62 ml) in portions over 3 hours was added attributively (3.33 g, 16,64 mmol). The mixture was stirred at room temperature for 2 hours. To the mixture was added aqueous NaHCO3(60 ml) and was extracted with her with ethyl acetate (2×50 ml). The combined extracts were washed Na2S2O4, brine, dried over MgSO4and concentrated under reduced pressure. The crude product was used for next reaction stage without further purification.

Stage C: tert-Butyl ether 4-{2-[5-(2-cyano-4-pertenece)indazol-1-yl]ethyl}piperazine-1-carboxylic acid. To a solution of 5-fluoro-2-[1-(2-oxoethyl)-1H-indazol-5-yloxy]benzonitrile (0,307 g, 1.04 mmol) and triacetoxyborohydride (0.66 g, 3.1 mmol) in dichloroethane (10 ml) was added tert-butyl ether piperazine-1-carboxylic acid (0.65 g, 3,49 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was extinguished Meon (2 ml) and was diluted with ethyl acetate (100 ml). The solution is washed with aqueous NaHCO3, brine, dried over MgSO4and concentrated under reduced pressure. The residue was subjected to chromatography elwira a mixture of ethyl acetate/hexane (2:3, with 1% of triethylamine) and getting to 0.29 g of product (yield 60%).

Stage D: tert-Butyl ether 4-{2-[5-(2-aminomethyl-4-pertenece)indazol-1-yl]ethyl}piperazine-1-carboxylic acid. To a solution of tert-butyl ester 4-{2-[5-(2-cyano-4-pertenece)indazol-1-yl]ethyl}piperazine-1-carboxylic acid (0,160 g, 0,344 the mole), CoBr2(0.008 g, 0,034 mmol), [2,2']bipyridinyl (0,016 g 0,010 mmol) in EtOH (6 ml) was added NaBH4(0,039 g, 1.0 mmol). The mixture was stirred for 3 hours at room temperature. The reaction extinguished Meon (3 ml) and acetic acid (10 drops). The solution was concentrated under reduced pressure and diluted with ethyl acetate. The mixture is washed with aqueous NaHCO3, brine, dried over MgSO4and concentrated under reduced pressure. The crude oil was subjected to chromatography elwira mixture of 1% triethylamine in ethyl acetate, the mixture Meon/CH2Cl2/hexane (1:15:15, 1% triethylamine), then the mixture Meon/CH2Cl2/hexane (1:10:10, 1% triethylamine). Pure product was obtained with the yield of 86%.

Stage E: 4-Nitrophenyloctyl ether (3-tert-butylisoxazole-5-yl)carbamino acid. A solution of 3-tert-butylisoxazole-5-ylamine (2.50 g, 17,83 mmol) in dichloromethane was treated with pyridine (2 ml, to 26.7 mmol)and then p-nitrophenylphosphate (3.77 g, 18,73 mmol). The mixture was stirred at room temperature for 2 hours. The reaction mixture was washed with 1 N. HCl, filtered and concentrated under reduced pressure. The residue is triturated with ether and collected by filtration, obtaining 2.2 g of product (yield 41%).

Stage F: tert-Butyl ether 4-[2-(5-{2-[3-(3-tert-butylisoxazole-5-yl)freedomites]-4-fervency}indazol-1-yl)ethyl]piperazine-1-carboxylic acid. A solution of tert-butyl is the first ether 4-{2-[5-(2-aminomethyl-4-pertenece)indazol-1-yl]ethyl}piperazine-1-carboxylic acid (0,050 g, 0,107 mmol) in dichloromethane (2 ml) was treated with 4-nitoinimoi ether (3-tert-butylisoxazole-5-yl)carbamino acid (of 0.081 g, 0,266 mmol) and stirred at room temperature for 24 hours. The mixture was diluted with ethyl acetate (60 ml), washed with 1 N. NaOH (5 ml), water (2×10 ml), brine, dried over MgSO4and concentrated under reduced pressure. The residue was subjected to chromatography elwira a mixture of acetone/hexane (2:3, then 1:1) and receiving 0,056 g of product (yield 83%).

Stage G: 1-(3-tert-Butylisoxazole-5-yl)-3-{5-fluoro-2-[1-(2-piperazine-1-retil)-1H-indazol-5-yloxy]benzyl}urea. tert-Butyl ester 4-[2-(5-{2-[3-(3-tert-butylisoxazole-5-yl)freedomites]-4-fervency}indazol-1-yl)ethyl]piperazine-1-carboxylic acid (0,056 g, 0,088 mmol) was treated with a mixture of TFU/CH2Cl2(1:1, 2 ml) and stirred at room temperature for 1 hour. The mixture was concentrated under reduced pressure and subjected to azeotropic distillation with toluene. The residue was diluted with ethyl acetate (40 ml) and washed with 1 N. NaOH and brine. The solution was concentrated under reduced pressure, getting 0,038 g of product (yield 80%). MS (IER+), found: m/z 536 (M+1).1H-NMR (400 MHz, CDCl3) δ 7.81 (s, 1H), 7.35 (d, 1H), 7.15 (dd, 1H), 7.08 (s, 1H), 7.05 (d, 1H), 6.88 (m, 1H), 6.76 (m, 1H), 6.28 (m, 1H), 5.99 (s, 1H), 4.46 (m, 4H), 2.86 (m, 2H), 2.79 (m, 4H), 2.43 (m, 4H), 1.26 (s, 9H).

Example 137

Obtain 1-(3-tert-butylisoxazole-5-yl)-3-{2-[1-(2-dimethylaminoethyl-1H-indazol-5-yloxy]-5-terbisil}urea (50d)

Stage A: 2-[1-(2-Dimethylaminoethyl)-1H-indazol-5-yloxy]-5-perbenzoate. A solution of 5-fluoro-2-[1-(2-oxoethyl)-1H-indazol-5-yloxy]benzonitrile (0,110 g, 0,372 mmol) (obtained in accordance with the procedure described in Example 136, stage a-b) and triacetoxyborohydride sodium (0.39 g, 1.9 mmol) in dichloroethane (3 ml) was treated with dimethylamine (0.17 g, 3.7 mmol) and stirred at room temperature for 3 hours. The reaction extinguished Meon (1 ml) and was diluted with ethyl acetate (30 ml). The solution is washed with aqueous NaHCO3, brine, dried over MgSO4and concentrated under reduced pressure. The residue was subjected to chromatography elwira with ethyl acetate and then a mixture of acetone/hexane (2:3 with 1% of triethylamine) and receiving 0,115 g of product (yield 95%).

Stage b: {2-[5-(2-Aminomethyl-4-pertenece)indazol-1-yl]ethyl}dimethylamine. To a cooled (0°C.) solution of 2-[1-(2-dimethylaminoethyl)-1H-indazol-5-yloxy]-5-perbenzoate (0,115 g, 0,303 mmol) in THF (3 ml) was added LAH (and 0.61 ml of 1 M solution in THF). The mixture was heated to room temperature and was stirred for 1.5 hours. The mixture is extinguished by water (23 ml), 3 N. NaOH (23 ml) and water (69 ml). Salt was removed by filtration, and the filtrate was concentrated under reduced pressure, getting 0,113 g of product (yield 97%).

Stage C: 1-(3-tert-Butylisoxazole-5-yl)-3-{2-[1-(2-dimethylaminoethyl)-1H-indazol-5-yloxy]-5-terbisil}urea. A solution of {2-[5-(2-aminomethyl-4-ftoh is noxi)indazol-1-yl]ethyl}dimethylamine (0,020 g, 0.061 mmol) in DMF (1 ml) was treated with 4-nitrophenyloctyl ether (3-tert-butylisoxazole-5-yl)carbamino acid (0,020 g 0,067 mmol) (obtained according to Example 136, step E). The mixture was stirred at room temperature for 18 hours in an atmosphere of N2. The reaction mixture was subjected to chromatography elwira a mixture of dichloromethane/ether (10:1)and then 5% Meon in dichloromethane and receiving 5.3 mg of pale yellow oil (yield 18%). MS (head+), found: m/z 495 (M+1).1H-NMR (400 MHz, DMSO-d6) δ 10.14 (s, 1H), 7.98 (s, 1H), 7.74 (d, 1H), 7.22 (d, 1H), 7.16 (m, 2H), 7.08 (m, 1H), 6.88 (m, 2H), 5.93 (s, 1H), 4.48 (t, 2H), 4.35 (d, 2H), 2.70 (t, 2H), 2.17 (s, 6N), 1.23 (s, 9H).

Example 138

Obtaining 1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-3-{5-fluoro-2-[1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yloxy]benzyl)urea (51d)

Stage A: 5-fluoro-2-[1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yloxy]benzonitrile. A solution of 5-fluoro-2-(1H-indazol-5-yloxy)benzonitrile (0,100 g, 0,395 mmol) in DMF (4 ml) was treated with NaH (0,022 g, 60%, of 0.56 mmol) and was stirred for 5 minutes. Added 2,2-dimethyloxetane (0.035 g, 0.48 mmol) and the solution was stirred at room temperature for 1 hour. Then the reaction mixture was heated up to 80°C for 1.5 hours. The solution was cooled to room temperature, diluted with ether (50 ml), washed with water (3×5 ml), brine, dried over MgSO4and concentrated under reduced pressure. The residue was subjected to chromatography elwira with whom ESU ethyl acetate/hexane (1:1) and receiving 0,070 g of product (yield 47%).

Stage b: 2-{1-[2-(tert-Butyldimethylsilyloxy)-2-methylpropyl]-1H-indazol-5-yloxy}-5-perbenzoate. To a cooled (0°C.) solution of 5-fluoro-2-[1-(2-hydroxy-2-methyl propyl)-1H-indazol-5-yloxy]benzonitrile (0,070 g, 0,215 mmol) and 2,6-lutidine (0,030 g, 0,284 mmol) in dichloromethane (2 ml) was added TBSOTf (0,063 g, 0,240 mmol). The reaction mixture was heated to room temperature and was stirred for 1 hour. The mixture was diluted with ether (50 ml) and washed with 0.2 N. HCl, NaHCO3and brine, dried over MgSO4and concentrated under reduced pressure. The residue was subjected to chromatography elwira a mixture of ether/hexane (1:3) and receiving 0,071 g of a pale yellow oil (yield 94%).

Stage C: 2-{1-[2-(tert-Butyldimethylsilyloxy)-2-methylpropyl]-1H-indazol-5-yloxy}-5-forbindelsen. To a cooled (0°C.) solution of 2-{1-[2-(tert-butyldimethylsilyloxy)-2-methylpropyl]-1H-indazol-5-yloxy}-5-perbenzoate (0,071 g rate £ 0.162 mmol) in THF (2 ml) was added LAH (0,32 ml of 1 M solution in THF). The solution was heated to room temperature and was stirred for 1 hour. The reaction mixture was cooled to 0°C and extinguished with water (12 ml), 3 N. NaOH (12 ml) and water (36 ml). Salt was removed by filtration, the filtrate was concentrated under reduced pressure and used in the next reaction stage without further purification.

Stage D: 2,2,2-Trichlorethylene ether (5-tert-butyl-2-methyl-2H-pyrazole-3-yl)carbamino KIS is the notes. To a cooled (10°C.) solution of 5-tert-butyl-2-methyl-2H-pyrazole-3-ylamine (3.75 g, 24.5 mmol) and NaOH (1.5 g in 20 ml water) in ethyl acetate (45 ml) was added 2,2,2-trihloretilamina (7,52 g, 35.5 mmol) for 5 minutes. The reaction mixture was heated to room temperature and was stirred for 2 hours. The mixture was diluted with ethyl acetate and the layers were separated. The organic layer was washed with water, brine, dried over MgSO4and concentrated under reduced pressure. The residue was diluted with a mixture of ethyl acetate/dichloromethane and treated with aminomethylated silica (10 g) for 1 hour. The mixture was filtered and the filtrate was concentrated under reduced pressure, obtaining the product.

Stage E: 1-(2-{1-[2-(tert-Butyldimethylsilyloxy)-2-methylpropyl]-1H-indazol-5-yloxy}-5-terbisil)-3-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)urea. A mixture of 2-{1-[2-(tert-butyldimethylsilyloxy)-2-methylpropyl]-1H-indazol-5-yloxy}-5-forbindelsen (0,072 g rate £ 0.162 mmol), 2,2,2-trichlorethylene ether (5-tert-butyl-2-methyl-2H-pyrazole-3-yl)carbamino acid (0,080 g, 0.24 mmol) and DIEA (0.06 ml, 0,324 mmol) in DMA (3 ml) was heated to 80°C for 16 hours. The mixture was diluted with ether (60 ml) and washed with water (3×5 ml), brine, dried over MgSO4and concentrated under reduced pressure. The residue was subjected to chromatography on silica, elwira a mixture of ethyl acetate/hexane (3:1) and receiving 0,084 g of product, yield 83%).

Stage F: 1-(5-tert-Butyl-2-methyl-2H-pyrazole-3-yl)-3-{5-fluoro-2-[1-(2-hydroxy-2-methylpropyl)-1H-indazol-5-yloxy]benzyl}urea. To a solution of 1-(2-{1-[2-(tert-butyldimethylsilyloxy)-2-methylpropyl]-1H-indazol-5-yloxy}-5-terbisil)-3-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)urea (0,084 g is 0.135 mmol) in dichloromethane (3 ml) was added TBAF (0,70 ml of 1 M solution in THF). The mixture was stirred at room temperature for 5 days. The reaction mixture was poured into NH4Cl and extracted with ethyl acetate (3×30 ml). The combined extracts were washed with brine, dried over MgSO4and concentrated under reduced pressure. The residue was subjected to chromatography on silica, elwira a mixture of acetone/hexane (2:1) and getting to 0.060 g of product (yield 87%). MS (IER+), found: m/z 509 (M+1).1H-NMR (400 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.98 (s, 1H), 7.74 (d, 1H), 7.17 (m, 3H), 7.08 (m, 1H), 6.85 (m, 2H), 5.95 (s, 1H), 4.66 (s, 1H), 4.33 (d, 2H), 4.30 (s, 2H), 2.50 (s, 3H), 1.18 (s, 9H), 1.12 (s, 6H).

The above description is considered only as illustrations of the principles of the invention. Furthermore, since numerous modifications and changes will be obvious to experts in the field of technology, it is not desirable to limit the invention to the exact construction and method as described above. Respectively, can be carried out in all suitable modifications and equivalents that are within the scope of the present invention, it is to defined by the following claims.

The words "include", "include", "includes", "including" and "includes" when used in this description and in the claims, are intended to indicate the presence of stated features, integers, components, or stages, but they do not preclude the presence or addition of one or more other features, integers, components, stages or groups.

1. The compound having the formula
,
or its pharmaceutically acceptable salt, where
Y represents C, N;
W represents C, N or O, provided that W represents N or O, Y represents S, and W represents S, Y represents N;
U represents CH or N;
V is a S-S or N;
X represents O, S, SO, SO2, NH, C=O, -C=NOR1or CHOR1;
In represents N or NH2when W represents S, or represents N, when W represents N, or absent when W represents O;
R1represents H, alkyl, or Zn-Ar1;
E represents N, Zn-NR2R3, Zn-(C=O)R4, Zn-(C=O)R5, Zn-OR6, Zn-SO2R4or R5;
Z represents alkylene having from 1 to 4 carbon atoms, optionally substituted by a group selected from HE shall do With 1-6of alkyl;
R2represents H, alkyl, Zn-heteroseksualci or Zn-Ar1;
R3represents H, alkyl, tert-butoxycarbonyl, methylsulphonyl or acetyl;
or R2together with R3and N form heteroseksualci;
R4is a natural or unnatural amino acid,
NHCH(R8)(CH2)mOR7or NR2R3;
where n means 0 or 1;
m means an integer from 1 to 4;
R5represents H, HE, alkyl, C1-6alkoxy, or Zn-heteroseksualci;
R6represents N, Zn-heteroseksualci or alkyl;
R7represents H or alkyl;
R8is a Zn-NR2R3;
Ar1represents aryl or heteroaryl;
And in the case when Y is S, has the following values: H, HE,
Zn-NR2R3, Zn-NR3(C=O)R3, Zn-SO2R10, Zn-OR10, Zn-(C=O)R9, alkyl, alkenyl, Zn-cycloalkyl, Zn-heteroseksualci or Zn-Ar1;
And in the case when Y is N, has the following values: N, Z,-NR2R3Z-NR3(C=O)R3, Zn-SO2R10, Z-OR10, Zn-(C=O)R9, alkyl, alkenyl, Zn-cycloalkyl, Zn-heteroseksualci or Z-Ar1;
R9PR is dstanley a N, HE, C1-6alkoxygroup or amino group, optionally substituted C1-6the alkyl or benzyl;
R10represents H, alkyl or aryl;
where alkenyl represents a C1-6alkenyl, which can be substituted by aryl;
where alkyl represents a C1-6alkyl and may be substituted by one or more than one group selected from halogen, cycloalkyl, geterotsiklicheskie, -COOH, -COOR (where R represents a C1-6alkyl), -CONH2, -CONH(C1-6alkyl), -CON(C1-6alkyl)(C1-6alkyl), amino group or hydroxy-group, where the amino group or a hydroxy-group may be optionally substituted by one or more than one group selected from C1-6of alkyl, benzyl or tert-butoxycarbonyl;
where cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;
where heteroseksualci represents a saturated 5-8 membered monocycle, which may be condensed with one six-membered aromatic ring and has, besides carbon atoms one to two heteroatoms selected from N, O and S, which may be substituted by groups selected from C1-6of alkyl, benzyl, tert-butoxycarbonyl or carbonyl group;
where heteroaryl represents an aromatic monocycle of 5-6 members or bicycl of 9-10 members, including in addition to carbon atoms of the nogo up to two heteroatoms, selected from N, O and S, which may be substituted by groups selected from halogen, C1-4of alkyl, C1-4alkoxy, C1-4alkylthio or1-4alkylsulfonyl;
where aryl is a 6 - or 10-membered aromatic ring which may be substituted by groups selected from halogen, C1-4of alkyl, C1-4alkoxy,
With1-4alkylthio or1-4alkylsulfonyl;
provided that when E represents hydrogen, and the compound of formula (I) is a compound of the formula
,
then And is a HE, Zn-NR2R3, Zn-NR3(C=O)R3, Zn-SO2R10, Zn-OR10, Zn-(C=O)R9, alkyl, allyl, Zn-cycloalkyl, Zn-heteroseksualci or Z-Ar1;
provided that when E represents hydrogen, and the compound of formula (I) is a compound of the formula
,
then the group Ar1represents an aryl, and a is other than hydrogen;
provided that when E represents hydrogen, and the compound of formula (I) is a compound of the formula
,
then a is other than hydrogen;
and provided that the compound of formula (I) is not 2-(1-methyl-1H-indazol-5-ylamino)benzoic acid, 5-(2,4-dichlorphenoxy)-1H-and dasol-1-acetic acid, 3-methyl-6-phenylsulfonylacetate or 6-(2-chloro-4-triptoreline)-3-methylbenzoxazolium.

2. The compound according to claim 1 of the formula
,
where E is a Zn-(C=O)R4or Zn-SO2R4and Z, n and R4are as defined in claim 1.

3. The compound according to claim 2, where E is a Zn-(C=O)R4.

4. The compound according to claim 3 of the formula
,
where a, b, X, R2, R3and Ar1are as defined in claim 1.

5. The compound according to claim 4 selected from:
amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid;
[5-(4-pertenece)-1-isobutyl-1H-indazol-6-yl]morpholine-4-yl-methanone;
[5-(4-pertenece)-1-isobutyl-1H-indazol-6-yl]-(4-methylpiperazin-1-yl)-methanone;
(1-benzylpiperidine-4-yl)amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid;
(2-benzylamino)amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid;
(2-piperidine-yl-ethyl) - amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid;
(2-pyrrolidin-1-retil)amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid;
(3-morpholine-4-ylpropyl)amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid;
(3-dimethylaminopropyl)amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid;
(2-dimethylaminoethyl)amide 5-(4-perfe is hydroxy)-1-isobutyl-1H-indazol-6-carboxylic acid;
methyl-(1-methylpiperidin-4-yl)amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid;
[3-(methylpentylamino)-propyl]amide 5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxylic acid;
tert-butyl ester 3-{[5-(4-pertenece)-1-isobutyl-1H-indazol-6-carbonyl]-amino}-pyrrolidine-1-carboxylic acid;
(2-dimethylaminoethyl)amide 5-(4-pertenece)-1-(2,2,2-triptorelin)-1H-indazol-6-carboxylic acid;
(2-dimethylaminoethyl)amide 5-(4-pertenece)-1-methyl-1H-indazol-6-carboxylic acid;
(2-dimethylaminoethyl)amide 5-(4-pertenece)-1H-indazol-6-carboxylic acid;
methyl ester of 4-amino-2-{[5-(4-pertenece)-1-isobutyl-1H-indazol-6-carbonyl]-amino}butyric acid;
methyl ester of 4-amino-2-{[5-(4-pertenece)-1-(2,2,2-triptorelin)-1H-indazol-6-carbonyl]-amino}butyric acid;
methyl ester of 4-amino-2-{[5-(4-pertenece)-1-methyl-1H-indazol-6-carbonyl]-amino} butyric acid;
(S)-N-(4-amino-1-hydroxybutane-2-yl)-5-(4-pertenece)-1-isobutyl-1H-indazol-6-carboxamide;
(S)-methyl-2-(5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxamido)-4-(dimethylamino)butanoate;
(S)-5-(2,4-divergence)-N-(4-(dimethylamino)-1-hydroxybutane-2-yl)-1-isobutyl-1H-indazol-6-carboxamide;
(1-hydroxymethyl-3-isopropylaminomethyl)amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid;
(S)-2-{[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carbonyl]-Amin is}-4-dimethylaminomethylene acid;
(1-hydroxymethyl-3-piperidine-1-ylpropyl)amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid;
(3-dimethylamino-1-dimethylcarbamoyl)amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid;
(3-dimethylamino-1-methylcarbamoylmethyl)amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid;
(1-carbarnoyl-3-dimethylaminopropyl)amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid;
[1-(2-dimethylaminoethyl)-2-hydroxy-2-methylpropyl]amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid;
{1-hydroxymethyl-3-[(2-methoxyethyl)methylamino]propyl}amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid; and
[3-dimethylamino-1-(2-hydrooximethylcarbamil)propyl]amide (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid.

6. The compound according to claim 5, which represents the (S)-5-(2,4-divergence)-1-isobutyl-1H-indazol-6-carboxylic acid (1-carbarnoyl-3-dimethylaminopropyl)amide.

7. The compound according to claim 2, where E is a Zn-SO2R4.

8. The connection according to claim 7, selected from:
(3-dimethylaminopropyl)amide 5-(2,4-divergence)-1-isobutyl-1H-indazol-6-sulfonic acid;
(S)-methyl-2-(5-(2,4-divergence)-1-isobutyl-1H-indazol-6-sulphonamido)-4-(dimethylamino)butanoate;
[2-(1-methylpyrrolidine-2-yl)-ethyl]amide 5-(2,4-divergence)-1-from the butyl-1H-indazol-6-sulfonic acid; and
(2-dimethylaminoethyl)amide 5-(2,4-divergence)-1-isobutyl-1H-indazol-6-sulfonic acid.

9. The compound according to claim 1 of the formula
,
where E represents N, Zn-NR2R3, Zn-(C=O)R5, Zn-OR6or R5; and Z, n, R2, R3, R5and R6are as defined in claim 1.

10. The connection according to claim 9, where E is a Zn-NR2R3.

11. The compound of claim 10 of the formula
,
where a, b, X, R2, R3and Ar1are as defined in claim 1.

12. The compound of claim 10 selected from:
[5-(4-pertenece)-1-isobutyl-1H-indazol-6-yl]methyl-(2-dimethylaminoethyl)amine;
N-(2-(dimethylamino)ethyl)-N-((5-(4-pertenece)-1-isobutyl-1H-indazol-6-yl)methyl)methanesulfonamide;
N-(2-(dimethylamino)ethyl)-N-((5-(4-pertenece)-1-isobutyl-1H-indazol-6-yl)methyl)ndimethylacetamide;
N'-[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-yl]-N,N-DIMETHYLPROPANE-1,3-diamine;
[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-yl]-piperidine-4-yl-amine and
[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-yl]-piperidine-3-ylmethylamino.

13. The connection according to claim 9, representing 5-(2,4-divergence)-1 - isobutyl - 1H-indazol-6-carboxylic acid.

14. The connection according to claim 9, where E is a Zn-OR6.

15. The connection 14 is selected from:
{3-[5-(2,4-divergence)1-isobutyl-1H-indazol-6-yloxy]-propyl}-dimethylamine;
5-(2,4-divergence)-1-isobutyl-6-(piperidine-4-ylethoxy)-1H-indazole;
5-(2,4-divergence)-1-isobutyl-6-(3-piperazine-1-yl-propoxy)-1H-indazole;
5-(2,4-divergence)-1-isobutyl-6-(morpholine-2-ylethoxy)-1H-indazole and 1-[5-(2,4-divergence)-1-isobutyl-1H-indazol-6-yloxy]-3-pyrrolidin-1-yl-propan-2-ol.

16. The connection according to claim 9, where E represents N.

17. The compound according to claim 1 of the formula
,,
,,
,,
,,
in which a, b, E, Ar1and R1are as defined in claim 1.

18. The connection 17 of the formula
,
in which a, b, E and Ar1are as defined in claim 1.

19. Connection p representing 5-(4-pertenece)-1H-indazol-3-ylamine.

20. The connection 17 of the formula
,or
,
in which a, b, E, and AG1are as defined in claim 1.

21. Connection claim 20, selected from 5-(4-perpenicular)-1H-indazole and 5-(4-perpenicular)-1-isopropyl-1H-indazole.

22. The connection 17 of the formula
,
in which a, b, E and Ar1are so the mi, as defined in claim 1.

23. The connection 17 of the formula
,
in which a, b, E and Ar1are as defined in claim 1.

24. The connection 17 of the formula
,
in which a, b, E, R1and Ar1are as defined in claim 1.

25. The connection 17 of the formula
,
in which a, b, E and Ar1are as defined in claim 1.

26. Connection A.25 chosen from:
(2,4-differenl)-(1-isobutyl-1H-indazol-5-yl)-amine;
(4-forfinal)-(1-isobutyl-1H-indazol-5-yl)-amine;
(2,4-dichlorophenyl)-(1-isobutyl-1H-indazol-5-yl)-amine and
(1-isobutyl-1H-indazol-5-yl)-O-tolyl-amine.

27. The compound according to claim 1 of the formula
,,
or,
in which a, b, X, Ar1and E are as defined in claim 1.

28. Connection item 27 formula
,
where a, b, X and Ar1are as defined in claim 1.

29. Connection item 27 formula
,
where a, b, E, X and Ar1are as defined in claim 1.

30. Connection item 27 formula
,
where a, b, E, X and Ar1are as defined in claim 1.

31. Connection item 30, chosen from:
6-(4-perpenicular)-3-(4-shall ethoxybenzyl)-1H)indazole;
[6-(4-perpenicular)-1H-indazol-3-yl]methanol;
6-(4-perpenicular)-3-methoxymethyl-1H-indazole;
6-(4-pertenece)-3-methyl-1H-indazole;
6-(4-chlorophenoxy)-3-methyl-1H-indazole;
3-methyl-6-(m-tolyloxy)-1H-indazole;
6-(3-pertenece)-3-methyl-1H-indazole;
6-(3-chlorophenoxy)-3-methyl-1H-indazole;
3-methyl-6-(3-(methylthio)phenoxy)-1H-indazole;
3-methyl-6-(3-(methylsulphonyl)phenoxy)-1H-indazole;
6-(4-fluoro-3-methylphenoxy)-3-methyl-1H-indazole;
3-ethyl-6-(4-perpenicular)-1H-indazole;
N-[6-(4-pertenece)-1H-indazol-3-yl]ndimethylacetamide;
2-[6-(4-pertenece)-1H-indazol-3-yl]isoindole-1,3-dione and
3-(1,3-dihydroindol-2-yl)-6-(4-pertenece)-1H-indazole.

32. Connection item 27 formula
,
where a, E, X and Ar1are as defined in claim 1.

33. Connection p chosen from:
3,6-diphenoxybenzene[d]isoxazol
N-(4-methoxyphenyl)-6-phenoxybenzyl[d]isoxazol-3-amine.

34. The pharmaceutical composition inhibiting MAR-kinase R containing compound according to any one of claims 1 to 33, together with a pharmaceutically acceptable diluent or carrier.

35. The use of compounds as defined in any one of claims 1 to 33, in the manufacture of drugs for the treatment R-mediated condition.

36. Use p where R-mediated condition is an inflammatory disease, an autoimmune disease, des is constructive bone violation, proliferative violation, infectious disease, viral disease, or neurodegenerative disease.

37. The compound having the formula:
,
or its pharmaceutically acceptable salt,
where Y represents CR1or NR2;
W represents CR3or Oh, provided that W represents Oh, when Y represents CR1and W represents CR3when Y represents NR2;
R3represents N or NH2;
R1represents H, HE, Zn-NRaRb, Zn-NRb(C=O)Rb, Zn-SO2Rg, Zn-ORg, Zn-(C=O)Re, alkyl, alkenyl, Zn-cycloalkyl, Zn-heteroseksualci or Zn-Ar1;
R2represents H, Z is-NRaRbZ-NRb(C=O)Rb, Zn-SO2Rg, Z-ORg, Zn-(C=O)Re, alkyl, alkenyl, Zn-cycloalkyl, Zn-heteroseksualci or Zn-Ar1;
Rarepresents H, alkyl, Zn-heteroseksualci or Zn-Ar1;
Rbrepresents H or alkyl;
or Ratogether with Rband N form heteroseksualci;
ReHE is a, H, C1-6alkoxygroup or amino group, optionally substituted C1-6the alkyl or benzyl;
Rgpredstavljaet a N, With1-6alkyl or phenyl, where phenyl optionally substituted with halogen or1-6alkoxygroup;
Z represents alkylene having from 1 to 4 carbon atoms, optionally substituted by a group selected from HE or1-6of alkyl;
n means 0 or 1;
Ar1represents aryl or heteroaryl;
U represents CH or N;
V represents CH or N;
X represents O, S, SO, SO2, NH or C=O;
G, K, J and T independently represent N or CRzprovided that when any such G, K, J and T are N, then the total number of G, K, J or T, which are N, does not exceed 1;
Rzrepresents H, F, Cl, Br, CF3, OR6, SR6lowest (1-C4)alkyl, CN or
NR6R7;
R6and R7independently represent H, CF3lowest (1-C4)alkyl chain which optionally separated by heteroatoms selected from N or O;
Q represents-NR8C(O)NH-, -NHC(O)-, -NR8SO2NH-, -NHSO2-or-CONR8-;
R8represents H or lower (1-C4)alkyl;
Rxrepresents -(CH2)m-;
m means 1-3;
Ryrepresents H, alkyl, Zn-cycloalkyl, Zn-heteroseksualci or Zn-Ar2;
Ar2represents aryl or Goethe is auril;
where, when Q is a-CONR8-, then Ryin combination with R8additionally represents heteroseksualci; and
where alkenyl represents a C1-6alkenyl, which can be substituted by aryl;
where alkyl represents a C1-6alkyl and may be substituted by one or more than one group selected from halogen, cycloalkyl, geterotsiklicheskie, amino or hydroxy-group, where the amino group or a hydroxy-group may be optionally substituted by one or more than one group selected from C1-6the alkyl or benzyl;
where cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl;
where heteroseksualci represents a saturated 5-8 membered monocycle, which may be condensed with one six-membered aromatic ring and has, besides carbon atoms one to two heteroatoms selected from N, O and S, which may be substituted by groups selected from C1-6of alkyl, benzyl, tert-butoxycarbonyl or carbonyl group;
where heteroaryl represents an aromatic monocycle of 5-6 members or bicycl of 9-10 members, including in addition to carbon atoms, from one to two heteroatoms selected from N, O and S, which Ar1may be substituted with halogen or1-4alkoxygroup, and for Ar2can imati-3 Deputy independently selected from F, Cl, Br, CF3CN, C1-6of alkyl, Zn-cycloalkyl, Zn-geterotsiklicheskie or Zn-Ar1;
where aryl is a 6 - or 10-membered aromatic ring, which for Ar1may be substituted with halogen or1-4alkoxygroup, and for Ar2may have 1-3 substituent, independently selected from F, Cl, Br, CF3CN, C1-6of alkyl, Zn-cycloalkyl, Zn-geterotsiklicheskie or Zn-Ar1.

38. The connection clause 37, where W represents CH2and Y represents NR2where R2is as defined in clause 37.

39. The connection clause 37 or 38, where G, J, K and T represent CRzwhere Rzis as defined in clause 37.

40. The connection clause 37, where X represents NH, S or O.

41. The connection clause 37, where Rxrepresents CH2and Q represents-NHCO-.

42. The connection at paragraph 41, where Ryrepresents isopropyl or.

43. The connection clause 37, where Rxrepresents CH2and Q represents-NR8CONH-, where R8is as defined in clause 37.

44. Connection p.43, where Ryrepresents a
,,,
or .

45. The connection clause 37, chosen from:
1-(5-tert-butyl-2-n-tolyl-2H-pyrazole-3-yl)-3-[2-(1-methyl-1H-indazol-5-yloxy)-pyridine-3-ylmethyl]urea;
2-(4-{2-[2-(1-cyclobutylmethyl-1H-indazol-5-yloxy)-5-forfinal]-acetyl}-piperazine-1-yl)-N-isopropylacrylamide;
2-[2-(1-isobutyl-1H-indazol-5-yloxy)-phenyl]-N-(4-(morpholine-4-ylphenyl)-ndimethylacetamide;
1-[5-cyclopropyl-2-(4-triptoreline)-2H-pyrazole-3-yl]-3-[5-fluoro-2-(1-methyl-1H-indazol-5-ylamino)benzyl]urea;
1-(5-tert-butyl-2-n-tolyl-2H-pyrazole-3-yl)-3-[2-(1-cyclobutylmethyl-1H-indazol-5-ylamino)-5-terbisil]urea;
1-(5-tert-butyl-2-n-chlorophenyl-2H-pyrazole-3-yl)-3-[2-(1-methyl-1H-indiso-5-ylsulphonyl)-5-terbisil]urea;
1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-3-{2-[1-(3-isopropylamino-propyl)-1H-indazol-5-ylamino]-benzyl}urea;
1-(5-tert-butyl-2-n-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)-benzyl]urea;
1-[5-tert-butyl-2-(4-chloro-phenyl)-2H-pyrazole-3-yl]-3-[5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)-benzyl]urea;
2-(1-cyclobutylmethyl-1H-indazol)-5-formanilide cyclopropanecarbonyl acid;
N-[5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)-benzyl]-3-trifluoromethyl-benzamide;
N-[2-(1-isobutyl-1H-indazol-5-yloxy)-benzyl]-2-(3-triptoreline)-ndimethylacetamide;
5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)-benzylamine 5-tert-butyl-1-pyridin-2-yl-1H-pyrazole-4-carboxylic acid;
2-cyclopropyl-N-[5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)b is nil]ndimethylacetamide;
3-chloro-N-[5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)benzyl]benzamide;
N-[5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)-benzyl]-4-trifluoromethyl-benzosulfimide;
N-[5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)-benzyl]-methanesulfonamide;
3-(5-tert-butyl-2-n-tolyl-2H-pyrazole-3-yl)-1-[5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)-benzyl]-1-metallocene;
1-(5-tert-butyl-2-n-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(1-methyl-1H-indazol-5-yloxy)-benzyl]-1-metallocene;
1-(5-tert-butyl-2-n-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(1-methyl-1H-pyrazolo[3,4-C]pyridine-5-yloxy)-benzyl]urea;
1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(3-pyrrolidin-1 ylmethylene[d]isoxazol-6-yloxy)-benzyl]urea;
1-(5-tert-butyl-2-n-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(3-pyrrolidin-1 ylmethylene[d]isoxazol-6-yloxy)-benzyl]urea;
1-(5-tert-butyl-2-n-tolyl-2H-pyrazole-3-yl)-3-[5-fluoro-2-(3-methyl-benzo[d]isoxazol-6-yloxy)-benzyl]urea;
2-(5-{2-[3-(5-tert-butyl-2-n-tolyl-2H-pyrazole-3-yl)-freedomites]-4-fervency}-indazol-1-yl)-N,N-dimethylacetamide;
1-(5-tert-butyl-isoxazol-3-yl)-3-[5-fluoro-2-(1-isobutyl-1H-indazol-5-yloxy)-benzyl]urea;
1-(3-tert-butyl-isoxazol-5-yl)-3-{5-fluoro-2-[1-(2-piperazine-1-yl-ethyl)-1H-indazol-5-yloxy]-benzyl}urea;
1-(3-tert-butyl-isoxazol-5-yl)-3-{2-[1-(2-dimethylaminoethyl)-1H-indazol-5-yloxy]-5-fluoro-benzyl}urea; and
1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-3-{5-fluoro-2-[1-(2-hydroxy-2-methylpropyl)-1H-in the azole-5-yloxy]-benzyl}urea.

46. The pharmaceutical composition inhibiting MAR-kinase R containing compound according to any one of p-45 together with a pharmaceutically acceptable diluent or carrier.

47. The use of compounds as defined in any of PP-45, in the manufacture of drugs for the treatment RZ-mediated condition.

48. Use p, where the specified R-mediated condition is an inflammatory disease, autoimmune disease, destructive bone violation, proliferative violation, infectious disease, viral disease, or neurodegenerative disease.
Priority items:

03.03.2003 according to claims 1-5, 9-12, 14, 16 to 36;

15.10.2003 on p-48;

25.02.2004 according to claims 1, 2, 5-8, 12-13, 15, 34-36, 45-48.



 

Same patents:

FIELD: pharmacology.

SUBSTANCE: invention relates to novel compounds - tetrahydronaphthyridine derivatives of formula (I) or their pharmaceutically acceptable salts, where R1 represents C1-6alkoxycarbonyl group optionally substituted with 1-5 substituents, etc; R2 represents C1-6alkyl group; R3 represents hydrogen or and all; R4 represents C1-4alkylene group; R5 represents optionally substituted unsaturated 5-8-member heterocyclic group containing 1-4 heteroatoms independently selected from oxygen and nitrogen atoms; R6, R7 and R8 represent independently hydrogen atom, hydroxygroup, cyanogroup, C1-6alkyl group, C1-6alkoxygroup, mono- or di- C1-6alkylcarbamoyl group or mono- or di- C1-6alkylaminogroup, optionally substituted with 1-6 substituents independently selected from halogen atom, C1-6alkoxygroup and aminogroup; R10 represents optionally substituted with 1-2 substituents phenyl group; which possess inhibiting activity with respect to cholesteryl ester transfer protein (CETP).

EFFECT: novel tetrahydronaphthyridine derivatives and method of obtaining them.

12 cl, 408 ex, 38 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to compounds with formula I, active towards receptors, activated by peroxisome proliferators (PPAR), and can be used in medicine, formula I, where U, W, X and Y represent CH, V represents CR8; R1 represents-C(O)OR or a carboxylic acid isoster, where R is a hydrogen atom, substituted alkyl, aryl or heteroaryl; R2 represents -S(O)2R21; R6 and R7 represent a hydrogen atom, substituted alkyl or cycloalkyl; R8 represents a hydrogen atom, halogen, -OR9, substituted inferior alkyl, cycloalkyl, heterocycloalkyl, phenyl, benzyl, heteroaryl or heteroaralkyl; R9 represents a substituted alkyl or cycloalkyl; R21 represents a substituted heteroaryl or phenyl; n equals 1.

EFFECT: obtaining new biologically active compounds and pharmaceutically active compositions based on these compounds.

46 cl, 134 ex, 4 tbl

FIELD: chemistry, pharmacology.

SUBSTANCE: present invention relates to new use of compounds of 2-arylacetic acid and amides with formula (I) and their pharmaceutically used salts, where A comprises an atom X and is phenyl or a 5-6 member heteroaromatic ring, optionally containing a heteroatom, chosen from N; corresponding positions on ring A are marked by numbers 1 and 2; atom X is chosen from N (nitrogen) and C (carbon); R represents a substituting group on ring A, chosen from: a group in 3 (meta) positions, chosen from a group comprising straight or branched C1-C5-alkyl, C2-C5-acyl; a group in 4 (para) positions, chosen from a group, comprising C1-C5-alkyl, C1-C5-alkanesulphonylamino, substituted with halogens; Hy represents a small hydrophobic group with steric inhibition constant ν between 0.5 and 0.9 (where ν is Charton steric constant for substitutes), comprising methyl, ethyl, chlorine, bromine, group Y chosen from O (oxygen) and NH; when Y represents O (oxygen), R' represents H (hydrogen); when Y represents NH, R' is chosen from groups: -H, - residue with formula SO2Rd, where Rd represents C1-C6-alkyl. The invention can be used in making medicinal agents, which are inhibitors of induced IL-8 PMN chemotaxis (CXCR1) or induced GRO-α PMN chemotaxis (CXCR2).

EFFECT: new use of compounds of 2-arylacetic acid and amides and their pharmaceutically used salts.

14 cl, 2 tbl, 44 ex, 4 dwg

FIELD: chemistry.

SUBSTANCE: invention refers to new spirocyclic cyclohexane derivatives of general formula I , where: R1-R3, R5-R10, W, X are disclosed in the claim 1 of formula.

EFFECT: compounds exhibit analgesic activity to be applied for making a medical product for pain therapy.

20 cl, 1 tbl, 54 ex

FIELD: chemistry.

SUBSTANCE: described are 2,4,6-phenyl-substituted cyclic ketoenols of formula (I, in which W, X, Y and CKE are given in invention formula. Also described are esters of acylamino acids of formula (II), substituted derivatives of phenylacetic acid of formula (XXIX), (XXVII), (XXXI), which are intermediate compounds for obtaining formula (I) compound.

EFFECT: obtaining herbicidal preparation containing combinations of biologically active substances, including (a), formula (I) compound and (b') improving compatibility with cultural plants mefenpyr-diethyl, with weight ratio 5-1:1-7.7.

9 cl, 46 tbl, 36 ex

FIELD: chemistry.

SUBSTANCE: described is compound of general formula , in which W and Z represent N, and X and Y represent CH; R represents halogen; R1 represents phenyl, substituted with 1-3 substituents, selected from halogen; R2 represents NR3R4; R3 and R4 independently represent H, C1-C8alkyl, C2-C8alkenyl, halogen(C1-C8)alkyl, C1-C4alkoxy(C1-C8)alkyl, C3-C8cycloalkyl, optionally substituted with methyl, or R3 and R4 together form C3-C7alkylene chain, optionally containing as substituent C1-C4alkyl group, or together with nitrogen atom, to which they are bound, R3 and R4 form morpholine or pyperazine-N-(C1-C4)alkyl (more preferably N-methyl) ring. Described is method of obtaining compound of general formula (I), intermediate chemical products, as well as fungicidal composition for plants and method to combat phytopathogenic fungi or their elimination, using compound of formula (I).

EFFECT: increase of compound fungicidal activity.

10 cl, 133 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: described is novel compound of formula (I)

or its pharmaceutically acceptable salt, values of radicals are given in invention formula Compound has ability to inhibit receptor mGluR5, which intends it for prevention and/or treatment of receptor mGluR5- associated disturbances. Also described is pharmaceutical composition, method of inhibiting activation of receptors mGluR5, using compound of formula (I). Described is method of obtaining compound of formula 1a or 1b structure.

EFFECT: increasing output of suitable product.

18 cl, 825 ex

FIELD: chemistry.

SUBSTANCE: invention refers to imidazoquinolines of formula (I) and (II) , as well as to tetrahydroimidazoquinolines of formula (III) wherein radicals and symbols possess values specified in formula of the invention. The given compounds and based pharmaceutical compositions representing subject of the present invention, can stimulate biosynthesis of various cytokines, particularly, α-interferon and are used in treating certain diseases, including virus diseases and cancerous diseases.

EFFECT: objects of invention are also methods of treating virus and cancerous diseases and intermediate compounds.

41 cl, 2 tbl, 37 ex

FIELD: chemistry.

SUBSTANCE: present invention refers to tetrahydroquinoline derivatives, described by formula (I) where t is equal to 0, 1 or 2; each R independently represents H, alkyl, alkenyl, alkinyl, halogenalkyl, cycloalkyl; n is equal to 0; R2 is chosen from the group consisting of H, alkyl, halogenalkyl, cycloalkyl, -Racycloalkyl, alkenyl, alkinyl, -RaAy, -RaOR5; where R2 is not substituted with amine or alkylamine; R3 represents H; each R4 independently represents halogen, halogenalkyl, alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkenyl, -A'y, -NHAy, -Het, -NHHet, -OR10, -NR6R7, -RaNR6R7, -C(O)NR6R7, -C(O)Ay, -C(O)Het; m is equal to 0, 1 or 2; each R5 independently represents H; p is equal to 0 or 1; Y represents NR10-, -O-, -C(O)NR10-, -NR10C(O)-, -C(O)- , - -NR10C(O)N(R10)-; X represents -N(R10)2, -RaN(R10)2, -AyN(R10)2, -RaAyN(R10)2, -AyRaN(R10)2, -RaAyRaN(R10)2, -Het, -RaHet, -HetN(R10)2, -RaHetN(R10)2, -HetRaN(R10)2, - RaHetRaN(R10)2; each Ra independently represents alkylen, optionally substituted with with one or more alkyl; each R10 independently represents H, alkyl, cycloalkyl, alkenyl, alkinyl, cycloalkenyl, -Racycloalkyl; each R6 and R7 is independently chosen from H, alkyl, alkenyl, alkinyl, cycloalkyl, cycloalkenyl, -Racycloalkyl, -RaNR8R9; each R8 and R9 is independently chosen from H or alkyl; each Ay independently represents optionally substituted aryl group; and each Het independently represents optionally substituted 4-, 5- or 6-merous heterocyclil or heteroaryl group where heteroatoms are chosen from N and O; or its pharmaceutically acceptable salt, or ester. Besides, there are disclosed pharmaceutical composition based on compound of formula (I), its application and methods of production.

EFFECT: new compound manifesting protective action against HIV-infection on target cell by chemoquine receptor and influencing binding of natural ligand or chemoquine and target cell receptor, such as CXCR4 and/or CCR5.

53 cl, 2 tbl, 105 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: there are disclosed compounds composed as to formula , where n and m stand for integer 1 to 3; z stands for integer 0 to 1; R is chosen from hydrogen, hydroxy or alkoxy; R2 stands for hydrogen; R3 and R4 are independently chosen from the group consisting of hydrogen, halogen; R5 is chosen from the group consisting of halogen, alkyl; R6 represents alkyl; E is chosen from the group specified in item 1 of formula of invention, A is chosen from N and C(R11), X is chosen from C, a stands for double bond and b stands for single bond; and Y is chosen from N(R1) provided when Y stands for N(R1), X stands for C, where R1 is chosen from C3-C6-cyclolkyl, phenyl; provided if A stands for C(R11), X stands for C, and Y stands for N(R1), then R11 and R1 can be bonded thus forming morpholinyl.

EFFECT: compounds possess antibacterial activity and are suitable as antibacterial means for treating bacterial infections in humans and animals.

13 cl, 10 tbl

FIELD: pharmacology.

SUBSTANCE: claimed invention relates to novel 2,4-pyridindiamine compounds of formula (1). In structural formula (I) L1 is direct bond; L2 is direct bond; R2 is phenyl group, three times substituted with three groups R8; R4 is X represents N; Y is selected from group consisting of O, NH, S, SO and SO2; Z is selected from group consisting of O, NH; on condition that if Y is selected from group consisting of NH, S, SO and SO2, Z is not the same as Y; R5 is selected from group consisting from R6, halogen; each R6 is independently selected from group consisting of hydrogen, halogen; R8 is selected from group consisting from Ra, Rb, Ra substituted with one or several similar or different groups Ra or Rb, -ORa, -O-CHRaRb; each R35 independently on others is selected from group consisting of hydrogen and R35, or in alternative case, two groups R35, bound to one and the same carbon atom are taken together with formation of oxogroup (=O), and the remaining two groups R35 each independently on each other are selected from group consisting from hydrogen and R8; each Ra is independently selected from group consisting of hydrogen, (C1-C6) alkyl, (C3-C8) cycloalkyl; each Rb is suitable group which is independently selected from group consisting of -ORd, halogen, -CF3, -C(O)NRcRc, and -OC(O)ORd; each Rc is independently protective group or Ra; each Rd is independently protective group or Ra; each index m is independently integer number from 1 to 3.

EFFECT: novel compounds can be used for treatment or prevention of autoimmune diseases, for instance such as rheumatoid arthritis and/or related to it symptoms, systemic lupus erythematosus and/or related to it symptoms, as well as and/or related to it symptoms.

41 cl, 14 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: described is novel compound of formula (I)

or its pharmaceutically acceptable salt, values of radicals are given in invention formula Compound has ability to inhibit receptor mGluR5, which intends it for prevention and/or treatment of receptor mGluR5- associated disturbances. Also described is pharmaceutical composition, method of inhibiting activation of receptors mGluR5, using compound of formula (I). Described is method of obtaining compound of formula 1a or 1b structure.

EFFECT: increasing output of suitable product.

18 cl, 825 ex

FIELD: chemistry; pharmacology.

SUBSTANCE: new compounds of formula (I) and its pharmaceutically acceptable salts. Offered compounds possess properties of bacterial gyrase and Topo-IV activity inhibitor. In general formula (I) , W is chosen from CH or CF; X represents CH; Z represents O or NH; R1 represents phenyl or 5-6-merous heteroaryl ring containing 1-3 nitrogen atoms where R1 is substituted with 0-3 groups independently chosen from -(T)y-Ar, R', oxo, C(O)R', OR', N(R')2, SR', CN or C(O)N(R')2; R2 is chosen from C1-3alkyl and C3-7-cycloalkyl; and ring A represents 5-6-merous heteroaryl ring containing 1-3 heteroatoms, independently chosen of nitrogen, oxygen or sulphur provided the specified ring has hydrogen bond acceptor in position adjacent to that of joining to B ring where ring A is substituted with 0-3 groups independently chosen from R', oxo, CO2R', OR', N(R')2, halogen, CN, C(O)N(R')2, NR'C(O)R', or NR'SO2R', and where two substitutes in adjacent positions of ring A, together can form 6-merous saturated heterocyclic or heteroaryl ring containing 1-2 nitrogen atoms.

EFFECT: pharmaceutical compositions with properties of bacterial gyrase and Topo-IV activity inhibitor containing disclosed compound as active component, method of gyrase and/or Toro IV-activity inhibition, method of bacteria number reduction.

25 cl, 3 tbl, 4 dwg, 29 ex

FIELD: medicine.

SUBSTANCE: formula bond

or it pharmaceutically comprehensible salt where value of radicals are specified in the invention formula is described. The bonds are effective as inhibitors of protein kinases FLT-3 or KIT. A way of inhibition of activity kinases FLT-3 or KIT in the biological sample in vitro and application of bonds for manufacture of a medical product, suitable for treatment or simplification of gravity of disease or a condition, the chosen acute myelogenetic leukosis, acute progranulocytic leukemia or acute lymphocytic leukosis or cancer of ovaries are described also.

EFFECT: rising of efficiency of a composition and the method of treatment.

11 cl, 86 ex

FIELD: medicine.

SUBSTANCE: invention offers analogues of quinazoline of the formula I

where A is bound at least with one of atoms of carbon in position 6 or 7 of the dicyclic ring; X represents N. A represents the group Q or Z including tautomeric group Z form where Q and Z, have the formulas resulted more low in which symbols and radicals, have the value specified in item 1 of the formula of the invention. R1 represents phenyl, substituted -(G)nOAr or -O(G)nAr and where phenyl is unessentially replaced by halogen or C1-C10alkyl; where G represents C1-C4alkylene, n is peer 0 or 1. And Ar represents phenyl either pyridyl or thiazolyl where Ar is unessentially substituted by 1-2 substituents chosen from halogen or C1-C10alkyl; R2 and R3 represent N. The bonds of the formula I are inhibitors of the receptor tyrosine kinases of type 1. The invention includes also a way of treatment of hyperproliferative diseases, such as a cancer, application of bonds of the formula 1 in manufacture of medical products and pharmaceutical composition on the basis of these bonds.

EFFECT: rising of efficiency of a composition and the method of treatment.

14 cl, 6 dwg, 63 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I) and their pharmaceutically acceptable salts. Claimed compounds have antibacterial effect. In formula (I) , X is ; R1 is i) hydrogen, ii) (CH2)nNR5R6, iv) NRCO2R, v) (C1-6alkyl)CN, CN, (CH2)pOH; Y is NR*, O or S(O)p; is phenyl or 5-6-member heteroaryl with N or S as heteroatoms; R3 is NR(C=X2)R12, NR*R12, or -(O)n-5-6-member heteroaryl with 1-3 heteroatoms selected out of N, O, which can be linked over either carbon atom or heteroatom; the indicated 5-6-member heteroaryl can be optionally substituted by 1-3 groups of R7; R4, R4a, R4b and R4c are independently i) hydrogen, ii) halogen; other radicals are defined in the claim.

EFFECT: pharmaceutical composition containing effective volume of the claimed compound.

13 cl, 1 dwg, 194 ex

FIELD: chemistry.

SUBSTANCE: in compound of formula I , R1 is hydrogen; R2 is phenyl substituted by trifluoromethyl and optionally by other substitute selected out of a group including lower hydroxyl alkyl, lower alkylamino, lower hydroxyl alkylamino, dilower alkylamino, 1H-imidazolyl, lower alkyl-1H-imidazolyl, carbamoyl, lower alkylcarbamoyl, pyrrolidino, piperazino, lower alkylpiperazino, morpholino, lower alkoxy, trilfuoro-lower alkoxy, phenyl, pyridyl and halogenyl; R4 is methyl; where 'lower' prefix denotes radical with up to 7 carbon atoms. Also invention concerns pharmaceutical composition and method of treatment, as well as application of the claimed compounds in obtaining pharmaceutical composition.

EFFECT: improved proteinkinase inhibition properties.

9 cl, 98 ex

FIELD: chemistry.

SUBSTANCE: present invention pertains to new macrocyclic compounds with formula (I): (where R3, R6, R7 and R21 can be identical or different from each other, and each of them assume values given in the description), their salts used in pharmacology and their hydrate. Compounds with formula (I) are capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, and can be used as therapeutic means of treating solid malignant tumours. The invention also relates to medicinal agents based on these compounds, prevention and treatment method and use of these compounds in making preparations for preventing and treating cancerous diseases.

EFFECT: obtaining compounds, capable of inhibiting angiogenesis, particularly VEGF production in hypoxic conditions, which can be used as therapeutic means of treating solid malignant tumours.

35 cl, 3 tbl, 147 ex

FIELD: chemistry.

SUBSTANCE: invention concerns compounds of the formula I , where R0 is 1) monocyclic 6-14-member aryl, where aryl is independently mono-, di- or trisubstituted by R8, 2) heterocyclyl out of group of benzothiazolyl, indazolyl, pyridyl, where the said heterocyclyl is independently non-substituted or mono-, di- or trisubstituted by R8, and other radicals referred to in point 1 of the claim; R8 is halogen; on condition that R8 is at least one halogen atom if R0 is monocyclic 6-14-member aryl; substructure in the formula I is 4-8-member saturated, partly non-saturated or aromatic cyclic group including 0, 1 heteroatom selected out of nitrogen or sulfur, and is non-substituted or substituted 1, 2, 3 times by R3; Q is -(C0-C2)alkylene-C(O)NR10-, methylene; R1 is hydrogen atom, -(C1-C4)alkyl, where alkyl is non-substituted or substituted one to three times by R13; R2 is a direct link; R1-N-R2-V can form 4-8-member cyclic group selected out of piperazine or piperidine group; R14 is halogen, =O, -(C1-C8)alkyl, -CN; V is 1) 6-14-member aryl, where aryl is independently non-substituted or mono-, di- or trisubstituted by R14, and other radicals referred to in point 1 of the claim; G is direct link, -(CH2)m-NR10, where m is 0 and R10 is hydrogen, -(CH2)m-C(O)-(CH2)n-, where m is 0 or 1, and n is 0, -(CH2)m-C(O)-NR10-(CH2)n-, where m is 0 or 1, and n is 0, 1 or 2, -(CH2)m-, where m is 1; M is 1) hydrogen atom, 2) 6-14-member aryl, and other radicals referred to in point 1 of the claim; R3 is 1) hydrogen atom, 2) halogen atom, 3) -(C1-C4)alkyl, where alkyl is non-substituted, and other radicals referred to in point 1 of the claim; R11 and R12 are independently the same or different and are 1) hyfrogen atom, 2) -(C1-C6)alkyl, where alkyl is non-substituted or monosubstituted by R13, and other radicals referred to in point 1 of the claim; or R11 and R12 can form 4-8-member monocyclic heterocyclic ring together with nitrogen atoms to which they are linked, and beside the nitrogen atom the ring can include one or two similar or different ring heteroatoms selected out of oxygen, sulfur and nitrogen; where the said heterocyclic ring is independently non-substituted or mono-, disubstituted by R13; R13 is halogen, =O, -OH, -CF3, -(C3-C8)cycloalkyl, -(C0-C3)alkylene-O-R10; R10 is hydrogen, -(C1-C6)alkyl; R15 and R16 are independently hydrogen, -(C1-C6)alkyl; R17 is -(C1-C6)alkyl, -(C3-C8)cycloalkyl; in all stereoisomer forms and their mixes at any ratio, and physiologically tolerable salts. Compounds of the formula I are reversible inhibitors of enzyme factor Xa (FXa) and/or factor VIIa (FVIIa) of blood clotting, and can be generally applied in states accompanied by undesirable factor Xa and/or factor VIla activity, or supposing factor Xa and/or factor VIla inhibition for treatment or prevention. In addition, invention concerns methods of obtaining compounds of the formula I, their application as agents in pharmaceutical compositions.

EFFECT: obtaining compounds applicable as agents in pharmaceutical compositions.

19 cl, 1 tbl, 169 ex

FIELD: chemistry.

SUBSTANCE: invention concerns new compounds of the formula (I), their isomers and pharmaceutically acceptable salts. In the general formula (I) A is (II) ; X1 is methylene; X2 is CN, CHO, C(O)R6; X6 is a link; R1 is R13C(O)-; R2 is hydrogen; R3 is selected out of group including H, phenyl-(C0-6)alkyl, (C1-6)alkyl, optionally substituted by -X6OR9 group; R4 is H or (C1-6)alkyl; or R3 and R4 form (C3-8)cycloalkylene together with carbon atom to which R3, R4 are linked; R5 is (C1-9)alkyl, benzyl. Invention also concerns compounds of formulae (la), (lb), (Ic), and pharmaceutical composition based on the claimed compounds.

EFFECT: new compounds inhibiting cathepsin.

22 cl, 2 dwg, 89 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

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