Antiviral compound

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds or their pharmaceutically acceptable salts where the compound has formula (I). The compounds have the properties of hepatitis C virus (HCV) replication inhibition and can be used for treating HCV-infection. In formula (I) B represents heterocyclyl selected from thieno, thiazolo, pyrazolo, pyrido and pyrimidogroup with B being optionally substituted by one or more R18, A represents phenyl which is optionally substituted by one or more R18; each W1 and W2 are independently selected from N or C(R33); Z represents -NH-; each R10 and R33 containing of hydrogen; X is selected from a group consisting of -Ls-O-, -Ls-S-; R22 means hydrogen or phenyl optionally substituted by one or more R26 ; Y is selected from a group consisting of -Ls-O-, -Ls-S-; -Ls-C(O)- and -Ls-NH(SO)2-; R50 represents -L1-A1, where L1 represents a bond, and A1 is selected from a group consisting of carbocyclyl where carbocyclyl represents phenyl or C3-C6carbocyclyl, banzimidazolyl and C1-C6alkyl optionally substituted by phenyl where A1 is optionally substituted by one or more R30 ; the substitute values are specified in the patent claim.

EFFECT: preparing the compounds exhibiting the properties of hepatitis C virus replication inhibition.

17 cl, 8 dwg, 255 ex

 

This application claims the priority of provisional application U.S. No. 60/752473, filed December 21, 2005, in the present description by reference in full.

The technical field to which the present invention

The present invention relates to compounds effective in inhibiting replication of hepatitis C virus (“HCV”). Also the present invention relates to methods of producing these compounds, compositions containing these compounds, intermediates for the synthesis of these compounds, and to methods of using these compounds/compositions for the treatment of HCV infection or mediated conditions/symptoms. In addition, the present invention relates to the use of these compounds to obtain drugs for treatment of HCV infection.

The level of technology

HCV, a human pathogen, is a RNA virus belonging to the genus Hepacivirus of the family Flaviviridae. The hallmark of HCV, like all other viruses of the family Flaviviridae, are virions, enclosed in a shell consisting of the RNA genome of positive polarity encoding all known specific virus proteins only, uninterrupted open reading frame. The open reading frame contains approximately 9500 nucleotides encoding the single largest item is libated, consisting of approximately 3000 amino acids. The polypeptide contains a capsid protein, membrane proteins E1 and E2, membrane-bound protein P7 and nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B. Cellular protease cleaves viral protein at the junction of the NS2-NS3, allowing the viral protease (NS3 protease) to mediate subsequent cleavage. Protein NS3 also has nucleotidyltransferase and RNA-helicase activity. NS2 and NS4A may also be associated with proteolytic activity. NS5A is a phosphoprotein that is involved in replication. NS5B is an RNA-dependent RNA polymerase. In U.S. patent No. 2004/0265792, published December 30, 2004, indicated that the inhibition of the above non-structural proteins can inhibit HCV replication.

HCV infection is associated with progressive liver disease, including cirrhosis and liver cell cancer. End-stage disease with HCV infection of the liver is the most frequent indication for liver transplantation in adults. In chronic hepatitis C therapy may be the injection of peginterferon-Alfa once a week in combination with a daily intake of ribavarin. Peginterferon-alpha is an interferon-alpha, attached to polyethylene glycol, providing a decrease in the rate of excretion of the drug from the body. This increases the likelihood of the implementation of the program mode of administration of the medicine and clinical antiviral activity compared to daily injections of interferon-alpha. But remain significant limitations on efficacy and tolerability, as a large number of patients have side effects, and decrease the amount of virus in the body is often insufficient.

Attempts were made to create medicines which are directed inhibit the function of hepatitis C. In U.S. patent No. 6323180, Boehringer Ingelheim, as inhibitors of serine protease of HCV for the treatment of HCV infection is indicated Tripeptide connection.

Another approach proposed in ISIS-14803 (Isis Pharmaceuticals), namely antisense inhibitor, complementary to the conserved sequence of the RNA of hepatitis C. This molecule binds to RNA virus and inhibits the expression of proteins necessary for replication.

Inhibition broadcast HC using yeast RNA, which binds to cellular proteins and prevents their interaction with internal customers landing ribosomes virus (IRES)that is described in the document Daset al., J. Virology, 72(7): 5638-5647 (1998).

For various biomedical applications have been proposed condensed bicyclic heterocyclic compounds. Examples of such heterocyclic compounds include compounds naphthiridine, pyridopyrimidines, pyrimidopyrimidine, pyrazolopyrimidine and thiazolo/thienopyrimidine.

Condensed bicyclic compounds n is piridinovogo type have been investigated for use in the treatment of diseases. For example, in the document Boots WO 93/13097, published on 8 July 1993, it was proposed to use as Antirheumatic means [1,8]naphthyridine compounds such as hydrochloride ethyl 4-(4-methoxyaniline)-6-ethoxy-7-methyl-1,8-naphthiridine-3-carboxylate. In the document, Boots WO 95/00511, published January 5, 1995, as Antirheumatic funds proposed use of substituted 4-aminopyridines with condensed rings, such as 3-ethoxy-5-(2-ethoxy-5-pyridylamino)-2-methyl-1,8-naphthiridine. In the document Zeneca WO 98/13350, published April 2, 1998, as protivoerosionnih funds proposed to use the connection [1,8]naphthiridine, such as the hydrochloride of 2-acetamido-5-(2-fluoro-5-hydroxy-4-methylaniline)-1,8-naphthiridine. In the document Neurogen WO 2004/055004, published July 1, 2004, as modulators of receptor capsaicin indicated connection naphthiridine, for example the specific compound 5-(4-triptoreline)-2-(3-triptorelin-2-yl)-[1,6]naphthiridine-7-carboxylic acid and 2-methoxymethyl-4-(4-triptoreline)-7-(3-triptorelin-2-yl)-[1,8]naphthiridine-3-carboxylic acid.

For use in the treatment of various diseases were investigated condensed bicyclic compounds pyridopyrimidines type. For example, Pfizer WO 98/05661, published February 12, 1998, as the e antagonists corticoliberin (hormone) CRF (CRH) for the treatment of Alzheimer's disease and obesity proposed compounds substituted pyridopyrimidines, such as [8-(1-ethylpropyl)-2-methyl-5,6,7,8-tetrahydropyrido(2,3-d)pyrimidine-4-yl]-(2,4,6-trimetilfenil)amine. In the document Pfizer WO 98/23613, published June 4, 1998, for the treatment of hyperproliferative diseases such as cancer, proposed condensed bicyclic pyrimidine compounds, including compounds perindoprilperindopril, such as (3-ethynylphenyl)pyrido[3,4-d]pyrimidine-4-ylamine. In U.S. patent No. 6169091, Glaxo Wellcome, published January 2, 2001, as tyrosine kinase inhibitors for the treatment of fibrosis, inflammation, nervous system disorders and cancer suggested bicyclic heteroaromatic compounds such as 4-(4-benzyloxyaniline)pyrido[2,3-d]pyrimidine. In the document, Eli Lilly WO 01/32632, published may 10, 2001, as mGluR1 antagonists for the treatment of neurological disorders, and mediated by dysfunction of glutamate, such as convulsions, migraine, psychosis, anxiety disorder and pain, the proposed connection 4-substituted pyrimidine, including hydrochloride, 2-trifluoromethyl-4-[2-(2-(2-chlorophenyl)ethylamino]pyrido[2,3-d]pyrimidine. In the document, Abbott Laboratories, WO 01/57040, published August 9, 2001, as inhibitors adenosines to treat the pain and inflammation of the proposed connection of 6,7-disubstituted-4-aminopyrido[2,3-d]pyrimidine, such as 4-amino-6-(4-were)-7-(4-bromophenyl)pyrido[2,3-d]pyrimidine. In the document Nurogen, WO 2004/055004, published July 1, 2004, as modulators of receptor capsaicin proposed connection perindoprilperindopril, such as 2-methyl-2-{4-[2-methyl-7-(3-methylpyridin-2-yl)pyrido[2,3-d]pyrimidine-4-ylamino]phenyl}propionic acid. In U.S. patent No. 6395733, Pfizer, published may 28, 2002, for the treatment of hyperproliferative diseases, such as cancer, proposed pyrimidine heterocyclic compounds with condensed rings, such as 3-chlorophenylurea[2,3-d]pyrimidine-4-ylamine.

Condensed bicyclic compounds pyrimidopyrimidine type were investigated for application to disinfection and treatment of diseases. For example, in U.S. patent No. 5350749, Dow Elanco, published on September 27, 1994, as fungicides, insecticides and miticides proposed connections 4-substituted-pyrimido[2,3-d]pyrimidine. In the document, Warner-Lambert WO 95/19774, published July 27, 1995, as tyrosine kinase inhibitors for treating cancer, restenosis of blood vessels and psoriasis proposed connection pyrimidopyrimidine, such as 4-benzylamino-7-methylaminopropyl[4,5-d]pyrimidine.

Condensed bicyclic compounds thienopyrimidines type have been investigated for use in the treatment of various diseases. For example, Warner-Lambert WO 95/19774, published July 27, 1995, as inhibitors of t is rosiekins for the treatment of cancer, restenosis of blood vessels and psoriasis proposed condensed heterocyclic pyrimidine compounds, including 4-(3-bromaniline)thieno[2,3-d]pyrimidine. In U.S. patent No. 6169091, Glaxo Wellcome, published January 2, 2001, as tyrosine kinase inhibitors for the treatment of fibrosis, inflammation, nervous system disorders and cancer suggested bicyclic heteroaromatic compounds, such as hydrochloride, 5-methyl-4-(4-fenoxedilom)thieno[2,3-d]pyrimidine. In the document, Eli Lilly WO 01/32632, published may 10, 2001, as mGluR1 antagonists for the treatment of neurological disorders associated with dysfunction of glutamate, such as convulsions, migraine, psychosis, anxiety disorder and pain, the proposed connection 4-substituted pyrimidine, such as hydrochloride of 6-methyl-4-[2,6-dichlorbenzene)ethylamino]thieno[2,3-d]pyrimidine.

In the document, Bristol-Myers Squibb WO 2004/014852, published February 19, 2004, as inhibitors of protein NS5A to prevent replication of HCV proposed aminothiazoline, including condensed bicyclic derivatives of 2-(4-AMINOPHENYL)-5H-thiazolo[2,3-6]hinzelin-3-one.

In the document, Bristol-Myers Squibb WO 2004/014313, published February 19, 2004, for the treatment of viral diseases proposed various kinds of combination therapy, including anti-HCV connection aminothiazoline inhibiting protein NS5A, in combination with other means, can affect the function of HCV.

The INVENTION

The present invention relates to compounds of formulas I, II, III, IV, V, VI, VII or VIII, the tautomers of these compounds and pharmaceutically acceptable salts of these compounds or tautomers. These compounds, tautomers or salts can be used alone or in combination with other medicaments or drugs, for inhibiting replication of HCV or other viruses. These compounds, tautomers or salts can also be used by themselves or in combination with other medicaments or drugs, for disorders of HCV or other viruses.

The present invention also relates to compositions that contain the compounds, tautomers or salts of the present invention. The composition of the present invention may include one or more of the compounds, tautomers or salts of the present invention. The composition of the present invention may also include one or more other antiviral, or therapeutic agents.

In addition, the present invention relates to methods of using compounds, tautomers or salts of the present invention or compositions containing the said compounds, tautomers or salts for inhibiting replication of HCV or other viruses. These methods include contactyou is of HCV or other viruses or cells, infected with HCV or other specified virus with an effective amount of compounds of tautomer or salt of the present invention, thereby inhibiting the replication of HCV or other specified virus.

The present invention also relates to methods of using compounds, tautomers or salts of the present invention or compositions containing the said compounds, tautomers or salts, for inhibiting the proliferation or transmission of HCV or other viruses. These methods include contacting HCV or another virus or contacting cells infected with HCV or other virus with an effective amount of compounds of tautomer or salt of the present invention, thereby inhibiting the proliferation or migration of HCV or other specified virus.

In addition, the present invention relates to methods of using compounds, tautomers or salts of the present invention or compositions containing the said compounds, tautomers or salts, for the treatment of viral infections caused by HCV or other viruses. These methods include the introduction to the patient an effective amount of compounds of tautomers or salts of the present invention, thus reducing the level of HCV or other viruses in the blood or tissues of the patient.

The present invention also relates to the use of compounds tout the Mer or salts of the present invention to obtain drugs for the treatment of viral infections caused by HCV or other viruses.

In addition, the present invention relates to methods of producing the compounds, tautomers or salts of the present invention and intermediates used in the above methods.

Other characteristics, objects and advantages of the present invention will be clear from the following further detailed description of the invention. However, it should be noted that detailed description of the invention, which shows the preferred embodiments of the invention, given for illustrative purposes only and is not limited to them. Various variations and modifications without leaving the scope of the invention, will be apparent to the person skilled in the art from the detailed description.

DETAILED description of the INVENTION

The following description is essentially illustrative and not intended to limit the proposed description, application or practice.

Connection

The present invention relates to compounds of the formula I, their tautomers and pharmaceutically acceptable salts of the compounds or tautomers

I

where each a and b is independently selected from carbocyclic or heterocyclyl and each optionally substituted by one or more R18where R18in each case, independently selected from the group comprised the soup from halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, quinil, carbocycle, heterocyclyl, -LS-O-RS, -LS-S-RS, -LS-C(O)RS, -LS-OC(O)RS, -LS-C(O)ORS, -LS-N(RSRS'), -LS-C(=NRSRS', -LS-S(O)RS, -LS-SO2RS, -LS-C(O)N(RSRS'), -LS-N(RS)C(O)RS'-LS-C(=NRS)N(RS'RS), -LS-N(RS')C(=NRSRS, -LS-N(RS)C(O)N(RS'RS), -LS-N(RS)SO2RS', -LS-SO2N(RSRS'and-LS-N(RS)SO2N(RS'RS);

each W1and W2independently selected from N or C(R33);

Z represents a bond, -CR41R41'- or-NR41-, where each R41and R41'independently selected from the group consisting of hydrogen, alkyl, alkenyl and quinil;

each R10and R33independently selected from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, quinil, carbocycle, heterocyclyl, -LS-O-RS, -LS-S-RS, -LS-C(O)RS, -LS-OC(O)RS, -LS-C(O)ORS, -LS-N(RSRS'), -LS-C(=NRSRS', -Lsub> S-S(O)RS, -LS-SO2RS, -LS-C(O)N(RSRS'), -LS-N(RS)C(O)RS'-LS-C(=NRS)N(RS'RS), -LS-N(RS')C(=NRSRS, -LS-N(RS)C(O)N(RS'RS), -LS-N(RS)SO2RS', -LS-SO2N(RSRS'), -LS-N(RS)SO2N(RS'RS), -LE-Q-LE'-(C3-C18carbocyclic) and LE-Q-LE'(M3-M18heterocyclyl);

X is selected from the group consisting of-LS-O-, -LS-S-, -LS-C(O)-, -LS-N(RS)-, -LS-N(RS)C(O)-, -LS-C(O)N(RS)-, -LS-N(RS)C(O)O-, -LS-OC(O)N(RS)-, -LS-N(RS)C(O)N(RS')-, -LS-C(=NRS)N(RS')-, -LS-N(RS')C(=NRS)-, -LS-S(O)-, -LS-SO2-, -LS-C(O)O -, and-LS-OC(O)-;

R22represents carbocyclic or heterocyclyl and optionally substituted by one or more R26where R26in each case, independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, quinil, -LS-O-RS, -LS-S-RS, -LS-C(O)RS, -LS-OC(O)RS, -LS-C(O)ORS, -LS-N(RSRS'), -LS-C(=NRSRS', -LS-S(O)RS, -L S-SO2RS, -LS-C(O)N(RSRS'), -LS-N(RS)C(O)RS', -LS-C(=NRS)N(RS'RS), -LS-N(RS')C(=NRSRS, -LS-N(RS)C(O)N(RS'RS), -LS-N=C(NRSRS')(NRSRS'), -LS-N(RS)SO2RS', -LS-SO2N(RSRS'), -LS-N(RS)SO2N(RS'RS), -LE-Q-LE'-(C3-C18carbocyclic) and LE-Q-LE'(M3-M18heterocyclyl); or R22represents alkyl, alkenyl or quinil and optionally substituted by one or more R26; or R22represents hydrogen;

Y is selected from the group consisting of-Ls-O-, -Ls-C(O)-, -Ls-S(O)2-, -Ls-S(O)-, -Ls-OS(O)2-, -Ls-OS(O)-, -Ls-C(O)O-, -Ls-OC(O)-, -Ls-OC(O)O-, -Ls-C(O)N(R15)-, -Ls-N(R15)C(O)-, -Ls-C(O)N(R15)O-, -Ls-N(R15)C(O)O-, -Ls-C(O)N(R15)N(R15')-, -Ls-S-, -Ls-C(S)-, -Ls-C(S)O-, -Ls-OC(S)-,-Ls-N(R15)-, -Ls-C(S)N(R15)-, -Ls-N(R15)C(S)-, -Ls-N(R15)S(O)-, -Ls-N(R15)S(O)2-, -Ls-S(O)2N(R15)-, -Ls-S(O)N(R15)-, -Ls-C(S)N(R15)O -, and-Ls-C(S)N(R15)N(R15')-, where each R15and R15'in each case, independently selected from the group consisting of hydrogen, alkyl, alkenyl and quinil;

R50represents-L1-A1where A1selected from the group consisting of carbocyclic, heterocyclic, alkyl, alkenyl and quinil, and L1selected from the group consisting of communication, alkylene, Alcanena and akinlana, where A1optionally substituted by one or more R30and R30in each case, independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkyl, alkenyl, quinil, -LS-O-RS, -LS-S-RS, -LS-C(O)RS, -LS-OC(O)RS, -LS-C(O)ORS, -LS-N(RSRS'), -LS-C(=NRSRS', -LS-S(O)RS, -LS-SO2RS, -LS-C(O)N(RSRS'), -LS-N(RS)C(O)RS', -LS-C(=NRS)N(RS'RS), -LS-N(RS')C(=NRSRS, -LS-N(RS)C(O)N(RS'RS), -LS-N(RS)SO2RS', -LS-SO2N(RSRS'), -LS-N(RS)SO2N(RS'RS), -LE-Q-LE'-(C3-C18carbocyclic) and LE-Q-LE'(M3-M18heterocyclyl), and where L1optionally substituted by one or more R38and R38in each case, independently selected from the group consisting of g is lagena, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, alkoxy, dialkoxy, alkylcarboxylic, alkoxycarbonyl, alkylcarboxylic, alkylamino, alkoxycarbonyl, -LS-O-RS, -LS-S-RS, -LS-C(O)RS, -LS-OC(O)RS, -LS-C(O)ORS, -LS-N(RSRS'), -LS-C(=NRSRS', -LS-S(O)RS, -LS-SO2RS, -LS-C(O)N(RSRS'), -LS-N(RS)C(O)RS', -LS-C(=NRS)N(RS'RS), -LS-N(RS')C(=NRSRS, -LS-N(RS)C(O)N(RS'RS), -LS-N(RS)SO2RS', -LS-SO2N(RSRS'), -LS-N(RS)SO2N(RS'RS), carbocycle, heterocyclyl, carbocyclic, geterotsiklicheskikh, -LE-Q-LE'-(C3-C18carbocyclic) and LE-Q-LE'(M3-M18heterocyclyl);

LSin each case, independently selected from the group consisting of communication, alkylene, Alcanena and akinlana;

each RS, RS'and RSin each case, independently selected from the group consisting of hydrogen, alkyl, alkenyl, quinil, alkoxy, dialkoxy, alkoxyalkyl, alkoxyalkyl, dialcoxyalcohols, alkylcarboxylic, alkylcarboxylic, alkoxycarbonyl, alkoxycarbonylmethyl, alkylboron is lexi, alkylcarboxylic, alkylamino, acylaminoalkyl, alkoxycarbonyl and alkoxycarbonylmethyl;

each LEand LE'in each case, independently selected from the group consisting of communication, alkylene, Alcanena and akinlana;

Q in each case independently selected from the group consisting of communication, alkylene, Alcanena, akinlana, -S-, -O-, -C(O)-, -N(RS)-, -N(RS)C(O)-, -C(O)N(RS)-, -N(RS)C(O)O-, -OC(O)N(RS)-, -N(RS)C(O)N(RS')-, -C(=NRS)N(RS')-, -N(RS')C(=NRS)-, -S(O)-, -SO2-, -O-SO2-, -SO2-O-, -O-S(O)-, -S(O)-O-, -C(O)O - and-OC(O)-;

each R10, R15, R15', R18, R26, R30, R33, R38, R41and R41'in each case optionally independently substituted by at least one Deputy, selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido; and

each C3-C18carballeira and M3-M18heterocyclyl group-LE-Q-LE'-(C3-C18carbocyclic) and LE-Q-LE'(M3-M18heterocyclyl) in each case optionally independently substituted by at least one Deputy, selected from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, is Lila, alkenyl, quinil, alkoxy, dialkoxy, alkoxyalkyl, dialcoxyalcohols, alkylcarboxylic, alkylcarboxylic, alkoxycarbonyl, alkoxycarbonylmethyl, alkylcarboxylic, alkylcarboxylic, alkylamino, acylaminoalkyl, alkoxycarbonyl and alkoxycarbonylmethyl.

In one of the embodiments the present invention relates to compounds of the formula I, their tautomers and pharmaceutically acceptable salts of the compounds or tautomers, where

each A and B is independently selected from C4-C11carbocycle or M4-M11heterocyclyl and each independently optionally substituted by one or more R18where R18independently selected in each instance from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil, C3-C6carbocycle, M3-M6heterocyclyl, -LS-O-RS, -LS-S-RS, -LS-C(O)RS, -LS-OC(O)RS, -LS-C(O)ORS, -LS-N(RSRS'), -LS-C(=NRSRS', -LS-S(O)RS, -LS-SO2RS, -LS-C(O)N(RSRS'), -LS-N(RS)C(O)RS', -LS-C(=NRS)N(RS'RS), -LS-N(RS')C(=NRSRS, -LS -N(RS)C(O)N(RS'RS), -LS-N(RS)SO2RS', -LS-SO2N(RSRS'and-LS-N(RS)SO2N(RS'RS);

each W1and W2independently selected from N or C(R33);

Z represents a bond, -CR41R41'- or-NR41-, where each R41and R41'independently selected from the group consisting of hydrogen, C1-C6of alkyl, C2-C6alkenyl and C2-C6the quinil;

each R10or R33independently selected from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil, C3-C6carbocycle, M3-M6heterocyclyl, -LS-O-RS, -LS-S-RS, -LS-C(O)RS, -LS-OC(O)RS, -LS-C(O)ORS, -LS-N(RSRS'), -LS-C(=NRSRS', -LS-S(O)RS, -LS-SO2RS, -LS-C(O)N(RSRS'), -LS-N(RS)C(O)RS', -LS-C(=NRS)N(RS'RS), -LS-N(RS')C(=NRSRS, -LS-N(RS)C(O)N(RS'RS), -LS-N(RS)SO2RS', -LS-SO2N(RSRS'), -LS-N(RS)SO2N(RS'RS), -LE-Q-Lsub> E'-(C3-C18carbocyclic) and LE-Q-LE'(M3-M18heterocyclyl);

X is selected from the group consisting of-LS-O-, -LS-S-, -LS-C(O)-, -LS-N(RS)-, -LS-N(RS)C(O)-, -LS-C(O)N(RS)-, -LS-N(RS)C(O)O-, -LS-OC(O)N(RS)-, -LS-N(RS)C(O)N(RS')-, -LS-C(=NRS)N(RS')-, -LS-N(RS')C(=NRS)-, -LS-S(O)-, -LS-SO2-, -LS-C(O)O -, and-LS-OC(O)-;

R22represents a C4-C11carbocyclic or M4-M11heterocyclyl and optionally substituted by one or more R26where R26in each case, independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil, -LS-O-RS, -LS-S-RS, -LS-C(O)RS, -LS-OC(O)RS, -LS-C(O)ORS, -LS-N(RSRS'), -LS-C(=NRSRS', -LS-S(O)RS, -LS-SO2RS, -LS-C(O)N(RSRS'), -LS-N(RS)C(O)RS', -LS-C(=NRS)N(RS'RS), -LS-N(RS')C(=NRSRS, -LS-N=C(NRSRS')(NRSRS'), -LS-N(RS)C(O)N(RS'RS), -LS-N(RS)SO 2RS', -LS-SO2N(RSRS'), -LS-N(RS)SO2N(RS'RS), -LE-Q-LE'-(C3-C18carbocyclic) and LE-Q-LE'(M3-M18heterocyclyl); or R22represents a C1-C6alkyl, C1-C6alkenyl or C1-C6quinil and optionally substituted by one or more R26; or R22represents hydrogen;

Y is selected from the group consisting of-LS-O-, -LS-C(O)-, -LS-S(O)2-, -LS-S(O)-, -LS-OS(O)2-, -LS-OS(O)-, -LS-C(O)O-, -LS-OC(O)-, -LS-OC(O)O-, -LS-C(O)N(R15)-, -LS-N(R15)C(O)-, -LS-C(O)N(R15)O-, -LS-N(R15)C(O)O-, -LS-C(O)N(R15)N(R15')-, -LS-S-, -LS-C(S)-, -LS-C(S)O-, -LS-OC(S)-, -LS-N(R15)-, -LS-C(S)N(R15)-, -LS-N(R15)C(S)-, -LS-N(R15)S(O)-, -LS-N(R15)S(O)2-, -LS-S(O)2N(R15)-, -LS-S(O)N(R15)-, -LS-C(S)N(R15)O -, and-LS-C(S)N(R15)N(R15')-, where each R15and R15'independently selected from the group consisting of hydrogen, C1-C6of alkyl, C2-C6alkenyl and C2-C6the quinil;

R50represents-L1-A1where A1selected from the group consisting of C4-C11carbocycle, M4-sub> 11heterocyclyl, C1-C6of alkyl, C2-C6alkenyl and C2-C6the quinil, and L1selected from the group consisting of ties, C1-C6alkylene, C2-C6Alcanena and C2-C6akinlana, where A1optionally substituted by one or more R30and R30in each case, independently selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil, -LS-O-RS, -LS-S-RS, -LS-C(O)RS, -LS-OC(O)RS, -LS-C(O)ORS, -LS-N(RSRS'), -LS-C(=NRSRS', -LS-S(O)RS, -LS-SO2RS, -LS-C(O)N(RSRS'), -LS-N(RS)C(O)RS', -LS-C(=NRS)N(RS'RS), -LS-N(RS')C(=NRSRS, -LS-N(RS)C(O)N(RS'RS), -LS-N(RS)SO2RS', -LS-SO2N(RSRS'), -LS-N(RS)SO2N(RS'RS), -LE-Q-LE'-(C3-C18carbocyclic) and LE-Q-LE'(M3-M18heterocyclyl), and where L1optionally substituted by one or more R38and R38in each case, independently selected from the group consisting of Gal which the gene oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-C6alkoxy, C1-C6dialkoxy, C1-C6alkylsulphonyl, C1-C6alkoxycarbonyl, C1-C6alkylcarboxylic, C1-C6alkylamino, C1-C6alkoxycarbonyl, -LS-O-RS, -LS-S-RS, -LS-C(O)RS, -LS-OC(O)RS, -LS-C(O)ORS, -LS-N(RSRS'), -LS-C(=NRSRS', -LS-S(O)RS, -LS-SO2RS, -LS-C(O)N(RSRS'), -LS-N(RS)C(O)RS', -LS-C(=NRS)N(RS'RS), -LS-N(RS')C(=NRSRS, -LS-N(RS)C(O)N(RS'RS), -LS-N(RS)SO2RS', -LS-SO2N(RSRS'), -LS-N(RS)SO2N(RS'RS), carbocycle, heterocyclyl, carbocyclic1-C6of alkyl, heterocyclyl1-C6of alkyl, -LE-Q-LE'-(C3-C18carbocyclic) and LE-Q-LE'(M3-M18heterocyclyl);

LSin each case, independently selected from the group consisting of ties, C1-C6alkylene, C2-C6Alcanena and C2-C6akinlana;

each RS, RS'and RSin each case, independently selected from the group consisting of water the ode, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil, C1-C6alkoxy, C1-C6dialkoxy, C1-C6alkoxyl1-C6of alkyl, C1-C6alkoxyl1-C6alkoxyl1-C6of alkyl, C1-C6toolboxes1-C6of alkyl, C1-C6alkylsulphonyl, C1-C6alkylcarboxylic1-C6of alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonyl1-C6of alkyl, C1-C6alkylcarboxylic, C1-C6alkylcarboxylic1-C6of alkyl, C1-C6alkylamino, C1-C6alkylamino1-C6of alkyl, C1-C6alkoxycarbonyl and C1-C6alkoxycarbonyl1-C6of alkyl;

each LEand LE'in each case, independently selected from the group consisting of ties, C1-C6alkylene, C2-C6Alcanena and C2-C6akinlana;

Q in each case independently selected from the group consisting of ties, C1-C6alkylene, C2-C6Alcanena, C2-C6akinlana, -S-, -O-, -C(O)-, -N(RS)-, -N(RS)C(O)-, -C(O)N(RS)-, -N(RS)C(O)O-, -OC(O)N(RS)-, -N(RS)C(O)N(RS')-, -C(=NRS)N(RS')-, -N(RS')C(=NRS)-, -S(O)-, -SO2-, -O-SO2-, -SO2-O-, -O-S(O)-, -S(O)-O-, -(O)O - and-OC(O)-;

each R10, R15, R15', R18, R26, R30R33, R38, R41and R41'in each case optionally independently substituted by at least one Deputy, selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido; and

each C3-C18carballeira and M3-M18heterocyclyl group-LE-Q-LE'-(C3-C18carbocyclic) and LE-Q-LE'(M3-M18heterocyclyl) in each case optionally independently substituted by at least one Deputy, selected from the group consisting of halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil, C1-C6alkoxy, C1-C6dialkoxy, C1-C6alkoxyl1-C6of alkyl, C1-C6toolboxes1-C6of alkyl, C1-C6alkylsulphonyl, C1-C6alkylcarboxylic1-C6of alkyl, C1-C6alkoxycarbonyl, C1-C6alkoxycarbonyl1-C6of alkyl, C1-C6alkylcarboxylic, C1-C6alkylcarboxylic1-C6of alkyl, C1-C6alkylamino, C1-C6alcelam the nose 1-C6of alkyl, C1-C6alkoxycarbonyl and C1-C6alkoxycarbonyl1-C6the alkyl.

In one of the examples of this variant implementation Y represents-LS-O-, -LS-S or-LS-N(R15)-, and R50represents-L1-A1where L1represents a bond, C1-C6alkylene, C2-C6albaniles or C2-C6akinyan and is optionally substituted by one or more R38and A1represents a C4-C11carbocyclic or M4-M11heterocyclyl and is optionally substituted by one or more R30.

In another example implementation of this option Y is a bond, and R50represents-L1-A1where L1represents a bond, C1-C6alkylene, C2-C6albaniles or C2-C6akinyan and is optionally substituted by one or more R38and A1represents a C4-C11carbocyclic or M4-M11heterocyclyl and is optionally substituted by one or more R30.

In another additional example of this variant implementation Y represents a bond, and R50represents-L1-A1where L1selected from the group consisting of communication, C1-C6alkylene, C2-C6Alcanena and C2-C6akinlana and is optionally substituted by one or more R38and A1represents hydrogen or R18.

In yet another example implementation of this option Y is selected from the group consisting of LS-S(O)2N(R15)-, -LS-OS(O)2-, -LS-OC(O)-, -LS-C(O)O-, -LS-C(O)- and-N(R15)C(O)O-.

In yet another additional example of this case for each A and B is independently selected from C5-C6carbocycle or M5-M6heterocyclyl and each independently is optionally substituted by one or more R18.

In another additional example of this variant implementation of W1and W2are N and Z represents-NR41-.

In yet another example of this variant implementation X represents-O - or-S -, and R22represents a C5-C6carbocyclic or M5-M6heterocyclyl and is optionally substituted by one or more R26.

In yet another example of this variant implementation of the code

represents a

where each W1, W2, W3and W4independently selected from N or C(R33); and

each R10, 17, R33and R35independently selected in each instance from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil, C3-C6carbocycle, M3-M6heterocyclyl, -LS-O-RS, -LS-S-RS, -LS-C(O)RS, -LS-OC(O)RS, -LS-C(O)ORS, -LS-N(RSRS'), -LS-C(=NRSRS', -LS-S(O)RS, -LS-SO2RS, -LS-C(O)N(RSRS'), -LS-N(RS)C(O)RS', -LS-C(=NRS)N(RS'RS), -LS-N(RS')C(=NRSRS, -LS-N(RS)C(O)N(RS'RS), -LS-N(RS)SO2RS', -LS-SO2N(RSRS'), -LS-N(RS)SO2N(RS'RS), -LE-Q-LE'-(C3-C18carbocyclic) and LE-Q-LE'(M3-M18heterocyclyl).

In yet another example of this variant implementation of the code

selected from the group consisting of

,,

and

where Q represents N or C(R33); and

each R10, R17, R33and R35nez the performance of selected in each case from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil, C3-C6carbocycle, M3-M6heterocyclyl, -LS-O-RS, -LS-S-RS, -LS-C(O)RS, -LS-OC(O)RS, -LS-C(O)ORS, -LS-N(RSRS'), -LS-C(=NRSRS', -LS-S(O)RS, -LS-SO2RS, -LS-C(O)N(RSRS'), -LS-N(RS)C(O)RS', -LS-C(=NRS)N(RS'RS), -LS-N(RS')C(=NRSRS, -LS-N(RS)C(O)N(RS'RS), -LS-N(RS)SO2RS', -LS-SO2N(RSRS'), -LS-N(RS)SO2N(RS'RS), -LE-Q-LE'-(C3-C18carbocyclic) and LE-Q-LE'(M3-M18heterocyclyl).

In an additional example of this case for each A and B is independently selected from C5-C6carbocycle or M5-M6heterocyclyl and each independently optionally substituted by one or more R18where

W1and W2represent N;

Z represents a-NR41-;

X represents-O - or-S-;

R22represents a C5-C6carbocyclic or M5 -M6heterocyclyl and optionally substituted by one or more R26;

Y represents a bond, -LS-O-, -LS-S or-LS-N(R15)-; and

A1represents a C5-C10carbocyclic or M5-M10heterocyclyl and is optionally substituted by one or more R30.

In another example of this case for each A and B is independently selected from C5-C6carbocycle or M5-M6heterocyclyl and each independently optionally substituted by one or more R18where

W1and W2represent N;

Z represents a-NR41-;

X represents-O - or-S-;

R22represents a

,or

where R48represents a hydroxy, amino, C1-C6alkylamino, C1-C6alkoxy, C1-C6alkoxycarbonyl or C1-C6alkylcarboxylic and R22(for example, R48or phenyl ring in R22) optionally substituted by one or more R26;

Y represents a bond, -LS-O-, -LS-S or-LS-N(R15)-; and

A1represents a C5-C10carbocyclic or M5-M10heterocyclyl and is not necessarily the replacement of the military by one or more R 30.

In another additional example of this variant implementation of the code

selected from the group consisting of

,,

and

where Q represents N or C(R33);

each R10, R17, R33and R35in each case, independently selected from the group consisting of hydrogen, halogen, oxo, thioxo, hydroxy, mercapto, nitro, cyano, amino, carboxy, formyl, phosphate, azido, C1-C6of alkyl, C2-C6alkenyl, C2-C6the quinil, C3-C6carbocycle, M3-M6heterocyclyl, -LS-O-RS, -LS-S-RS, -LS-C(O)RS, -LS-OC(O)RS, -LS-C(O)ORS, -LS-N(RSRS'), -LS-C(=NRSRS', -LS-S(O)RS, -LS-SO2RS, -LS-C(O)N(RSRS'), -LS-N(RS)C(O)RS', -LS-C(=NRS)N(RS'RS), -LS-N(RS')C(=NRSRS, -LS-N(RS)C(O)N(RS'RS), -LS-N(RS)SO2RS', -LS-SO2N(RSRS'), -LS-N(RS)SO2N(RS'RS), -LE-Q-LE'-(C3-C18carbocyclic) and LE-Q-LE'(M3-M18heterocyclyl);

A submitted is a C 5-C6carbocyclic or M5-M6heterocyclyl and is optionally substituted by one or more R18;

Z represents a-NR41-;

X represents-O - or-S-;

R22represents a

,orwhere R48represents a hydroxy, amino, C1-C6alkylamino, C1-C6alkoxy, C1-C6alkoxycarbonyl or C1-C6alkylcarboxylic, and R22(for example, R48or phenyl ring in R22is optionally substituted by one or more R26;

Y represents a bond, -LS-O-, -LS-S or-LS-N(R15)-; and

A1represents a C5-C10carbocyclic or M5-M10heterocyclyl and is optionally substituted by one or more R30.

In another embodiment, the present invention relates to a family of compounds pyridopyrimidines-AMINOPHENYL ether, tautomers of these compounds, or pharmaceutically acceptable salts of the compounds or tautomers, where the connection of this family correspond to the structure of formula II:

II

where R6selected from the group consisting of hydrogen and cyano;

R8selected from groups who, consisting of hydrogen and arylalkyl;

R25selected from the group consisting of hydrogen and alkyl;

R37selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and cycloalkyl;

R42selected from the group consisting of arylsulfonyl, heteroarylboronic, aryloxy; where R42optionally substituted by one or more substituents independently selected from R46;

R46represents one or more substituents selected from the group consisting of hydrogen, hydroxy, amino, halogen, dialkylamino, alkoxycarbonyl;

R70selected from the group consisting of aryl and heterocycle; where R70optionally substituted R75;

R75represents one or more substituents independently selected from the group consisting of hydrogen, halogen, alkoxy, cyano, alkyl, halogenoalkane and aryl.

In the subfamily of this variant implementation in formula II, R6selected from the group consisting of hydrogen and cyano;

R8selected from the group consisting of hydrogen and phenylmethyl;

R25selected from the group consisting of hydrogen and methyl;

R37selected from the group consisting of hydrogen, methyl, ethyl, tert-butyl, isopropyl, hydroxymethylation and cyclohexyl;

R42selected from the group consisting of phenylsulfonyl, phenoxy and PIR is madinalake;

R46selected from the group consisting of hydrogen, hydroxy, amino, N,N-dimethylamino and tert-butoxycarbonylamino;

R70selected from the group consisting of phenyl, thiazolyl, pyridinyl, tetrahydropyranyl, naphthyl, chinoline and tanila;

R75represents one or more substituents selected from the group consisting of hydrogen, methyl, butyl, hydroxy, methoxy, bromine, chlorine, fluorine, cyano, trifloromethyl and phenyl.

In yet another embodiment, the present invention relates to a family of compounds pyridopyrimidines-aminophenylalanine ether, tautomers of these compounds, or pharmaceutically acceptable salts of the compounds or tautomers, where the connection of this family correspond to the structure of formula III:

III

where R80selected from the group consisting of hydrogen, alkylcarboxylic and halogenfree.

In the subfamily implementation of this option in the formula III, R80selected from the group consisting of hydrogen, methylcarbamyl and Bromphenol.

In yet another embodiment, the present invention relates to a family of compounds triazolopyrimidine-AMINOPHENYL and thienopyrimidine-AMINOPHENYL, tautomers of these compounds, or pharmaceutically acceptable salts of the compounds or tautomers, where the connection of this family with the have the structure of formula IV:

IV

where Q is selected from the group consisting of N and CH;

R1selected from the group consisting of alkylsulfanyl, cyanoacetylene and alkyl;

R19selected from the group consisting of alkyl, halogenoalkane;

R56selected from the group consisting of hydrogen, hydroxy, alkyl, alkylcarboxylic.

In the subfamily implementation of this option in the formula IV, R1selected from the group consisting of methylsulfonyl, cyanomethylene, propyl and butyl;

R19selected from the group consisting of methyl, brompheniramine;

R56selected from the group consisting of hydrogen, hydroxy, methyl, methylcobalamine.

In yet another embodiment, the present invention relates to a family of compounds pyrimidopyrimidine-AMINOPHENYL, tautomers of these compounds, or pharmaceutically acceptable salts of the compounds or tautomers, where the connection of this family correspond to the structure of formula V:

V

where R5selected from the group consisting of hydrogen and alkylsulfanyl;

R29selected from the group consisting of alkyl, Allakaket, halogen, halogenoalkane;

R47selected from the group consisting of alkyl, halogenoalkane, alkylsulfanyl, arylalkylamine and heterocycle;

R64selected from the group consisting of hydrogen, alkoxy and alkyl;

R66selected from the group consisting of hydrogen, hydroxy, aryloxy, alkylsulfonate, alkylarylsulfonate, halogenated.sulphonated, cyano, Allakaket, alkylcarboxylic, halogen and alkyl;

R81selected from the group consisting of hydrogen, alkoxy and carbonyl.

In the subfamily implementation of this option in the formula V R5selected from the group consisting of hydrogen and methylsulfonyl;

R29selected from the group consisting of methyl, ethyl, fluorine, phenylmethoxy, brompheniramine;

R47selected from the group consisting of hydrogen, propyl, isopropyl, ethylsulfanyl, piperidinyl, morpholinyl, gafftopsail and phenylmethylsulfonyl;

R64selected from the group consisting of hydrogen, methoxy, hydroxy and methoxy;

R66selected from the group consisting of hydrogen, methyl, hydroxy, methoxy, phenoxy, phenylmethoxy, vinylsulfonate, isopropylphenoxy, methylcarbamoylmethyl, brompheniramine, cyano, methylcobalamine and fluorine;

R81selected from the group consisting of hydrogen, tert-butoxy and carbonyl.

In another embodiment, the present invention relates to a family of compounds pyrazolopyrimidine-AMINOPHENYL, tautomers of the compounds, or pharmaceutically pickup is acceptable salts of the compounds or tautomers, where compounds of this family correspond to the structure of formula VI:

VI

where R73represents alkyl;

R76selected from the group consisting of hydroxy, alkylaminocarbonyl, alkylcarboxylic.

In the subfamily implementation of this option in the formula VI, R73selected from the group consisting of methyl and butyl;

R76selected from the group consisting of hydroxy, methylaminomethyl, methylcobalamine.

In yet another embodiment, the present invention relates to a family of compounds pyridopyrimidines-AMINOPHENYL, tautomers of the compounds or pharmaceutically acceptable salts of the compounds or tautomers, where the connection of this family correspond to the structure of formula VII:

VII

where A is selected from the group consisting of O and S;

R21selected from the group consisting of hydrogen and hydroxy;

or R21taken together with R39forms a 5 to 12-membered heterocycle, containing at least two heteroatoms selected from the group consisting of O, N and S; where the heterocycle optionally substituted aryl, or halogen; or

R39selected from the group consisting of hydrogen, alkyl, arylalkyl, dialkylamino, heteroaryl, halogenmethyl, galogenzameshchennye, arylsulfonate, alkylcarboxylic of cycloalkylcarbonyl, arylalkanolamine, halogenmethyl, alkoxycarbonyl and NH-R99;

R99selected from the group consisting of hydrogen, arylalkyl, cycloalkenyl, aryl, heteroaryl, halogenoalkane, arylalkylamine and alkylglycerol;

R67selected from the group consisting of hydrogen, alkyl, cycloalkyl and alkylcyclohexane;

R96selected from the group consisting of hydrogen, hydroxy, amino, alkoxy, arylsulfonate, alkylcarboxylic, alkoxy, halogen, alkoxycarbonyl, halogenocarboxylic, Allakaket.

In the subfamily implementation of this option in the formula VII, R21selected from the group consisting of hydrogen and hydroxy, or if R21taken together with R39then forms benzoxazolyl, optionally substituted phenyl or bromine; or

R39selected from the group consisting of hydrogen, methyl, phenylethenyl, N,N-dipropylamino, pyrrolyl, brompheniramineodeine, vinylsulfonate, tert-BUTYLCARBAMATE, N-cyclohexyloxycarbonyl, N-cyclopentanecarbonyl, formatactionname, methoxycarbonylamino, methoxycarbonyl and bromobenzimidazole;

R67selected from the group consisting of hydrogen, methyl, ethyl, isopropyl, tert-butyl, sec-butyl, cyclopropyl, cyclobutyl and methylcyclopropyl;

R96selected from the group consisting of toroda, hydroxy, amino, vinylsulfonate, methylcobalamine, methoxy, fluorine, tert-butoxycarbonylamino, trichlorocarbanilide, phenylmethoxy;

R99selected from the group consisting of hydrogen, phenylmethyl, phenylethyl, cyclopentylmethyl, furanyl, teinila, Naftali, brompheniramine, phenylethylamine, methylpred[2,3-d]pyrimidinyl.

In yet another embodiment, the present invention relates to a family of compounds pyridopyrimidines-AMINOPHENYL, tautomers of these compounds, or pharmaceutically acceptable salts of the compounds or tautomers, where the connection of this family correspond to the formula VIII:

VIII

where R23selected from the group consisting of hydrogen, alkoxyaryl, alkoxyalkyl, hydroxyarylalkyl, halogenoalkane, cyanoacrylate, Allakaket;

R31selected from the group consisting of hydrogen and halogen;

R49selected from the group consisting of hydrogen, Allakaket, halogenoalkanes, alkoxycarbonyl, arylalkyl, arylalkyl, halogen, cyano, halogenoalkanes, alkyl, alkoxycarbonyl, halogenmethyl and alkoxycarbonyl;

R52selected from the group consisting of hydrogen, halogen, alkyl, hydroxyalkoxy, aryloxy, hydroxyalkyloxy, alkoxyalkyl, Ala is karilatsi, alkilaminometilen, arylalkyl, heteroaryl, aminoacylase;

R77selected from the group consisting of hydrogen, alkyl and cycloalkyl.

In the subfamily implementation of this option in the formula VIII, R23selected from the group consisting of hydrogen, methoxyphenyl, methoxyphenylalanine, hydroxyphenylacetamide, forfenimex, diftorhinolonom, cyanophenylacetic, phenylmethoxy, brompheniramine, methoxyphenylacetic;

R31selected from the group consisting of hydrogen, chlorine and fluorine;

R49selected from the group consisting of hydrogen, methyl, phenylmethoxy, brompheniramine, chlorpheniramine, methoxyphenylethylamine, ftorhinolonami, phenylethenyl, phenylethyl, chlorine, fluorine, bromine, cyano, bromperoxidase and hydroxyphenylacetamide.

R52selected from the group consisting of hydrogen, fluorine, bromine, methyl, phenoxy, hydroxyphenoxy, hydroxyechinenone, methoxyphenethyl, methoxyphenoxy, N-methyl-N-4-formatexception, phenylmethyl and thiazolidinedione;

R77selected from the group consisting of hydrogen, methyl and isopropyl.

Salts of the compounds of the present invention

Compounds of the present invention or their tautomers can be used in the form of salts. Depending on the specific compound, the salt of this soedineniya to have advantages due to one or more physical properties of salt, such as the increase in pharmaceutical stability at different temperatures and humidity or a desirable solubility in water or oil. In some cases salt compounds can also be used as an auxiliary agent for dissolving, cleaning and/or repair the connection.

If the salt is intended for introduction to the patient, the salt preferably is pharmaceutically acceptable. Pharmaceutically acceptable salts include, but are not limited to, salts, commonly used for the formation of salts of alkali metals and/or for the formation of additive salts of free acids or free bases. Generally, these salts can be obtained in the usual way with the compound of the present invention by reacting, for example, the appropriate acid or base and connections.

Pharmaceutically acceptable additive salts of the compounds of the present invention can be derived from inorganic or organic acids. Examples of suitable inorganic acids include hydrochloric, Hydrobromic, yodiewonderdog acid, nitric, carbonic, sulfuric and phosphoric acid. Suitable organic acids typically include, for example, organic acids are aliphatic, cycloaliphatic, aromatic, analiticheskogo, heterocyclic, carbon is th and sulfonic class. Specific examples of suitable salts of organic acids include acetate, triptorelin, formate, propionate, succinate, glycolate, gluconate, digluconate, lactate, malate, tartaric acid, citrate, ascorbate, glucuronate, maleate, fumarate, pyruvate, aspartate, glutamate, benzoate, Anthranilic acid, mesilate, stearate, salicylate, p-hydroxybenzoate, phenylacetate, mandelate, embonate (pamoate), methanesulfonate, aconsultant, bansilalpet, Pantothenate, toluensulfonate, 2-hydroxyethanesulfonic, sulfanilic, cyclohexanesulfonic, elganowo acid, b-hydroxybutiric acid, galactarate, galacturonic, adipate, alginate, bisulfate, butyrate, comfort, camphorsulfonate, cyclopentanepropionate, dodecyl sulphate, glucoheptonate, glycyrrhizinate, hemisulfate, heptanoate, hexanoate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, undecanoate.

Pharmaceutically acceptable basic salt additive compounds of the present invention include, for example, metal salts and organic salts. Preferred metal salts include, but are not limited to, salts of alkali metals (group Ia), salts of alkaline earth metals (group IIa) and other physiologically acceptable metal salts. Such salts can be obtained from aluminum, calcium, lithium, mA the tion, potassium, sodium and zinc. Non-limiting examples of preferred organic salts can be derived from tertiary amines and Quaternary amine salts, such as tromethamine, diethylamine, N,N'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine) and procaine. Basic nitrogen-containing groups can be quaternity with such agents as lower halides of Akilov (C1-C6) (for example, methyl, ethyl, propyl and butylchloride, bromides and iodides), diallylsulfide (e.g., dimethyl, diethyl, dibutil and dimycolate), halides, long-chain (e.g., decyl, lauryl, myristyl and sterilgarda, bromides and iodides), kalkilya halides (e.g. benzyl and phenetermine) and others.

The solvate, prodrugs and isomers

Compounds of the present invention, their tautomers and their salts can also be in the form of a solvate with water, for example hydrates, or with organic solvents such as methanol, ethanol or acetonitrile, forming, respectively, methanolate, ethanolate or acetonitrile. Compounds of the present invention may be in any form of MES or mixtures thereof.

In one aspect of the compounds of the tautomers or salts of the present invention can be in the form of prodrugs. Some aliphatic or aromatic complex E. the Ira obtained from the acid groups of compounds of the present invention. Others are aliphatic or aromatic esters of hydroxyl or amino group of the compounds of the present invention. The present invention also relates to the phosphate prodrugs of hydroxyl groups of the compounds of the present invention.

Compounds according to the invention can contain asimmetricheskii substituted carbon atoms, known as chiral centers. These chiral centers are denoted as “R” or “S” depending on the configuration of substituents around the chiral carbon atom. Used in the present description, the terms “R” and “S” denote the configuration defined in the “Nomenclature of Organic Chemistry, Section E: Stereochemistry, Recommendations 1974, Pure Appl. Chem., 45: 11-30 (1976). Compounds of the present invention can be, without limitation, in the form of single stereoisomers (for example, a single enantiomer or a single diastereomers)in the form of mixtures of stereoisomers (e.g., any mixture of enantiomers or diastereomers or in the form of racemic mixtures. Any single stereoisomers, mixtures and racemates are included in the scope of the present invention. Under the compounds defined in the present description as single stereoisomers, understand connections, which are in a form essentially free from other stereoisomers (for example, other enantiomers or diastereomers). “), The Wu free” means, that at least 80% of the compound in the composition is in the form of the desired stereoisomer; preferably, at least 90% of the compound in the composition is in the form of the desired stereoisomer; and, more preferably, at least 95%, 96%, 97%, 98% or 99% of compound in the composition is in the form of the desired stereoisomer. If the stereochemistry of the chiral(s) C(s)present in the chemical structure, is not defined, it is assumed that the chemical structure includes compounds in any stereoisomeric form at each chiral center present in the chemical structure.

Specific stereoisomers of the compounds of the present invention can be obtained using a large number of methods known in this field. These methods include, but are not limited to, stereospecific synthesis, chromatographic separation of the diastereomers, the chromatographic separation of enantiomers, the conversion of enantiomers in an enantiomeric mixture of the diastereomers followed by separation of the diastereomers by chromatography and recovery of individual enantiomers, and enzymatic separation.

Stereospecific synthesis usually involves the use of suitable optically pure (enantiomerically pure) or substantially optically pure substances and the synthesis reaction, which does not cause the azeezaly or stereochemical inversion at the chiral centers. Stereoisomeric mixtures of compounds, including racemic mixtures obtained in the synthesis reaction, can be separated, for example, chromatographic methods, well known to specialists in this field. Chromatographic separation of the enantiomers can be chiral chromatography on polymers, most of which are commercially available. In a non-limiting example, the racemate is placed in the solution and placed on a column containing a chiral stationary phase. Then the enantiomers can be divided HPLC.

The separation of enantiomers can be accomplished by conversion of the enantiomers in a mixture of the diastereomers by reaction with chiral auxiliary reagents. The resulting diastereomers can be divided column chromatography or by crystallization/recrystallization. This technique can be used if designed for the separation of compounds containing carboxyl, amino or hydroxyl group which will form a salt or a covalent bond with a chiral auxiliary reagent. Non-limiting examples of suitable chiral auxiliary reagents include pure chiral amino acids, organic carboxylic acids or organosulfate acid. After separation of the diastereomers by chromatography to separate the enantiomers m is able to be restored. Often chiral auxiliary reagent can be recovered and used again.

Enzymes such as esterase, phosphatase or lipase, can be used to separate the derivatives of the enantiomers in an enantiomeric mixture. For example, the derived complex ester carboxyl group of compounds, intended to separate, can be treated with enzyme selectively hydrolyzes only one of the enantiomers of the mixture. Obtained enantiomerically pure acid is then separated from neitralizuyushchego of ester.

Alternatively, the salts of the enantiomers in the mixture can be obtained by any method known in this field, including processing carboxylic acid with a suitable optically pure base, such as alkaloids or penicillin, followed by precipitation or crystallization/recrystallization enantiomerically pure salts. Methods suitable for separating a mixture of stereoisomers including a racemic mixture, represented in Enantiomers, Racemates, and Resolutions (Jacqueset al., 1981, John Wiley and Sons, New York, NY).

The compound of the present invention may have one or more unsaturated carbon-carbon double bonds. All isomers of double bonds, such as CIS(Z)- and TRANS(E)-isomers and their mixtures, refer to the listed compounds, unless otherwise noted. In addition, if the connection there is in several tautomeric forms, the specified connection is not limited to any particular tautomerism, and includes all tautomeric forms.

Some compounds according to the invention may exist in different stable conformational forms which may be divisible. Torsional asymmetry due to restricted rotation around the asymmetric unit of communication, for example, by steric hindrance or tension rings, can give different conformers. Compounds according to the invention includes each conformational isomer of these compounds and mixtures thereof.

Some compounds according to the invention can also exist in zwitter-ionic form, and in the scope of the invention includes each of zwitter-ionic form of these compounds and mixtures thereof.

Definitions

Compounds according to the present invention is mainly described herein using standard nomenclature. In the case of the above compounds with asymmetric(s) centre(s) should be aware that all stereoisomers of the compounds and their mixtures are within the scope of the present invention, unless specifically indicated otherwise. Non-limiting examples of stereoisomers include enantiomers, diastereomers, CIS-TRANS-isomers. If such a connection exists in various tautomeric forms, it is assumed that the connection includes setautomin form. Specific compounds are described herein using a General formula that contain variables (e.g., R10, A, L1, X or Y). Unless otherwise specified, each variable within such a formula is defined independently of any other variable, and any variable that occurs more than once in a formula, in each case determined independently. If the substituents described as “independently selected from” the group, each Deputy is selected independently of the other. Each Deputy, therefore, may be the same or different from each other(their) successor(s).

The number of carbon atoms in the hydrocarbon Deputy can be identified by the prefix “Cx-Cy”, where x is the minimum number, and y is the maximum number of carbon atoms in the substituent. Thus, for example, “C1-C6alkyl” refers to alkyl Deputy containing 1-6 carbon atoms. As another example, C3-C6cycloalkyl denotes a saturated hydrocarbon ring containing 3-6 carbon atoms of the ring. The prefix multicomponent Deputy refers only to the first component immediately following the prefix. For example, the term “alkylaryl” consists of two components: alkyl and aryl. Thus, for example, C1-C6alkylaryl the apply is to C 1-C6the alkyl attached to the main part of the molecule through an aryl group. Similarly, alkyls6-C10aryl refers to an alkyl group attached to the molecule via C6-C10aryl group. Similarly, the prefix “halogen” halogenoacetyl indicates that the component alkoxy substituted by one or more halogenoalkane, while the prefix “halogen” alkoxylalkyl indicates that the alkyl substituted by one or more halogenoalkane.

If the item description connect two other elements depicted chemical structure of the left component of a connector is a component that is attached to the left element of the depicted structure. For example, if a chemical structure is a X-L-Y and L are denoted as methylacrylate, the chemical compound is X-methyl-aryl-ethyl-Y.

If the connection element is depicted in the structure is a tie, then the left element in the depicted structure is directly connected with the right element of the depicted structure. For example, if a chemical structure is depicted as X-L-Y and L are defined as communication, chemical structure is X-Y. Another example, if the chemical group represented as-L-X and L are defined as communication, chemical group-X. E is e one example, if the chemical structure is depicted as X-L1-L2-Y, X-L1-L2-L3-Y or X-L1-L2-...-LN-Y, and L1, L2, L3,... LNdefined as communication, chemical structure is X-Y.

If to describe the Deputy used chemical formula, then dash to the right (or left) side of the formula indicates a part of a group that has a free(s) value(s).

If the Deputy is described as “substituted,” the non-hydrogen radical is instead one or more hydrogen radicals of carbon, nitrogen or oxygen substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent, in which at least one non-hydrogen radical is instead of hydrogen(s) of the radical(s) on the alkyl substituent. For example, monitorall represents alkyl substituted by one fluorine radicals, and diferuloyl represents alkyl, substituted with two fluorine radicals. It should be stated that if the Deputy has two or more substituents, each non-hydrogen radical may be the same or different, if not stated otherwise.

Deputy “may be substituted”if it contains at least one atom of carbon, nitrogen or oxygen, which is associated with one or more atoms of bodoro the A.

If the Deputy is described as “optionally substituted”, the Deputy may be either substituted or unsubstituted. If the Deputy is described as optionally substituted, up to a specific number of non-hydrogen radicals, the Deputy may be either unsubstituted or substituted by up to a specific number of non-hydrogen radicals, or the maximum number of substitutable positions on the Deputy, in any case, no more than this number. Thus, for example, if the Deputy described as heteroaryl, optionally substituted with up to three non-hydrogen radicals, any heteroaryl with fewer than three possible substitution position may be optionally substituted with as many non-hydrogen radicals, how many heteroaryl is possible to override provisions. For example, tetrazolyl (which has only one possible replacement for the position) can be optionally substituted with one non-hydrogen radical. Another example, if the nitrogen in the amino group, which is described as optionally substituted up to two non-hydrogen radicals, the nitrogen of the primary amino group is optionally substituted up to two non-hydrogen radicals, whereas the nitrogen of the secondary amino group is optionally substituted one non-hydrogen radical.

The term “alkenyl” (by itself or combined with other term(s)) denotes a hydrocarbon Deputy with a straight or branched chain, containing one or more double bonds and from 2 to 20 carbon atoms, usually 2 to 8 carbon atoms and more often 2-6 carbon atoms. Each carbon-carbon double bond within alkenylphenol group may have either CIS-or TRANS-geometry relative to the groups substituted on carbon double connection. Non-limiting examples of such substituents include ethynyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl and 3-butenyl.

The term “albaniles” (by itself or in combination with other term(s)) refers to a divalent unsaturated hydrocarbon group, which may be linear or branched and which has at least one carbon-carbon double bond. Alkenylamine group typically contains from 2 to 20 carbon atoms, usually 2 to 8 carbon atoms and more often 2-6 carbon atoms. Non-limiting examples alkenylamine groups include-C(H)=C(H)-, -C(H)=C(H)-CH2-, -C(H)=C(H)-CH2-CH2-, -CH2-C(H)=C(H)-CH2-, -C(H)=C(H)-CH(CH3)- and-CH2-C(H)=C(H)-CH(CH2CH3)-.

The term “alkoxy” (by itself or in combination with other term(s)) refers to an alkyl group attached to the main part of the molecule through oxygraph (that is,- O-alkyl). Non-limiting examples of such a substituent include methoxy (-O-CH3), ethoxy, n-propoxy, isopropoxy, n-butoxy, from which aloxi, Deut-butoxy and tert-butoxy.

The term “alkoxyalkyl” (by itself or in combination with other term(s)) refers to alkoxygroup attached to the main part of the molecule through alkylenes group. Non-limiting examples of alkoxyalkyl include tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl and ethoxymethyl.

The term “alkoxycarbonyl” (by itself or in combination with other term(s)) refers to alkoxygroup attached to the main part of the molecule via a carbonyl group (i.e ─C(O)─O─alkyl). Typical examples of alkoxycarbonyl include, but are not limited to, methoxycarbonyl, etoxycarbonyl

and tert-butoxycarbonyl.

The term “alkoxycarbonyl” (by itself or in combination with other term(s)) belongs to N(RARB)-, where RArepresents an alkyl-O-C(O)-, and RBrepresents an alkyl-O-C(O) -, or hydrogen. RAand RBmay be the same or different.

The term “alkoxycarbonylmethyl” (by itself or in combination with other term(s)) belongs to N(RARB-alkylene-, where RArepresents an alkyl-O-C(O)-, and RBrepresents an alkyl-O-C(O) -, or hydrogen. RAand RBmay be the same or different.

The term “alkoxycarbonyl” (by himself or in what Oceanie with other term(s)) refers to alkoxycarbonyl group, attached to the main part of the molecule through alkylenes group. Typical examples of alkoxycarbonyl include, but are not limited to, 2-methoxy-2-oxoethyl, 2-ethoxy-2-oxoethyl, 3-methoxy-3-oxopropyl, 3 ethoxy-3-oxopropyl, 4-ethoxy-2-(etoxycarbonyl)-4-oxobutyl, 5-methoxy-5-oxopent and 6-methoxy-6-oxohexyl.

The term “alkyl” (alone or in combination with other term(s)) means a saturated hydrocarbon Deputy with a straight or branched chain, usually containing 1-20 carbon atoms, more often from 1 to 8 carbon atoms and more frequently 1-6 carbon atoms. Non-limiting examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl and octyl.

The term “alkylamino” (by itself or in combination with other term(s)) refers to-NRARBwhere RArepresents alkyl and RBrepresents hydrogen or alkyl. RAand RBmay be the same or different. For example, C1-C6alkylamino refers to ─NRARBwhere RArepresents a C1-C6alkyl, and RBrepresents hydrogen or C1-C6alkyl.

The term “acylaminoalkyl” (by itself or in combination with other term(s)) belongs to N(RARB-alkylene-, where RAPR is dstanley an alkyl, and RBrepresents hydrogen or alkyl. RAand RBmay be the same or different. Thus, C1-C6alkylamino1-C6alkyl refers to N(RARB)-C1-C6alkylene-, in which RArepresents a C1-C6alkyl, and RBrepresents hydrogen or C1-C6alkyl.

The term “alkylaryl” (by itself or in combination with other term(s)) refers to an alkyl group attached to the molecule via a carbonyl group (C(O)-alkyl). Typical examples of alkylcarboxylic include, but are not limited to, acetyl, ethylcarboxyl

,

1-oxopropyl, 2,2-dimethyl-1-oxopropyl, 1-oxobutyl and 1-oxopent.

The term “alkylcarboxylic” (by itself or in combination with other term(s)) refers to alkylcarboxylic group attached to the molecule through alkylenes group. Typical examples of alkylcarboxylic include, but are not limited to, 2-oxopropyl, 3,3-dimethyl-2-oxopropyl, 3-oxobutyl and 3-oxopent.

The term “alkylcarboxylic” (by itself or in combination with other term(s)) refers to alkylcarboxylic group attached to the main part of the molecule through oxygraph. Typical examples of alkylcarboxylic clucalc, but not limited to, atomic charges, ethylcarbonate and tert-BUTYLCARBAMATE.

The term “alkylcarboxylic” (by itself or in combination with other term(s)) refers to alkylcarboxylic attached to the main part of the molecule through alkylenes group. Typical examples of alkylcarboxylic include, but are not limited to, 2-(atomic charges)ethyl, 3-(atomic charges)propyl and 3-(propionyloxy)propyl.

The terms “alkylene” or “alkylene” (by itself or in combination with other term(s)) denote divalent group derived from a straight or branched saturated hydrocarbon chains, typically containing 1-20 carbon atoms, more often from 1 to 8 carbon atoms and more frequently 1-6 carbon atoms. Typical examples of alkylene include, but are not limited to, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2- and-CH2CH(CH3)CH2-.

The term “quinil” (by itself or in combination with other term(s)) denotes a hydrocarbon Deputy with a straight or branched chain, containing one or more triple ties and usually 2-20 carbon atoms, usually 2 to 8 carbon atoms and more often 2-6 carbon atoms. Non-limiting examples of such substituents include ethinyl, 1-PROPYNYL, 2-PROPYNYL, 3-PROPYNYL, decenyl, 1-butenyl, 2-butyn is l and 3-butynyl.

The terms “akinyan” (by itself or in combination with other term(s)) refers to a divalent unsaturated hydrocarbon group, which may be linear or branched and which has at least one carbon-carbon triple bond. Typical alkenylamine groups include, for example, -C≡C-, -C≡C-CH2-, -C≡C-CH2-CH2-, -CH2-C≡C-CH2-, -C≡C-CH(CH3)- and-CH2-C≡C-CH(CH2CH3)-.

The term “amino” (alone or in combination with other term(s)) denotes-NH2. The term “monosubstituted amino” (alone or in combination with other term(s)) denotes aminosalicyclic in which one hydrogen radical is replaced with the non-hydrogen substituent. The term “disubstituted amino” (alone or in combination with other term(s)) denotes aminosalicylic, in which both hydrogen atoms replaced with non-hydrogen substituents, which may be the same or different.

The term “aminocarbonyl” (by itself or in combination with other term(s)) means-C(O)-NH2that can also be represented as

The term “aminoalkyl” (by itself or in combination with other term(s)) denotes alkylene-NH2.

The term “aminoalkylsilanes” (by itself or in combination with other Ter the other(s)) means-C(O)-alkylene-NH 2. For example, “aminomethylpropanol” can be represented as

The term “aminosulfonyl” (by itself or in combination with other term(s)) means-S(O)2-NH2that can also be represented as

The term “aryl” (by itself or in combination with other term(s)) refers to an aromatic carbocyclic group containing 6-14 carbon atoms of the ring. Non-limiting examples of arrow include phenyl, naphthalenyl, anthracene and indenyl. Aryl group may be associated with the main molecular group via any substitutable carbon atom of the group.

The term “arylalkyl” (by itself or in combination with other term(s)) refers to an aryl group attached to the molecule through alkylenes group. Typical examples of substituted/unsubstituted arylalkyl include, but are not limited to, benzyl, 4-(benzyloxy)benzyl, 4-methoxybenzyl, 4-hydroxybenzyl, 3-(1,3-benzodioxol-5-yl)-2-methylpropyl, 3-(phenoxy)benzyl, 3-(1,3-benzodioxol-5-yl)propyl, 2-phenylethyl, 3-phenylpropyl, 2-naphthylmethyl, 3,5-di-tert-butyl-2-hydroxybenzyl, 3-methoxybenzyl, 3,4-dimethoxybenzyl, 4-(dimethylamino)benzyl, 4-[3-(dimethylamino)propoxy]benzyl, (6-methoxy-2-naphthyl)methyl and 2-naphthas-2-ileti.

The term “arylalkylamines” (CE is e or in combination with other term(s)) refers to arylalkyl group, attached to the main part of the molecule via a carbonyl group (i.e arylalkyl─C(O)─). Typical examples of arylalkylamine include, but are not limited to, 2-naphthylacetyl and phenylacetyl.

The term “Allakaket” (by itself or in combination with other term(s)) refers to arylalkyl group attached to the main part of the molecule through oxygraph (i.e. arylalkyl─O─). Typical examples of Allakaket include, but are not limited to, 2-phenylethane, 3-naphthas-2-ylpropionic and 5 phenylpentane.

The term “allakariallak” (by itself or in combination with other term(s)) refers to arielalexisxrp attached to the main part of the molecule through alkylenes group. Typical examples of allakariallak include, but are not limited to, benzoyloxymethyl, 2-(benzyloxy)ethyl and (2 venlafaxi)methyl.

The term “arylethoxysilanes” (by itself or in combination with other term(s)) refers to arielalexisxrp attached to the main part of the molecule via a carbonyl group. Typical examples of arylalkanolamine include, but are not limited to, benzyloxycarbonyl and naphthas-2-ylmethoxycarbonyl.

The term “arylcarbamoyl” (by itself or in combination with other term(s)) refers to an aryl group attached to the main part of the molecule cher the C of the carbonyl group. Typical examples of arylcarbamoyl include, but are not limited to, benzoyl and naphtol.

The term “aryloxy” (by itself or in combination with other term(s)) refers to an aryl group attached to the main part of the molecule through oxygraph. Typical examples of substituted/unsubstituted, aryloxy include, but are not limited to, phenoxy, naphthyloxy, 3 bromophenoxy, 4-chlorophenoxy, 4-methylphenoxy and 3.5-dimethoxyphenoxy.

The term “aryloxyalkyl” (by itself or in combination with other term(s)) refers to alloctype attached to the main part of the molecule through alkylenes group. Typical examples of aryloxyalkyl include, but are not limited to, 2-phenoxyethyl, 3-naphthas-2-aloxiprin and phenoxymethyl.

The term “aryloxyalkyl” (by itself or in combination with other term(s)) refers to alloctype attached to the main part of the molecule via a carbonyl group.

The term “aristeo” (by itself or in combination with other term(s)) refers to an aryl group attached to the molecule via a sulfur atom (i.e. aryl-S-). Typical examples of aaltio include, but are not limited to, phenylthio, naphthalene-1-ylthio and naphthalene-2-ylthio.

The term “alltoall” (by itself or in combination with other term(s)) refers to aryl─S─and the kilen─. Typical examples of alltoall include, but are not limited to, (phenylthio)methyl, 2-(phenylthio)ethyl and 3-(phenylthio)propyl.

The term “alltoallv” (by itself or in combination with other term(s)) refers to arylthioureas group attached to the main part of the molecule through oxygraph.

The term “aristolakia” (by itself or in combination with other term(s)) refers to alltournative attached to the main part of the molecule through alkylenes group.

The terms “carbocycle”, or “carbocyclic”or “carbocyclic” (alone or in combination with other term(s)) refer to a saturated (e.g., “cycloalkyl”), partially saturated (e.g., “cycloalkenyl” or “cycloalkenyl”) or completely unsaturated (e.g., “aryl”) ring system containing zero heteroatoms in the ring and usually 3-18 carbon atoms of the ring. “Ring atoms” or “members of the ring are atoms linked together to form a ring or rings of a cyclic substituent. The carbocyclic group may, without limitation, include a single ring or two or more condensed rings, or rings associated bridge connection, or spirocerca. Carbocyclic may contain 3-14 ring members (i.e. C3-C14carbocyclic, such as C3-C14qi is loukil), 3-10 member ring (that is, C3-C10carbocyclic, such as C3-C10cycloalkyl), 3-8 member ring (that is, C3-C8carbocyclic, such as C3-C8cycloalkyl), 3-6 member ring (that is, C3-C6carbocyclic, such as C3-C6cycloalkyl), 4-10 ring members (i.e. C4-C10carbocyclic, such as C4-C10cycloalkyl and C4-C10cycloalkenyl), 4-8 member ring (that is, C4-C8carbocyclic, such as C4-C8cycloalkyl and C4-C8cycloalkenyl), or a 5-7 member ring (that is, C5-C7carbocyclic, such as C5-C7cycloalkyl, C5-C7cycloalkenyl and phenyl). Substituted carbocyclic may have either CIS-or TRANS-geometry. Typical examples carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexadienyl, substituted, decahydronaphthalene, octahedrons, cyclohexenyl, phenyl, naphthyl, fluorenyl, indanyl, 1,2,3,4-tetrahydronaphthyl, indenyl, isoindolyl, bicycloalkyl, anthracene, phenanthrene, benzonitrile (also known as “phenalenyl”), decaline and nobinary. Carbonilla group can be attached to the main part of the molecule through any substitutable carbon ATO the group.

The term “carbocyclic” (by itself or in combination with other term(s)) refers to carbonitrile group attached to the molecule through alkylenes group. For example, C3-C10carbocyclic1-C6alkyl refers to C3-C10carbonitrile group attached to the molecule via C1-C6alkylen. Similarly, C5-C7carbocyclic1-C6alkyl refers to C5-C7carbonitrile group attached to the molecule via C1-C6alkylen.

The term “carbocyclic” (by itself or in combination with other term(s))refers to carbocyclization group attached to the main part of the molecule through oxygraph (i.e. carbocyclization-O-). For example, C3-C10carbocyclic1-C6alkoxy refers to C3-C10carbocyclic1-C6alkyl group attached to the main part of the molecule through oxygraph. Similarly, C5-C7carbocyclic1-C6alkoxygroup applies to C5-C7carbocyclic1-C6alkyl group attached to the main part of the molecule through oxygraph.

The term “barbiecollector.com” (by itself or in combination with other term(s)) refers to the carb is ticllacocha, attached to the main part of the molecule through alkylenes group (i.e. carbocyclization-O-alkylene-). For example, C3-C10carbocyclic1-C6alkoxyl1-C6alkyl refers to C3-C10carbocyclic1-C6alkoxygroup attached to the main part of the molecule via C1-C6alkylenes group.

The term “caroticocavernous” (by itself or in combination with other term(s)) refers to carbazochrome attached to the main part of the molecule via a carbonyl group (C(O)-O-alkalinisation). For example, C3-C10carbocyclic1-C6alkoxycarbonyl applies to C3-C10carbocyclic1-C6alkoxygroup attached to the main part of the molecule via a carbonyl group. As non-limiting examples, fenilalaninammonii” can be represented as

The term “carbocyclization” (by itself or in combination with other term(s)) refers to carbocyclization group attached to the molecule via a carbonyl group (C(O)-alkalinisation). For example, “phenylethylamine” can be represented as

The term “carbonyliron” (by itself or with the conjunction with other term(s)) refers to carbonitrile group, attached to the main part of the molecule via a carbonyl group (i.e carbocyclic-C(O)-). For example, “phenylcarbinol” can be represented as:

.

The term “carbocyclic” (by itself or in combination with other term(s)) refers to carbonitrile group attached to the main part of the molecule through oxygraph (i.e. carbocyclic-O-).

The term “carbocyclization” (by itself or in combination with other term(s)) refers to carbazochrome attached to the main part of the molecule through alkylenes group (i.e carbocyclic-O-alkylene-).

The term “carbocyclization” (by itself or in combination with other term(s)) refers to carbazochrome attached to the main part of the molecule via a carbonyl group (C(O)-O-carbocyclic). For example, “vinyloxycarbonyl” can be represented as

The term “carbocyclic” (by itself or in combination with other term(s)) refers to carbonitrile group attached to the molecule via a sulfur atom (i.e carbocyclic-S-).

The term “carbonylations” (by itself or in combination with other term(s)) refers to carbocyclization-S-.

The term “carbazolyletilmetacrilate” (by itself or the combination with other term(s)) refers to carbocyclic-alkylen-S-alkylene-.

The term “carbocyclic” (by itself or in combination with other term(s)) refers to caractristique attached to the main part of the molecule through alkylenes group (i.e carbocyclic-S-alkylene-).

The term “carbonitridation” (by itself or in combination with other term(s)) refers to carbonitrile group attached to the molecule through another Carballino group (i.e carbocyclic-carbocyclic-). For example, C3-C10carbocyclic5-C7carbocyclic applies to C3-C10carbonitrile group attached to the molecule via C5-C7Carballino group (that is, C3-C10carbocyclic─C5-C7carbocyclic─).

The term “caroticocavernous” (by itself or in combination with other term(s)) refers to caroticocavernous group attached to the molecule through alkylenes group.

The term “barbiecollector.com” (by itself or in combination with other term(s)) refers to carbocyclic-alkylen-O-carbocyclic-alkylen-. For example, C3-C10carbocyclic1-C6alkoxyl5-C7carbocyclic3-C4alkyl refers to C3-C10carbocyclic-C1-C6alkylen-O-C 5-C7carbocyclic-C3-C4alkylen-.

The term “(carbocyclic)carbocyclic” (by itself or in combination with other term(s)) refers to carbocyclic-alkylen-carbocyclic-alkylen-. For example, C3-C10carbocyclic1-C6alkyls5-C7carbocyclic3-C4alkyl refers to C3-C10carbocyclic-C1-C6alkylen-C5-C7carbocyclic-C3-C4alkylen-.

The term “carbazolilalkylmethacrylat” (by itself or in combination with other term(s)) refers to carbocyclic-alkylen-O-heterocyclyl-alkylene-.

The term “caroticocavernous” (by itself or in combination with other term(s)) refers to carbocyclic-C(O)-heterocyclyl-alkylene-.

The term “barbiecollector.com” (by itself or in combination with other term(s)) refers to carbocyclic-heterocyclic-alkylen-.

The term “carbazolilalkylmethacrylat” (by itself or in combination with other term(s)) refers to carbocyclic-C(O)-carbocyclic-alkylen-. For example, C3-C10carbonyliron4-C8carbocyclic1-C6alkyl refers to C3-C10carbocyclic-C(O)-C4-C8carbocyclic-C1-C6alkylen-.

The term “(carbocyclic)heterocycle is alkyl” (alone or in combination with other term(s)) refers to carbocyclic-alkylen-heterocyclyl-alkylene.

The term “carbonyl” (by itself or in combination with other term(s)) refers to-C(O)-, which also may be depicted as

The term “carboxy” (by itself or in combination with other term(s)) means-C(O)-OH, which can also be represented as

The term “carboxylic” (by itself or in combination with other term(s)) refers to carboxylate attached to the main part of the molecule through alkylenes group. Typical examples of carboxyethyl include, but are not limited to, carboxymethyl, 2-carboxyethyl and 3-carboxypropyl.

The term “cyclic amino” (alone or in combination with other term(s)) denotes heterocyclyl fragment containing at least one nitrogen atom in the ring, with the remaining ring atoms are carbon and, optionally, nitrogen, or sulfur. Non-limiting examples of such groups include groups of piperidinyl, piperazinil and thiazine.

The term “cycloalkenyl” (by itself or in combination with other term(s)) refers to non-aromatic, partially unsaturated carbocycles Deputy without heteroatoms as ring members, and usually with 4-18 carbons as members of the ring. Typical examples cycloalkenyl groups include, but they do not exhaust anchovetta, cyclobutenyl, cyclopentenyl, cyclohexenyl and octahydronaphthalene.

The term “cycloalkyl” (by itself or in combination with other term(s)) refers to a saturated carbocycles group containing zero heteroatoms in the ring and usually 3-18 carbon as ring members. Non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, decaline and nobinary.

The term “cycloalkylcarbonyl” (by itself or in combination with other term(s)) refers to cycloalkyl group attached to the molecule via a carbonyl group.

The term “cyano” (by itself or in combination with other term(s)) denotes CN, which also can be represented

The term “dialkylamino” (by itself or in combination with other term(s)) refers to-NRARBwhere RAand RBindependently selected from alkyl groups.

The term “dialkylaminoalkyl” (by itself or in combination with other term(s)) refers to dialkylamino attached to the main part of the molecule via a carbonyl group (i.e., N(RARB)-C(O)-, where RAand RBindependently selected from alkyl groups).

The term “formyl” (by itself or in combination with other term(s)) is tositsa to the group-C(O)H.

The term “halogen” (by itself or in combination with other term(s)) means a fluorine radical (which may be depicted as-F), chlorine radical (which may be depicted as -- Cl), bromine radical (which may be depicted as-Br), or radical iodine (which may be depicted as-I).

The prefix “halogen” indicates that the Deputy, to which is prefixed, substituted by one or more independently selected halogenoalkane. For example, “halogenated” (by itself or in combination with other term(s)) denotes Deputy alkyl in which at least one hydrogen radical is replaced by halogenoalkanes. Non-limiting examples of halogenation include chloromethyl, 1-bromacil, vermeil, deformity, trifluoromethyl and 1,1,1-triptorelin. In another example, halogenoalkane” (by itself or in combination with other term(s)) denotes Deputy alkoxy, in which at least one hydrogen radical is replaced by halogenoalkanes. Non-limiting examples of substituents of halogenoalkane include chloromethoxy, 1 bromoethoxy, formatosi, deformedarse, triptoreline (also known as “performative”) and 1,1,1,-triptoreline. It should be noted that if the Deputy substituted by more than one halogenoalkanes, such halogenoalkane may be the same or different (the if not stated otherwise).

The prefix “pagelogin” indicates that each of the hydrogen radical on the Deputy, to which is prefixed, replaced independently selected halogenoalkanes, i.e. each hydrogen radical on the Deputy replaced by halogenoalkanes. If all halogenoalkane are the same, then the prefix usually indicates halogenerator. Thus, for example, the term “PERFLUORO” means that each hydrogen radical Deputy, to which is prefixed, substituted by a fluorine radical. For example, the term “perfluoroalkyl” means the Deputy alkyl, in which the radical is replaced by fluorine each hydrogen radical. Non-limiting examples performanceline substituents include trifluoromethyl (-CF3), perforator, performatic, peritonitis and perforater. Another example, the term “performace” means the Deputy alkoxy, in which each of the hydrogen radical is replaced by fluorine radical. Non-limiting examples of performancesarticle include triptoreline (-O-CF3), perftoruglerodov, perforbalance, performamce, performancex.

The terms “heterocycle”, or “heterocycle”, or “heterocyclyl” (by itself or in combination with other term(s)) refer to a saturated (e.g., “heteroseksualci”), partially unsaturated (e.g., “geteroseksualen” what if “heteroseksualnymi”) or completely unsaturated (e.g., “heteroaryl”) ring system, typically containing 3-18 ring atoms in which at least one atom of the ring is a heteroatom (nitrogen, oxygen or sulfur), and the remaining ring atoms independently selected from the group consisting of carbon, nitrogen, oxygen and sulfur. Heterocyclyl group can be attached to the main part of the molecule through any capable of substitution of the carbon atom or nitrogen group, provided that formed a stable molecule.

Heterocyclyl may be, without limitation, a single ring, which usually contains 3-14 ring atoms (i.e., M3-M14heterocyclyl), 3-8 ring atoms (i.e., M3-M8heterocyclyl), 3-6 ring atoms (i.e., M3-M6heterocyclyl) or 5-6 ring atoms (i.e., M5-M6heterocyclyl). Non-limiting examples heterocyclyl with single ring include furanyl, dihydrofurane, tetrahydrofuranyl, pyrrolyl, isopropyl, pyrrolidyl, pyrrolidinyl, imidazolyl, isoimidazole, imidazolines, imidazolidinyl, pyrazolyl, pyrazolyl, pyrazolidine, triazole, tetrazole, ditolyl, oxacillin, oxazolyl, isoxazolyl, thiazolyl, isothiazolin, thiazolyl, isothiazolines, diazolidinyl, isothiazolinones, thiadiazolyl, oxadiazolyl, oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl (WPI also the walls as assimil”), 1,2,5-oxadiazolyl (also known as “furutani”) and 1,3,4-oxadiazolyl), oxadiazolyl (including 1,2,3,4-oxadiazolyl and 1,2,3,5-oxadiazolyl), doxazosin (including 1,2,3-doxazosin, 1,2,4-doxazosin, 1,3,2-doxazosin and 1,3,4-doxazosin), oxathiolane, pyranyl (including 1,2-pyranyl and 1,4-pyranyl), dihydropyran, pyridinyl, piperidinyl, diazines (including pyridazinyl (also known as “1,2-diazines”), pyrimidinyl (also known as “1,3-diazines”) and pyrazinyl (also known as 1,4-diazines”)), piperazinil, triazinyl (including s-triazinyl (also known as “1,3,5-triazinyl”), as triazinyl (also known 1,2,4-triazinyl) and v-triazinyl (also known as “1,2,3-triazinyl, oxazinyl (including 1,2,3-oxazinyl, 1,3,2-oxazinyl, 1,3,6-oxazinyl (also known as “Pantokrator”), 1,2,6-oxazinyl and 1,4-oxazinyl), isoxazolyl (including o-isoxazolyl and p-isoxazine), oxazolidinyl, isoxazolidine, oxathiazine (including 1,2,5-oxathiazine or 1,2,6-oxathiazine), oxadiazolyl (including 1,4,2-oxadiazine and 1,3,5,2-oxadiazolyl), morpholinyl, azepine, oxepin, tiepins and diazepines.

Heterocyclyl may also include, without limitation, two or more rings fused together, such as, for example, naphthyridines (including [1,8] naphthyridine and [1,6] naphthyridine), thiazolidinediones, thienopyrimidines, pyrimidopyrimidine, pyridopyrimidines, piraso pyrimidinyl, indolizinyl, pyridinyl, pirenopolis, 4H-hemolysins, purinol, pyridopyrimidines (including pyrido[3,4-b]pyridinyl, pyrido[3,2-b]pyridinyl, and pyrido[4,3-b]pyridinyl), pyridopyrimidines and pteridinyl. Other non-limiting examples heterocyclyl with condensed rings include benzododecinium heterocyclyl, such as indolyl, isoindolyl, indolinyl (also known as “pseudohistory”), isoindolyl (also known as “respiratory”), benzathine (including chinoline (also known as “1-benzathine”) and ethenolysis (also known as “2-benzazolyl”)), phthalazine, honokalani, benzodiazines (including cinnolines (also known as “1,2-benzodiazines”) and hintline (also known as “1,3-benzodiazepin”)), benzopyranyl (including “chromanin” and “Isopropenyl”), benzothiophene (also known as “thiochroman”), benzoxazolyl, indicazioni (also known as “benzisoxazole”), Anthranilic, benzodioxolyl, benzodioxane, benzoxadiazole, benzofuranyl (also known as “coumaroyl”), isobenzofuranyl, benzothiazyl (also known as “benzothiophenes”, “tianeptine and benzothiophenes”), isobenzofuranyl (also known as “isobenzofuranyl”, “socionatural and isobenzofuranyl”), benzothiazolyl, benzotriazolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl (including the 1,3,2-benzoxazines, 1,4,2-benzoxazine, 2,3,1-benzoxazine and 3,1,4-benzoxazine), benzisoxazole (including 1,2-benzisoxazoles and 1,4-benzisoxazol), tetrahydroisoquinoline, carbazolyl, xantener and acridines.

The term heterocyclyl with two fused rings” (by itself or in combination with other term(s)) means a saturated, partially saturated or aromatic heterocyclyl containing two condensed rings. Non-limiting examples heterocyclyl with two fused rings include naphthyridine (including [1,8] naphthyridine and [1,6] naphthyridine), thiazolidinediones, thienopyrimidines, pyrimidopyrimidine, pyridopyrimidines, pyrazolopyrimidines, indolizinyl, pyridinyl, pirenopolis, 4H-hemolysins, purinol, pyridopyrimidines, pteridinyl, indolyl, isoindolyl, indolinyl, isoindolyl, benzathine, phthalazine, honokalani, hintline, benzodiazines, benzopyranyl, benzothiophene, benzoxazole, indicazioni, Anthranilic, benzodioxolyl, benzodioxane, benzoxadiazole, benzofuranyl, isobenzofuranyl, benzothiazyl, isobenzofuranyl, benzothiazolyl, benzotriazolyl, benzoimidazolyl, benzotriazolyl, benzoxazolyl, benzisoxazoles and tetrahydroisoquinolines.

As members of the ring heterocyclyl may contain one or more sulfur atoms; and in some cases, the atom(s) sulfur oxide(s) to S or SO 2. Heteroatom(s) of nitrogen in heterocyclyl can be quaternity or not quaternity, and can be oxidized to N-oxide or not oxidized. In addition, the heteroatom(s) of the nitrogen may be N-protected or not protected.

As used herein, the number of atoms of the ring in heterocyclyl fragment can be determined using the prefix “Mx-My”, where x is the minimum number, and y is equal to the maximum number of atoms of the ring in heterocyclyl fragment.

The term “heterocyclics” (by itself or in combination with other term(s)) refers to geteroseksualnoe group attached to the main part of the molecule through oxygraph.

The term “geterotsiklicheskikh” (by itself or in combination with other term(s)) refers to geterotsiklicheskikh attached to the main part of the molecule through alkylenes group (i.e., heterocyclyl-alkylene-O-alkylene-).

The term “geterotsiklicheskikh” (by itself or in combination with other term(s)) refers to geterotsiklicheskikh attached to the main part of the molecule via a carbonyl group (i.e., heterocyclyl-alkylene-O-C(O)-).

The term “heteroseksualci” (by itself or in combination with other term(s)) refers to heterocyclyl attached to the main part of the molecule through alkylen the new group (for example, heterocycles1-C6alkyl).

The term “geterotsiklicheskikh” (by itself or in combination with other term(s)) refers to geteroseksualnoe group attached to the molecule via a carbonyl group (i.e.,- C(O)-alkylene-heterocyclyl).

The term “heterocyclicamines” (by itself or in combination with other term(s)) refers to heterocyclyl attached to the main part of the molecule via a carbonyl group (i.e.,- C(O)-heterocyclyl).

The terms “heterocyclic” or “(heterocycle)hydroxy” (by itself or in combination with other term(s)) refers to heterocyclyl group attached to the main part of the molecule through oxygraph.

The term “(heterocycle)oxyalkyl” (by itself or in combination with other term(s)) refers to heterocyclisation attached to the main part of the molecule through alkylenes group (i.e., heterocyclyl-O-alkylene-).

The term “(heterocycle)oxycarbonyl” (by itself or in combination with other term(s)) belongs to (heterocycle)exigrep attached to the main part of the molecule via a carbonyl group (i.e., heterocyclyl-O-C(O)-).

The term “heterozygotic” (by itself or in combination with other term(s)) refers to heterocyclyl attached to the main part of the molecule is via S.

The term “geterotsiklicheskikh” (by itself or in combination with other term(s)) refers to heterocyclyl-alkylene-S-.

The term “geterotsiklicheskikh” (by itself or in combination with other term(s)) refers to heterocyclyl-alkylene-S-alkylene-.

The term “geterotsiklicheskie” (by itself or in combination with other term(s)) refers to heterocicluri attached to the main part of the molecule through alkylenes group (i.e., heterocyclyl-S-alkylene-).

The term “heterocyclization” (by itself or in combination with other term(s)) refers to heterocyclyl attached to the main part of the molecule through Carballino group (i.e., heterocyclization-).

The term “geterotsiklicheskikh” (by itself or in combination with other term(s)) refers to heterocyclizations group attached to the molecule through alkylenes group (i.e., heterocyclyl-carbocyclic-alkylen-).

The term “(heterocycle)alkoxycarbonylmethyl” (by itself or in combination with other term(s)) refers to heterocycle-alkylene-O-carbocyclic-alkylen-.

The term “(heterocycle)karbonilkarboksilatnykh” (by itself or in combination with other term(s)) refers to heterocycle-C(O)-carbocyclic-alkylen-.

The term “(heterocycle)heteroseksualci” (by itself or in combination with other term(s)) refers to heterocycle-heterocycle-alkylene-.

The term “(heterocycle)alkoxycarbonylmethyl” (by itself or in combination with other term(s)) refers to heterocycle-alkylene-O-heterocycle-alkylene-.

The term “(heterocycle)carbonylmetallate” (by itself or in combination with other term(s)) refers to heterocycle-C(O)-heterocycle-alkylene─.

The term “(heteroseksualci)carbocyclic” (by itself or in combination with other term(s)) refers to heterocycle-alkylene-carbocyclic-alkylen-.

The term “(heteroseksualci)heteroseksualci” (by itself or in combination with other term(s)) refers to heterocycle-alkylene-heterocycle-alkylene-. Thus, for example, (M3-M10heterocycles1-C6alkyl)M5-M6heterocycles1-C3alkyl denotes the M3-M10heterocycle─C1-C6alkylen─M5-M6heterocycle─C1-C3alkylen─.

The term “heteroaryl” (by itself or in combination with other term(s)) denotes aromatic heterocyclyl, usually containing 5-18 ring atoms. Heteroaryl may be a single ring or two or more condensed rings. Non-limiting examples of five-membered heteroaryl include imidazolyl; furanyl; thiophenyl (or thienyl or thiopurines); pyrazolyl; oxazolyl; isoxazolyl; thiazolyl; 1,2,3-, 1,2,4-, ,2,5- and 1,3,4-oxadiazolyl; and isothiazole. Non-limiting examples of six-membered heteroaryl include pyridinyl; pyrazinyl; pyrimidinyl; pyridazinyl; and 1,3,5-, 1,2,4 - and 1,2,3-triazinyl. Non-limiting examples 6/5-membered condensed ring heteroaryl include benzothiophene, isobenzofuranyl, benzisoxazole, benzoxazole, purines and Anthranilic. Non-limiting examples 6/6-membered condensed ring heteroaryl include chinoline; ethenolysis; and benzoxazines (including cinnolines and hintline).

The term “heteroaromatic” (by itself or in combination with other term(s)) refers to heteroaromatic attached to the main part of the molecule through oxygraph (i.e., heteroaryl-alkylene-O-). Typical examples of heteroaromatics include, but are not limited to, 2-pyridine-3-ylethoxy, 1,3-thiazole-5-ylethoxy, 3-quinoline-3-ylpropionic and 5-pyridin-4-alpenstrasse.

The term “heteroarylboronic” (by itself or in combination with other term(s)) refers to heteroarylboronic attached to the main part of the molecule through alkylenes group (i.e., heteroaryl-alkylene-O-alkylene-). Typical examples of heterokedasticity include, but are not limited to, (2-pyridin-3-ylethoxy)methyl, (3-quinoline-3-ylpropionic)methyl, (1,3-thiazol-5-ylethoxy)methyl and 2-(5-pyridin-4-alpenstrasse)ethyl.

the Term “heteroarylboronic” (by itself or in combination with other term(s)) refers to heteroarylboronic, attached to the main part of the molecule via a carbonyl group (i.e., heteroaryl-alkylene-O-C(O)-). Typical examples of heteroarylboronic include, but are not limited to, (2-pyridin-3-ylethoxy)carbonyl, (3-quinoline-3-ylpropionic)carbonyl, 2-(1,3-thiazol-5-ylethoxy)carbonyl and (5-pyridin-4-alpenstrasse)carbonyl.

The term “heteroaromatic” (by itself or in combination with other term(s)) refers to a heteroaryl group attached to the molecule through alkylenes group. Typical examples of heteroaromatic include, but are not limited to, 3-hyalinella, 3-pyridinylmethyl, 4-pyridinylmethyl, 1H-imidazol-4-ylmethyl, 1H-pyrrol-2-ylmethyl, pyridine-3-ylmethyl and 2-pyrimidine-2-ylpropyl.

The term “heteroarylboronic” (by itself or in combination with other term(s)) refers to heteroallyl group attached to the molecule via a carbonyl group (i.e., heteroaryl-alkylene-C(O)-).

The term “heteroarylboronic” (by itself or in combination with other term(s)) refers to a heteroaryl group attached to the molecule via a carbonyl group. Typical examples of heteroarylboronic include, but are not limited to, pyridine-3-ylcarbonyl, (1,3-thiazol-5-yl)carbonyl and quinoline-3-ylcarbonyl.

The term “heteroaryl the hydroxy” (by itself or in combination with other term(s)) refers to a heteroaryl group, attached to the main part of the molecule through oxygraph. Typical examples of heteroaromatic include, but are not limited to, pyridine-3-yloxy and quinoline-3-yloxy.

The term “heteroepitaxial” (by itself or in combination with other term(s)) refers to heteroanalogues attached to the main part of the molecule through alkylenes group (i.e., heteroaryl-O-alkylene-).

The term “heteroarylboronic” (by itself or in combination with other term(s)) refers to heteroanalogues attached to the main part of the molecule via a carbonyl group (i.e., heteroaryl-O-C(O)-).

The term “heteroaromatic” (by itself or in combination with other term(s)) refers to a heteroaryl group attached to the molecule through an-S-.

The term “heteroalicyclic” (by itself or in combination with other term(s)) refers to heteroaryl-alkylene-S-.

The term “heteroepitaxial” (by itself or in combination with other term(s)) refers to heteroaryl-alkylene-S-alkylene-.

The term “heteroalicyclic” (by itself or in combination with other term(s)) refers to heteroanalogues attached to the main part of the molecule through alkylenes group (i.e., heteroaryl-S-alkylene-).

The term “hydrogen” (by itself or combined in the and to the other term(s)) refers to a hydrogen radical and may be depicted as-H.

The term “hydroxy” (by itself or in combination with other term(s)) refers to-OH.

The term “hydroxyalkyl” (by itself or in combination with other term(s)) refers to alkyl Deputy, in which one or more hydrogen radicals are replaced by ─OH. Typical examples of hydroxyalkyl include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and 2-ethyl-4-hydroxyethyl.

The term “keto” (by itself or in combination with other term(s)) denotes coradical and can be represented as =O.

The term “aminoalkyl” (by itself or in combination with other term(s)) refers to the radical of the formulawhere H can be optionally substituted with alkyl or hydroxy, and in these cases, the Deputy will be alkylamidoamines or hydroxyarylalkyl, respectively.

The term “nitro” (by itself or in combination with other term(s)) denotes ─NO2.

The term “oxo” (by itself or in combination with other term(s)) refers to a group =O (i.e.,).

The term “hydroxy” (by itself or in combination with other term(s)) refers to-O-.

The term “propargyl” (by itself or in combination with other term(s)) denotes a monovalent radical, depicted as-CH2-CH≡CH.

The term“sulfonyl” (by itself or in combination with other term(s)) means-S(O) 2-which can also be represented as

The term “sulfinil” (by itself or in combination with other term(s)) means-S(O)-, which also may be depicted as

The term “thio” or “TIA” (by itself or in combination with other term(s)) means-S.

The term “thiol,” “mercapto” or “sulfhydryl” (by itself or in combination with other term(s)) denotes Deputy sulfhydryl, (i.e.,- SH). Thus, for example, tjoelker denotes Deputy alkyl in which one or more hydrogen radicals is replaced by-SH, with alkylthio refers to alkyl-S-.

The term “dialkoxy” (by itself or in combination with other term(s)) refers to an alkyl group attached to the molecule through an-S-. Typical examples of dialkoxy include, but are not limited to, methylthio, ethylthio, butylthio.

The term “toolboxitem” (by itself or in combination with other term(s)) refers to dialkoxy attached to the main part of the molecule through alkylenes group (i.e., alkyl-S-alkylene-).

The term “thiocarbonyl” (by itself or in combination with other term(s)) denotes a carbonyl, in which the oxygen atom replaced by sulfur. Such Deputy may show the AK-C(S)-, and can be represented as

The term “pharmaceutically acceptable” is used as an adjective, meaning that the defined noun suitable for use as a pharmaceutical product or as part of a pharmaceutical product.

The term “therapeutically effective amount” refers to the total amount of each active substance, sufficient to achieve a significant effect in the patient, for example to reduce the amount of virus.

The term “prodrug” refers to derivatives of the compounds according to the invention, which have chemically or metabolically otsepleniya group, and becomes by selvolina or under the influence of physiological conditions of a connection according to the invention that is pharmaceutically activein vivo. The prodrug compounds can be obtained by conventional methods by reacting the functional group of compounds (such as amino, hydroxy or carboxypropyl). Proletarienne derived often gives advantages in terms of solubility, tissue compatibility or delayed release in the mammalian organism (see Bungard, H., Design of prodrugs, p.7-9, 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to specialists in this field, such as, for example, challenging the esters, obtained by reacting the parent compound acid and a suitable alcohol, or amides obtained by reacting the parent compound of the acid with the appropriate amine. Examples of prodrugs include, but are not limited to, acetate, formate, benzoate or other acylated derivatives of alcohol or amidofunctional groups of compounds according to the invention.

The term “MES” refers to the physical Association of a compound of the present invention with one or more solvent molecules either organic or inorganic. This physical Association often includes hydrogen bond. In certain cases, the MES can be selected, for example, if one or more molecules of the MES is integrated into the crystal lattice of the crystalline body. “MES” includes both a liquid phase and allocated a solvate. Examples of the solvate include, but are not limited to, hydrates, ethanolate and methanolate.

The term “chiral” refers to molecules that do not have a plane of symmetry and, therefore, do not have analogues mirror image. Chiral molecule can exist in two forms: clockwise rotating and such.

The term “stereoisomer” refers to isomers whose atoms are connected in the same order, but have different three-dimensional structure. The terminology is “stereoisomer” includes, for example, enantiomers and diastereoisomers.

The term “CIS-TRANS isomer” refers to stereoisomers that differ in the stereochemistry of the double bond or ring. CIS-TRANS isomers are also called geometric isomers.

The term “enantiomer” refers to stereoisomers of chiral substances, which is mirroring.

The term “diastereoisomer” refers to stereoisomers that are not enantiomers or mirror images of each other.

The term “racemic mixture” refers to a mixture consisting of equal parts of (+) and (-) enantiomers of chiral substances. Even if individual molecules are chiral, racemic mixture is optically inactive.

The term “tautomer” refers to isomers that are vzaimoprevrascheny. For example, enols and ketones are tautomers, as they turn each other in the processing of either acid or base.

The term “positional isomer” refers to any of two or more structural isomers that differ in the position of a particular substituent or group. Functional groups can be attached to structurally inequivalent positions of the carbon skeleton. For example, [1,3]imidazole represented asand [1,4] imidazole represented asare positional isomers.

The term “N-protective group” or “N-protected” refers to the groups capable of protecting the amino group against undesirable reactions. Commonly used N-protective groups are described in Greene and Wuts, Protecting Groups in Chemical Synthesis (3rded., John Wiley & Sons, NY (1999), cited in the present description by reference in full. Non-limiting examples of N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, TRIFLUOROACETYL, trichloroacetyl, phthalyl, o-nitrophenoxyacetic, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, or 4-nitrobenzoyl; sulfonylurea groups, such as benzazolyl or p-toluensulfonyl; sulfanilimide groups, such as phenylsulfinyl (phenyl-S-) or triphenylmethylchloride (trityl-S-); sulfinyl groups such as p-methylphenylsulfonyl (p-were-S(O)-) or tert-butylsulfonyl (t-Bu-S(O)-); carbamate-forming group, such as benzyloxycarbonyl, p-chlorobenzenesulfonyl, p-methoxybenzenesulfonyl, p-nitrobenzyloxy, 2-nitrobenzenesulfonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxyphenylacetone, 3,5-dimethoxybenzoquinone, 2,4-dimethoxybenzoquinone, 4-methoxybenzenesulfonyl, 2-nitro-4,5-dimethoxybenzonitrile, 3,4,5-trimethoxybenzylamine, 1-(p-biphenylyl)-1-methylethanolamine, dimethyl-3,5-dimethoxy unselectable, benzylaminocarbonyl, tert-butyloxycarbonyl, diisopropylperoxydicarbonate, isopropoxycarbonyl, etoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichlorocyanuric, phenoxycarbonyl, 4-nitrophenoxyacetic, fluorenyl-9-methoxycarbonyl, cyclopentanecarbonyl, adamantanecarbonyl, cyclohexyloxycarbonyl, or phenylthiocarbamyl; alkyl groups such as benzyl, p-methoxybenzyl, triphenylmethyl, or benzoyloxymethyl; p-methoxyphenyl; and silyl groups such as trimethylsilyl. Preferred N-protective groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, tert-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).

Under "General methods of synthesis examples were used the following abbreviations:

AcOH=acetic acid

ATM.=atmosphere

Boc=N-tert-butoxycarbonyl (protective group)

CDI=1,1'-carbonyldiimidazole

CH2Cl2=methylene chloride (dichloromethane)

CuI=iodide copper [copper iodide(I)]

DCE=1,2-dichloroethane

DEAD=diethylazodicarboxylate

DMA=N, N-dimethylacetamide

DMAP=4-dimethylaminopyridine

DMF=N,N-dimethylformamide

DMSO=dimethyl sulfoxide

EDCI=hydrochloride (N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide

EMME=diethyl ether 2-ethoxymethylenemalonic acid

Et3N=triethylamine

Ether=diethyl ether

EtI=this is the iodide

EtOAc=ethyl acetate

EtOH=ethanol

Fe=iron

Fe(AcAc)3=iron (III)-acetylacetonate

Chloride Fmoc=9-fluorenylmethoxycarbonyl

HOBt=N-hydroxybenzotriazole

the basis Hunga=N,N-diisopropylethylamine

IPA=isopropyl alcohol

K2CO3=potassium carbonate

KOH=potassium hydroxide

LDA=liedeseplein

MeOH=methanol

MsCl=chloride methanesulfonyl

NaH=sodium hydride

NH2OH·HCl=hydroxylamine hydrochloride

NMP=1-methyl-2-pyrrolidinone

Mg2SO4=magnesium sulfate

Na2SO4=sodium sulfate

NH3=ammonium

NH4Cl=chloride ammonium

NH4OH=hydroxide ammonium

PG=protective group such as Boc or Troc-

POCl3=oxychloride phosphorus

R-MgCl=Grignard reagent

R-I=alkylated or substituted alkylated

SnCl2=chloride divalent tin (tin chloride (II))

TFU=triperoxonane acid

THF(THF=tetrahydrofuran

TLC=thin layer chromatography

triflate anhydride = anhydride triftormetilfullerenov acid

Troc=2,2,2-trichlorocyanuric-(protective group)

General methods of synthesis and examples

The following methods of synthesis and diagrams illustrate the most common methods, which can be obtained the compounds of the present invention. Original products can be obtained from commercial sources or obtained by methods well what about the well-known specialist in this field. As an example, you can use the way of synthesis, similar to the ways shown below, together with the methods of synthesis known in the field of synthesis of organic compounds, or their variants, obvious to a person skilled in this field.

In the present invention refers to compounds obtained by any method of synthesis or metabolic process. Metabolic processes include processes occurring in the body of a person or animal (in vivo), or the processesin vitro.

If described herein Deputy is not suitable for use in the synthesis method of the present invention, the Deputy may be protected by a suitable protective group that is stable to the reaction conditions used in these ways. The protective group can be removed at the appropriate point in the sequence of reactions to obtain the desired intermediate product or the target compounds. Suitable protective groups and methods of introducing or removing the protective substituents well known in this field, examples of which are listed in the document, Greene and Wuts,above.

The formation of compounds of formulas I-VIII

The compounds of formula I can be synthesized by interaction

where W1, W2, A, B, X, Y, R10, R and R50have the same meaning as described in the above embodiments, implementation or examples, and K represents Cl or other halogen. Similarly, compounds of formulas II-VIII may be obtained by interaction,,,,or,,,,,or

respectively.

The synthesis of compounds of formulas I-VIII are given as examples in schemes 1-8. Typical compounds of formula I, where

represents a

R10, R17and R35such as defined above, and Z represents NR41can be obtained using the procedure presented in figure 1.

Scheme 1

Amines of formula (2), in which R41represents hydrogen, can be treated by the compounds N,N-dimethylformamidine formula (1) in the presence of acid, such as, but not limited to, acetic acid, at elevated temperature (e.g. from about 80º C d is about about 150ºc), thus, giving the compounds of formula (3). Acetic acid can act as a solvent. Other suitable solvents may also be used in this reaction.

N-alkylation of compounds of formula (2), in which R41represents hydrogen, gives compound of formula (2) or (3)in which R41represents alkyl. This method can be accelerated by using an alkylating agent of formula R41X1where X1represents halogen, tosylate, triflate or mesilate, in the presence of a base such as, but not limited to, an organic base such as triethylamine or Diisopropylamine, or inorganic base such as sodium carbonate, cesium or potassium hydroxide, in a suitable solvent and at a temperature in the range from about room temperature up to approximately 100°C.

Scheme 2

The connection is obtained N,N-dimethylformamidine formula (1) can be carried out by the method presented in scheme 2. Ketones of the formula (4) and esters of the formula (5) in the presence of a base such as, but not limited to, the hydrate of sodium or potassium (or metallic sodium) at about 0°C in a suitable solvent, such as, but not limited to, diethyl ether, gave the salt of the formula (6), where M is potassium or sodium. The connection is ormula (6) was treated with 2-cyanoacetamide in the presence of piperidineacetate by boiling under reflux with getting the NITRILES of the formula (7a) and (7b). The regioisomers (7a) and (7b) can be separated at this time or later in the path of synthesis, using methods of purification known to the person skilled in the art. The compounds of formula (7a) can be either converted into compounds of the formula (8), in which X2represents Cl, by treatment with phosphorus oxychloride or the compounds of formula (8), in which X2represents Br, by treatment with tetrabutylammonium bromide and phosphorus pentoxide in a suitable solvent at reflux. A solution of compounds of the formula (8), where X2represents Cl or Br, and liquid ammonia interacted in a sealed vessel at high pressure at elevated temperature, for example at about 130°C, to obtain the compounds of formula (9). The compounds of formula (9) and N,N-dimethylformamide, dimethylacetal in a solvent such as, but not limited to, toluene, at reflux gave the compound N,N-dimethylformamidine formula (1).

Scheme 3

The compounds of formula (2), in which R41represents hydrogen and X represents O or S, can be obtained from compounds of the formula (10) in accordance with scheme 3, where R101represents a removable group, such as, but not limited to, halogen, triflate or mesyl is t (the last two can be obtained from the corresponding alcohol, using methods known to the person skilled in the art)by two-stage synthesis, namely by nitrogroup reduction with subsequent substitution of R101or substitution of R101subsequent reduction of the nitro group.

The substitution of R101the group R22XH, where X represents O or S, can be accelerated in the presence of a suitable base, such as, but not limited to, carbonate or bicarbonate of potassium, cesium or sodium, or sodium hydride or potassium and, optionally, in the presence of 18-crown-6, at elevated temperature. The reaction can be usually carried out in a solvent such as, but not limited to, N,N-dimethylformamide or dimethylsulfoxide, at a temperature from about room temperature up to about 180°C. the Interaction can be carried out in a solvent such as, but not limited to, N,N-dimethylformamide or dimethylsulfoxide, at a temperature from about room temperature up to about 180°C. the Reaction can also be carried out in a microwave oven. It is clear that the compounds of formula (11) can also be obtained by the reaction of compounds of the formula (10), where R101represents a ─X─H, with compounds of formula R22X3where X3represents a removable group, such as, but not limited to, halogen, triflate or mesilate, using the above reaction conditions. Zam is well reactionary groups can also be carried out in the presence of a metal catalyst, such as, but not limited to, metallic copper, CuI or palladium acetate, optionally in the presence of a ligand such as, but not limited to, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl or three-tert-butylphosphine and, optionally, in the presence of a base such as, but not limited to, pyridine, triethylamine, tert-piperonyl sodium, cesium carbonate or sodium hydride. The reaction is usually carried out at a temperature from about room temperature up to about 180°C, in a solvent such as, but not limited to, toluene or N,N-dimethylformamide.

The restoration of the nitro group can be accomplished by treatment of nitro compounds by condensing agent such as, but not limited to, iron powder/ammonium chloride or tin chloride (II), in a suitable solvent.

It is also understood that the compounds of the formula (10) can be converted into compounds of the formula (2) first, the restoration of functional nitro group, and then by substitution of functional groups using reaction conditions described above.

Getting AMINOPHENYL-condensing agents (10, 11 and 12)

It is possible to use a large variety of AMINOPHENYL-condensing agents. The agents in figure 3 are examples of this diversity.

When usual obtain the compound substituted 2-chloronitrobenzene in dimethylformamide (DMF) was treated with thiophenolate intothree is at about 50°C for about 2 hours, cooled and diluted with methylene chloride, washed with water, dried over sodium sulfate, filtered and concentrated under vacuum to obtain compound substituted-2-phenylsulfonylacetate. This compound is nitrobenzene was then restored with ferrous chloride tin (SnCl2) or iron (Fe) in ethanol. The pH value of the reaction mixture was brought to 12 with 1N sodium hydroxide, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under vacuum to obtain compound substituted-2-phenylsulfonylacetate10.

Similarly the corresponding compound substituted-2-hydroxyitraconazole was dissolved in dimethylformamide was subjected to reaction with a solution of peroxide sodium was stirred and heated to 100°C for about 5 days. The reaction mixture was cooled and was diluted with methylene chloride, washed with water, dried over sodium sulfate, filtered and concentrated under vacuum to obtain compound substituted-2-Phenoxyethanol. This compound is nitrobenzene was then restored chloride divalent tin (SnCl2) and iron (Fe) in ethanol. The pH value of the reaction mixture was brought to 12 with 1N sodium hydroxide, extracted with ethyl acetate, dried over sodium sulfate, filtered and concentrated under vacuum to receive the receiving compounds substituted-2-proximamente 12.

Similarly, any connection10in which R9represents a hydroxy or protected hydroxyl may be further modified by alkylation of the hydroxy-group, using substituted benzylbromide, to obtain the corresponding compounds of 5-substituted-phenoxy-2-substituted-phenylsulfonylacetate11.

Scheme 4

R9defined above;

X is a HE, NH2, Other, halogen, alkyl or alkoxy;

R represents alkyl, alkoxy, bromine, fluorine, chlorine or cyano.

Obtaining compounds of 7-substituted-4-AMINOPHENYL-substituted-pyrido[2,3-d]pyrimidine

Characteristic obtaining the compounds 7-substituted-4-AMINOPHENYL-substituted-pyrido[2,3-d]pyrimidine (scheme 6) involves the condensation of a substituted aminophenylalanine agent (as described in scheme 4) and connect the 6-substituted-2-amidino-3-cyanopyridine9(scheme 5).

As described in figure 4, it is possible to use a large variety aminophenylarsonic agents.

Getting 7-substituted-4-AMINOPHENYL-substituted-pyrido[2,3-d]pyrimidines can be carried out by the condensation of a compound of N,N-dimethylformamidine9with various condensing agents described in scheme 4.

Obtaining compounds N,N-dimethylformamidine924. Connection24can be either converted to 2-chloropyridin using phosphorus oxychloride (as shown in figure 5), or 2-bromopyridin. 2-Bromopyridin received, the processing solution of toluene connection24and exposing its interaction with tetrabutylammonium bromide and phosphorus pentoxide by heating under reflux for about 5 hours. The reaction mixture was cooled, added water and the mixture was stirred for about the olo 2 hours at room temperature. The reaction mixture was diluted with toluene, the organic layer was separated, washed with saturated saline and dried over magnesium sulfate, filtered and concentrated under vacuum to obtain 2-bromopyridine. Ethanolic solution of either 2-chloropyridine or 2-bromopyridine and liquid ammonia interacted in a sealed vessel under high pressure at about 130°C for about 20 hours. The reaction mixture was concentrated under vacuum, and the residue was washed with water and dried to obtain 6-substituted-2-amino-nicotinanilide25. Connection25and N,N-dimethylformamide acetal was dissolved in toluene and heated under reflux for about 3 hours. The resulting solution was cooled to room temperature and concentrated under vacuum to obtain a 6-substituted-3-cyano-2-yl-N,N-dimethylformamidine9.

Scheme 5

R7selected from the group consisting of hydrogen, alkyl, halogenoalkane, alkoxy, cycloalkyl, alkoxycarbonylmethyl, alkoxycarbonylmethyl, cyanoacetylurea, cyanoalanine, hydroxyalkyl, morpholino, hydrazino, acylaminoalkyl, alkoxyalkyl and aryl.

As described above, obtaining 7-substituted-4-AMINOPHENYL-substituted-pyrido[2,3-d]pyrimidines can be performed with or substituted 6-C is displaced-3-cyanopyridine-2-yl-N,N-dimethylformamidine 9as shown in scheme 5, with various condensing agents, some of which is presented in scheme 4. This condensation reaction is presented in scheme 6.

When usual obtain the connection9and AMINOPHENYL-condensing agent, similar to the agents presented in figure 4, was dissolved in acetic acid and stirred at 130°C for about 15 minutes. The mixture was cooled to room temperature, acetic acid was removed under vacuum and the resulting residue was purified by chromatography with reversed phase. At this time, can be removed any functional protective group such as Boc, Troc, or other group, any known method of obtaining the final products.

Scheme 6

R7, R9X and R are defined above

Typical compounds of formula I where ring B

represents a five-membered ring heterocycle, and W1represents CH, R10, R17and R35as defined above, and Z represents NR41can be obtained using the procedure presented in figure 7, and obtaining them is in the interaction alkylenediamine heterocycles, such as13,acid, Meldrum and triethylorthoformate and heating to approximately 100°C. the Reaction mixture was concentrated which was purified by chromatography to obtain the ether aminomethylenemalonate acid 14. Connection14then was dissolved in diphenyl ether and the resulting solution was heated up to 250°C for about 30 minutes with obtaining15. A mixture of compound15mixed with phosphorus oxychloride (POCl3) and was heated to about 50°C under stirring for 6 hours, cooled and extinguished, pouring out onto the ice. The mixture was then cooled, bringing the pH to 10 with concentrated ammonium hydroxide and was extracted with methylene chloride, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain16. When the characteristic obtaining the connection16and aminotadalafil condensing agent, similar to the agents described in figure 4, are condensed with 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane Tris(dibenzylideneacetone)dipalladium and tert-piperonyl sodium in a solvent, typically toluene, and the like, to obtain the21.

Scheme 7

Typical compounds of formula I where ring B

represents a five-membered ring heterocycle, and W1represents N, R10, R17and R35as defined above, and Z represents NR41can be obtained using the procedure presented in figure 8, and obtaining them is in the interaction alkylaminocarbonyl the heterocycles, such as17,with formamide at reflux. Pyrimidine product18then interacted with phosphorus oxychloride (POCl3with getting condensing partner19. When the characteristic connection19and AMINOPHENYL condensing agent, similar to the agents described in scheme 4, was dissolved in ethanol and heated under reflux for 12 hours to obtain20.

Scheme 8

Typical compounds of formula I where ring B

represents a five-membered ring heterocycle, and W1 represents N or CH, R10, R17 and R35, such as described above, and Z represents NR41, can be obtained

Optimal reaction conditions and the reaction time of each stage can vary depending on the specific reagents and substituents present in the used reagents. Unless otherwise stated, solvents, temperatures and other reaction conditions can be readily selected by the person skilled in the art. The reaction can be carried out by conventional means, for example by removing the solvent from the precipitate and additional cleaning techniques commonly used in this field, such as, but not limited to, crystallization, distillation, extraction, RA is Tirana and chromatography.

It should be noted that the above embodiments of and circuits, and the following examples are given only as examples and are not limiting. Various changes and modifications without leaving the scope of the present invention, will be apparent to the person skilled in the art based on the present description.

Example 1

4-Amino-N-[2-(4-hydroxyphenylethyl)-5-were]-2-(2-methoxyethylamine)pyrimidine-5-carboxamide

The product from example 156 (42 mg, 0.1 mmol) in 2-methoxyethylamine (1 ml) was heated at 180ºC for 2 hours in a microwave oven. The solvent was evaporated and the residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (15 mg, 28%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 2,31 (c, 3H), 3,28 (c, 3H), 3,49 (m, 4H), 6,86 (m, 3H), 7,28 (m, 4H), 8,17 (c, user., 3H), 8,73 (c, user., 1H), 9,75 (c, user., 2H), 11,33 (c, user., 1H);

MS (ESI+) m/z 425 (M+H)+.

Example 2

4-Amino-2-butylamino-N-[2-(4-hydroxyphenylethyl)-5-were]pyrimidine-5-carboxamide

The product from example 156 (42 mg, 0.1 mmol) in butylamine (1 ml) was heated at 180ºC for 2 hours in a microwave oven. The solvent was evaporated and the residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (13 mg, 24%).

1H NMR (300 MHz, DMSO-d6) δ ppm: of 0.90 (t, J=7,35 G is, 3H), of 1.29 (m, 2H)and 1.51 (m, 2H), 2,30 (c, 3H), of 3.32 (m, 2H), 6,85 (m, 3H), 7,27 (m, 4H), 8,15 (c, user., 3H), 8,71 (c, user., 1H), of 9.55 (c, user., 1H), 9,92 (c, user., 1H), 11,23 (c, user., 1H);

MS (ESI+) m/z 423 (M+H)+.

Example 3

N-{4-[4-Methyl-2-(6-propertiee[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenyl}ndimethylacetamide

Example 3a

Ethyl 2-amino-5-propylthiophene-3-carboxylate

A solution of equimolar amounts of ethylcyanoacrylate and sulfur in dimethylformamide at ambient temperature was treated with triethylamine (0.5 equivalent), followed by heating to 50°C was added dropwise valeric aldehyde (1 equivalent). After 3 hours the reaction extinguished with water and was extracted with ethyl acetate. The organic layer was concentrated to obtain specified in the connection header.

Example 3b

6-Propertiee[2,3-d]pyrimidine-4-ol

The product from example 3a were subjected to interaction with excessive amounts of formamide by heating under reflux for 3 hours. The reaction mixture was extinguished with water and the precipitate was collected by filtration and washed with water and dried under vacuum to obtain specified in the connection header.

Example 3c

4-Chloro-6-propertiee[2,3-d]pyrimidine

The product of example 3b was subjected to interaction with excess POCl3when heated under reflux for 3 hours, then at room temperature for 16 hours, the Reaction mixture was poured into ice and distributed between water and ethyl acetate. The organic layer was concentrated to obtain specified in the connection header.

Example 3d

N-{4-[4-Methyl-2-(6-propertiee[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenyl}ndimethylacetamide

The product of example 3c was subjected to interaction with the product of example 7b in ethanol under reflux for 16 hours. The reaction mixture was concentrated to obtain specified in the connection header.

Example 4

(6-Butyltin[2,3-d]pyrimidine-4-yl)-(5-methyl-2-phenylsulfanyl)Amin

Specified in the title compound was obtained in accordance with the methods described in example 3, using hexanal instead of valeric aldehyde in example 3a.

Example 5

(5-Methyl-2-phenylsulfanyl)-(2-propitiatio[5,4-b]pyridin-7-yl)Amin

Example 5A

Methyl ether butyryloxy acid

A suspension of glycine hydrochloride (1,00 g 7,964 mmol) in methylene chloride (40 ml), cooled to 0 ° C in an atmosphere of nitrogen, was treated with triethylamine (of 4.44 ml, 31,86 mmol) and butyryl chloride (0,93 ml, 8,76 mmol)and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution (50 ml), water (50 ml) and saturated salt solution. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to item is the receiving specified in the connection header. Purification with flash chromatography on silica gel with a mixture of 25% ethyl acetate/methylene chloride gave specified in the title compound as a colourless oil (0,776 g, 4,88 mmol, 61%).

Example 5B

Methyl ether dibutylaminoethanol acid

A solution of the product of example 5A (0,774 g 4,862 mmol) in anhydrous THF(TGF) (50 ml) was treated with reagent Lawesson (1,338 g to 3.209 mmol), then heated under reflux in nitrogen atmosphere for 30 minutes. The reaction mixture was cooled to 0oC and slowly added dropwise a saturated aqueous solution of sodium bicarbonate (40 ml). The mixture was stirred at room temperature for 15 minutes and then was extracted with ethyl acetate (100 ml) and the organic extract was washed with saturated aqueous sodium bicarbonate solution (50 ml), water (2×25 ml) and saturated salt solution. Dried the organic phase over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain specified in the connection header. Purification with flash chromatography on silica gel with a mixture of 1% ethyl acetate/methylene chloride gave specified in the title compound as a colourless oil (0,790 g 4,508 mmol, 93%).

Example 5C

2-Dibutylaminoethanol

A solution of the product of example 5B (0,788 g 4,496 mmol) in methanol (30 ml) was saturated with gaseous ammonia and the reaction mixture was stirred in a closed trial is th vessel at room temperature for 17 hours. The solvent was concentrated under vacuum to obtain specified in the connection header and the solid was purified flash chromatography on silica gel with a mixture of 10% methanol/methylene chloride to obtain specified in the connection header in the form of solids, white (500 mg, of 3.12 mmol, 69%).

Example 5D

2-Propertiesa-5-ylamine

A solution of the product of example 5C (395 mg, 2,465 mmol) in anhydrous ethyl acetate (12 ml) was treated with tribromide phosphorus (0,189 ml, 1,972 mmol) under nitrogen atmosphere and stirred at room temperature for 20 minutes. Additionally added tribromide phosphorus (0,050 ml) and left to mix for 5 minutes. The reaction mixture was diluted with ethyl acetate (50 ml) and washed with saturated aqueous sodium bicarbonate (25 ml). The aqueous washing was extracted with ethyl acetate (2×50 ml) and the organic extracts were combined and washed with saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to obtain specified in the connection header. Purification with flash chromatography on silica gel with a mixture of 3% methanol/methylene gave specified in the header of the product (175 mg, of 1.23 mmol, 50%).

Example 5E

2,2-Dimethyl-5-[(2-propertiesa-5-ylamino)methylene]-[1,3]dioxane-4,6-dione

A solution of the product of example 5D (212,7 mg, 1,496 mmol) in anhydrous ethanol (5 ml) processing ivali acid Meldrum (237 mg, 1,645 mmol) and triethylorthoformate (0.25 ml, 1,496 mmol) at room temperature and the reaction mixture was heated in a preheated 100 ° C oil bath. After 15 minutes the reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator under vacuum. Purification with flash chromatography on silica gel with a gradient mixture of 10%-20% ethyl acetate/methylene chloride gave specified in the title compound in the form of solid yellow-white color (240 mg, 0,8099 mmol, 54%).

Example 5F

2-Propyl-4H-thiazolo[5,4-b]pyridine-7-he

In heated under reflux diphenyl ether (5 ml) under nitrogen atmosphere was added the product of example 5E (230 mg, 0,7781 mmol). After heating under reflux for 5 minutes the solution was cooled in an ice bath and diluted with hexane (50 ml). The obtained solid Golden color was collected by vacuum filtration and thoroughly washed with hexane to obtain specified in the title compound (125 mg, 0,644 mmol, 83%).

Example 5G

7-Chloro-2-propitiatio[5,4-b]pyridine

The product of example 5F (123 mg, 0,6332 mmol) and phosphorus oxychloride (2 ml) was heated under reflux for 1 hour in nitrogen atmosphere. The solution was cooled in an ice bath, was treated with ice and the pH was brought to 7 with 6N. an aqueous solution of sodium hydroxide. Were extracted with methylenchlorid is ω (3×50 ml) and the combined organic extracts were dried over anhydrous sodium sulfate, was filtered and concentrated under vacuum to obtain specified in the title compound as brown oil (120 mg, 0,564 mmol, 89%).

Example 5H

4-Methyl-2-nitro-1-phenylsulfanyl

The solution thiophenolate sodium (3,96 g, 30 mmol) in 60 ml of DMF was heated at 50ºC with 4-chloro-3-nitrotoluene (2.65 ml, 20 mmol) under stirring for 2 days. Was cooled to room temperature and was diluted in CH2Cl2. Washed with water and the organic layer was dried over Na2SO4. Was filtered and concentrated under vacuum to obtain specified in the connection header (4,29 g, 87%).

1H NMR (300 MHz, CDCl3) δ ppm: 2,36 (c, 3H), 6,76 (d, J=8,09 Hz, 1H), 7,16 (d, J=8,46 Hz, 1H), 7,45 (m, 3H), 7,58 (m, 2H), 8,03 (c, 1H).

Example 5I

5-Methyl-2-phenolsulfonephthalein

A solution of the product from example 5H (1,17 g, 7.0 mmol) in 25 ml of absolute EtOH and SnCl2(3.58 g, to 29.8 mmol) was stirred at room temperature for 16 hours. With the help of 1H. NaOH pH is brought to 12 and was extracted with EtOAc. Dried over Na2SO4, filtered and concentrated under vacuum to obtain specified in the title compound (835 mg, 82%).

1H NMR (300 MHz, CDCl3) δ ppm: 2,30 (2, 3H), 6,62 (d, J=8,83 Hz, 1H), 6,69 (c, 1H), 7,10 (m, 3H), 7,21 (m, 2H), 7,54 (d, J=7,72 Hz, 2H).

Example 5J

(5-Methyl-2-phenylsulfanyl)-(2-propitiatio[5,4-b]pyridin-7-yl)Amin

In purged with dry nitrogen, the vessel is loaded and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane (38 mg, 0,111 mmol), Tris(dibenzylideneacetone)dipalladium (25,4 mg, 0,0277 mmol) and tert-piperonyl sodium (and 82.4 mg, 0,8322 mmol). Using the pipette solution was added the product of example 5G (118 mg, 0,5548 mmol) in anhydrous toluene (2 ml) and a solution of the product from example 5I (107,5 mg, 0,4993 mmol) in toluene (3 ml). The reaction mixture was heated under reflux on a pre-heated up to 120oWith an oil bath for 18 hours, cooled to room temperature, treated with additional quantity of Tris(dibenzylideneacetone)diplegia (25,4 mg) and heated under reflux for a further 2.5 hours. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator under vacuum. Purification with flash chromatography on silica gel with a gradient mixture of 1-3% ethyl acetate/methylene chloride gave specified in the title compound (29 mg, 0,074 mmol, 15%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1.00 and (t,J=to 7.35 Hz, 3H), 1,71-1,90 (m, 2H), 2,38 (c, 3H), 3,05 (t,J=7,35 Hz, 2H), 6.87 in (q,J=5,52 Hz, 1H), 7,07 (DD,J=to $ 7.91, 1,29 Hz, 1H), 7,12-7,31 (m, 5H), 7,37-7,46 (m, 2H), 8,15 (l,J=5,52 Hz, 1H), charged 8.52 (c, 1H);

MS (DCI/NH3) m/z 392 (M+H)+.

Example 6

4-[4-Methyl-2-(2-propitiatio[5,4-b]pyridine-7-ylamino)phenylsulfonyl]phenol

Example 6a

4-Methyl-2-nitrophenyloctyl ether triftormetilfullerenov acid

A solution of 4-methyl-2-NITROPHENOL (6.0 g, 39,1 mmol) and Et3N (16,38 ml, 117,5 mmol) in 100 ml of CH 2Cl2in an atmosphere of N2processed triftormetilfullerenov anhydride (7,25 ml, to 43.1 mmol) at 0ºC for 30 minutes. Extinguished by the addition of MeOH. Sequentially washed with 10% citric acid, 0.5 M KOH and water. Dried over MgSO4, filtered and concentrated under vacuum to obtain specified in the title compound, which was purified by chromatography on a column of silica gel, elwira CH2Cl2, getting yellow oil (11,22 g, 100%).

Example 6b

4-(4-Methyl-2-nitrophenyloctyl)phenol

The product from example 6a (11,22 g, or 39.3 mmol) and 4-mercaptoethanol (4,96 g, or 39.3 mmol) in 100 ml EtOH was treated with Na2CO3and heated overnight under reflux. Was cooled to room temperature and extinguished with water. Was Extracted With EtOAc. Dried over MgSO4, filtered and concentrated under vacuum to obtain specified in the title compound, which was purified by chromatography on a column of silica gel, elwira a mixture of 25% EtOAc/hexane, obtaining oil red (8.65 g, 85%).

Example 6c

4-(2-Amino-4-methylphenylsulfonyl)phenol

The product from example 6b (8.65 g, 31,3 mmol) was restored using SnCl2in accordance with the method described in example 5I, obtaining specified in the connection header in the form of a solid white color (8,51 g, 100%).

Example 6d

4-(4-methyl-2-(2-what ropelato[5,4-b]pyridine-7-ylamino)phenylthio)phenol

In purged with dry nitrogen, the vessel was loaded 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane (40,4 mg, the amount of 0.118 mmol), Tris(dibenzylideneacetone)dipalladium (27 mg, 0,0295 mmol) and tert-piperonyl sodium (87,7 mg, 0,885 mmol). Using the pipette solution was added the product of example 5G (output reached 125.5 mg, 0,590 mmol) in anhydrous toluene (5 ml), then the product from example 6c (136 mg, 0,590 mmol). The reaction mixture was heated under reflux on a pre-heated up to 110 º C oil bath for 14 hours, cooled to room temperature, and treated with additional 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane (40,4 mg) and Tris(dibenzylideneacetone)dipalladium (27 mg) and heated under reflux for a further 7 hours. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator under vacuum. Purification with flash chromatography on silica gel with a gradient mixture of 15-30% ethyl acetate/methylene chloride gave the crude substance. Purification with flash chromatography on silica gel with a gradient mixture of 1-2% methanol/methylene chloride gave the desired specified in the title compound as a pale yellow solid (20 mg, 0,049 mmol, 8%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,03 (t,J=to 7.35 Hz, 3H), 1,76-of 1.94 (m, 2H), 2,31 (c, 3H), 3,10 (t,J=7,35 Hz, 2H), 5,76 (c, 1H), 6,67-of 6.73 (m, 2H), of 6.96? 7.04 baby mortality (m, 1H), 7,08-7,14 (m, 1H), 7,20 (m,J=8,46 Hz, 2H), 7,29 (c, 1H), 8,14 (l,J=5,52 Hz, 1H, 8,55 (c, 1H), 9,73 (c, 1H);

MS (DCI/NH3) m/z 408 (M+H)+.

Example 7

N-{4-[4-Methyl-2-(2-propitiatio[5,4-b]pyridine-7-ylamino)phenylsulfonyl]phenyl}ndimethylacetamide

Example 7a

N-[4-(4-Methyl-2-nitrophenyloctyl)phenyl]ndimethylacetamide

The product from example 6a (1 g, 3,51 mmol) was subjected to interaction with N-(4-mercaptophenyl)ndimethylacetamide (0.65 g, 351 mmol) for 18 hours in accordance with the method described in example 6b, obtaining specified in the title compound (1.04 g, 98%).

Example 7b

N-[4-(2-Amino-4-methylphenylsulfonyl)phenyl]ndimethylacetamide

The product from example 7a (0,30 g, 1 mmol) was subjected to interaction with SnCl2as described in example 5I, obtaining specified in the title compound (0.27 g, 100%) as a yellow oil, which was used without further purification.

Example 7c

N-(4-(4-methyl-2-(2-propitiatio[5,4-b]pyridine-7-ylamino)phenylthio)phenyl)ndimethylacetamide

In purged with dry nitrogen, the vessel was loaded 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane (38,6 mg, 0,1128 mmol), Tris(dibenzylideneacetone)dipalladium (from 25.8 mg, 0,0282 mmol) and tert-piperonyl sodium (83,8 mg, 0,8463 mmol). Using the pipette solution was added the product of example 5G (120 mg, 0,5642 mmol) in anhydrous toluene (5 ml), then the product from example 7b (130 mg, 0,4773 mmol). The reaction mixture was heated in a pre-heated to 100ºC oil bath for 2.5 hours, Oh what was Adali to room temperature, additionally processed 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane (38,6 mg), Tris(dibenzylideneacetone)dipalladium (from 25.8 mg) and the original aniline (130 mg) and heated at 100ºC for another 18 hours. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator under vacuum. Purification with flash chromatography on silica gel with a gradient mixture of from 40 to 60% ethyl acetate/methylene chloride gave the desired specified in the title compound as brown foam (26 mg, 10%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 1,01 (t,J=to 7.35 Hz, 3H), 1,73 is 1.91 (m, 2H), 2,01 (c, 3H), 2,34 (c, 3H), of 3.07 (t,J=rate of 7.54 Hz, 2H), 6,78 (l,J=5,52 Hz, 1H), 6,97-to 7.09 (m, 1H), 7,16-7,30 (m, 3H), of 7.36 (c, 1H), 7,51 (l,J=8,82 Hz, 2H), 8,15 (l,J=5,52 Hz, 1H), 8,53 (c, 1H), 9,99 (c, 1H);

MS (DCI/NH3) m/z 449 (M+H)+.

Example 8

N-{4-[4-Methyl-2-(2-methyl-2H-pyrazolo[3,4-b]pyridine-4-ylamino)phenylsulfonyl]phenyl}ndimethylacetamide

Example 8a

2,2-Dimethyl-5-[(1-methyl-1H-pyrazole-3-ylamino)methylene]-[1,3]dioxane-4,6-dione

A mixture of 1-methyl-1H-pyrazole-3-ylamine (1,05 g to 10.8 mmol), 2,2-dimethyl-[1,3]dioxane-4,6-dione (1,71 g, to 11.9 mmol) and triethylorthoformate (1,60 g to 10.8 mmol)in 25-ml vessel with a round bottom was heated on an oil bath at 100ºC for 15 minutes. The mixture was cooled to room temperature and was added EtOH (10 ml). The reaction mixture was heated to dissolve all solids and then again about what was ladli to room temperature. The formed solid was isolated by filtration, washed with ethanol and dried to obtain specified in the connection header (1,81 g, 66% yield).

Example 8b

2-Methyl-2,7-dihydropyrazolo[3,4-b]pyridine-4-one

A mixture of the product of example 8a (1.50 g, 5,97 mmol) and diphenyl ether (25 ml) was heated under reflux for 1 hour, removing the obtained acetone by distillation. Then the solvent decantation and the remaining solid residue was dissolved in dichloromethane (5 ml) and was purified by chromatography on silica gel, elwira gradient 0-10% MeOH/CH2Cl2with obtaining specified in the connection header (0,360 g, 40% yield).

Example 8c

4-Chloro-2-methyl-2H-pyrazolo[3,4-b]pyridine

A mixture of the product of example 8b (0,177 g, 1,19 mmol) and phosphorus oxychloride (3 ml) was heated under reflux for 30 minutes and then cooled to room temperature. The reaction mixture was poured on ice, the pH was brought to 8 by adding 1N. an aqueous solution of sodium hydroxide and was extracted with dichloromethane (3×30 ml). The combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure to obtain specified in the connection header (0,170 g, 88% yield).

Example 8d

N-{4-[4-Methyl-2-(2-methyl-2H-pyrazolo[3,4-b]pyridine-4-ylamino)phenylsulfonyl]phenyl}ndimethylacetamide

A mixture of the product of example 8 (47,3 mg, 0,282 mmol), the product of example 7b (84,6 mg, 0,310 mmol), Pd2(dba)3(12.9 mg, 0,0141 mmol), tert-butoxide sodium (67,8 mg, 0,706 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane (19.3 mg, 0,0564 mmol) in toluene (4 ml) was degirolami left at high pressure in a nitrogen atmosphere and was heated under reflux for 2 hours. Added additional amount of Pd2(dba)3(4.0 mg, 0,0044 mmol) and PN3 (4.5 mg, of 0.013 mmol), the reaction mixture was heated under reflux for a further 2 hours. Then the mixture was cooled to room temperature and distributed between ethyl acetate (30 ml) and water (30 ml). The aqueous phase was extracted with ethyl acetate and the combined organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, elwira a mixture of 5% MeOH/CH2Cl2with obtaining specified in the connection header (0,0195 g, 17% yield).

1H NMR (300 MHz, DMSO-d6) δ ppm: 2,03 (c, 3H), 2,29 (c, 3H), 4,11 (c, 3H), 5,97 (l,J=5,15 Hz, 1H), 6,94-7,00 (m, 1H), 7,05 (DD,J=8,09, to 1.47 Hz, 1H), 7,19 (c, 1H), 7,26 (l,J=8,82 Hz, 2H), 7,56 (l,J=8,82 Hz, 2H), 8,09 (l,J=5,15 Hz, 1H), 8,20 (c, 1H), 8,80 (c, 1H), 10,04 (c, 1H);

MS (ESI+) m/z 404,1(M+H)+.

Example 9

4-[4-Methyl-2-(2-methyl-2H-pyrazolo[3,4-b]pyridine-4-ylamino)phenylsulfonyl]phenol

A mixture of the product of example 8c (62,1 mg, 0,371 mmol), the product of the example 6c (85,7 mg, 0,371 mmol), Pd2(dba)3(to 16.9 mg, 0,0185 mmol), tert-piperonyl sodium (89,0 mg, 0,926 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane (25,4 mg, 0,0741 mmol) in toluene (3 ml) was degirolami left at high pressure in a nitrogen atmosphere and was heated under reflux for 2 hours. Added additional amount of Pd2(dba)3(7,0 mg, 0,0076 mmol) and 2,8,9-triisobutyl-2,5,8,9-tetraaza-1-phosphabicyclo[3,3,3]undecane (15 mg, 0,044 mmol), the reaction mixture was heated under reflux for a further 2 hours. Then the mixture was cooled to room temperature and distributed between ethyl acetate (30 ml) and water (30 ml). The aqueous phase was extracted with ethyl acetate and the combined organic phase was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, elwira gradient mixture of 2-5% MeOH/CH2Cl2with obtaining specified in the connection header (0,0279 g, 21% yield).

1H NMR (300 MHz, DMSO-d6) δ ppm: 2,27 (c, 3H), 4,11 (c, 3H), of 5.92 (d,J=5,15 Hz, 1H), 6.75 in-6,85 (m, 3H), 7,02 (DD,J=8,27, to 0.92 Hz, 1H), 7,14 (c, 1H), 7.18 in-7,27 (m, 2H), 8,09 (l,J=5,15 Hz, 1H), 8,20 (c, 1H), 8,77 (c, 1H), 9,82 (c, 1H);

MS (ESI+) m/z 363,0 (M+H)+(ESI-) m/z 360,9 (M-H)-.

Example 10

4-[4-(4-Methoxybenzyloxy)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)Fe is ylsulphonyl]phenol

Example 10A

2-Amino-6-methylnicotinamide

2-Chloro-6-methylnicotinamide (25 g, 0,164 mol) and liquid ammonia (250 ml) in 500 ml of ethanol was subjected to interact in a tightly closed pressure vessel at 130ºC for 20 hours. The reaction mixture was concentrated under vacuum and the residue was washed with water (2×50 ml), then dried in a vacuum oven for 24 hours to obtain specified in the connection header in the form of a solid light-yellow (18 g, 82%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 2,30 (c, 3H), of 6.52 (d,J=7.7 Hz, 1H), 6,78 (c, 2H), 7,73 (l,J=7.7 Hz, 1H).

Example 10B

N'-(3-Cyano-6-methylpyridin-2-yl)-N,N-dimethylformamide

A solution of the product of example 10A (10 g, 75,19 mmol) andN,N-dimethylformamidine (11 ml, 82,71 mmol) in toluene (100 ml) was heated under reflux for 6 hours. After cooling to room temperature the solution was concentrated under vacuum to obtain specified in the connection header in a solid yellow color (13,78 g, 98%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 2,41 (c, 3H), 3,06 (c, 3H), 3,14 (c, 3H), 6.87 in (q,J=7.7 Hz, 1H), 7,89 (l,J=8,1 Hz, 1H), 8,59 (c, 1H).

Example 10C

1-Chloro-4-(4-methoxybenzyloxy)-2-nitrobenzene

A solution of 4-chloro-3-NITROPHENOL (0.5 g, is 2.88 mmol), 1-chloromethyl-4-methoxybenzene (0,496 g, 3,17 mmol), potassium carbonate (1.19 g, 8,64 mmol) and iodide to tetrabutyl one (0.005 g, 0,0135 mmol) inN,N-dimethylformamide (5 ml) was stirred at room temperature for 16 hours. Then to the solution was added ice water (10 ml) and the obtained solid substance was collected by filtration and dried in a vacuum oven to obtain specified in the connection header (0,812 g, 96%).

Example 10D

4-[4-(4-Methoxybenzyloxy)-2-nitrophenyloctyl]phenol

A solution of the product of example 10C (0,812 g, was 2.76 mmol), 4-hydroxythiophenol (0,419, of 3.32 mmol) and cesium carbonate (2.16 g, only 6.64 mmol) inN,N-dimethylformamide (5 ml) was heated to 100ºC for 16 hours. After cooling to room temperature the mixture was poured into ice water (20 ml) and the resulting solution was acidified using 1N aqueous solution of hydrochloric acid. Then the solution was extracted with ethyl acetate (3×10 ml), the combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to obtain specified in the title compound (1.06 g, 100%).

Example 10E

4-[2-Amino-4-(4-methoxybenzyloxy)phenylsulfanyl]phenol

A solution of the product of example 10D (1.06 g, was 2.76 mmol), iron powder (0,63 g, 11,04 mmol) and ammonium chloride (0.18 g, of 3.31 mmol) in a solution of methanol (18 ml), tetrahydrofuran (18 ml) and water (6 ml) was heated under reflux for 3 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a layer of celite. The filtrate was concentrated under Vacu the IOM to volume, equal to 10 ml, the solution was diluted with water (50 ml) and was extracted with ethyl acetate (2×50 ml). The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to obtain specified in the connection header (0,99 g, 100%).

Example 10F

4-[4-(4-Methoxybenzyloxy)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

A solution of the product of example 10B (28.4 mg, 0,151 mmol) and the product of example 10E (53,3 mg, 0,151 mmol) in acetic acid (1 ml) was stirred on an oil bath preheated to 130ºC for 20 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum and the resulting residue triturated in methanol to obtain specified in the title compound as light brown solid (26.5 mg, 35%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 9,92 (c, 1H), 9,63 (c, 1H), to 8.70 (d, J=8,09 Hz, 1H), 8,55 (c, 1H), 7,52 (d, J=8,46 Hz, 1H), 7,38 (d, J=8,82 Hz, 2H), 7,27 (c, 1H), 7,06-to 7.18 (m, 3H), 6,94 (d, J=8,46 Hz, 3H), 6,61-6,72 (m, 2H), 5,02 (c, 2H), 3.75 to (c, 3H), 2,66 (c, 3H);

MS (ESI+) m/z 497,2 (M+H)+ (ESI-) m/z 495,3 (M-H)-.

Example 11

3-[4-(4-Hydroxyphenylethyl)-3-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

Example 11A

3-[3-Amino-4-(4-hydroxyphenylethyl)phenoxymethyl]benzonitrile

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 3-bromomethylbiphenyl using the conditions described in example 10C,with 3-(4-chloro-3-nitrophenoxy)benzonitrile, which is processed sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 11B

3-[4-(4-Hydroxyphenylethyl)-3-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

The product of example 11A were subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 11A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified preparative HPLC with a reversed phase column (Waters Symmetry C8 (25 mm×100 mm, particle size 7 μm)using a gradient mixture of from 10% to 100% acetonitrile/0.1% of triperoxonane acid in water over 8 minutes (10 minutes travel time) at a flow rate of approximately 40 ml/min with obtaining specified in the header connection in the form of salts triperoxonane acid (20 mg, 23%).

1H NMR (300 MHz, DMSO-d6) δ ppm: is 11.39 (c, 1H), 9,70 (c, 1H), 8,89 (d, J=8,46 Hz, 1H), 8,77 (c, 1H), 7,92 (c, 1H), 7,75-7,86 (m, 3H), 7.62mm (t, J=7,72 Hz, 1H), 7.18 in-7,29 (m, 2H), 7.03 is-7,14 (m, 3H), 6,55-6,69 (m, 2H), 5,18 (c, 2H), 2,74 (c, 3H);

MS (ESI+) m/z 492,1 (M+H)+ (ESI-) m/z 490,2 (M-H)-.

Example 12

4-[2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-(pyridine-2-ylethoxy)phenylsulfanyl]phenol

Example 12A

4-[2-Amino-4-(pyridine-2-ylethoxy)phenylsulfanyl]phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 2-bromomethylphenyl hydrobromide salt, the use of the UYa conditions, described in example 10C, obtaining 2-(4-chloro-3-nitrophenoxy)pyridine, which was treated sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 12B

4-[2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-(pyridine-2-ylethoxy)phenylsulfanyl]phenol

The product of example 12A was subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 12A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (15 mg, 17%).

1H NMR (300 MHz, DMSO-D6) δ ppm: was 2.76 (c, 3H), 5,19 (c, 2H), 6,63 (d, J=8,82 Hz, 2H), 6,98-7,17 (m, 3H), 7,20 (d, J=2.57 m Hz, 1H), 7,22-7,30 (m, 1H), 7,38 (DD, J=to 6.43, 4,96 Hz, 1H), 7,53 (d, J=7,72 Hz, 1H), 7,71-7,94 (m, 2H), 8,58 (d, J=Android 4.04 Hz, 1H), 8,82 (c, 1H), 8,93 (d, J=7,72 Hz, 1H), 9,71 (users, 1H), 11,66 (users, 1H);

MS (ESI+) m/z 468(M+H)+.

Example 13

4-[4-(4-tert-Butylbenzyl)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 13A

4-[2-Amino-4-(4-tert-butylbenzoate)phenylsulfanyl]phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 1-methyl bromide-4-tert-butylbenzyl using the conditions described in example 10C, to obtain 4-(4-tert-butylbenzyl)-1-chloro-2-nitrobenzene, which was treated sequentially ways the AMI, described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 13B

4-[4-(4-tert-Butylbenzyl)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 13A was subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 13A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (52 mg, 36%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1.28 (in c, 9H), 2,74 (c, 3H), of 5.06 (c, 2H), 6,63 (l,J=8,46 Hz, 2H), 7,00 for 7.12 (m, 3H), 7,15-7,27 (m, 2H), 7,30-7,47 (m, 5H), 7,79 (l,J=8,46 Hz, 1H), 8,77 (c, 1H), 8,89 (l,J=8,46 Hz, 1H), RS 9.69 (c, 1H);

MS (ESI+) m/z 523 (M+H)+.

Example 14

4-[4-(2-Bromobenzylamine)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 14A

4-[2-Amino-4-(2-bromobenzylamine)phenylsulfanyl]phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 1-bromo-2-bromomethylphenyl using the conditions described in example 10C, to obtain 4-(2-bromobenzylamine)-1-chloro-2-nitrobenzene, which was treated sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 14B

4-[4-(2-Bromobenzylamine)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

About the TPC of example 14A was subjected to interaction with the product of example 10B way described in example 10F, using the product of example 14A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (42 mg, 39%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,68 (c, 3H), 5,13 (c, 2H), 6,67 (m, 2H), of 6.96 (d, J=7.68 per Hz, 1H), 7,14 (m, 3H), 7,30 (m, 2H), 7,44 (m, 1H), to 7.59 (m, 2H), 7,68 (d, J=7.68 per Hz, 1H), 8,59 (c, 1H), 8,73 (d, J=8,09 Hz, 1H), 9,66 (c, 1H), 10,27 (c, 1H);

MS (ESI+) m/z 545, 547 (M+H)+.

Example 15

4-[4-(3-Bromobenzylamine)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 15A

4-[2-Amino-4-(3-bromobenzylamine)phenylsulfanyl]phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 1-bromo-3-bromomethylphenyl using the conditions described in example 10C, to obtain 4-(3-bromobenzylamine)-1-chloro-2-nitrobenzene, which was treated sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 15B

4-[4-(3-Bromobenzylamine)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 15A was subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 15A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified the title compound as a salt triperoxonane acid (25 mg, 23%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,72 (c, 3H), 5,13 (c, 2H), 6,65 (m, 2H), 7,11 (m, 5H), 7,40 (m, 2H), 7,54 (d, J=7,72 Hz, 1H), 7,66 (c, 1H), 7,72 (d, J=8,82 Hz, 1H), 8,71 (c, 1H), 8,84 (d, J=8,09 Hz, 1H), 9,68 (c, 1H), 11,04 (m, 1H);

MS (ESI+) m/z 545, 547 (M+H)+.

Example 16

4-[4-(4-Bromobenzylamine)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 16A

4-[2-Amino-4-(4-bromobenzylamine)phenylsulfanyl]phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 1-bromo-4-bromomethylphenyl using the conditions described in example 10C, to obtain 4-(4-bromobenzylamine)-1-chloro-2-nitrobenzene, which was treated sequentially by the methods described in the examples 10D and 10E with obtaining specified in the header of the product.

Example 16B

4-[4-(4-Bromobenzylamine)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 16A was subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 16A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (19 mg, 17%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,72 (c, 3H), 5,13 (c, 2H), 6,63 (m, 2H), 7,03 (DD, J=8,82, to 2.57 Hz, 1H), 7,10 (m, 2H), 7,21 (d, J=8,46 Hz, 2H), 7,40 (m, 2H), 7,54 (d, J=8,09 Hz, 1H), 7,66 (c, 1H), 7,73 (d, J=8,46 Hz, 1H), 8,72 (c, 1H), 8,84 (d, J=8,46 Hz, 1H), RS 9.69 (c, 1H), 11,08 (m, 1H);

MS (ESI+) m/z 55, 547 (M+H)+.

Example 17

4-[4-(2-Methylbenzylamino)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 17A

4-[2-Amino-4-(2-methylbenzylamino)phenylsulfanyl]phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 1-methyl bromide-2-methylbenzoate using the conditions described in example 10C, to obtain 1-chloro-4-(2-methylbenzylamino)-2-nitrobenzene, which was treated sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 17B

4-[4-(2-Methylbenzylamino)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 17A was subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 17A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (35 mg, 36%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,32 (c, 3H), 2,71 (c, 3H), 5,09 (c, 2H), 6,65 (m, 2H), 7,03 (DD, J=8,82, to 2.57 Hz, 1H), 7,11 (m, 2H), from 7.24 (m, 5H), 7,41 (d, J=6,99 Hz, 1H), 7,69 (d, J=8,46 Hz, 1H), 8,69 (c, 1H), 8,82 (d, J=8,82 Hz, 1H), 9,67 (c, 1H), 10,84 (c, 1H);

MS (ESI+) m/z 481 (M+H)+.

Example 18

4-[4-(3-Methylbenzylamino)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 18A

4-[2-Amino-4-(3-methylbenzylamino)phenylsulfanyl]the dryer is l

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 1-methyl bromide-3-methylbenzoate using the conditions described in example 10C, to obtain 1-chloro-4-(3-methylbenzylamino)-2-nitrobenzene, which was treated sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 18B

4-[4-(3-Methylbenzylamino)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 18A was subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 18A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (37 mg, 39%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,31 (c, 3H), 2,73 (c, 3H), 5,07 (c, 2H), only 6.64 (m, 2H), 7,16 (m, 9H), of 7.75 (d, J=8,46 Hz, 1H), 8,73 (c, 1H), 8,86 (d, J=8,46 Hz, 1H), RS 9.69 (c, 1H), 11,16 (c, 1H);

MS (ESI+) m/z 481 (M+H)+.

Example 19

4-[4-(4-Methylbenzylamino)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 19A

4-[2-Amino-4-(4-methylbenzylamino)phenylsulfanyl]phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 1-methyl bromide-4-methylbenzoate using the conditions described in example 10C, to obtain 1-chloro-4-(4-methylbenzylamino)-2-nitrobenzene, which was treated sequentially with the people, described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 19B

4-[4-(4-Methylbenzylamino)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 19A were subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 19A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (29 mg, 30%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,30 (c, 3H), 2,67 (c, 3H), of 5.05 (c, 2H), only 6.64 (m, 2H), 6,94 (d, J=7,38 Hz, 1H), 7,17 (m, 6H), 7,33 (d, J=8,09 Hz, 2H), 7,56 (d, J=8,46 Hz, 1H), 8,57 (c, 1H), 8,72 (d, J=8,09 Hz, 1H), 9,63 (c, 1H), 10,12 (c, 1H);

MS (ESI+) m/z 481 (M+H)+.

Example 20

2-[4-(4-Hydroxyphenylethyl)-3-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

Example 20A

2-[3-Amino-4-(4-hydroxyphenylethyl)phenoxymethyl]benzonitrile

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 2-bromomethylbiphenyl using the conditions described in example 10C, obtaining 2-(4-chloro-3-nitrophenoxy)benzonitrile that processed sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 20B

2-[4-(4-Hydroxyphenylethyl)-3-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)pheno is simetal]benzonitrile

The product of example 20A was subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 20A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (21 mg, 16%).

1H NMR (300 MHz, DMSO-D6) δ ppm: to 9.93 (c, 1H), 9,63 (c, 1H), up 8.75 (d, J=8,46 Hz, 1H), 8,57 (c, 1H), 7,60 (d, J=8,09 Hz, 1H), 7,38 (d, J=8,46 Hz, 2H), 7,27 (c, 1H), 7,05-7,19 (m, 3H), 6,85-7,00 (m, 3H), to 6.67 (d, J=8,82 Hz, 2H), 5,02 (c, 2H), 3.75 to (c, 3H), 3,14 of 3.28 (m, 1H), 1,32 (d, J=6,62 Hz, 6H);

MS (ESI+) m/z 492,2 (M+H)+ (ESI-) m/z 490,2 (M-H)-.

Example 21

4-[4-(4-Hydroxyphenylethyl)-3-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

Example 21A

4-[3-Amino-4-(4-hydroxyphenylethyl)phenoxymethyl]benzonitrile

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 4-bromomethylbiphenyl using the conditions described in example 10C, to obtain 4-(4-chloro-3-nitrophenoxy)benzonitrile that processed sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 21B

4-[4-(4-Hydroxyphenylethyl)-3-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

The product of example 21A was subjected to interaction with the product of example 10B in the manner described in example 10F, ispolzuemogo example 21A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (15 mg, 14%).

1H NMR (300 MHz, DMSO-D6) δ ppm: of 11.69 (c, 1H), 9,72 (c, 1H), to 8.94 (d, J=8,46 Hz, 1H), 8,83 (c, 1H), 7,78-of 7.96 (m, 3H), 7,63 (d, J=8,46 Hz, 2H), 7,22-7,27 (m, 1H), 7,18 (d, J=2.57 m Hz, 1H), 7,06-7,13 (m, 3H), 6,59-6,66 (m, 2H), 5,23 (c, 2H), was 2.76 (c, 3H);

MS (ESI+) m/z 492,1 (M+H)+ (ESI-) m/z 490,1 (M-H)-.

Example 22

4-[4-[1-(4-Bromophenyl)ethoxy]-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 22A

1-Bromo-4-(1-bromacil)benzene

A solution of 1-(4-bromophenyl)ethanol (4,21 g of 20.9 mmol) in 15 ml of CH2Cl2were subjected to interaction with 15 ml of 1,0M PBr3in CH2Cl2at room temperature for 4 hours. Extinguished, pouring on ice, and the pH was brought to 9 with 5% aqueous NaHCO3. Was extracted with CH2Cl2and dried over Na2SO4, filtered and concentrated under vacuum to obtain specified in the title compound (4.1 g, 75%).

Example 22B

4-[1-(4-Bromophenyl)ethoxy]-1-chloro-2-nitrobenzene

The product from example 22A (995 mg, of 3.77 mmol) was subjected to interaction with 4-chloro-3-NITROPHENOL (650 mg, of 3.77 mmol) in 15 ml DMF with K2CO3(10.4 g, of 3.77 mmol) at 80ºC for 3 hours. Was cooled to room temperature and diluted with water. Was extracted with CH2Cl2, washed with water couple is e times. Dried over Na2SO4, filtered and concentrated under vacuum to obtain specified in the title compound (1.24 g, 92%).

Example 22C

4-{4-[1-(4-Bromophenyl)ethoxy]-2-nitrophenyloctyl}phenol

The product from example 22B (1,15 g, up 3.22 mmol) was subjected to interaction with 4-mercaptophenyl (403 mg, up 3.22 mmol) and K2CO3(890 mg, 6,44 mmol) in 25 ml DMF at 80º C for 18 hours. Was cooled to room temperature and poured into water. Was extracted with CH2Cl2and washed several times with water. Dried over Na2SO4, filtered and concentrated under vacuum to obtain specified in the title compound (980 mg, 68%).

Example 22D

4-[2-Amino-4-(1-phenylethane)phenylsulfanyl]phenol

The product from example 22C (560 mg, 1.25 mmol) was subjected to interaction with Fe (279 mg, 5.0 mmol) and NH4Cl (76 mg, of 1.40 mmol) in 5 ml of MeOH/5 ml THF/2.5 ml of water in accordance with the method described in example 10E, obtaining specified in the title compound as a solid (439 mg, 84%).

Example 22E

4-[4-[1-(4-Bromophenyl)ethoxy]-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 22D (204 mg, 0.49 mmol) was subjected to interaction with the product from example 10B (93 mg, 0.49 mmol) according to method described in example 10F, obtaining crude specified in the title compound, which was purified with the aid of the using HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (38 mg, 12%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 11,24 (users, 1H), to 9.70 (s, 1H), 8,83 (d, J=8,09 Hz, 1H), total of 8.74 (c, 1H), 7,76 (d, J=8,45 Hz, 1H), 7,55 (d, J=8,46 Hz, 2H), 7,37 (d, J=8,46 Hz, 2H), to 7.09 (m, 4H), 6,93 (DD, J=6,62 Hz, J=2.20 Hz, 1H), 6,63 (d, J=8,82 Hz, 2H), 5,51 (sq, J=6.25 Hz, 2H), 2,73 (c, 3H), 1,53 (d, J=6.25 Hz, 3H);

MS (ESI+) m/z 559, 561 (M+H-TFA)+; (ESI-) m/z 557, 559 (M-H-TFA)-.

Example 23

4-[4-[1-(4-Forfinal)ethoxy]-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 23A

4-{2-Amino-4-[1-(4-forfinal)ethoxy]phenylsulfanyl}phenol

A solution of 1-(4-forfinal)ethanol were converted into 1-(1-bromacil)-4-torbenson using the conditions described in example 22A, which is processed sequentially by the methods described in the examples 22B-22D, obtaining specified in the header of the product.

Example 23B

4-[4-[1-(4-Forfinal)ethoxy]-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 23A (207 mg, 0,584 mmol) was subjected to interaction with the product from example 10B (110 mg, 0,584 mmol) according to method described in example 10F, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (30 mg, 35%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 1,54 (l,J=6.25 Hz, 3H), 2,73 (c, 3H), of 5.53 (sq,J=6,13 Hz, 1H), 6,63 (l,J=8,82 Hz, 2H), 6,93 (DD,J=8,82, to 2.57 Hz, 1H), 7,05-7,14 (m, 4H), 7,18 (t,J=9,01 Hz, 2H), 7,41-,49 (m, 2H), 7,76 (l,J=8,46 Hz, 1H), 8,73 (c, 1H), 8,84 (l,J=8,46 Hz, 1H), 9,71 (c, 1H);

MS (ESI+) m/z 497 (MH)-.

Example 24

4-[4-[1-(3-Forfinal)ethoxy]-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 24A

4-{2-Amino-4-[1-(3-forfinal)ethoxy]phenylsulfanyl}phenol

A solution of 1-(3-forfinal)ethanol were converted into 1-(1-bromacil)-3-torbenson using the conditions described in example 22A, which is processed sequentially by the methods described in the examples 22B-22D, obtaining specified in the header of the product.

Example 24B

4-[4-[1-(3-Forfinal)ethoxy]-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 24A (226 mg, 0,637 mmol) was subjected to interaction with the product from example 10B (120 mg, 0,637 mmol) according to method described in example 10F, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (87 mg, 22%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1.55V (l,J=6,62 Hz, 3H), 2,72 (c, 3H), 5,54 (sq,J=6,13 Hz, 1H), only 6.64 (d,J=8,46 Hz, 2H), 6,91 (DD,J=8,82, to 2.57 Hz, 1H), 7,06-to 7.15 (m, 5H), 7,20-7,28 (m, 2H), 7,35-7,44 (m, 1H), of 7.70 (d,J=8,46 Hz, 1H), 8,68 (c, 1H), 8,81 (l,J=8,46 Hz, 1H), 9,73 (c, 1H);

MS (ESI+) m/z 499 (M+H)+.

Example 25

4-[4-(2-Chlorothiazole-5-ylethoxy)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 2A

4-[2-Amino-4-(2-chlorothiazole-5-ylethoxy)phenylsulfanyl]phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 5-methyl bromide-2-chlorothiazole (obtained in accordance with the way Kim, H.-J., Liu, S., Keum, Y.-S., Qing, X.J. Agric. Food Chem.2003,51, 1823-1830)using the conditions described in example 10C, to obtain 2-chloro-5-(4-chloro-3-nitrophenoxy)thiazole, which is processed sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 25B

4-[4-(2-Chlorothiazole-5-ylethoxy)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 25A was subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 25A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,71 (c, 3H), 5,34 (c, 2H), 6,66 (d, J=8,46 Hz, 2H), 7,01 (DD, J=8,64, 2,02 Hz, 1H), 7,06-7,28 (m, 4H), to 7.68 (d, J=8,46 Hz, 1H), 7,80 (c, 1H), 8,67 (c, 1H), 8,82 (d, J=8,46 Hz, 1H), 9,70 (c, 1H), 10,81 (users, 1H);

MS (ESI+) m/z 508 (M+H)+.

Example 26

4-[2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-(3-triftormetilfosfinov)phenylsulfanyl]phenol

Example 26A

4-[2-Amino-4-(3-triftormetilfosfinov)phenylsulfanyl]phenol

A solution of 4-chloro-3-n is travenol were subjected to interaction with 1-chloromethyl-3-triftorperasin, using the conditions described in example 10C, to obtain 1-chloro-2-nitro-4-(3-triftormetilfosfinov)benzene, which is processed sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 26B

4-[2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-(3-triftormetilfosfinov)phenylsulfanyl]phenol

The product of example 26A was subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 26A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (9,9 mg, 9%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,74 (c, 3H), 5,22 (c, 2H), only 6.64 (d, J=8,46 Hz, 2H), 7,10 (d, J=8,82 Hz, 3H), 7,19-7,30 (m, 2H), 7,62-7,72 (m, J=7,35 Hz, 2H), 7,72-to 7.84 (m, 4H), 8,75 (c, 1H), 8,88 (d, J=7,35 Hz, 1H), RS 9.69 (c, 1H);

MS ESI+ m/z 535 (M+H)+, ESI - m/z 533 (M-H)-.

Example 27

4-[4-Benzyloxy-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 27A

4-(2-Amino-4-benzyloxycarbonyl)phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with bromomethylphenyl using the conditions described in example 10C, to obtain 4-benzyloxy-1-chloro-2-nitrobenzene, which was treated sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header is VCE product.

Example 27B

4-[4-Benzyloxy-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 27A was subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 27A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (73 mg, 25%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,70 (c, 3H), 5,11 (c, 2H), 6,65 (d, J=8,46 Hz, 2H), 6,98 (d, J=7,72 Hz, 1H), 7,10 (d, J=8,46 Hz, 2H), 7,18 (d, J=8,46 Hz, 1H), 7,24 (c, 1H), 7,28-7,51 (m, 5H), 7,63 (d, J=8,82 Hz, 1H), 8,64 (c, 1H), 8,78 (d, J=8,82 Hz, 1H), 9,65 (c, 1H), 10,56 (users, 1H);

MS (ESI+) m/z 467(M+H)+.

Example 28

4-[4-(3-Forbindelse)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 28A

4-[2-Amino-4-(3-forbindelse)phenylsulfanyl]phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 1-methyl bromide-3-florasulam using the conditions described in example 10C, to obtain 1-chloro-4-(3-forbindelse)-2-nitrobenzene, which was treated sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 28B

4-[4-(3-Forbindelse)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 28A were subjected to interaction with the product of example 10B with the special described in example 10F, using the product of example 28A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (41 mg, 42%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,72 (c, 3H), 5,14 (c, 2H), 6,65 (m, 2H), 7,02 (DD, J=8,64, 2.76 Hz, 1H), 7,10 (m, 2H), 7.23 percent (m, 5H), 7,44 (m, 1H), 7,71 (d, J=8,46 Hz, 1H), 8,69 (c, 1H), 8,83 (d, J=8,46 Hz, 1H), RS 9.69 (c, 1H), 10,96 (c, 1H);

MS (ESI+) m/z 485 (M+H)+.

Example 29

4-[2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-(tetrahydrofuran-2-ylethoxy)phenylsulfanyl]phenol

Example 29A

4-[2-Amino-4-(tetrahydrofuran-2-ylethoxy)phenylsulfanyl]phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 2-promoterdriven using the conditions described in example 10C, obtaining 2-(4-chloro-3-nitrophenoxy)of tetrahydrofuran, which was treated sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 29B

4-[2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-(tetrahydrofuran-2-ylethoxy)phenylsulfanyl]phenol

The product of example 29A was subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 29A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified with the aid of the using HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (29 mg, 17%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,55-of 1.84 (m, 1H), 1,84-2,07 (m, 1H), 2,67 (c, 3H), 3,59-3,71 (m, 2H), of 3.73-a 3.83 (m, 1H), 3,85-was 4.02 (m, 2H), 4,15 (DD,J=to 6.43, to 4.23 Hz, 2H), 6,66 (l,J=8,46 Hz, 2H), 6.87 in (DD,J=8,64, 2.76 Hz, 1H), 7,02-to 7.15 (m, 2H), 7,12-7,24 (m, 2H), 7,53 (l,J=8,46 Hz, 1H), 8,56 (c, 1H), 8,71 (l,J=8,46 Hz, 1H), 9,62 (c, 1H), 9,92 (c, 1H);

MS (ESI+) m/z 461 (M+H)+.

Example 30

4-[2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-(naphthalene-1-ylethoxy)phenylsulfanyl]phenol

Example 30A

4-[2-Amino-4-(naphthalene-1-ylethoxy)phenylsulfanyl]phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 1-chloromethylation using the conditions described in example 10C, obtaining 1-(4-chloro-3-nitrophenoxy)naphthalene, which is processed sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 30B

4-[2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-(naphthalene-1-ylethoxy)phenylsulfanyl]phenol

The product of example 30A was subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 30A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (31 mg, 25%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,68 (c, 3H), 5.56mm (c, 2H), to 6.67 (d, J=8,82 Hz, 2H), 7,01-7,16 (m, 3H), 7,16-7,24 (m, 1H), 7,35 (c, 1H), 7,45-to 7.6 (m, 4H), of 7.69 (d, J=6,62 Hz, 1H), 7,87-8,02 (m, 2H), 8,05-to 8.14 (m, 1H), 8,59 (c, 1H), total of 8.74 (d, J=8,46 Hz, 1H), 9,65 (c, 1H), 10,23 (c, 1H); MS (ESI+) 517(M+H)+.

Example 31

4-[4-(3-Methoxybenzyloxy)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 31A

4-[2-Amino-4-(3-methoxybenzyloxy)phenylsulfanyl]phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 1-chloromethyl-3-methoxybenzyl using the conditions described in example 10C, to obtain 1-chloro-4-(3-methoxybenzyloxy)-2-nitrobenzene, which was treated sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 31B

4-[4-(3-Methoxybenzyloxy)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 31A was subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 31A instead of the product of example 10E, obtaining a solid substance, which is triturated in methanol to obtain specified in the title compound (24 mg, 26%).

1H NMR (300 MHz, DMSO-D6) δ ppm: to 9.93 (c, 1H), 9,63 (c, 1H), 8,71 (d, J=8,09 Hz, 1H), 8,55 (c, 1H), 7,53 (d, J=8,09 Hz, 1H), 7,26-7,35 (m, 2H), 7,15 (d, J=8,46 Hz, 1H), 7,07-7,13 (m, 2H), 6,98? 7.04 baby mortality (m, J=5,15 Hz, 2H,), of 6.96 (c, 1H), 6.90 to (DD, J=8,09, to 2.57 Hz, 1H), 6,62-of 6.71 (m, 2H), 5,08 (c, 2H), 3.75 to (c, 3H), 2,67 (c, 3H);

MS (ESI+) m/z 497,2 (M+H)+ (ESI-) m/z 495,2(M-H)-.

Example 32

4-[2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-(quinoline-2-ylethoxy)phenylsulfanyl is]phenol

Example 32A

4-[2-Amino-4-(quinoline-2-ylethoxy)phenylsulfanyl]phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with cleaners containing hydrochloride salt of 2-chloromethylpyridine using the conditions described in example 10C, obtaining 2-(4-chloro-3-nitrophenoxy)quinoline, which is processed sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 32B

4-[2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-(quinoline-2-ylethoxy)phenylsulfanyl]phenol

The product of example 32A was subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 32A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (13 mg, 27%).

1H NMR (500 MHz, DMSO-D6) δ ppm: 2,75 (c, 3H), 5,39 (c, 2H), 6,62 (d, J=8.54 in Hz, 2H), to 7.09 (d, J=8.54 in Hz, 2H), 7,14 (DD, J=8,54, of 2.44 Hz, 1H), 7,22-7,28 (m, 2H), 7,63 (t, J=to 7.93 Hz, 1H), 7,68 (d, J=8.54 in Hz, 1H), 7,74-7,81 (m, 1H), 7,83 (d, J=8.54 in Hz, 1H), 8,00 (t, J=to 7.93 Hz, 2H), 8,44 (d, J=8.54 in Hz, 1H), 8,76 (c, 1H), of 8.92 (d, J=8.54 in Hz, 1H), 9,68 (c, 1H), 11,64 (users, 1H);

MS (ESI+) 518(M+H)+.

Example 33

4-[4-(Biphenyl-4-ylethoxy)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 16B (form of the free acid, to 0.055 g, 0.1 mmol), phenylboric acid (of 0.017 g, 0.14 mmol, the cesium carbonate (0.05 g, 0.15 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0,007 g, 0.01 mmol) were combined inN,N-dimethylformamide (1 ml) and was heated to 100ºC for 24 hours. After cooling to room temperature the mixture was poured into ice water (20 ml) and the resulting solution was acidified using 1N. aqueous solution of hydrochloric acid. Then the solution was extracted with ethyl acetate (3×10 ml), the combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (10 mg, 15%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,67 (c, 3H), 5,16 (c, 2H), 6,60-6,72 (m, 2H), 6,98 (d, J=8,09 Hz, 1H), 7,06-7,22 (m, 3H), 7,27-7,41 (m, 2H), 7,47 (t, J=rate of 7.54 Hz, 2H), 7,54 (d, J=8,46 Hz, 3H), 7,60-7,73 (m, 4H), 8,58 (c, 1H), 8,72 (d, J=8,09 Hz, 1H), for 9.64 (c, 1H), 10,08 (c, 1H);

MS (ESI +) m/z 543 (M+H+)+.

Example 34

4-[4-(5-Chlorothiophene-2-ylethoxy)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 34A

4-[2-Amino-4-(5-chlorothiophene-2-ylethoxy)phenylsulfanyl]phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 2-chloro-5-chloromethylstyrene using the conditions described in example 10C, to obtain 2-chloro-5-(4-chloro-3-nitrophenoxy)thiophene, which is processed sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 34B

4-[4-(5-Chlorothiophene-2-ylethoxy)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenolphthalein]phenol

The product of example 34A was subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 34A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (6.6 mg, 10%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,72 (c, 3H), 5.25 in (c, 2H), 6,65 (d, J=8,46 Hz, 2H), 6,97-7,14 (m, 4H), 7,19 (d, J=8,46 Hz, 2H), 7,72 (d, J=8,09 Hz, 1H), 8,71 (c, 1H), 8,84 (d, J=8,46 Hz, 1H), RS 9.69 (c, 1H), br11.01 (users, 1H);

MS (ESI+) m/z 543 (M+H)+.

Example 35

4-[4-(4-Forbindelse)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 35A

4-[2-Amino-4-(4-forbindelse)phenylsulfanyl]phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 1-methyl bromide-4-florasulam using the conditions described in example 10C, to obtain 1-chloro-4-(4-forbindelse)-2-nitrobenzene, which was treated sequentially by the methods described in the examples 10D and 10E, obtaining specified in the header of the product.

Example 35B

4-[4-(4-Forbindelse)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 35A was subjected to interaction with the product of example 10B way, opeaning example 10F, using the product of example 35A instead of the product of example 10E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (40 mg, 41%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,69 (c, 3H), 5,09 (c, 2H), 6,65 (m, 2H), 6,97 (DD, J=8,64, 2,39 Hz, 1H), to 7.09 (m, 2H), 7,21 (m, 4H), to 7.50 (m, 2H), to 7.61 (d, J=8,46 Hz, 1H), 8,61 (c, 1H), up 8.75 (d, J=8,46 Hz, 1H), 9,65 (c, 1H), 10,41 (c, 1H);

MS (ESI+) m/z 485 (M+H)+.

Example 36

3-[4-(4-Hydroxyphenylethyl)-3-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

Example 36A

4-Methyl-3-oxopent, sodium salt

Dried in the flame of a 100-ml vessel equipped with a 25-ml additional funnel was purged with gaseous nitrogen and loaded anhydrous diethyl ether (40 ml), then was added sodium plates (1.65 g, 0,0725 mol). The reaction mixture was cooled to a temperature bath with a mixture of ice/water and slowly dropwise added to the solution of methylisobutylketone (6,244 g, 0,0725 mol) and ethylformate (5,481 g, 0,0725 mol) in anhydrous diethyl ether (5 ml) for 1.5 hours at 0ºC. After complete addition, the cooling bath was removed and the reaction mixture was stirred at room temperature overnight. Then add an additional amount of ether (10 ml) for dispersion of the resulting sludge and solid matter quickly is delali vacuum filtration. The solid is washed with a small amount of ether and then dried in a vacuum desiccator for one hour to obtain specified in the header of the product in the form of solid substances not quite white (5.35 g, 54% yield). This substance was used in the next stage without additional purification.

Example 36B

6-Isopropyl-2-oxo-1,2-dihydropyridines-3-carbonitril

A solution of the product of example 36A (5.35 g, 0,0393 mol) and 2-cyanoacetamide (3,47 g, 0,0413 mol) in water (35 ml) was stirred at room temperature for 10 minutes. To this mixture was added 2.5 ml of the original piperidineacetate solution (obtained from 9,8 ml of piperidine, 6 ml of acetic acid and 10 ml of water) and the solution was heated under reflux for 2 hours. Then the mixture was cooled to room temperature and the pH was brought to 4 by the addition of glacial acetic acid. The obtained solid light yellow color was isolated by vacuum filtration, washed with water (2×30 ml) and dried under vacuum to obtain specified in the header of the product (4,36 g, 68%).

Example 36C

2-Bromo-6-isopropylaminomethyl

A solution of the product of example 36B (4.35 g, 0,0269 mol), tetrabutylammonium bromide (10.4 g, 0,0323 mol) and phosphorus pentoxide (8,01 g, 1.05 mol) in toluene (80 ml) was heated under reflux for 5 hours. Then the reaction mixture was cooled to room temp the atmospheric temperature, was added water (80 ml) and the mixture was stirred for 2 hours at room temperature. The reaction mixture was diluted with toluene (20 ml) and the organic layer was separated. The aqueous layer was washed with toluene (50 ml) and the combined organic layers were washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to obtain specified in the header of the product as a yellow oil (5,64 g, 93%).

Example 36D

2-Amino-6-isopropylaminomethyl

A solution of the product of example 36C (21 g, 0,093 mol) and liquid ammonia (250 ml) in 500 ml of ethanol was subjected to interact in a tightly closed pressure vessel at 130ºC for 20 hours. The reaction mixture was concentrated under vacuum and the residue was ground into a fine powder, then washed with water (2×50 ml) and dried in a vacuum oven for 24 hours to obtain specified in the connection header in the form of a solid beige color (14 g, 93%).

Example 36E

N'-(3-Cyano-6-isopropylpyridine-2-yl)-N-N-dimethylformamide

A solution of the product of example 36D (7,1 g 0,044 mol) andN,N-dimethylformamidine (6,44 ml, 0,0484 mol) in toluene (100 ml) was heated under reflux for 3 hours. The resulting solution was cooled to room temperature and concentrated under vacuum to obtain is shown in the title compound (9.5 g, 100%) as a thick brown oil, which hardened on standing. Although NMR showed the purity of this substance, it contains a small amount of brightly colored impurities. It can be purified by chromatography on silica gel (gradient ethyl acetate/hexane) to obtain the oil is light yellow in color, which hardened on standing (after chromatography, the yield of about 70%).

Example 36F

3-(4-Chloro-3-nitrophenoxy)benzonitrile

Specified in the title compound was obtained in accordance with the method described in example 10C, using 3-bromomethylbiphenyl instead of 1-chloromethyl-4-methoxybenzene (0,813 g, 98%).

Example 36G

3-[4-(4-Hydroxyphenylethyl)-3-nitrophenoxy]benzonitrile

Specified in the title compound was obtained in accordance with the method described in example 10D, using 3-(4-chloro-3-nitrophenoxy)benzonitrile instead of 1-chloro-4-(4-methoxybenzyloxy)-2-nitrobenzene (1.07 g, 100%).

Example 36H

3-[3-Amino-4-(4-hydroxyphenylethyl)phenoxymethyl]benzonitrile

Specified in the title compound was obtained in accordance with the method described in example 10E, using 3-[4-(4-hydroxyphenylethyl)-3-nitrophenoxy]benzonitrile instead of 4-[4-(4-methoxybenzyloxy)-2-nitrophenyloctyl]phenol (0.97 g, 98%).

Example 36I

3-[4-(4-Hydroxyphenylethyl)-3-(7-what isopropylpyridine[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

A solution of the product of example 36E (47,4 mg, 0,219 mmol) and the product of example 36H them (76.3 mg, 0,219 mmol) in acetic acid (1 ml) was stirred on an oil bath preheated to 130ºC for 15 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum and the resulting residue was purified preparative HPLC with a reversed phase column (Waters Symmetry C8 (25 mm×100 mm, particle size 7 μm)using a gradient mixture of from 10% to 100% acetonitrile/0.1% of triperoxonane acid in water for 8 minutes (travel time 10 minutes) at a flow rate of approximately 40 ml/min, obtaining specified in the connection header in the form of a salt triperoxonane acid (14 mg, 10%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 10,94 (c, 1H), RS 9.69 (c, 1H), 8,88 (d, J=8,46 Hz, 1H), 8,70 (c, 1H), 7,92 (c, 1H), 7,72-7,87 (m, 3H), 7.62mm (t, J=7,72 Hz, 1H), 7,15-7,28 (m, J=8,82 Hz, 2H), 7,08-to 7.15 (m, 2H), 6,99-7,06 (m, 1H), 6,61-6,72 (m, 2H), 5,18 (c, 2H), 3,19-3,30 (m, 1H), 1,34 (d, J=6,99 Hz, 6H);

MS(ESI) m/z 520,3 (M+H)+ (ESI-) m/z 518,3 (M-H)-.

Example 37

4-[2-(7-Isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-4-(2-methoxybenzyloxy)phenylsulfanyl]phenol

Example 37A

4-[2-Amino-4-(2-methoxybenzyloxy)phenylsulfanyl]phenol

A solution of 4-chloro-3-NITROPHENOL were subjected to interaction with 1-methyl bromide-2-methylbenzoate using the conditions described in example 10C, to obtain 1-chloro-4-(2-methylbenzylamino)-2-nitrobenzene, which was treated sequentially ways, op the toboggan in the examples 10D and 10E, obtaining specified in the header of the product.

Example 37B

4-[2-(7-Isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-4-(2-methoxybenzyloxy)phenylsulfanyl]phenol

The product of example 37A was subjected to interaction with the product of example 36E method described in example 36I, using the product of example 37A instead of the product of example 36H, obtaining a solid substance, which is triturated in methanol to obtain specified in the title compound (31 mg, 31%).

1H NMR (500 MHz, DMSO-D6) δ ppm: 9,88 (c, 1H), to 9.57 (c, 1H), 8,73 (d, J=5,49 Hz, 1H), 8,56 (c, 1H), 7,58 (d, J=7,32 Hz, 1H), 7,40 (DD, J=7,63, of 1.53 Hz, 1H), 7,31-7,37 (m, 1H), 7,30 (c, 1H), 7,18 (d, J=6,10 Hz, 1H), 7,11 (d, J=8.54 in Hz, 2H), 7,05 (d, J=to 7.93 Hz, 1H), 6,97 (t, J=7,32 Hz, 1H), 6,93 (c, 1H), to 6.67 (d, J=8.54 in Hz, 2H), 5,06 (c, 2H), 3,80 (c, 3H), 3,16-of 3.25 (m, 1H), 1,33 (d, J=of 6.71 Hz, 6H);

MS (ESI+) m/z 525,2 (M+H)+ (ESI-) m/z 523,2 (M-H)-.

Example 38

4-[2-(7-Isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-4-(4-methoxybenzyloxy)phenylsulfanyl]phenol

The product from example 10E were subjected to interaction with the product of example 36E in accordance with the method described in example 36I, using the product of example 10E instead of the product of example 36H, obtaining a solid substance, which is triturated in methanol to obtain specified in the title compound (43 mg, 49%).

1H NMR (300 MHz, DMSO-D6) δ ppm: to 9.93 (c, 1H), 9,63 (c, 1H), up 8.75 (d, J=8,46 Hz, 1H), 8,57 (c, 1H), 7,60 (d, J=8,09 Hz, 1H), 7,38 (d, J=8,46 Hz, 2H), 7,27 (c, 1H), 7,05-7,19 (m, 3H), 6,85-7,00 (m, 3H), to 6.67 (d, J=8,82 Hz, 2H), 5,02 (c, 2H), 3.75 to (c, 3H), 3,14 of 3.28 (m, 1H), and 32 (d, J=6,62 Hz, 6H);

MS (ESI+) m/z 525,3 (M+H)+ (ESI-) m/z 523,3 (M-H)-.

Example 39

4-[2-(7-Isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-4-(1-phenylethane)phenylsulfanyl]phenol

Example 39A

4-[2-Amino-4-(1-phenylethane)phenylsulfanyl]phenol

A solution of 1-(3-forfinal)ethanol were converted into 1-(1-bromacil)-3-torbenson using the conditions described in example 22A, which is processed sequentially by the methods described in the examples 22B-22D, obtaining specified in the header of the product.

Example 39B

4-[2-(7-Isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-4-(1-phenylethane)phenylsulfanyl]phenol

The product from example 39A was subjected to interaction with the product from example 36E in accordance with the method described in example 36I, using the product of example 39A instead of the product of example 36H, with raw is specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: of 1.34 (d, J=6,99 Hz, 6H), of 1.55 (d, J=6.25 Hz, 3H), 3,14-3,29 (m, 1H), 5,49 (sq, J=6,37 Hz, 1H), 6,63 (d, J=8,82 Hz, 2H), 6.89 in (DD, J=8,82, to 2.57 Hz, 1H), to 7.09 (DD, J=9,01, 2.76 Hz, 3H), 7,19-of 7.48 (m, 6H), of 7.75 (d, J=8,82 Hz, 1H), 8,67 (c, 1H), 8,83 (d, J=8,46 Hz, 1H), 9,67 (c, 1H), 10,85 (c, 1H);

MS ESI+ (m/z 509, ESI (m/z 507.

Example 40

4-[4-[1-(4-Bromophenyl)ethoxy]-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 22D (211 mg, 0,506 mm is l) were subjected to interaction with the product from example 36E (109 mg, 0,506 mmol) according to method described in example 36I, using the product of example 22D instead of the product of example 36H, with raw is specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (150 mg, 42%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 10,87 (users, 1H), 9,68 (s, 1H), 8,83 (d, J=8,45 Hz, 1H), 8,67 (c, 1H), of 7.75 (d, J=7,72 Hz, 1H), 7,55 (d, J=8,46 Hz, 2H), 7,37 (d, J=8,46 Hz, 2H), to 7.09 (m, 4H), 6.89 in (DD, J=8,46 Hz, J=2,20 Hz, 1H), 6,66 (d, J=8,82 Hz, 2H), 5,50 (sq, J=6.25 Hz, 2H), 3,25 (Sept., J=6,99 Hz, 1H), 1,53 (d, J=6.25 Hz, 3H), of 1.34 (d, J=6,99 Hz, 6H).

MS (ESI+) m/z 587, 589 (M+H-TFA)+; (ESI-) m/z 585, 587 (M-H-TFA)-.

Example 41

4-[4-[1-(3-Forfinal)ethoxy]-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 24A (197 mg, 0,555 mmol) was subjected to interaction with the product from example 36E (120 mg, 0,555 mmol) according to method described in example 36I, using the product of example 24A instead of the product of example 36H, with raw is specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (100 mg, 28%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,34 (l,J=6,99 Hz, 6H), 1.55V (l,J=6,62 Hz, 3H), 3,19-of 3.32 (m,J=13,70, 6,94, 6,94 Hz, 1H), of 5.53 (sq,J=6,62 Hz, 1H), only 6.64 (d,J=8,46 Hz, 2H), 6,91 (DD,J=8,82, to 2.57 Hz, 1H), 7,09 (l,J=8,46 Hz, 5H), 7,19-7,29 (m, 2H), 7,39 (DD,J=8,09, 5.8 Hz, 1H), 7,78 (l,J=8,46 Hz, 1H), 8,68 (c, 1H), cent to 8.85 (d,J=8,46 Hz, 1H), 9,70 (c, 1H);

MS (ESI+) m/z 527 (M+H)+.

Example 42

4-[2-(7-Isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-4-(3-triftormetilfosfinov)phenylsulfanyl]phenol

The product from example 26A was subjected to interaction with the product from example 36E in accordance with the method described in example 36I, using the product of example 26A instead of the product of example 36H, with raw is specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (22 mg, 21%).

1H NMR (300 MHz, DMSO-D6) δ ppm: of 1.34 (d, J=6,99 Hz, 6H), 5,22 (c, 2H), 6,65 (d, J=8,46 Hz, 2H), 7,01-7,13 (m, 3H), 7,20 (d, J=8,82 Hz, 2H), 7,66 (d, J=7,35 Hz, 1H), 7,70-of 7.82 (m, 4H), 8,68 (c, 1H), 8,87 (d, J=8,46 Hz, 1H), 9,68 (c, 1H);

MS ESI+ m/z 563 (M+H)+, ESI - m/z 561 (M-H)-.

Example 43

4-[4-(3-Forbindelse)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 57D were subjected to interaction with the product from example 36E in accordance with the method described in example 36I, using the product of example 57D instead of the product of example 36H, with raw is specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (26 mg, 51%).

1H NMR (300 MHz, DMSO-D6) δ ppm: to 1.35 (d, J=6,99 Hz, 6H), of 3.28 (m, 1H), 5,14 (c, 2H), 6,65 (m, 2H), 7,16 (m, 8H), 7,44 (who, 1H), 7,81 (d, J=8,46 Hz, 1H), 8,73 (c, 1H), 8,90 (d, J=8,46 Hz, 1H), RS 9.69 (c, 1H), 11,08 (c, 1H);

MS (ESI+) m/z 513 (M+H)+.

Example 44

4-[4-(4-Forbindelse)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 35A was subjected to interaction with the product of example 36E method described in example 36I, using the product of example 35A instead of the product of example 36H, with raw is specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (23 mg, 45%).

1H NMR (300 MHz, DMSO-D6) δ ppm: to 1.35 (d, J=6,99 Hz, 6H), 3,26 (m, 1H), 5,09 (c, 2H), 6,62 (m, 2H), 7,14 (m, 7H), of 7.48 (m, 2H), 7,81 (d, J=8,46 Hz, 1H), 8,73 (c, 1H), 8,90 (d, J=8,46 Hz, 1H), 9,68 (c, 1H), 11,12 (c, 1H);

MS (ESI+) m/z 513 (M+H)+.

Example 45

4-[4-[1-(4-Forfinal)ethoxy]-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 23A (180 mg, 0,510 mmol) was subjected to interaction with the product from example 36E (110 mg, 0,510 mmol) according to method described in example 36I, using the product of example 23A instead of the product of example 36H, with raw is specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (35 mg, 12%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,35 (l,J=6,99 Hz, 6H), and 1.54 (d,J=6,62 Hz, 3H), 3,23-to 3.34 (m, 1H), 5,52 (sq,J=5,88 Hz, 1H),6,63 (l, J=8,82 Hz, 2H), 6,94 (DD,J=8,82, to 2.57 Hz, 1H), was 7.08 (m,J=8,82 Hz, 4H), 7,14 (l,J=4,78 Hz, 1H), 7,17-7,21 (m, 1H), 7,41-7,49 (m, 2H), 7,86 (l,J=8,82 Hz, 1H), 8,76 (c, 1H), 8,91 (l,J=8,46 Hz, 1H);

MS (ESI+) m/z 527 (M+H)+.

Example 46

4-[2-(7-Isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-4-(3-methoxybenzyloxy)phenylsulfanyl]phenol

The product of example 31A was subjected to interaction with the product of example 36E method described in example 36I, using the product of example 31A instead of the product of example 36H, with raw is specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (23 mg, 45%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 10,98 (c, 1H), 9,67 (c, 1H), 8,88 (d, J=8,09 Hz, 1H), 8,70 (c, 1H), 7,78 (d, J=8,09 Hz, 1H), 7,31 (t, J=8,09 Hz, 1H), 7,15-7,24 (m, J=8,82 Hz, 2H), 7,06-to 7.15 (m, 2H), 6,95-7,05 (m, J=6,62 Hz, 3H), 6.90 to (DD, J=7,72, of 2.21 Hz, 1H), 6,54-of 6.73 (m, 2H), 5,09 (c, 2H), 3.75 to (c, 3H), 3,19 of 3.28 (m, 1H), 1,34 (d, J=6,99 Hz, 6H);

MS (ESI+) m/z 525,2 (M+H)+ (ESI-) m/z 523,2 (M-H)-.

Example 47

4-[4-(3-Bromobenzylamine)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 15A was subjected to interaction with the product of example 36E method described in example 36I, using the product of example 15A instead of the product of example 36H, with raw is specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt of triperoxonane the th acid (16 mg, 28%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,33 (d, J=6,62 Hz, 6H), 3,21 (m, 1H), 5,13 (c, 2H), of 6.68 (d, J=8,82 Hz, 2H), 6,95 (DD, J=8,64, 2.76 Hz, 1H), 7,12 (m, 3H), 7,34 (m, 2H), 7,50 (m, 2H), 7,60 (d, J=8,82 Hz, 1H), (c, 1H), 8,57 (c, 1H), 8,76 (d, J=8,46 Hz, 1H), 9,65 (c, 1H), 9,95 (c, 1H);

MS (ESI+) m/z 573, 575 (M+H)+.

Example 48

4-[4-(4-Bromobenzylamine)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 16A was subjected to interaction with the product of example 36E method described in example 36I, using the product of example 16A instead of the product of example 36H, with raw is specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (28 mg, 49%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,32 (d, J=6,99 Hz, 6H), up 3.22 (m, 1H), 5,10 (c, 2H), to 6.67 (d, J=8,46 Hz, 2H), 6,94 (DD, J=8,82, to 2.57 Hz, 1H), 7,12 (m, 3H), 7,28 (d, J=2.57 m Hz, 1H), 7,41 (d, J=8,46 Hz, 2H), to 7.59 (m, 3H), 8,56 (c, 1H), up 8.75 (d, J=8,46 Hz, 1H), 9,65 (c, 1H), 9,94 (c, 1H);

MS (ESI+) m/z 573, 575 (M+H)+.

Example 49

4-[4-(4-Hydroxyphenylethyl)-3-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

The product of example 21A was subjected to interaction with the product of example 36E method described in example 36I, using the product of example 21A instead of the product of example 36H, with raw is specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt trifter kusnoy acid (32 mg, 26%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 10,91 (c, 1H), RS 9.69 (c, 1H), 8,87 (d, J=9,19 Hz, 1H), 8,69 (c, 1H), 7,88 (d, J=8,09 Hz, 2H), to 7.77 (d, J=8,46 Hz, 1H), to 7.64 (d, J=8,46 Hz, 2H), 7,15-7,26 (m, J=8,82 Hz, 2H), 7,08-7,15 (m, 2H), 7,01 (d, J=8,82 Hz, 1H), 6,58-6,72 (m, 2H), 5,23 (c, 2H), 3,20-of 3.31 (m, 1H), 1,34 (d, J=6,99 Hz, 6H);

MS (ESI+) m/z 520,2 (M+H)+ (ESI-) m/z 518,2 (M-H)-.

Example 50

2-[4-(4-Hydroxyphenylethyl)-3-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

The product of example 20A was subjected to interaction with the product of example 36E method described in example 36I, using the product of example 20A instead of the product of example 36H, with raw is specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (11 mg, 9%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 11,30 (c, 1H), 9,71 (c, 1H), 8,93 (d, J=8,82 Hz, 1H), 8,76 (c, 1H), 7,92 (d, J=7,35 Hz, 1H), to 7.84 (d, J=8,82 Hz, 1H), 7,72-7,80 (m, 2H), to 7.59 (DDD, J=7,72, 6,25, 2,58 Hz, 1H), 7,19-7,28 (m, 2H), 7,06-7,17 (m, 3H), 6,64-6,69 (m, 2H), 5.25 in (c, 2H), 3,22-to 3.33 (m, 1H), 1,35 (d, J=6,99 Hz, 6H);

MS (ESI+) m/z 520,2 (M+H)+ (ESI-) m/z 518,2 (M-H)-.

Example 51

4-[4-Benzyloxy-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 27A was subjected to interaction with the product of example 36E method described in example 36I, using the product of example 27A instead of the product of example 36H, obtaining a solid substance, which is triturated in methanol to obtain specified in sialometaplasia.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,32 (d, J=6,62 Hz, 6H), 3,10-3,30 (m, 1H), 5,11 (c, 2H), to 6.67 (d, J=8,82 Hz, 2H), 6.90 to-6,99 (m, 1H), 7,07-7,19 (m, 1H), 7,11 (d, J=8,82 Hz, 2H), 7.23 percent-7,52 (m, 6H), to 7.59 (d, J=8,09 Hz, 1H), 8,56 (c, 1H), up 8.75 (d, J=8,09 Hz, 1H), for 9.64 (c, 1H), 9,95 (c, 1H);

MS (DCI/NH3) m/z 495 (M+H)+.

Example 52

3-[3-[7-(1-Hydroxy-1-methylethyl)pyrido[2,3-d]pyrimidine-4-ylamino]-4-(4-hydroxyphenylethyl)phenoxymethyl]benzonitrile

The product from example 36E (45,9 mg, 0,212 mmol) and the product from example 36H (of 73.5 mg, 0,212 mmol) in acetic acid (1 ml) was gradually heated from room temperature to 130ºC in an oil bath for 15 minutes, then was heated at 130ºC for another 1.5 hours. Then the mixture was cooled to room temperature, concentrated under vacuum to obtain crude specified in the title compound, which was purified preparative HPLC with a reversed phase column (Waters Symmetry C8 (25 mm×100 mm, particle size 7 μm)using a gradient mixture of from 10% to 100% acetonitrile/0.1% of triperoxonane acid in water over 8 minutes (10 minutes travel time) at a flow rate of approximately 40 ml/min, obtaining specified in the connection header in the form of a salt triperoxonane acid (22 mg, 20%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 11,76 (c, 1H), 9,72 (c, 1H), 9,06 (d, J=8,09 Hz, 1H), 8,83 (c, 1H), to 8.20 (d, J=8,46 Hz, 1H), 7,92 (c, 1H), 7,75-7,88 (m, 2H), 7,63 (t, J=7,72 Hz, 1H), 7,21-7,26 (m, 1H), 7,19 (d, J=2.57 m Hz, 1H), 7,07-to 7.15 (m, 3H), only 6.64 (d, J=8,46 Hz, 2H), 5,18 (c, 2H), and 1.56 (c, 6H);

MS (ESI) m/z 536,2 (M+H)+, (ESI-) m/z 5342 (M-H)-.

Example 53

2-[3-[7-(1-Hydroxy-1-methylethyl)pyrido[2,3-d]pyrimidine-4-ylamino]-4-(4-hydroxyphenylethyl)phenoxymethyl]benzonitrile

The product of example 20A was subjected to interaction with the product of example 36E method described in example 52, using the product of example 20A instead of the product of example 36H, with raw is specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (11 mg, 11%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 11,73 (c, 1H), 9,75 (c, 1H), 9,05 (d, J=8,46 Hz, 1H), 8,84 (c, 1H), to 8.20 (d, J=8,82 Hz, 1H), 7,92 (d, J=7,35 Hz, 1H), 7,69-to 7.84 (m, 2H), 7,54-to 7.64 (m, 1H), 7.23 percent-7,27 (m, 1H), 7,21 (d, J=2.57 m Hz, 1H), 7,10-7,17 (m, 3H), 6,64-6,69 (m, 2H), 5.25 in (c, 2H), and 1.56 (c, 6H);

MS (ESI+) m/z 536,2 (M+H)+ (ESI-) m/z 534,3 (M-H).

Example 54

4-[3-[7-(1-Hydroxy-1-methylethyl)pyrido[2,3-d]pyrimidine-4-ylamino]-4-(4-hydroxyphenylethyl)phenoxymethyl]benzonitrile

The product of example 21A was subjected to interaction with the product of example 36E method described in example 52, using the product of example 21A instead of the product of example 36H, with raw is specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (10 mg, 10%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 11,64 (c, 1H), 9,73 (c, 1H), 9,05 (c, 1H), 8,82 (c, 1H), 8,19 (d, J=8,82 Hz, 1H), 7,88 (d, J=8,09 Hz, 2H), to 7.64 (d, J=8,46 Hz, 2H), 7.23 percent (d, J=8,82 Hz, 1H), 7,18 (q, j =2.57 m Hz, 1H),? 7.04 baby mortality-to 7.15 (m, 3H), 6,62-6,69 (m, 2H), 5,23 (c, 2H), 2,54 (c, 1H), and 1.56 (c, 6H);

MS (ESI+) m/z 536,2 (M+H)+ (ESI-) m/z 534,2 (M-H)-.

Example 55

4-[2-[7-(1-Hydroxy-1-methylethyl)pyrido[2,3-d]pyrimidine-4-ylamino]-4-(2-methoxybenzyloxy)phenylsulfanyl]phenol

The product of example 37A was subjected to interaction with the product of example 36E method described in example 52, using the product of example 37A instead of the product of example 36H, obtaining a solid substance, which is triturated in methanol to obtain specified in the title compound (8 mg, 8%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 11,81 (c, 1H), 9,40-9,95 (m, 1H), 9,06 (d, J=8,46 Hz, 1H), cent to 8.85 (c, 1H), 8,21 (d, J=8,46 Hz, 1H), 7,31-7,44 (m, 2H), 7,25 (d, J=8,46 Hz, 1H), 7,15 (d, J=2.57 m Hz, 1H), 7,02-7,14 (m, 4H), 6,97 (t, J=rate of 7.54 Hz, 1H), 6,61 is 6.67 (m, 2H), of 5.05 (c, 2H), 3,80 (c, 3H), 2,54 (c, 1H), and 1.56 (c, 6H);

MS (ESI+) m/z 541,2 (M+H)+ (ESI-) m/z 539,2 (M-H)-.

Example 56

4-{4-(4-Bromobenzylamine)-2-[7-(1-hydroxy-1-methylethyl)pyrido[2,3-d]pyrimidine-4-ylamino]phenylsulfanyl}phenol

The product of example 16A was subjected to interaction with the product of example 36E method described in example 52, using the product of example 16A instead of the product of example 36H, with raw is specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (8 mg, 13%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1.55V (c, 6H), 2,08 (c, 1H), 5,10 (c, 2H), 6,65 (d, J=8,46 Hz, 2H), 7,13 (m, 5H), 7,41 (d, J=8,46 Hz, 2H), 7,60 (d, J=8,09 Hz, 2H), 8,15 (d, J=8,46 Hz, 1H), 8,7 (c, 1H), 9,00 (d, J=8,46 Hz, 1H), 9,70 (c, 1H), 11,43 (c, 1H);

MS (ESI+) m/z 589, 591 (M+H)+.

Example 57

4-[4-(3-Forbindelse)-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 57A

N'-(3-Cyano-2-yl)-N,N-dimethylformamide

A solution of 2-aminonicotinamide (5 g, 42 mmol) andN,N-dimethylformamidine (6,13 ml, 46.2 mmol) in toluene (20 ml) was heated under reflux for 3 hours. After cooling to room temperature the solution was concentrated under vacuum to obtain specified in the connection header (7,3 g, 100%).

Example 57B

1-Chloro-4-(3-forbindelse)-2-nitrobenzene

Specified in the title compound was obtained in accordance with the method described in example 10C, using 1-methyl bromide-3-torbenson instead of 1-chloromethyl-4-methoxybenzene (0.56 g, 100%).

Example 57C

4-[4-(3-Forbindelse)-2-nitrophenyloctyl]phenol

Specified in the title compound was obtained in accordance with the method described in example 10D, using 1-chloro-4-(3-forbindelse)-2-nitrobenzene instead of 1-chloro-4-(4-methoxybenzyloxy)-2-nitrobenzene (0,57 g, 77%).

Example 57D

4-[2-Amino-4-(3-forbindelse)phenylsulfanyl]phenol

Specified in the title compound was obtained in accordance with the method described in example 10E, using 4-[4-(3-forbindelse)-2-nitrophenyloctyl]phenol instead of 4-[4-(4-methoxybenzyloxy is)-2-nitrophenyloctyl]phenol (0,501 g, 96%).

Example 57E

4-[4-(3-Forbindelse)-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

A solution of the product from example 57A (35 mg, 0.2 mmol) and the product from example 57D (68 mg, 0.2 mmol) in acetic acid (1 ml) was gradually heated from room temperature to 130oC on an oil bath for 15 minutes, then was heated at 130oC for another 1.5 hours. Then the mixture was cooled to room temperature, concentrated under vacuum to obtain crude specified in the title compound, which was purified preparative HPLC with a reversed phase column (Waters Symmetry C8 (25 mm×100 mm, particle size 7 μm)using a gradient from 10% to 100% acetonitrile/0.1% of triperoxonane acid in water over 8 minutes (10 minutes travel time) at a flow rate of approximately 40 ml/min, obtaining specified in the connection header in the form of a salt triperoxonane acid (28 mg, 30%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 5,14 (c, 2H), 6,65 (m, 2H), 7,14 (m, 8H), 7,49 (m, 1H), 7,66 (m, 1H), 8,61 (c, 1H), 8,88 (l,J=7,47 Hz, 1H), 9,07 (c, 1H), 9,65 (c, 1H), 10,34 (c, 1H);

MS (ESI) m/z 471 (M+H)+.

Example 58

4-[4-(2-Methylbenzylamino)-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 17A was subjected to interaction with the product of example 57A in the manner described in example 57E, using the product of example 17A instead of the product of example 57D, raw is specified in the header with the organisations, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (50 mg, 54%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,31 (c, 3H), 5,09 (c, 2H), 6,66 (m, 2H), 7,01 (m, 1H), 7,19 (m, 7 H), 7,42 (d, J=6,99 Hz, 1H), 7,71 (DD, J=to $ 7.91, to 4.23 Hz, 1H), 8,63 (c, 1H), 8,89 (d, J=7,35 Hz, 1H), which is 9.09 (c, 1H), 9,66 (c, 1H), 10,50 (c, 1H);

MS (ESI+) m/z 467 (M+H)+.

Example 59

4-[4-(4-Methylbenzylamino)-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 19A were subjected to interaction with the product of example 57A in the manner described in example 57E, using the product of example 19A instead of the product of example 57D, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (45 mg, 48%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,30 (c, 3H), of 5.05 (c, 2H), 6,65 (m, 2H), 7,10 (m, 7H), 7,33 (d, J=8,07 Hz, 2H), 7,69 (DD, J=8,27, to 4.23 Hz, 1H), 8,62 (c, 1H), 8,87 (d, J=7,72 Hz, 1H), 9,07 (c, 1H), for 9.64 (c, 1H), 10,42 (c, 1H);

MS (ESI+) m/z 467 (M+H)+.

Example 60

4-[4-(2-Bromobenzylamine)-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 14A was subjected to interaction with the product of example 57A in the manner described in example 57E, using the product of example 14A instead of the product of example 57D, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the header joint is in the form of a salt triperoxonane acid (40 mg, 38%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 5,13 (c, 2H), 6,66 (m, 2H), 6,99 (d, J=8,43 Hz, 1H), 7,15 (m, 3H), 7,35 (m, 3H), of 7.64 (m, 3H), at 8.60 (c, 1H), cent to 8.85 (d, J=7,32 Hz, 1H), 9,07 (c, 1H), 9,66 (c, 1H), 10,28 (c, 1H);

MS (ESI+) m/z 531, 533 (M+H)+.

Example 61

3-[4-(4-Hydroxyphenylethyl)-3-(pyrido[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

The product from example 36H and the product from example 57A was subjected to interaction in accordance with the method described in example 57E, using the product of example 36H instead of the product of example 57D, obtaining a solid substance, which is triturated in methanol to obtain specified in the title compound (44 mg, 44%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 10,08 (c, 1H), 9,65 (c, 1H), 9,06 (c, 1H), 8,86 (c, 1H), 8,58 (c, 1H), 7,92 (c, 1H), to 7.77-7,86 (m, 2H), 7,54-of 7.70 (m, J=7,72, 7,72 Hz, 2H), 7,28 (c, 1H), 7,07-7,19 (m, 3H), 6,97 (c, 1H), 6,63-6,72 (m, 2H), 5,18 (c, 2H);

MS (ESI+) m/z 478,2 (M+H)+, (ESI-) m/z 476,1 (M-H)-.

Example 62

4-[4-(3-Methylbenzylamino)-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 18A was subjected to interaction with the product of example 57A in the manner described in example 57E, using the product of example 18A instead of the product of example 57D, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (50 mg, 54%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,31 (c, 3H), 5,07 (c, 2H), 6,65 (m, 2H), 7,12 (m, 9H), 7,78 (DD, J=8,10 Hz, of 4.77 Hz, 1H), 8,72 (c, 1H), to 8.94 (d, J=7,47 Hz, 1H), 9,12 (d, J=3.15 Hz, 1H), 9,67 (c, 1H), 11,03 (c, 1H);

MS (ESI+) m/z 467 (M+H)+.

Example 63

4-[4-(4-Methoxybenzyloxy)-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 10E and the product from example 57A was subjected to interaction in accordance with the method described in example 57E, using the product of example 10E instead of the product of example 57D, obtaining a solid substance, which is triturated in methanol to obtain specified in the title compound (49 mg, 55%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 10,07 (c, 1H), 9,63 (c, 1H), 9,05 (c, 1H), 8,83 (c, 1H), 8,58 (c, 1H), to 7.64 (c, 1H), 7,38 (d, J=8,46 Hz, 2H), 7,20-7,29 (m, 1H), 7,12-to 7.18 (m, 1H), 7,06 for 7.12 (m, 2H), 6.90 to-6,99 (m, 3H), 6,62-6,69 (m, 2H), 5,02 (c, 2H), 3.75 to (c, 3H);

MS (ESI+) m/z 483,2 (M+H)+, (ESI-) m/z 481,2 (M-H)-.

Example 64

4-[4-(2-Methoxybenzyloxy)-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product of example 37A was subjected to interaction with the product of example 57A in the manner described in example 57E, using the product of example 37A instead of the product of example 57D, obtaining a solid substance, which is triturated in methanol to obtain specified in the title compound (47 mg, 56%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 10,08 (c, 1H), 9,63 (c, 1H), 9,07 (c, 1H), cent to 8.85 (d, J=6,62 Hz, 1H), 8,59 (c, 1H), to 7.64 (c, 1H), 7,41 (DD, J=7,35, to 1.47 Hz, 1H), 7,30-7,38 (m, 1H), 7,24 (c, 1H), 7,16 (d, J=8,46 Hz, 1H), 7,08-7,14 (m, 2H), 7,05 (d, J=8,09 Hz, 1H), 6.89 in-7,01 (m, J=7,54, rate of 7.54 Hz, 2H), 6,61-of 6.71 (m, 2H), of 5.05 (c, 2H), 3,80 (c, 3H);

MS (ESI+) m/z 483,2 (M+H)+, (ESI-) m/z 481,2 (M-H)-.

Example 65

4-[4-(hydroxyphenylethyl)-3-(pyrido[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

The product of example 21A was subjected to interaction with the product of example 57A in the manner described in example 57E, using the product of example 21A instead of the product of example 57D, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (6 mg, 6%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 11,17 (c, 1H), RS 9.69 (c, 1H), which is 9.09-9,20 (m, J=3,68 Hz, 1H), 8,97 (d, J=8,82 Hz, 1H), total of 8.74 (c, 1H), 7,78-of 7.96 (m, 3H), of 7.64 (d, J=8,46 Hz, 2H), 7,20 (d, J=8,46 Hz, 2H), 7,07-7,16 (m, 2H,), 7,03 (d, J=6.25 Hz, 1H), 6,57-6,70 (m, 2H), 5,23 (c, 2H);

MS (ESI+) m/z 478,2 (M+H)+, (ESI-) m/z 476,2 (M-H)-.

Example 66

4-[4-(3-Methoxybenzyloxy)-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 31A and the product from example 57A was subjected to interaction in accordance with the method described in example 57E, using the product of example 31A instead of the product of example 57D, obtaining a solid substance, which is triturated in methanol to obtain specified in the title compound (38 mg, 45%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 10,07 (c, 1H), 9,63 (c, 1H), 9,07 (c, 1H), 8,86 (d, J=7,72 Hz, 1H), 8,59 (c, 1H), to 7.64 (c, 1H), 7.23 percent and 7.36 (m, 2H), 7,16 (DD, J=8,64, 1.65 Hz, 1H), 7,07-7,13 (m, 2H), 6,93-7,05 (m, 3H), 6,89 (DD, J=8,27, 2,02 Hz, 1H), 6,61-of 6.71 (m, 2H), 5,08 (c, 2H), 3.75 to (c, 3H);

MS (ESI+) m/z 483,2 (M+H)+, (ESI-) m/z 481,2 (M-H)-.

Example 67

4-[4-(4-Bromobenzylamine)-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 16A and the product p is example 57A was subjected to interaction in accordance with the method, described in example 57E, using the product of example 16A instead of the product of example 57D, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (11 mg, 16%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 5,09 (c, 2H), 6,66 (d, J=8,46 Hz, 2H), 6,94 (c, 1H), 7,11 (d, J=8,46 Hz, 3H), 7,25 (c, 1H), 7,41 (d, J=8,09 Hz, 2H), EUR 7.57-of 7.69 (m, 3H), 8,59 (c, 1H), 8,84 (c, 1H), 9,06 (c, 1H), for 9.64 (c, 1H), 10,07 (c, 1H);

MS ESI+ m/z 531 (M+H)+, ESI - m/z 529 (M-H)-.

Example 68

4-[4-(3-Bromobenzylamine)-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 15A and the product from example 57A was subjected to interaction in accordance with the method described in example 57E, using the product of example 15A instead of the product of example 57D, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (40 mg, 16%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 5,12 (c, 2H), to 6.67 (d, J=8,46 Hz, 2H), 6,94 (c, 1H), 7,12 (d, J=8,46 Hz, 3H), 7,26 (c, 1H), was 7.36 (t, J=7,72 Hz, 1H), 7,45 (c, 1H), 7,54 (d, J=6,62 Hz, 1H), 7,66 (c, 2H), 8,57 (c, 1H), 8,83 (c, 1H), 9,04 (c, 1H), for 9.64 (c, 1H), 10,08 (c, 1H);

MS ESI+ m/z 531 (M+H)+, ESI - m/z 529 (M-H)-.

Example 69

4-[4-Benzyloxy-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 27A and the product from example 57A was subjected to interaction in accordance with the method description is authorized in example 57E, using the product of example 27A instead of the product of example 57D, obtaining specified in the title compound, which was isolated as a salt of acetic acid (79 mg, 48%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 5,10 (c, 3H), 6,61-6,72 (m, 2H), 6,93 (d, J=9,56 Hz, 1H), 7,11 (d, J=8,46 Hz, 4H), 7,24 (c, 1H), 7,32-7,47 (m, 5H), to 7.59-to 7.68 (m, 1H), 8,54 (c, 1H), 8,83 (d, J=9,56 Hz, 1H), 9,04 (c, 1H);

ESI+ m/z 453 (M+H)+, ESI - m/z 451 (M-H)-.

Example 70

4-[4-[1-(4-Bromophenyl)ethoxy]-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 22D (153 mg, 0,367 mmol) was subjected to interaction with the product from example 57A (63 mg, 0,367 mmol) according to method described in example 57E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (97 mg, 40%).

1H NMR (300 MHz, DMSO-d6) δ ppm: or 10.60 (users, 1H), 9,67 (c, 1H), which is 9.09 (c, 1H), 8,88 (d, J=8,46 Hz, 1H), 8,64 (c, 1H), 7,73 (m, J=3,31 Hz, 1H), 7,54 (d, J=8,46 Hz, 2H), was 7.36 (d, J=8,46 Hz, 2H), 7,11 (m, 4H), 6,86 (d, J=9,19 Hz, 1H), 6,64 (d, J=8,46 Hz, 2H), 5,51 (sq, J=6,62 Hz, 1H), 1,53 (d, J=6,62 Hz, 3H);

MS (ESI+) m/z 545, 547 (M+H-TFA)+; (ESI-) m/z 543, 545 (M-H-TFA)-.

Example 71

4-[4-[1-(4-Forfinal)ethoxy]-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 23A (180 mg, 0,803 mmol) was subjected to interaction with the product from example 57A (140 mg, 0,803 mmol) according to method described in example 57E, from raw is shown in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (60 mg, 12%).

1H NMR (500 MHz, DMSO-D6) δ ppm: 1,53 (l,J=6,35 Hz, 3H), 5,51 (square, 1H), 6,61 (l,J=8,79 Hz, 2H), 6,74-PC 6.82 (m, 1H), 6,93 (DD,J=8,79, of 2.44 Hz, 1H), 7,06-to 7.09 (m, 3H), 7,11-7,19 (m, 2H), 7,44 (DD,J=8,54, 5,62 Hz, 2H), 7,83-7,86 (m,J=8,54, 5,13 Hz, 1H), 8,75 (c, 1H), 8,96 (l,J=to 7.32 Hz, 1H), 9,14 (l,J=2,93 Hz, 1H);

MS (ESI+) m/z 485.

Example 72

4-[4-[1-(3-Forfinal)ethoxy]-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 24A (285 mg, 0.80 mmol) was subjected to interaction with the product from example 57A (140 mg, 0,803 mmol) according to method described in example 57E, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (150 mg, 31%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1.55V (l,J=6.25 Hz, 3H), of 5.53 (sq,J=6,13 Hz, 1H), 6,65 (l,J=8,46 Hz, 2H), 6,85 (l,J=6,99 Hz, 1H), 7.03 is-to 7.18 (m, 4H), 7,21-7,29 (m, 2H), 7,37 was 7.45 (m, 1H), to 7.67 (DD,J=8,09, to 4.41 Hz, 1H), 8,57 (c, 1H), 8,81 (c, 1H), 9,06 (c, 1H), 9,66 (c, 1H);

MS (ESI+) m/z 485 (M+H)+.

Example 73

(5-Benzyloxy-4-chloro-2-forfinal)-(7 methylpyridin[2,3-d]pyrimidine-4-yl)Amin

Example 73A

2-Chloro-4-forfinally ether ethyl ether carbon dioxide

To a solution of 2-chloro-4-terfenol (0.8 ml, of 7.64 mmol) and triethylamine (1.3 ml, 9,16 mmol) in dichloromethane (10ml) at 0ºC was added dropwise ethylchloride (0.9 ml, 9,16 mmol). The ice bath was removed and the solution was left to warm to room temperature and was stirred for another 16 hours. Then to the mixture was added dichloromethane (20 ml), the organic solution was washed with saturated saline (50 ml), dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to obtain specified in the header of the product as oil (1.65 g, 100%).

Example 73B

2-Chloro-4-fluoro-5-nitrophenyloctyl ether ethyl ether carbon dioxide

A solution of the product from example 73A (0.88 g, a 4.03 mmol) in concentrated sulfuric acid (2 ml) was cooled in an ice bath, was slowly added fuming nitric acid (0,27 ml of 6.45 mmol) to maintain the temperature at 0ºC. The mixture was stirred for another 2 hours, then to the solution was added ice water (10 ml) and the obtained solid substance was collected by filtration, washed with water and dried in a vacuum oven to obtain specified in the title compound (0.87 g, 82%).

Example 73C

2-Chloro-4-fluoro-5-NITROPHENOL

To a solution of the product from example 73B (0.87 g, 3,30 mmol) in methanol (20 ml) and water (1 ml) was added sodium bicarbonate (2,22 g of 26.4 mmol) and the mixture was stirred at room temperature for 16 hours. Then the methanol was removed under vacuum, to the mixture was added dichloromethane (20 ml), the organic solution was washed with saturated saline (50 ml), su is or over anhydrous magnesium sulfate, was filtered and concentrated under vacuum to obtain specified in the header of the product (of 0.62 g, 98%).

Example 73D

1-Benzyloxy-2-chloro-4-fluoro-5-nitrobenzene

Specified in the title compound was obtained in accordance with the method described in example 10C, using benzylbromide and the product from example 73C instead of 1-chloromethyl-4-methoxybenzene and 4-chloro-3-NITROPHENOL (0,72 g, 79%).

Example 73E

5-Benzyloxy-4-chloro-2-forfinally

Specified in the title compound was obtained in accordance with the method described in example 10D, using the product from example 73D instead of 1-chloro-4-(4-methoxybenzyloxy)-2-nitrobenzene (77 mg, 100%).

Example 73F

(5-Benzyloxy-4-chloro-2-forfinal)-(7 methylpyridin[2,3-d]pyrimidine-4-yl)Amin

A solution of the product of example 10B (17 mg, 0,0927 mmol) and the product of example 73E (28 mg, 0,111 mmol) in acetic acid (1 ml) was stirred on an oil bath preheated to 130ºC for 15 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (8.1 mg, 17%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 2,72 (c, 3H), 5,19 (c, 2H), 7,28-7,53 (m, 6H), 7,66 (d, J=9,56 Hz, 1H), of 7.70 (d, J=8,82 Hz, 1H), 8,73 (c, 1H), 8,84 (d, J=8,09 Hz, 1H), 10,85 (c, 1H);

MS(ESI) m/z 395 (M+H)+.

Example 74

(5-Benzyloxy--chloro-2-forfinal)pyrido[2,3-d]pyrimidine-4-ylamine

Specified in the title compound was obtained in accordance with the method described in example 73F, using the product from example 57A instead of the product from example 10B (7.9 mg, 19%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 5,19 (c, 2H), 7,20-rate of 7.54 (m, 6H), the 7.65 (d, J=9,56 Hz, 1H), 7,78 (DD, J=8,27, 4,60 Hz, 1H), 8,73 (c, 1H), 8,95 (d, J=8,09 Hz, 1H), 9,12 (d, J=3,31 Hz, 1H), 10,82 (c, 1H);

MS (ESI+) m/z 381 (M+H)+.

Example 75

(5-Benzyloxy-2,4-differenl)-(7 methylpyridin[2,3-d]pyrimidine-4-yl)Amin

Example 75A

2,4-Differenly ether ethyl ether carbon dioxide

Specified in the title compound was obtained in accordance with the method described in example 73A, using 2,4-diferena instead of 2-chloro-4-terfenol (1.48 g, 96%).

Example 75B

2,4-Debtor-5-nitrophenyloctyl ether ethyl ether carbon dioxide

Specified in the title compound was obtained in accordance with the method described in example 73B.

Example 75C

2,4-Debtor-5-NITROPHENOL

Specified in the title compound was obtained in accordance with the method described in example 73C, using the product from example 73B instead of the product 313B (0,59 g, 89%).

Example 75D

1-Benzyloxy-2,4-debtor-5-nitrobenzene

Specified in the title compound was obtained in accordance with the method described in example 73D, using the product from example 75C instead of the product 313C (0.56 g, 63%).

Example 75E

5-Benzyloxy-2,4-dipertanyakan

Specify the OU in the title compound was obtained in accordance with the method, described in example 73E, using the product from example 75D instead of the product 313D (89 mg, 100%).

Example 75F

(5-Benzyloxy-2,4-differenl)-(7 methylpyridin[2,3-d]pyrimidine-4-yl)Amin

Specified in the title compound was obtained in accordance with the method described in example 73F, using the product from example 75E instead of the product from example 73E. The obtained residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (7.4 mg, 16%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 2,72 (c, 3H), 5,17 (c, 2H), 7,19-of 7.60 (m, 7H), 7,71 (d, J=8,46 Hz, 1H), 8,75 (c, 1H), cent to 8.85 (d, J=8,46 Hz, 1H), 10,84 (c, 1H);

MS(ESI) m/z 379 (M+H)+.

Example 76

(5-Benzyloxy-2,4-differenl)pyrido[2,3-d]pyrimidine-4-ylamine

A solution of the product of example 57A (17 mg, 0,099 mmol) and the product of example 73E (28 mg, 0,119 mmol) in acetic acid (1 ml) was stirred on an oil bath preheated to 130ºC for 15 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (21,4 mg, 45%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 5,17 (c, 2H), 7,19-to 7.61 (m, 7H), 7,80 (DD, J=8,09, to 4.41 Hz, 1H), 8,77 (c, 1H), 8,97 (d, J=7,35 Hz, 1H), 9,14 (d, J=2,94 Hz, 1H), 10,88 (c, 1H);

MS (ESI+) m/z 365 (M+H)+.

Example 77

4-{2-[Benzyl-(7-methylpurine[2,3-d]pyrimidine-4-yl)amino-4-benzyloxyaniline}phenol

To a solution of the product of example 27 (26,3 mg, holding 0.062 mmol), benzylbromide (0,0075 ml, holding 0.062 mmol) and potassium carbonate (8.6 mg, holding 0.062 mmol) inN,N-dimethylformamide (0.5 ml) was stirred at room temperature for 16 hours. Then the mixture was poured into ice water (10 ml) and the resulting solution was acidified using 1N. aqueous solution of hydrochloric acid. Then the solution was extracted with ethyl acetate (3×10 ml), the combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to obtain crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (6,7 mg, 18%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,74 (c, 3H), 5,10 (c, 2H), 5,69 (c, 1H), 6,65 (l,J=8,82 Hz, 2H), 7,02-to 7.18 (m, 2H), 7,14-7,26 (m, 1H), 7,26-7,58 (m, 12H), 7,86 (c, 1H), 8,93 (c, 1H), 9,23 (c, 1H), 9,73 (c, 1H), 12,09 (c, 1H);

MS (ESI+) m/z 557 (M+H)+.

Example 78

(5-Benzyloxy-2-bromophenyl)-(7 methylpyridin[2,3-d]pyrimidine-4-yl)Amin

Example 78A

5-Benzyloxy-2-brompheniramine

Specified in the title compound was obtained in accordance with the method described in Boger, D.L., Wysocki, J., Ishizaki, T.J. Am. Chem. Soc.112, 1990, p. 5230-5240. The resulting number was 4,58 g, 48%.

Example 78B

(5-Benzyloxy-2-bromophenyl)-(7 methylpyridin[2,3-d]pyrimidine-4-yl)Amin

The product from example 78A (2.0 g, 7.19 mmol) and the product from example 10B (1.35 g, 7.19 mmol) in acetic Ki the lot (15 ml) was gradually heated from room temperature to 130ºC in an oil bath for 15 minutes, then was heated at 130ºC for another 1.5 hours. Then the mixture was cooled to room temperature, concentrated under vacuum to obtain crude specified in the title compound (3.4 g sticky syrup red, 100%), part of which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (81 mg).

1H NMR (300 MHz, DMSO-d6) δ ppm: 2,74 (c, 3H), 5,14 (c, 2H), 7,06 (DD, J=8,8, 2,9 Hz, 1H), 7.23 percent (m, 1H), 7,41 (m, 5H), of 7.70 (d, J=8,8 Hz, 1H), 7,78 (d, J=8.5 Hz, 1H), 8,79 (c, 1H), 8,91 (d, J=8,8 Hz, 1H), 11,40 (users, 1H);

MS (ESI+) m/z 421/423 (M+H)+.

Example 79

2-Chloro-N-[3-(pyrido[2,3-d]pyrimidine-4-ylamino)phenyl]benzamide

Example 79A

N-(3-AMINOPHENYL)-2-chlorobenzamide

Specified in the title compound was obtained in accordance with the method described in example 254A, using 2-chlorobenzylchloride instead of 4-bromobenzonitrile, then restored the nitrogroup in the manner described in example 255B obtaining specified in the header of the product.

Example 79B

2-Chloro-N-[3-(pyrido[2,3-d]pyrimidine-4-ylamino)phenyl]benzamide

The product from example 79A was subjected to interaction with the product from example 57A in the manner described in example 254C, using the product from example 79A instead of the product from example 254B, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt is referencesee acid (18 mg, 22%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 7,45-rate of 7.54 (m, 4H), 7,56 to 7.62 (m, 3H), 7,83-of 7.90 (m, 1H), 8,25-8,29 (m, 1H), 8,93 (c, 1H), 9,12-9,18 (m, 2H), 10,70 (c, 1H), 11,23 (c, 1H);

MS ESI+ m/z 376 (M+H)+, ESI - m/z 374 (M-H)-.

Example 80

2-Bromo-N-[3-(pyrido[2,3-d]pyrimidine-4-ylamino)phenyl]benzamide

Example 80A

N-(3-AMINOPHENYL)-2-bromobenzene

Specified in the title compound was obtained in accordance with the method described in example 254A, using 2-bromobenzoate instead of 4-bromobenzonitrile, then restored the nitrogroup in the manner described in example 255B, obtaining specified in the header of the product.

Example 80B

2-Bromo-N-[3-(pyrido[2,3-d]pyrimidine-4-ylamino)phenyl]benzamide

The product from example 80A was subjected to interaction with the product from example 57A in the manner described in example 254C, using the product from example 80A instead of the product from example 254B, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (18 mg, 22%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 7,44-rate of 7.54 (m, 4H), 7,56-of 7.60 (m, 2H), 7,74 (DD, J=to $ 7.91, to 0.92 Hz, 1H), 7,82-7,89 (m, 1H), 8,27 (c, 1H), 8,92 (c, 1H), 9,11-9,19 (m, 2H), is 10.68 (c, 1H), 11,20 (c, 1H);

MS ESI+ m/z 420 (M+H)+, ESI - m/z 418 (M-H)-.

Example 81

2-Methoxy-N-[3-(pyrido[2,3-d]pyrimidine-4-ylamino)phenyl]benzamide

Example 81A

N-(3-AMINOPHENYL)-2-methoxybenzamide

Specified in the title compound was obtained according to the accordance with the method, described in example 254A, using 2-methoxybenzoate instead of 4-bromobenzonitrile, then restored the nitrogroup, the method described in example 255B, obtaining specified in the header of the product.

Example 81B

2-Methoxy-N-[3-(pyrido[2,3-d]pyrimidine-4-ylamino)phenyl]benzamide

The product from example 81A was subjected to interaction with the product from example 57A in the manner described in example 254C, using the product from example 81A instead of the product from example 254B, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (26 mg, 33%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 3,90 (c, 3H), was 7.08 (t, J=6,99 Hz, 1H), 7,20 (d, J=8,46 Hz, 1H), 7,41-7,56 (m, 4H), a 7.62 (DD, J=7,54, 1.65 Hz, 1H), 7,88 (dt, 1H), 8,28 (c, 1H), 8,94 (c, 1H), 9,12-9,19 (m, 2H), 10,30 (c, 1H), 11,30 (c, 1H);

MS ESI+ m/z 372 (M+H)+, ESI - m/z 370 (M-H)-.

Example 82

3-Methoxy-N-[3-(pyrido[2,3-d]pyrimidine-4-ylamino)phenyl]benzamide

Example 82A

N-(3-AMINOPHENYL)-3-methoxybenzamide

Specified in the title compound was obtained in accordance with the method described in example 254A, using 3-methoxybenzoate instead of 4-bromobenzonitrile, then restored the nitrogroup, the method described in example 255B, obtaining specified in the header of the product.

Example 82B

3-Methoxy-N-[3-(pyrido[2,3-d]pyrimidine-4-ylamino)phenyl]benzamide

The product p is the iMER 82A was subjected to interaction with the product from example 57A way described in example 254C, using the product from example 82A instead of the product from example 254B, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (35 mg, 45%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 3,85 (c, 3H), 7,18 (DD, J=7,54, 2,02 Hz, 1H), 7,42-7,51 (m, 3H), 7,53-to 7.61 (m, 3H), of 7.82 (DD, J=7,72, 5,15 Hz, 1H), 8,32 (t, J=1,84 Hz, 1H), 8,89 (c, 1H), which is 9.09-9,17 (m, 2H), 10,38 (c, 1H), 10,99 (c, 1H);

MS ESI+ m/z 372 (M+H)+, ESI - m/z 370 (M+H).

Example 83

3-Fluoro-N-[3-(pyrido[2,3-d]pyrimidine-4-ylamino)phenyl]benzamide

Example 83A

N-(3-AMINOPHENYL)-3-perbenzoic

Specified in the title compound was obtained in accordance with the method described in example 254A, using 3-perbenzoate instead of 4-bromobenzonitrile, then restored the nitrogroup in the manner described in example 255B, obtaining specified in the header of the product.

Example 83B

3-Fluoro-N-[3-(pyrido[2,3-d]pyrimidine-4-ylamino)phenyl]benzamide

The product from example 83A were subjected to interaction with the product from example 57A in the manner described in example 254C, using the product from example 83A instead of the product from example 254B, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (21 mg, 28%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 7,41-7,53 (m, 2H), 7,54-the 7.65 (m, 3H), to 7.77-7,86 (m, 3H), 8,33(c, 1H), 8,89 (c, 1H), 9,10-9,16 (m, 2H), 10,48 (c, 1H), 10,97 (c, 1H);

MS ESI+ m/z 360 (M+H)+, ESI - m/z 358 (M-H)-.

Example 84

4-[4-Benzylamino-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 84A

4-(4-Amino-2-nitrophenyloctyl)phenol

A solution of 4-chloro-3-nitroaniline (1.0 g, 5,79 mmol), 4-hydroxythiophenol (0.75 g, 6,00 mmol), cesium carbonate (3.9 g, 12 mmol) in dimethyl sulfoxide (10 ml) was heated at 100ºC for 16 hours. Then to the solution was added ice water (50 ml) and the resulting suspension was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. Drying substance was filtered and the solvent was removed under vacuum to obtain specified in the connection header in a solid red color (1.45 g, 92%).

Example 84B

4-(4-Benzylamino-2-nitrophenyloctyl)phenol

A solution of the product of example 84A (to 0.63 g, 2.4 mmol), benzaldehyde (0.24 g, 2.3 mmol) and cyanoborohydride sodium (0.15 g, 2.4 mmol) in methanol (10 ml)containing 1% acetic acid was stirred at room temperature for 16 hours. The reaction mixture was extinguished with water (20 ml) and the resulting solution was concentrated under vacuum to obtain a solid yellow color. The solid was dissolved in ethyl acetate (50 ml) and washed with water, 10% bicarbonato the sodium and 10% sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum to obtain the oil is light yellow in color. The oil was purified by chromatography on silica gel, elwira 1% methanol in methylene chloride, to obtain specified in the connection header (0,63 g, 77%).

Example 84C

4-(4-Amino-4-benzylaminocarbonyl)phenol

A solution of the product of example 84B (0.5 g, 1.4 mmol), iron powder (0,49 g, a total of 8.74 mmol) and ammonium chloride (0.50 g, 9.3 mmol) in a solution of methanol (10 ml), tetrahydrofuran (10 ml) and water (5 ml) was heated under reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a layer of celite. The filtrate was concentrated under vacuum to a volume of 10 ml, the solution was diluted with water (50 ml) and was extracted with ethyl acetate (2×50 ml). The combined extracts were washed with 10% sodium chloride, then dried over magnesium sulfate, filtered and concentrated under vacuum to obtain specified in the connection header (0,30 g, 66%).

Example 84D

4-[4-Benzylamino-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

A solution of the product from example 10B (30 mg strength of 0.159 mmol) and the product from example 84C (56,5 mg, 0,17 mmol) in acetic acid (2 ml) was stirred on an oil bath preheated to 130ºC for 20 minutes. Then the mixture was cooled to room t is mperature, acetic acid was removed under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (12 mg, 10%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,71 (c, 3H), 4,50 (c, 2H), 6,60-6,69 (m, 2H), 6.73 x-6,85 (m, 2H),? 7.04 baby mortality-7,29 (m, 6H), 7,31-7,40 (m, 2H), 7,46 (d, J=7,35 Hz, 2H), 8,54 (c, 1H), 8,75 (c, 1H), 9,74 (c, 1H);

MS(ESI) m/z 466 (M+H)+, (ESI-) m/z 464 (M-H)-.

Example 85

N1-Benzyl-4-(4-benzyloxycarbonyl)-N3-(7-methylpurine[2,3-d]pyrimidine-4-yl)benzene-1,3-diamine

Example 85A

4-(2-Amino-4-nitrophenylarsonic)phenol

A solution of 2-chloro-5-nitroaniline (3 g, of 17.4 mmol), 4-hydroxythiophenol (2.4 g, 19.0 mmol), cesium carbonate (12,35 g, 38 mmol) in dimethylformamide (35 ml) was heated at 100ºC for 16 hours. Then to the solution was added ice water (200 ml) and the resulting suspension was added ethyl acetate (200 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, dried over anhydrous sodium sulfate. Drying substance was filtered and the solvent was removed under vacuum to obtain yellow oil. The oil was purified by chromatography on silica gel, elwira a mixture of methylene chloride/methanol (97:3), obtaining specified in the connection header a solid yellow (2.1 g, 46%).

Example 85B

2-(4-Benzyloxycarbonyl)-5-nitrophenylamino

A suspension containing the product in use is at 85A (0.2 g, 0,763 mmol) and cesium carbonate (0.25 g, 0,763 mmol) in dimethylformamide (5 ml)was treated with benzylbromide (0,091 ml, 0,763 mmol) and the resulting suspension was stirred 18 hours at room temperature. Then to the solution was added ice water (50 ml) and the resulting suspension was added ethyl acetate (50 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, dried over anhydrous sodium sulfate. Drying substance was filtered and the solvent was removed under vacuum to obtain specified in the connection header in a solid yellow color(0.24 g, 89%).

Example 85C

[2-(4-Benzyloxycarbonyl)-5-nitrophenyl]-(7-methylpurine[2,3-d]pyrimidine-4-yl)Amin

A solution of the product from example 10B (62 mg, 0,331 mmol) and the product of example 85B (120 mg, 0,331 mmol) in acetic acid (1 ml) was stirred on an oil bath preheated to 130ºC for 20 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum to obtain specified in the title compound as brown oil (0.15 g, 92%). The compound was used without purification in the next stage.

Example 85D

4-(4-Benzyloxycarbonyl)-N3-(7-methylpurine[2,3-d]pyrimidine-4-yl)benzene-1,3-diamine

A solution of the product from example 85C (0,150 g, 0,303 mmol), iron powder (0.10 g, of 1.86 mmol) and ammonium chloride (0,10g, to 1.98 mmol) in a solution of methanol (2 ml), tetrahydrofuran (2 ml) and water (1 ml) was heated under reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a layer of celite. The filtrate was concentrated under vacuum to a volume of 10 ml, the solution was diluted with water (50 ml) and was extracted with ethyl acetate (2×50 ml). The combined extracts were washed with 10% sodium chloride, then dried over magnesium sulfate, filtered and concentrated under vacuum to obtain specified in the title compound (0.06 g, 42%).

Example 85E

N1-Benzyl-4-(4-benzyloxycarbonyl)-N3-(7-methylpurine[2,3-d]pyrimidine-4-yl)benzene-1,3-diamine

The mixture of compounds obtained in example 85D (0.06 g, 0,130 mmol), benzaldehyde (0,013 g, 0,130 mmol) and cyanoborohydride sodium (0,0081 g, 0.13 mmol) in methanol (1 ml)containing 1 drop of acetic acid was stirred 18 hours at room temperature. The solvent was removed under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (12 mg, 17%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,69 (c, 3H), 4,30 (c, 2H), 4,96 (c, 2H), 6,60 (DD, J=8,46, to 2.57 Hz, 1H), 6,72-6,89 (m, 3H), 6,94-to 7.09 (m, 2H), 7,19-7,29 (m, 1H), 7,29-7,46 (m, 11H), 7,63 (d, J=8,46 Hz, 1H), 8,61 (c, 1H), 8,71 (d, J=8,82 Hz, 1H), 10,69 (c, 1H).

Example 86

4-[4-[(Furan-3-ylmethyl)amino]-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)panels JPanel]phenol

Example 86A

4-[2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-nitrophenylarsonic]phenol

A solution of the product from example 10B (340 mg, of 1.80 mmol) and the product from example 85A (480 mg, of 1.80 mmol) in acetic acid (10 ml) was stirred on an oil bath preheated to 130ºC for 30 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum to obtain specified in the title compound as brown oil (0.65 g, 89%).

Example 86B

4-[4-Amino-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

A suspension of the product from example 86A (0,19 g, 0,469 mmol) and 10% Pd/C (0.025 g) in acetic acid (3 ml) were placed in an atmosphere of hydrogen with stirring for 2 hours at room temperature. The suspension was filtered and the solvent was removed under vacuum to obtain solid brown color in the form of the acetate salt specified in the title compound (0.21 g, 91%).

Example 86C

4-[4-[(Furan-3-ylmethyl)amino]-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

A solution of the product from example 86B (69,7 mg, 0,141 mmol), 3-furaldehyde (13.5 mg, 0,141 mmol) and cyanoborohydride sodium (8,7 mg, 0,141 mmol) in 2 ml of methanol was stirred 18 hours at room temperature. The solvent was evaporated under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection in the form of salts triperoxonane acid (16 mg, 14%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,75 (c, 3H), 3,85 (c, 1H), 4.09 to (c, 2H), 6,47 (c, 1H), 6,53 (d, J=8,82 Hz, 2H), 6,62 to 6.75 (m, 2H), 6,94 (d, J=8,46 Hz, 3H), 7,21-7,32 (m, 1H), to 7.61 (c, 1H), 7,83 (d, J=8,46 Hz, 1H), 8,77 (c, 1H), 8,88 (c, 1H), 9,51 (c, 1H), 11,68 (c, 1H).

Example 87

4-{2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-[(thiophene-3-ylmethyl)amino]phenylsulfonyl}phenol

A solution of the product from example 86B and 3-thiophenecarboxaldehyde subjected interaction in accordance with the method described in example 86C, using 3-thiophenecarboxaldehyde instead of 3-furaldehyde, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (26 mg, 37%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,74 (c, 3H), 3,74 (c, 1H), 4.26 deaths (c, 2H), of 6.52 (d, J=8,82 Hz, 3H), 6,64-6,76 (m, 1H), 6,86-of 6.99 (m, 3H), 7,02-7,14 (m, 1H), 7,19-7,34 (m, 1H), 7,42-rate of 7.54 (m, 1H), 7,82 (d, J=8,09 Hz, 1H), 8,76 (c, 1H), 8,90 (c, 1H), 9,51 (c, 1H), 11,65 (c, 1H).

Example 88

4-{2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-[(naphthalene-1-ylmethyl)amino]phenylsulfonyl}phenol

A solution of the product from example 86B and 1-naphthaldehyde subjected interaction in accordance with the method described in example 86C, using 1-naphthaldehyde instead of 3-furaldehyde, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (18 mg, 12%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,73 (c, 3H), 4,73 (c 1H), 6,39 (c, 1H), 6,45-6,60 (m, 2H), 6,67-to 6.80 (m, 1H), 6,88-6,98 (m, 2H), 7,17-7,34 (m, 1H), 7,43-rate of 7.54 (m, 1H), 7,51-7,71 (m, 4H), 7,71-7,83 (m, 1H), 7,83 (d, J=8,82 Hz, 1H), 7.95 is-of 8.09 (m, 2H), 8,10-8,18 (m, 1H), by 8.22 (d, J=8,09 Hz, 1H), 8,76 (c, 1H), 8,82-8,89 (m, 1H), 9,51 (c, 1H), 11,64 (c, 1H).

Example 89

4-[4-[(Furan-2-ylmethyl)amino]-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

A solution of the product from example 86B and 2-furaldehyde subjected interaction in accordance with the method described in example 86C, using 2-furaldehyde instead of 3-furaldehyde, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (18 mg, 16%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,69-of 2.81 (m, 3H), 4.26 deaths (c, 2H), 6,27-6,44 (m, 1H), 6,45-6,59 (m, 2H), 6,46-6,60 (m, 3H), 6,68-of 6.78 (m, 2H), 6.89 in-7,00 (m, 2H), 7,20-7,33 (m, 1H), to 7.59 (c, 1H), to 7.84 (d, J=8,09 Hz, 1H), 8,77 (c, 1H), 8,89 (c, 1H), 11,73 (c, 1H).

Example 90

4-{2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-[(thiophene-2-ylmethyl)amino]phenylsulfonyl}phenol

A solution of the product from example 86B and 2-thiophenecarboxaldehyde subjected interaction in accordance with the method described in example 86C, using 2-thiophenecarboxaldehyde instead of 3-furaldehyde, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (11 mg, 16%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,64-of 2.86 (m, 3H), 4,47 (c, 2H), 6,46-to 6.57 (m, 2H), 6,4-of 6.78 (m, 3H), 6.87 in-7,00 (m, 3H), 7,02-7,13 (m, 2H), 7,19-7,31 (m, 2H), 7,32-of 7.48 (m, 1H), 7,82 (d, J=8,82 Hz, 1H), 8,77 (c, 1H), 8,89 (c, 1H), 9,50 (c, 1H), 11,68 (c, 1H).

Example 91

4-[4-(4-Bromobenzylamine)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 91A

4-[4-(4-Bromobenzylamine)-2-nitrophenyloctyl]phenol

A solution of the product from example 84A and 4-bromobenzaldehyde subjected interaction in accordance with the method described in example 84B, using 4-bromobenzaldehyde instead of the product from example 84A, to obtain the crude product, which was purified by chromatography on silica gel, elwira 2% methanol in methylene chloride, to obtain specified in the connection header in a solid yellow color (0.11 g, 73%).

Example 91B

4-[2-Amino-4-(4-bromobenzylamine)phenylsulfanyl]phenol

A solution of the product from example 91A was subjected to interaction in accordance with the method described in example 84C, obtaining specified in the title compound (0.17 g, 76%).

Example 91C

4-[4-(4-Bromobenzylamine)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

A solution of the product of example 10B (50 mg, 0,266 mmol) and the product of example 91B (110 mg, 0,266 mmol) in acetic acid (2 ml) was stirred on an oil bath preheated to 130ºC for 20 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum and obtained the initial residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (22 mg, 15%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,73 (c, 3H), 4.26 deaths (c, 2H), 6,53 (d, J=8,46 Hz, 2H), 6,54-6,69 (m, 2H), 6,85-7,03 (m, 2H), 7.23 percent (d, J=8,46 Hz, 1H), 7,30 (d, J=8,46 Hz, 3H), 7,46-to 7.61 (m, 2H), 7,78 (d, J=8,46 Hz, 1H), 8,73 (c, 1H), 8,89 (d, J=19,12 Hz, 1H), 9,51 (c, 1H), 11,46 (c, 1H).

Example 92

N1-Benzyl-4-(4-methoxybenzenesulfonyl)-N3-(7-methylpurine[2,3-d]pyrimidine-4-yl)benzene-1,3-diamine

4-(4-Methoxybenzenesulfonyl)-3-nitrophenylamino

Example 92A

A solution of 4-chloro-3-nitroaniline (1.0 g, 5,79 mmol), 4-methoxythiophene (0.84 g, 6,00 mmol), cesium carbonate (1,95 g, 6,00 mmol) in dimethylformamide (10 ml) was heated at 100ºC for 16 hours. Then to the solution was added ice water (50 ml) and the resulting suspension was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. Drying substance was filtered and the solvent was removed under vacuum to obtain specified in the connection header in the form of a solid color red (1.5 g, 94%).

Example 92B

Benzyl-[4-(4-methoxybenzenesulfonyl)-3-nitrophenyl]Amin

A solution of the product of example 92A (0.50 g, is 1.81 mmol), benzaldehyde (0,19 g, is 1.81 mmol) and cyanoborohydride sodium (0.11 g, 1.8 mmol) in methanol (10 ml)containing 1% acetic acid was stirred at room temperature for 16 hours. The reaction mixture was extinguished with water (20 ml) and the resulting solution koncentrira is whether under vacuum to obtain a solid yellow color. The solid was dissolved in ethyl acetate (50 ml) and washed with water, 10% sodium bicarbonate and 10% sodium chloride. The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent was removed under vacuum to obtain the oil is light yellow in color. The oil was purified by chromatography on silica gel, elwira 1% methanol in methylene chloride, to obtain specified in the connection header in the form of solids brown-red (0,62 g, 91%).

Example 92C

N1-Benzyl-4-(4-methoxybenzenesulfonyl)benzene-1,3-diamine

A solution of the product of example 92B was subjected to interaction in accordance with the method described in example 84C, obtaining specified in the connection header (0,49 g, 89%).

Example 92D

N1-Benzyl-4-(4-methoxybenzenesulfonyl)-N3-(7-methylpurine[2,3-d]pyrimidine-4-yl)benzene-1,3-diamine

A solution of the product of example 10B (27.8 mg, 0,148 mmol) and the product of example 92C (49 mg, 0,148 mmol) in acetic acid (2 ml) was stirred on an oil bath preheated to 130ºC for 20 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (15 mg, 14%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,64-of 2.81 (m, 3H), 3,56-3,71 (m, 3H), 4,29 (c, 2H), 6,61 to 6.75 (m, 3H), 6,95-7,07 (m, 2H), 7,16-7,45 (who, 8H), 7,76 (d, J=8,46 Hz, 1H), 8,69 (c, 1H), 8,80 (d, 1H), 11,34 (c, 1H).

Example 93

N1-Benzyl-4-(4-methoxyphenoxy)-N3-(7-methylpurine[2,3-d]pyrimidine-4-yl)benzene-1,3-diamine

Example 93A

4-(4-Methoxyphenoxy)-3-nitrophenylamino

A solution of 4-chloro-3-nitroaniline (1.0 g, 5,79 mmol), 4-methoxyphenol (0.74 g, 6,00 mmol), cesium carbonate (1,95 g, 6,00 mmol) in dimethylformamide (10 ml) was heated at 100oC for 16 hours. Then to the solution was added ice water (50 ml) and the resulting suspension was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. Drying substance was filtered and the solvent was removed under vacuum to obtain specified in the connection header in a solid red color (1.1 g, 73%).

Example 93B

N1-Benzyl-4-(4-methoxyphenoxy)benzene-1,3-diamine

A solution of the product from example 93A subjected interaction in accordance with the method described in example 92B, using the product from example 93A instead of the product from example 92A, which was restored in accordance with the method described in example 84C, obtaining specified in the title compound (0.05 g, 12%).

Example 93C

N1-Benzyl-4-(4-methoxyphenoxy)-N3-(7-methylpurine[2,3-d]pyrimidine-4-yl)benzene-1,3-diamine

A solution of the product of example 10B and product for example the 93B subjected interaction in accordance with the method, described in example 92D, using the product from example 93B instead of the product from example 92C, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (8 mg, 18%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,55 of 2.68 (m, 3H), 3,61 (c, 3H), 4.26 deaths (d, J=5,88 Hz, 2H), 6,27 (t, J=5,88 Hz, 1H), 6,50 (DD, J=8,64, 2.76 Hz, 1H), 6,64-6,87 (m, 6H), 7,18 was 7.45 (m, 6H), 8,48 (c, 1H), to 8.57 (d, J=8,46 Hz, 1H), 9,59 (c, 1H).

Example 94

N1-Benzyl-4-(4-benzyloxyphenyl)-N3-(7-methylpurine[2,3-d]pyrimidine-4-yl)benzene-1,3-diamine

Example 94A

4-(4-Benzyloxyphenyl)-3-nitrophenylamino

A solution of 4-chloro-3-nitroaniline (2.0 g, 11,16 mmol), 4-benzyloxyphenol (2.55 g, of 12.76 mmol), powdered potassium hydroxide (0,94 g, Ls 16.80 mmol) in dimethylformamide (15 ml) was heated at 120ºC for 20 hours. Then to the solution was added ice water (50 ml) and the resulting suspension was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. Drying substance was filtered and the solvent was removed under vacuum to obtain specified in the connection header in the form of tverdogo substances dark red (2,07 g, 53%).

Example 94B

N1-Benzyl-4-(4-benzyloxyphenyl)benzene-1,3-diamine

A solution of the product from example 94A was subjected to interaction in accordance with the method described in the example 92B, using the product from example 94A instead of the product from example 92A, which was restored in accordance with the method described in example 84C, obtaining specified in the title compound (0.6 g, 91%).

Example 94C

N1-Benzyl-4-(4-benzyloxyphenyl)-N3-(7-methylpurine[2,3-d]pyrimidine-4-yl)benzene-1,3-diamine

A solution of the product of example 10B and the product from example 94B subjected interaction in accordance with the method described in example 92D, using the product from example 94B instead of the product from example 92C, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (12 mg, 10%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,70 (c, 3H), 4,27 (c, 2H), 4,94 (c, 2H), 4,99-5,12 (m, 1H), only 6.64 (DD, J=8,82, to 2.94 Hz, 1H), 6,70-6,92 (m, 9H), 6.90 to-7,00 (m, 1H), 7,16-7,29 (m, 1H), 7,31-7,42 (m, 5H), of 7.70 (d, J=8,46 Hz, 1H), 8,67-8,86 (m, 2H), 11,22 (c, 1H).

Example 95

4-[4-Amino-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 95A

4-[2-(7-Isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-4-nitrophenylarsonic]phenol

A solution of the product from example 10B (340 mg, 2,31 mmol) and the product of example 85A (610 mg, 2,30 mmol) in acetic acid (10 ml) was stirred on an oil bath preheated to 130ºC for 10 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum to obtain specified in the connection header in VI is e oil brown (0,92 g, 92%).

Example 95B

4-[4-Amino-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

A suspension of the compound obtained in example 95A (0.7 g, of 1.73 mmol)and 10% Pd/C (100 mg) in acetic acid (10 ml) and methanol (10 ml) were placed in an atmosphere of hydrogen from the container under stirring for 20 hours at room temperature. The suspension was filtered and the solvent was removed under vacuum to obtain specified in the connection header in the form of a salt of acetic acid (540 mg, 63%).

1H NMR (300 MHz, DMSO-D6) δ ppm: to 1.35 (d, J=7,0 Hz, 6H), 1.91 a (c, 6H), of 3.27 (m, 1H), 6,55 (d, J=8,8 Hz, 2H), 6,62 (m, 1H), 6,69 (m, 1H), 6,95 (d, J=8,8 Hz, 2H), 7,20 (d, J=8.5 Hz, 1H), 7,87 (d, J=8.5 Hz, 1H), 7,95 (c, 1H), 8,75 (c, 1H), 8,99 (m, 1H), 9,52 (c, 1H), 11,57 (users, 1H);

MS (ESI+) m/z 404 (M+H)+.

Example 96

4-[2-(7-Isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-4-penicillinresistant]phenol

The solution containing the product from example 95B (65 mg, 0,124 mmol), phenylacetaldehyde (15 mg, 0,124 mmol) and cyanoborohydride sodium (10 mg, 0,199 mmol) in 2 ml of methanol, stirred 18 hours at room temperature. The solvent was evaporated under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (25 mg, 32%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1.28 (in d, 6H), 2,31-2,48 (m, 1H), 2,78-of 2.93 (m, 2H), 3,16-to 3.35 (m, 2H), 4,17 is 4.36 (m, 2H), 4,73-4,91 (m, 1H), 6,47-6,59 (m, 2H), 6,61-6,74 (m, 1H), 6,86-7,01 (m, 2H), 7,10 (d, J=Hz 6,99, 1H), 7,15-7,27 (m, 1H), 7,19-7,9 (m, 6H), 7,89 (d, J=8,46 Hz, 1H), 8,77 (c, 1H), 8,96 (c, 1H), 9,50 (c, 1H), of 11.61 (c, 1H).

Example 97

4-[4-(Cyclopentylmethyl)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The solution containing the product from example 95B were subjected to interaction with cyclopentanecarboxaldehyde in accordance with the method described in example 96, using cyclopentanecarboxaldehyde instead of phenylacetaldehyde, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (11 mg, 9%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,26 was 1.43 (m, 6H), 1,53 (c, 4H), of 1.75 (d, J=3,31 Hz, 4H), 2,01-2,19 (m, 1H), 2,92 (d, J=6,99 Hz, 2H), 3,20-to 3.36 (m, 1H), 6,53 (d, J=8,82 Hz, 2H), 6,58-of 6.73 (m, 1H), 6.87 in-7,00 (m, 2H), 6,98-7,13 (m, 1H), 7,17 and 7.36 (m, 1H), 7,89 (c, 1H), 8,15 (c, 1H), 8,77 (c, 1H), 8,95 (c, 1H), 9,49 (c, 1H), 10,98 (c, 1H), 11,68 (c, 1H).

Example 98

N1-Benzyl-N3-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)-4-(4-methoxybenzenesulfonyl)benzene-1,3-diamine

A solution of the product from example 36E (40,4 mg, 0,187 mmol) and the product of example 92C (of 62.8 mg, 0,187 mmol) in acetic acid (2 ml) was stirred on an oil bath pre-heated to 140ºC for 45 minutes. The reaction mixture was cooled to room temperature, diluted with hexane (50 ml), concentrated on a rotary evaporator and was co-evaporated with a mixture of methylene chloride/hexane (4×). The residue was dried under vacuum, then purified flash chromatography on silica gel with a gradient mixture of the t 15% to 20% ethyl acetate/methylene chloride as eluent to obtain specified in the connection header in a solid yellow color (up 29.6 mg, 31%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,31 (l,J=6,99 Hz, 6H), 3,11-3,26 (m, 1H), 3,64 (c, 3H), 4,30 (l,J=5,88 Hz, 2H), 6,53 (DD,J=8,46, to 2.57 Hz, 1H), 6,66-of 6.78 (m, 3H), 6,95 (l,J=of 2.21 Hz, 1H), 7,03 (l,J=8,82 Hz, 2H), 7,12-7,28 (m, 2H), 7,28-7,44 (m, 4H), 7,54 (e,J=8,46 Hz, 1H), 8,50 (c, 1H), 8,65 (l,J=8,46 Hz, 1H), 9,75 (c, 1H);

MS (DCI/NH3) m/z 508 (M+H)+.

Example 99

4-[2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-pyrrol-1-intenlational]phenol

To a solution of the product from example 86B (50 mg, 0,101 mmol) and succinic dialdehyde (40% solution in water) (0,065 ml, 0,303 mmol) in toluene (5 ml) and methanol (3 ml) was added 4Å molecular sieves (100 mg). Then the mixture was heated to 60ºC for 7 hours, cooled to room temperature, the solvent was removed under vacuum, was added 0.1 G. of aqueous solution of hydrochloric acid (20 ml) and the mixture was extracted with dichloromethane (2×25 ml) and dioxane (25 ml). The combined organic extracts were dried and concentrated under vacuum, and then the obtained residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (14 mg, 26%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,68 (c, 3H), of 6.26 (m, 2H), 6,77 (d, J=8.5 Hz, 2H), 7,05 (d, J=8.5 Hz, 1H), 7,24 (d, J=8.5 Hz, 2H), 7,37 (m, 2H), of 7.48 (DD, J=8,6, and 2.4 Hz, 1H), EUR 7.57 (d, J=8.5 Hz, 1H), 7,73 (d, J=2.6 Hz, 1H), 8,57 (c, 1H), 8,80 (d, J=8,4 Hz, 1H), 9,81 (c, 1H), 10,11 (c, 1H);

MS (ESI+) m/z 426 (M+H)+.

Example 100

4-[2,4-Bis-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]the dryer is l

To a solution of the product from example 86B (50 mg, 0,101 mmol) and the product from example 10B (19 mg, 0,101 mmol) in acetic acid (1 ml) was heated to 120ºC for 2 hours. After cooling to room temperature the solvent was removed under vacuum and was added methanol (2 ml). The obtained solid was collected and triturated in methanol to obtain specified in the connection header in the form of a solid light brown color (12 mg, 23%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,67 (c, 3H), 2,68 (m, 3H), of 6.75 (d, J=8,8 Hz, 2H), 6,83 (m, 1H), 7,12 (m, 1H), 7,21 (d, J=8,8 Hz, 2H), 7,34 (m, 1H), 7,58 (m, J=8,8 Hz, 2H), 8,73 (c, 1H), 8,81 (m, 1H), 8,88 (m, 1H), 9,76 (c, 1H), 10,13 (c, 1H), 11,95 (users, 1H);

MS (ESI+) m/z 519 (M+H)+.

Example 101

4-[4-(4-Bromobenzylamine)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The solution containing the product from example 95B were subjected to interaction with 4-bromobenzaldehyde in accordance with the method described in example 96, using 4-bromobenzaldehyde instead of phenylacetaldehyde, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (7 mg, 3%).

1H NMR (300 MHz, DMSO-D6) δ ppm: to 1.35 (d, J=6.6 Hz, 6H), 3,30 (m, 1H), 6,55 (d, J=8.5 Hz, 2H), of 6.68 (m, 1H), 6,76 (d, J=8,8 Hz, 2H), 6,91 (m, 1H), 6,98 (d, J=8.5 Hz, 2H), 7,27 (d, J=8,8 Hz, 2H), 7,32 (m, 1H), 7,56 (m, 2H), 8,78 (c, 1H), at 9.53 (m, 1H);

MS (ESI+) m/z 574 (M+H)+.

Example 102

4-[4-Methyl-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)f is ylsulphonyl]phenol

To a solution of the product from example 10B (100 mg, 0,575 mmol) and the product from example 6c (146 mg, 0,632 mmol) in acetic acid (1 ml) was heated at 130ºC for 1 hour. The mixture is then left to ohlashatsya to room temperature, then to the solution was added methanol (5 ml) and the resulting solid was collected and washed with methanol to obtain specified in the title compound (120 mg, 56%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,29 (c, 3H), 2,66 (c, 3H), 6.73 x (d, J=8,8 Hz, 2H), 6,93 (m, 1H), 7,03 (m, 1H), 7,18 (d, J=8.5 Hz, 2H), 7,26 (c, 1H), 7,53 (d, J=8.5 Hz, 1H), 8,53 (c, 1H), 8,77 (m, 1H), 9,76 (users, 1H), 9,96 (users, 1H);

MS (ESI)m/z 375 (M+H)+.

Example 103

(5-Methyl-2-phenylsulfanyl)-(7 methylpyridin[2,3-d]pyrimidine-4-yl)Amin

A solution of the product from example 10B (90 mg, 0,517 mmol) and the product from example 5I (122 mg, 0,569 mmol) in acetic acid (1 ml) was heated at 130ºC for 1 hour. Then the mixture was left to cool to room temperature, the obtained solid substance was collected and washed with methanol, then 50 mg of the substance was dissolved in dioxane (2 ml) was added hydrochloric acid, then the solvent was removed under vacuum to obtain specified in the connection header in the form of cleaners containing hydrochloride salt.

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,37 (c, 3H), 2,74 (c, 3H), 7,18 (m, 5H), from 7.24 (m, 1H), 7,37 (m, 2H), 7,81 (d, J=8.5 Hz, 1H), 8,80 (c, 1H), 8,99 (d, J=8.5 Hz, 1H), 11,82 (users, 1H); MS (ESI)m/z 359 (M+H)+.

Example 104

[3-(3-Bromperoxidase)phenyl]-(7-methylpurine[2,3-d-4-yl)Amin

Example 104A

1-Nitro-3-(3-bromperoxidase)benzene

A solution of 3-nitrobenzaldehyde (1.0 g, 5.83 mmol), 3-bromophenol (1.01 g, 5.83 mmol) and potassium carbonate (806 mg, 5.83 mmol) in acetone (25 ml) was heated under reflux for 23 hours. After cooling, the solid was filtered and the filtrate was concentrated under vacuum to obtain a yellow residue, which was dissolved in ethyl acetate (50 ml) and washed with 1N. aqueous solution of sodium hydroxide (25 ml) and water (25 ml), then dried and concentrated under vacuum to obtain specified in the connection header in the form of a solid white color (1.64 g, 91%).

Example 104B

3-(3-Bromperoxidase)phenylamine

A solution of the product from example 104A (1.64 g, 5,32 mmol), iron powder (1,49 g, 26,62 mmol) and ammonium chloride (430 mg, 7,98 mmol) in a mixture of tetrahydrofuran (20 ml), water (6 ml) and ethanol (20 ml) was heated under reflux for 3 hours. The mixture was cooled to room temperature, filtered through a layer of celite, which was washed with ethanol, and the obtained filtrate was concentrated under vacuum. Then the substance was dissolved in water (50 ml) and was extracted with ethyl acetate (50 ml), the organic layer was dried and concentrated under vacuum to obtain specified in the title compound as yellow oil (1,43 g, 97%).

Example 104C

[3-(3-Bromophenoxy the l)phenyl]-(7-methylpurine[2,3-d]pyrimidine-4-yl)Amin

To a solution of the product from example 10C (50 mg, 0,266 mmol) and the product from example 104B (74 mg, 0,266 mol) in acetic acid (3 ml) was heated up to 130ºC for 30 minutes. After cooling to room temperature the solution was concentrated under vacuum and purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (62 mg, 44%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,71 (c, 3H), 5,20 (c, 2H), 7,05 (m, 1H), 7,16 (m, 1H), 7,24 (m, 2H), 7,33 (m, 1H), 7,49 (t, J=7.7 Hz, 1H), of 7.70 (d, J=8.5 Hz, 1H), 7,79 (m, 1H), 7,84 (c, 1H), 8,83 (c, 1H), 8,96 (d, J=8,4 Hz, 1H), 10,75 (users, 1H);

MS (ESI)m/z 421/423 (M+H)+.

Example 105

(3'-Methoxy-5-methylbiphenyl-3-yl)-(7 methylpyridin[2,3-d]pyrimidine-4-yl)Amin

Example 105A

3-Bromo-5-methylphenylamine

Specified in the title compound was obtained from 3-bromo-5-nitrotoluene (1.08 g, 5.0 mmol)using the conditions described in example 104B, obtaining specified in the title compound as orange oil (0.8 g, 86%).

Example 105B

(3-Bromo-5-were)-(7 methylpyridin[2,3-d]pyrimidine-4-yl)Amin

The product from example 105A (0.8 g, 4.3 mmol) was subjected to interaction with the product from example 10C in the manner described in example 104C, using the product from example 105A instead of the product from example 104B, to obtain a crude residue, which was purified by chromatography on silica gel, elwira a mixture of 99:1 dichloromethane/methanol, to obtain specified in the header with the organisations in the form of a yellow powder (1.1 g, 77%).

Example 105C

(3'-Methoxy-5-methylbiphenyl-3-yl)-(7 methylpyridin[2,3-d]pyrimidine-4-yl)Amin

The product of example 105B (of 0.066 g, 0.2 mmol), 3-methoxy phenylboric acid (0,043 g, 0.28 mmol), cesium carbonate (0.1 g, 0.3 mmol) and dichlorobis(triphenylphosphine)palladium(II) (of 0.014 g, 0.02 mmol) were combined inN,N-dimethylformamide (1 ml) and heated to 100oC for 24 hours. After cooling to room temperature the mixture was poured into ice water (20 ml) and the resulting solution was acidified using 1N. aqueous solution of hydrochloric acid. Then the solution was extracted with ethyl acetate (3×10 ml), the combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (12 mg, 13%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,45 (c, 3H), 2,75 (c, 3H), 3,83 (c, 3H), 6,98 (DD, J=7,72, of 2.21 Hz, 1H), 7,20 (d, J=2,21 Hz, 1H), 7,25 (d, J=8,09 Hz, 1H), 7,41 (t, J=to $ 7.91 Hz, 1H), of 7.48 (c, 1H), 7,56 (c, 1H), 7,82 (d, J=5,15 Hz, 1H), 7,83 (d, J=3,31 Hz, 1H), 8,96 (c, 1H), 9,03 (d, J=8,46 Hz, 1H), 11,34 (c, 1H);

MS (ESI)m/z 357 (M+H)+.

Example 106

{2-2-(4-Methoxyphenyl)ethyl]-5-were}-(7-methylpurine[2,3-d]pyrimidine-4-yl)Amin

Example 106A

1-[2-(4-Methoxyphenyl)vinyl]-4-methyl-2-nitrobenzene

A solution of 1-bromo-4-methyl-2-nitrobenzene (0,76 g, 3.5 mmol), 1-methoxy-4-vinylbenzene (0,59 g, 4.4 mmol), triethylamine (0.88 g, 8,8 mmol), tri-o-toolpost is on (0,022 g) and palladium acetate (0.008 g) in N,N-dimethylformamide (7 ml) were placed in the pressure vessel was purged with nitrogen for 10 minutes. The vessel was tightly closed and heated at 120ºC for 16 hours. The mixture was distributed between water and ethyl acetate, bringing the pH to 3. The organic layer was washed with saturated saline solution, dried (sodium sulfate) and filtered through a layer of silica gel. The filtrate was evaporated under vacuum and the residue is triturated in a mixture of hexane/ethyl acetate (9:1) to obtain the specified title compound (0.55 g, 58%).

Example 106B

2-[2-(4-Methoxyphenyl)ethyl]-5-methylphenylamine

A solution of the product from example 106A (164 mg, 0.6 mmol) and 10% palladium-on-coal (50 mg) in ethanol (20 ml) was subjected to hydrogenation using hydrogen from a cylinder within three days. The solvent was filtered through celite, washed with ethanol and evaporated under vacuum to obtain specified in the title compound (140 mg, 97%).

Example 106C

{2-[2-(4-Methoxyphenyl)ethyl]-5-were}-(7-methylpurine[2,3-d]pyrimidine-4-yl)Amin

The product from example 106B were subjected to interaction with the product from example 10C in the manner described in example 104C, using the product from example 106B instead of the product from example 104B, to obtain a crude residue, which was purified by chromatography on silica gel, elwira a mixture of 99:1 dichloromethane/methanol, to obtain specified in the title compound (53 mg, 69%).

<> 1H NMR (300 MHz, DMSO-D6) δ ppm: 2,30 (c, 3H), 2,69 (m, 7H), 3,64 (c, 3H), 6,69 (d, J=8,8 Hz, 2H), 6.89 in (d, J=8,8 Hz, 2H), was 7.08 (d, J=7.7 Hz, 1H), 7,13 (c, 1H), 7,22 (d, J=7.7 Hz, 1H), 7,53 (d, J=8.5 Hz, 1H), 8,50 (c, 1H), 8,79 (d, J=8.5 Hz, 1H), 9,83 (c, 1H);

(ESI+) m/z 385 (M+H)+.

Example 107

4-[4-Methyl-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 6c was subjected to interaction with the product from example 57A in the manner described in example 10F, using the product from example 6c instead of the product from example 10E and using the product from example 57A instead of the product from example 10B to obtain a crude residue, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,31 (c, 3H), 6,61-of 6.78 (m, 2H), 7,02 (d, J=8,09 Hz, 1H), 7,11-7,20 (m, 3H), 7,24 (c, 1H), 7,87 (DD, J=8,46, to 4.41 Hz, 1H), 8,79 (c, 1H), 9,03 (d, J=8,46 Hz, 1H), 9,14-9,19 (m, 1H), 9,79 (c, 1H);

MS (ESI+) m/z 361 (M+H)+.

Example 108

(5-Methyl-2-phenylsulfonyl)pyrido[2,3-d]pyrimidine-4-ylamine

The product from example 5I were subjected to interaction with the product from example 57A in the manner described in example 10F, using the product from example 5I instead of the product from example 10E and using the product from example 57A instead of the product from example 10B, to obtain a crude residue, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DM is About-D6) δ ppm: 2,37 (c, 3H), 7,09-7,27 (m, 6H), 7,35 (d, J=7,72 Hz, 2H), 7,83 (DD, J=8,09, to 4.41 Hz, 1H), 8,75 (c, 1H), 8,96 (d, J=7,72 Hz, 1H), 9,13 (d, J=3,31 Hz, 1H);

MS (ESI+) m/z 345 (M+H)+.

Example 109

N-{4-[4-Methyl-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenyl}ndimethylacetamide

The product from example 7b were subjected to interaction with the product from example 57A in the manner described in example 10F, using the product from example 7b instead of the product from example 10E and using the product from example 57A instead of the product from example 10B, to obtain a crude residue, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,02 (c, 3H), 2,34 (c, 3H), 7,13-to 7.35 (m, 5H), 7,46 (d, J=8,46 Hz, 2H), 7,87 (DD, J=8,09, to 4.41 Hz, 1H), 8,80 (c, 1H), 9,01 (d, J=8,09 Hz, 1H), 9,15 (d, J=3,31 Hz, 1H), 9,99 (c, 1H);

MS (ESI+) m/z 402 (M+H)+.

Example 110

4-[2-(7-Isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenol

The product from example 6c was subjected to interaction with the product from example 36E method described in example 36I, using the product from example 6c instead of the product from example 36H, obtaining a crude residue, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: to 1.35 (d, J=6,62 Hz, 6H), 2,31 (c, 3H), 3,29 (t, J=6,89 Hz, 1H), 6,70 (d, J=8,82 Hz, 2H), 7,01 (d, J=8,09 Hz, 1H), 7,17 (d, J=8,82 Hz, 2H), 7,13-7,22 (m, 2H), 7.23 percent (c, 1H), 7,87 (d, J=8,82 is C, 1H), 8,79 (c, 1H), 8,97 (d, J=8,82 Hz, 1H), 9,80 (c, 1H), 11,42 (c, 1H);

MS (ESI+) m/z 403 (M+H)+.

Example 111

2-Chloro-4-[2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenol

To a solution of the product from example 110 (50 mg, 0,124 mmol) in acetic acid (1.5 ml) was added dropwise sulfurylchloride (0.01 ml, 0,124 mmol) at room temperature. The mixture was stirred for another 30 minutes, then concentrated under vacuum and purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (19 mg, 28%).

1H NMR (300 MHz, DMSO-D6) δ ppm: to 1.35 (d, J=6.6 Hz, 6H), 2,34 (c, 3H), 3,30 (m, 1H), PC 6.82 (d, J=8.5 Hz, 1H), was 7.08 (DD, J=8,5, 2.2 Hz, 1H), 7,17 (m, 1H), from 7.24 (m, 3H), a total of 8.74 (c, 1H), to 8.94 (d, J=8.5 Hz, 1H), 10,50 (c, 1H), 11,42 (users, 1H);

MS (ESI+) m/z 437 (M+H)+.

Example 112

2,6-Dichloro-4-[2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenol

To a solution of the product from example 110 (50 mg, 0,124 mmol) in acetic acid (1.5 ml) was added dropwise sulfurylchloride (0,02 ml, 0,248 mmol) at room temperature. The mixture was stirred for another 30 minutes, then concentrated under vacuum and purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (17 mg, 23%).

1H NMR (300 MHz, DMSO-D6) δ ppm: to 1.35 (d, J=6.6 Hz, 6H), 2,37 (c, 3H), of 3.28 (m, 1H), 7,12 (c, 1H), 7,28 (m, 2H), 7,46 (d, J=8,1 Hz, 1H), 7,83 (d, J=8.5 Hz, 1H), 8,70 (c, 1H), 8,88 (d, J=8,8 Hz, 1H), 10,38 (c, 1H), 11,22 (ush the D.C, 1H);

MS (ESI+) m/z 472 (M+H)+.

Example 113

4-[4-Hydroxymethyl-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 113A

Methyl ester of 4-(4-hydroxyphenylethyl)-3-nitrobenzoic acid

A solution of methyl ester 4-chloro-3-nitrobenzoic acid (4.0 g, 18,55 mmol) in anhydrous N,N-dimethylformamide (25 ml) was treated with 4-mercaptophenyl (2,34 g, 18,55 mmol) and cesium carbonate (9,07 g, 27,83 mmol) at room temperature for 23 hours. Then the solvent was removed on a rotary evaporator under vacuum, the residue was treated with water (100 ml) and the pH was brought to 3 with 1N. aqueous HCl. The aqueous solution was extracted with ethyl acetate (2×100 ml) and the combined organic extracts were washed with saturated brine (50 ml). The organic layer was dried over magnesium sulfate, filtered and concentrated on a rotary evaporator to obtain the product as a orange oil mixed with N,N-dimethylformamide (7,28 g).

Example 113B

Methyl ester of 3-amino-4-(4-hydroxyphenylethyl)benzoic acid

A suspension of the product of example 113A (in the form of mono-DMF adduct) (7,25 g, 19,23 mmol) of ammonium chloride (1.54 g, 28.8 mmol) and iron powder (lower than the 5.37 g, 96,15 mmol) in tetrahydrofuran (75 ml), water (25 ml) and ethanol (75 ml) was heated under reflux for 3 hours. The reaction mixture was cooled to room the first temperature and the mixture was filtered through a layer of celite, which was then washed with methanol and the filtrate was concentrated to a solid under vacuum. Then the residue was dissolved in water (100 ml) and was extracted with dichloromethane (2×50 ml). The combined organic extracts were washed with saturated brine (25 ml), dried over magnesium sulfate, filtered and concentrated under vacuum to obtain specified in the connection header in the form of a solid white color (4,2 g, 79%).

Example 113C

4-(2-Amino-4-hydroxymethanesulfinic)phenol

To the product from example 113B (500 mg, 1.82 mmol) in tetrahydrofuran (50 ml) was added dropwise a solution of lithium aluminum hydride (1,0M in THF, 1.8 ml, 1.82 mmol) at room temperature, then the mixture was heated to 70ºC for 4 hours. Then the solution was carefully added water (25 ml) and the organic layer was separated, dried and concentrated under vacuum to obtain specified in the title compound (295 mg, 66%).

Example 113D

4-[4-Hydroxymethyl-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 113C were subjected to interaction with the product from example 36E method described in example 36I, using the product from example 113C instead of the product from example 36H, obtaining a crude residue, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane sour is s (30 mg, 31%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,36 (d, J=7,0 Hz, 6H), 3,30 (m, 1H), 4,50 (c, 2H), 6,72 (d, J=8.5 Hz, 2H), 7,05 (d, J=8,1 Hz, 1H), 7,19 (d, J=8.5 Hz, 2H), 7,27 (m, 1H), 7,35 (c, 1H), 7,87 (d, J=8.5 Hz, 1H), 8,79 (c, 1H), 8,98 (m, 1H), 9,82 (c, 1H), 11,43 (users, 1H);

MS (ESI+) m/z 419 (M+H)+.

Example 114

4-(4-Hydroxyphenylethyl)-3-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)benzyl ester of acetic acid

The product from example 113C were subjected to interaction with the product from example 36E method described in example 36I, using the product from example 113C instead of the product from example 36H, obtaining a crude residue, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (12 mg, 11%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,36 (d, J=6.6 Hz, 6H), 2.05 is (c, 3H), 3,30 (m, 1H), 5,07 (c, 2H), of 6.71 (d, J=8.5 Hz, 2H), 7,03 (d, J=8,1 Hz, 1H), 7,19 (d, J=8.5 Hz, 2H), 7,27 (m, 1H), 7,40 (m, 1H), 7,95 (d, J=8,8 Hz, 1H), 8,89 (c, 1H), 9,02 (d, J=8,8 Hz, 1H), 9,75 (users, 1H), to 11.79 (users, 1H);

MS (ESI+) m/z 461 (M+H)+.

Example 115

N-{4-[2-(7-Isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenyl}ndimethylacetamide

The product from example 7b were subjected to interaction with the product from example 36E method described in example 36I, using the product from example 7b instead of the product from example 36H, obtaining a crude residue, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1/sup> H NMR (300 MHz, DMSO-D6) δ ppm: to 1.35 (d, J=6,99 Hz, 6H), 2,02 (c, 3H), 2,33 (c, 3H), of 3.28 (t, J=6,89 Hz, 1H), 7,18 (c, 1H), 7,20 (d, J=8,46 Hz, 2H), 7,28 (c, 1H), 7,46 (d, J=8,46 Hz, 2H), 7,86 (d, J=8,46 Hz, 1H,) 8,79 (c, 1H), 8,93 (d, J=8,82 Hz, 1H), 9,99 (c, 1H), 11,46 (c, 1H);

MS (ESI+) m/z 444 (M+H)+.

Example 116

(7 Isopropylpyridine[2,3-d]pyrimidine-4-yl)-[2-(4-methoxyphenoxy)-5-were]Amin

Example 116A

1-(4-Methoxyphenoxy)-4-methyl-2-nitrobenzene

4-Methoxyphenol were subjected to interaction with 1-fluoro-4-methyl-2-nitrobenzene in accordance with the method described in example 122a, using 4-methoxyphenol instead of hydroquinone, obtaining specified in the connection header.

Example 116B

2-(4-Methoxyphenoxy)-5-methylphenylamine

The product from example 116A restored in accordance with the method described in example 104B, using the product from example 116A instead of the product from example 104A, obtaining specified in the connection header.

Example 116C

(7 Isopropylpyridine[2,3-d]pyrimidine-4-yl)-[2-(4-methoxyphenoxy)-5-were]Amin

The product from example 116B were subjected to interaction with the product from example 36E method described in example 36I, using the product from example 116B instead of the product from example 36H, obtaining a crude residue, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,33 (d, J=6,99 Hz, 6H), 2,33 (c,3H), 3,26 (dt, J=13,74, 6.85 Hz, 1H), 3,67 (c, 3H), 6,77-of 6.96 (m, 5H), 7,18 (DD, J=8,46, of 2.21 Hz, 1H), 7,33 (d, J=1,84 Hz, 1H), 7,83 (d, J=8,46 Hz, 1H), 8,84 (c, 1H), 8,91 (d, J=8,82 Hz, 1H), 11,33 (c, 1H);

MS (ESI)m/z 401 (M+H)+.

Example 117

4-[2-(7-Isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-4-methylphenoxy]phenol

The product from example 122b were subjected to interaction with the product from example 36E method described in example 36I, using the product from example 122b instead of the product from example 36H, obtaining a crude residue, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,33 (d, J=6,99 Hz, 6H), 2,32 (c, 3H), of 3.27 (t, J=6,89 Hz, 1H), 6,67 (m, 2H), 6.75 in-6,85 (m, 3H), 7,16 (DD, J=8,46, of 1.84 Hz, 1H), 7,31 (d, J=1,47 Hz, 1H), to 7.84 (d, J=8,46 Hz, 1H), cent to 8.85 (c, 1H), to 8.94 (d, J=8,46 Hz, 1H), 9.28 are (c, 1H);

MS (ESI)m/z 387 (M+H)+.

Example 118

(7 Isopropylpyridine[2,3-d]pyrimidine-4-yl)-[2-(4-methoxybenzenesulfonyl)-5-were]Amin

The product from example 6a (5.0 g, 175 mmol) was subjected to interaction with 4-methoxybenzamide (2,45 g, 175 mmol) for 18 hours in accordance with the method described in example 6b, obtaining 1-(4-methoxybenzenesulfonyl)-4-methyl-2-nitrobenzene, which was restored using SnCl2in accordance with the method described in example 5I, obtaining 2-(4-methoxybenzenesulfonyl)-5-methylphenylamine.

2-(4-Methoxybenzenesulfonyl)-5-methylphenylamine subjected to the interaction of the product from example 36E way described in example 36I, using 2-(4-methoxybenzenesulfonyl)-5-methylphenylamine instead of the product from example 36H, obtaining a crude residue, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: to 1.35 (d, J=6,62 Hz, 6H), 2,33 (c, 3H), of 3.28 (t, J=6,89 Hz, 1H), 3,69 (c, 3H), for 6.81 (d, J=9,19 Hz, 2H), 7,06-7,20 (m, 2H), 7.23 percent (d, J=8,82 Hz, 2H), 7,26 (c, 1H), a 7.85 (d, J=8,46 Hz, 1H), 8,76 (c, 1H), to 8.94 (d, J=8,46 Hz, 1H), 11,36 (c, 1H); MS (ESI)m/z 417 (M+H)+.

Example 119

(7 Cyclopropylamino[2,3-d]pyrimidine-4-yl)-(5-methyl-2-phenylsulfanyl)Amin

Example 119A

N'-(3-Cyano-6-cyclopropylamino-2-yl)-N,N-dimethylformamide

Cyclopropylmethyl subjected interaction in accordance with the methods described in the examples 36A-36E, obtaining specified in the connection header.

Example 119B

(7 Cyclopropylamino[2,3-d]pyrimidine-4-yl)-(5-methyl-2-phenylsulfanyl)Amin

The product from example 5I were subjected to interaction with the product from example 119A method described in example 102, using the product from example 5I instead of the product from example 6c and using the product from example 119A instead of the product from example 10B, to obtain a crude residue, which was purified by rubbing in methanol to obtain specified in the connection header.

1H NMR (300 MHz, DMSO-D6) δ ppm: of 1.05 to 1.19 (m, 4H), 2,22-to 2.41 (m, 1H), 2,35 (c, 3H), 7,05-7,31 (m, 7H), and 7.3 (c, 1H), 7,58 (d, J=8,46 Hz, 1H), 8,50 (c, 1H), 8,65 (d, J=8,46 Hz, 1H), of 10.21 (c, 1H);

MS (ESI)m/z 385 (M+H)+.

Example 120

4-[2-(7-Cyclopropylamino[2,3-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenol

The product from example 6c was subjected to interaction with the product from example 119A method described in example 102, using the product from example 119A instead of the product from example 10B, to obtain a crude residue, which was purified by rubbing in methanol to obtain specified in the connection header.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,05-1,22 (m, J=1,84 Hz, 4H), 2,24-2,39 (m, 1H), 2,29 (c, 3H), 6.73 x (d, J=8,82 Hz, 2H), 6,91 (d, J=8,09 Hz, 1H),? 7.04 baby mortality (DD, J=8,09, to 1.47 Hz, 1H), 7,17 (d, J=8,82 Hz, 2H), 7,25 (c, 1H), EUR 7.57 (d, J=8,82 Hz, 1H), 8,49 (c, 1H), 8,71 (d, J=8,46 Hz, 1H), 9,74 (c, 1H), 9,92 (c, 1H);

MS (ESI)m/z 401 (M+H)+.

Example 121

N-{4-[2-(7-Cyclopropylamino[2,3-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenyl}ndimethylacetamide

The product from example 7b were subjected to interaction with the product from example 119A method described in example 102, using the product from example 7b instead of the product from example 6c and using the product from example 119A instead of the product from example 10B, to obtain a crude residue, which was purified by rubbing in methanol to obtain specified in the connection header.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,13 (d, J=6.25 Hz, 4H), 2,02 (c, 3H), 2,22-of 2.38 (m, 1H), 2,31 (c, 3H), 7,07 (c, 2H), 7,20 (d, J=8,82 Hz, 2H), 7,30 (c, 1H), 7,50 (d, J=8,82 Hz, 2H), 7,56 (d, J=8,46 Hz, 1H), 8,49 (c, 1H), 8,68 (d, J=8,82 Hz, 1H), 9,99 (c, 2H);

MS (SI+) m/z 442 (M+H)+.

Example 122

4-[2-(7-Cyclopropylamino[2,3-d]pyrimidine-4-ylamino)-4-methylphenoxy]phenol

Example 122a

4-(4-Methyl-2-nitrophenoxy)phenol

A solution of hydroquinone (3.2 g, 29,0 mmol) and K2CO3(8.0 g, 54,0 mmol) in 40 ml of DMF was heated at 100ºC with 1-fluoro-4-methyl-2-nitrobenzene (3.0 g, and 19.3 mmol) under stirring for 24 hours. Was cooled to room temperature and diluted with EtOAc. Washed with water and the organic layer was dried over MgSO4. Was filtered and concentrated under vacuum to obtain specified in the title compound, which was purified by chromatography on a column of silica gel, elwira a mixture of 5% EtOAc/hexane to obtain orange oil (1.89 g, 40%).

Example 122b

4-(2-Amino-4-methylphenoxy)phenol

The product from example 122a (1.89 g, 7,71 mmol) was restored using SnCl2in accordance with the method described in example 5I, obtaining specified in the connection header in the form of a solid white color (1.42 g, 86%).

Example 122c

4-(2-(7-cyclopropylamino[2,3-d]pyrimidine-4-ylamino)-4-methylphenoxy)phenol

The product from example 122b were subjected to interaction with the product from example 119A method described in example 102, using the product from example 122b instead of the product from example 6c and using the product from example 119A instead of the product from example 10B, to obtain a crude residue, which was purified Rast is Raneem in methanol to obtain specified in the connection header.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,03-of 1.18 (m, J=6.25 Hz, 4H), of 2.20 to 2.35 (m, 1H), 2,30 (c, 3H), 6,57-6,85 (m, 5H), 7,03 (DD, J=8,27, 1.65 Hz, 1H), was 7.36 (d, J=1,84 Hz, 1H), 7,52 (d, J=8,46 Hz, 1H), 8,50 (c, 1H), 8,65 (d, J=8,46 Hz, 1H), 9,18 (c, 1H), 9,70 (c, 1H);

MS (ESI)m/z 385 (M+H)+.

Example 123

(7 Cyclopropylamino[2,3-d]pyrimidine-4-yl)-[2-(4-methoxyphenoxy)-5-were]Amin

The product from example 116B were subjected to interaction with the product from example 119A method described in example 102, using the product from example 116B instead of the product from example 6c and using the product from example 119A instead of the product from example 10B, to obtain a crude residue, which was purified by rubbing in methanol to obtain specified in the connection header.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,02-1,20 (m, J=6.25 Hz, 4H), 2.21 are is 2.37 (m, 1H), 2,31 (c, 3H), 3,66 (c, 3H), 6.75 in-6,92 (m, 5H), 7,06 (DD, J=8,64, to 0.92 Hz, 1H), 7,37 (c, 1H), 7,51 (d, J=8,46 Hz, 1H), 8,49 (c, 1H), 8,63 (d, J=8,82 Hz, 1H), 9,74 (c, 1H);

MS (ESI)m/z 399 (M+H)+.

Example 124

(7 Cyclopropylamino[2,3-d]pyrimidine-4-yl)-[2-(4-perpenicular)-5-were]Amin

The product from example 6a (5,00 g, 17,53 mmol) was subjected to interaction with 4-portifino (2.24 g, 17,53 mmol) instead of thiophenol in accordance with the method described in example 5H, within 18 hours to obtain 1-(4-perpenicular)-4-methyl-2-nitrobenzene, which was purified by chromatography on a column of silica gel, elwira a mixture of 5% EtOAc/hexane to obtain a solid substance (3,39 g, 74%). 1-(4-Forfei sulfanyl)-4-methyl-2-nitrobenzene was restored using SnCl 2in accordance with the method described in example 5I, obtaining 2-(4-perpenicular)-5-methylphenylamine.

2-(4-Perpenicular)-5-methylphenylamine were subjected to interaction with the product from example 119A method described in example 102, using 2-(4-perpenicular)-5-methylphenylamine instead of the product from example 6c and using the product from example 119A instead of the product from example 10B, to obtain a crude residue, which was purified by rubbing in methanol to obtain specified in the connection header.

1H NMR (300 MHz, DMSO-D6) δ ppm: 0,96-1,19 (m, J=6.25 Hz, 4H), 2,22-to 2.42 (m, 1H), 2,33 (c, 3H), 7,02-7,28 (m, 6H), 7,33 (c, 1H), 7,56 (d, J=8,46 Hz, 1H), 8,46 (c, 1H), 8,66 (d, J=8,09 Hz, 1H), there is a 10.03 (c, 1H);

MS (ESI)m/z 403 (M+H)+.

Example 125

(7 Cyclopropylamino[2,3-d]pyrimidine-4-yl)-[2-(4-methoxybenzenesulfonyl)-5-were]Amin

2-(4-Methoxybenzenesulfonyl)-5-methylphenylamine (example 118) were subjected to interaction with the product from example 119A method described in example 102, using 2-(4-methoxybenzenesulfonyl)-5-methylphenylamine instead of the product from example 6c and using the product from example 119A instead of the product from example 10B, to obtain a crude residue, which was purified by rubbing in methanol to obtain specified in the connection header.

1H NMR (300 MHz, DMSO-D6) δ ppm: 0,96-of 1.30 (m, J=5,52 Hz, 4H), 2.21 are to 2.42 (m, 1H), 2,31 (c, 3H), 3,71 (c, 3H), 6,85 (d, J=8,82 Hz, 2H), 6,99 for 7.12 (m, 2H), 7,24 (d, J=8,82 Hz, 2H), 7,63 (d, J=8,46 Hz, 1H), 8,5 (c, 1H), 8,72 (d, J=8,46 Hz, 1H), 10,33 (c, 1H);

MS (ESI)m/z 415 (M+H)+.

Example 126

[2-(4-Methoxyphenoxy)-5-were]-(7-methylpurine[2,3-d]pyrimidine-4-yl)Amin

The product from example 116B were subjected to interaction with the product from example 10C in the manner described in example 104C, using the product from example 116B instead of the product from example 104B, to obtain a crude residue, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,33 (c, 3H), 2,72 (c, 3H), 3,68 (c, 3H), 6,80-to 6.95 (m, 5H), 7,18 (DD, J=8,46, of 2.21 Hz, 1H), 7,34 (d, J=1,84 Hz, 1H), 7,76 (d, J=8,46 Hz, 1H), cent to 8.85 (c, 2H), 11,32 (c, 1H).

Example 127

4-[2-(7-tert-Butylperoxide[2,3-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenol

Example 127A

N'-(6-tert-butyl-3-cyano-2-yl)-N,N-dimethylformamide

3,3-Dimethyl-2-butanone were subjected to interaction in accordance with the methods described in the examples 36A-36E, obtaining specified in the connection header.

Example 127B

4-[2-(7-tert-Butylperoxide[2,3-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenol

The product from example 6c was subjected to interaction with the product from example 127A by the method described in example 36I, using the product from example 6c instead of the product from example 36H and using the product from example 127A instead of the product from example 276E, to obtain a crude residue, which was purified POM is by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (40 mg, 29%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,44 (c, 9H), 2,31 (c, 3H), of 6.71 (d, J=8.5 Hz, 2H), 7,00 (d, J=8,1 Hz, 1H), 7,16 (m, 1H), 7,18 (d, J=8,8 Hz, 2H), 7.23 percent (c, 1H), 8,01 (d, J=7,6 Hz, 1H), 8,75 (c, 1H), 8,97 (d, J=8,8 Hz, 1H), 9,79 (c, 1H), 11,22 (users, 1H);

MS (ESI)m/z 417 (M+H)+.

Example 128

(5-Methyl-2-phenylsulfanyl)-(7 profileid[2,3-d]pyrimidine-4-yl)Amin

The product was obtained by the method according to example 36A, using 2-pentanon instead of methylisobutylketone, to obtain the intermediate compound, which was then subjected to interaction in accordance with the methods described in the examples 36A-36E.

Example 128A

N'-(3-Cyano-6-propylpyridine-2-yl)-N,N-dimethylformamide

The product was obtained by the method according to example 36A, using 2-pentanon instead of methylisobutylketone, to obtain the intermediate compound, which was then subjected to interaction in accordance with the methods described in the examples 36A-36E.

Example 128B

(5-Methyl-2-phenylsulfanyl)-(7 profileid[2,3-d]pyrimidine-4-yl)Amin

The product from example 5I (49 mg, 0,231 mmol) and the product from example 128A (50 mg, 0,231 mmol) was dissolved in acetic acid (1 ml) and was heated up to 130ºC for 1.5 hours. After cooling to room temperature the solvent, acetic acid, formed solid substance was collected by filtration to obtain specified in the connection header in the form of a salt of acetic acid (68 mg, 62%).

1H the Mr (300 MHz, DMSO-D6) δ ppm: to 0.94 (t, J=7.4 Hz, 3H), 1,79 (m, 2H), 1,88 (c, 6H), 2,35 (c, 3H), 2,88 (t, J=7,6 Hz, 2H), 7,18 (m, 5H), 7.23 percent (m, 2H), 7,37 (c, 1H), 7,51 (d, J=8,1 Hz, 1H), 8,48 (c, 1H), 8,69 (d, J=8,5 Hz, 1H);

MS (ESI)m/z 387 (M+H)+.

Example 129

3-[4-Methyl-2-(7-propellered[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 6a (10,14 g of 35.6 mmol) was subjected to interaction with 3-(4-methyl-2-nitrophenyloctyl)phenol (4,48 g of 35.6 mmol) for 18 hours in accordance with the method described in example 6b, with 3-(4-methyl-2-nitrophenyloctyl)phenol (7,88 g, 85%), which was restored using SnCl2in accordance with the method described in example 5I, with 3-(2-amino-4-methylphenylsulfonyl)phenol.

3-(2-amino-4-methylphenylsulfonyl)phenol (49 mg, 0,231 mmol) and the product from example 128A (50 mg, 0,231 mmol) was dissolved in acetic acid (1 ml) and was heated up to 130ºC for 1.5 hours. After cooling to room temperature the solvent, acetic acid, formed solid substance was collected by filtration to obtain specified in the connection header in the form of a salt of acetic acid (78 mg, 68%).

1H NMR (300 MHz, DMSO-D6) δ ppm: of 0.95 (t, J=7,3 Hz, 3H), 1,79 (m, 2H), 1,88 (c, 6H), 2.40 a (c, 3H), 2,88 (t, J=7,6 Hz, 2H), to 6.57 (m, 3H), 7,00 (t, J=7.7 Hz, 1H), 7,13 (m, 1H), 7,26 (d, J=7.7 Hz, 1H), 7,38 (c, 1H), 7,51 (d, J=8.5 Hz, 1H), 8,50 (c, 1H), to 8.70 (d, J=8.5 Hz, 1H);

MS (ESI)m/z 403 (M+H)+.

Example 130

N-{4-[4-Methyl-2-(7-propellered[2,3-d]pyrimidine-4-ylamino)panels JPanel]phenyl}ndimethylacetamide

The product from example 7b (49 mg, 0,231 mmol) and the product from example 128A (50 mg, 0,231 mmol) was dissolved in acetic acid (1 ml) and was heated up to 130ºC for 1.5 hours. After cooling to room temperature and removal of solvent, acetic acid under vacuum, the oil was added methanol (3 ml), which led to the formation of a solid substance, which is triturated in methanol to obtain specified in the connection header, 80 mg, 78%).

1H NMR (300 MHz, DMSO-D6) δ ppm: of 0.95 (t, J=7.4 Hz, 3H), 1,89 (m, 2H), 2,02 (c, 3H), 2,32 (c, 3H), 2,89 (t, J=7.5 Hz, 2H), 7,06 (c, 2H), 7,21 (t, J=8.5 Hz, 2H), 7,30 (c, 1H), 7,50 (d, J=8,8 Hz, 2H), 7,52 (m, 1H), charged 8.52 (c, 1H), total of 8.74 (d, J=7.7 Hz, 1H), 10,00 (c, 1H);

MS (ESI)m/z 444 (M+H)+.

Example 131

4-[4-Methyl-2-(7-propellered[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 6c (49 mg, 0,231 mmol) and the product from example 128A (50 mg, 0,231 mmol) was dissolved in acetic acid (1 ml) and was heated up to 130ºC for 1.5 hours. After cooling to room temperature, the solvent, acetic acid, formed solid substance was collected by filtration to obtain specified in the connection header in the form of a salt of acetic acid (77 mg, 68%).

1H NMR (300 MHz, DMSO-D6) δ ppm: to 0.96 (t, J=7.4 Hz, 3H), of 1.80 (m, 2H), 1,88 (c, 6H), 2.40 a (c, 3H), 2,90 (t, J=7,6 Hz, 2H), 6,74 (d, J=8.5 Hz, 2H), make 6.90 (d, J=8,1 Hz, 1H), 7,03 (m, 1H), 7,18 (d, J=8,8 Hz, 2H), 7,22 (c, 1H), 7,54 (d, J=8,1 Hz, 1H), 8,53 (c, 1H), 8,78 (d, J=8.5 Hz, 1H);

MS (ESI)m/z 403 (M+H)+.

Example 132

N-{4-[-Hydroxy-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenyl}ndimethylacetamide

A mixture of 2-methyl-4-nitro-5-chlorophenol (1.5 g, 8.0 mmol), 4-acetamidophenol (1.6 g, 8,8 mmol) and cesium carbonate (5,74 g, 17.6 mmol) in DMF (10 ml) was heated for 2.5 hours at 100ºC. The mixture was cooled, diluted with ethyl acetate (100 ml) and the organic layer was washed with water and aqueous 10% solution of sodium chloride, then dried over anhydrous sodium sulfate. Drying substance was filtered and the solvent was removed under vacuum to obtain N-[4-(5-hydroxy-4-methyl-2-nitrophenyloctyl)phenyl]ndimethylacetamide in the form of a solid (2.5 g, 81%). A solution of N-[4-(5-hydroxy-4-methyl-2-nitrophenyloctyl)phenyl]ndimethylacetamide (2.5 g, of 6.45 mmol), iron powder (1,79 g, 32 mmol) and ammonium chloride (0,514 g, 9.6 mmol) in a solution of methanol (10 ml), tetrahydrofuran (10 ml) and water (5 ml) was heated under reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a layer of celite. The filtrate was concentrated under vacuum to a volume of 10 ml, the solution was diluted with water (50 ml) and was extracted with ethyl acetate (2×50 ml). The combined extracts were washed with 10% sodium chloride, then dried over magnesium sulfate, filtered and concentrated under vacuum to obtain N-[4-(2-amino-5-hydroxy-4-methylphenylsulfonyl)phenyl]ndimethylacetamide (1.7 g, 91%).

N-[4-(2-Amino-5-hydroxy-4-methylphenylsulfonyl)phenyl]ndimethylacetamide were subjected to interaction with the product from example 36E is a procedure, described in example 36I, using N-[4-(2-amino-5-hydroxy-4-methylphenylsulfonyl)phenyl]ndimethylacetamide instead of the product from example 36H, obtaining a crude residue, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: of 1.34 (d, J=6,99 Hz, 6H), 2,03 (c, 3H), 2,11 (c, 3H), 3.27 to (c, 1H), 6,63 (c, 1H), 7,12 (c, 1H), 7,25 (d, J=8,82 Hz, 2H), 7,51 (d, J=8,82 Hz, 2H), a 7.85 (d, J=8,46 Hz, 1H), 8,80 (c, 1H), to 8.94 (d, J=8,46 Hz, 1H), 9,75 (c, 1H), 10,02 (c, 1H), 11,36 (c, 1H);

MS (ESI)m/z 460 (M+H)+.

Example 133

N1-(4-benzyloxyphenyl)-N2-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)-4,N1the xylene-1,2-diamine

Example 133A

(4-Benzyloxyphenyl)-(4-methyl-2-nitrophenyl)amine

A mixture of 4-methyl-2-nitroaniline (1,006 g 6,612 mmol), 4-benzyloxyphenol (5,794 g, for 22.02 mmol), copper iodide (62,9 mg, 0,3306 mmol), potassium carbonate (0,914 g 6,612 mmol) and anhydrous o-xylene (18 ml) was heated at 150 º C for 24 hours. Additionally added copper iodide (30 mg) and heated for 6 hours at 160º. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator under vacuum. The residue was purified flash chromatography on silica gel using a mixture of 1:1 methylene chloride/hexane as eluent, to obtain specified in the connection header in the form of oil red, which slowly crystallize ALOS (1.23 g, 56%).

Example 133B

(4-Benzyloxyphenyl)methyl-(4-methyl-2-nitrophenyl)amine

To a suspension of sodium hydride (60% dispersion in mineral oil, 55 mg, 1,372 mmol) in N,N-dimethylformamide (3 ml) at room temperature under nitrogen atmosphere was added a solution of the product from example 133A (229,4 mg, 0,6861 mmol) in anhydrous N,N-dimethylformamide (3 ml). The reaction mixture was stirred at room temperature for 1 hour, then added methyliodide (0,171 ml, 2,744 mmol) and left to mix at room temperature for 2 hours. The solvent was removed on a rotary evaporator under vacuum. The residue was treated with water (30 ml) and was extracted with methylene chloride (50 ml). The organic phase is washed with water (30 ml), dried over anhydrous magnesium sulfate, filtered and concentrated on a rotary evaporator under vacuum to obtain specified in the connection header in the form of a solid dark red (239 mg, 100%).

Example 133C

(4-Benzyloxyphenyl)methyl-(4-methyl-2-AMINOPHENYL)amine

Mixture of product example 133B (129,4 mg, 0,3714 mmol), iron powder (128 mg, 2,284 mmol), ammonium chloride (130 mg, 2,433 mmol) in water (1 ml) and ethanol (2 ml) was heated at 70 º C in nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature and was filtered under vacuum, the residue was washed with methanol. The filtrate kontsentrirovaniya vacuum and azeotropic drove with toluene (50 ml). The residue was purified flash chromatography on silica gel, using as eluent methylene chloride, to obtain specified in the connection header in the form of a waxy solid (85 mg, 72%).

Example 133D

N1-(4-Benzyloxyphenyl)-N2-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)-4,N1the xylene-1,2-diamine

A solution of the product from example 36E (28 mg, 0,1297 mmol) and the product from example 133C (41.3 mg, 0,1297 mmol) in acetic acid (1 ml) was stirred on an oil bath pre-heated to 140ºC for 1 hour. The reaction mixture was cooled to room temperature, diluted with hexane (50 ml), concentrated on a rotary evaporator under vacuum and was co-evaporated with a mixture of methylene chloride/hexane (4×). The residue was dried, then purified flash chromatography on silica gel, using as eluent a mixture of 20% ethyl acetate/methylene chloride, to obtain specified in the connection header in the form of a solid yellow (35 mg, 55%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,27 (l,J=6,62 Hz, 6H), 2,34 (c, 3H), is 3.08 (c, 3H), 3,06-up 3.22 (m, 1H), 4,79 (c, 2H), 6,50 (l,J=9,19 Hz, 2H), 6,60 (l,J=8,82 Hz, 2H), 7,05-7,17 (m, 2H), 7,25-7,37 (m, 5H), 7,41 (l,J=8,46 Hz, 1H), 7,47 (c, 1H), 8,42 (l,J=8,46 Hz, 1H), charged 8.52 (c, 1H), was 9.33 (c, 1H);

MS (DCI/NH3) m/z 490 (M+H)+.

Example 134

(2-Benzyl-5-were)-(7 isopropylpyridine[2,3-d]pyrimidine-4-yl)Amin

Example 134A/p>

2-Benzyl-5-methylphenylamine

A solution of lithium aluminum hydride in tetrahydrofuran (1,0 M of 2.54 ml, 2.54 mmol) with a pipette and added to a vessel containing aluminium chloride (534 mg, 4,005 mmol) under nitrogen atmosphere and cooled in a bath at 0OC. After leaving the mixture to cool for 5 minutes slowly dropwise added a solution of 2-amino-4-methylbenzophenone (200 mg, 0,9467 mmol) in tetrahydrofuran (4 ml) at 0OC. Then the reaction mixture was heated at 50 º C for 30 minutes. The reaction mixture was cooled to room temperature and added wet ethyl ether (5 ml). The reaction mixture was carefully poured into water (20 ml) and was extracted with ethyl ether (2×50 ml). The combined ether extracts were washed with saturated saline (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator under vacuum. Purification with flash chromatography on silica gel using a mixture of 40:60 hexane/methylene chloride as eluent, gave specified in the title compound as an oil (94 mg, 50%).

Example 134B

(2-Benzyl-5-were)-(7 isopropylpyridine[2,3-d]pyrimidine-4-yl)Amin

A solution of the product from example 36E (34,6 mg, 0,160 mmol) and the product from example 134A (of 31.6 mg, 0,160 mmol) in acetic acid (1 ml) was stirred on an oil bath pre-heated to 140ºC for 1 hour. The reaction mixture was cooled to room the second temperature, was diluted with hexane (50 ml), concentrated on a rotary evaporator under vacuum and was co-evaporated with a mixture of methylene chloride/hexane (4×). The residue was dried, then purified flash chromatography on silica gel using a mixture of 2% methanol/methylene chloride as eluent, to obtain specified in the title compound as a pale yellow solid (50 mg, 85%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1.32 to (q,J=6,99 Hz, 6H), 2,30 (c, 3H), 3,12 of 3.28 (m, 1H), a 3.87 (c, 2H), 6,95-7,20 (m, 8H), EUR 7.57 (c, 1H), of 8.47 (c, 1H), total of 8.74 (d,J=8,46 Hz, 1H), 9,81 (c, 1H);

MS (DCI/NH3) m/z 369 (M+H)+.

Example 135

(7 Cyclohexylurea[2,3-d]pyrimidine-4-yl)-(5-methyl-2-phenylsulfanyl)Amin

Example 135A

N'-(3-Cyano-6-cyclohexylpiperidine-2-yl)-N,N-dimethylformamide

1-Cyclohexylethane subjected interaction in accordance with the methods described in the examples 36A-36E, obtaining specified in the connection header.

Example 135B

(7 Cyclohexylurea[2,3-d]pyrimidine-4-yl)-(5-methyl-2-phenylsulfanyl)Amin

To a solution of the product from example 135A (56,0 mg, 0,2322 mmol) in acetic acid (4 ml) was added the product from example 5I (50.0 mg, 0,2322 mmol) and the mixture was stirred on an oil bath preheated to 130ºC for 15 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum and the resulting residue was purified by HPLC with TA with obtaining specified in the connection header in the form of a salt triperoxonane acid (20 mg, 20%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,38-is 1.51 (m, 2H), 1,57 was 1.69 (m, 2H), 1,70-1,80 (m, 2H), 1,80-1,99 (m, 6H), 2,33-to 2.40 (m, 3H), 7,12-7,17 (m, 1H), 7,12-7,26 (m, 3H), 7,30-7,33 (m, 1H), 7,33-7,38 (m, 2H), 8,68 is 8.75 (m, 1H), 8,82-of 8.90 (m, 1H);

MS (DCI/NH3) m/z 427 (M+H)+.

Example 136

4-[2-(7-Cyclohexylurea[2,3-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenol

The product from example 135A was subjected to interaction with the product from example 6c in accordance with the method described in example 135B, using the product from example 6c instead of the product from example 5I, obtaining specified in the connection header in the form of a salt triperoxonane acid (20 mg, 20%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,38-of 1.52 (m, 2H), 1.55V and 1.80 (m, 3H), 1,80 is 1.91 (m, 2H), 1.91 a-2,03 (m, 3H), 2,30 (c, 3H), 3,26-3,47 (m, 1H), 6,66-6,74 (m, 2H), 6,74-for 6.81 (m, 1H), of 6.96-7.03 is (m, 1H), 7,10-7,14 (m, 1H), 7,14-7,21 (m, 3H), 7,21-7,26 (m, 1H), 8,72-8,80 (m, 1H), 8,90-8,97 (m, 1H), 9,78 (c, 1H);

MS (DCI/NH3) m/z 443 (M+H)+.

Example 137

N-{4-[2-(7-Cyclohexylurea[2,3-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenyl}ndimethylacetamide

The product from example 135A was subjected to interaction with the product from example 7b in accordance with the method described in example 135B, using the product from example 7b instead of the product from example 5I, obtaining specified in the connection header in the form of a salt triperoxonane acid (21 mg, 25%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,28-of 1.52 (m, 3H), 1,53-to 1.79 (m, 3H), 1,79-of 1.97 (m, 4H), 2,02 (c, 3H), 2,32 (c, 3H), 2,79-to 2.94 (m, 1H), 7.03 is for 7.12 (m, 1H), 7,20 (m,J=8,46 Hz, 2H), 7,31 (c, H), 7,50 (d,J=8,82 Hz, 2H), 7,56 (l,J=8,46 Hz, 1H), 8,54 (c, 1H), 8,76 (l,J=8,82 Hz, 1H), 9,99 (c, 2H);

MS (DCI/NH3) m/z 484 (M+H)+.

Example 138

N-{4-[2-(7-Cyclobutylamine[2,3-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenyl}ndimethylacetamide

Example 138A

N'-(3-Cyano-6-cyclobutylmethyl-2-yl)-N,N-dimethylformamide

1-Cyclobutylamine subjected interaction in accordance with the methods described in the examples 36A-36E, obtaining specified in the connection header.

Example 138B

N-{4-[2-(7-Cyclobutylamine[2,3-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenyl}ndimethylacetamide

The product from example 138A were subjected to interaction with the product from example 7b in accordance with the method described in example 135B, using the product from example 7b instead of the product from example 5I and using the product from example 138A instead of the product from example 135A, obtaining specified in the connection header in the form of a salt triperoxonane acid (30 mg, 36% yield).

1H NMR (500 MHz, DMSO-D6) δ ppm: 0,86 (t,J=7,02 Hz, 1H), 1,86-to 1.98 (m, 1H), 2,02 (c, 3H), 2.06 to to 2.18 (m, 1H), 2,34 (c, 3H), 2,37-2,47 (m, 4H), 3,80-was 4.02 (m, 1H), 7,13-7,25 (m, 4H), 7,29 (c, 1H), 7,45 (l,J=8,54 Hz, 2H), 7,78 (l,J=8,54 Hz, 1H), 8,80 (c, 1H), 8,92 (l,J=8,54 Hz, 1H), 9,98 (c, 1H);

MS (DCI/NH4) m/z 456 (M+H)+.

Example 139

4-[2-(7-Cyclobutylamine[2,3-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenol

The product from example 138A were subjected to interaction with the product for approx the ru 6c in accordance with the method, described in example 135B, using the product from example 6c instead of the product from example 5I and using the product from example 138A instead of the product from example 135A, obtaining specified in the connection header in the form of a salt triperoxonane acid (30 mg, 33%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1.85 to a 2.01 (m, 1H), 2,03-of 2.24 (m, 1H), 2,31 (c, 3H), 2,36 is 2.46 (m, 4H), 3,81 is 4.13 (m, 2H), 6,70 (l,J=8,46 Hz, 2H), 7,02 (l,J=of 8.09 Hz, 1H), 7,17 (l,J=8,46 Hz, 3H), 7,24 (c, 1H), 7,82 (l,J=8,46 Hz, 1H), 8,82 (c, 1H), 8,97 (l,J=8,46 Hz, 1H), 9,72-to 9.93 (m, 1H);

MS (DCI/NH4) m/z 415 (M+H)+.

Example 140

(7-dt-Butylperoxide[2,3-d]pyrimidine-4-yl)-(5-methyl-2-phenylsulfanyl)Amin

Example 140A

N'-(6-sec-Butyl-3-cyano-2-yl)-N,N-dimethylformamide

3-Methylpentan-2-he was subjected to interaction in accordance with the methods described in the examples 36A-36E, obtaining specified in the connection header.

Example 140B

(7-dt-Butylperoxide[2,3-d]pyrimidine-4-yl)-(5-methyl-2-phenylsulfanyl)Amin

The product from example 140A was subjected to interaction with the product from example 5I in accordance with the method described in example 135B, using the product from example 140A instead of the product from example 135A, obtaining specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 0,83 (t,J=of 7.35 Hz, 3H), 1.32 to (q,J=of 6.99 Hz, 3H), 1,59 is 1.75 (m, 1H), 1,75-of 1.95 (m, 1H), 2,37 (c, 3H), 2.95 and-of 3.12 (m, 2H), 7,11-7,22 (m, 5H), 7,25 (d J=6,62 Hz, 1H), 7,31-7,46 (m, 2H), 7,81 (l,J=8,82 Hz, 1H), 8,76 (c, 1H), 8,91 (l,J=8,46 Hz, 1H);

MS (DCI/NH4) m/z 401 (M+H)+.

Example 141

N-{4-[2-(7-dt-Butylperoxide[2,3-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenyl}ndimethylacetamide

The product from example 140A was subjected to interaction with the product from example 7b in accordance with the method described in example 135B, using the product from example 7b instead of the product from example 5I and using the product from example 140A instead of the product from example 135A, obtaining specified in the connection header in the form of a salt triperoxonane acid (37 mg, 45%).

1H NMR (500 MHz, DMSO-D6) δ ppm: 0,84 (t,J=to 7.32 Hz, 3H), 1,33 (l,J=of 6.71 Hz, 3H), 1,62 to 1.76 (m, 1H), 1,77 is 1.91 (m, 1H), 2,34 (c, 3H), 2.49 USD (c, 3H), 2,96-3,14 (m, 1H), 7,11-7,25 (m, 4H), 7,28 (c, 1H), 7,46 (l,J=9,16 Hz, 2H), 7,83 (l,J=8,54 Hz, 1H), 8,79 (c, 1H), to 8.94 (d,J=to 7.93 Hz, 1H), becomes 9.97 (c, 1H), 11,31-of 11.69 (m, 1H);

MS (DCI/NH4) m/z 458 (M+H)+.

Example 142

N-(4-{4-Methyl-2-[7-(1-methylcyclopropyl)pyrido[2,3-d]pyrimidine-4-ylamino]phenylsulfanyl}phenyl)ndimethylacetamide

Example 142A

N'-[3-Cyano-6-(1-methylcyclopropyl)pyridine-2-yl]-N,N-dimethylformamide

1-(1-Methylcyclopropyl)Etalon subjected interaction in accordance with the methods described in the examples 36A-36E, obtaining specified in the connection header.

Example 142B

N-(4-{4-Methyl-2-[7-(1-methylcyclopropyl)pyrido[2,3-d]pyrimidine-4-ylamino]phenylsulfanyl}phenyl)ndimethylacetamide

The product p is the iMER 142A were subjected to interaction with the product from example 7b in accordance with the method, described in example 135B, using the product from example 7b instead of the product from example 5I and using the product from example 142A instead of the product from example 135A, obtaining specified in the connection header in the form of a salt triperoxonane acid (30 mg, 50%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 0.79, which is of 0.91 (m, 1H), 1,08-1,19 (m, 2H), 1,19-of 1.30 (m, 1H), 1,37 of 1.50 (m, 2H), 1.61 of (c, 3H), 2,02 (c, 1H), 2,33 (c, 3H), 7,10-7,24 (m, 4H), 7,28 (c, 1H), 7,45 (l,J=8,82 Hz, 2H), 7,85 (l,J=8,46 Hz, 1H), 8,78 (c, 1H), 8,89 (l,J=9,19 Hz, 1H), 9,99 (c, 1H);

MS (DCI/NH4) m/z 456 (M+H)+.

Example 143

4-{4-Methyl-2-[7-(1-methylcyclopropyl)pyrido[2,3-d]pyrimidine-4-ylamino]phenylsulfanyl}phenol

The product from example 142A were subjected to interaction with the product from example 6c in accordance with the method described in example 135B, using the product from example 6c instead of the product from example 5I and using the product from example 142A instead of the product from example 135A, obtaining specified in the connection header in the form of a salt triperoxonane acid (20 mg, 37%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 0.77-a of 0.91 (m, 1H), 1,07-of 1.18 (m, 2H), 1,38-of 1.52 (m, 2H), 1.61 of (c, 3H), 2,31 (c, 3H), 6,70 (l,J=8,46 Hz, 2H), 7,02 (l,J=of 8.09 Hz, 1H), 7,10-7,21 (m,J=8,46 Hz, 3H), 7.23 percent (c, 1H), 7,86 (l,J=8,82 Hz, 1H), 8,78 (c, 1H), 8,93 (l,J=8,82 Hz, 1H), 9,82 (c, 1H);

MS (DCI/NH4) m/z 415 (M+H)+.

Example 144

3-{4-Methyl-2-[7-(1-methylcyclopropyl)pyrido[2,3-d]pyrimidine-4-ylamino]phenylsulfanyl}phenol

The product from example 142A were subjected vzaimodeistvie 3-(2-amino-4-methylphenylsulfonyl)phenol (example 129) in accordance with the method, described in example 135B, using 3-(2-amino-4-methylphenylsulfonyl)phenol instead of the product from example 5I and using the product from example 142A instead of the product from example 135A, obtaining specified in the connection header in the form of a salt triperoxonane acid (20 mg, 37%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 0.77-a of 0.92 (m, 1H), of 1.35 to 1.48 (m, 2H), 1,60 (c, 3H), 2,36 (c, 3H), 6,41 of 6.68 (m, 3H), 6.90 to-7,05 (m, 1H), 7.23 percent (l,J=6,62 Hz, 1H), 7,29-7,42 (m, 2H), to 7.77 (d,J=of 9.56 Hz, 1H), 8,68 (c, 1H), 8,82 (l,J=7,72 Hz, 1H), 9,52 (c, 1H);

MS (DCI/NH4) m/z 415 (M+H)+.

Example 145

(7 Arilpirido[2,3-d]pyrimidine-4-yl)-(5-methyl-2-phenylsulfanyl)Amin

Example 145A

N'-(3-Cyano-6-ethylpyridine-2-yl)-N,N-dimethylformamide

A solution of the product from example 10B (0,942 g, 5.0 mmol) in anhydrous tetrahydrofuran (50 ml) was cooled to-78ºC under nitrogen atmosphere. To this solution was slowly dropwise added to the solution of diisopropylamide lithium (3.0 ml of a 2.0 M solution in a mixture of toluene/hexane/heptane, 6.0 mmol, 1.2 EQ.). After complete addition, the reaction mixture was stirred at-78ºC for 1 hour and then was added dropwise methyliodide (1.42 g, 10.0 mmol, 2.0 EQ.). The reaction mixture was stirred for another 1.5 hours at-78ºC, during which all solids were dissolved. Then the reaction vessel was removed from the cooling bath was added a saturated aqueous solution of ammonium chloride (25 ml) and water (25 ml). The reaction mixture was extracted with er what ilaclama (3×100 ml) and the combined organic layers were washed with saturated salt solution, was dried over anhydrous magnesium sulfate, filtered and evaporated under vacuum. The residue was purified by chromatography on silica gel, elwira mixture 3/2 hexane:ethyl acetate, to obtain specified in the title compound (0.87 g, 86% yield).

Example 145B

(7 Arilpirido[2,3-d]pyrimidine-4-yl)-(5-methyl-2-phenylsulfanyl)Amin

The product from example 145A were subjected to interaction with the product from example 5I in accordance with the method described in example 135B, using the product from example 145A instead of the product from example 135A, obtaining specified in the connection header in the form of a salt triperoxonane acid (20 mg, 33%).

1H NMR (500 MHz, DMSO-D6) δ ppm: 1,34 (t,J=to 7.93 Hz, 3H), 2,35 (c, 3H), 3,01 (sq,J=to 7.93 Hz, 2H), 7,09-7,29 (m, 6H), was 7.36 (c, 1H), 7,78 (l,J=8,54 Hz, 1H), 8,75 (c, 1H), 8,88 (l,J=8,54 Hz, 1H);

MS (DCI/NH4) m/z 373 (M+H)+.

Example 146

N-{4-[2-(7-Arilpirido[2,3-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenyl}ndimethylacetamide

The product from example 145A were subjected to interaction with the product from example 7b in accordance with the method described in example 135B, using the product from example 7b instead of the product from example 5I and using the product from example 145A instead of the product from example 135A, obtaining specified in the connection header in the form of a salt triperoxonane acid (20 mg, 29%).

1H NMR (500 MHz, DMSO-D6) δ ppm: of 1.34 (m, 3H), 2,37 (c, 3H), 3,01 (sq,J=to 7.93 Hz, 2H), 7,12-7,28 (m, 5H), 7,35(c, 1H), was 7.36 (c, 1H), 7,78 (l,J=8,54 Hz, 1H), 8,75 (c, 1H), 8,88 (l,J=8,54 Hz, 1H);

MS (DCI/NH4) m/z 430 (M+H)+.

Example 147

4-[4-(6-Bromo-1H-benzoimidazol-2-yl)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenoxy]phenol

Example 147A

4-(4-Benzyloxyphenyl)-3-nitrobenzaldehyde

A mixture of 4-chloro-3-nitrobenzaldehyde (1,00 g 5,389 mmol), 4-(benzyloxy)phenol (to 1.187 g, 5,928 mmol) and potassium carbonate (0,744 g 5,389 mmol) in anhydrous pyridine (10 ml) was heated under reflux in nitrogen atmosphere for 30 minutes. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator under vacuum. The residue was treated in ethyl acetate (100 ml) and washed with 1N. aqueous solution of hydrochloric acid (2×50 ml), water (50 ml) and saturated saline (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. Purification with flash chromatography on silica gel, using methylene chloride as eluent, gave specified in the title compound in the form of solid yellow (1,625 g, 86%).

Example 147B

2-[4-(4-Benzyloxyphenyl)-3-nitrophenyl]-6-bromo-1H-benzoimidazol

A solution of 4-bromo-1,2-benzydamine (214 mg, 1,145 mmol) in N,N-dimethylformamide (12 ml)containing water (0.4 ml), was treated with the product of example 147A (400 mg, 1,145 mmol) and OXONE (458 mg, 0,7443 mmol) and the reaction mixture is displaced is ivali at room temperature for 30 minutes. Then added water (40 ml) and the reaction mixture was stirred for 10 minutes. The mixture was filtered under vacuum and the solid is washed with water, then dried under vacuum. Purification by chromatography on silica gel using a gradient mixture of 3% to 4% ethyl acetate/methylene chloride as eluent, gave specified in the title compound in the form of solid yellow (305 mg, 51%).

Example 147C

2-(4-Benzyloxyphenyl)-5-(6-bromo-1H-benzoimidazol-2-yl)phenylamine

The product of example 147B (374 mg, 0,723 mmol), iron powder (248 mg, of 4.45 mmol) and ammonium chloride (253 mg, 4,74 mmol) in water (5 ml) and ethanol (10 ml) was heated at 80 ° C for 45 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 ml) and washed with water (2×50 ml) and saturated saline (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator under vacuum to obtain specified in the connection header in the form of a solid Golden color (327 mg, 93%).

Example 147D

[2-(4-Benzyloxyphenyl)-5-(6-bromo-1H-benzoimidazol-2-yl)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

A solution of the product from example 36E (26,7 mg, 0,123 mmol) and the product of example 147C (60 mg, 0,123 mmol) in acetic acid (2 ml) was stirred on an oil bath pre-heated to 140ºC in those which begins 30 minutes. The reaction mixture was cooled to room temperature, diluted with hexane (50 ml), concentrated on a rotary evaporator under vacuum and was co-evaporated with a mixture of methylene chloride/hexane (4×). The residue was dried under vacuum, then purified by chromatography on silica gel using a mixture of 3% methanol/methylene chloride as eluent, to obtain specified in the connection header in the form of a solid yellow-white (59 mg, 73%).

Example 147E

4-[4-(6-Bromo-1H-benzoimidazol-2-yl)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenoxy]phenol

A solution of the product from example 147D (38,8 mg, 0,059 mmol) and pentamethylbenzene (87 mg, 0,5901 mmol) in triperoxonane acid (5 ml) was stirred at room temperature for 2 hours. The solvent was removed on a rotary evaporator under vacuum and was co-evaporated with a mixture of methylene chloride/hexane (2×). The obtained solid is triturated in hexane (3×) and was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (22 mg, 47%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,36 (l,J=of 6.99 Hz, 6H), 3,20-3,39 (m, 1H), 6,78 (l,J=8,82 Hz, 2H), 6,95 (l,J=9,19 Hz, 2H), 7,02 (l,J=8,82 Hz, 1H), was 7.36 (DD,J=8,64, 2,02 Hz, 1H), 7,55 (l,J=8,46 Hz, 1H), 7,78 (l,J=of 1.47 Hz, 1H), to $ 7.91 (d,J=8,82 Hz, 1H), 8,11 (DD,J=8,64, 2,02 Hz, 1H), 8,35 (l,J=1,84 Hz, 1H), 8,94 (c, 1H), 9,03 (l,J=8,82 Hz, 1H), 9,46 (users, 1H), 11,63 (users, H);

MS (APCI+) m/z 567/569 (M+H)+.

Example 148

4-[4-(6-Bromo-1H-benzoimidazol-2-yl)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenoxy]phenol

The product from example 147C were subjected to interaction with the product from example 10B in the manner described in example 147D, using the product from example 10B instead of the product from example 36E, obtaining [2-(4-benzyloxyphenyl)-5-(6-bromo-1H-benzoimidazol-2-yl)phenyl]-(7-methylpurine[2,3-d]pyrimidine-4-yl)amine, which was subjected to dibenzylamino in accordance with the method described in example 147E, to obtain the crude product, which was purified by HPLC with TFA obtaining specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,74 (c, 3H), 6,77 (l,J=9,19 Hz, 2H), 6,95 (l,J=8,82 Hz, 2H), 7,01 (l,J=8,82 Hz, 1H), 7,35 (DD,J=8,46, of 1.84 Hz, 1H), 7,54 (e,J=8,82 Hz, 1H), 7,74-a 7.85 (m, 2H), 8,10 (DD,J=8,82, of 2.21 Hz, 1H), at 8.36 (d,J=of 2.21 Hz, 1H), 8,90 (c, 1H), 8,95 (l,J=8,46 Hz, 1H), 9,45 (users, 1H), 11,35 (users, 1H);

MS (ESI+) m/z 539/541 (M+H)+.

Example 149

4-(4-Aminophenylalanine)-N-(4-bromophenyl)-3-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)benzosulfimide

Example 149A

N-(4-Bromophenyl)-4-chloro-3-nitrobenzenesulfonamide

A solution of 4-chloro-3-nitrobenzenesulfonamide (2,561 g, 10 mmol) in acetic acid (20 ml) was treated with 4-bromoaniline (1,72 g, 10 mmol) and anhydrous sodium acetate (1.23 g, 15 mmol), then heated the 100 owithin 30 minutes. The reaction mixture was cooled to room temperature and acetic acid was removed on a rotary evaporator under vacuum. The residue was treated in ethyl acetate (100 ml) and washed with water (2×25 ml) and saturated brine (25 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum, the oil was co-evaporated with a mixture of methylene chloride/hexane. Purification by chromatography on silica gel, using methylene chloride, then with a mixture of 5% ethyl acetate/methylene chloride as eluent gave specified in the title compound in the form of solid yellow (2,038 g, 52%).

Example 149B

4-(4-Aminophenylalanine)-N-(4-bromophenyl)-3-nitrobenzenesulfonamide

A mixture of the product of example 149A (500 mg, amounted to -1,277 mmol), 4-aminothiophenol (240 mg, 1,915 mmol) and anhydrous sodium acetate (524 mg, 6,384 mmol) in anhydrous ethanol (9 ml) was heated under reflux in nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature and ethanol was removed on a rotary evaporator under vacuum. The residue was treated in ethyl acetate (100 ml) and washed with water (2×50 ml) and saturated saline (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under vacuum, the joint process of evaporation of oil with a mixture of methylene chloride/hexane Dawa what about specified in the title compound in the form of an orange foam (613 mg, 100%).

Example 149C

Tert-butyl ester {4-[4-(4-bromophenylacetate)-2-nitrophenyloctyl]phenyl}carbamino acid

A solution of the product of example 149B (613 mg, amounted to -1,277 mmol) in anhydrous 1,4-dioxane (10 ml) was treated with di-tert-butyl dicarbonate (418 mg, 1.92 mmol) at room temperature, then the reaction mixture was heated under reflux in nitrogen atmosphere for 3 hours. The reaction mixture was cooled to room temperature, it was added di-tert-butyl dicarbonate (500 mg) and the reaction mixture was heated under reflux for 17 hours. The reaction mixture was cooled to room temperature and the solvent was removed on a rotary evaporator under vacuum. Purification of the residue by chromatography on silica gel using a mixture of 3% ethyl acetate/methylene chloride as eluent, gave specified in the title compound in the form of solid yellow (512 mg, 69%).

Example 149D

Tert-butyl ester {4-[2-amino-4-(4-bromophenylacetate)phenylsulfonyl]phenyl}carbamino acid

The product of example 149C (510 mg, 0,879 mmol), iron powder (302 mg, 5.40 mmol) and ammonium chloride (308 mg, USD 5.76 mmol) in water (4 ml) and ethanol (8 ml) was heated at 80 ° C for 40 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 ml) and washed with water (2×50 ml) and saturated salt dissolve the Ohm (50 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator under vacuum to obtain specified in the title compound as white foam (436 mg, 90%).

Example 149E

Tert-butyl ester {4-[4-(4-bromophenylacetate)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenyl}carbamino acid

A solution of the product from example 36E (59 mg, 0,2725 mmol) and the product from example 149D (150 mg, 0,2725 mmol) in acetic acid (4 ml) was stirred on an oil bath pre-heated to 140ºC for 25 minutes. The reaction mixture was cooled to room temperature, diluted with hexane (100 ml), concentrated on a rotary evaporator under vacuum and was co-evaporated with a mixture of methylene chloride/hexane (4×). The residue was dried under vacuum, then purified by chromatography on silica gel using a mixture of 4% methanol/methylene chloride as eluent, to obtain specified in the title compound as light brown solid (67 mg, 34%).

Example 149F

4-(4-Aminophenylalanine)-N-(4-bromophenyl)-3-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)benzosulfimide

The product from example 149E (44 mg, 0.061 mmol) was treated with triperoxide acid (2 ml) in methylene chloride (2 ml) at room temperature for 30 minutes. The solvents were removed on a rotary operitel is under vacuum and the remaining oil was dried under high vacuum. Purification by chromatography on silica gel using a mixture of 5% methanol/methylene chloride as eluent, gave specified in the title compound in the form of salts triperoxonane acid (25 mg, 48%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,35 (l,J=6,62 Hz, 6H), 3,13-to 3.38 (m, 1H), 6,63 (l,J=8,46 Hz, 2H), 6.87 in (q,J=7,72 Hz, 1H), 7,01-to 7.09 (d,J=8,82 Hz, 2H), 7,12 (l,J=8,46 Hz, 2H), 7,44 (l,J=8,82 Hz, 2H), to 7.61 (DD,J=7,72, to 1.47 Hz, 1H), 7,71 (c, 1H), 7,81 (DD,J=6,62, to 1.47 Hz, 1H), 8,66-8,80 (m, 1H), 8,90 (l,J=of 6.99 Hz, 1H), 10,55 (c, 1H);

MS (ESI+) m/z 621/623 (M+H)+.

Example 150

4-(4-Aminophenylalanine)-N-(4-bromophenyl)-3-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)benzosulfimide

The product from example 149D were subjected to interaction with the product from example 10B in the manner described in example 149E, using the product from example 10B instead of the product from example 36E, obtaining tert-butyl ester {4-[4-(4-bromophenylacetate)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenyl}carbamino acid, which removed the protective group in accordance with the method described in example 149F, then chromatography on silica gel gave specified in the title compound in the form of salts triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,74 (c, 3H), only 6.64 (d,J=8,46 Hz, 2H), 6.89 in (q,J=of 8.09 Hz, 1H), 7,05 (l,J=9,19 Hz, 2H), 7,12 (l,J=8,82 Hz, 2H), 7,44 (l,J=8,82 Hz, 2H), 7,63 (DD,J=7,72, 0,74 Hz, 1H), 7,74 (c, 1H), 7,79 (DD,J=7,72, 1,10 Hz, 1H), 8,7-8,83 (m, 1H), 8,88 (l,J=of 8.09 Hz, 1H), 10,55 (c, 1H);

MS (ESI+) m/z 593/595 (M+H)+.

Example 151

4-[4-Chloro-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenoxy]phenol

Example 151A

4-(4-Chloro-2-nitrophenoxy)phenol

A solution of hydroquinone (1,21 g to 0.011 mol) and potassium hydroxide (0,894 g, 0,0159 mol) in anhydrous dimethyl sulfoxide (7 ml) was heated at 120 ºC for 30 minutes in nitrogen atmosphere. Was added dropwise a solution of 2,5-dichloronitrobenzene (1.90 g, 0,0099 mol) in dimethyl sulfoxide (3 ml) for 30 minutes at 120 ºC, then left the reaction mixture was mixed for 1 hour at the same temperature. Then the reaction mixture was cooled in an ice bath and poured into 30 ml of ice water. The mixture was acidified with concentrated hydrochloric acid to pH 1 and extracted with ethyl ether (2×50 ml). The combined ether extracts were washed with water (3×150 ml), dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator under vacuum. Purification of the residue by chromatography on silica gel, using methylene chloride as the eluent gave the product as light brown solid (1,34 g, 51%).

Example 151B

4-(2-Amino-4-chlorphenoxy)phenol

A mixture of the product of example 151A (400 mg, 1,506 mmol) and iron powder (336 mg, of 6.02 mmol) in acetic acid (10 ml) and ethanol (10 ml) was heated under reflux in nitrogen atmosphere during the 25 minutes. The reaction mixture was cooled to room temperature, diluted with water (50 ml) and treated with solid sodium carbonate until then, until the pH was not equal to 6. Were extracted with ethyl acetate (2×50 ml) and the organic phase was washed with saturated saline (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator under vacuum. A joint process of evaporation of the resulting oil with a mixture of methylene chloride/hexane gave specified in the title compound as light brown solid (355 mg, 100%).

Example 151C

4-[4-Chloro-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenoxy]phenol

A solution of the product from example 36E (38 mg, 0,177 mmol) and the product from example 151B (42 mg, 0,177 mmol) in acetic acid (2 ml) was stirred on an oil bath pre-heated to 140ºC for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with hexane (100 ml), concentrated on a rotary evaporator under vacuum and was co-evaporated with a mixture of methylene chloride/hexane (4×). The residue was dried under high vacuum, then purified by rubbing in a mixture of 40% ethyl acetate/methylene chloride to obtain specified in the connection header in the form of a solid beige color (49 mg, 65%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,31 (l,J=of 6.99 Hz, 6H), 3,10-3,29 (m, 1H), 6,70 (l,J=8,82 Hz, 2H), 6,76-of 6.90 (m, 3H), 7,24 (DD,J=/i> 8,64, 2,39 Hz, 1H), 7,55 (l,J=8,82 Hz, 1H), 7,71 (users, 1H), 8,59 (users, 1H), 8,73 (l,J=of 8.09 Hz, 1H), 9,31 (users, 1H), 9,89 (users, 1H);

MS (DCI/NH3) m/z 407 (M+H)+.

Example 152

4-(4-Hydroxyphenoxy)-3-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)benzonitrile

Example 152A

4-(4-Hydroxyphenoxy)-3-nitrobenzonitrile

A solution of hydroquinone (1,21 g to 0.011 mol) and potassium hydroxide (0,894 g, 0,0159 mol) in anhydrous dimethyl sulfoxide (8 ml) was heated at 90ºC for 30 minutes in nitrogen atmosphere. Was added dropwise a solution of 4-chloro-3-nitrobenzonitrile (1,806 g, 0,0099 mol) in dimethyl sulfoxide (8 ml) for 30 minutes at 90ºC, then left the reaction mixture was mixed for 1 hour at the same temperature. Then the reaction mixture was cooled in an ice bath and poured into 30 ml of ice water. The mixture was acidified with concentrated hydrochloric acid to pH 3 and extracted with ethyl ether (3×100 ml). The combined ether extracts were washed with water (3×150 ml) and saturated saline (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator under vacuum. Purification by chromatography on silica gel using a mixture of 4% ethyl acetate/methylene chloride as eluent gave the product as a solid orange color (0,984 g, 39%).

Example 152B

3-Amino-4-(4-hydroxyphenoxy)benzonitrile

The product of example 15A (500 mg, 1,952 mmol) was subjected to hydrogenation in methanol (20 ml) with hydrogen (1 ATM, balloon) and 10% palladium-on-coal (50 mg) over 30 minutes. The reaction mixture was filtered under vacuum through a 0,45□ PTFE-membrane and the catalyst was washed with methanol. The filtrate was concentrated on a rotary evaporator under vacuum to obtain specified in the connection header in a solid pink beige (437 mg, 99%).

Example 152C

4-(4-Hydroxyphenoxy)-3-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)benzonitrile

A solution of the product from example 36E (41 mg, 0,1896 mmol) and the product from example 152B (42.9 mg, 0,1896 mmol) in acetic acid (2 ml) was stirred on an oil bath pre-heated to 140ºC, for 1.5 hours. The reaction mixture was cooled to room temperature, diluted with hexane (100 ml), concentrated on a rotary evaporator under vacuum and was co-evaporated with a mixture of methylene chloride/hexane (4×). The residue was dried under high vacuum. Purification by chromatography on silica gel using a mixture of 30% ethyl acetate/methylene chloride as eluent, gave specified in the title compound in the form of a solid white color (16 mg, 21%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,31 (l,J=of 6.99 Hz, 6H), 3,11 of 3.28 (m, 1H), 6,77 (l,J=8,82 Hz, 2H), 6,85 (l,J=8,46 Hz, 1H), 6,93 (l,J=8,46 Hz, 2H), to 7.64 (DD,J=17,28, 8,46 Hz, 2H), 8,12 (c, 1H), 8,66 (c, 1H), 8,81 (l,J=of 8.09 Hz, 1H), for 9.47 (c, 1H),9,99 (c, 1H);

MS (DCI/NH3) m/z 398 (M+H)+.

Example 153

(5-Bromo-2-phenoxyphenyl)pyrido[2,3-d]pyrimidine-4-ylamine

5-Bromo-2-phenoxybenzamine were subjected to interaction with the product from example 57A in the manner described in example 57E, using 5-bromo-2-phenoxybenzamine instead of the product from example 57D, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 6,94-7,03 (m, J=8,09, 5,88 Hz, 3H), 7,07 (t, J=7,35 Hz, 1H), 7,24 and 7.36 (m, 2H), 7,54 (DD, J=8,82, of 2.21 Hz, 1H), to 7.77 (DD, J=8,46, to 4.41 Hz, 1H), 7,83 (d, J=2,21 Hz, 1H), 8,82 (c, 1H), 8,89 (d, J=7,35 Hz, 1H), 9,10 (d, J=2.57 m Hz, 1H);

MS (ESI)m/z 394 (M+2)+.

Example 154

(5-Chloro-2-phenoxyphenyl)pyrido[2,3-d]pyrimidine-4-ylamine

5-Chloro-2-phenoxyphenyl were subjected to interaction with the product from example 57A in the manner described in example 57E, using 5-chloro-2-phenoxyphenyl instead of the product from example 57D, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 6,97 (d, J=7,72 Hz, 2H), 7,00-7,11 (m, 2H), 7.24 to 7,34 (m, J=8,09, of 8.09 Hz, 2H), 7,41 (DD, J=8,82, to 2.57 Hz, 1H), 7,69-to 7.77 (m, 2H), 8,77 (c, 1H), cent to 8.85 (d, J=8,46 Hz, 1H), remaining 9.08 (d, J=3,31 Hz, 1H);

MS (ESI)m/z 349 (M+H)+.

Example 155

1-{3-[4-Chloro-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenoxy]phenyl}ethanol

1-[4-(2-And the Ino-4-chlorophenoxy)phenyl]ethanol was subjected to interaction with the product from example 36E in accordance with the method, described in example 152C, using 1-[4-(2-amino-4-chlorophenoxy)phenyl]ethanol instead of the product from example 152B, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,16 (l,J=6,62 Hz, 3H), 1,31 (l,J=6,99 Hz, 6H), 3,17 of 3.28 (m, 1H), 4,60 (square, 1H), for 6.81 (m, 1H), 6,94 (c, 1H), 7,01 (l,J=7,72 Hz, 1H), 7,06 (l,J=8,82 Hz, 1H), 7.23 percent (t,J=to $ 7.91 Hz, 1H), 7,43 (DD,J=8,82, to 2.57 Hz, 1H), 7,72 (m, 1H), 7,76 (c, 1H), 8,79 (c, 1H), 8,82 (c, 1H);

MS (ESI-) m/z 433 (M-H)-.

Example 156

4-[2-(7-Ethylsulfonylimidazo[4,5-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenol

Example 156A

4-Amino-2-ethylsulfonylimidazo-5-carbonitril

The solution of the hydrobromide of 2-ethyl-2-thiopseudourea (1.52 g, 8,19 mmol) (ethoxymethylene)malononitrile (1.0 g, 8,19 mmol) and N,N-diisopropylethylamine (3,57 ml, 20,05 mmol) in ethanol (20 ml) was stirred at room temperature for 3.5 hours. The obtained solid was collected, washed with ethanol and dried under vacuum to obtain specified in the title compound as a pale yellow solid (580 mg, 39%).

Example 156B

N'-(5-Cyano-2-ethylsulfonylimidazo-4-yl)-N,N-dimethylformamide

A solution of the product from example 156A (200 mg, 1.11 mmol) and N,N-dimethylformamidine (0.15 ml, 1.11 mmol) in toluene (10 ml) was heated to the reflux condenser is m for 2.5 hours. After cooling to room temperature the solution was concentrated under vacuum to obtain specified in the title compound as a colourless solid (260 mg, 100%).

Example 156C

4-[2-(7-Ethylsulfonylimidazo[4,5-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenol

A solution of the product from example 6c (54 mg, 0,234 mmol) and the product from example 156B (50 mg, 0,213 mmol) in acetic acid (2 ml) was heated at 130ºC for 1.5 hours. Then the solution was left to cool to room temperature, acetic acid was removed under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (51 mg, 45%).

1H NMR (300 MHz, DMSO-d6) δ ppm: to 1.38 (t, J=7.4 Hz, 3H), 2,30 (c, 3H), 3,23 (sq, J=7,3 Hz, 2H), 6,72 (d, J=8,8 Hz, 2H), 6,98 (d, J=8,1 Hz, 1H), 7,10 (m, 1H), 7,18 (d, J=8.7 Hz, 2H), 7,21 (c, 1H), 8,62 (c, 1H), 9,70 (c, 1H), 9,78 (users, 1H), 10,85 (c, 1H);

MS (ESI)m/z 422 (M+H)+.

Example 157

(7 Ethylsulfonylimidazo[4,5-d]pyrimidine-4-yl)-[5-methyl-2-(4-phenoxyphenylacetic)phenyl]amine

Example 157a

5-Methyl-2-(4-phenoxyphenylacetic)phenylamine

The product from example 6c (0,500 g, at 1.91 mmol) was dissolved in CH2Cl2together with phenylboric acid (0,701 g, 5,74 mmol), copper acetate(II) (0,659 g, a 3.83 mmol) and triethylamine (0,387 g, a 3.83 mmol). Was stirred at room temperature for 48 hours, during which we use and another 2 equivalents of each reagent. Was stirred at room temperature for another 16 hours, during which he added the other 2 equivalents of each reagent. Was stirred at room temperature for another 16 hours. The reaction mixture was diluted with water and extracted with ethyl acetate, dried over Na2SO4, filtered and concentrated under vacuum to obtain crude product, which was purified by chromatography on a column of silica gel, elwira a mixture of 20% EtOAc/hexane (0,100 g, 15%). The product was recovered using SnCl2in accordance with the method described in example 5I, obtaining specified in the title compound (90 mg, 98%).

Example 157b

7-(Ethylthio)-N-(5-methyl-2-(4-phenoxyphenyl)phenyl)pyrimido[4,5-d]pyrimidine-4-amine

A solution of the product from example 156B and the product from example 157a subjected interaction in accordance with the method described in example 156C, using the product from example 157a instead of the product from example 6c, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (16 mg, 21%).

1H NMR (300 MHz, DMSO-D6) δ ppm: to 1.37 (t, J=7,35 Hz, 3H), 2,34 (c, 3H), 3,22 (sq, J=7,35 Hz, 2H), PC 6.82 (m, 2H), 6,93 (m, 2H), 7,29 (m, 8H), to 8.57 (c, 1H), for 9.64 (c, 1H), 10,66 (c, 1H);

MS (ESI+) m/z 498 (M+H)+.

Example 158

4-[4-Methyl-2-(7-piperidine-1-imperiled[4,5-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

A solution of the product from example 156C (42 mg, 0.1 mmol) in piperidine (1 ml) was heated in a microwave oven (microwave CEM Discover) at 180ºC for 2 hours. The solution was concentrated under vacuum and the residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (17 mg, 38%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,64 (m, 6H), 2,30 (c, 3H), of 3.96 (m, 4H), 6,72 (m, 2H), 7,01 (d, J=7,72 Hz, 1H), 7,17 (m, 4H), 8,59 (c, 1H), at 9.53 (c, 1H), 9,83 (c, 1H), 11,43 (c, 1H);

(ESI+) m/z 445 (M+H)+.

Example 159

4-[2-(7-Ethylsulfonylimidazo[4,5-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenyl ester of propane-2-sulfonic acid

The product from example 156C (0,042 g, 0.1 mmol), isopropylacetanilide (0,014 g, 0,105 mmol), 4-dimethylaminopyridine (0.002 g, 0.01 mmol) and diisopropylethylamine (0.04 g, 0.3 mmol) in 1,2-dichloroethane (2.0 ml) was stirred for 1 h, then poured into water (20 ml) and was extracted with ethyl acetate (3×10 ml). The combined extracts were dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (15 mg, 23%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,27 of 1.46 (m, 9H), 2,37 (c, 3H), 3,20 (sq, J=7,35 Hz, 2H), 3,56-3,70 (m, 1H), 7,09-7,20 (m, 2H), 7,19-7,29 (m, 3H), 7,34 (c, 1H), 7,39 (d, J=8,09 Hz, 2H), 8,56 (c, 1H), being 9.61 (c, 1H), of 10.72 (c, 1H);

MS (ESI)m/z 528 (M+H)+.

Example 160

4-[2-(7-Ethylsulfanyl is pyrimido[4,5-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenyl ether 4-acetamidobenzenesulfonyl acid

The product from example 156C were subjected to interaction with 4-acetamidobenzenesulfonyl in accordance with the method described in example 159 using 4-acetamidobenzenesulfonyl instead of isopropylacetanilide, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (31 mg, 50%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,36 (t, J=7,35 Hz, 3H), 2,10 (c, 3H), 2,35 (c, 3H), 3,20 (sq, J=7,35 Hz, 2H), 6,85 (d, J=8,82 Hz, 2H), 7,13 (d, J=8,82 Hz, 2H), 7,26 (m, 3H), 7,71 (m, 2H), 7,81 (m, 2H), charged 8.52 (c, 1H), 9,59 (c, 1H), 10,48 (c, 1H), 10,71 (c, 1H);

MS (ESI+) m/z 619 (M+H)+.

Example 161

4-[4-Methyl-2-(7-morpholine-4-imperiled[4,5-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

A solution of the product from example 156C in morpholine (1 ml) was heated in a microwave oven (microwave CEM Discover) at 180ºC for 2 hours. The solution was concentrated under vacuum and the residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (29 mg, 65%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,30 (c, 3H), of 3.73 (t, J=to 4.41 Hz, 4H), 3,94 (users, 4H), 6,72 (d, J=8,82 Hz, 2H), 7,02 (d, J=8,09 Hz, 1H), 7,18 (m, 4H), 8,61 (c, 1H), to 9.57 (c, 1H), 9,85 (c, 1H), 11,47 (c, 1H);

MS (ESI+) m/z 447 (M+H)+.

Example 162

4-[2-(7-Ethylsulfonylimidazo[4,5-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenyl ether of benzosulfimide acid

The product from example 156C, for example, the Ali interaction with benzosulphochloride in accordance with the method, described in example 159 using benzosulphochloride instead of isopropylacetanilide to obtain crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (27 mg, 48%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,36 (t, J=7,35 Hz, 3H), 2,36 (c, 3H), 3,20 (sq, J=7,35 Hz, 2H), 6,85 (m, 2H), 7,11 (m, 2H), 7,20 (d, J=7,72 Hz, 1H), 7,35 (m, 2H), 7,65 (m, 2H), 7,86 (m, 3H), 8,51 (c, 1H), 9,58 (c, 1H), 10,65 (c, 1H);

MS (ESI+) 562 (M+H)+.

Example 163

4-[2-(7-Ethylsulfonylimidazo[4,5-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenyl ether 4-bromobenzophenone acid

The product from example 156C were subjected to interaction with 4-bromobenzylcyanide in accordance with the method described in example 159 using 4-bromobenzonitrile instead of isopropylacetanilide, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,36 (t, J=7,35 Hz, 3H), 2,37 (c, 3H), 3,20 (sq, J=7,35 Hz, 2H), 6.87 in (m, 2H), 7,12 (m, 2H), 7,19 (d, J=7,05 Hz, 1H), was 7.36 (m, 2H), 7,71 (m, 2H), 7,87 (m, 2H), 8,51 (c, 1H), 9,60 (c, 1H), 10,61 (c, 1H);

MS (ESI+) m/z 640/642 (M+H)+.

Example 164

Tert-butyl ether (7 ethylsulfonylimidazo[4,5-d]pyrimidine-4-yl)-[2-(4-hydroxyphenylethyl)-5-were]carbamino acid

The product of example 156C were subjected to interaction with di-the RET- BUTYLCARBAMATE and triethylamine in tetrahydrofuran at room temperature for 16 hours. Then the mixture was poured into water (10 ml) and the resulting solution was extracted with ethyl acetate (3×10 ml), the combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to obtain specified in the connection header.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1.52m (t, J=7,35 Hz, 3H), 1,62 (c, 9H), 2.50 each (c, 3H), 3,35 (sq, J=7,35 Hz, 2H), 7,21 (d, J=8,46 Hz, 2H), 7,41 (m, 5H), 8,71 (c, 1H), 9,80 (c, 1H), of 10.72 (c, 1H);

MS (ESI+) m/z 522 (M+H)+.

Example 165

{4-[2-(7-Ethylsulfonylimidazo[4,5-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenoxy}acetonitrile

The product from example 164 (52 mg, 0.1 mmol), bromoacetonitrile (0,008 ml, 0.12 mmol), cesium carbonate (0,065 g, 0.2 mmol) and tetrabutylammonium iodide (0.001 g) inN,N-dimethylformamide (2 ml) was stirred at room temperature for 2 hours. The mixture was distributed between water and ethyl acetate. The organic layer was washed with saturated saline solution, dried (sodium sulfate), filtered and evaporated under vacuum. To the residue was added dichloromethane (2.5 ml) and triperoxonane acid (2.5 ml), then stirred at room temperature for 1 hour. The solvent was evaporated under vacuum and the residue was purified by HPLC with TFA to obtain specified in the title compound (9 mg, 20%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,42 (t, J7,35 Hz, 3H), 2,24 (c, 3H), 3,29 (sq, J=7,35 Hz, 2H), 5.25 in (c, 2H), for 6.81 (m, 5H), 7,20 (d, J=8,46 Hz, 2H), 8.34 per (c, 1H), 9,25 (c, 1H), 9,75 (c, 1H);

MS (ESI+) m/z 461 (M+H)+.

Example 166

[2-(4-Benzyloxycarbonyl)-5-were]-(7-ethylsulfonylimidazo[4,5-d]pyrimidine-4-yl)Amin

The product from example 164 was subjected to interaction with benzylbromide in accordance with the method described in example 165, using benzylbromide instead of bromoacetonitrile, to obtain the crude product, which was purified by chromatography on silica gel using a mixture 98/2 dichloromethane/methanol as eluent, to obtain the specified title compound (15 mg, 29%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,20 (t, J=7,35 Hz, 3H), and 2.27 (c, 3H), is 3.08 (sq, J=7,35 Hz, 2H), 5,44 (c, 2H), 6,74 (d, J=8,46 Hz, 2H), to 6.95 (m, 3H), 7,20 (d, J=8,46 Hz, 2H), 7,35 (m, 5H), 8,77 (c, 1H), 9,42 (c, 1H), 9,81 (c, 1H);

MS (ESI+) m/z 512 (M+H)+.

Example 167

4-[4-(3-Bromobenzylamine)-2-(2-methylsulfonylmethane[4,5-d]pyrimidine-7-ylamino)phenylsulfonyl]phenol

Example 167A

N'-(5-Cyano-2-methylsulfonylmethyl-4-yl)-N,N-dimethylformamide

Specified in the title compound was obtained by reacting 4-amino-2-methylsulfonylmethyl-5-carbonitrile with N,N-dimethylformamidine, the method described in example 156B, obtaining specified in the title compound as white foam (0,132 g, 99%).

Example 167B

4-[4-(3-Bromobenzylamine)-2-(2-methylsulfonylmethane[4,5-d]pyrimidine-7-ylamino)Hairdryer who sulfanyl]phenol

A solution of the product from example 167A (66,0 mg, 0.29 mmol) and the product from example 15A (118 mg, 0.29 mmol) in acetic acid (1 ml) was stirred at pre-heated to 140ºC oil bath for 20 minutes. The mixture was cooled and concentrated under vacuum. Then the obtained residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (34 mg, 17%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,75 (c, 3H), 5,12 (c, 2H), 6,70 (d, J=8,82 Hz, 1H), of 6.96-7,05 (m, 2H), 7,07-7,16 (m, 3H), 7,33 (t, J=7,72 Hz, 1H), 7,41-7,46 (m, 1H), 7,51 (d, J=7,72 Hz, 1H), 7,63 (c, 1H), of 8.47 (c, 1H), 9,73 (c, 2H);

MS (ESI)m/z 583/585 (M+H)+.

Example 168

4-[4-(4-Bromobenzylamine)-2-(2-methylsulfonylmethane[4,5-d]pyrimidine-7-ylamino)phenylsulfonyl]phenol

A solution of the product from example 167A and the product from example 16A was subjected to interaction in accordance with the method described in example 167B, using the product from example 16A instead of the product from example 15A, with the receipt of raw material, which was purified by rubbing in methanol to obtain specified in the connection header in the form of a solid white color (46 mg, 27%).

1H NMR (300 MHz, DMSO-D6) δ ppm: was 2.76 (c, 3H), 5,09 (c, 2H), 6,70 (d, J=8,46 Hz, 2H), 6,91-of 7.24 (m, 5H), 7,38 (d, J=8,09 Hz, 2H), 7,56 (d, J=8,09 Hz, 2H), 8,46 (c, 1H), 9,71 (c, 2H);

MS (ESI)m/z 583/585 (M+H)+.

Example 169

4-[4-Methyl-2-(2-methylsulfonylmethane[4,5-d]pyrimidine-7-ylamino)phenylsulfonyl]phenol

A solution of the product according to claim what the iMER 167A and the product from example 6c was subjected to interaction in accordance with the method, described in example 167B, using the product from example 6c instead of the product from example 15A, with the receipt of raw material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (17 mg, 11%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,27 (c, 3H), was 2.76 (c, 3H), 6,76 (d, J=8,46 Hz, 2H), PC 6.82 (d, J=8,09 Hz, 1H), 7,06-7,22 (m, 4H), 8,49 (c, 1H), 9,86 (c, 2H);

MS (ESI)m/z 413 (M+H)+.

Example 170

N-{4-[4-Methyl-2-(2-methylsulfonylmethane[4,5-d]pyrimidine-7-ylamino)phenylsulfonyl]phenyl}ndimethylacetamide

A solution of the product from example 167A and the product from example 7b were subjected to interaction in accordance with the method described in example 167B, using the product from example 7b instead of the product from example 15A, with the receipt of raw material, which was purified by rubbing in methanol to obtain specified in the title compound (110 mg, 83%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,03 (c, 3H), 2,29 (c, 3H), was 2.76 (c, 3H), of 6.96 (d, J=8,09 Hz, 1H), 7,14 (d, J=8,09 Hz, 1H), 7.18 in-7,26 (m, J=8,82 Hz, 3H), 7,54 (d, J=8,46 Hz, 2H), 8,45 (c, 1H), 9,74 (c, 1H), 10,04 (c, 1H);

MS (ESI)m/z 454 (M+H)+.

Example 171

N-{4-[2-(1-tert-Butyl-1H-pyrazolo[3,4-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenyl}ndimethylacetamide

Example 171A

N'-(2-tert-butyl-4-cyano-2H-pyrazole-3-yl)-N,N-dimethylformamide

Specified in the title compound was obtained by reacting 5-amino-1-tert-butyl-1H-pyrazole-4-carbonitrile with N,N-dimethylformamidine the LEM, the method described in example 156B, obtaining specified in the connection header.

Example 171B

N-{4-[2-(1-tert-butyl-1H-pyrazolo[3,4-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenyl}ndimethylacetamide

A solution of the product from example 171A and the product from example 7b were subjected to interaction in accordance with the method described in example 167B, using the product from example 7b instead of the product from example 15A and using the product from example 171A instead of the product from example 167A, to obtain a crude material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (54 mg, 32%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,74 (c, 9H), 2,03 (c, 3H), 2,41 (c, 3H), 7,13 (d, J=8,82 Hz, 2H), 7,49 (m, 4H), 7.62mm (c, 1H), to 8.41 (c, 1H), of 8.47 (c, 1H), 8,76 (c, 1H), 10,06 (c, 1H), accounted for 10.39 (c, 1H);

MS (ESI+) m/z 447 (M+H)+.

Example 172

4-[2-(1-tert-Butyl-1H-pyrazolo[3,4-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenol

A solution of the product from example 171A and the product from example 6c was subjected to interaction in accordance with the method described in example 167B, using the product from example 6c instead of the product from example 15A and using the product from example 171A instead of the product from example 167A, to obtain a crude material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (40 mg, 25%).

1H NMR (300 MHz, LCA is-D6) δ ppm: 1,76 (c, 9H), 2,38 (c, 3H), to 6.67 (d, J=8,82 Hz, 2H), 7,07 (d, J=8,82 Hz, 2H), 7,34 (d, J=8,09 Hz, 1H), 7,50 (d, J=8,09 Hz, 1H), 7,58 (c, 1H), 8,43 (c, 1H), 8,49 (c, 1H), 8,75 (c, 1H), to 9.91 (c, 1H), the 10.40 (c, 1H);

MS (ESI+) m/z 406 (M+H)+.

Example 173

4-[2-(7-Isopropylpyridine[4,5-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenol

Example 173A

N'-(5-Cyano-2-isopropylpyrimidine-4-yl)-N,N-dimethylformamide

Specified in the title compound was obtained by reacting 4-amino-2-isopropylpyrimidine-5-carbonitrile with N,N-dimethylformamidine, the method described in example 156B, obtaining specified in the connection header.

Example 173B

4-[2-(7-Isopropylpyridine[4,5-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenol

A solution of the product from example 173A and the product from example 6c was subjected to interaction in accordance with the method described in example 167B, using the product from example 6c instead of the product from example 15A and using the product from example 173A instead of the product from example 167A, to obtain a crude material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (39 mg, 38%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,36 (d, J=6,62 Hz, 6H), 2,30 (c, 3H), 3,29 (m, 1H), 6,70 (d, J=8,46 Hz, 2H), 6,98 (d, J=8,09 Hz, 1H), 7,17 (m, 4H), 8,72 (c, 1H), 9,76 (c, 1H), 9,90 (c, 1H), 11,13 (c, 1H);

MS (ESI+) m/z 404 (M+H)+.

Example 174

4-[4-Benzyloxy-2-(7-isopropylpyridine[4,5-d]pyrimidine-4-ylamino)panels lpanel]phenol

A solution of the product from example 173A and the product from example 27A was subjected to interaction in accordance with the method described in example 167B, using the product from example 27A instead of the product from example 15A and using the product from example 173A instead of the product from example 167A, to obtain a crude material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (10 mg, 20%).

1H NMR (300 MHz, DMSO-D6) δ ppm: to 1.35 (d, J=6,99 Hz, 6H), of 3.27 (m, 1H), 5,11 (c, 2H), only 6.64 (d, J=8,46 Hz, 2H), 7,06 (m, 5H), 7,40 (m, 5H), 8,64 (c, 1H), 9,65 (c, 1H), 9,84 (c, 1H), 10,88 (c, 1H);

MS (ESI+) m/z 496 (M+H)+.

Example 175

N-{4-[2-(7-Ethylsulfanyl-5-methylsulfonylamino[4,5-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenyl}ndimethylacetamide

Example 175A

N'-(5-Cyano-2-ethylsulfanyl-6-methylsulfonylamino-4-yl)-N,N-dimethylformamide

Specified in the title compound was obtained by reacting 4-amino-2-ethylsulfanyl-6-methylsulfonylamino-5-carbonitrile with N,N-dimethylformamidine the method described in example 156B, obtaining specified in the connection header.

Example 175B

N-{4-[2-(7-Ethylsulfanyl-5-methylsulfonylamino[4,5-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenyl}ndimethylacetamide

A solution of the product from example 175A and the product from example 7b were subjected to interaction in accordance with the method described in p is the iMER 167B, using the product from example 7b instead of the product from example 15A and using the product from example 175A instead of the product from example 167A, to obtain a crude material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (23 mg, 35%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,36 (t, J=7,35 Hz, 3H), 2,03 (c, 3H), 2,24 (c, 3H), 2.40 a (c, 3H), 3,18 (sq, J=7,35 Hz, 2H), 6,84 (m, 3H), 7,19 (d, J=8,46 Hz, 2H), 7,49 (d, J=8,46 Hz, 2H), 7,82 (c, 1H), becomes 9.97 (c, 1H), 12,25 (c, 1H);

MS (ESI+) m/z 509 (M+H)+.

Example 176

4-[2-(7-Ethylsulfanyl-5-methylsulfonylamino[4,5-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenol

A solution of the product from example 175A and the product from example 6c was subjected to interaction in accordance with the method described in example 167B, using the product from example 6c instead of the product from example 15A and using the product from example 175A instead of the product from example 167A, to obtain a crude material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (19 mg, 31%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,36 (t, J=7,35 Hz, 3H), 2,21 (c, 3H), 2,44 (c, 3H), 3,19 (sq, J=7,11 Hz, 2H), 6,70 (m, 5H), 7,18 (d, J=8,46 Hz, 2H), 7,84 (c, 1H), 9,67 (c, 1H), 12,24 (c, 1H);

MS (ESI+) m/z 468 (M+H)+.

Example 177

N-{4-[2-(2-Cyanometallates[4,5-d]pyrimidine-7-ylamino)-4-methylphenylsulfonyl]phenyl}ndimethylacetamide

Example 177A

N'-(5-Cyano-2-cyanomethyl thaitesol-4-yl)-N,N-dimethylformamide

Specified in the title compound was obtained by reacting 4-amino-2-cyanometallates-5-carbonitrile with N,N-dimethylformamidine the method described in example 156B, obtaining specified in the connection header.

Example 177B

N-{4-[2-(2-Cyanometallates[4,5-d]pyrimidine-7-ylamino)-4-methylphenylsulfonyl]phenyl}ndimethylacetamide

A solution of the product from example 177A and the product from example 7b were subjected to interaction in accordance with the method described in example 167B, using the product from example 7b instead of the product from example 15A and using the product from example 177A instead of the product from example 167A, to obtain a crude material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (64 mg, 52%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,03 (c, 3H), 2,30 (c, 3H), 4,54 (c, 2H), 6,95 (d, J=8,09 Hz, 1H), 7,15 (d, J=8,09 Hz, 1H), 7.23 percent (m, 3H), 7,55 (d, J=8,46 Hz, 2H), 8,51 (c, 1H), to 9.91 (c, 1H), 10,04 (c, 1H);

MS (ESI+) m/z 479 (M+H)+.

Example 178

{7-[2-(4-Hydroxyphenylethyl)-5-methylphenylamine]thiazolo[4,5-d]pyrimidine-2-ylsulphonyl}acetonitrile

A solution of the product from example 177A and the product from example 6c was subjected to interaction in accordance with the method described in example 167B, using the product from example 6c instead of the product from example 15A and using the product from example 177A instead of the product Primera, with the receipt of raw material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (62 mg, 56%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,27 (c, 3H), 4,54 (c, 2H), 6,77 (m, 3H), 7,18 (m, 4H), 8,53 (c, 1H), 9,85 (c, 1H), becomes 9.97 (c, 1H);

MS (ESI+) m/z 438 (M+H)+.

Example 179

4-[4-Benzyloxy-2-(7-Heptafluoropropane[4,5-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 179A

N'-(5-Cyano-2-Heptafluoropropane-4-yl)-N,N-dimethylformamide

Specified in the title compound was obtained by reacting 4-amino-2-Heptafluoropropane-5-carbonitrile with N,N-dimethylformamidine the method described in example 156B, obtaining specified in the connection header.

Example 179B

4-[4-Benzyloxy-2-(7-Heptafluoropropane[4,5-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

A solution of the product from example 179A and the product from example 27A was subjected to interaction in accordance with the method described in example 167B, using the product from example 27A instead of the product from example 15A and using the product from example 179A instead of the product from example 167A, to obtain a crude material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (24 mg, 39%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 5,11 (c, 2H), is 6.61 (d, J=8,46 Hz, 2H),? 7.04 baby mortality (DD, J=8,82, to 2.57 Hz, 1), 7,10 (d, J=8,46 Hz, 2H), 7,17 (d, J=2.57 m Hz, 1H), 7.23 percent (d, J=8,82 Hz, 1H), 7,40 (m, 5H), 8,79 (c, 1H), 9,63 (c, 1H), 10,12 (c, 1H), br11.01 (c, 1H);

MS (ESI+) m/z 622 (M+H)+.

Example 180

(7 Isopropylpyridine[4,5-d]pyrimidine-4-yl)-[5-methyl-2-(4-phenoxyphenylacetic)phenyl]amine

A solution of the product from example 173A and the product from example 157a subjected interaction in accordance with the method described in example 167B, using the product from example 157a instead of the product from example 15A and using the product from example 173A instead of the product from example 167A, to obtain a crude material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: of 1.34 (d, J=6,99 Hz, 6H), 2,34 (c, 3H), 3,24 (m, 1H), for 6.81 (d, J=8,82 Hz, 2H), 6,94 (d, J=7,72 Hz, 2H), 7,28 (m, 8H), 8,63 (c, 1H), 9,83 (c, 1H), 10,78 (c, 1H);

MS (ESI+) m/z 480 (M+H)+.

Example 181

(7 Ethylsulfonylimidazo[4,5-d]pyrimidine-4-yl)-[3-(4-methoxybenzenesulfonyl)-5-were]Amin

Example 181A

1-(4-Methoxybenzenesulfonyl)-3-methyl-5-nitrobenzene

4-Methoxy thiophenol copper (0,94 g, 4,63 mmol), which was obtained by reflux of excess 4-methoxythiophene with copper oxide in ethanol overnight and highlighting the desired product by filtration, and 3-bromo-5-nitrotoluene (1.0 g, 4,63 mmol)obtained in the second stage of the 3-nitro-4-aminotoluene, as described inJ. Am. Chem. Soc. Vol. 78pp 1992, 1956, was heated up to 165ºC in a mixture of quinoline (5 ml) and pyridine (1 ml) for 2 hours. After quenching with an aqueous solution of HCl desired product was isolated by chromatography on silica gel using a mixture of ethyl acetate/hexane as eluent, to obtain the specified title compound (0.96 g, 75%).

Example 181B

3-(4-Methoxybenzenesulfonyl)-5-methylphenylamine

The product from example 181A restored in accordance with the method described in example 147C, using the product from example 181A instead of the product from example 147B, obtaining specified in the connection header.

Example 181C

(7 Ethylsulfonylimidazo[4,5-d]pyrimidine-4-yl)-[3-(4-methoxybenzenesulfonyl)-5-were]Amin

The product from example 181B were subjected to interaction with the product from example 156B in accordance with the method described in example 156C, using the product from example 181B instead of the product from example 6c, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (500 MHz, DMSO-D6) δ ppm: to 1.37 (t, J=to 7.32 Hz, 3H), 2,28 (c, 3H), 3,21 (sq, J=to 7.32 Hz, 2H), 3,79 (c, 3H), 6,83 (c, 1H), 7,03 (d, J=9,16 Hz, 2H), 7,42-7,53 (m, 4H), 8,71 (c, 1H), 9,72 (c, 1H), accounted for 10.39 (c, 1H);

MS (ESI+) m/z 436 (M+H)+.

Example 182

(7 Ethylsulfonylimidazo[4,5-d]pyrimidine-4-yl)-[3-(3-methoxybenzenesulfonyl)-5-were]Amin

Example 182A

-(3-Methoxybenzenesulfonyl)-5-methylphenylamine

3-Methoxy thiophenol copper were subjected to interaction with 3-bromo-5-nitrotoluene in accordance with the method described in example 181A, using 3-methoxy thiophenol copper instead of 4-methoxy thiophenolate copper, to obtain 1-(3-methoxybenzenesulfonyl)-3-methyl-5-nitrobenzene, which was restored in accordance with the method described in example 181B, obtaining specified in the connection header.

Example 182B

(7 Ethylsulfonylimidazo[4,5-d]pyrimidine-4-yl)-[3-(3-methoxybenzenesulfonyl)-5-were]Amin

The product from example 182A were subjected to interaction with the product from example 156B in accordance with the method described in example 156C, using the product from example 182A instead of the product from example 6c, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: to 1.37 (t, J=7,35 Hz, 3H), 2,33 (c, 3H), 3,21 (sq, J=7,11 Hz, 2H), 3,74 (c, 3H), 6,84-of 6.96 (m, J=1,10 Hz, 3H), 7,05 (c, 1H), 7,32 (DD, J=9,01, 7,17 Hz, 1H), 7,60 (c, 1H), 7,65 (c, 1H), a total of 8.74 (c, 1H), 9,74 (c, 1H), 10,47 (c, 1H);

MS (ESI+) m/z 436 (M+H)+.

Example 183

(7 Benzylmaleimide[4,5-d]pyrimidine-4-yl)-(5-ethyl-2-phenylsulfanyl)Amin

Example 183A

5-Ethyl-2-phenolsulfonephthalein

Thiophenol sodium were subjected to interaction with 1-chloro-4-ethyl-2-nitrobenzene in accordance with the method described in note the re 5H, using 1-chloro-4-ethyl-2-nitrobenzene instead of 4-chloro-3-nitrotoluene, to obtain 4-ethyl-2-nitro-1-phenolsulfonate, which was restored in accordance with the method described in example 5I, obtaining specified in the connection header.

Example 183B

4-Amino-2-benzylmaleimide-5-carbonitril

A solution of the hydrochloride of 2-benzyl-2-thiopseudourea (5.0 g, 24,67 mmol) (ethoxymethylene)malononitrile (3,01 g, 24,67 mmol) and N,N-diisopropylethylamine (10,75 ml, 61,68 mmol) in ethanol (50 ml) was stirred at room temperature for 18 hours. The obtained solid was collected, washed with ethanol and dried under vacuum to obtain specified in the connection header (2,69 g, 45%).

Example 183C

N'-(2-Benzylmethyl-5-cyanopyrimidine-4-yl)-N,N-dimethylformamide

A solution of the product from example 183B were subjected to interaction with N,N-dimethylformamidine in accordance with the method described in example 156B, using the product from example 183B instead of the product from example 156B, obtaining specified in the connection header.

Example 183D

(7 Benzylmaleimide[4,5-d]pyrimidine-4-yl)-(5-ethyl-2-phenylsulfanyl)Amin

The product from example 183A were subjected to interaction with the product from example 183C in accordance with the method described in example 156C, using the product from example 183A instead of productio example 6c and using the product from example 183C instead of the product from example 156B, obtaining a crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

MS (ESI+) m/z 482 (M+H)+.

Example 184

(7 Benzylmaleimide[4,5-d]pyrimidine-4-yl)-[2-(4-methoxybenzenesulfonyl)-5-were]Amin

The product from example 183C was subjected to interaction with 2-(4-methoxybenzenesulfonyl)-5-methylphenylamine (example 118) in accordance with the method described in example 156C, using 2-(4-methoxybenzenesulfonyl)-5-methylphenylamine instead of the product from example 6c and using the product from example 183C instead of the product from example 156B, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

MS (ESI+) m/z 498 (M+H)+.

Example 185

(7 Benzylmaleimide[4,5-d]pyrimidine-4-yl)-(5-fluoro-2-phenylsulfanyl)Amin

Example 185A

5-fluoro-2-phenolsulfonephthalein

4-fluoro-2-NITROPHENOL were subjected to interaction in accordance with methods similar to those described in examples 6a, 6b and 6c, using sensation instead of 4-mercaptoethanol and 4-fluoro-2-NITROPHENOL instead of 4-methyl-2-NITROPHENOL, obtaining specified in the connection header.

Example 185B

(7 Benzylmaleimide[4,5-d]pyrimidine-4-yl)-(5-fluoro-2-phenylsulfanyl)Amin

Product Primera were subjected to interaction with the product from example 203A in accordance with the method, described in example 156C, using the product from example 203A instead of the product from example 6c and using the product from example 185A instead of the product from example 156B, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

MS (ESI+) m/z 472 (M+H)+.

Example 186

(7 Benzylmaleimide[4,5-d]pyrimidine-4-yl)-[2-(4-perpenicular)-5-were]Amin

The product from example 183C was subjected to interaction with 2-(4-perpenicular)-5-methylphenylamine (example 124) in accordance with the method described in example 156C, using 2-(4-perpenicular)-5-methylphenylamine instead of the product from example 6c and using the product from example 183C instead of the product from example 156B, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

MS (ESI+) m/z 486 (M+H)+.

Example 187

(7 Benzylmaleimide[4,5-d]pyrimidine-4-yl)-(5-methyl-2-m-tolilsulfonil)Amin

The product from example 183C was subjected to interaction with 5-methyl-2-m-tolylsulfochloride in accordance with the method described in example 156C, using 5-methyl-2-m-tolilsulfonil instead of the product from example 6c and using the product from example 183C instead of the product from example 156B, with raw PR is the product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

MS (ESI+) m/z 482 (M+H)+.

Example 188

(7 Benzylmaleimide[4,5-d]pyrimidine-4-yl)-(5-methyl-2-phenylsulfanyl)Amin

The product from example 183C was subjected to interaction with the product from example 5I in accordance with the method described in example 156C, using the product from example 5I instead of the product from example 6c and using the product from example 183C instead of the product from example 156B, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

MS (ESI+) m/z 468 (M+H)+.

Example 189

3-[2-(7-Benzylmaleimide[4,5-d]pyrimidine-4-ylamino)-4-methylphenylsulfonyl]phenol

The product from example 183C was subjected to interaction with 3-(2-amino-4-methylphenylsulfonyl)phenol (example 129) in accordance with the method described in example 156C, using 3-(2-amino-4-methylphenylsulfonyl)phenol instead of the product from example 6c and using the product from example 183C instead of the product from example 156B, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

MS (ESI+) m/z 484 (M+H)+.

Example 190

(7 Benzylmaleimide[4,5-d]pyrimidine-4-yl)-[3-(3-meth is kivenlahti)-5-were]Amin

The product from example 183C was subjected to interaction with the product from example 182A in accordance with the method described in example 156C, using the product from example 182A instead of the product from example 6c and using the product from example 183C instead of the product from example 156B, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,34 (c, 3H), 3,74 (c, 3H), to 4.52 (c, 2H), 6,84-6,97 (m, J=1,10 Hz, 3H), 7,05 (c, 1H), 7,21-7,39 (m, 4H), 7,46-7,53 (m, 2H), to 7.61 (c, 1H), 7,66 (c, 1H), 8,76 (c, 1H), 9,77 (c, 1H), 10,47 (c, 1H);

MS (ESI+) m/z= 498 (M+H)+.

Example 191

(7 Benzylmaleimide[4,5-d]pyrimidine-4-yl)-[3-(4-methoxybenzenesulfonyl)-5-were]Amin

The product from example 183C was subjected to interaction with the product from example 181B in accordance with the method described in example 156C, using the product from example 181B instead of the product from example 6c and using the product from example 183C instead of the product from example 156B, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,28 (c, 3H), 3,79 (c, 3H), to 4.52 (c, 2H), 6,83 (c, 1H),? 7.04 baby mortality (d, J=8,82 Hz, 2H), 7,19-7,38 (m, 2H), 7,41-of 7.55 (m, 5H), a total of 8.74 (c, 1H), 9,75 (c, 1H), 10,42 (c, 1H);

MS (ESI+) m/z 497 (M+H)+.

Example 192

(7 Benzylmaleimide[4,5-d]pyrimidine-4-yl)-[2-(4-labels is iproxy)-5-were]Amin

The product from example 183C was subjected to interaction with the product from example 116B in accordance with the method described in example 156C, using the product from example 116B instead of the product from example 6c and using the product from example 183C instead of the product from example 156B, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

MS (ESI+) m/z 482 (M+H)+.

Example 193

(7 Benzylmaleimide[4,5-d]pyrimidine-4-yl)-(5-methyl-2-p-tolilsulfonil)Amin

The product from example 183C was subjected to interaction with 5-methyl-2-p-tolylsulfochloride in accordance with the method described in example 156C, using 5-methyl-2-p-tolilsulfonil instead of the product from example 6c and using the product from example 183C instead of the product from example 156B, to obtain the crude product, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

MS (ESI+) m/z 482 (M+H)+.

Example 194

4-[4-(3-Bromobenzylamine)-2-(pyrimido[4,5-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 194A

N'-(5-Cyanopyrimidine-4-yl)-N,N-dimethylformamide

Specified in the title compound was obtained by reacting 4-amino-5-pyrimidinecarbonitrile (Aldrich) with N,N-dimethylformamidine, method, described is the example 156B, obtaining specified in the connection header.

Example 194B

4-[4-(3-Bromobenzylamine)-2-(pyrimido[4,5-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 194A were subjected to interaction with the product from example 15A in accordance with the method described in example 156C, using the product from example 15A instead of the product from example 6c and using the product from example 194A instead of the product from example 156B, to obtain the crude product, which was purified by HPLC with NH4OAc obtaining specified in the connection header.

1H NMR (300 MHz, DMSO-D6) δ ppm: 5,12 (c, 2H), only 6.64 (d, J=8,82 Hz, 2H), 6,93? 7.04 baby mortality (m, 1H), 7,10 (d, J=8,82 Hz, 2H), 7,14-of 7.23 (m, 2H), was 7.36 (t, J=7,72 Hz, 1H), 7,43-7,49 (m, 1H), 7,54 (dt, J=7,81, to 1.61 Hz, 1H), 7,65 (d, J=1,47 Hz, 1H), 9,04 (m, 1H), 9,63 (c, 1H), 10,29 (m, 1H);

MS (ESI-) m/z 531 (M-H)-.

Example 195

4-[4-Benzyloxy-2-(pyrimido[4,5-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 194A were subjected to interaction with the product from example 27A in accordance with the method described in example 156C, using the product from example 27A instead of the product from example 6c and using the product from example 194A instead of the product from example 156B, to obtain the crude product, which was purified by HPLC with NH4OAc obtaining specified in the connection header.

1H NMR (300 MHz, DMSO-D6) δ ppm: 5,10 (c, 2H), 6,63 (d, J=8,46 Hz, 2H), 6,94-7,05 (m, 1H), 7,10 (d, J=8,82 Hz, 2H), 7,18 (d, J=7,72 Hz, 2H), 7,29-7,51 (m, 5H), 9,05 (who, 1H), 9,63 (c, 1H), 9,92 (c, 1H), 10,66 (c, 1H);

MS (ESI-) m/z 452 (M-H)-.

Example 196

(7 Isopropylpyridine[2,3-d]pyrimidine-4-yl)-[3-(4-methoxybenzenesulfonyl)-5-were]Amin

The product from example 181B were subjected to interaction with the product from example 36E method described in example 36I, using the product from example 181B instead of the product from example 36H, with the receipt of raw material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (500 MHz, DMSO-D6) δ ppm: 1,33 (d, J=of 6.71 Hz, 6H), 2,29 (c, 3H), 3,25 (KVK, J=7,02, of 6.90 Hz, 1H), 3,79 (c, 3H), 6,88 (c, 1H), 7,03 (d, J=9,16 Hz, 2H), 7,42 (d, J=to 7.93 Hz, 2H), 7,45 (d, J=8.54 in Hz, 2H), to 7.77 (d, J=8,54 Hz, 1H), 8,81 (c, 1H), 8,95 (d, J=8.54 in Hz, 1H), a 10.74 (c, 1H);

MS (ESI+) m/z 417 (M+H)+.

Example 197

4-[3-(7-Isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-5-methylphenylsulfonyl]phenol

Example 197A

4-(3-Amino-5-methylphenylsulfonyl)phenol

The product from example 181B (0.5 g, 2.0 mmol) in dichloromethane was treated with tribromide boron (10 mmol) at room temperature for 1 hour. The solution was extracted with water, then the organic solution was dried and concentrated to obtain specified in the connection header.

Example 197B

4-[3-(7-Isopropylbenzo[2,3-d]pyrimidine-4-ylamino)-5-methylphenylsulfonyl]phenol

The product from example 197A were subjected to interaction with the product from example 36E by the method described in examples is e 36I, using the product from example 197A instead of the product from example 36H, with the receipt of raw material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,35 (c, 3H), 1,33 (c, 3H), 2,28 (c, 3H), 3.27 to (KVK, J=6,86 Hz, 1H), 6,79-6,91 (m, 1H), 6,86 (d, J=8,82 Hz, 2H), 7,30 (c, 1H), was 7.36 (d, J=8,46 Hz, 2H), 7,35 (c, 1H), 7,83 (d, J=8,46 Hz, 1H), 8,87 (c, 1H), 8,98 (d, J=8,82 Hz, 1H), 9,92 (c, 1H), 11,06 (c, 1H);

MS (ESI-) m/z 403 (M+H)+.

Example 198

4-[5-(3-Forbindelse)-2-(4-hydroxyphenylethyl)phenylamino]-7-methylpurine[2,3-d]pyrimidine-6-carbonitrile

Example 198A

N'-(3,5-dicyano-6-methylpyridin-2-yl)-N,N-dimethylformamide

A solution of 2-amino-6-methylpyridine-3,5-dicarbonitrile (0,158 g, 1.0 mmol) andN,N-dimethylformamidine (0,119 g, 1.0 mmol) in toluene (10 ml) was heated under reflux for 6 hours. After cooling to room temperature the solution was concentrated under vacuum to obtain specified in the connection header in a solid brown color (0.2 g, 94%).

Example 198B

4-[5-(3-Forbindelse)-2-(4-hydroxyphenylethyl)phenylamino]-7-methylpurine[2,3-d]pyrimidine-6-carbonitrile

The product of example 198A were subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 198A instead of the product of example 10E, raw, washes the VA, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (18 mg, 29%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,82 (c, 3H), 5,13 (c, 2H), only 6.64 (d, J=8,46 Hz, 2H), 6,99 (d, J=9,56 Hz, 1H), to 7.09 (d, J=8,82 Hz, 2H), 7,12-7,21 (m, 3H), 7,29 (d, J=7,72 Hz, 2H), 7,39-7,53 (m, 1H), 8,63 (c, 1H), 9,36 (c, 1H), for 9.64 (c, 1H), 10,33 (c, 1H).

Example 199

[3-(3-Forbindelse)phenyl]-(7-methylpurine[2,3-d]pyrimidine-4-yl)Amin

Example 199A

(3 Forbindelse)-3-nitrobenzene

A solution of 3-NITROPHENOL (0,278 g, 2.0 mmol), 1-methyl bromide-3-fervently (0,258 ml, 2.1 mmol), potassium carbonate (0,553 g, 4.0 mmol) and tetrabutylammonium iodide (0.001 g) inN,N-dimethylformamide (5 ml) was stirred at room temperature for 16 hours. Then to the solution was added ice water (10 ml) and the obtained solid substance was collected by filtration and dried in a vacuum oven to obtain specified in the connection header with a quantitative yield.

Example 199B

(3 Forbindelse)-3-aminobenzoyl

To a solution of the product from example 199A (0,494 g, 2.0 mmol), iron powder (0.56 g, 10.0 mmol) and ammonium chloride (0.54 g, 10.0 mmol) in a solution of methanol (20 ml), tetrahydrofuran (20 ml) and water (10 ml) was heated under reflux for 2 hours. The resulting mixture was filtered through a layer of celite and the filtrate was concentrated. Then added ethyl acetate was stirred for 30 minutes, filter the Wali and concentrated under vacuum to obtain specified in the connection header (0,405 g, 93%).

Example 199C

[3-(3-Forbindelse)phenyl]-(7-methylpurine[2,3-d]pyrimidine-4-yl)Amin

The product of example 199B were subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 199B instead of the product of example 10E, with the receipt of raw material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (32 mg, 89%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,74 (c, 3H), 5,18 (c, 2H), 6,98 (m, 1H), 7,18 (m, 1H), 7,42 (m, 6H), 7,79 (d, J=8,46 Hz, 1H), 8,92 (c, 1H), 9,00 (d, J=8,82 Hz, 1H), 11,16 (c, 1H);

MS (ESI+) m/z 361 (M+H)+.

Example 200

[3-(3-Forbindelse)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

The product from example 199B were subjected to interaction with the product from example 36E method described in example 36I, using the product from example 199B instead of the product from example 36H, with the receipt of raw material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: of 1.34 (d, J=6,99 Hz, 6H), 3,26 (m, 1H), 5,18 (c, 2H), 6,93 (m, 1H), 7,17 (m, 1H), 7,42 (m, 6H), 7,79 (d, J=8,46 Hz, 1H), cent to 8.85 (c, 1H), 9,00 (d, J=8,46 Hz, 1H), 10,76 (c, 1H);

MS (ESI+) m/z 389 (M+H)+.

Example 201

[3-(3-Forbindelse)phenyl]pyrido[2,3-d]pyrimidine-4-ylamine

The product of example 199B were subjected to interaction with the product of example 57A in the manner described in example 57E, IP is by using the product of example 199B instead of the product of example 57D, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 5,18 (c, 2H), 6,98 (m, 1H), 7,18 (m, 1H), 7,42 (m, 6H), 7,87 (DD, J=8,27, 4,60 Hz, 1H), 8,93 (c, 1H), 9,14 (m, 2H), 11,12 (c, 1H);

MS (ESI+) m/z 347 (M+H)+.

Example 202

[3-(4-Forbindelse)phenyl]pyrido[2,3-d]pyrimidine-4-ylamine

Example 202A

3-(4-Forbindelse)phenylamine

3-NITROPHENOL were subjected to interaction with 1-methyl bromide-4-florasulam in accordance with the method described in example 199A, using 1-methyl bromide-4-torbenson instead of 1-methyl bromide-3-fervently, then restored in accordance with the method described in example 199B obtaining specified in the connection header.

Example 202B

[3-(4-Forbindelse)phenyl]pyrido[2,3-d]pyrimidine-4-ylamine

The product of example 202A were subjected to interaction with the product of example 57A in the manner described in example 57E, using the product of example 202A instead of the product of example 57D, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (20 mg, 58%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 5,13 (c, 2H), 6,92 (m, 1H), 7,24 (m, 2H), 7,38 (m, 2H), 7,55 (m, 3H), 7,80 (DD, J=8,27, 4,60 Hz, 1H), 8,87 (c, 1H), 9,07 (DD, J=8,27, 1.65 Hz, 1H), 9,12 (DD, J=To 4.41, 1.84 G is, 1H), 10,69 (c, 1H);

MS (ESI+) m/z 347 (M+H)+.

Example 203

[3-(3,5-Deferasirox)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

Example 203A

3-(3,5-Deferasirox)phenylamine

3-NITROPHENOL were subjected to interaction with 1-methyl bromide-3,5-differentlal in accordance with the method described in example 199A, using 1-methyl bromide-3,5-differenza instead of 1-methyl bromide-3-fervently, then restored in accordance with the method described in example 199B obtaining specified in the connection header.

Example 203B

[3-(3,5-Deferasirox)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

The product from example 203A were subjected to interaction with the product from example 36E method described in example 36I, using the product from example 203A instead of the product from example 36H, with the receipt of raw material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (26 mg, 67%).

1H NMR (300 MHz, DMSO-D6) δ ppm: to 1.35 (d, J=6,99 Hz, 6H), 3,26 (m, 1H), 5,19 (c, 2H), 6,95 (m, 1H), 7,20 (m, 3H), 7,38 (m, 2H), 7,54 (c, 1H), 7,82 (d, J=8,46 Hz, 1H), 8,86 (c, 1H), 9,02 (d, J=8,46 Hz, 1H), 10,89 (c, 1H);

MS (ESI+) m/z 407 (M+H)+.

Example 204

[3-(3,5-Deferasirox)phenyl]-(7-methylpurine[2,3-d]pyrimidine-4-yl)Amin

The product of example 203A were subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 203A is the place of the product of example 10E, with the receipt of raw material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,73 (c, 3H), 5,19 (c, 2H), 6,95 (m, 1H), 7,21 (m, 3H), 7,38 (m, 2H), 7,55 (c, 1H), of 7.75 (d, J=8,46 Hz, 1H), 8,87 (c, 1H), 8,98 (d, J=8,46 Hz, 1H), 10,90 (c, 1H);

MS (ESI+) m/z 379 (M+H)+.

Example 205

[3-(3,5-Deferasirox)phenyl]pyrido[2,3-d]pyrimidine-4-ylamine

The product of example 203A were subjected to interaction with the product of example 57A in the manner described in example 57E, using the product of example 203A instead of the product of example 57D, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 5,19 (c, 2H), 6,94 (m, 1H), 7,21 (m, 3H), 7,39 (d, J=5,15 Hz, 2H), 7,58 (c, 1H), 7,81 (DD, J=8,09, to 4.41 Hz, 1H), 8,87 (c, 1H), 9,10 (m, 2H), 10,79 (c, 1H);

MS (ESI+) m/z 365 (M+H)+.

Example 206

4-[3-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

Example 206A

4-(3-Aminophenoxy)benzonitrile

3-NITROPHENOL were subjected to interaction with 4-bromomethylbiphenyl in accordance with the method described in example 199A, using 4-bromomethylbiphenyl instead of 1-methyl bromide-3-fervently, then restored in accordance with the method described in example 199B, obtaining specified in the header with the unity.

Example 206B

4-[3-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

The product of example 206A were subjected to interaction with the product of example 10B in the manner described in example 10F, using the product of example 206A instead of the product of example 10E, with the receipt of raw material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,71 (c, 3H), 5,27 (c, 2H), 6,92 (m, 1H), 7,38 (m, 2H), to 7.59 (c, 1H), 7,68 (m, 3H), 7,89 (d, J=8,46 Hz, 2H), 8,83 (c, 1H), 8,95 (d, J=8,82 Hz, 1H), at 10.64 (c, 1H);

MS (ESI+) m/z 368 (M+H)+.

Example 207

4-[3-(Pyrido[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

The product of example 206A were subjected to interaction with the product of example 57A in the manner described in example 57E, using the product of example 206A instead of the product of example 57D, obtaining crude specified in the title compound, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 5,27 (c, 2H), 6,93 (m, 1H), 7,38 (m, 2H), 7,60 (c, 1H), to 7.67 (d, J=8,46 Hz, 2H), 7,80 (DD, J=8,46, to 4.41 Hz, 1H), of 7.90 (d, J=8,46 Hz, 2H), 8,86 (c, 1H), 9,07 (DD, J=8,46, 1.65 Hz, 1H), 9,13 (DD, J=to 4.41, 1.65 Hz, 1H), of 10.72 (c, 1H);

MS (ESI+) m/z 354 (M+H)+.

Example 208

3-[3-(7-Isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

Example 208A

3-(3-Aminophenoxy)bentonite the

3-NITROPHENOL were subjected to interaction with 3-bromomethylbiphenyl in accordance with the method described in example 199A, using 3-bromomethylbiphenyl instead of 1-methyl bromide-3-fervently, then restored in accordance with the method described in example 199B, obtaining specified in the connection header.

Example 208B

3-[3-(7-Isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

The product from example 208A were subjected to interaction with the product from example 36E method described in example 36I, using the product from example 208A instead of the product from example 36H, with the receipt of raw material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (22 mg, 56%).

1H NMR (300 MHz, DMSO-D6) δ ppm: of 1.34 (d, J=6,99 Hz, 6H), 3,26 (m, 1H), 5,22 (c, 2H), 6,93 (m, 1H), 7,38 (m, 2H), 7.62mm (m, 2H), to 7.77 (d, J=8,46 Hz, 1H), to 7.84 (m, 2H), 7,95 (c, 1H), 8,83 (c, 1H), 8,99 (d, J=8,46 Hz, 1H), 10,67 (c, 1H);

MS (ESI+) m/z 396 (M+H)+.

Example 209

2-[3-(Pyrido[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

Example 209A

2-(3-Aminophenoxy)benzonitrile

3-NITROPHENOL were subjected to interaction with 2-bromomethylbiphenyl in accordance with the method described in example 199A, using 2-bromomethylbiphenyl instead of 1-methyl bromide-3-fervently, then restored in accordance with the method described in example 19B obtaining specified in the connection header.

Example 209B

2-[3-(Pyrido[2,3-d]pyrimidine-4-ylamino)phenoxymethyl]benzonitrile

The product from example 209A were subjected to interaction with the product from example 36E method described in example 36I, using the product from example 209A instead of the product from example 36H, with the receipt of raw material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 5,30 (c, 2H), 7,02 (m, 1H), 7,42 (m, 2H), to 7.59 (m, 2H), 7,78 (m, 2H), a 7.85 (DD, J=8,46, to 4.41 Hz, 1H), 7,94 (d, J=7,72 Hz, 1H), 8,92 (c, 1H), 9,14 (m, 2H), 11,03 (c, 1H);

MS (ESI+) m/z 354 (M+H)+.

Example 210

(3-Benzyloxyphenyl)-(7 isopropylpyridine[2,3-d]pyrimidine-4-yl)Amin

Example 210A

3-Benzyloxyaniline

3-NITROPHENOL were subjected to interaction with bromomethylphenyl in accordance with the method described in example 199A using bromeilles instead of 1-methyl bromide-3-fervently, then restored in accordance with the method described in example 199B, obtaining specified in the connection header.

Example 210B

(3-Benzyloxyphenyl)-(7 isopropylpyridine[2,3-d]pyrimidine-4-yl)Amin

The product from example 210A were subjected to interaction with the product from example 36E method described in example 36I, using the product from example 210A instead of the product from example 36H, with the receipt of raw material, which was purified by HPLC with TFA to what rucenim specified in the connection header in the form of a salt triperoxonane acid (5 mg, 10%).

1H NMR (500 MHz, DMSO-D6) δ ppm: 1,33 (d, J=at 6.84 Hz, 6H), 3,25 (cut, J=6,84 Hz, 1H), 5,13 (c, 2H), 6.89 in-6,94 (m, J=R $ 2.20, 2.20 Hz, 1H), 7,33-7,41 (m, 5H), 7,45-of 7.48 (m, J=to 7.32 Hz, 2H), 7,54-7,58 (m, J=2,44, of 2.44 Hz, 1H), 7,76 (d, J=8,30 Hz, 1H), 8,84 (c, 1H), 9,02 (d, J=8,30 Hz, 1H);

MS ESI+ m/z 371 (M+H)+, ESI - m/z 369 (M-H)-.

Example 211

[3-(3-Bromobenzylamine)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

Example 211A

3-(3-Bromobenzylamine)phenylamine

3-NITROPHENOL were subjected to interaction with 1-bromo-3-bromomethylphenyl in accordance with the method described in example 199A, using 1-bromo-3-bromeilles instead of 1-methyl bromide-3-fervently, then restored in accordance with the method described in example 199B, obtaining specified in the connection header.

Example 211B

[3-(3-Bromobenzylamine)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

The product from example 211A were subjected to interaction with the product from example 36E method described in example 36I, using the product from example 211A instead of the product from example 36H, with the receipt of raw material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (1 mg, 1%).

1H NMR (300 MHz, DMSO-D6) δ ppm: of 1.34 (d, J=6,99 Hz, 6H), 5,16 (c, 2H), 6,94 (TD, J=4,50, 2,39 Hz, 1H), 7,39 (TD, J=7,63, 3,86 Hz, 3H), 7,46-7,51 (m, 1H), 7,53-EUR 7.57 (m, 2H), 7,69 (c, 1H), 7,80 (d, J=8,46 Hz, 1H), 8,86 (c, 1H), 9,01 (d, J=8,46 Hz, 1H), 10,84 (c, 1H);

MS ESI+ m/z 451 (M+H)+, ESI - m/z 449 (M-H)-.

Primer

(7 Isopropylpyridine[2,3-d]pyrimidine-4-yl)-[3-(3-methoxybenzyloxy)phenyl]amine

Example 212A

3-(3-Methoxybenzyloxy)phenylamine

3-NITROPHENOL were subjected to interaction with 1-methyl bromide-3-methoxybenzoate in accordance with the method described in example 199A, using 1-methyl bromide-3-methoxybenzoyl instead of 1-methyl bromide-3-fervently, then restored in accordance with the method described in example 199B, obtaining specified in the connection header.

Example 212B

(7 Isopropylpyridine[2,3-d]pyrimidine-4-yl)-[3-(3-methoxybenzyloxy)phenyl]amine

The product from example 212A were subjected to interaction with the product from example 36E method described in example 36I, using the product from example 212A instead of the product from example 36H, with the receipt of raw material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (8 mg, 9%).

1H NMR (300 MHz, DMSO-D6) δ ppm: to 1.35 (d, J=6,99 Hz, 6H), 3,76 (c, 3H), 5,12 (c, 2H), 6.87 in-6,98 (m, 2H), 7,00-7,06 (m, 2H), was 7.36 (dt, J=19,85, of 8.09 Hz, 3H), 7,52 (c, 1H), 7,82 (d, J=8,82 Hz, 1H), 8,88 (c, 1H), 9,02 (d, J=8,46 Hz, 1H), 10,94 (c, 1H);

MS ESI+ m/z 401 (M+H)+, ESI - m/z 399 (M-H)-.

Example 213

[3-(4-Bromobenzylamine)phenyl]pyrido[2,3-d]pyrimidine-4-ylamine

Example 213A

3-(4-Bromobenzylamine)phenylamine

3-NITROPHENOL were subjected to interaction with 1-bromo-4-bromomethylphenyl in accordance with the method described in the ore 199A, using 1-bromo-4-bromeilles instead of 1-methyl bromide-3-fervently, then restored in accordance with the method described in example 199B obtaining specified in the connection header.

Example 213B

[3-(4-Bromobenzylamine)phenyl]pyrido[2,3-d]pyrimidine-4-ylamine

The product from example 213A were subjected to interaction with the product from example 36E method described in example 36I, using the product from example 213A instead of the product from example 36H, with the receipt of raw material, which was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 5,13 (c, 2H), PC 6.82 (DD, J=8,09, of 1.84 Hz, 1H), 7,32 (t, J=8,09 Hz, 1H), 7,45 (d, J=8,46 Hz, 3H), to 7.61 (d, J=8,46 Hz, 2H), of 7.64-7,71 (m, 2H), 9,01 (DD, J=8,46, of 1.84 Hz, 1H), remaining 9.08 (DD, J=4,23, 1.65 Hz, 1H), 10,01 (c, 1H);

MS ESI+ m/z 407 (M+H)+, ESI+ m/z 429 (M+Na)+, ESI - m/z 405 (M-H)-.

Example 214

[2-(4-Aminophenylalanine)-5-benzyloxyphenyl]-(7-methylpurine[2,3-d]pyrimidine-4-yl)Amin

Example 214A

4-Benzyloxy-1-chloro-2-nitrobenzene

A solution of 4-chloro-3-NITROPHENOL (2.0 g, 11.5 mmol), 1-bromoethylene (2,01 g, 11.5 mmol), potassium carbonate (1.65 g, 12,0 mmol) and tetrabutylammonium iodide (0.005 g, 0,0135 mmol) inN,N-dimethylformamide (5 ml) was stirred at room temperature for 16 hours. Then to the solution was added ice water (10 ml) and the obtained solid substance was collected by filtration and sushi is whether in a vacuum oven to obtain specified in the title compound (3.0 g, 99%).

Example 214B

4-(4-Benzyloxy-2-nitrophenyloctyl)phenylamine

A solution of the compound obtained in example 214A (1.0 g, of 3.80 mmol), 4-aminothiophenol (0.5 g, 4.00 mmol), cesium carbonate (1.3 g, 4 mmol) in dimethylformamide (10 ml) was heated at 40 for 16 hours. Then to the solution was added ice water (50 ml) and the resulting suspension was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride, then dried over anhydrous sodium sulfate. Drying substance was filtered and the solvent was removed under vacuum to obtain specified in the title compound as orange oil (1.1 g, 83%).

Example 214C

Tert-butyl ester [4-(4-benzyloxy-2-nitrophenyloctyl)phenyl]carbamino acid

A solution of the compound from example 214B (1.1 g, 3.1 mmol) was treated with Boc anhydride (0.9 g, 4.00 mmol) in dioxane (15 ml) and heated under reflux hours. The next day the solvent was removed under vacuum to obtain specified in the connection header in the form of butter, light brown (1.4 g, 100%).

Example 214D

Tert-butyl ester [4-(2-amino-4-benzyloxycarbonyl)phenyl]carbamino acid

A solution of the product of example 214C (1.4 g, to 3.09 mmol), iron powder (0,70 g, 12 mmol) and ammonium chloride (0.18 g, to 3.41 mmol) in a solution of methanol (10 ml), is tetrahydrofuran (10 ml) and water (5 ml) was heated under reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a layer of celite. The filtrate was concentrated under vacuum to a volume of 10 ml, the solution was diluted with water (50 ml) and was extracted with ethyl acetate (2×50 ml). The combined extracts were washed with 10% sodium chloride, then dried over magnesium sulfate, filtered and concentrated under vacuum to obtain specified in the title compound (1.1 g, 90%).

Example 214E

[2-(4-Aminophenylalanine)-5-benzyloxyphenyl]-(7-methylpurine[2,3-d]pyrimidine-4-yl)Amin

A solution of the product from example 10B (67 mg, 0,355 mmol) and the product from example 214D (150 mg, 0,355 mmol) in acetic acid (1 ml) was stirred on an oil bath preheated to 130ºC for 10 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum and the resulting residue was treated with 50% TFA in CH2Cl2(2 ml) for 30 minutes at room temperature. The solvent was evaporated under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (25 mg, 12%).

1H NMR (300 MHz, DMSO-D6) δ ppm: was 2.76 (c, 3H), 5,10 (c, 2H), 6,46-of 6.61 (m, 2H), 6,97 for 7.12 (m, 3H), 7,10-7,22 (m, 2H), 7,29-7,51 (m, 6H), a 7.85 (d, J=8,46 Hz, 1H), 8,80-of 8.90 (m, 2H), 8,95 (d, J=8,46 Hz, 1H), 11,70 (c, 1H).

Example 215

[2-(4-Aminophenylalanine)-5-benzyloxyphenyl]-(7-isopropylbenzo[2,3-d]pyrim the DIN-4-yl)Amin

A solution of the product from example 36E (80 mg, 0,368 mmol) and the product from example 214D (160 mg, 0,368 mmol) in acetic acid (2 ml) was stirred on an oil bath preheated to 130ºC for 10 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum and the residue was treated with 50% TFA in CH2Cl2(2 ml) for 30 minutes at room temperature. The solvent was evaporated under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (22 mg, 10%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,36 (d, J=6,62 Hz, 6H), 3,19-to 3.38 (m, 1H), 5,10 (c, 2H), 6,41-of 6.61 (m, 2H), 6,92-to 7.18 (m, 5H), 7,27-7,52 (m, 6H), to $ 7.91 (d, J=8,46 Hz, 1H), 8,84 (c, 1H), 9,01 (c, 1H), 11,64 (c, 2H).

Example 216

[2-(4-Aminophenylalanine)-5-(1-phenylethane)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

Example 216A

1-Chloro-2-nitro-4-(1-phenylethane)benzene

A solution of 4-chloro-3-NITROPHENOL (2.0 g, 11.5 mmol), 1-brahmativartate (3.2 g, 17.3 mmol), sodium carbonate (1.80 g, 17,0 mmol) in acetone (20 ml) was heated under reflux for 18 hours. The reaction mixture was cooled, the solids were filtered off and the filtrate was concentrated to obtain a viscous syrup under vacuum. The residue was dissolved in ether (80 ml) and washed with water (20 ml) and a solution of 30% KOH (2×20 ml) and the solvent was concentrated under vacuum to item is the receiving specified in the title compound as an oily residue (3,01 g, 94%).

Example 216B

4-[2-Nitro-4-(1-phenylethane)phenylsulfanyl]phenylamine

A solution of the compound from example 216A (1.86 g, 6.95 mmol), 4-aminothiophenol (0.88 g, 7,00 mmol), cesium carbonate (2.3 g, 7,00 mmol) in dimethylformamide (10 ml) was heated at 40 for 16 hours. Then to the solution was added ice water (50 ml) and the resulting suspension was treated with ethyl acetate (100 ml). The layers were separated and the organic layer was washed with 10% sodium bicarbonate and 10% sodium chloride and dried over anhydrous sodium sulfate. Drying substance was filtered and the solvent was removed under vacuum to obtain specified in the title compound as orange oil (2.35 g, 92%).

Example 216C

Tert-butyl ester {4-[2-nitro-4-(1-phenylethane)phenylsulfonyl]phenyl}carbamino acid

A solution of the compound from example 216B (2.35 g, 6.4 mmol) was treated with Boc anhydride (1.7 g, of 7.70 mmol) in dioxane (20 ml) and was heated under reflux for 18 hours. The next day the solvent was removed under vacuum to obtain specified in the title compound as a light brown oil (1.78 g, 60%).

Example 216D

Tert-butyl ester {4-[2-amino-4-(1-phenylethane)phenylsulfonyl]phenyl}carbamino acid

A solution of the product from example 216C (1.78 g, of 3.80 mmol), iron powder (0.85 grams, of 15.3 mmol) and ammonium chloride (0.25 g, of 4.57 mmol) in a solution of methanol(10 ml), tetrahydrofuran (10 ml) and water (5 ml) was heated under reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a layer of celite. The filtrate was concentrated under vacuum to a volume of 10 ml, the solution was diluted with water (50 ml) and was extracted with ethyl acetate (2×50 ml). The combined extracts were washed with 10% sodium chloride, then dried over magnesium sulfate, filtered and concentrated under vacuum to obtain specified in the connection header (0,53 g, 32%).

Example 216E

[2-(4-Aminophenylalanine)-5-(1-phenylethane)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

A solution of the product from example 36E (57 mg, 0,265 mmol) and the product from example 216D (116 mg, 0,265 mmol) in acetic acid (2 ml) was stirred on an oil bath preheated to 130ºC for 10 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum and the residue was treated with 50% TFA in CH2Cl2(2 ml) for 30 minutes at room temperature. The solvent was evaporated under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (18 mg, 11%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1.30 on (m, 3H), of 1.31 (d, 6H), 3,18-to 3.34 (m, 1H), 5,48 (c, 1H), 6,50 (c, 1H), 6,86-was 7.08 (m, 3H), 7,10 (d, J=5,15 Hz, 2H), 7,22-to 7.50 (m, 5H), 7,86 (c, 1H), of 8.37 (c, 1H), 8,48 (c, 1H), 8,78 (c, 1H), 8,94 (c, 1H) 11,19 (c, 1H).

Example 217

[2-(2-Amino-6-chloropyrimidine-4-ylsulphonyl)-5-benzyloxyphenyl]-(7-methylpurine[2,3-d]pyrimidine-4-yl)Amin

Example 217A

4-Benzyloxy-2-nitrophenylamino

A solution containing 4-amino-3-NITROPHENOL (1,09 g, 7,07 mmol), benzylbromide (1.28 g, 7.5 mmol and cesium carbonate (2,43 g, 7.5 mmol) was stirred for 4 days at room temperature. After completion of the reaction, the reaction mixture was poured into ice water (500 ml)was stirred for 1 hour and the resulting solid was filtered and dried under vacuum to obtain specified in the title compound (1.1 g, 64%).

Example 217B

Tetrafluoroborate 4-benzyloxy-2-nitrobenzaldehyde

The product from example 217A (0.5 g, 2.05 mmol) was dissolved in THF (10 ml) and added dropwise to a cooled (-20ºC) to the solution containing boron TRIFLUORIDE athirat (1.1 ml, 8.20 mmol) and tert-butylnitrite (0.6 ml, to 4.92 mmol)over 5 minutes. The resulting mixture was stirred for 10 minutes at -20 ░ C, then 2 hours at 10ºC. Then the reaction mixture was poured into hexane (100 ml) and the solid was filtered, washed with ether and dried under vacuum to obtain specified in the connection header (0,61 g, 87%).

Example 217C

4-(4-Benzyloxy-2-nitrophenyloctyl)-6-chloropyrimidine-2-ylamine

To the solution containing thioacetate potassium (0.04 g, 0,350 mmol)in dimethylsulfoxide (1 ml) was added dropwise Astor product from example 217B (0.1 g, 0,290 mmol) in dimethyl sulfoxide (1 ml). The reaction mixture immediately began to barbthroat. After the termination of ozonation and the mixture was stirred for 90 minutes at room temperature. Then, the resulting dark green mixture was treated with aqueous 3M potassium hydroxide solution (0.1 ml) and stirred an additional 80 minutes, after which was added solid 4,6-dichloro-2-aminopyrimidine and the mixture was stirred another 60 minutes. The reaction mixture was diluted with ethyl acetate (50 ml), washed with water (20 ml), a solution of 10% sodium bicarbonate and 10% sodium chloride, dried over sodium sulfate, filtered and the solvent was removed under vacuum to obtain specified in the connection header in a solid brown color (0.1 g, 88%).

Example 217D

4-(2-Amino-4-benzyloxycarbonyl)-6-chloropyrimidine-2-ylamine

A solution of the product from example 217C (0.1 g, 0,257 mmol), iron powder (0,058 g of 1.03 mmol) and ammonium chloride (0,017 g, 0,310 mmol) in a solution of methanol (5 ml), tetrahydrofuran (5 ml) and water (2 ml) was heated under reflux for 1.5 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a layer of celite. The filtrate was concentrated under vacuum to a volume of 10 ml, the solution was diluted with water (50 ml) and was extracted with ethyl acetate (2×50 ml). The combined extracts were washed with 10% sodium chloride, the eat was dried over magnesium sulfate, was filtered and concentrated under vacuum to obtain specified in the title compound (0.04 g, 43%).

Example 217E

[2-(2-Amino-6-chloropyrimidine-4-ylsulphonyl)-5-benzyloxyphenyl]-(7-methylpurine[2,3-d]pyrimidine-4-yl)Amin

A solution of the product from example 10B (21 mg, 0,112 mmol) and the product from example 217D (40 mg, 0,112 mmol) in acetic acid (1 ml) was stirred on an oil bath preheated to 130ºC for 10 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum and the resulting residue was treated with 50% TFA in CH2Cl2(2 ml) for 30 minutes at room temperature. The solvent was evaporated under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (5 mg, 7%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 2,66 (c, J=6.25 Hz, 3H), to 5.21 (c, 2H), 6,53 (c, 1H), 7,07 (c, 1H), 7,14 (DD, J=8,64, 2.76 Hz, 1H), 7,25-to 7.61 (m, 6H), 7,62-7,72 (m, 1H), charged 8.52 (c, 1H), 8,66 (d, J=8,82 Hz, 1H), 8,71 (c, 1H), 8,88 (d, J=8,46 Hz, 1H), of 10.05 (c, 1H).

Example 218

4-[4-(3-Bromobenzylamine)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenoxy]phenol

Example 218A

4-[4-(3-Bromobenzylamine)-2-nitrophenoxy]phenol

A solution of hydroquinone (276,4 mg, 2,510 mmol) in anhydrous to 3.64 mmol) and heated in nitrogen atmosphere at 120 ºC for 30 minutes. A solution of 4-(3-bromobenzylamine)-1-chloro-2-nitrobenzene (example 15A) (774 mg, at 2.59 mmol) in dimethyl sulfoxide (4 ml) was added dropwise via additional funnel over 30 minutes at 120 ºC, then the mixture was stirred at this temperature for 1 hour. The reaction mixture was cooled in an ice bath, then poured into ice water (20 ml) and the pH was brought to 2 with concentrated hydrochloric acid. The mixture was extracted with ethyl ether (3×100 ml), the combined ethereal extracts were washed with water (3×100 ml) and saturated saline (50 ml), dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator under vacuum. Purification of the residue with flash chromatography on silica gel using a mixture of 3% ethyl acetate/methylene chloride as eluent, gave specified in the title compound in the form of solid dark yellow (386 mg, 0,927 mmol, 41%).

Example 218B

4-[2-Amino-4-(3-bromobenzylamine)phenoxy]phenol

Mixture of product example 218A (384,6 mg, 0,924 mmol), iron powder (317,4 mg, 5,683 mmol) and ammonium chloride (323,7 mg, 6,052 mmol) in water (3 ml) and ethanol (6 ml) was heated at 70 º C in nitrogen atmosphere for 1 hour. The reaction mixture was cooled to room temperature and was filtered under vacuum, the residue was washed with methanol. The filtrate was concentrated under vacuum and the azeotropic drove with toluene (50 ml). The residue was purified flash chromatography on silica gel using a gradient mixture of 7% to 10% ethyl acetate/methylene chloride as eluent, to obtain specified in the header joint is in the form of a solid beige color (272 mg, 0,704 mmol, 76%).

Example 218C

4-[4-(3-Bromobenzylamine)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenoxy]phenol

A solution of the product from example 36E (25 mg, 0,116 mmol) and the product from example 218B (44,6 mg, 0,116 mmol) in acetic acid (1 ml) was stirred on an oil bath pre-heated to 140ºC for 1 hour. The reaction mixture was cooled to room temperature, diluted with hexane (50 ml), concentrated on a rotary evaporator and was co-evaporated with a mixture of methylene chloride/hexane (4×). The residue was dried under high vacuum overnight, then was purified flash chromatography on silica gel using a mixture of 3% methanol/methylene chloride as eluent, to obtain specified in the title compound as a pale yellow solid (34 mg, 0,0613 mmol, 53%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1.30 on (e,J=6,62 Hz, 6H), 3,09 of 3.28 (m, 1H), 5,12 (c, 2H), 6,62 (l,J=9,20 Hz, 2H), 6,76 (l,J=8,82 Hz, 2H), 6,82-6,97 (m, 2H), to 7.32 and 7.36 (m, 1H), 7,39 (l,J=7,72 Hz, 1H), 7,45-7,58 (m, 3H), 7,68 (c, 1H), 8,57 (c, 1H), 8,72 (l,J=8,82 Hz, 1H), 9,14 (c, 1H), 9,75 (c, 1H);

MS (ESI+) m/z 557/559 (M+H)+.

Example 219

4-[4-(4-Bromobenzylamine)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenoxy]phenol

Example 219A

4-[2-Amino-4-(4-bromobenzylamine)phenoxy]phenol

4-(4-Bromobenzylamine)-1-chloro-2-nitrobenzene (example 16A) were subjected to interaction with hydroquinone in accordance with the method described in example 39A,and restored in accordance with the method, described in example 39B, obtaining specified in the header of the product.

Example 219B

4-[4-(4-Bromobenzylamine)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenoxy]phenol

The product from example 219A were subjected to interaction with the product from example 36E in accordance with the method described in example 39C, using the product from example 219A instead of the product from example 218B, obtaining specified in the title compound after chromatography on silica gel (38 mg, 59%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1.30 on (e,J=6,99 Hz, 6H), 3,10-of 3.27 (m, 1H), 5,09 (c, 2H), 6,56 of 6.66 (m, 2H), 6,70-6,79 (m, 2H), for 6.81-6,97 (m, 2H), 7,32 (l,J=to 2.57 Hz, 1H), 7,43 (l,J=8,46 Hz, 2H), 7,53 (l,J=8,46 Hz, 1H), 7,60 (l,J=8,46 Hz, 2H), 8,57 (c, 1H), 8,72 (l,J=8,46 Hz, 1H), 9,14 (c, 1H), 9,74 (c, 1H);

MS (ESI+) m/z 557/559 (M+H)+.

Example 220

4-[4-Benzyloxy-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenoxy]phenol

Example 220A

4-(2-Amino-4-benzyloxyphenyl)phenol

4-Benzyloxy-1-chloro-2-nitrobenzene (example 27A) were subjected to interaction with hydroquinone in accordance with the method described in example 39A, and restored in accordance with the method described in example 39B, obtaining specified in the header of the product.

Example 220B

4-[4-Benzyloxy-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenoxy]phenol

The product from example 220A were subjected to interaction with the product from example 36E in accordance with the FPIC of the BOM, described in example 39C, using the product from example 220A instead of the product from example 218B, obtaining specified in the title compound after chromatography on silica gel (58 mg, 65%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 1.30 on (e,J=6,99 Hz, 6H), is 3.08-of 3.27 (m, 1H), 5,10 (c, 2H), 6,62 (d, J=9,2 Hz, 2H), 6,74 (d, J=9,2 Hz, 2H), for 6.81-6,98 (m, 2H), 7,26-to 7.61 (m, 7H), to 8.57 (c, 1H), 8,72 (l,J=8,46 Hz, 1H), 9,13 (c, 1H), 9,75 (c, 1H);

MS (DCI/NH3) m/z 479 (M+H)+.

Example 221

4-[4-Benzyloxy-2-(7-arilpirido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 27A was subjected to interaction with the product from example 145A method described in example 10F, using the product from example 27A instead of the product from example 10E and using the product from example 145A instead of the product from example 10B, obtaining specified in the header of the product.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1.32 to (t,J=7,72 Hz, 3H), 2.95 and (sq,J=7,72 Hz, 2H), 5,11 (c, 2H), 6,65 (l,J=8,82 Hz, 2H), 6,91-7,05 (m, 1H), 7,10 (l,J=8,46 Hz, 2H), 7,32-to 7.50 (m, 6H), 8,12 (l,J=6,99 Hz, 1H), 8,66-8,77 (m, 1H), 9,04 (l,J=8,82 Hz, 1H), 9,63 (c, 1H), 10,28 (c, 1H);

MS (APCI) m/z 481 (M+H)+.

Example 222

4-[4-Benzyloxy-2-(7-cyclohexylurea[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 27A was subjected to interaction with the product from example 135A by the method described in example 10F, using the product from example 27A instead of the product from example 10E and using the product from example 135A instead of the product oprimary 10B, obtaining specified in the header of the product.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,23-is 1.51 (m, 4H), 1,53-to 1.79 (m, 4H), 1,80-2,00 (m, 2H), 2.77-to to 3.02 (m, 1H), 5,10 (c, 2H), 6,67 (l,J=8,46 Hz, 2H), 6,88-7,01 (m, 1H), 7,11 (l,J=8,82 Hz, 2H), 7,22-7,31 (m, 1H), 7,32-7,49 (m, 6H), 7,56 (l,J=7,72 Hz, 1H), 8,55 (c, 1H), 8,73 (l,J=8,09 Hz, 1H), 9,94 (c, 1H);

MS (APCI) m/z 535 (M+H)+.

Example 223

4-[4-Benzyloxy-2-(7-dt-butylperoxide[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 27A was subjected to interaction with the product in example 140A by the method described in example 10F, using the product from example 27A instead of the product from example 10E and using the product from example 140A instead of the product from example 10B, obtaining specified in the header of the product.

1H NMR (300 MHz, DMSO-D6) δ ppm: 0,82 (t,J=to 7.35 Hz, 3H), of 1.30 (d,J=6,62 Hz, 3H), 1,58-of 1.73 (m, 1H), 1,75-to 1.87 (m, 1H), 2,89-is 3.08 (m, 1H), 5,11 (c, 2H), 6,67 (l,J=8,82 Hz, 2H), 6,85-7,03 (m, 1H), 7,11 (l,J=8,46 Hz, 2H), 7,30-to 7.50 (m, 6H), 7,56 (l,J=8,82 Hz, 1H), 8,56 (c, 1H), up 8.75 (d,J=8,46 Hz, 1H), for 9.64 (c, 1H), 9,95 (c, 1H);

MS (APCI) m/z

Example 224

4-[4-(2-Chlorothiazole-5-ylethoxy)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 224A

4-[2-Amino-4-(2-chlorothiazole-5-ylethoxy)phenylsulfanyl]phenol

Specified in the title compound was obtained by the method described in example 16A using benzylbromide instead of 2-chloro-5-brometalia, obtaining specified in the connection header (0,38 g, 64%).

P the emer 224b

4-[4-(2-Chlorothiazole-5-ylethoxy)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

A solution of the product of example 36E (40,4 mg, 0,187 mmol) and the product of example 224A (68 mg, 0,187 mmol) in acetic acid (1 ml) was stirred on an oil bath preheated to 130 º C for 10 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (31 mg, 30%).

1H NMR (300 MHz, DMSO-d6) δ ppm: to 1.35 (d, J=6,99 Hz, 6H), 3,17-to 3.36 (m, 1H), 5,35 (c, 2H), 6,55 (d, J=7,72 Hz, 1H), 6,58-6,74 (m, 2H), 7,00-7,30 (m, 4H), 7.68 per-to 7.95 (m, 2H), 8,76 (c, 1H), to 8.94 (d, J=8,46 Hz, 1H), 9,73 (c, 1H), 11,34 (c, 1H);

MS (ESI+) m/z 536 (M+H)+ (ESI-) m/z 534 (M-H)-.

Example 225

4-[4-(6-Chloropyridin-2-ylethoxy)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 225a

4-[2-Amino-4-(6-chloropyridin-2-ylethoxy)phenylsulfanyl]phenol

Specified in the title compound was obtained by the method described in example 16A, replacing benzylbromide 2-chloro-5-bromomethylphenyl, obtaining specified in the connection header (0,63 g, 73%).

Example 225b

4-[4-(6-Chloropyridin-2-ylethoxy)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

A solution of the product of example 10B (37 mg, 0,197 mmol) and the product of example 225a (70,7 mg, 0,197 mmol) in acetic sour is e (2 ml) was stirred on an oil bath the pre-heated up to 130ºC for 20 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (20 mg, 20%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 2,70 (c, 3H), 5,18 (c, 2H), 6,65 (d, J=8,82 Hz, 2H), 7,02 (d, J=8,09 Hz, 1H), 7,11 (d, J=8,82 Hz, 2H), 7,19 (d, J=8,82 Hz, 1H), 7,25 (c, 1H), 7,52 (DD, J=13,60, 7,72 Hz, 2H), to 7.67 (d, J=8,09 Hz, 1H), 7,93 (t, J=7,72 Hz, 2H), 8,65 (c, 1H), 8,80 (d, J=8,09 Hz, 1H), 9,68 (c, 1H);

MS (ESI+) m/z 502 (M+H)+ (ESI-)m/z 500 (M-H)-.

Example 226

4-[4-(6-Chloropyridin-2-ylethoxy)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

A solution of the product of example 36E (36 mg, has 0.168 mmol) and the product of example 225a (60 mg, has 0.168 mmol) in acetic acid (1 ml) was stirred on an oil bath preheated to 130ºC for 10 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (31 mg, 30%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 1,16 (d, J=6,99 Hz, 3H), of 1.36 (d, J=6,62 Hz, 3H), 3,20-3,40 (m, 1H), 5,18 (c, 1H), 6,55 (d, J=7,72 Hz, 1H), only 6.64 (d, J=8,82 Hz, 2H), 6,77 (c, 1H),? 7.04 baby mortality-to 7.18 (m, 2H), 7,15-7,29 (m, 2H), 7,52 (DD, J=10,48, to $ 7.91 Hz, 2H), to 7.77 (d, J=7,72 Hz, 1H), to 7.93 (t, J=7,72 Hz, 2H), 8,82 (c, 1H), 8,97 (c, 1H), 9,72 (c, 1H), 11,66 (c, 1H);

MS (ESI+) m/z 530 (M+H)+ (ESI-) m/z 528(M-H)-.

Example 227

4-[2-(7-Tert-butylperoxide[2,3-d]pyrimidine-4-ylamino)-4-(3-forbindelse)phenylsulfanyl]phenol

The product from example 127A (110 mg, 0,478 mmol) was subjected to interaction with the product from example 28A (164 mg, 0.48 mmol) in 1 ml of glacial acetic acid was heated at 120ºC for 13 minutes. Was cooled to room temperature and acetic acid removed under vacuum. The crude product was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (134 mg, 44%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 1,43 (c, 9H), 5,14 (c, 2H), 6,65 (d, J=to 8.45 Hz, 2H), 7,17 (m, 4H), 7,29 (d, J=to 8.45 Hz, 2H), 7,44 (d, J=to 8.45 Hz, 2H), to 7.99 (d, J=7,80 Hz, 1H), 8,72 (c, 1H), 8,93 (d, J=8,45 Hz, 1H), 9,68 (c, 1H), 10,90 (users, 1H);

MS (ESI+) m/z 527 (M+H-TFA)+; (ESI-) m/z 525 (M-H-TFA)-.

Example 228

4-[4-[1-(3-Bromophenyl)ethoxy]-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 228a

1-(1-Bromacil)-4-torbenson

To a solution of 1-(3-bromophenyl)ethanol (7.0 g, 34,0 mmol) in dichloromethane (40 ml) was added dropwise tribromide phosphorus (77 g, 34,0 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water. The aqueous phase was podslushivaet bicarbonate of sodium. The aqueous phase was extracted with dichloromethane. The organic phase is washed with water, saturated salt solution and dried over sodium sulfate, filtered and concentrated under VA what womam obtaining specified in the title compound (7.8 g, 80%).

Example 228b

4-[1-(3-Bromophenyl)ethoxy]-1-chloro-2-nitrobenzene

To the product of example 228a (7.8 g, 30 mmol) in DMF (50 ml) was added 4-chloro-3-NITROPHENOL (5,14 g, 30.0 mmol) and K2CO3(8,18 g, 60 mmol). The mixture was heated at 80ºC for 16 hours. The reaction mixture was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2×) and the combined phases were washed with water, saturated salt solution and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by chromatography on silica gel, elwira (hexane/ethyl acetate 90:10) to obtain the specified title compound (7.0 g, 66%).

Example 228c

4-{4-[1-(3-Bromophenyl)ethoxy]-2-nitrophenyloctyl}phenol

To the product of example 228b (5.0 g, 14.0 mmol) in DMF (50 ml) was added 4-mercaptoethanol (1.7 g, 14.0 mmol) and K2CO3(3.8 g, 28 mmol). The mixture was heated at 80 ° C for 16 hours. The reaction mixture was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2×) and the combined phases were washed with water, saturated salt solution and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by chromatography on silica gel, elwira mixture (hexane/ethyl acetate/methanol 75:15:5) to obtain the specified title compound (5.2 g, 83%).

Example 228d

4-{2-Amino-4-[1-(3-bromophenyl)e is the hydroxy]phenylsulfanyl}phenol

The product from example 228c (5,4 g, 12.2 mmol) was subjected to interaction with Fe and NH4Cl as described in example 10E, obtaining specified in the title compound (3.6 g, 76%).

Example 228e

4-[4-[1-(3-Bromophenyl)ethoxy]-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 57A (125 mg, to 0.72 mmol) was subjected to interaction with the product of example 228d (298 mg, to 0.72 mmol) in acetic acid (10 ml) at 125º in a tightly closed vessel for 5 minutes to obtain a crude specified in the title compound, which was purified by HPLC with TFA to obtain the product as triperoxonane acid (120 mg, 31%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 1,54 (l,J=6.25 Hz, 3H), 5,52 (sq,J=6.25 Hz, 1H), 6,66 (l,J=8,82 Hz, 2H), 6,85 (c, 1H), 7,07 for 7.12 (m, 3H), 7,19 (c, 1H), 7,32 (t,J=7,72 Hz, 1H), 7,39-7,49 (m, 2H), to 7.61 (c, 2H), 8,57 (c, 1H), 8,80 (c, 1H), 9,06 (c, 1H), 9,65 (c, 1H);

MS (ESI-) m/z 545 (M-H)-.

Example 229

4-[4-[1-(3-Bromophenyl)ethoxy]-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 10B (110 mg, of 0.58 mmol) was subjected to interaction with the product of example 228d (243 mg, of 0.58 mmol) in acetic acid (10 ml) at 125º in a tightly closed vessel for 5 minutes to obtain a crude specified in the title compound, which was purified by HPLC with TFA to obtain the product as triperoxonane acid (100 mg, 30%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 1,3 (e, J=6.25 Hz, 3H), 2,53 (c, 3H), 5,31 (sq,J=to 6.43 Hz, 1H), 6,44 (l,J=8,82 Hz, 2H), of 6.68 (DD,J=8,82, to 2.57 Hz, 1H), 6,85-6,92 (m, 3H), 6,95 (l,J=to 2.57 Hz, 1H), 7,11 (t,J=7,72 Hz, 1H), 7,19-7,27 (m, 2H), 7,40 (c, 1H), 7,44 (l,J=8,46 Hz, 1H), 8,44 (c, 1H), 8,56 (l,J=8,46 Hz, 1H); MS (ESI+) m/z 560 (M+H)+.

Example 230

4-[4-[1-(3-Bromophenyl)ethoxy]-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 36E (130 mg, of 0.60 mmol) was subjected to interaction with the product of example 228d (250 mg, of 0.60 mmol) in acetic acid (10 ml) at 125ºC in a tightly closed vessel for 5 minutes to obtain a crude specified in the title compound, which was purified by HPLC with TFA to obtain the product as triperoxonane acid (140 mg, 39%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 1,34 (l,J=6,99 Hz, 6N), and 1.54 (d,J=6.25 Hz, 3H), 3,26 (square, 1H), 5,52 (sq,J=6,62 Hz, 1H), 6,65 (l,J=8,46 Hz, 2H), 6,92 (DD,J=8,82, to 2.94 Hz, 1H), 7,10 (m, 4H), 7,32 (t,J=7,72 Hz, 1H), 7,39-to 7.50 (m, 2H), 7,60 (c, 1H), 7,79 (l,J=8,46 Hz, 1H), 8,70 (c, 1H), 8,86 (l,J=8,46 Hz, 1H), 9,72 (c, 1H); MS (ESI+) m/z 588 (M+H)+.

Example 231

4-[4-(3-Bromobenzylamine)-2-(7-tert-butylperoxide[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 127A (147 mg, 0,63 mmol) and the product from example 15A (256 mg, 0,63 mmol) was heated in 2 ml of glacial acetic acid at 120ºC for 15 minutes. Was cooled to room temperature and acetic acid removed under vacuum. The crude product was purified by OSU HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (45 mg, 10%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 1,43 (c, N), 5,13 9 (c, 2H), 6,66 (d, J=8,83 Hz, 2H), 7,01 (d, J=6,62 Hz, 1H), 7,11 (d, J=8,83 Hz, 2H), 7,19 (m, 1H), 7,37 (m, 1H), 7,46 (d, J=7,72 Hz, 1H), 7,54 (d, J=6,62 Hz, 1H), 7,66 (c, 1H), of 7.95 (d, J=8,09 Hz, 1H), 8,69 (c, 1H), 8,88 (d, J=8,83 Hz, 1H), 9,68 (c, 1H);

MS (ESI+) m/z 587, 589 (M+H-TFA)+; (ESI-) m/z 585, 587 (M-H-TFA)-.

Example 232

4-[4-(3-Bromperoxidase)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 232A

4-[2-Amino-4-(3-bromperoxidase)phenylsulfanyl]phenol

A solution of 4-[4-(3-bromperoxidase)-2-nitrophenyloctyl]phenol (325 mg, 0,752 mmol), iron filings (210 mg, 3,76 mmol) and ammonium chloride (60 mg, 1.13 mmol) in tetrahydrofuran (5 ml), water (1.5 ml) and ethanol (5 ml) was heated under reflux for 2.5 hours. After cooling to room temperature the solution was filtered through a layer of celite, which was washed with methanol. Then the filtrate was concentrated under vacuum, then dissolved in water (20 ml) and was extracted with ethyl acetate (2×20 ml). The organic extracts were dried and concentrated under vacuum to obtain specified in the title compound as a pale yellow solid (240 mg, 79%).

Example 232B

4-[4-(3-Bromperoxidase)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

A solution of the product from example 232A (85 mg, 0,211 mmol) and the product from example 36E (46 mg, 0,211 mmol) in acetic acid (3 ml) heated the Ali at 130ºC for 15 minutes. Then the solution was left to cool to room temperature, acetic acid was removed under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (63 mg, 43%).

1H NMR (300 MHz, DMSO-d6) δ ppm: to 1.35 (d, J=7,0 Hz, 6H), of 3.25 (m, 1H), 5,13 (c, 2H), 6,77 (d, J=8,8 Hz, 2H), 7,02 (d, J=8.1 Hz, 2H), 7,15 (m, 1H), 7.23 percent (m, 4H), of 7.36 (m, 1H), 7,46 (c, 1H), 7,83 (d, J=8,8 Hz, 1H), 8,76 (c, 1H), of 8.95 (d, J=8,8 Hz, 1H), 9,88 (c, 1H), 11,22 (users, 1H);

MS (ESI)m/z 573/575 (M+H)+.

Example 233

4-[4-(3-Bromperoxidase)-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

A solution of the product from example 232A (60 mg, 0,149 mmol) and the product from example 10B (28 mg, 0,149 mmol) in acetic acid (3 ml) was heated at 130ºC for 15 minutes. Then the solution was left to cool to room temperature, acetic acid was removed under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (46 mg, 47%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 2,72 (c, 3H), 5,12 (c, 2H), 6,77 (d, J=8.5 Hz, 2H), 7,02 (m, 2H), 7,16 (m, 1H), 7.23 percent (m, 4H), of 7.36 (m, 1H), 7,47 (c, 1H), of 7.70 (d, J=8,8 Hz, 1H), 8,70 (c, 1H), 8,86 (d, J=8.5 Hz, 1H), 9,87 (c, 1H), 10,95 (users, 1H);

MS (ESI)m/z 545/547 (M+H)+.

Example 234

4-[4-(2,5-Deferasirox)-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 234a

2-methyl bromide-1,4-differenza

It races the thief (2.5-differenl)methanol (4.8 g, 33.6 mmol) in dichloromethane (40 ml) was added dropwise tribromide phosphorus (94 g, 33.6 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water. The aqueous phase was podslushivaet bicarbonate of sodium. The aqueous phase was extracted with dichloromethane. The organic phase was concentrated under reduced pressure. The residue was purified by chromatography on silica gel, elwira (hexane/ethyl acetate 90:10) to obtain the specified title compound (3.5 g, 50%).

Example 234b

1-Chloro-4-(2,5-forbindelse)-2-nitrobenzene

To the product of example 234a (2.2 g, 10.4 mmol) in DMF (50 ml) was added 4-chloro-3-NITROPHENOL (1.8 g, 10.4 mmol) and K2CO3(2,87 g of 20.8 mmol). The mixture was heated at 80ºC for 16 hours. The reaction mixture was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2×) and the combined phases were washed with water, saturated salt solution and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by chromatography on silica gel, elwira (hexane/ethyl acetate 90:10) to obtain specified in the connection header (2,48 g, 66%).

Example 234c

4-[4-(2,5-Deferasirox)-2-nitrophenyloctyl]phenol

To the product of example 234b (2.5 g, 8.3 mmol) in DMF (50 ml) was added 4-mercaptoethanol (1.0 g, 8.3 mmol) and K2CO3(2.3 g, 16.5 mmol). The mixture was heated n and 80º C for 16 hours. The reaction mixture was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2×) and the combined phases were washed with water, saturated salt solution and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified flash chromatography, elwira (hexane/ethyl acetate/methanol 75:15:5) to obtain the specified title compound (1.7 g, 52%).

Example 234d

4-[2-Amino-4-(2,5-deferasirox)phenylsulfanyl]phenol

The product from example 234c (1.70 g, 4.2 mmol) was subjected to interaction with Fe and NH4Cl by the method described in example 10E, obtaining specified in the title compound (1.3 g, 84%).

Example 234e

4-[4-(2,5-Deferasirox)-2-(pyrido[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 57A (100 mg, or 0.57 mmol) was subjected to interaction with the product of example 234d (206 mg, or 0.57 mmol) in acetic acid (10 ml) at 125ºC in a tightly closed vessel for 5 minutes to obtain a crude specified in the title compound, which was purified by HPLC with TFA to obtain the product as triperoxonane acid (140 mg, 39%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 5,13 (c, 2N), to 6.67 (d,J=8,46 Hz, 2H), 6,93-7,01 (m, 1H), 7,10-7,16 (m, 3H), 7,22-7,37 (m, 4H), 7,41-7,52 (m,J=5,79, 5,79, 2.76 Hz, 1H), to 7.64 (DD,J=8,09, to 4.41 Hz, 1H), 8,53 (c, 1H), 8,84 (l,J=7,72 Hz, 1H), 9,05 (c, 1H);

MS (ESI+) m/z 489 (M+H)+.

Example 235

4-4-(2,5-Deferasirox)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 36E (100 mg, 0.46 mmol) was subjected to interaction with the product of example 234d (206 mg, 0.46 mmol) in acetic acid (10 ml) at 125ºC in a tightly closed vessel for 5 minutes to obtain a crude specified in the title compound, which was purified by HPLC with TFA to obtain the product as triperoxonane acid (140 mg, 39%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 1,34 (l,J=6,62 Hz, 6H), 5,14 (c, 2H), 6,66 (l,J=8,46 Hz, 2H), 7,06 (l,J=to 2.57 Hz, 1H), 7,12 (l,J=8,46 Hz, 2H), 7,21-7,35 (m, 4H), 7,44 (c, 1H), to 7.77 (d,J=8,46 Hz, 1H), 8,69 (c, 1H), 8,88 (l,J=8,46 Hz, 1H), 9,70 (c, 1H);

MS (ESI+) m/z 531 (M+H)+.

Example 236

4-[4-(2-Chloro-5-forbindelse)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 236a

2-methyl bromide-1-chloro-4-torbenson

To a solution of (2-chloro-5-forfinal)methanol (5.0 g, 31,1 mmol) in dichloromethane (40 ml) was added dropwise tribromide phosphorus (87 g, and 31.1 mmol). The mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into ice water. The aqueous phase was podslushivaet bicarbonate of sodium. The aqueous phase was extracted with dichloromethane. The organic phase was concentrated under reduced pressure. The residue was purified by chromatography on silica gel, elwira (hexane/ethyl acetate 90:10) to obtain the specified title compound (5.75 g, 82.5 per cent).

Example 236b

1-Chloro-4-(2-chloro-5-forbindelse)-2-neither Robinson

To the product of example 236a (5.7 g, of 25.7 mmol) in DMF (50 ml) was added 4-chloro-3-NITROPHENOL (4,46 g of 25.7 mmol) and K2CO3(7,10 g, 51,4 mmol). The mixture was heated at 80ºC for 16 hours. The reaction mixture was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2×) and the combined phases were washed with water, saturated salt solution and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by chromatography on silica gel, elwira (hexane/ethyl acetate 90:10) to obtain the specified title compound (7.0 g, 86%).

Example 236c

4-[4-(2-Chloro-5-forbindelse)-2-nitrophenyloctyl]phenol

To the product of example 236b (2.5 g, 8.3 mmol) in DMF (50 ml) was added 4-mercaptoethanol (1.0 g, 8.3 mmol) and K2CO3(2.3 g, 16.5 mmol). The mixture was heated at 80ºC for 16 hours. The reaction mixture was cooled and poured into water. The aqueous phase was extracted with ethyl acetate (2×) and the combined phases were washed with water, saturated salt solution and dried over sodium sulfate. The organic phase was concentrated under reduced pressure. The residue was purified by chromatography on silica gel, elwira (hexane/ethyl acetate/methanol (70:25:5) to obtain the specified title compound (5.0 g, 78%).

Example 236d

4-[2-Amino-4-(2-chloro-5-forbindelse)phenylsulfanyl]phenol

The product from example 236c (4,2 g, 10.2 mmol) in what was vergili interaction with Fe and NH 4Cl by the method described in example 10E, obtaining specified in the title compound (3.0 g, 77%).

Example 236e

4-[4-(2-Chloro-5-forbindelse)-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 36E (125 mg, to 0.72 mmol) was subjected to interaction with the product of example 236d (298 mg, to 0.72 mmol) in acetic acid (10 ml) at 125º in a tightly closed vessel for 5 minutes to obtain a crude specified in the title compound, which was purified by adding ethyl ether to the residue to give the desired product in the form of acetic acid (225 mg, 66%).

1H NMR (300 MHz, DMSO-d6) δ ppm: 1.32 to (q,J=6,99 Hz, 6H), 3,21 (square, 1H), 5,15 (c, 2H), 6,69 (l,J=8,46 Hz, 2H), 6,99 (DD, 1H), 7,13 (l,J=8,46 Hz, 4H), 7,25-7,35 (m, 2H), 7,49 (DD,J=9,38, 3,13 Hz, 1H), 7,54 to 7.62 (m,J=8,82, 5,15 Hz, 3H), 8,55 (1H, s), (1, a total of 8.74 (c, 1H), 9,66 (c, 1H), 9,98 (c, 1H);

MS (ESI-) m/z 547 (M+H)+.

Example 237

4-[5-Benzyloxy-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Example 237A

4-Benzyloxy-2-fluoro-1-nitrobenzene

A mixture of 3-fluoro-4-NITROPHENOL (0,30 g, at 1.91 mmol), benzylbromide (0.36 g, 2.10 mmol, 1.1 equiv.) potassium carbonate (0,792 g, 5,73 mmol, 3.0 EQ.) and tetrabutylammonium iodide (5.0 mg, 0.014 mmol, 0.007 equiv.) in dimethylformamide (5 ml) was stirred at room temperature for 16 hours. To the reaction mixture were added water (20 ml) and the resulting solid precipitate was isolated by vacuu is owned by filtration and dried to obtain specified in the connection header (0,455 g, 96%) as a solid yellow color.

Example 237B

4-(5-Benzyloxy-2-nitrophenyloctyl)phenol

The product of example 237A (0,301 g, 1,22 mmol), 4-mercaptoethanol (0,184 g of 1.46 mmol, 1.2 EQ.) and cesium carbonate (0,952 g of 2.92 mmol, 2.4 EQ.) in dimethylformamide (10 ml) was heated on an oil bath at 100ºC for 3 hours and then cooled to room temperature. Was added water (20 ml) and the mixture was stirred at room temperature for 2 hours and the resulting solid was isolated by vacuum filtration and dried to obtain specified in the connection header (0,405 g, 94%) as a solid yellow color.

Example 237C

4-(2-Amino-5-benzyloxycarbonyl)phenol

The product of example 237B (0,390 g, 1.10 mmol), iron powder (0,248 g, to 4.41 mmol, 4.0 EQ.) and ammonium chloride (0,071 g of 1.32 mmol, 1.2 EQ.) in tetrahydrofuran (6 ml), methanol (6 ml) and water (2 ml) was heated under reflux for 16 hours and then cooled to room temperature. The reaction mixture was filtered through celite, washed with methanol and the filtrate was evaporated under reduced pressure to obtain specified in the connection header (0,340 g, 95%) as a gray powder, which is used in the following reactions without further purification.

Example 237D

4-[5-Benzyloxy-2-(7-isopropylbenzo[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

P is oduct example 237C (0,0908 g, 0,281 mmol) and the product of example 36E (0,0607 g, 0,281 mmol) in glacial acetic acid (2 ml) was heated on an oil bath at 140ºC for 10 minutes, cooled to room temperature and evaporated under reduced pressure. The residue was purified column chromatography on silica gel, elwira a mixture of 5% methanol/dichloromethane to obtain specified in the connection header (0,0368 g, 27%) as a solid brown color.

1H NMR (300 MHz, DMSO-D6) δ ppm: 9,88 (c, 2H), 8,82 (l,J=8,46 Hz, 1H), charged 8.52 (c, 1H), 7,58 (l,J=8,46 Hz, 1H), 7,28-7,42 (m, 5H), 7,19-7,28 (m, 3H), 6.87 in (DD,J=8,64, 2.76 Hz, 1H), 6.75 in-6,84 (m, 2H), 6,38 (l,J=to 2.57 Hz, 1H), 4,99 (c, 2H), 3,14-of 3.27 (m, 1H), 1,32 (l,J=6,99 Hz, 6H);

MS (ESI+) m/z 495,2 (M+H)+, (ESI-) m/z 493,2 (M-H)-.

Example 238

4-[2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-steelfinish]phenol

Example 238A

4-(4-Bromo-2-nitrophenyloctyl)phenol

A mixture of 4-bromo-1-fluoro-2-nitrobenzene (of 0.44 g, 2.0 mmol), 4-mercaptoethanol (0,303 g, 2.4 mmol) and cesium carbonate (1.56 g, 4.8 mmol, 2.4 EQ.) in dimethylformamide (10 ml) was heated on an oil bath heated to 100ºC for 3 hours and then cooled to room temperature. The reaction mixture was poured into ice water (50 ml), the pH was brought to 3 by addition of 1N. an aqueous solution of hydrochloric acid and was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over anhydrous magnesium sulfate, filtrowanie was evaporated to obtain specified in the connection header in the form of a thick yellow oil (0,70 g, >100%)which was used without further purification.

Example 238B

4-(2-Amino-4-brompheniramine)phenol

Mixture of product example 238A (0,302 g, 0,926 mmol), iron powder (0,208 g, 3.7 mmol, 4.0 EQ.) and ammonium chloride (0,059 g, 1.11 mmol, 1.2 EQ.) in a mixture of methanol (6 ml), tetrahydrofuran (6 ml) and water (2 ml) was heated under reflux for 5 hours and then cooled to room temperature. The reaction mixture was filtered through celite and the filter bed was washed with methanol (25 ml). The filtrate was evaporated under reduced pressure to obtain a glassy solid brown (0.27 g, 99%), which ispolzovali without additional purification.

Example 238C

4-[4-Bromo-2-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

Mixture of product example 238B (0,158 g of 0.533 mmol) and the product from example 10B (0,100 g of 0.533 mmol) in glacial acetic acid (2 ml) was heated on an oil bath heated to 130ºC for 30 minutes. Added additional amount of the product from example 10B (to 0.060 g, 0,319 mmol) and the reaction mixture was heated for a further 30 minutes at 130ºC. Then the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue is triturated in 2-propanol and the resulting solid was isolated by vacuum filtration and dried to obtain specified the title compound (0.083 g, 36% yield) as a solid beige color.

Example 238D

4-[2-(7-Methylpurine[2,3-d]pyrimidine-4-ylamino)-4-steelfinish]phenol

Mixture of product example 238C (0,0791 g, 0,180 mmol), styrene (0,176 g, 1,69 mmol, 9,4 equiv.) the palladium(II) acetate (6.2 mg, 0,0276 mmol, of 0.15 equiv.) three-o-tolylphosphino (13.3 mg, 0,0437 mmol, 0.24 equiv.) and aminobutiramida ethylamine (0,697 g, 0,539 mmol, 3.0 EQ.) in dimethylformamide (2 ml) was heated on an oil bath heated to 130ºC, for 98 hours. Then the mixture was cooled to room temperature and the solvent was evaporated in a stream of nitrogen gas. The residue was distributed between ethyl acetate and water and the aqueous layer was additionally extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (6,1 mg, 10% yield).

1H NMR (300 MHz, DMSO-D6) δ ppm: 11,27 (c, 1H), 9,89 (c, 1H), 8,93 (l,J=8,09 Hz, 1H), 8,79 (c, 1H), 7,78 (l,J=8,82 Hz, 1H), 7,66 (c, 1H), 7,58 (l,J=7,35 Hz, 2H), 7,52 (DD,J=8,09, to 1.47 Hz, 1H), 7,37 (t,J=7,35 Hz, 2H), 7,19-7,31 (m, 5H), 7,00 (l,J=8,09 Hz, 1H), 6.73 x-for 6.81 (m, 2H), 2,75 (c, 3H).

Example 239

(7 Methylpyridin[2,3-d]pyrimidine-4-yl)-(2-phenylsulfanyl-5-stillfeel)Amin

Example 239A

(5-Bromo-2-phenylsulfanyl)-(7 methylpyridin[2,3-d]pyrimidine-4-yl)Amin

5-Bromo-2-(phenylthio)Ben is alamin received in accordance with the methods, similar to that described in examples 6a, 6b and 6c, using sensation instead of 4-mercaptoethanol and 4-bromo-2-NITROPHENOL instead of 4-methyl-2-NITROPHENOL.

A mixture of the product from example 10B (0,188 g, 1.0 mmol) and 5-bromo-2-(phenylthio)benzenamine (0,280 g, 1.0 mmol) in glacial acetic acid (2 ml) was heated on an oil bath heated to 130ºC for 30 minutes. Then the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue is triturated in methanol and the resulting solid was isolated by vacuum filtration and dried to obtain specified in the connection header (0,276 g, 65% yield) as a solid beige color.

Example 239B

(7 Methylpyridin[2,3-d]pyrimidine-4-yl)-(2-phenylsulfanyl-5-stillfeel)Amin

Mixture of product example 239A (to 0.127 g, 0.30 mmol), styrene (of 0.133 g of 1.27 mmol, 4.3 EQ.), the palladium(II) acetate (5.3 mg, 0,0236 mmol, 0.08 equiv.) threeo-tolylphosphino (17,7 mg, 0,058 mmol, 0,19 EQ.) triethylamine (0,0913 g, 0.90 mmol, 3.0 EQ.) in dimethylformamide (3 ml) was heated on an oil bath heated to 130ºC, for 98 hours. Then the mixture was cooled to room temperature and the solvent was evaporated in a stream of nitrogen gas. The residue was distributed between ethyl acetate and water and the aqueous layer was additionally extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate is, filtered and evaporated. The residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (4.0 mg, 2.4 per cent).

1H NMR (300 MHz, DMSO-D6) δ ppm: 11,21 (c, 1H), cent to 8.85 (d,J=8,46 Hz, 1H), total of 8.74 (c, 1H), 7.68 per for 7.78 (m, 2H), 7,55-the 7.65 (m,J=to 7.35 Hz, 3H), 7,19-7,46 (m, 11H), 2,72 (c, 3H);

MS (ESI+) m/z 447,2 (M+H)+, (ESI-) m/z 445,2 (M-H)-.

Example 240

(7 Methylpyridin[2,3-d]pyrimidine-4-yl)-(3-stillfeel)Amin

Example 240A

(3-Bromophenyl)-(7 methylpyridin[2,3-d]pyrimidine-4-yl)Amin

A mixture of the product from example 10B (0,206 g of 1.09 mmol) and 3-bromaniline (0,188 g of 1.09 mmol) in glacial acetic acid (1 ml) was heated on an oil bath heated to 130ºC, for 15 minutes. Then the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue is triturated in methanol and the resulting solid was isolated by vacuum filtration and dried to obtain specified in the title compound (0.126 g, 37%) as a solid beige color.

Example 240B

(7 Methylpyridin[2,3-d]pyrimidine-4-yl)-(3-stillfeel)Amin

Mixture of product example 240A (0,063 g, 0.20 mmol), styrene (0,0412 g, 0.40 mmol, 2.0 EQ.), the palladium(II) acetate (0.9 mg, 0.004 percent mmol, 0.02 equiv.) threeo-tolylphosphino (2.4 mg, 0,008 mmol, of 0.04 EQ.) triethylamine (0,0607 g to 0.60 mmol, 3.0 EQ.) in dimethylformamide (2 ml) was heated on an oil bath 120ºC for 4 hours. Then the mixture was cooled to room temperature and the solvent was evaporated in a stream of nitrogen gas. The residue was distributed between ethyl acetate and water and the aqueous layer was additionally extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was recrystallized from methanol and dried to obtain specified in the connection header in the form of a crystalline substance in yellow (11.8 mg, 17%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 10,01 (c, 1H), 8,89 (l,J=8,46 Hz, 1H), 8,72 (c, 1H), 8,03 (c, 1H), 7,72-a 7.85 (m,J=6,07, 2.76 Hz, 1H), to 7.64 (d,J=6,99 Hz, 2H), EUR 7.57 (d,J=8,82 Hz, 1H), 7,35-7,49 (m, 4H), 7.24 to 7,35 (m, 3H), 2,63-to 2.74 (m, 3H);

MS (ESI+) m/z 339,1 (M+H)+, (ESI-) m/z sauce 337,1 (M-H)-.

Example 241

(2-Methyl-5-fenetylline)-(7 methylpyridin[2,3-d]pyrimidine-4-yl)Amin

Example 241A

1-Methyl-2-nitro-4-steelbezel

A mixture of 4-bromo-2-nitrotoluene (0,432 g, 2.0 mmol), styrene (0,250 g is 2.40 mmol, 1.2 equiv.) the palladium(II) acetate (4.5 mg, at 0.020 mmol, 0.01 equiv.) threeo-tolylphosphino (12,2 mg, 0.04 mmol, 0.02 EQ.) triethylamine (0,405 g, 4.0 mmol, 2.0 equiv.) in dimethylformamide (2 ml) was heated on an oil bath at 120ºC for 4 hours. Then the mixture was cooled to room temperature and the solvent was evaporated in a stream of nitrogen gas. The residue was distributed between ethyl acetate and water and the aqueous layer was additionally extragere the Lee ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was purified by chromatography on silica gel, elwira gradient mixture of hexane/ethyl acetate to obtain specified in the connection header in a solid yellow color (166 mg, 35% yield).

Example 241B

2-Methyl-5-penicillamin

Mixture of product example 241A (0,166 g, 0,694 mmol) and 10% palladium-on-coal (18,4 mg of 0.025 EQ.) in ethanol (10 ml) was stirred in hydrogen atmosphere for 16 hours. Then the reaction mixture was filtered through celite and the solvent was evaporated under reduced pressure to obtain specified in the connection header in the form of oil light red (0,141 g, 96% yield).

Example 241C

(2-Methyl-5-fenetylline)-(7 methylpyridin[2,3-d]pyrimidine-4-yl)Amin

A mixture of the product from example 10B (0,041 g, 0.22 mmol) and the product from example 241B (0,046 g, 0.22 mmol) in glacial acetic acid (1 ml) was heated on an oil bath at 130ºC for 15 minutes. Then the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue is triturated in methanol and the resulting solid was isolated by vacuum filtration and dried to obtain specified in the connection header (0,0121 g, 16% yield) as a solid light orange color.

1H NMR (300 MHz, CHCl3-d)δ ppm: 8,84 (c, 1H), 8,23 (l,J=8,46 Hz, 1H), 7,44 (c, 1H), 7,15-7,37 (m, 8H), 7,07 (DD,J=7,72, to 1.47 Hz, 1H), 2,93 (c, 4H), 2,78 (c, 3H), 2,28 (c, 3H);

MS (ESI+) m/z 355,3 (M+H)+, (ESI-) m/z 353,2 (M-H)-.

Example 242

(7 Isopropylpyridine[2,3-d]pyrimidine-4-yl)-(2-methyl-5-fenetylline)Amin

Mixture of product example 241B (46.2 mg, 0,219 mmol) and the product from example 36E (47,3 mg, 0,219 mmol) in glacial acetic acid (1 ml) was heated on an oil bath at 130ºC for 15 minutes. Then the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (0,0131 g, 10%).

1H NMR (300 MHz, DMSO-D6) δ ppm: 11,09 (c, 1H), to 8.94 (d,J=8,46 Hz, 1H), total of 8.74 (c, 1H), 7,82 (l,J=8,46 Hz, 1H), 7,12-7,35 (m, 8H), 3,21-to 3.33 (m, 1H), 2,89 (c, 4H), 2,15 (c, 3H), of 1.35 (d,J=6,62 Hz, 6H);

MS (ESI+) m/z 383,2 (M+H)+, (ESI-) m/z 381,3 (M-H)-.

Example 243

(5-Methyl-2-phenylsulfanyl)-(7-propylpiperidine-4-yl)Amin

Example 243A

N'-(3-Cyano-6-propylpyrazine-2-yl)-N,N-dimethylformamide

A mixture of 3-amino-5-propylpyrazine-2-carbonitrile (0,140 g, 0,863 mmol) (obtained according to the method of Taylor and LaMattina,JOC1977,47, 1523), and dimethylformamide, dimethylacetal (0,123 g, 1.04 mmol, 1.2 EQ.) in toluene (10 ml) was heated under reflux for 2 hours. The mixture was cooled to room temp the atmospheric temperature and the solvent was evaporated under reduced pressure to obtain specified in the connection header (0,188 mg, 100%) as a thick oil.

Example 243B

(5-Methyl-2-phenylsulfanyl)-(7-propylpiperidine-4-yl)Amin

Mixture of product example 243A (38,2 mg, 0,176 mmol) and the product of example 5I (to 41.6 mg, rate of 0.193 mmol, 1.1 EQ.) in acetic acid (1 ml) was heated under reflux for 1.5 hours. The reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure. The resulting residue is triturated in methanol to obtain specified in the title compound (19 mg, 28% yield) as a solid beige color.

1H NMR (300 MHz, DMSO-D6) δ ppm: 0,97 (t,J=to 7.35 Hz, 3H), 1,76-1,90 (m, 2H), 2,42 (c, 3H), 2,94 was 3.05 (m, 2H), 7,08-7,28 (m, 6H), 7,55 (l,J=8,09 Hz, 1H), 8,45 (c, 1H), 8,81 (c, 1H), 8,89 (c, 1H), 10,32 (c, 1H).

MS (ESI+) m/z 388,1 (M+H)+(ESI-) m/z 386,1 (M-H)-.

Example 244

4-[4-Benzyloxy-2-(7-isopropylpyridine-4-ylamino)phenylsulfonyl]phenol

Example 244A

3-Amino-5-isopropyl-4-oxypertine-2-carbonitril

A mixture of 2-hydroxyimino-3-methylbutyraldehyde (1,93 g, a 16.8 mmol)(obtained by the method Nakamura,Agric. Biol. Chem. 1961,25, 665-670) and 2-aminomalononitrile tosilata (4,25 g, a 16.8 mmol) ini-propanol (40 ml) was stirred at room temperature for 18 hours. The obtained solid was isolated by vacuum filtration and washedi-propanol and dried with air to obtain specified in the connection header (0,525 g, 18% o whom d) in the form of a white solid.

Example 244B

3-Amino-5-isopropylpyrazine-2-carbonitril

A solution of the product from example 244A (0,525 g, 2,95 mmol) in tetrahydrofuran (30 ml) was stirred at a bath temperature of ice water. To this solution quickly was added dropwise to trichloride phosphorus (4.0 g, 2.6 ml, 29.5 mmol, 10 EQ.). The reaction mixture was stirred at room temperature for 16 hours and then the solvent and excess reagent was evaporated. The obtained residue was distributed between ethyl acetate and polysystem aqueous solution of sodium bicarbonate. The aqueous phase was extracted with ethyl acetate (3×100 ml) and the combined organic layers were dried over anhydrous magnesium sulfate, filtered and evaporated to obtain specified in the connection header (0,370 g, 77% yield) as a solid light brown color.

Example 244C

N'-(3-Cyano-6-isopropylpyridine-2-yl)-N,N-dimethylformamide

Mixture of product example 244B (0,37 g, 2.28 mmol) and dimethylformamide of dimethylacetal (0,30 g, 2.5 mmol, 1.1 EQ.) in toluene (25 ml) was heated under reflux for about 1.75 hours. Then the reaction mixture was cooled to room temperature and the solvent was evaporated under reduced pressure to obtain specified in the title compound (0.50 g, 100%) as a thick oil red-brown color, which is used in the following reactions without complement the school clean.

Example 244D

4-[4-Benzyloxy-2-(7-isopropylpyridine-4-ylamino)phenylsulfonyl]phenol

Mixture of product example 244C (56,2 mg, 0,259 mmol) and the product from example 27A in acetic acid (1 ml) was heated under reflux for 2 hours. The reaction mixture was cooled to room temperature and evaporated under reduced pressure. The resulting residue is triturated in methanol to obtain specified in the connection header (of 55.5 mg, 53% yield) as a solid beige color.

1H NMR (300 MHz, DMSO-D6) δ ppm: 10,37 (c, 1H), 9,65 (c, 1H), 9,03 (c, 1H), 8,80 (c, 1H), 8,31 (c, 1H), 7,38 (d,J=8,09 Hz, 1H), 7,21 (l,J=8,82 Hz, 2H), 7,03 (DD,J=8,09, to 1.47 Hz, 1H), 6,68 (l,J=8,82 Hz, 2H), 3,35-of 3.46 (m, 1H), 2,37 (c, 3H), 1,38 (l,J=6,62 Hz, 6H).

MS (ESI+) m/z 404,2 (M+H)+(ESI-) m/z 402,3 (M-H)-.

Example 245

[2-(4-Aminophenoxy)-5-(6-bromo-1H-benzoimidazol-2-yl)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

Example 245A

Tert-butyl ester [4-(4-formyl-2-nitrophenoxy)phenyl]carbamino acid

A mixture of 4-chloro-3-nitrobenzaldehyde and tert-butyl methyl ether (4-hydroxyphenyl)carbamino acid was subjected to interact together in DMSO with the addition of KOH to obtain specified in the header of the product.

Example 245B

Tert-butyl ester {4-[2-amino-4-(6-bromo-1H-benzoimidazol-2-yl)phenoxy]phenyl}carbamino acid

The product from example 245A subjected mutual is action in accordance with the methods, described in the examples 147B and 147C, obtaining specified in the header of the product.

Example 245C

[2-(4-Aminophenoxy)-5-(6-bromo-1H-benzoimidazol-2-yl)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

The product from example 245B were subjected to interaction with the product from example 36E in HOAc and was placed on pre-heated to 120ºC oil bath. The solvent was removed in a current of N2. The product was removed the protective group by dissolving in a 1:1 mixture of TFA in DCM and stirred at room temperature. The crude substance was purified by HPLC with TFA to obtain specified in the header of the product as a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: to 1.35 (d, J=6,99 Hz, 6N), 3,21-3,39 (m, 1H), 6.87 in? 7.04 baby mortality (m, 4H), to 7.09 (d, J=8,46 Hz, 1H), was 7.36 (DD, J=8,82, of 1.84 Hz, 1H), 7,56 (d, J=8,46 Hz, 1H), 7,78 (d, J=1,47 Hz, 1H), 7,89 (d, J=8,46 Hz, 1H), 8,14 (DD, J=8,82, of 1.84 Hz, 1H), of 8.37 (d, J=1,84 Hz, 1H), 8,90 (c, 1H), 9,00 (d, J=8,09 Hz, 1H);

MS (ESI+) m/z 568,2 (M+H)+.

Example 246

4-[4-Benzyloxy-2-(7-tert-butylperoxide[2,3-d]pyrimidine-4-ylamino)phenylsulfonyl]phenol

The product from example 27A was heated at 130ºC in acetic acid the product from example 127A for 15 minutes, then the mixture was cooled to room temperature, the solvent was removed and the residue was purified column chromatography on silica gel with obtaining specified in the header of the product.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,38 (c, N), 5,11 (c, 2H), 6,60-6,74 (m, 2H), 6,94 (d, J=7,35 Hz, 1H), 7,06-719 (m, 3H), 7,27-to 7.50 (m, 6N), 7,78 (d, J=8,09 Hz, 1H), 8,56 (c, 1H), 8,75 (c, 1H), for 9.64 (c, 1H), 9,95 (c, 1H);

MS (ESI+) m/z 509 (M+H)+.

Example 247

2-(4-Aminophenylalanine)-5-(2-chlorothiazole-5-ylethoxy)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

Example 247A

Tert-butyl ester {4-[2-amino-4-(2-chlorothiazole-5-ylethoxy)phenylsulfonyl]phenyl}carbamino acid

2-Chloro-5-(4-chloro-3-nitrophenoxy)thiazole (example 25A) were subjected to interaction with 4-aminothiophenol in anhydrous ethanol and heated under reflux in a nitrogen atmosphere. The reaction mixture was cooled to room temperature and ethanol was removed on a rotary evaporator. The residue was treated with water and extracted with ethyl acetate. The combined organic extracts were washed with saturated saline, dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. Rubbing solids in a mixture of 4% ethyl acetate/methylene chloride gave 4-(4-((2-chlorothiazole-5-yl)methoxy)-2-nitrophenylthio)aniline. A mixture of 4-(4-((2-chlorothiazole-5-yl)methoxy)-2-nitrophenylthio)aniline and di-tert-BUTYLCARBAMATE in 1,4-dioxane was heated under reflux in a nitrogen atmosphere, and then further added Boc anhydride and the reaction mixture was left to warm to reflux. The reaction mixture was cooled to room temperature and the solvent was removed on a rotor of the second evaporator in a vacuum. The obtained solid is triturated in a mixture of 2.5% ethyl acetate/methylene chloride to obtain tert-butyl 4-(4-((2-chlorothiazole-5-yl)methoxy)-2-nitrophenylthio)phenylcarbamate. A suspension of 4-(4-((2-chlorothiazole-5-yl)methoxy)-2-nitrophenylthio)phenylcarbamate, iron powder and ammonium chloride in water and ethanol was heated. The reaction mixture was cooled to room temperature. The mixture was diluted with ethyl acetate and washed with water and saturated salt solution. The organic phase was dried, filtered and concentrated under vacuum to obtain specified in the connection header.

Example 247B

[2-(4-Aminophenylalanine)-5-(2-chlorothiazole-5-ylethoxy)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

The product from example 247A were heated at 130ºC in acetic acid the product from example 36E for 15 minutes, then the mixture was cooled to room temperature, the solvent was removed under vacuum and added to a mixture of dichloromethane/triperoxonane acid 1/1 and then the residue was stirred at room temperature for 2 hours, then the solvent was removed under vacuum and the residue was purified by HPLC with TFA to obtain specified in the header of the product as a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,36 (d, J=6,99 Hz, 6H), 3,20-3,37 (m, 1H), 3.75 to (c, 2H), 5,33 (c, 2H), 6,53 (d, J=8,46 Hz, 2H), 6,99 for 7.12 (m, 5H), 7,14 (c, 1H), 7,80 (c, 1H), 7,92 (d, J=8,82 Hz, 1H), 8,83 (c, 1H), 9,01 (c, 1H), are 11.62 (c, H);

MS (ESI+) m/z 535 (M+H)+.

Example 248

Tert-butyl ester {4-[2-(7-tert-butylperoxide[2,3-d]pyrimidine-4-ylamino)-4-(2-chlorothiazole-5-ylethoxy)phenylsulfonyl]phenyl}carbamino acid

The product from example 247A were heated at 130ºC in acetic acid the product from example 127A for 15 minutes, then the mixture was cooled to room temperature, the solvent was removed and the residue was purified by HPLC with TFA to obtain specified in the header of the product as a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: USD 1.43 (d, J=11,40 Hz, 15 NM), 2,73 (c, 1H), are 5.36 (c, 2H), 7,00 (d, 1H), 7,13 (d, J=8,46 Hz, 2H), 7,25 (d, 1H), 7,33 (d, J=8,46 Hz, 3H), 7,81 (c, 2H), 8,62 (c, 1H), 8,78 (c, 1H), 9,39 (c, 1H), 10,49 (users, 1H); MS (ESI+) m/z 649 (M+H)+.

Example 249

[2-(4-Aminophenylalanine)-5-(2-chlorothiazole-5-ylethoxy)phenyl]-(7-tert-butylperoxide[2,3-d]pyrimidine-4-yl)Amin

The product from example 248 was added to a mixture of dichloromethane/triperoxonane acid 1/1 and the solution was stirred at room temperature for 2 hours, then solvent was removed under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the header of the product as a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,44 (c, 6H), of 2.51 at 2.59 (m, 1H), 3.72 points (c, 2H), 5,33 (c, 2H), 6,24 (DD, J=8,82, to 2.94 Hz, 1H), 6.42 per (d, J=2,94 Hz, 1H), 6,53 (d, J=8,46 Hz, 2H), 6,98 for 7.12 (m, 3H), 7,14 (c, 1H), 7,74 is 7.85 (m, 1H), of 8.09 (d, J=8,46 Hz, 1H), 8,83 (c, 1H), 9,03 (c, 1H), 11,65 (c, 1H);

MS (ESI+) m/z 549 (M+H)+.

[2-(4-Aminophenylalanine)-5-(6-bromo-1H-benzoimidazol-2-yl)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

Example 250A

Tert-butyl ester [4-(4-formyl-2-nitrophenyloctyl)phenyl]carbamino acid

A mixture of 4-chloro-3-nitrobenzaldehyde and 4-aminothiophenol subjected together to the interaction in accordance with the method described in example 216B, using 4-chloro-3-nitrobenzaldehyde instead of the product from example 216A, which was then subjected to the conditions described in example 216C, obtaining specified in the header of the product.

Example 250B

[2-(4-Aminophenylalanine)-5-(6-bromo-1H-benzoimidazol-2-yl)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

The product from example 250A subjected interaction in accordance with the methods described in the examples, 147B, 147C and 147C, to obtain a crude residue, which was purified by HPLC with TFA to obtain specified in the header of the product as a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: to 1.38 (d, J=6,62 Hz, 6N), 3,26 is 3.40 (m, 1H), only 6.64 (d, J=8,46 Hz, 2H), 7,03 (d, J=8,46 Hz, 1H), 7,17 (d, J=8,46 Hz, 2H), 7,35 (DD, J=8,46, of 1.84 Hz, 1H), 7,54 (d, J=8,82 Hz, 1H), to 7.77 (d, J=1,84 Hz, 1H), 7,94 (d, J=8,46 Hz, 1H), 8,03 (DD, J=8,46, of 1.84 Hz, 1H), 8,18 (c, 1H), 8,89 (c, 1H), 9,05 (d, J=8,82 Hz, 1H);

MS (ESI+) m/z 584 (M+H)+.

Example 251

[2-(4-Aminophenylalanine)-5-(3-forbindelse)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

Example 251A

Tert-BU is silt ester {4-[2-amino-4-(3-forbindelse)phenylsulfonyl]phenyl}carbamino acid

The product from example 57B were subjected to interaction with 4-aminothiophenol in accordance with the method described in example 214B, then the interaction in accordance with the methods described in the examples 214C and 214D, obtaining specified in the header of the product.

Example 251B

[2-(4-Aminophenylalanine)-5-(3-forbindelse)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

The product from example 251A was heated at 130ºC in acetic acid the product from example 36E for 15 minutes, then the mixture was cooled to room temperature, the solvent was removed under vacuum and added to a mixture of dichloromethane/triperoxonane acid 1/1 and then the residue was stirred at room temperature for 2 hours, then the solvent was removed under vacuum and the residue was purified column chromatography on silica gel with obtaining specified in the header of the product.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1.26 in-the 1.44 (d, 6N), 3,23-3,37 (m, 1H), 5,13 (c, 2H), 6,44-of 6.61 (m, 2H), of 6.96-7,10 (m, 3H), 7,10-7,22 (m, 2H), 7.24 to 7,35 (m, 3H), 7,35 (d, J=6.25 Hz, 1H), 7,43 (DD, J=to $ 7.91, 5,70 Hz, 2H), 7,92 (c, 1H), 8,18 (d, J=8,82 Hz, 1H), 8,83 (c, 1H), 9,03 (c, 1H);

MS (ESI+) m/z 512 (M+H)+.

Example 252

[2-(4-Aminophenylalanine)-5-(3-forbindelse)phenyl]-(7-tert-butylperoxide[2,3-d]pyrimidine-4-yl)Amin

The product from example 251A was heated at 130ºC in acetic acid the product from example 127A for 15 minutes, then the mixture was cooled to room temperature, actuarial was removed under vacuum and added to a mixture of dichloromethane/triperoxonane acid 1/1 and then the residue was stirred at room temperature for 2 hours, then the solvent was removed under vacuum and the residue was purified by HPLC with TFA to obtain specified in the header of the product as a salt triperoxonane acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,38-1,50 (m, N), 5,12 (c, 2H), 6,44-of 6.61 (m, 3H), of 6.96 for 7.12 (m, 3H), 7,19 (c, 3H), 7.23 percent-7,33 (m, 3H), 7,38-to 7.50 (m, 2H), 8,00 (c, 1H), 8,76 (c, 1H), 8,96 (c, 1H);

MS (ESI+) m/z 526 (M+H)+.

Example 253

[5-Benzyloxy-2-(4-dimethylaminobenzylidene)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

Example 253A

5-Benzyloxy-2-(4-dimethylaminobenzylidene)phenylamine

The product from example 214B (1.0 g, 0,284 mmol) was placed in a vessel together with formic acid (5 ml), dioxane (5 ml) and 37% aqueous formaldehyde solution (5 ml). The vessel was tightly closed and heated to 110ºC for 20 minutes. The mixture was cooled to room temperature, the solvent was removed and the resulting residue was purified column chromatography on silica gel, then restored the nitrogroup in accordance with the method described in example 214D, obtaining specified in the header of the product (411 mg, 43%).

Example 253B

[5-Benzyloxy-2-(4-dimethylaminobenzylidene)phenyl]-(7-isopropylbenzo[2,3-d]pyrimidine-4-yl)Amin

Mixture of product example 253A and the product from example 36E in glacial acetic acid was heated in a preheated up to 130ºC oil bath for 20 minutes. Then the reaction mixture is cooled is about room temperature and the solvent was evaporated under vacuum to obtain specified in the connection header in the form of a salt of acetic acid.

1H NMR (300 MHz, DMSO-D6) δ ppm: 1,36 (d, J=7,0 Hz, 6H), 2,81 (c, 6H), 3,30 (m, 1H), 5,10 (c, 2H), 6,45 (d, J=9,2 Hz, 2H), 7,07 (d, J=8,8 Hz, 2H), 7,12 (m, 2H), 7,25 (d, J=8,8 Hz, 1H), 7,40 (m, 5H), 7,94 (m, 1H), 8,78 (c, 1H), 8,99 (m, 1H), 11,70 (users, 1H);

MS (ESI) m/z 522 (M+H)+.

Example 254

4-Bromo-N-[3-(pyrido[2,3-d]pyrimidine-4-ylamino)phenyl]benzamide

Example 254A

4-Bromo-N-(3-nitrophenyl)benzamide

Specified in the title compound was obtained in accordance with the method described in example 255A, using 3-nitrophenylamino instead of 4-Fluoro-3-nitroaniline and using 4-bromobenzoate instead of 3 triftormetilfullerenov, obtaining specified in the header of the product (3,373 g, 90%).

Example 254B

4-Bromo-N-(3-AMINOPHENYL)benzamide

Specified in the title compound was obtained in accordance with the method described in example 255B, using the product from example 254A instead of the product from example 255A, obtaining specified in the header of the product (1.8 g, 80%).

Example 254C

4-Bromo-N-[3-(pyrido[2,3-d]pyrimidine-4-ylamino)phenyl]benzamide

A solution of the product from example 57A (40,0 mg, 0,212 mmol) and the product of example 254B (61,0 mg, 0,212 mmol) in acetic acid (1 ml) was stirred on an oil bath preheated to 130ºC for 20 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the header is soedineniya in the form of a salt triperoxonane acid (25.0 mg, 30%).

1H NMR (300 MHz,DMSO-D6) δ ppm: 7,45 (t,J=8,09 Hz, 1H), 7,52-to 7.61 (m, 2H), 7,74-7,86 (m, 3H), 7,94 (l,J=8,82 Hz, 2H), 8,33 (t,J=1,84 Hz, 1H), 8,88 (c, 1H), which is 9.09-9,17 (m, 2H), 10,48 (c, 1H), 10,94 (c, 1H);

MS (ESI+) m/z 420 (M+H)+, (ESI-) m/z 417 (M-H)-.

Example 255

N-[4-(4-Hydroxyphenylethyl)-3-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenyl]-3-cryptomelane

Example 255A

N-(4-Fluoro-3-nitrophenyl)-3-cryptomelane

A solution of 4-fluoro-3-nitroaniline (2.00 g, 12.8 mmol), 3-triftormetilfullerenov (1,895 ml, 12.8 mmol), base Hunya (4,463 ml, 25.6 mmol) in tetrahydrofuran (50 ml) was stirred at room temperature for 1 hour. Then to the solution was added water (450 ml) and the obtained solid substance was collected by filtration and dried in a vacuum oven to obtain specified in the connection header (3,311 g, 97%).

Example 255B

N-[4-(4-Hydroxyphenylethyl)-3-nitrophenyl]-3-cryptomelane

A solution of the product of example 255A (2.00 g, 5,80 mmol), 4-hydroxythiophenol (0,732 g, 5,80 mmol) and potassium carbonate (1,604 g, 11.6 mmol) inN,N-dimethylformamide (40 ml) was heated to 80ºC for 2 hours. After cooling to room temperature the mixture was poured into ice water (100 ml). Then the solution was extracted with ethyl acetate (3×150 ml), the combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to obtain specified in the header connect the deposits (2,52 g, 100%).

Example 255C

N-[3-Amino-4-(4-hydroxyphenylethyl)phenyl]-3-cryptomelane

A solution of the product of example 255B (0,660 g of 1.52 mmol), iron powder (0,339 g, 6,07 mmol) and ammonium chloride (0,099 g, 1.82 mmol), a solution of tetrahydrofuran (18 ml) and water (6 ml) was heated under reflux for 3 hours. The resulting mixture was diluted with methanol (50 ml) and filtered through a layer of celite. The filtrate was diluted with water (50 ml) and was extracted with dichloromethane (2×100 ml). The combined extracts were dried over magnesium sulfate, filtered and concentrated under vacuum to obtain specified in the connection header (0,60 g, 97%).

Example 255D

N-[4-(4-Hydroxyphenylethyl)-3-(7-methylpurine[2,3-d]pyrimidine-4-ylamino)phenyl]-3-cryptomelane

A solution of the product from example 10B (40,0 mg, 0,212 mmol) and the product from example 255C (86,0 mg, 0,212 mmol) in acetic acid (1 ml) was stirred on an oil bath preheated to 130ºC for 20 minutes. Then the mixture was cooled to room temperature, acetic acid was removed under vacuum and the resulting residue was purified by HPLC with TFA to obtain specified in the connection header in the form of a salt triperoxonane acid (11 mg, 10%).

1H NMR (300 MHz,DMSO-D6) δ ppm: 2,74 (c, 3H), 6,70 (l,J=8,82 Hz, 2H), 7,18 (l,J=8,46 Hz, 3H), of 7.64 (DD,J=8,46, of 2.21 Hz, 1H), 7,79 (t,J=7,72 Hz, 2H), 7,93-8,07 (m,J=6,62 Hz, 2H), ,21-8,30 (m, 2H), 8,78 (c, 1H), 8,92 (l,J=7,72 Hz, 1H), 9,79 (c, 1H), 10,67 (c, 1H), 11,17-11,50 (m, 1H);

MS (ESI+) m/z 548,2 (M+H)+ (ESI-) m/z 546,2 (M-H)-.

Biological research

Typical compounds according to the invention were analyzed in accordance with the techniques described below.

We used the following abbreviations:

IC50The concentration leading to 50% inhibition
TC50The concentration resulting in 50% toxicity
DMEMModified by way of Dulbecco Wednesday Needle™
RNARibonucleic acid
RT-PCRPolymerase chain reaction with reverse transcription
SEAPSecretiruema alkaline phosphatase

The genome of the hepatitis C virus encodes a large polypeptide, which after processing provides the necessary functional components for the synthesis of a child RNA. Breeding cell lines producing high and stable levels subgenomic RNA (HCV replicons), were obtained from cells human hepatoma (Huh7), as described in Ikedaet al. J. Virology, 76(6): 2997-3006 (2002) and Blightet al., Science, 290: 1972-1974 (2000). Consider that the mechanism of RNA replication in these cell lines is the same with full replication HCV RNA in infected hepatocytes. Compounds of the present invention are inhibitors of HCV RNA replication in replicon assays, described below.

Evaluation of inhibitors of the HCV replicon HCV

The inhibitory effect of typical compounds according to the invention were evaluated for replicons genotype 1a and 1b HCV. They were also assessed by using MTT analysis for cytotoxicity against host cells. Cell lines were maintained in accordance with the methods described Yiet al., Virology, 304(2): 197-210 (2002).

A. Analysis of RNA and analysis of SEAP

The purpose of these analyses was to assess the effectiveness of the compounds to inhibit the replication of replicons genotype 1A and 1b HCVin vitro.

Cells with replicons genotype 1a and/or 1b were placed in a 96-well plate containing DMEM with 5% fetal bovine serum, in the amount of 3-5×103cells per well. The next day the culture medium was removed and replaced with fresh medium containing eight serial dilutions of the compounds. Untreated control culture was treated in the same way, but did not add the inhibitor to the environment. Plates were incubated in an incubator CO2when 37º. On day 4 in each well after removal of cultural the second medium was added 100 μl of buffer for lysis (RTL) (Qiagen). RNA was purified according to the manufacturer's instructions (Qiagen RNAeasy) and suirable in 200 μl of water. Determine the level of HCV RNA in a portion (5 μl 200 μl) RNA purified by the method of RT-PCR in real time. Primers and probes were obtained on the basis of the specific sequence 5'-untranslated region (5'UTR). The reaction RT-PCR was performed at 48°C for 30 minutes, then 40 cycles, setting 95°C, 15 s; 54°C, 30 s; and 72°C, 40 C. alternatively, the measured activity of SEAP in each culture supernatant after four days of incubation with the compound in accordance with manufacturer's instructions. Expected percent reduction in HCV RNA or SEAP in the presence of the compound and the concentration leading to 50% inhibition (IC50), was calculated using nonlinear regression analysis using the Prism program (version 4,0, software, GraphPad, San Diego, CA).

When testing with the use of the method described above is typical compounds of the present invention inhibited the replication of HCV replicon when the value of the IC50in the range from about 0.3 nm to about 100 μm.

B. Cytotoxic analysis

The purpose of this analysis was to demonstrate the toxicity of compounds on cells of the hosts that carry the virus,in vitro.

The cytotoxicity of the compounds was measured using analysis of cell proliferation, based on mitochondrial the different enzymes/analysis of viability in cells with replicon. Briefly, the cells with the HCV replicon were placed in a 96-well plate containing DMEM with 5% FCS, in the amount of 3-5×103cells per well. Day 1 culture medium was removed and replaced with fresh medium containing eight serial dilutions of the compounds. Untreated control culture was treated in the same way, but did not add the inhibitor to the environment. Plates were incubated in an incubator CO2at 37 degrees C. On day 4 in each well was added a basic salt solution of tetrazole, MTT (4 mg/ml in PBS, Sigma cat.# M 2128) in an amount of 25 μl per well. Die additionally incubated for 4 hours, and treated with 20% SDS plus 0,02N HCl 50 ál per well for lizirovania cells. After incubation overnight, the optical density was measured by reading the plates at a wavelength of 570/650 nm. The percentage recovery of the dye formazan blue relative to the control was calculated and calculated the concentration leading to 50% toxicity (TC50with the help of the analysis of nonlinear regression using the program Prism (version 4,0, software, GraphPad, San Diego, CA).

When testing using the above method, the value TC50typical compounds of the present invention was larger than the corresponding values IC50these compounds.

Pharmaceutical compositions and the use of

The present image is eenie relates to pharmaceutical compositions, containing compounds according to the invention. As a non-limiting example, a pharmaceutical composition of the present invention contains one or more compounds of the present invention, where each connection independently selected from formulas I, II, III, IV, V, VI, VII or VIII. Preferably, each connection independently selected from examples 1-255.

The present invention also relates to pharmaceutical compositions containing pharmaceutically acceptable salt, solvate or prodrug compounds of the present invention. Pharmaceutically acceptable salts can be zwitter-ions or can be derived from pharmaceutically acceptable inorganic or organic acids or bases. Preferably acceptable salt of the compounds according to the invention retains the biological effectiveness of the free acid or base compounds, without causing non-specific toxicity, irritation or allergic reactions, has a suitable ratio of benefit/risk and has effectiveness for intended use and is not undesirable biological or other point of view. Non-limiting examples of pharmaceutically acceptable salts include, but are not limited to, the following salts: acetate, adipate, alginate, citrate, aspartate, benzoate, bansilalpet, bisulfate, butyrate, comfort, camphor ulpanat, digluconate, cyclopentanepropionate, dodecyl sulphate, aconsultant, glucoheptonate, glycyrrhizinate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonic (isetionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, p-toluensulfonate, undecanoate. Basic groups containing nitrogen, can also be quaternity such agents as lower halides of Akilov (for example, methyl, ethyl, propyl or butylchloride, bromides or iodides), diallylsulfide (e.g., dimethyl, diethyl, dibutil or dimycolate), halides Akilov long chain (e.g., decyl, lauryl, myristyl or stearylamine, bromides or iodides), halides aralkyl (for example, benzyl or phenetermine). Other salts that can be used in the present invention include the salts of alkali or alkaline earth metals such as sodium, potassium, calcium or magnesium, or organic bases. Examples of acids that may be used to form a pharmaceutically acceptable additive, acid salts include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, oxalic acid, maleic acid, succinic acid is, citric acid or other suitable inorganic or organic acid.

The present invention also relates to pharmaceutical compositions containing the compound of the invention (or its salt, MES or prodrug) and another therapeutic agent. In a non-limiting example, a pharmaceutical composition of the present invention comprises 1, 2, 3 or more of the compounds according to the invention (or a salt, solvate or prodrug) and 1, 2, 3 or more other therapeutic agents. As a non-limiting example, these other therapeutic agent can be selected from antiviral agents (e.g., anti-HIV funds or other anti-HCV), immunomodulators, anti-cancer or chemotherapeutic agents, or anti-inflammatory drugs. Specific examples of other therapeutic agents include, but are not limited to, ribavirin; interferons (such as IFN alpha 2a or 2b); protease inhibitors; immunosuppressive means; antibodies (for example, therapeutic monoclonal or chimeric antibodies); antisense or siRNA; inhibitors of HIV; inhibitors of hepatitis B (HBV); means for treatment of cirrhosis and inflammation of liver; IFN omega (BioMedicines Inc., Emeryville, CA); BILN-2061, an inhibitor of serine protease (Boehringer Ingelheim Pharma KG, Ingelheim, Germany); Summetrel, antiviral agent (Endo Pharmaceuticals Holdings Inc., Chadds Ford, PA); ROF is Ron, A IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); pegasis, PEG IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); pegasis and ribavirin, PEG IFN-Alfa-2a/ribavirin (F. Hoffmann-La Roche LTD, Basel, Switzerland); CellCept, immunosuppressant HCV IgG (F. Hoffmann-La Roche LTD, Basel, Switzerland); wellferon, lymphoblastic IFN-alpha n1 (GlaxoSmithKline plc, Uxbridge, UK); Albuferon-alpha, albumin IFN-alpha 2b (Human Genome Sciences, Inc., Rockville, MD); levovirin, ribavirin (ICN Pharmaceuticals, Costa Mesa, CA); IDN-6556, an inhibitor of caspase (Idun Pharmaceuticals Inc., San Diego, CA); IP 501, antifibrotics tool (Indevus Pharmaceuticals Inc., Lexington, MA); action, INF-gamma (InterMune Inc., Brisbane, CA); infergen A, IFN of alfacon-1 (InterMune Pharmaceuticals Inc., Brisbane, CA); ISIS 14803, an antisense oligonucleotide (ISIS Pharmaceuticals Inc., Carlsbad, CA/Elan Pharmaceuticals Inc., New York, NY); JTK-003, RdRp inhibitor (Japan Tobacco Inc., Tokyo, Japan); pegasis and zeplin, PEG IFN-alpha 2a/immune modulator (Maxim Pharmaceuticals inc., San Diego, CA); caplen, immune modulator (Maxim Pharmaceuticals Inc., San Diego, CA); civacir, immunosupressor HCV IgG (Nabi Biopharmaceuticals Inc., Boca Raton, FL); intron a and zadaxin IFN-alpha 2b/alpha 1-thymosin (RegeneRx Biopharmiceuticals Inc., Bethesda, MD/SciClone Pharmaceuticals Inc., San Mateo, CA); levovirin, the IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); viramidine, the IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); heptazyme, the ribozyme (Ribozyme Pharmaceuticals Inc., Boulder, CO); intron A, IFN-alpha 2b (Schering-Plough Corporation, Kenilworth, NJ); PEG-intron, PEG IFN-alpha-2b (Schering-Plough Corporation, Kenilworth, NJ); Rebetron, IFN-Alfa-2b/ribavirin (Schering-Plough Corporation, Kenilworth, NJ); ribavirin (Schering-Plough Corporation, Kenilorth, NJ); PEG-intron/ribavirin, PEG IFN-Alfa-2b/ribavirin (Schering-Plough Corporation, Kenilworth, NJ); zadatim, immune modulator (SciClone Pharmaceuticals Inc., San Mateo, CA); Rebif, interferon-beta 1a (Serono, Geneva, Switzerland); IFN-beta and EMZ701, IFN-beta and EMZ701 (Transition Therapeutics Inc., Ontario, Canada); T67, the inhibitor of beta-tubulin (Tularik Inc., South San Francisco, CA); VX-497, IMPDH inhibitor (Vertex Pharmaceuticals Inc., Cambridge, MA); VX-950/LY-570310, an inhibitor of serine proteases (Vertex Pharmaceuticals Inc., Cambridge, MA/Eli Lilly and Co., Inc., Indianapolis, IN); Omniture, natural IFN-alpha (Viragen Inc., Plantation, FL); XTL-002, monoclonal antibody (XTL Biopharmaceuticals);

(herein designated as compound VX-950,

Vertex Pharmaceuticals Inc.);

(herein designated as compound SCH503034, Schering-Plough Co.); and

(herein designated as compound GS9137, Gilead Sciences, Inc., Foster City, CA). Any other desirable therapeutic agent may also be included in the pharmaceutical composition of the present invention.

In one of the embodiments of the pharmaceutical composition of the present invention contains one or more compounds of the present invention (or a salt, solvate or prodrug) and one or more other antiviral agents.

In another embodiment, the pharmaceutical composition of the present invention contains the one or more compounds of the present invention (or their salts, the solvate or prodrug) and one or more other anti-HCV. In one example, each connection according to the present invention are independently selected from formulas I, II, III, IV, V, VI, VII, or VIII, or examples 1-255 and every other remedy against HCV independently selected from inhibitors of RNA-dependent RNA polymerase of HCV (e.g., polymerase inhibitors nucleoside or non-nucleoside type), HCV protease inhibitors, or inhibitors of helicase HCV.

In another embodiment, the pharmaceutical composition of the present invention contains one or more compounds of the present invention (or a salt, solvate or prodrug) and two or more other anti-HCV inhibitors. Preferably, each connection according to the present invention are independently selected from formulas I, II, III, IV, V, VI, VII, or VIII, or from examples 1-255. Other inhibitors of anti-HCV can be selected from inhibitors of the same class (for example, all selected from inhibitors of RNA-dependent RNA polymerase of HCV or HCV protease inhibitors), or selected from inhibitors of different classes (for example, one or more selected from inhibitors of RNA-dependent RNA polymerase of HCV, and the other is selected from protease inhibitors HCV).

In yet another embodiment, the pharmaceutical composition of the present invention contains at least one connection is of the present invention or its salt, MES or prodrug) and at least one inhibitor of RNA-dependent RNA polymerase of HCV. Preferably, each connection according to the present invention are independently selected from formulas I, II, III, IV, V, VI, VII, or VIII, or examples 1-255.

In another embodiment, the pharmaceutical composition of the present invention contains at least one compound of the present invention or its salt, MES or prodrug) and at least one HCV protease inhibitor. Preferably, the compound of the present invention selected from formulae I, II, III, IV, V, VI, VII, or VIII, or examples 1-255.

In yet another embodiment, the pharmaceutical composition of the present invention contains at least one compound of the present invention or its salt, MES or prodrug), at least one inhibitor of RNA-dependent RNA polymerase of HCV and at least one HCV protease inhibitor. Preferably, the compound of the present invention selected from formulae I, II, III, IV, V, VI, VII, or VIII, or examples 1-255.

In yet another embodiment, the pharmaceutical composition of the present invention contains at least one compound of the present invention or its salt, MES or prodrug) and two or more anti-HCV, each of which is independently selected from inhibitors of RNA-dependent the NC-HCV polymerase or protease inhibitors of HCV. Preferably, the compound of the present invention selected from formulae I, II, III, IV, V, VI, VII, or VIII, or examples 1-255.

In yet another embodiment, the pharmaceutical composition of the present invention contains at least one compound of the present invention or its salt, MES or prodrug) and three or more other anti-HCV, each of which is independently selected from inhibitors of RNA-dependent RNA polymerase of HCV or HCV protease inhibitors. Preferably, the compound of the present invention selected from formulae I, II, III, IV, V, VI, VII, or VIII, or examples 1-255.

Non-limiting examples of inhibitors of RNA-dependent RNA polymerase of HCV include compounds described in WO0190121(A2), US6348587B1, WO0160315, WO0132153, EP1162196A1 and WO0204425. Non-limiting examples of HCV protease inhibitors include BILN-2061, VX-950 and SCH503034.

In another embodiment, the pharmaceutical composition of the present invention contains at least one compound of the present invention or its salt, MES or prodrug) and one or more other antiviral agents, such as anti-HBV or HIV. Non-limiting examples of anti-HBV include adefovir, lamivudine and tenofovir. Non-limiting examples of drugs against HIV include ritonavir, lopinavir, indinavir, nelfinavir, saquinavir, and pranavi, atazanavir, tipranavir, TMC-114, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide, T-1249 and other protease inhibitors, reverse transcriptase, integrase or merged inhibitors HIV. Other desirable antiviral agents may also be included in the pharmaceutical composition, which is obvious to the expert in this field.

In one of the embodiments of the pharmaceutical composition of the present invention contains at least one compound of the present invention selected from formulae I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or its salt, MES or prodrug, and at least one tool against HBV. In another embodiment, the pharmaceutical composition of the present invention contains at least one compound of the present invention selected from formulae I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or its salt, MES or prodrug, and at least one anti-HIV agent. In yet another embodiment, the pharmaceutical composition of the present invention contains at least one compound of the present invention selected from formulae I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or its salt, MES or prodrug, and at least one with adsto against hepatitis A, hepatitis D, hepatitis E, or hepatitis G.

In yet another embodiment, the pharmaceutical composition of the present invention contains at least one compound of the present invention selected from formulae I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or its salt, MES or prodrug, and at least one agent suitable for the treatment of inflammation of the liver.

The pharmaceutical composition of the present invention typically includes a pharmaceutically acceptable carrier or excipient. Non-limiting examples of suitable pharmaceutically acceptable carriers/excipients include sugars (e.g. lactose, glucose or sucrose, starches (e.g. corn starch or potato starch), cellulose or its derivatives (for example, sodium carboxymethylcellulose, ethylcellulose or cellulose acetate), oils (e.g. peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil or soybean oil), glycols (e.g. propylene glycol), buffering agents (such as magnesium hydroxide or aluminum hydroxide), agar, alginic acid, powdered tragakant, malt, gelatin, talc, cocoa butter, pyrogen-free water, isotonic solution, ringer's solution, ethanol or phosphate buffer solutions. Lubricants, colorants, releasing agents, and the coefficients of the coating, sweeteners, flavors or fragrance substances or preservatives and antioxidants can also be included in the pharmaceutical composition of the present invention, which is obvious to a person skilled in this field.

The pharmaceutical composition of the present invention can be administered to the patient in various ways, such as oral, parenteral, sublingual, rectal, local, or via inhalation of spray. The local application can include the use of transdermal administration, such as transdermal patches or apparatus for iontophoresis. Parenteral administration includes, but is not limited to, subcutaneous, intravenous, intramuscular or intrasternal introduction injection or infusion methods.

The pharmaceutical compositions of the present invention can be obtained depending on ways of introduction of ways, well known in this field. For example, sterile injected by the injection of the drug can be obtained in the form of sterile injected by the injection of water or oil suspensions, using suitable dispersing or wetting agents and suspendresume substances. Suppositories for rectal injection can be obtained by mixing the drug with a suitable, not causing irritating excipient, such as cocoa butter or polietilenglikoli, which maintain a solid form at ordinary temperature but become liquid at rectal temperature and therefore will melt in the rectum and release the drug. Solid dosage forms for oral administration can consist of capsules, tablets, pills, powders or granules. In such solid dosage forms the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Solid dosage forms may also contain other substances in addition to the inert diluents, such as lubricants. In the case of capsules, tablets and pills, the dosage forms may also contain buffer substances. Tablets and pills can additionally contain intersolubility coverage. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs containing inert diluents commonly used in this field. Liquid dosage forms may also contain wetting, emulsifying, suspendida, sweetening, flavoring or fragrance substances. The pharmaceutical compositions of the present invention can also be administered in the form of liposomes, as described in U.S. patent No. 6703403. The composition is karstenii funds which can be used in the present invention, is described, for example, Hoover, John E., Remington's Pharmaceutical Sciences (Mack Publishing Co., Easton, PA: 1975) and Lachman, L., eds., Pharmaceutical Dosage Forms (Marcel Decker, New York, N.Y., 1980).

The present invention also relates to methods of using compounds of the present invention (or salts, solvate, or prodrugs) to inhibit the replication of HCV. In one of the embodiments the methods include contacting the HCV virus with an effective amount of the compounds of the present invention (or salts, MES or prodrugs), thus inhibiting the replication of HCV virus. In another embodiment, the methods include contacting cells infected with HCV with an effective amount of the compounds of the present invention (or salts, MES or prodrugs), thus inhibiting the replication of HCV virus in the cells. In yet another embodiment, the methods include contacting the HCV virus or infected cells with an effective amount of two or more compounds of the present invention (or salts, solvate, or prodrugs), thus inhibiting the replication of HCV virus. Used herein, the term “inhibition” refers to a significant reduction, or reducing, inhibiting activity (e.g., viral replication). the most typical cases of the compounds of the present invention can reduce viral replication of HCV (e.g., in the analysis of the HCV replicon as described above) at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or more.

Compounds of the present invention can inhibit all subtypes of HCV. Examples of subtypes of HCV, which can be processed in accordance with the present invention include, but are not limited to, HCV genotypes 1, 2, 3, 4, 5 and 6, including HCV genotypes 1a, 1b, 2a, 2b, 2c or 3a. In one of the embodiments, the compound or compounds of the present invention (or a salt, solvate or prodrug used for inhibiting replication of HCV genotype 1a. In another embodiment, the compound or compounds of the present invention (or a salt, solvate or prodrug used for inhibiting replication of HCV genotype 1b. In yet another embodiment, the compound or compounds of the present invention (or a salt, solvate or prodrug used for inhibition of replication of both HCV genotypes 1a and 1b.

The present invention also relates to methods of using compounds of the present invention (or salts, solvate, or prodrugs) for the treatment of HCV infection. These methods typically include the introduction of a therapeutically effective amount of the compounds of the present invention (or salts, MES or prodrugs) the patient is HCV, thereby reducing the level of HCV virus in the blood is, or liver of the patient. Used in this document, the term “treatment” refers to treatment, reducing, inhibiting the progress of, or preventing disease or condition, or one or more symptoms of such disease or condition that applies to this term. The term “treatment” refers to the act of treatment. In one of the embodiments the methods include the introduction of a therapeutically effective amount of two or more compounds of the present invention (or salts, solvate, or prodrugs) to a patient suffering from HCV, thereby reducing the level of HVC virus in the blood or liver of the patient. Preferably, the compound(I)used(s) in these ways, has(s) of formulas I, II, III, IV, V, VI, VII or VIII or selected(s) of the compounds of examples 1-255, or is(are) a salt, MES or prodrug.

In another aspect, the present invention relates to methods of using pharmaceutical compositions of the present invention for the treatment of HCV infection. For this purpose, you can use any pharmaceutical composition described in the present description. These methods typically include the introduction of a therapeutically effective amount of the pharmaceutical composition of the present invention to a patient suffering from HCV, thereby reducing the level of HCV virus in the blood or liver of the patient. If the farm is Titicaca composition includes other(s) therapeutic(s) agent(a), you may also be directed to other disease, disorder or condition of the patient.

In one of the embodiments of the pharmaceutical composition that is administered comprises at least one compound of the present invention selected from formulae I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or its salt, MES or prodrug, and at least one anti-HCV agent selected from inhibitors of RNA-dependent RNA polymerase of HCV, HCV protease inhibitors or inhibitors of helicase HCV. In another embodiment, the pharmaceutical composition that is administered comprises at least one compound of the present invention selected from formulae I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or its salt, MES or prodrug, and at least two anti-HCV, each of which is independently selected from inhibitors of RNA-dependent RNA polymerase of HCV, HCV protease inhibitors or inhibitors of helicase HCV. In yet another embodiment, the pharmaceutical composition that is administered comprises at least one compound of the present invention selected from formulae I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or its salt, MES or prodrug, and 1, 2 or more inhibitors of RNA-dependent RNA polymerase of HCV (e.g., inhibitors described in WO0190121(A2), US6348587B1, WO0160315, W0132153, EP1162196A1 and WO0204425). In yet another embodiment, the pharmaceutical composition that is administered comprises at least one compound of the present invention selected from formulae I, II, III, IV, V, VI, VII or VIII or examples 1-255, or its salt, MES or prodrug, and 1, 2 or more HCV protease inhibitors (e.g., BILN-2061, VX-950 and SCH503034).

In yet another embodiment, the pharmaceutical composition that is administered comprises at least one compound of the present invention selected from formulae I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or its salt, MES or prodrug, and at least one antiviral agent selected from anti-HIV funds, anti-HBV funds funds against hepatitis A, hepatitis D, hepatitis E, or hepatitis G.

In another aspect the present invention relates to a method of applying a compound(s) according to the present invention and the other(s), therapeutic(them) for the treatment of HCV infection. The methods include the introduction of a therapeutically effective amount of the compound(s) according to the present invention and the other(s), therapeutic () means the patient suffering from HCV, thereby reducing the level of HVC virus in the blood or liver of the patient. Each connection according to the present invention or its salt, MES or prodrug) and other(s) therapeutic(s) agent(a) may b the th United in the overall composition and administered to a patient simultaneously. They can also be entered simultaneously in different compositions. In addition, you can enter them in sequence.

In one of the embodiments of the input(s) compound(I) of the present invention include(s) one or more compounds selected from formulas I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or salt, solvate or prodrug, and other(s) input(s) therapeutic(s) tool(s) include(s) one or more means selected from inhibitors of RNA-dependent RNA polymerase of HCV, HCV protease inhibitors or inhibitors of HCV helicase. In another embodiment, the input(s) compound(I) of the present invention include(s) one or more compounds selected from formulas I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or salt, solvate or prodrug, and the other(s) enter therapeutic(s) tool(s) include(s) two or more means selected from inhibitors of RNA-dependent RNA polymerase of HCV, HCV protease inhibitors or inhibitors of helicase HCV. In yet another embodiment, the input(s) compound(I) of the present invention include(s) one or more compounds selected from formulae I, II, III, IV, V, VI, VII or VIII or examples 1-255, or salt, solvate or prodrug, and other(s) input(s) therapeutic(s) means(a) includes one, two or more inhibitions-dependent RNA polymerase of HCV (e.g., the inhibitors described in WO0190121(A2), US6348587B1, WO0160315, WO0132153, EP1162196A1 and WO0204425). In yet another embodiment, the input(s) compound(I) of the present invention include(s) one or more compounds selected from formulae I, II, III, IV, V, VI, VII or VIII or from examples 1-255, or salt, solvate or prodrug, and other(s) input(s) therapeutic(s) tool(s) include(s) one, two or more HCV protease inhibitors (e.g., BILN-2061, VX-950 and SCH503034).

The compound of the present invention or its salt, MES or prodrug) may also be administered in conjunction with other desirable drugs, such as anti-HIV, anti-HBV funds funds against hepatitis A, hepatitis D, hepatitis E, hepatitis G, or other antiviral drugs.

The compound of the present invention or its salt, MES or prodrug may be administered to the patient in a single dose or divided doses. The usual daily dose may range, without limitation, from 0.1 to 200 mg/kg body weight, for example from 0.25 to 100 mg/kg of body weight. Composition of unit dose can contain these quantities or Dolny unit to receive a daily dose. Preferably, each dose contains sufficient amounts of the compounds of the present invention, which effectively reduces the level of HVC virus in the blood of ribechini patient. The amount of the active ingredient or active ingredients that are combined to obtain a single dosage form may vary depending on the recipient and the particular route of administration. It is clear that a particular level of dose for a particular patient will depend upon a variety of factors including the activity of the specific compound, the age, body weight, General health, sex, diet, time of administration, route of administration, rate of excretion, combination with other drugs and the severity of the particular disease, which is directed treatment.

In another embodiment, compounds of formulas I, II, III, IV, V, VI, VII or VIII or pharmaceutically acceptable salts, stereoisomers or tautomers may be entered in only one active pharmaceutical agents or used in combination with one or more other means for treatment of infections or symptoms mediated by other RNA-containing viruses.

Treatment or prevention of infection caused by RNA-containing viruses, can be combined therapy containing a therapeutically effective amount of a first anti-viral agents, provided that one or more of the compounds or their salts are compounds of formulas I, II, III, IV, V, VI, VII or VIII, instead of the ones with a therapeutically effective amount of the second means, provided that one or more compounds selected from the group consisting of a different antiviral agents; immune modulator recipient; derived interferon, such as interferon-alpha, pegylated-interferon-alpha, interferon-beta and interferon-gamma; cytokine; vaccines; nucleoside analogue; inhibitors of key enzymes that lead to dysfunction HCV, examples of which are the enzymes metalloprotease HCV, serine protease of HCV, insertunorderedlist (IMPDH) and HCV helicase; inhibitors of proteins of viral particles, such as protein HCV NS4B and NS5a protein of HCV; and means which inhibit the function of HCV, such as the penetration of HCV, HCV Assembly and release of HCV. Also these include vaccines containing the HCV antigens or combinations of antigens and adjuvants against HCV. In addition, they include tools that interact with components of the host cells and inhibit the synthesis of viral proteins by inhibiting internal website landing ribosomes virus (IRES), the initiating stage broadcast replication of the HCV virus or blocking the maturation and release of viral particles, together with the means directed on membrane proteins viroporins family, such as, for example, HCV P7.

In one of the embodiments the present invention relates to a method of treatment or prevention, and the burden, caused by RNA-containing virus comprising the administration to a patient a therapeutically effective amount of compounds of formulas I, II, III, IV, V, VI, VII or VIII or its pharmaceutically acceptable salt.

In another embodiment, the present invention relates to a method of treatment or prevention of infection caused by RNA-containing virus comprising co-administration to the patient of one or more means selected from the group consisting of an immune modulator recipient and second antiviral agents, or combinations thereof, and a therapeutically effective amount of compounds of formulas I, II, III, IV, V, VI, VII or VIII or its pharmaceutically acceptable salt.

In yet another embodiment, the present invention relates to a method of treatment or prevention of infection caused by RNA-containing virus comprising co-administration to the patient of one or more means selected from the group consisting of interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine and a vaccine containing antigen and adjuvant, and a second antiviral agents, or combinations thereof, with a therapeutically effective amount of the compounds of formula I, II, III, IV, V, VI, VII or VIII or pharmaceutically acceptable salt.

In yet another embodiment, the present izopet the tion relates to a method of treatment or prevention of infection, caused by RNA-containing virus comprising co-administration to the patient of one or more means selected from the group consisting of an immune modulator recipient and a second antiviral agent that inhibits replication of HCV by inhibiting the functions of host cells associated with viral replication, or a combination thereof, with a therapeutically effective amount of compounds of formulas I, II, III, IV, V, VI, VII or VIII or its pharmaceutically acceptable salt.

In another embodiment, the present invention relates to a method of treatment or prevention of infection caused by RNA-containing virus comprising co-administration to the patient means or combination of means to cure or reduce symptoms of HCV infection including cirrhosis and inflammation of liver, with a therapeutically effective amount of compounds of formulas I, II, III, IV, V, VI, VII or VIII or its pharmaceutically acceptable salt.

In another embodiment, the present invention relates to a method of treatment or prevention of infection caused by RNA-containing virus comprising co-administration to the patient of one or more means, which is effective for the treatment of a patient of a disease caused by the hepatitis B virus (HBV)infection, with a therapeutically effective amount of compounds of formulas I, II, III, IV, V, VI, VII or VIII Il is its pharmaceutically acceptable salt.

In yet another embodiment, the present invention relates to a method of treatment or prevention of infection caused by RNA-containing virus comprising co-administration to the patient of one or more means, which is effective for the treatment of a patient of a disease caused by the human immunodeficiency virus (HIV), together with a therapeutically effective amount of compounds of formulas I, II, III, IV, V, VI, VII or VIII or its pharmaceutically acceptable salt.

The phrase “combination therapy” involves the introduction of each successive image in a mode that provides a satisfactory effect of combinations of drugs, and also involves the simultaneous introduction of these tools almost simultaneously, for example, oral administration or one capsule with a fixed ratio of these active agents, or taking multiple capsules of each product. “Combination therapy” also includes joint or sequential introduction of oral, intravenous, intramuscular or other parenterally in the body, including direct absorption through mucous membrane, for example, sinus cavities. Sequential introduction also includes combinations of drugs, in which individual tools can be entered at different times and/or different and ways, but which act in combination with the favourable effect, for example, by simultaneous effect of pharmacokinetic or pharmacodynamic effects of each tool.

The present invention also relates to the use of compounds according to the invention or their pharmaceutically acceptable salts, solvate or prodrugs to obtain drugs for treating HCV, or other viral infections. In one of the embodiments the present invention relates to the use of compounds of the present invention selected from formulae I, II, III, IV, V, VI, VII or VIII or its salts, MES or prodrugs to obtain drugs for the treatment of HCV infection. In another embodiment, the present invention relates to the use of two or more compounds of the present invention (or salts, solvate, or prodrugs) to obtain drugs for the treatment of HCV infection, where each of the two or more compounds independently selected from formulas I, II, III, IV, V, VI, VII or VIII.

In yet another embodiment, the present invention relates to the use of at least one compound of the present invention (or salts, MES or prodrugs) and at least one additional therapeutic agent to obtain medicinal cf is DSTV for treatment of HCV infection. Preferably, the compound(I) of the present invention is selected from compounds of formulas I, II, III, IV, V, VI, VII or VIII, and additional therapeutic(s) tool(s) may be selected, for example, but not limited to, antiviral agents (e.g., anti-HIV funds or other anti-HCV), immunomodulators, anti-cancer or chemotherapeutic agents, and anti-inflammatory drugs. Specific examples of other therapeutic agents include, but are not limited to, ribavirin; interferons (such as IFN alpha 2a or 2b); protease inhibitors; immunosuppressive means; antibodies (for example, therapeutic monoclonal or chimeric antibodies); antisense or siRNA; inhibitors of HIV; inhibitors of hepatitis B (HBV); means for treatment of cirrhosis and inflammation of liver; IFN omega (BioMedicines Inc., Emeryville, CA); BILN-2061, an inhibitor of serine protease (Boehringer Ingelheim Pharma KG, Ingelheim, Germany); Summetrel, antiviral agent (Endo Pharmaceuticals Holdings Inc., Chadds Ford, PA); Roferon A interferon-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); pegasis, PEG IFN-alpha 2a (F. Hoffmann-La Roche LTD, Basel, Switzerland); pegasis and ribavirin, PEG IFN-Alfa-2a/ribavirin (F. Hoffmann-La Roche LTD, Basel, Switzerland); CellCept, immunosuppressant HCV IgG (F. Hoffmann-La Roche LTD, Basel, Switzerland); wellferon, lymphoblastic IFN-alpha n1 (GlaxoSmithKline plc, Uxbridge, UK); Albuferon-alpha, albumin IFN-alpha 2b (Human Genome Sciences, Inc., Rockville, MD); levovirin, ribavirin (ICN Pharmceuticals, Costa Mesa, CA); IDN-6556, an inhibitor of caspase (Idun Pharmaceuticals Inc., San Diego, CA); IP 501, antifibrotics tool (Indevus Pharmaceuticals Inc., Lexington, MA); action, INF-gamma (InterMune Inc., Brisbane, CA); infergen A, IFN of alfacon-1 (InterMune Pharmaceuticals Inc., Brisbane, CA); ISIS 14803, an antisense oligonucleotide (ISIS Pharmaceuticals Inc., Carlsbad, CA/Elan Pharmaceuticals Inc., New York, NY); JTK-003, RdRp inhibitor (Japan Tobacco Inc., Tokyo, Japan); pegasis and zeplin, PEG IFN-alpha 2a/immune modulator (Maxim Pharmaceuticals inc., San Diego, CA); caplen, immune modulator (Maxim Pharmaceuticals Inc., San Diego, CA); civacir, immunosupressor HCV IgG (Nabi Biopharmaceuticals Inc., Boca Raton, FL); intron a and zadaxin IFN-alpha 2b/alpha 1-thymosin (RegeneRx Biopharmiceuticals Inc., Bethesda, MD/SciClone Pharmaceuticals Inc., San Mateo, CA); levovirin, the IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); viramidine, the IMPDH inhibitor (Ribapharm Inc., Costa Mesa, CA); heptazyme, the ribozyme (Ribozyme Pharmaceuticals Inc., Boulder, CO); intron A, IFN-alpha 2b (Schering-Plough Corporation, Kenilworth, NJ); PEG-intron, PEG IFN-alpha-2b (Schering-Plough Corporation, Kenilworth, NJ); Rebetron, IFN-Alfa-2b/ribavirin (Schering-Plough Corporation, Kenilworth, NJ); ribavirin (Schering-Plough Corporation, Kenilworth, NJ); PEG-intron/ribavirin, PEG IFN-Alfa-2b/ribavirin (Schering-Plough Corporation, Kenilworth, NJ); zadatim, immune modulator (SciClone Pharmaceuticals Inc., San Mateo, CA); Rebif, interferon-beta 1a (Serono, Geneva, Switzerland); IFN-beta and EMZ701, IFN-beta and EMZ701 (Transition Therapeutics Inc., Ontario, Canada); T67, the inhibitor of beta-tubulin (Tularik Inc., South San Francisco, CA); VX-497, IMPDH inhibitor (Vertex Pharmaceuticals Inc., Cambridge, MA); VX-950/LY-570310, an inhibitor of serine proteases (Vertex Pharmaceuticals Inc., Cambridge, A/Eli Lilly and Co., Inc., Indianapolis, IN); Omniture, natural IFN-alpha (Viragen Inc., Plantation, FL); XTL-002, monoclonal antibody (XTL Biopharmaceuticals); compound VX-950 (Vertex Pharmaceuticals Inc.); connection SCH503034 (Schering-Plough Co.); and the connection GS9137 (Gilead Sciences, Inc., Foster City, CA).

In yet another embodiment, the present invention relates to the use of at least one compound of the present invention (or salts, MES or prodrugs) and at least one additional antiviral agents to obtain drugs for the treatment of viral infections. Preferably, the compound(I) of the present invention is selected from compounds of formulas I, II, III, IV, V, VI, VII or VIII, and the additional antiviral agent(s) may be selected, without limitation, anti-HCV or against HIV. In one example the present invention relates to the use of at least one compound of the present invention selected from formulae I, II, III, IV, V, VI, VII or VIII or its salts, MES or prodrugs), and at least one additional anti-HCV to obtain drugs for the treatment of HCV infection. Non-limiting examples of anti-HCV include inhibitors of RNA-dependent RNA polymerase of HCV (e.g., polymerase inhibitors nucleoside or non-nucleoside type) or protease inhibitors of HCV. In another example, us is Aasee the invention relates to the use of at least one compound of the present invention, selected from formulas I, II, III, IV, V, VI, VII or VIII or its salts, MES or prodrugs), and at least two or more additional anti-HCV to obtain drugs for the treatment of HCV infection. Each of the additional anti-HCV can be independently selected from inhibitors of RNA-dependent RNA polymerase of HCV or HCV protease inhibitors.

In yet another embodiment, the present invention relates to the use of at least one compound of the present invention selected from formulae I, II, III, IV, V, VI, VII or VIII or its salts, MES or prodrugs), and at least one anti-HIV means to obtain drugs for the treatment of HIV or HCV infection. In yet another embodiment, the present invention relates to the use of at least one compound of the present invention selected from formulae I, II, III, IV, V, VI, VII or VIII or its salts, MES or prodrugs), and at least one tool against hepatitis A, hepatitis B, hepatitis D, hepatitis E hepatitis G to obtain drugs for the treatment of viral hepatitis. In yet another embodiment, the present invention relates to the use of at least one compound of the present invention selected from formulae I, II, III, IV, V, VI, VII or VIII or its salts, Salvatore prodrugs), and at least one agent for treating liver inflammation, to obtain drugs for the treatment of hepatitis C.

The above description of the present invention is given only for illustration and description and is not exhaustive or limit the invention in practice. Modifications and variations are possible in light of the described information or can be found in the practical implementation of the invention. Therefore, it should be noted that the scope of the invention defined by the claims and equivalent objects.

1. The compound or pharmaceutically acceptable salt of the compound, where the compound has formula I

where is heterocyclyl selected from thieno, triazolo, pyrazolo, pyrido and pyramidographia, and optionally substituted by one or more R18,
Rather it represents a phenyl, which is optionally substituted by one or more R18,
R18independently selected in each instance from the group consisting of halogen, hydroxy, C1-C4of alkyl, possibly substituted with halogen, C3-C6carbocycle, possibly substituted C1-C4by alkyl, -Ls-O-Rs, -Ls-S-Rsand piperidine;
each W1and W2independently selected from N or C(R33);
Z represents-N-;
each R10and R33selected from the group consisting of hydrogen;
X is selected from the group consisting of Ls-O-, -Ls-S-;
R22means hydrogen or phenyl, optionally substituted by one or more R26where R26independently selected in each instance from the group consisting of halogen, hydroxy, amino, C1-C4of alkyl, -Ls-O-Rs, -LE-Q-LE'-(carbocyclic), where carbocyclic means phenyl, and-LE-Q-LE'-(heterocyclyl), where heterocyclyl represents a thiazole;
Y is selected from the group consisting of Ls-O-, -Ls-S-, -Ls-C(O) -, and-Ls-NH(SO)2-;
R50represents-L1-And1where L1represents a bond, And1selected from the group consisting of carbocyclic where carbocyclic represents phenyl or3-C6carbocyclic, benzimidazolyl and C1-C6of alkyl, possibly substituted by phenyl, where a1optionally substituted by one or more R30and R30independently selected in each instance from the group consisting of halogen, hydroxy, cyano, amino, C1-C4of alkyl, -Ls-N(RsRs'), -Ls-C(O)N(RsRs'), -LE-Q-LE'-(carbocyclic), where carbocycle selected from the group consisting of phenyl and naphthyl, and-LE-Q-LE'-(heterocyclyl), where GE is eroticly selected from the group consisting of thiophene, furan, quinoline, thiazole;
each Rsand Rs'independently selected in each instance from the group consisting of hydrogen and C1-C4of alkyl, possibly substituted by cyano;
Lsindependently selected in each instance from the group consisting of ties, With1-C4alkylene and C1-C4Alcanena;
each LEand LE'independently selected in each instance from the group consisting of ties, With1-C4alkylene and C1-C4Alcanena;
Q is independently selected in each instance from the group consisting of-O-, -N(Rs)- ,- N(Rs)C(O)-, -C(O)N(Rs)-, -N(Rs)C(O)O - and-C(O)O-;
each R10, R18, R26, R30and R33optionally independently substituted in each case at least one Deputy, selected from the group consisting of halogen, hydroxy, cyano, amino and carboxy;
and
each carbocyclic and heterocyclyl fragment in LE-Q-LE-(carbocyclic) and LE-Q-LE'-(heterocyclyl) optionally independently substituted in each case at least one Deputy, selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C1-C6the alkyl and C1-C6alkoxy.

2. The compound or pharmaceutically acceptable salt according to claim 1, where
And1selected from the group consisting of phenyl, C3 -C6cycloalkyl and benzimidazolyl.

3. The compound or pharmaceutically acceptable salt according to claim 2, where W1and W2represent N.

4. The compound or pharmaceutically acceptable salt according to claim 3, where X represents-O - or-S-, and R22represents phenyl.

5. The compound or pharmaceutically acceptable salt according to one of claim 2 to 4, where
selected from the group consisting of

and
and where R10represents hydrogen; and
each R17and R35independently selected in each instance from the group consisting of C1-C4of alkyl, possibly substituted with halogen, C3-C6carbocycle, possibly substituted C1-C4by alkyl, -Ls-S-Rsand piperidine.

6. The compound or pharmaceutically acceptable salt according to claim 5, where R22representsand optionally substituted by one or more R26.

7. The compound or pharmaceutically acceptable salt of the compound, where the compound has formula II:
where
each R6and R8represents hydrogen;
R25selected from the group consisting of hydrogen and C1-C4alkyl is;
R37selected from the group consisting of hydrogen, C1-C4of alkyl, hydroxy-C1-C4the alkyl and C3-C6cycloalkyl;
R42selected from the group consisting of phenoxy, naphthoxy, thiazolidone, phenylsulfanyl and pyrimidinemethanol; where R42optionally substituted by one or more substituents independently selected from R46;
R46represents one or more substituents selected from the group consisting of hydrogen, hydroxy, amino, halogen, di-C1-C4alkylamino and C1-C4alkoxycarbonyl;
R70selected from the group consisting of phenyl, thiazolyl, pyridinyl, tetrahydrofuranyl, benzimidazolyl, naphthyl, chinoline and tanila; where R70represents an optionally substituted R75;
R75represents one or more substituents independently selected from the group consisting of hydrogen, halogen, C1-C4alkoxy, cyano, C1-C4of alkyl, halogen-(C1-C4of alkyl and phenyl.

8. The compound or pharmaceutically acceptable salt of the compound, where the compound has formula III:

where R80selected from the group consisting of hydrogen, C1-C4alkylcarboxylic and halogenfree.

9. The compound or pharmaceutically acceptable the traveler salt compounds, where the compound has formula IV:

where Q is selected from the group consisting of N and CH;
R1represents a C1-C4alkyl;
R19selected from the group consisting of C1-C4the alkyl and galgenfrist1-C4alkoxy; and
R56selected from the group consisting of hydrogen, hydroxy and C1-C4the alkyl.

10. The compound or pharmaceutically acceptable salt of the compound, where the compound has formula V:

where R5selected from the group consisting of hydrogen and C1-C4alkylsulfanyl;
R29selected from the group consisting of C1-C4of alkyl, panels1-C4alkoxy, halogen and halogenfree-C1-C4alkoxy;
R47selected from the group consisting of C1-C4of alkyl, halogen-C1-C4of alkyl, C1-C4alkylsulfonyl, phenyl-C1-C4alkylsulfanyl and piperidine;
R64represents hydrogen;
R66selected from the group consisting of hydrogen, hydroxy, halogen and C1-C4of alkyl; and
R81represents hydrogen.

11. The compound or pharmaceutically acceptable salt of the compound, where the compound has formula VI:

where R73represents a C1-C4alkyl; and
R76selected from the group consisting of hydroxy, C1-C4alkylaminocarbonyl and C1-C4alkylcarboxylic.

12. The compound or pharmaceutically acceptable salt of the compound, where the compound has formula VII:

where a is selected from the group consisting of O and S;
R21selected from the group consisting of hydrogen and hydroxy;
R39selected from the group consisting of hydrogen, C1-C4of alkyl, phenylalkyl, C1-C4dialkylamino, heteroaryl, halogenmethyl, halogennitromethyl, vinylsulfonate,1-C4alkylcarboxylic,3-C6cycloalkylcarbonyl, generalquartiermeister,1-C4alkoxycarbonyl and NH-R99where heteroaryl selected from the group consisting of thiophenyl, chinoline, benzimidazolyl, pyrrolyl and thiazolyl;
R99selected from the group consisting of hydrogen, panels1-C4of alkyl, C3-C6cycloalkenyl, phenyl, naphthyl, heteroaryl, halogenofullerene, panels1-C4alkylamino and C1-C4alkylglycerol where heteroaryl selected from the group consisting of thiophenyl, chinoline, furanyl, pyrrolidinedione and thiazolyl;
R67selected from the group consisting of hydrogen, C1-C4of alkyl, C3-C6cycloalkyl and C1-C alkyl-C3-C6cycloalkyl; and
R96selected from the group consisting of hydrogen, hydroxy, amino, C1-C4alkoxy, C1-C4alkylcarboxylic, halogen, funeralcare.

13. The compound or pharmaceutically acceptable salt of the compound, where the compound has formula VIII:

where R23selected from the group consisting of hydrogen, C1-C4the alkoxyphenyl, C1-C4alkoxylalkyl, hydroxyphenylacetamide, halogenfrei-C1-C4alkoxy, cyanophenyl-C1-C4alkoxy, funeralcare;
R31selected from the group consisting of hydrogen and halogen;
R49selected from the group consisting of hydrogen, phenyl-C1-C4alkoxy, halogennitroalkane,1-C4alkoxyglycerols, phenyl-C1-C4alkenyl, phenyl-C1-C4of alkyl, halogen, cyano, halogenosilanes1-C4of alkyl, C1-C4of alkyl, C1-C4alkoxysilane and C1-C4alkoxycarbonyl;
R52selected from the group consisting of hydrogen, halogen, C1-C4of alkyl, hydroxyphenoxy, phenyloxy, hydroxys1-C4alkylphenoxy,1-C4alkoxyphenyl1-C4of alkyl, C1-C4alkoxyphenyl,1-C4Ala is fenil-C 1-C4alkoxyamino, aminophenoxy; and
R77selected from the group consisting of hydrogen, C1-C4the alkyl and C3-C6cycloalkyl.

14. Pharmaceutical composition having the properties of an inhibitor of HCV viral infection, containing the compound or pharmaceutically acceptable salt according to any one of claims 1 to 13 in an effective amount.

15. Method of inhibiting replication of HCV virus comprising contacting the HCV virus with an effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 13, thereby inhibiting replication of the given virus.

16. A method of treating HCV infection, comprising introducing an effective amount of a compound or pharmaceutically acceptable salt according to any one of claims 1 to 13 to a patient suffering from HCV.

17. The use of compound or pharmaceutically acceptable salt according to any one of claims 1 to 13 to obtain drugs for treating HCV infection or inhibiting the replication of HIV.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula where R1 denotes CH3; R2 denotes halogen or CN; R3 denotes H or CH3; R4 denotes H or CH3; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition and use of compounds of formula (I) in preparing a medicinal agent, having CX3CR1 receptor antagonist activity.

EFFECT: compounds can be used as CX3CR1 receptor antagonists.

13 cl, 1 tbl, 10 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula in which Q together with carbon and nitrogen atoms whereto attached forms a 9-10-member bicyclic heterocycle, and R1 and R2, R3, R4, R5 and R6 are as specified in cl.1 of the patent claim, or to its enantiomers, or a mixture of its enantiomers, or to its pharmaceutically acceptable salt. Also, an invention refers to a method for activation of glucokinase activity in mammals, by introduction of the compound described above, to a method of treating the pathological conditions associated with glucokinase activity and impaired glucose tolerance by means of introduction of the compound of formula I, to a pharmaceutical composition on the basis of the presented compounds, and also to application of the compounds of formula I for preparing the pharmaceutical composition.

EFFECT: there are produced and described new compounds which are activators of glucokinase activity and can be used as therapeutic agents for preventing and treating impaired glucose tolerance, insulin-independent diabetes and obesity.

14 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula (I), which can be used as a medicinal agent having PI3-kinase inhibiting properties. In general formula (I)

,

A denotes N, Ra denotes C1-C8alkyl, phenyl substituted with 1-2 residues selected from a group comprising halogen and C1-C6halogenalkyl, Rb denotes hydrogen, R1 denotes hydrogen or C1-C8alkyl, R2 denotes hydrogen or a substitute selected from a group comprising: C1-C8alkyl, substituted with one substitute selected from C1-C6alkoxy group, -(CO)-O-C1-C6alkyl, N(C1-C6alkyl)2; 6-member heterocycloalkyl containing a nitrogen atom as a heteroatom, substituted with 1-2 substitutes selected from an oxo group and phenyl; (5-6-member heterocycloalkyl containing 1-2 heteroatoms selected from nitrogen and oxygen)-C1-C4alkyl, optionally substituted with 1-2 substitutes independently selected from -(CO)-O-C1-C6alkyl, C1-C6alkyl, -(CO)-O-benzyl, oxo group, benzyl substituted with C1-C6alkyl, 6-member heteroaryl containing 2 nitrogen atoms as heteroatoms; phenyl which is optionally substituted with 1 substitute selected from a 6-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, optionally substituted with -(CO)-O-C1-C6alkyl, (5-6-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, substituted with C1-C6alkyl)-C1-C4alkyl, optionally substituted with an oxo group, -(C1-C4alkyl)-NR7-(CO)O-C1-C6alkyl; phenyl-C1-C5alkyl, optionally substituted with 1-2 substitutes selected from NH2, N(C1-C6alkyl)2, C1-C6alkyl, N(C1-C6alkyl)2-C1-C6alkyl, OR7, OCF3, haloC1-C6alkyl, CN, SO2R7, NR7COR8, CONH2, NR7-(CO)O-C,-C6alkyl; -(C1-C4alkyl)-NR7-(CO)O-C1-C6alkyl, 5-member heteroaryl containing 2 nitrogen atoms as heteroatoms, (5-6-member heterocycloalkyl containing 1-2 heteroatoms independently selected from nitrogen and oxygen), optionally substituted with an oxo group, (5-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms substituted with 1-3 substitutes independently selected from oxo group, C1-C6alkyl)-C1-C4alkyl, -C(O)-NH-(C3-C8cycloalkyl), -C(O)-NH-(C1-C6alkyl), -C(O)-N(C1-C6alkyl)2, COR7, NR7(CO)NR8R9; (5-6-member heteroaryl containing 1-4 heteroatoms independently selected from nitrogen, sulphur and oxygen)-C1-C6alkyl, optionally substituted with 1-2 substitutes selected from C1-C6alkyl, C3-C8cycloalkyl, CN and OH; (9-member heteroaryl containing a nitrogen atom as a heteroatom)-C1-C4alkyl; C3-C8cycloalkyl, optionally substituted with a 5-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, substituted with an oxo group; C3-C8cycloalkyl-C1-C4alkyl, optionally substituted with 1 substitute selected from C1-C4alkyl-(CO)OR8, NR (CO)OR8; 1,3-benzodioxole-C1-C4alkyl; 1,4-benzodioxane-C1-C4alkyl; isoindoline-C1-C4alkyl substituted with 1 CO-NH2 substitute; or R1 and R2 together form a 5- or 6-member saturated ring which optionally contains an additional heteroatom selected from oxygen and nitrogen, and optionally substituted with 1-3 substitutes independently selected from OH, C1-C6alkyl, (CO)OR8, (C1-C4alkyl)-(CO)OR8, NR7(CO)OR8, -(C1-C4alkyl)-NR7(CO)OR8, NR7COR8, -(C1-C4alkyl)-NR7COR8, -NH-C(O)CF3, -CH(OH)-phenyl, NR7(CO)NR8R9, NR7(CO)CH2NR8R8, -NR7(SO2)R8, phenyl, optionally substituted C1-C6alkoxy, OH, 9-10-member bicyclic heteroaryl containing 1-2 nitrogen atoms as heteroatoms, optionally substituted with a phenyl oxo group, substituted with a hydroxy group, -CH2-isoquinoline, substituted with an oxo group, 5-member heterocycloalkyl containing 2 nitrogen atoms as heteroatoms, substituted with an oxo group, -CH2-O-(phenyl, substituted with 3 substitutes independently selected from halogen and amino); or R1 and R2 together form a saturated 9-11-member spirocyclic system with 1-2 additional nitrogen heteroatoms, substituted with 1-2 substitutes independently selected from -C1-C6alkyl, OH, oxo group and phenyl; or R2 denotes a residue selected from a group of residues of general formulae:

, , , , , and , where X denotes C1-C7alkylene, Q denotes C1-C7alkylene, R3, R4 have identical or different values and denote hydrogen or a substitute selected from a group comprising C1-C8alkyl, 9-member bicyclic heteroaryl containing 2 nitrogen atoms as heteroatoms, substituted with C1-C6alkyl, phenyl substituted with C1-C4alkyl, 6-member heteroaryl containing 2 nitrogen atoms as heteroatoms, 5-member heterocyclyl containing 1 nitrogen atom as a heteroatom, (C3-C8cycloalkyl)-C1-C4alkyl-, or R3, R4 together form a 6-member saturated ring containing an oxygen atom as an additional heteroatom, R7, R8, R9 have identical or different values and denote hydrogen or a substitute selected from a group comprising C1-C8alkyl, 5-6-member heterocycloalkyl containing 1-2 heteroatoms independently selected from nitrogen and oxygen, C3-C8cycloalkyl, C1-C6haloalkyl, C3-C8cycloalkyl- C1-C4alkyl-, C1-C4alkoxy-C1-C4alkyl-.

EFFECT: high efficiency of using the disclosed compounds in preparing a medicinal agent.

10 cl, 1 tbl, 299 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula

, where R1 denotes a lower alkyl; R2 denotes phenyl or a 5- or 6-member heteroaryl containing 1-2 N atoms or 1 N atom and 1 S atom as heteroatoms, which may be unsubstituted or substituted with a substitute selected from halogen or lower alkyl; R3 denotes hydrogen, phenyl or a 5-6-member heteroaryl containing 1-2 N atoms and 1 O atom as heteroatoms, which can be unsubstituted or substituted with a substitute selected from 1-2 halogen atoms, lower alkyl or a S(O)2-lower alkyl group; as well as pharmaceutically acceptable salts thereof. The invention also relates to a pharmaceutical composition, having metabotropic glutamate receptor mGluR5 antagonist properties, which contains the compound of formula (I) as active component and pharmaceutically acceptable excipients.

EFFECT: possibility of using said derivatives as mGluR5 receptor antagonists.

25 cl, 2 dwg, 1 tbl, 30 ex

FIELD: chemistry.

SUBSTANCE: described are novel substituted naphthyridines of general formula E: (radicals R1 and R3 are described in the claim), pharmaceutically acceptable salts thereof, a pharmaceutical composition containing said compounds, and use of the novel compounds to prepare a medicinal agent for treating or preventing malignant tumours in mammals.

EFFECT: compounds inhibit Akt acitivity, in particular, the compounds selectively inhibit one or two isoforms of Akt and can be used in medicine.

5 cl, 14 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: in formula (I) , the ring A represents 6-members aryl or 5-6-members heteroaryl containing 1-2 heteroatoms selected from nitrogen and sulphur; Q means C3-8 cycloalkyl, 5-6-members heterocycle containing 1 heteroatom selected from oxygen, nitrogen or sulphur, C1-6 alkyl or C2-6 alkenyl; the ring T represents 5, 6, 9 or 10-members heteroaryl or 9-members heterocycle optionally additionally substituted by 1-3 heteroatoms independently selected from nitrogen or sulphur. The values of other substitutes are specified in the patent claim. Also, the invention refers to methods for preparing oxime derivatives of general formula (I), to pharmaceutical compositions containing the compound of the invention as an active ingredient and to applications of the compounds of the invention in preparing a drug.

EFFECT: compounds of the invention exhibit properties of a glucokinase activator.

33 cl, 1499 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

wherein Q together with carbon and nitrogen atoms whereto attached forms a 5-6-members monocyclic heteroaromatic ring; or Q together with carbon and nitrogen atoms whereto attached forms a 9-10-members bicyclic heterocycle; R1 and R2 independently mean hydrogen, halogen, alkyl, alkyl substituted by one or more halogen, alkoxygroup, alkoxygroup substituted by alkoxygroup, alkylthiogroup, sulphonyl, free or etherified carboxygroup, carbamoyl, sulohamoyl, morpholinyl or pyridinyl; or R2 is absent; R3 means (C3-C6)cycloalkyl; R4 means hydrogen, halogen, lower alkyl or lowest alkyl substituted by one or more halogen; R5 means (C3-C6cycloalkyl, (C6-C10) aryl, (C3-C10)heterocyclyl or (C1-C6)alkyl optionally substituted by (C1-C6)alkoxygroup, (C3-C7)cycloalkyl, (C6-C10)aryl or (C3-C10)heterocyclyl; R6 means free or etherified carboxygroup; and n is an integer equal to 1-6; or to its enanthiomer, or a mixture of its enanthiomers, or its pharmaceutically acceptable salt. Besides, the invention refers to a method of glucokinase activation in mammals, to a method of treating pathological conditions associated with glucokinase activation in mammals and impaired glucose tolerance, as well as to a pharmaceutical composition based on these compounds and to application of said compositions for preparing a drug.

EFFECT: there are produced and described new compounds which are activators and can be used as therapeutic agents for treating the glucokinase mediated pathological conditions.

31 cl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a derivative of 5-substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine of formula

and its optical isomers and pharmaceutically acceptable salts where R1 represents CH3 or CH3CH2; R2 represents H, 2-F, 2-Cl, 3-F, 3-OCN3, 3-CN, 3-CF3, 3-CONH2 or 3-SO2CH3; R3 represents H or CH3; R4 represents H or CH3; and R5 represents H; or when R4 represents CH3, R5 represents H or F. Also, the invention refers to methods for producing the compounds of formula (I) and to pharmaceutical compositions exhibiting CX3CR1 receptor antagonist properties containing the compounds of formula (I).

EFFECT: production of 5-substituted 7-amino-[1,3]thiazolo[4,5-d]pyrimidine as selective CX3CR1 receptor antagonists.

15 cl, 2 tbl, 18 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds (la) of formula applied as tyrosine kinase c-Met inhibitors. , where: LA is selected from ,

or ; RA is selected from:

or each RA2 and RA6 represents hydrogen; RA3 represents RAr; or RA3, RA4 and carbon atoms whereto attached form 6-members aryl, optionally substituted, in the amount up to 4 by independent groups RAr, or a 5-6-members heterocyclyl or heteroaryl ring containing at least one O, N or S atom; R represents -OH; RA5 represents hydrogen or RAr; LB represents a covalent bond or -N(R*)-; RB represents halogen, NH2 or C1-8aliphatic group, optionally substituted by R; a 6-10-members aryl ring; a 3-7-members carbocyclyl ring, a 5-10-members heteroaryl ring containing 1-4 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms, where each said aryl or heteroaryl ring is optionally substituted, in the amount up to five by independent groups RAr; R represents halogen, -R°, -SR°, Ph, optionally substituted R° or -C(O)OR°; each RAr is independently selected from halogen, -R°, -OR°, -SR°, Ph, optionally substituted in the amount up to five by independent groups -R°, -CN, -N(R°)2 or -C(O)OR°; or two adjacent groups RAr taken together, represent 1,2-methylenedixy or 1,2-ethylenedixy; each R* represents hydrogen; and each R° represents independently hydrogen, an optionally substituted C1-6aliphatic radical or an unsubstituted 5-6-members heteroaryl or heterocyclic ring containing 1-3 heteroatoms independently selected from nitrogen, oxygen and sulphur atoms.

EFFECT: invention refers to pharmaceutically acceptable compositions containing the compounds under the invention, and methods of application of the compositions in treatment of various proliferative disorders.

10 cl, 4 tbl, 548 ex, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention relates to azole derivatives of formula I , where: A denotes S, O; W denotes -(C=O)-; X are identical or different and denote =C(-R)- or =N-; Y denotes -O- or -NR1-; R denotes hydrogen, halogen, (C1-C6)-alkyl, nitro; R1 denotes hydrogen; R2 denotes (C5-C16)-alkyl, (C1-C4)alkyl-phenyl, where phenyl can be optionally mono- or poly-substituted with (C1-C6)-alkyl; R3 denotes hydrogen; or R2 and R3 together with the nitrogen atom bearing them can form a monocyclic saturated 6-member ring system, where separate members of this ring system can be substituted with 1 group selected from the following: -CHR5-, -NR5-; R5 denotes (C1-C6)-alkyl, trifluoromethyl; and physiologically acceptable salts thereof. The invention also pertains to methods of producing said compounds and a medicinal agent based on said compounds.

EFFECT: novel compounds and a medicinal agent based on said compounds are obtained, which can be used as hormone-sensitive lipase (HSL) or endothelial lipase (EL) inhibitors.

12 cl, 11 ex

FIELD: chemistry.

SUBSTANCE: method is realised by treating a compound of formula

with boronic acid or ether thereof of formula

,

in which two OR15 groups together with the boron atom with which they are bonded form a pinacolato boronate ester group in the presence of a Pd catalyst. The invention relates to a method of producing a pharmaceutically acceptable salt of thieno[3,2-d]pyrimidine of formula

.

The invention also relates to a pharmaceutical composition, having phosphatidyl inositol-3-kinase inhibitor activity, containing thieno[3,2-d]pyrimidine of formula (I) as an active ingredient, a method of preparing said composition and use of thieno[3,2-d]pyrimidine of formula (I) or pharmaceutically acceptable salt thereof in producing a medicinal agent for inhibiting phosphatidyl inositol-3-kinase.

EFFECT: use of the derivative as a phosphatidyl inositol-3-kinase inhibitor.

11 cl, 13 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formulae and including their stereoisomers, as well as pharmaceutically acceptable salt, where X denotes O or S; R1 is selected from H, F, CI, Br, I, CN, -CR14R15-NR16R17, -CR14R15-NHR10, -(CR14R15)NR10R11, -(CR14R15)nNR12C(=Y)R10, -(CR14R15)nNR12S(O)2R10, -(CR14R15)mOR10, -(CR14R15)nS(O)2R10, -C(OR10)R11R14, -C(R14)=CR18R19, -C(=Y)OR10, -C(=Y)NR10R11, -C(=Y)NR12OR10, -C(=O)NR12S(O)2R10, -C(=O)NR12(CR14R15)mNR10R11, -NHR12, -NR12C(=Y)R10, -S(O)2R10, -S(O)2NR10R11, C2-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C4 carbocyclyl, piperidinyl, thiopyranyl, phenyl or C5-C6 heteroaryl; R2 is selected from H, C2-C12 alkyl and thiazolyl; R3 denotes a condensed bicyclic heteroaryl selected from indazole, indole, benzoimidazole, pyrrolopyridine, imidazopyridine and quinoline; R10, R11 and R12 independently denote H, C2-C12 alkyl, C3 carbocyclyl, heterocyclyl selected from pyrrolidine, morpholine and piperazine, phenyl or heteroaryl selected from pyrazole, pyridine, benzothiophene; or R10 and R11 together with a nitrogen atom with which they are bonded possibly form a saturated C3-C6 heterocyclic ring, possibly containing one additional ring atom selected from N or O, where said heterocyclic ring is possibly substituted with one or more groups independently selected from oxo, (CH2)mOR10, NR10R11, SO2R10, C(=O)R10, NR12S(O)R11, C(=Y)NR10R11, C1-C12 alkyl and heterocyclyl selected from pyrrolidine; R14 and R15 are independently selected from H or C1-C12 alkyl; R16 and R17 independently denote H or phenyl; R18 and R19 together with a carbon atom with which they are bonded form a C3-C20 heterocyclic ring, where said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, phenyl, heteroaryl, piperidinyl and condensed bicyclic heteroaryl possibly substituted with one or more groups independently selected from F, CI, Br, I, CF3, -C(=Y)R10, -C(=Y)OR10, oxo, R10, -C(=Y)NR10R11, -(CR14R15)nNR10R11, -NR10R11, -NR12C(=Y)R10, -NR12C(=Y)NR10R11, -NR12SO2R10, OR10, SR10, -S(O)2R10, -S(O)2NR10R11, possibly substituted with carbocyclyl, selected from cyclopropyl, possibly substituted heterocyclyl selected from piperazine, possibly substituted with alkyl and alkylsulphonyl, pyrrolidine, morpholine, piperdine, possibly substituted CH3, phenyl and possibly substituted heteroaryl selected from imidazole and triazole; Y denotes O; m equals 0, 1 or 2; n equals 1 and t equals 2. The invention also relates to a pharmaceutical composition which modulates lipid kinase activity, based on said compounds.

EFFECT: obtaining novel compounds and a composition based on said compounds, which can be used to treat lipid kinase-mediated diseases, for example, cancer.

48 cl, 2 tbl, 372 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a method for producing prasugrel hydrochloride which involves the following stages: (i) chlorination of a compound described by formula (III) by addition of an chlorinating agent, optionally drop-by-drop, in a solvent; (ii) reaction of the prepared compound of formula (IV) and a compound described by general formula (V) where R means a protective group for hydroxyl, or its salt in a solvent in the presence of a base; (iii) acetylation of the prepared compound described by general formula (II) by reaction with an acetylation agent in a solvent in the presence of a base and an acetylation catalyst; and (iv) addition of hydrochloric acid, optionally drop-by-drop, to the prepared compound described by formula (I) in a solvent to produce prasugrel hydrochloride described by formula (1a), and differs by the fact that at the stage (i) temperature during addition of the chlorinating agent, optionally drop-by-drop, ranges within -20°C to 5°C, and reaction temperature after addition of the chlorinating agent, optionally drop-by-drop, ranges within -20°C to 5°C. The invention also concerns a product containing prasugrel hydrochloride and CATP in an amount no more than 0.3 %, to the pharmaceutical composition suitable for prevention or treatment of thrombosis or embolism on the basis of the specified product.

EFFECT: production of low-CATP prasugrel hydrochloride.

31 cl, 3 dwg, 1 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, more specifically to a method of olanzapine purification which involves mixing olanzapine with an organic acid in an organic solvent or a mixture of organic solvents to prepare acid-additive olanzapine salt, precipitation and isolation of acid-additive olanzapine salt and transforming acid-additive olanzapine salt in olanzapine; the organic acid is carboxylic acid which is selected from the group including oxalic, fumaric and benzoic acid.

EFFECT: invention refers to methods for producing pure olanzapine, intermediate products and acid-additive olanzapine salts which in turn can find application for producing pure olanzapine used for preparing a drug for treating mental disorders and conditions.

38 cl, 1 tbl, 25 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula , where X denotes S; R1 and R2 taken together with atoms to which they are bonded form a 5-member carbocycle, substituted with up to two substitutes selected from alkyl and CF3; R3 is selected from a group consisting of a hydrogen atom and C1-8-alkyl; R3a denotes a hydrogen atom; R4 denotes a hydrogen atom; R4a denotes a hydrogen atom; R5 denotes a hydrogen atom; R5a denotes a hydrogen atom; R6 denotes a hydrogen atom; R6a denotes a hydrogen atom; R7 denotes a hydrogen atom; or pharmaceutically acceptable salts thereof. The invention also relates to compounds of the given formula, compounds selected from the group, as well as a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds which modulate serotonin receptor activity.

6 cl, 19 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (1) (lb) in which A denotes a benzene ring; Ar denotes naphthalenyl which optionally contains 1-3 substitutes independently selected from a group comprising C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, hydroxy group, C1-C6alkoxy group, halogen, heteroalkyl, heteroalkoxy group, nitro group, cyano group, amino- and mono- or di- C1-C6alkyl-substuted amino group; R1 denotes hydrogen, halogen, C1-C6alkyl, C1-C6alkoxy group, carboxy group, heteroalkyl, hydroxy group optionally substituted with heterocyclylcarbonyl-C1-C6alkyl or R1 denotes N(R')(R")-C1-C6alkyl or N(R')(R")-carbonyl- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cycloalkyl, C3-C7cycloalkyl-C1-C6alkyl, heteroalkyl, phenyl-C1-C6alkyl; or R1 denotes R'-CO-N(R")-C1-C6alkyl, R'-O-CO-N(R")- C1-C6alkyl- or R'-SO2-N(R")- C1-C6alkyl-, in which R' and R" are independently selected from a group comprising hydrogen, C1-C6alkyl, C3-C7cyclalkyl, C3-C7cycloalkyl- C1-C6alkyl or optionally substituted phenyl; R2, R2' and R2" independently denote hydrogen, halogen, cyano group, C1-C6alkyl, halogenated C1-C6alkyl or C1-C6alkoxy group; n equals 1; and pharmaceutically acceptable salts thereof. The invention also relates to use of compounds in any of claims 1-9, as well as to a pharmaceutical composition.

EFFECT: obtaining novel biologically active compounds with chymase inhibiting activity.

14 cl, 128 ex

Organic compounds // 2430921

FIELD: chemistry.

SUBSTANCE: invention relates to an azathiabenzo-azulene derivative of formula I

,

where R3 denotes C1-C6alkyl, R4 denotes OH, R5 denotes halogen and R6 denotes H or halogen, or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds, having anti-inflammatory or analgesic action.

EFFECT: obtained compounds and pharmaceutical composition can be used to treat arthritis and arthritis-related conditions, and for relieving inflammation and pain associated with acute inflammation of body parts, primarily joints, as a result of injury or as a result of arthritic conditions or other diseased conditions.

17 cl, 8 tbl, 9 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing prasugrel hydrochloride of the formula:

,

with low content of "ОХТР", involving preparation of free prasugrel containing "ОХТР" from 2-silyloxy-5-(α-cyclopropylcarbonyl-2-fluorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine, dissolving the obtained free prasugrel in an inert solvent and optionally adding hydrochloric acid in drops to the solution for reaction.

EFFECT: novel method of producing prasugrel with low content of impurities, specifically "ОХТР" by-product.

2 cl, 6 dwg, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of the formula I

, where: m equals 0, 1 or 2, where if m=0, disappears such that an open ring or single bond forms, n equals 0, 1 or 2, wherein when n=0, disappears such that an open ring or single bond forms; m' and n' are independently equal to 0, 1 or 2; X denotes a carbon atom; Y denotes a carbon or sulphur atom; provided that m and n are not equal to 0 at the same time; denotes a single or double bond, if needed; --- absence of a bond or a single bond, if needed; R1 is selected from a group comprising CN, Hal, OAIk, OH, NRCN, C(CN)=C(OH)(OAlk), SR, NRR', (Alk)p-C(O)NRR', piperidine, wherein Alk is optionally substituted with Hal or OAlk, where p=0 or 1; R3, R4, R5 and R6 are identical or different and are independently selected from a group comprising H, OAIk, Alk, Hal, OH; R2 is selected from a group comprising H and O, and p'=0 or 1; R7 is selected from a group comprising H, O, OH, N-OH, N-aryl, N-OAlk, N-O-aryl, N-O-Alk-aryl, N-NR-CONRR', N-O-CO-Alk, or 2 R7, bonded with the same Y, together form lioksalan; wherein said Alk is optionally substituted with OAlk, -CO-(NR-Alk-CO)p'-OAlk, and p'=0 or 1; R and R', which are identical or different, are independently selected from a group comprising H, and Alk; or pharmaceutically acceptable salt or optical isomer or diastereomer thereof, except those compounds for which: R3, R4, R5, R6=H, R1=CN, denotes a single bond, and denotes -C(=N-(2,4,6-trimethylphenyl))-, -C(=N-(2,6- dimethylphenyl))-, -C(=N-(2,6-diethylphenyl))-, -C(=N(2-methylphenyl))-, -C(=N(2-ethylphenyl))-, -C(=N-(2-trifluoromethylphenyl))-, -C(=N-(2-isopropylphenyl))-, -C(=N-phenyl)-, -C(=N-(naphthyl)- or -C(=O)-, -CH2-, or R3, R5, R6=H, R4=OMe, R1=CN, denotes a single bond, and denotes -C(=O)-, or R3, R4, R5, R6=H, R1=NH2, denotes a single bond, and denotes -CH2- or -CH2-CH2-; or R3, R4, R5, R6=H, R,=NH2, denotes -CH2- or -CH2-CH2-, and denotes a single bond. The invention also relates to a cysteine protease based pharmaceutical composition based on compounds of formula I, use of the compound of formula I to prepare a drug for inhibiting cysteine protease, for treating and preventing cancer, as well as inflammatory diseases and others.

EFFECT: novel compounds which can be used in medicine are obtained and described.

38 cl, 43 ex, 2 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula (I) and to their pharmaceutically acceptable salts exhibiting PI3 kinase inhibitor activity. In the formula (I), A represents a thiophen ring; n=1; R1 represents , where m=1; R30 represents H; R4 And R5 together with N atom whereto attached form a 5- or 6-members N-containing heterocyclic group which includes 0 or 1 additional heteroatom selected from N and O which is unsubstituted or substituted by one or more substitutes selected from C1-6alkyl, C1-6alkoxy, -N(R"')-alk-OR, -alk-OR, -O-alk-OR, -alk-C(O)NR2, -C(O)NR2, -alk-Het, -N(R)-Het, -O-Het, -N(R)-C(O)- alk-OR, -NR-S(O)2R, -N(R)-alk-S(O)2R, -N(R)-alk-OR, -alk-NR'R", -N(R"')-S(O)2R, S(O)2R"', -S(O)2-alk-ORf 5- or 6-members N-containing heterocyclic group, 5- or 6-members N-containing heteroaryl group which includes 0 or 1 additional heteroatom selected from N, O or S, oxo(=O), -SO2NR2, -SO2-alk-NR2 where alk means a C1-6alkylene chain; Het means a 5- or 6-members N-containing heteroaryl group or furan optionally substituted by C1-6alkyl; R means H or C1-6alkyl, or when 2 groups R are bound with N, they together with N atom form a saturated 5- or 6-members N-containing heterocyclic group; each R' and R" means independently H, C1-6alkyl or C1-6alkoxy; R'" represents C1-6alkyl, a 5- or 6-merous saturated N-containing heterocyclic group, or a 5- or 6-merous N-containing heteroaryl group; R2 means where R6 and R7 together with N atom whereto attached form a morpholine group; R3 represents an indazole group.

EFFECT: development of the effective method of preparing the compounds of formula (I), and their application for preparing a drug, a pharmaceutical composition, and a method of inhibition.

10 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to imidazopyridines of formula I

and to their pharmaceutically acceptable salts where Z1 represents CR1; R1 represents H; R1' represents H; Z2 represents CR2; Z3 represents CR3 or N; R2 and R3 are independently selected from H, halogen; R4 represents H; Y represents W-C(O)-; W represents or , R5 represents H; X1 is selected from R11' and -OR11'; each R11 independently represents H, C1-C12alkyl, C2-C8alkenyl; X4 represents , R6 represents H, halogen, cyclopropyl or -(CR19R20)n-SR16; R6 represents H, halogen; p represents 0, 1, 2 or 3; n represents 0, 1 or 2; where each specified alkyl in R11 is independently substituted by one or two groups independently selected from halogen, -(CR19R20)nOR16 and R21; each R16 independently represents H, C1-C12alkyl; R19 and R20 are independently selected from H, C1-C12alkyl; R21 represents cyclopropyl.

EFFECT: invention refers to a pharmaceutical composition for treating hyperproliferative disorder.

10 cl, 25 ex

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