N-phenyl-dioxox-hydropyrimidine used as hepatitis c virus inhibitor (hcv)

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of structural formula I, their pharmaceutically acceptable salts and crystalline forms, which possess the properties of HCV polymerase inhibitor. In formula I is specified in a group consisting of a single carbon-carbon bond and a double carbon-carbon bond; R1 represents hydrogen; R2 is specified in a group consisting of hydrogen and halo; R3 represents hydrogen; R4 is specified in a group consisting of halo, C1-C6alkyl, C1-C6alkylsulphonyl and 5-6-merous heteroaryl containing heteroatom specified in N, O and S, wherein alkyl is optionally substituted by one or more hydroxy; R5 is specified in a group consisting of hygrogen, hydroxy, C1-C6alkyloxy and halo; L is specified in a group consisting of C(RA)=C(RB), ethylene and cyclopropyl-1,2-ene; RA and RB are independently specified in a group consisting of hydrogen, C1-C6alkyl, C1-C6alkyloxy and halo; R6 represents C6aryl optionally substituted by one or more substitutes independently specified in a group consisting of RE, RF, RG, RH, RI and RJ; the substitutes RE, RF, RG, RH, RI and RJ are presented in the patent claim.

EFFECT: invention refers to the pharmaceutical composition containing the above compounds, to using the compounds for inhibiting HCV RNA-polymerase and treating hepatitis C and to a method of preparing the above compounds.

40 cl, 23 dwg, 7 tbl, 40 ex

 

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[0001] this patent application claims the priority of provisional patent application U.S. No. 60/972,887 (filed September 17, 2007), and provisional patent application U.S. No. 61/096,794 (filed September 13, 2008). The full text of these applications are incorporated by reference in this application.

The SCOPE TO WHICH the INVENTION RELATES.

[0002] the Present invention relates to: (a) to compounds and their salts, which, among other things, are used as inhibitors of hepatitis C virus (HCV); (b) to intermediate compounds used for obtaining such compounds and salts; (C) compositions containing such compounds and salts; (d) methods of producing such intermediates, compounds, salts, and compositions; (e) the ways in which such compounds, salts, and compositions; and (f) the sets containing such compounds, salts and compositions.

PREREQUISITES TO the CREATION of INVENTIONS

[0003] Hepatitis C is a portable blood infectious viral disease caused by hepatotropic virus called HCV. To date, we know of at least six different genotypes of HCV (with several subtypes within each genotype). In North America the predominant HCV genotype 1A, followed by HCV genotypes 1b, 2A, 2b, and 3A. In the United States, HCV genotypes 1, 2 and 3 is vlahuta the most common, approximately 80% of patients with hepatitis C have HCV genotype 1. In Europe, is the predominant HCV genotype 1b, followed by HCV genotypes 2A, 2b, 2c and 3A. HCV genotypes 4 and 5 are found almost exclusively in Africa. As discussed below, the HCV genotype of the patient is clinically important in determining the potential patient's response to treatment and the required duration of such treatment.

[0004] HCV infection can cause liver inflammation (hepatitis), which is often asymptomatic, but chronic hepatitis can lead to cirrhosis of the liver (fibrosis scarring of the liver), liver cancer and/or liver failure. According to the world Health Organization, approximately 170 million people worldwide are chronically infected with HCV, approximately about three to four million people newly infected each year around the world. In accordance with the data of the Centers for disease control and prevention, approximately four million people in the United States are infected with HCV. Widespread joint infection with human immunodeficiency virus (HIV), and indicators of HCV infection among HIV-positive populations are higher.

[0005] There is a small chance of spontaneous liberation from the virus, but the majority of patients with chronic hepatitis C and not bavetta from it without treatment. Indications for treatment usually include confirmed HCV infection and constantly do not correspond to the norm of the functional liver samples. There are two regimens, which are primarily used in the treatment of hepatitis C: monotherapy (using interferon funds-either "normal" or paglinawan interferon durable), and combination therapy using interferon tools and ribavirin). Interferon, which is injected into the bloodstream, works by stimulating the immune response to HCV; and it is believed that ribavirin, which is used orally, works by preventing the replication of HCV. Taken separately, ribavirin is not effectively suppresses the levels of HCV, and the combination interferon/ribavirin is more effective than interferon. Usually, hepatitis C treated with combination paglinawan interferon Alfa and ribavirin for 24 or 48 weeks, depending on HCV genotype.

[0006] the Goal of treatment is sustained virologic response - meaning that HCV not detected in the blood after treatment. After treatment with combination paglinawan interferon alpha and ribavirin, sustained cure rates (sustained virologic response) approximately 75% or better, meet people with HCV genotypes 2 and 3 through 24 weeks of treatment, note the RNO 50% in people with HCV genotype 1 in the treatment of 48 weeks, and about 65% of people with HCV genotype 4 through 48 weeks of treatment.

[0007] the Treatment can be tough, especially for those who have a history of drug or alcohol abuse, and because interferon and ribavirin have numerous side effects. Common side effects associated with interferon include flu-like symptoms, extreme fatigue, nausea, loss of appetite, problems with the thyroid gland, high blood sugar, hair loss and skin reactions at the injection site. Possible serious side effects associated with interferon include psychosis (e.g., suicidal behavior), heart problems (eg, heart attack, low blood pressure, damage to other internal organs, problems with blood (for example, a dangerous decrease in blood counts), and the emergence or worsening of autoimmune disease (e.g. rheumatoid arthritis). Side effects associated with ribavirin include anemia, fatigue, irritability, skin rashes, nasal congestion, sinusitis and cough. Ribavirin can also cause pathology childbirth, so avoid pregnancy female patients and female partners of men during treatment and for six months after.

[0008] Some patients do not complete treatment in the later serious side effects, discussed above; other patients (patients with no clinical response) despite treatment, continue to have detectable levels of HCV; and in other patients (patients with recurrent disease) during treatment virus "appears", but the virus is sometimes returned after completion of the treatment regimen. Thus, there remains a need for alternative compounds, compositions and methods of treatment (used either in combination or in place of the interferon funds and/or ribavirin) to relieve symptoms of hepatitis C, thereby providing a partial or complete relief of symptoms. The present invention relates to compounds (including their salts), the compositions and methods of treatment, which are mainly directed to this need.

SUMMARY of the INVENTION

[0009] the Present invention relates to compounds whose structure corresponds to the formula I:

.

[0010] In the formula I:

selected from the group consisting of single carbon-carbon links and double carbon-carbon linkages;

R1selected from the group consisting of hydrogen, methyl and nitrogen-protecting group;

R2selected from the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl and cyclobutyl;

R3selected from the group sotoyama is hydrogen, halo, oxo, and methyl;

R4selected from the group consisting of halo, alkyl, alkenyl, quinil, nitro, cyano, azido, alkyloxy, alkenylacyl, alkyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocycle, and heterocycle where:

(a) amino, aminocarbonyl and aminosulfonyl optionally substituted:

(1) one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil and alkylsulfonyl, or

(2) two substituents that, together with aminoazoles form adnakolava heterocyclyl, and

(b) alkyl, alkenyl, quinil, alkyloxy, alkenylacyl, alkyloxy and alkylsulfonyl, optionally substituted by one or more substituents independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocycle and heterocycle where:

amino optionally substituted:

(1) one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, alkylcarboxylic, alkylsulfonyl,allyloxycarbonyl, carbocycle, heterocyclyl, carbocyclic and geterotsiklicheskikh, or

(2) two substituents that, together with aminoazoles form adnakolava a heterocycle, and

(C) carbocyclic and heterocyclyl optionally substituted substituents, up to three, independently researched the MoE selected from the group consisting of alkyl, alkenyl, quinil, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocycle and heterocycle where:

amino optionally substituted:

(1) one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, alkylcarboxylic, alkylsulfonyl, allyloxycarbonyl, carbocycle, heterocyclyl, carbocyclic and geterotsiklicheskikh, or

(2) two substituents that, together with aminoazoles form adnakolava a heterocycle;

R5selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, quinil, alkyloxy, alkenylacyl, alkyloxy, alkylsulfonate, carbocyclization, haloalkaliphilic, and halo;

L is selected from the group consisting of C(RA)=C(RB), ethylene and cyclopropyl-1,2-ene;

RAand RBindependently selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C6-alkyloxy,3-C8-cycloalkyl and halo, where:

C1-C6-alkyl optionally substituted by one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, oxo, amino, cyano, allyloxycarbonyl, alkylcarboxylic, alkyloxy, carbocycle and heterocycle;

R6selected from the group consisting of C5-C6here is Boticelli, 5-6-membered heterocyclyl fused 2-ring carbocycle, and condensed 2-ring heterocyclyl, where each such Deputy optionally substituted by one or more substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK;

each REindependently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido, aldehydo where:

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil;

each RFindependently selected from the group consisting of alkyl, alkenyl and quinil where:

each such Deputy optionally substituted by one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo; amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, allyloxycarbonyl, alkenylboronic, alkyloxyaryl, alkylcarboxylic, alkenylboronic, alkylcarboxylic, alkyloxy, alkenylacyl, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl where:

amino, imino, aminosulfonyl, aminocarbonyl, carbocyclic and heterocyclyl optionally substituted by one or more substituents independently selected from the group status is the present from alkyl, alkenyl, quinil, alkylsulfonyl, alkanesulfonyl, alkylsulfonyl, alkylsulfonyl, hydroxy, alkyloxy,

where:

amino part of alkylsulfonyl optionally substituted Deputy selected from the group consisting of alkyl, alkenyl and quinil;

each RGindependently selected from the group consisting of carbocyclic and heterocyclyl where:

each such Deputy optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, quinil, carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, allyloxycarbonyl, alkenylboronic, alkyloxyaryl, alkylcarboxylic, alkenylboronic, alkylcarboxylic, alkyloxy, alkenylacyl, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl where:

amino, aminosulfonyl and aminocarbonyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, quinil, alkylsulfonyl, alkanesulfonyl and alkylsulfonyl;

each RHindependently selected from the group consisting of alkyloxy, alkenylacyl, alkyloxy, alkylsulfonate, alkanesulfonyl, alkylsulfonate where:

each such Deputy optionally substituted by one or more substituents, an independent is selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, allyloxycarbonyl, alkenylboronic, alkyloxyaryl, alkylcarboxylic, alkenylboronic, alkylcarboxylic, alkyloxy, alkenylacyl, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl where:

amino, aminosulfonyl and aminocarbonyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, quinil, alkylsulfonyl, alkanesulfonyl and alkylsulfonyl;

each RIindependently selected from the group consisting of alkylcarboxylic, alkenylamine, alkynylaryl, aminocarbonyl, allyloxycarbonyl, carbocisteine and geterotsiklicheskikh where:

(a) alkylsulphonyl, alkenylboronic and alkenylboronic optionally substituted by one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, allyloxycarbonyl, alkenylboronic, alkyloxyaryl, alkylcarboxylic, alkenylboronic, alkylcarboxylic, alkyloxy, alkenylacyl, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl, and

(b) aminocarbonyl optionally substituted by one or two substituents, independently selected from the group consisting of and the of alkyl, alkenyl, quinil, alkyloxyalkyl, carbocycle, heterocyclyl, alkylsulfonyl, alkylsulfonyl where:

carbocyclic and heterocyclyl optionally substituted by one or more substituents independently selected from the group consisting of halo, alkyl and oxo;

each RJindependently selected from the group consisting of carbocyclization, heterocyclization, alkylcarboxylic, alkenylamine, alkylcarboxylic, allyloxycarbonyl, alkenylcarbazoles, alkyloxycarboxylic, alkylenediamine, alkanesulfonyl, alkylsulfonyl, aminocarbonyl, allyloxycarbonyl, alkylsulfonamides, alkanesulfonyl, alkylsulfonamides where:

(a) the amino portion of such substituents optionally is substituted by the Deputy, is independently selected from the group consisting of carbocyclic, geterotsiklicheskikh, alkylcarboxylic, aminocarbonylmethyl, alkyl, alkenyl, quinil, alkylcarboxylic, alkenylamine, alkynylaryl, allyloxycarbonyl, allyloxycarbonyl, alkylcarboxylic and alkylsulfonyl where:

(1) carbonilla part of carbocyclic and heterocyclyl part of geterotsiklicheskikh optionally substituted by one or more substituents, independently selected from groups who, consisting of alkyl, alkenyl, quinil, carboxy, hydroxy, alkyloxy, alkenylacyl, alkyloxy, halo, nitro, cyano, azido, oxo and amino, and

(2) the amino portion of aminocarbonylmethyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil,

(b) alkyl, Alchemilla and Alchemilla portion of such substituents optionally is substituted by one or more substituents independently selected from the group consisting of carboxy, halo, oxo, amino, allyloxycarbonyl, alkylcarboxylic, hydroxy, alkyloxy, carbocycle, heterocyclyl and cyano, where:

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, alkyloxy, alkenylacyl, alkyloxy where:

alkyl optionally substituted by one or more hydroxy;

(c) carballeira and heterocyclyl portions of such substituents optionally is substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, quinil, carboxy, hydroxy, alkyloxy, alkenylacyl, alkyloxy, halo, nitro, cyano, azido and amino, where:

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil; and

each RKindependent is selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkanesulfonyl and alkylsulfonyl where:

(a) alkylsulfonyl, alkanesulfonyl and alkylsulfonyl optionally substituted by one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, allyloxycarbonyl, alkenylboronic, alkyloxyaryl, alkylcarboxylic, alkenylboronic, alkylcarboxylic, alkyloxy, alkenylacyl, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl where:

amino, aminosulfonyl and aminocarbonyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl and quinil; and

(b) aminosulfonyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil.

[0011] the Present invention also relates to the salts (including pharmaceutically acceptable salts) of compounds of the present invention.

[0012] the Present invention also relates to compositions (including pharmaceutical compositions) which contain one or more compounds and/or salts of the present invention, and, optionally, one or more additional therapeutic agents.

[0013] the Present invention t is the train refers to sets, which contain one or more compounds and/or salts of the present invention, and, optionally, one or more additional therapeutic agents.

[0014] the Present invention also relates to methods of using compounds, salts, compositions and/or kits of the present invention, for example, for the inhibition of the replication of the RNA of the virus (including HCV), treatment of diseases treatable by inhibition of polymerase ribonucleic acid (RNA) HCV (including hepatitis C).

[0015] the Present invention also relates to the use of one or more compounds and/or salts of the present invention to obtain drugs. The medicinal product may not contain one or more additional therapeutic agents. In some embodiments, implementation, this drug is applicable for the treatment of hepatitis C.

[0016] Additional advantages of Applicants invention will be apparent to the person skilled in the art from the text of this patent application.

BRIEF DESCRIPTION of DRAWINGS

[0017] Figure 1 shows an illustrative x-ray powder diffraction for deviations disodium salt of compound IB-L1-1.1.

[0018] Figure 2 shows an illustrative x-ray powder diffraction for chetyrehbalnoy disodium is Oli compound IB-L1-1.1.

[0019] Figure 3 shows an illustrative TGA profile chetyrehbalnoy disodium salt of compound IB-L1-1.1.

[0020] Figure 4 shows an illustrative x-ray powder diffraction for chetyrehbalnoy Pikalevo salt of compound IB-L1-1.1.

[0021] Figure 5 shows an illustrative x-ray powder diffraction for the three-hydrate montalieu salt of compound IB-L1-1.1.

[0022] Figure 6 shows an illustrative x-ray powder diffraction for the dihydrate montalieu salt of compound IB-L1-1.1.

[0023] Figure 7 shows an illustrative TGA profile of the dihydrate montalieu salt of compound IB-L1-1.1.

[0024] Figure 8 shows an illustrative x-ray powder diffraction for 1/7 potassium salt of compound IB-L1-1.1.

[0025] Figure 9 shows an illustrative x-ray powder diffraction for chetyrehbalnoy monomethylamine salt of compound IB-L1-1.1.

[0026] Figure 10 shows an illustrative TGA profile chetyrehbalnoy monomethylamine salt of compound IB-L1-1.1.

[0027] Figure 11 shows an illustrative x-ray powder diffraction for the sample a polymorphic compound IB-L1-1.1.

[0028] Figure 12 shows an illustrative profile of differential scanning calorimetry of the sample a polymorphic compound IB-L1-1.1.

[0029] Figure 3 shows an illustrative x-ray powder diffraction for the sample In the polymorphic compound IB-L1-1.1.

[0030] Figure 14 shows an illustrative x-ray powder diffraction for the sample With polymorphic compound IB-L1-1.1.

[0031] Figure 15 shows an illustrative x-ray powder diffraction for the sample D polymorphic compound IB-L1-1.1.

[0032] Figure 16 shows an illustrative x-ray powder diffraction for the sample And hydrate of compound IB-L1-1.1.

[0033] Figure 17 shows an illustrative TGA profile of the sample And the hydrate of compound IB-L1-1.1.

[0034] Figure 18 shows an illustrative x-ray powder diffraction for the sample In the hydrate of compound IB-L1-1.1.

[0035] Figure 19 shows an illustrative TGA profile of the sample of the hydrate of compound IB-L1-1.1.

[0036] Figure 20 shows an illustrative x-ray powder diffraction for the sample With hydrate of compound IB-L1-1.1.

[0037] Figure 21 shows an illustrative TGA profile of the sample With hydrate of compound IB-L1-1.1.

[0038] Figure 22 shows an illustrative x-ray powder diffraction for the sample D of the hydrate of compound IB-L1-1.1.

[0039] Figure 23 shows an illustrative x-ray powder diffraction for the sample E hydrate of compound IB-L1-1.1.

DETAILED description of the INVENTION

[0040] the Present detailed description is for reference only specifications the sheets in this field with the invention of the Applicants, its principles and its practical application, so that other experts in this field could adapt and apply the invention in its numerous forms that can best meet the requirements of practical application. This description and the specific examples are intended for illustration only. The present invention, therefore, is not limited to the variants of the implementation described in this application, and can be modified in various ways.

A. Definition.

[0041] the Term "alkyl" (alone or in combination with another term (terms)) means a saturated hydrocarbon Deputy with a straight or branched chain, usually containing from 1 to 20 carbon atoms, more usually from about 1 to 8 carbon atoms, and even more usually from about 1 to 6 carbon atoms. Examples of such substituents include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, ISO-amyl, and hexyl. In this definition, throughout the text of the detailed description of the Applicants presented illustrative examples. The provision of such illustrative examples should not be interpreted so that the presented examples are the only options available to the specialist in this field.

[0042] the Term "alkenyl" (separately Il is in combination with another term (terms)) means the hydrocarbon Deputy with a straight or branched chain, containing one or more double bonds and typically from 2 to about 20 carbon atoms, more usually from about 2 to about 8 carbon atoms, and even more usually from about 2 to about 6 carbon atoms. Examples of such substituents include ethynyl (vinyl), 2-propenyl, 3-propenyl, 1,4-pentadienyl, 1,4-butadienyl, 1-butenyl, 2-butenyl and 3-butenyl.

[0043] the Term "quinil" (alone or in combination with another term (terms)) means the hydrocarbon Deputy with a straight or branched chain, containing one or more triple ties and typically from 2 to about 20 carbon atoms, more usually from about 2 to about 8 carbon atoms, and even more usually from about 2 to about 6 carbon atoms. Examples of such substituents include ethinyl, 2-PROPYNYL, 3-PROPYNYL, 2-butynyl and 3-butynyl.

[0044] the Term "carbocyclic" (alone or in combination with another term (terms)) means a saturated cyclic (i.e., "cycloalkyl"), partially saturated cyclic (i.e., "cycloalkenyl"), or fully unsaturated (i.e., "aryl") hydrocarbon Deputy containing from 3 to 14 ring carbon atoms ("ring atoms" are the atoms linked together to form a ring or rings of cyclic substituent). Carbocyclic can be a single ring, which is usually sod is RIT from 3 to 6 ring atoms. Examples of such odnoyaytsevyh carbocyclic include cyclopropyl (cyclopropyl), cyclobutyl (cyclobutyl), cyclopentyl (cyclopentenyl), cyclopentenyl, cyclopentadienyl, cyclohexyl (cyclohexanol), cyclohexenyl, cyclohexadienyl and phenyl. Alternative carbocyclic can be a 2 or 3 rings fused together, such as naphthalenyl, tetrahydronaphthalene (tetralinyl), indenyl, indanyl (dihydroindeno), anthracene, phenanthrene and declines.

[0045] the Term "cycloalkyl" (alone or in combination with another term (terms)) means a saturated cyclic hydrocarbon Deputy containing from 3 to 14 ring carbon atoms. Cycloalkyl may be a single carbon ring, which usually contains from 3 to 6 ring carbon atoms. Examples odnoyaytsevyh of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Alternative cycloalkyl can represent 2 or 3 carbon rings fused together, for example, declines.

[0046] the Term "aryl" alone or in combination with another term (terms)) means an aromatic carbocyclic containing from 6 to 14 ring carbon atoms. Examples of arrow include phenyl, naphthalenyl and indenyl.

[0047] In some cases, the number of carbon atoms in the hydrocarbon substituent (e.g. alkyl, alkenyl, quinil or cycloalkyl) is specified with the index "Cx-Cy- "where x is the minimum and mean maximum number of carbon atoms in the substituent. Thus, for example, "C1-C6-alkyl" refers to alkyl Deputy containing from 1 to 6 carbon atoms. Explaining more, With3-C6-cycloalkyl means a saturated hydrocarbon ring containing from 3 to 6 ring carbon atoms.

[0048] the Term "hydrogen" (alone or in combination with another term (terms)) means a hydrogen radical and may be referred to.

[0049] the Term "hydroxy" (alone or in combination with another term (terms)) means IT.

[0050] the Term "nitro" (alone or in combination with another term (terms)) means-NO2.

[0051] the Term "cyano" (alone or in combination with another term (terms)) means-CN, which may also be referred to as-C≡N.

[0052] the Term "keto" (alone or in combination with another term (terms)) means oxo radical and may be denoted as a =O.

[0053] the Term "carboxy" (alone or in combination with another term (terms)) means-C(O)-HE.

[0054] the Term "amino" (alone or in combination with another term (terms)) means-NH2.

[0055] the Term "imino" (alone or in combination with another term (that is mine)) mean =NH.

[0056] the Term "amidoamine" (alone or in combination with another term (terms)) mean =NNH2.

[0057] the Term "halogen" or "halo" (alone or in combination with another term (terms)) means a fluorine radical (which may be denoted as F), chlorine radical (which may be denoted as Cl), bromine radical (which may be designated as-Br), or a radical of iodine (which may be denoted as I).

[0058] the Deputy is "replaced" if it contains at least one carbon atom or nitrogen, which is associated with one or more hydrogen atoms. Thus, for example, hydrogen, halogen and cyano do not fall under this definition. In addition, the sulfur atom heterocyclyl containing such an atom is substituted by one or two oxo substituents.

[0059] In those cases, if the Deputy is described as "substituted", is not a hydrogen radical is in the place of a hydrogen radical on the carbon or the nitrogen substituent. Thus, for example, a substituted alkyl substituent is an alkyl substituent, in which at least one hydrogen radical is in the place of the hydrogen of the alkyl radical at the Deputy. For clarification, monitorall represents an alkyl substituent with fluorine radicals, and diferuloyl represents alkyl, substituted two radika the AMI fluorine. It should be clear that in the case when there is more than one replacement for the Deputy, this is not a hydrogen radical may be identical or different (unless specified otherwise).

[0060] if the Deputy is described as "optionally substituted", the Deputy may be, either (1) unsubstituted, or (2) substituted. If the Deputy is described as optionally substituted, up to a specific number of hydrogen radicals, the Deputy may be, either (1) unsubstituted; or (2) substituted by up to a specific number of hydrogen radicals, or until the maximum number of substitutable positions on the Deputy, whichever is less. Thus, for example, if the Deputy is described as heteroaryl, optionally substituted up to 3 is not hydrogen radicals, any heteroaryl less than 3 substituted provisions would be optional substituted only up to the number of non-hydrogen radicals, how many heteroaryl has substituted provisions. For clarification, tetrazolyl (which has only one substitutable position may be optionally substituted up to not one hydrogen radical. For further clarification, if aminoazo described as optionally substituted up to 2 is not hydrogen radicals, the primary aminoazo is optionally substituted up to not vodicnik radicals, then as a secondary aminoazo will be optional substituted only up to 1 is not a hydrogen radical.

[0061] In the present patent application uses the terms "office" and "radical" are used interchangeably.

[0062] the Prefix "halo" indicates that substituent attached to this console, substituted by one or more independently selected halogen radicals. For example, haloalkyl means alkyl substituent, in which at least one hydrogen radical is replaced with a halogen radical. Examples of haloalkyl include chloromethyl, 1-bromacil, vermeil, deformity, trifluoromethyl and 1,1,1-triptorelin. It should be clear that if the Deputy substituted by more than one halogen radical, these halogen radicals may be the same or different (unless specified otherwise).

[0063] Console pergola" indicates that each of the hydrogen radical on the Deputy, to which this attachment is attached, replaced with independently selected halogen radicals, i.e., each hydrogen radical on the Deputy replaced by a halogen radical. If all halogen radicals are the same, this console will usually denote a halogen radical. Thus, for example, the term "PERFLUORO" means that each hydrogen radical on the Deputy, is attached to this console substituted by fluorine radical. For clarification, the term "perfluoroalkyl" means an alkyl substituent, in which the fluorine radical is in the place of each a hydrogen radical.

[0064] the Term "carbonyl" (alone or in combination with another term (terms)) means-C(O)-.

[0065] the Term "aminocarbonyl" (alone or in combination with another term (terms)) means-C(O)-NH2.

[0066] the Term "hydroxy" (alone or in combination with another term (terms)) means the ether substituent and may be marked with-O-.

[0067] the Term "alkoxy" alone or in combination with another term (terms)) means alkylating Deputy, i.e.,- O-alkyl. Examples of such a substituent include methoxy (-O-CH3), ethoxy, n-propoxy, isopropoxy, p-butoxy, out-butoxy, sec-butoxy and tert-butoxy.

[0068] the Term "alkylaryl" (alone or in combination with another term (terms)) means-C(O)-alkyl.

[0069] the Term "aminoalkylsilanes" (alone or in combination with another term (terms)) means-C(O)-alkyl-NH2.

[0070] the Term "alkoxycarbonyl" (alone or in combination with another term (terms)) means-C(O)-O-alkyl.

[0071] the Term "carbonyliron" (alone or in combination with another term (terms)) means-C(O)-carbocyclic.

[0072] Similarly, the term "heterocalixarenes" (alone or in combination with other terminology is ω (terms)) means-C(O)-heterocyclyl.

[0073] the Term "carbocyclization" (alone or in combination with another term (terms)) means-C(O)-alkyl-carbocyclic.

[0074] Similarly, the term "geterotsiklicheskikh" (alone or in combination with another term (terms)) means-C(O)-alkyl-heterocyclyl.

[0075] the Term "carbocyclization" (alone or in combination with another term (terms)) means-C(O)-O-carbocycle.

[0076] the Term "caroticocavernous" (alone or in combination with another term (terms)) means-C(O)-O-alkyl-carbocyclic.

[0077] the Term "thio" or "TIA" (alone or in combination with another term (terms)) means teefury Deputy, i.e., the essential Vice, where the divalent sulfur atom is in place of the ether oxygen atom. Such Deputy may be designated as-S-. This is, for example, "alkyl-thio-alkyl" means alkyl-8-alkyl (alkyl-effect-free remedy alkyl).

[0078] the Term "thiol" or "sulfhydryl" (alone or in combination with another term (terms)) means sulfhydryl Deputy, and may be denoted as SH.

[0079] the Term "(thiocarbonyl)" (alone or in combination with another term (terms)) denotes a carbonyl, in which the oxygen atom has been replaced by sulfur. Such Deputy may be denoted as C(S).

[0080] the Term "sulfonyl" (alone or in combination with other t what rbinom (terms)) means-S(O) 2.

[0081] the Term "aminosulfonyl" (alone or in combination with another term (terms)) means-S(O)2-NH2.

[0082] the Term "sulfinil" or "sulfoxide" (alone or in combination with another term (terms)) means-S(O)-.

[0083] the Term "heterocyclyl" (alone or in combination with another term (terms)) means a saturated (i.e., "geterotsyklicescoe"), partially saturated (i.e., "geterotsyklicescoe"), or fully unsaturated (i.e., "heteroaryl") ring structure of 3 to 14 ring atoms. At least one of the ring atoms is a heteroatom (i.e., oxygen, nitrogen or sulfur), the remaining ring atoms independently selected from the group consisting of carbon, oxygen, nitrogen and sulphur.

[0084] Heterocyclyl can be a single ring, which usually contains from 3 to 7 atoms in the ring, more usually from 3 to 6 atoms in the ring and even more usually from 5 to 6 atoms in the ring. Examples odnoyaytsevyh heterocyclyl include furanyl, dihydrofurane, tetrahydrofuranyl, thiophenyl (thiopurines), dihydrothiophene, tetrahydrothiophene, pyrrolyl, pyrrolidyl, pyrrolidinyl, imidazolyl, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolyl, pyrazolidine, triazole, tetrazole, oxazole, oxazolidine, isoxazolidine, isoxazolyl, thiazolyl, isothiazolin, TIA is oliner, isothiazolines, diazolidinyl, isothiazolinones, thiadiazolyl, oxadiazolyl (including 2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl (furutani), or 1,3,4-oxadiazolyl), oxadiazolyl (including 1,2,3,4-oxadiazolyl or 1,2,3,5-oxadiazolyl), doxazosin (including 1,2,3-doxazosin, 1,2,4-doxazosin, 1,3,2-doxazosin or 1,3,4-doxazosin), oxadiazolyl, oxacillin, oxathiolane, pyranyl, dihydropyran, tiopronin, tetrahydropyranyl, pyridinyl (azinyl), piperidinyl, diazines (including pyridazinyl (1,2-diazines), pyrimidine (1,3-diazines) or pyrazinyl (1,4-diazines)), piperazinil/Gresini (including 1,3,5-triazinyl, 1,2,4-triazinyl and 1,2,3-triazinyl)), oxazinyl (including 1,2-oxazinyl, 1,3-oxazinyl or 1,4-oxazinyl)), oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxathiazine or 1,2,6-oxathiazine)), oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazine, 1,4,2-oxadiazine or 1,3,5-oxadiazine)), morpholinyl, azepine, oxepin, tiepins and diazepines.

[0085] Heterocyclyl alternative can be a 2 or 3 rings fused together, such as indolizinyl, pirenopolis, 4H-hemolysins, purinol, naphthyridine, pyridopyrimidines (including [3,4-b]-pyridinyl, pyrido[3,2-b]-pyridinyl, or pyrido[4,3-b]-pyridinyl), and pteridinyl. Other examples heterocyclyl with kondensierten the mi rings, include benzo-condensed heterocyclyl, such as indolyl, isoindolyl (isopentanol, pseudoisotopy), indolinyl (pseudointimal), isoindolyl (respiratory), benzathine (including chinoline (1-benzazolyl) or ethenolysis (2-benzazolyl)), phthalazine, honokalani, hintline, benzodiazines (including cinnolines (1,2-benzodiazines) or hintline (1,3-benzodiazepin)), benzopyranyl (including chromanol or isopropanol), benzoxazine (including 1,3,2-benzoxazines, 1,4,2-benzoxazine, 2,3,1-benzoxazine or 3,1,4-benzoxazine), and benzisoxazole (including 1,2-benzisoxazol or 1,4-benzisoxazol).

[0086] the Term heterocyclyl 2-condensed rings" (alone or in combination with another term (terms)) means a saturated, partially saturated or arithmetiles containing 2 condensed ring. Examples heterocyclyl with 2 of the condensed rings include indolizinyl, hemolysins, purinol, naphthyridine, pteridine, indolyl, isoindolyl, indolizinyl, isoindolyl, phthalazine, honokalani, hintline, benzodiazines, benzopyranyl, benzothiophene, benzoxazole, Anthranilic, benzodioxolyl, Anthranilic, benzodioxolyl, benzodioxane, benzoxadiazole, benzofuranyl, isobenzofuranyl, benzothiazolyl, benzotriazolyl, benzimidazolyl, benzotriazolyl, benzotriazol the sludge, benzoxazines and tetrahydroisoquinolines.

[0087] the Term "heteroaryl" (alone or in combination with another term (terms)) means an aromatic heterocyclyl containing from 5 to 14 atoms in the ring. Heteroaryl can be a single ring or 2 or 3 condensed rings. Examples of heteroaryl substituents include 6-membered ring substituents such as pyridyl, Persil, pyrimidinyl, pyridazinyl and 1,3,5-, 1,2,4 - or 1,2,3-triazinyl; 5-membered ring substituents such as imidazol, furanyl, thiophenyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, 1,2,3-, 1,2,4-, 1,2,5 - or 1,3,4-oxadiazolyl and isothiazole; alternates with 6/5-membered condensed rings, such as benzothiophenes, benzisoxazole, benzoxazole, purines and Anthranilic; and 6/6-membered condensed rings, such as benzopyranyl, chinoline, ethenolysis, cinnoline, hintline and benzoxazines.

[0088] the set-top box attached to a multicomponent Deputy applies only to the first component. For clarification, the term "alkylsilanes" contains two components: alkyl and cycloalkyl. Thus, the prefix C1-C6- C1-C6-alkylcyclohexane means that the alkyl component of alkylcyclohexane contains from 1 to 6 carbon atoms; console C1-C6-does not describe cycloalkenyl to the ponent. For further clarification, the prefix "halo" haloalkoxy indicates that only the alkoxy component alkoxyalkyl Deputy substituted by one or more halogen radicals. If the halogen substitution may alternatively or additionally occur on the alkyl component, the Deputy would be described as "halogen-substituted alkoxyalkyl" and not "haloalkoxy". And finally, if the halogen substitution may only occur on the alkyl component, the Deputy would instead be described as "alkoxyalkyl".

[0089] If the substituents described as "independently selected" from the group, each Deputy is chosen independently of the other. Each Deputy, therefore, may be identical to or different from another Deputy (deputies).

[0090] In cases where for a description of the Deputy of the use of the word, the rightmost component described substituent represents a component that has a free valence.

[0091] In cases where for a description of the Deputy used the chemical formula, the dash on the left side of the formula indicates the part of the Deputy, which has a free valence.

[0092] In cases when a chemical formula is used to describe a boundary between two other elements depicted chemical structure is, the leftmost dash Deputy indicates the part of the Deputy, which is associated with the left element in the depicted structure. Dash on the far right, on the other hand, indicates the part of the Deputy, which is associated with the right element in the depicted structure. For clarification, if depicted chemical structure is a X-L-Y, a L is described as-C(O)-N(H)-, then the chemical would be a X-C(O)-N(H)-y

[0093] With reference to the use of the words "include" or "includes" or "contains" in the present patent application (including the claims). Applicants note that unless the context requires otherwise, those words are used on the basis and clear understanding that they should be interpreted inclusively rather than exclusively, and Applicants have in mind that each of these words is interpreted thus in the interpretation of the present patent application, including the following claims.

[0094] the Software ChemDraw was used to compile the names of the compounds in the present patent application.

[0095] the Term "non-crystalline" as applied to the connection, refers to a solid state in which the molecules of the compounds presented in an unordered structure and do not form a distinguishable crystal lattice or unit cell. Inthenews the th diffraction, non-crystalline compound does not have any characteristic crystalline peaks.

[0096] the Term "crystalline form" as applied to the connection, refers to a solid state in which molecules connections are with the formation of distinguishable crystal lattice (i) containing distinct unit cell, and (and) give the peaks on the x-ray, when exposed to x-ray radiation.

[0097] the Term "purity", except as specifically provided otherwise, means a chemical purity of the compounds in accordance with conventional HPLC analysis.

[0098] the Term "phase purity" means the purity of a solid state connection with respect to a particular crystalline or non-crystalline forms of the compounds defined using analytical methods x-ray powder diffraction.

[0099] the Term "vasovasostomy" refers to the purity relative to other forms compounds in the solid state, and does not necessarily imply a high degree of chemical purity with respect to other compounds.

[00100] the Term "PXRD" means x-ray powder diffraction.

[00101] the Term "TGA" means thermogravimetric analysis.

[00102] the Term "DSC" means differential scanning calorimetry.

C. Connection.

[00103] the Present invention is due in part to link the m which are derivatives of phenyl-uracil, the structure of which corresponds to the formula I:

.

[00104] In these compounds, theselected from the group consisting of single carbon-carbon links and double carbon-carbon connection.

[00105] In some embodiments, the implementationrepresents a single carbon-carbon bond. In these variants of implementation, the structure of the compounds of formula I correspond to the following formula (i.e., formula IA):

.

[00106] In other embodiments, the implementationis a double carbon-carbon bond. In these variants of implementation, the structure of the compounds of formula I correspond to the following formula (i.e., formula IB):

.

B1. Deputy R1.

[00107] R1selected from the group consisting of hydrogen, methyl and nitrogen-protecting group.

[00108] In some embodiments, implementation, R1represents hydrogen.

[00109] In some embodiments, implementation, R1represents methyl.

[00110] In some embodiments, implementation, R1selected from the group consisting of hydrogen and methyl.

[00111] In some embodiments, implementation, R1represents a nitrogen-protecting the th group. In these embodiments, implementation, these compounds are used as intermediates for producing compounds of formula I. the Nitrogen-protecting group suitable for producing compounds of formula I, known to specialists in this field.

B2. Deputy R2.

[00112] R2selected from the group consisting of hydrogen, halo, hydroxy, methyl, cyclopropyl and cyclobutyl.

[00113] In some embodiments, implementation, R2represents hydrogen.

[00114] In some embodiments, implementation, R2represents halo. In some such embodiments, implementation, R2selected from the group consisting of fluorine and chlorine. In other such embodiments, implementation, R2represents fluorine. In other such embodiments, implementation, R2represents chlorine. In other such embodiments, implementation, R2represents bromine. In additional such embodiments, implementation, R2represents iodine.

[00115] In some embodiments, implementation, R2represents hydroxy.

[00116] In some embodiments, implementation, R2represents methyl.

[00117] In some embodiments, implementation, R2is cyclopropyl.

[00118] In some embodiments, implementation, R2is cyclobutyl.

[00119] In some vari is ntah implementation R2selected from the group consisting of hydrogen, methyl, hydroxy and halo. In some such embodiments, implementation, R2selected from the group consisting of hydrogen, methyl, hydroxy, fluorine and chlorine. In other such embodiments, implementation, R2selected from the group consisting of hydrogen, methyl, hydroxy and fluorine. In other such embodiments, implementation, R2selected from the group consisting of hydrogen, methyl, hydroxy, and chlorine. In other such embodiments, implementation, R2selected from the group consisting of hydrogen, methyl, hydroxy and bromine. In additional such embodiments, implementation, R2selected from the group consisting of hydrogen, methyl, hydroxy and iodine.

[00120] In some embodiments, implementation, R2selected from the group consisting of hydrogen, methyl and halo. In some such embodiments, implementation, R2selected from the group consisting of hydrogen, methyl, fluorine and chlorine. In other such embodiments, implementation, R2selected from the group consisting of hydrogen, methyl and fluorine. In other such embodiments, implementation, R2selected from the group consisting of hydrogen, methyl and chlorine. In other such embodiments, implementation, R2selected from the group consisting of hydrogen bromide and bromine. In additional such embodiments, implementation, R2selected from the group consisting of hydrogen, methyl and the ode.

[00121] In some embodiments, implementation, R2selected from the group consisting of hydrogen and halogen. In some such embodiments, implementation, R2selected from the group consisting of hydrogen, fluorine and chlorine. In other such embodiments, implementation, R2selected from the group consisting of hydrogen and fluorine. In other such embodiments, implementation, R2selected from the group consisting of hydrogen and chlorine. In other such embodiments, implementation, R2selected from the group consisting of hydrogen and bromine. In additional such embodiments, implementation, R2selected from the group consisting of hydrogen iodine.

B3. Deputy R3.

[00122] R3selected from the group consisting of hydrogen, halo, oxo, and methyl. In some such embodiments, implementation, R3selected from the group consisting of hydrogen, fluorine, oxo, and methyl. In other such embodiments, implementation, R3selected from the group consisting of hydrogen, chlorine, oxo, and methyl. In other such embodiments, implementation, R3selected from the group consisting of hydrogen, bromine, oxo, and methyl. In other such embodiments, implementation, R3selected from the group consisting of hydrogen, iodine, oxo, and methyl.

[00123] In some embodiments, implementation, R3selected from the group consisting of hydrogen, halo, and oxo. In some such embodiments, implementation,R 3selected from the group consisting of hydrogen, fluorine and oxo. In other such embodiments, implementation, R3selected from the group consisting of hydrogen, chlorine and oxo. In other such embodiments, implementation, R3selected from the group consisting of hydrogen, bromine and oxo. In other such embodiments, implementation, R3selected from the group consisting of hydrogen, iodine, and oxo.

[00124] In some embodiments, implementation, R3selected from the group consisting of hydrogen and methyl.

[00125] In some embodiments, implementation, R3represents hydrogen.

[00126] In some embodiments, implementation, R3represents methyl.

[00127] In some embodiments, implementation, R3represents oxo.

[00128] In some embodiments, implementation, R3represents halo. In some such embodiments, implementation, R3represents fluorine. In other such embodiments, implementation, R3represents chlorine. In other such embodiments, implementation, R3represents bromine. In additional such embodiments, implementation, R3represents iodine.

B4. Deputy R4.

[00129] R4selected from the group consisting of halo, alkyl, alkenyl, quinil, nitro, cyano, azido, alkyloxy, alkenylacyl, alkyloxy, amino, aminocarbonyl, aminosulfonyl, and killalpaninna, carbocycle, and heterocycle where:

(a) amino, aminocarbonyl, and aminosulfonyl optionally substituted:

(1) one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, and alkylsulfonyl, or

(2) two substituents that, together with aminoazoles form adnakolava a heterocycle,

(b) alkyl, alkenyl, quinil, alkylate, alkenylacyl, alkyloxy, and alkylsulfonyl, optionally substituted by one or more substituents independently selected from the group consisting of halo, okeo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocycle, and heterocycle where:

amino optionally substituted:

(1) one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, alkylcarboxylic, alkylsulfonyl,allyloxycarbonyl, carbocycle, heterocyclyl,carbocyclic, and geterotsiklicheskikh, or

(2) two substituents that, together with aminoazoles form adnakolava a heterocycle, and

(c) carbocyclic and heterocyclyl optionally substituted by substituents with up to three independently selected from the group consisting of alkyl, alkenyl, quinil, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocycle, and heterocycle where:

amino optionally substituted:

1) one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, alkylcarboxylic, alkylsulfonyl,allyloxycarbonyl, carbocycle, heterocyclyl, carbocyclic and geterotsiklicheskikh, or

(2) two substituents that, together with aminoazoles form adnakolava a heterocycle.

[00130] In some embodiments, implementation, R4selected from the group consisting of halo, alkyl, alkenyl, quinil, nitro, cyano, azido, alkyloxy, alkenylacyl, alkyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocycle and heterocycle where:

amino, aminocarbonyl, and aminosulfonyl optionally substituted:

(1) one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil and alkylsulfonyl, or

(2) two substituents that, together with aminoazoles form adnakolava a heterocycle.

[00131] In some embodiments, implementation, R4selected from the group consisting of halo, alkyl, alkenyl, quinil, nitro, cyano, azido, alkyloxy, alkenylacyl, alkyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocycle and heterocycle where:

alkyl, alkenyl, quinil, alkyloxy, alkenylacyl, alkyloxy and alkylsulfonyl, optionally substituted by one or more substituents independently selected from the group consisting of the halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocycle and heterocycle where:

amino optionally substituted:

(1) one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, alkylcarboxylic, alkylsulfonyl, allyloxycarbonyl, carbocycle, heterocyclyl, carbocyclic and geterotsiklicheskikh, or

(2) two substituents that, together with aminoazoles form adnakolava a heterocycle.

[00132] In some embodiments, implementation, R4selected from the group consisting of halo, alkyl, alkenyl, quinil, nitro, cyano, azido, alkyloxy, alkenylacyl, alkyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocycle and heterocycle where:

carbocyclic and heterocyclyl optionally substituted by substituents with up to three independently selected from the group consisting of alkyl, alkenyl, quinil, halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, trimethylsilyl, carbocycle and heterocycle where:

amino optionally substituted:

(1) one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, alkylcarboxylic, alkylsulfonyl,allyloxycarbonyl, carbocycle, heterocyclyl, carbocyclic and geterotsiklicheskikh, or

(2) two substituents that, together with aminoazoles form adnakolava a heterocycle.

[00133] In some embodiments, implementation, R4selected from the group consisting of halo, alkyl, alkenyl, quinil, nitro, cyano, azido, alkyloxy, alkenylacyl, alkyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocycle and heterocycle where:

(a) amino, aminocarbonyl, and aminosulfonyl optionally substituted:

(1) one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil, or,

(2) two substituents that, together with aminoazoles form adnakolava a heterocycle; and

(b) alkyl, alkenyl, quinil, alkyloxy, alkenylacyl, alkyloxy, alkylsulfonyl, carbocyclic, and heterocyclyl optionally substituted by substituents with up to three independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, carbocycle, and heterocycle, where amino optionally substituted:

(1) one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, alkylcarboxylic, alkylsulfonyl,allyloxycarbonyl, carbocycle, heterocyclyl, carbocyclic, and geterotsiklicheskikh, or,

(2) two substituents that, together with aminoazoles form adnakolava a heterocycle.

[00134] In some embodiments, implementation, R4selected from the group consisting of halo, is Lila, alkenyl, quinil, nitro, cyano, azido, alkyloxy, alkenylacyl, alkyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocycle and heterocycle where:

amino, aminocarbonyl and aminosulfonyl optionally substituted:

(1) one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil, or,

(2) two substituents that, together with aminoazoles form adnakolava a heterocycle.

[00135] In some embodiments, implementation, R4selected from the group consisting of halo, alkyl, alkenyl, quinil, nitro, cyano, azido, alkyloxy, alkenylacyl, alkyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocycle and heterocycle where:

alkyl, alkenyl, quinil, alkylate, alkenylacyl, alkyloxy, alkylsulfonyl, carbocyclic, and heterocyclyl optionally substituted by substituents with up to three independently selected from the group consisting of halo, oxo, nitro, cyano, azido, hydroxy, amino, alkyloxy, carbocycle, and heterocycle, where amino optionally substituted:

(1) one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, alkylcarboxylic, alkylsulfonyl,allyloxycarbonyl, carbocycle, heterocyclyl,carbocyclic, and geterotsiklicheskikh, or,

(2) two to cover the firs, together with aminoazoles form adnakolava a heterocycle.

[00136] In some embodiments, implementation, R4selected from the group consisting of halo, C1-C4-alkyl, C2-C4-alkenyl,2-C4-quinil, amino, C1-C4-alkylsulfonyl,3-C6-carbocycle, and 5-6-membered heterocyclyl where:

(a) amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, and alkylsulfonyl,

(b) (C1-C4-alkyl, C2-C4alkenyl, and C2-C4-quinil optionally substituted by one or more substituents independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and

(c)3-C6-carbocyclic and 5-6-membered heterocyclyl optionally substituted by substituents with up to three independently selected from the group consisting of alkyl, alkenyl, quinil, halo, and amino, where:

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, and alkylsulfonyl.

[00137] In some embodiments, implementation, R4selected from the group consisting of C1-C4-alkyl, C2-C4-alkenyl,2-C4-quinil, amino, C1-C4-Ala is sulfonyl, With3-C6-carbocycle, and 5-6-membered heterocyclyl where:

(a) amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, and alkylsulfonyl,

(b) (C1-C4-alkyl, C2-C4alkenyl, and C2-C4-quinil optionally substituted by one or more substituents independently selected from the group consisting of halo, okeo, hydroxy, alkyloxy, and trimethylsilyl, and

(c)3-C6-carbocyclic and 5-6-membered heterocyclyl optionally substituted by substituents with up to three independently selected from the group consisting of alkyl, alkenyl, quinil, halo, and amino, where:

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, and alkylsulfonyl.

[00138] In some embodiments, implementation, R4selected from the group consisting of halo, C1-C4-alkyl, C3-C6-carbocycle, and 5-6-membered heterocyclyl where:

(a)1-C4-alkyl optionally substituted by substituents with up to three independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and

(b) (C3-C6-carbocyclic and 5-6-membered heterocyclyl optionally substituted by one or more replace the s, independently selected from the group consisting of alkyl, halo, and alkylsulfonyl.

[00139] In some embodiments, implementation, R4selected from the group consisting of halo, C1-C4-alkyl, C3-C6-carbocycle, and 5-6-membered heterocyclyl where:

(a)1-C4-alkyl optionally substituted by one or two substituents, independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and

(b) (C3-C6-carbocyclic and 5-6-membered heterocyclyl optionally substituted Deputy selected from the group consisting of alkyl, halo, and alkylsulfonyl.

[00140] In some embodiments, implementation, R4selected from the group consisting of C1-C4-alkyl, C3-C6-carbocycle, and 5-6-membered heterocyclyl where:

(a)1-C4-alkyl optionally substituted by substituents with up to three independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy, and trimethylsilyl, and

(b) (C3-C6-carbocyclic and 5-6-membered heterocyclyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl, halo, and alkylsulfonyl.

[00141] In some embodiments, implementation, R4selected from the group consisting of halo, tert-butyl,3-C6-carbó is Ollila, and 5-6-membered heterocyclyl where:

With3-C6-carbocyclic and 5-6-membered heterocyclyl optionally substituted Deputy selected from the group consisting of alkyl, halo, alkylsulfonyl.

[00142] In some embodiments, implementation, R4selected from the group consisting of tert-butyl,3-C6-carbocycle, and 5-6-membered heterocyclyl where:

With3-C6-carbocyclic and 5-6-membered heterocyclyl optionally substituted Deputy selected from the group consisting of alkyl, halo, alkylsulfonyl.

[00143] In some embodiments, implementation, R4selected from the group consisting of halo, alkyl, haloalkyl, carboxyethyl, hydroxyalkyl, alkyloxyalkyl, trimethylsilylethynyl, alkylcarboxylic, carbocycle, alkylchlorosilanes, heterocyclyl, halocarbonyl, alkylsulfonyl, and alkylsulfonyl.

[00144] In some embodiments, implementation, R4selected from the group consisting of halo, alkyl, alkenyl, quinil, nitro, cyano, azido, alkyloxy, alkenylacyl, alkyloxy, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocycle, and heterocycle.

[00145] In some embodiments, implementation, R4selected from the group consisting of halo, C1-C4-alkyl, C2-C4-alkenyl,2-C4-quinil, amino, C1-C43-C6-carbocycle, and 5-6-membered heterocyclyl. In some such embodiments, implementation, R4selected from the group consisting of halo, C1-C4-alkyl, C2-C4-alkenyl,2-C4-quinil, amino, C1-C4-alkylsulfonyl,6-carbocycle, and 5-6-membered heterocyclyl. In another such embodiment, R4selected from the group consisting of halo, C1-C4-alkyl, C2-C4-alkenyl,2-C4-quinil, amino, C1-C4-alkylsulfonyl, phenyl and 5-6-membered heteroaryl.

[00146] In some embodiments, implementation, R4selected from the group consisting of C1-C4-alkyl, C2-C4-alkenyl,2-C4-quinil, amino, C1-C4-alkylsulfonyl,3-C6-carbocycle, and 5-6-membered heterocyclyl. In some such embodiments, implementation, R4selected from the group consisting of C1-C4-alkyl, C2-C4-alkenyl,2-C4-quinil, amino, C1-C4-alkylsulfonyl,6-carbocycle, and 5-6-membered heterocyclyl. In another such embodiment, R4selected from the group consisting of C1-C4-alkyl, C2-C4-alkenyl,2-C4-quinil, amino, C1-C4-alkylsulfonyl, FeNi is a, and 5-6-membered heteroaryl.

[00147] In some embodiments, implementation, R4selected from the group consisting of halo, C1-C4-alkyl, C3-C6-carbocycle and 5-6-membered heterocyclyl. In some such embodiments, implementation, R4selected from the group consisting of halo, C1-C4-alkyl, C6-carbocycle and 5-6-membered heterocyclyl. In other such embodiments, implementation, R4selected from the group consisting of halo, C1-C4-alkyl, phenyl and 5-6 - membered heteroaryl.

[00148] In some embodiments, implementation, R4selected from the group consisting of C1-C4-alkyl, C3-C6-carbocycle and 5-6-membered heterocyclyl. In some such embodiments, implementation, R4selected from the group consisting of C1-C4-alkyl, C6-carbocycle and 5-6-membered heterocyclyl. In other such embodiments, implementation, R4selected from the group consisting of C1-C4-alkyl, phenyl and 5-6-membered heteroaryl.

[00149] In some embodiments, implementation, R4selected from the group consisting of halo, tert - butyl,3-C6-carbocycle and 5-6-membered heterocyclyl. In some such embodiments, implementation, R4selected from the group consisting of halo, tert-butyl,6-carbocycle and 5-6-membered heterocyclyl. In other that the variants of implementation, R4selected from the group consisting of halo, tert-butyl, phenyl and 5-6-membered heteroaryl.

[00150] In some embodiments, implementation, R4selected from the group consisting of tert-butyl,3-C6-carbocycle and 5-6-membered heterocyclyl. In some such embodiments, implementation, R4selected from the group consisting of tert-butyl,6-carbocycle and 5-6-membered heterocyclyl. In other such embodiments, implementation, R4selected from the group consisting of tert-butyl, phenyl and 5-6-membered heteroaryl.

[00151] In some embodiments, implementation, R4selected from the group consisting of C3-C6-carbocycle and 5-6-membered heterocyclyl. In some such embodiments, implementation, R4selected from the group consisting of C6-carbocycle and 5-6-membered heterocyclyl. In other such embodiments, implementation, R4selected from the group consisting of phenyl and 5-6-membered heteroaryl.

[00152] Suitable carbocyclic for the above embodiments include, for example, cyclopropyl and phenyl.

[00153] Suitable heterocyclyl for the above embodiments include, for example, furanyl, thienyl and pyridinyl.

[00154] In some embodiments, implementation, R4selected from the group consisting of halo, alkyl, and alkyloxy.

[00155] In some embodiments, the wasp is estline, R4represents alkyl.

[00156] In some embodiments, implementation, R4represents tert-butyl.

B5. Deputy R5.

[00157] R5selected from the group consisting of hydrogen, hydroxy, alkyl, alkenyl, quinil, alkyloxy, alkenylacyl, alkyloxy, alkylsulfonate, carbocyclization, haloalkaliphilic, and halogen.

[00158] In some embodiments, implementation, R5selected from the group consisting of hydrogen, hydroxy, alkyloxy and halogen. In some such embodiments, implementation, R5selected from the group consisting of hydrogen, hydroxy, alkyloxy and fluorine. In other such embodiments, implementation, R5selected from the group consisting of hydrogen, hydroxy, alkyloxy and fluorine. In other such embodiments, implementation, R5selected from the group consisting of hydrogen, hydroxy, alkyloxy and chlorine. In other such embodiments, implementation, R5selected from the group consisting of hydrogen, hydroxy, alkyloxy and bromine. In additional such embodiments, implementation, R5selected from the group consisting of hydrogen, hydroxy, alkyloxy and iodine.

[00159] In some embodiments, implementation, R5selected from the group consisting of hydrogen, hydroxy, methoxy and halogen. In some such embodiments, implementation, R5selected from the group consisting of hydrogen which, hydroxy, methoxy and fluorine. In other such embodiments, implementation, R5selected from the group consisting of hydrogen, hydroxy, methoxy and chlorine. In other such embodiments, implementation, R5selected from the group consisting of hydrogen, hydroxy, methoxy and bromine. In additional such embodiments, implementation, R5selected from the group consisting of hydrogen, hydroxy, methoxy and iodine.

[00160] In some embodiments, implementation, R5selected from the group consisting of hydrogen, hydroxy, alkyloxy. In some such embodiments, implementation, R5selected from the group consisting of hydrogen, herokee, methoxy, ethoxy.

[00161] In some embodiments, implementation, R5represents hydrogen.

[00162] In some embodiments, implementation, R5represents hydroxy.

[00163] In some embodiments, implementation, R5represents alkyloxy.

[00164] In some embodiments, implementation, R5represents methoxy.

[00165] In some embodiments, implementation, R5represents ethoxy.

B6. Deputy L.

[00166] L is selected from the group consisting of C(RA)=C(RB), ethylene and cyclopropyl-1,2-ene, where RAand RBdescribed below.

[00167] In some embodiments, implementation, L is a C(RA)=C(RB), where RAand RBthe consideration is us below. In these variants of implementation, the compounds of formula I correspond in structure to formula I-L1:

.

[00168] In some such embodiments, the implementation, the compounds correspond in structure to formula IA-L1:

.

[00169] In other such embodiments, the implementation, the compounds correspond in structure to formula IB-L1:

.

[00170] Typically, the compounds of formula I-L1 is more effective if R6and phenyl-uracil are on opposite sides of the double bond (i.e., in the TRANS configuration relative to the double bond).

[00171] In some embodiments, implementation, L is an ethylene. In these variants of implementation, the compounds of formula I correspond in structure to formula I-L5-2:

.

[00172] In some such embodiments, the implementation, the compounds correspond in structure IA-L5-2:

.

[00173] In other such embodiments, the implementation, the compounds correspond in structure to formula IB-L5-2:

.

[00174] In some embodiments, implementation, L is cyclopropyl-1,2-ene. In these variants of implementation, the compounds of formula I correspond in structure to formula I-L8:

.

[00175] In some such embodiments implement the program, the compounds correspond in structure to formula IA-L8:

.

[00176] In other such embodiments, the implementation, the compounds correspond in structure to formula IB-L8:

.

V7. The substituents RAand RB.

[00177] RAand RBindependently selected from the group consisting of hydrogen, C1-C6-alkyl, C1-C6-alkyloxy,3-C8-cycloalkyl, and halo, where:

C1-C6-alkyl optionally substituted by one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, oxo, amino, cyano, allyloxycarbonyl, alkylcarboxylic, alkyloxy, carbocycle, and heterocycle.

[00178] In some embodiments, the implementation of one of RAand RBrepresents hydrogen and the other is selected from the group consisting of C1-C6-alkyl, C1-C6-alkyloxy,3-C8-cycloalkyl and halo, where:

C1-C6-alkyl optionally substituted by one or more substituents independently selected from the group consisting of carboxy, halo, hydroxy, nitro, oxo, amino, cyano, allyloxycarbonyl, alkylcarboxylic, alkyloxy, carbocycle, and heterocycle.

[00179] In some embodiments, implementation, RAand RBindependently selected from the group consisting of hydrogen,C 1-C6-alkyl, C1-C6-alkyloxy,3-C8-cycloalkyl, and halo.

[00180] In some of the above embodiments, RArepresents hydrogen. In another of the above embodiments, RBrepresents hydrogen.

[00181] In some embodiments, the implementation of one of RAand RBrepresents hydrogen and the other is selected from the group consisting of hydrogen, methyl, methoxy, and halo.

[00182] In some embodiments, implementation, RArepresents hydrogen, a RBselected from the group consisting of methyl, methoxy, and halo. In some such embodiments, implementation, RBselected from the group consisting of methyl, methoxy and fluorine. In other such embodiments, implementation, RBselected from the group consisting of methyl, methoxy and chlorine. In other such embodiments, implementation, RBselected from the group consisting of methyl, methoxy, and bromine. In additional such embodiments, implementation, RBselected from the group consisting of methyl, methoxy, and iodine. In these additional embodiments, implementation, RBselected from the group consisting of methyl, methoxy, chlorine and fluorine.

[00183] In some embodiments, implementation, RBrepresents hydrogen, a RAselected from the group consisting of methyl, methoxy, and halo. is some such embodiments, implementation, RAselected from the group consisting of methyl, methoxy and fluorine. In other such embodiments, implementation, RAselected from the group consisting of methyl, methoxy and chlorine. In other such embodiments, implementation, RAselected from the group consisting of methyl, methoxy, and bromine. In additional such embodiments, implementation, RAselected from the group consisting of methyl, methoxy, and iodine. In these additional embodiments, implementation, RAselected from the group consisting of methyl, methoxy, chlorine and fluorine.

[00184] In some embodiments, implementation, RArepresents hydrogen, and RBrepresents hydrogen.

B8. Deputy R6.

[00185] R6selected from the group consisting of C5-C6-carbocycle, 5-6-membered heterocyclyl fused 2-ring carbocycle and condensed 2-ring heterocyclyl, where each such Deputy optionally substituted by one or more substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RKwhere RE, RF, RG, RH, RI, RJand RKconsidered below. In some such embodiments, the implementation5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic and condensed 2-ring is howling heterocyclyl not replaced. In other such embodiments, the implementation5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic and condensed 2-ring heterocyclyl replaced by Deputy selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In other such embodiments, the implementation5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic and condensed 2-ring heterocyclyl replaced by Deputy selected from the group consisting of RE, RF, RI, RJand RK. In other such embodiments, the implementation5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic, and condensed 2-ring heterocyclyl replaced by Deputy selected from the group consisting of RE, RFand RJ. In other such embodiments, the implementation5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic, and condensed 2-ring heterocyclyl replaced by Deputy selected from the group consisting of RFand RJ. In other such embodiments, the implementation5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic and condensed 2-ring heterocyclization R J. In other such embodiments, the implementation5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted by two substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In other such embodiments, the implementation5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted by two substituents, independently selected from the group consisting of RE, RF, RI, RJand RK. In other such embodiments, the implementation5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted by two substituents, independently selected from the group consisting of RE, RFand RJ. In other such embodiments, the implementation5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted by two substituents, independently selected from the group consisting of RFand RJ. In additional such embodiments, the implementation5-C6-carbocyclic, 5-6-membered, heterotic the sludge, condensed 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted with three substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In additional such embodiments, the implementation5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted with three substituents, independently selected from the group consisting of RE, RF, RI, RJand RK. In additional such embodiments, the implementation5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted with three substituents, independently selected from the group consisting of RE, RFand RJ. In additional such embodiments, the implementation5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted with three substituents, independently selected from the group consisting of RFand RJ. In additional such embodiments, the implementation5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic and condensed 2-kolicevo heterocyclyl substituted by one, two or three substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In additional such embodiments, the implementation5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic and condensed 2 - ring heterocyclyl substituted one, two or three substituents, independently selected from the group consisting of RE, RF, RI, RJand RK. In additional such embodiments, the implementation of C5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted one, two or three substituents, independently selected from the group consisting of RE, RFand RJ. In additional such embodiments, the implementation5-C6-carbocyclic, 5-6-membered heterocyclyl fused 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted one, two or three substituents, independently selected from the group consisting of RFand RJ.

[00186] In some embodiments, implementation, R6selected from the group consisting of C5-C6-carbocycle and 5-6-membered heterocyclyl, where each such Deputy optionally substituted one or breathability, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In some such embodiments, the implementation5-C6-carbocyclic and 5-6 clinnyricinclus not replaced. In other such embodiments, the implementation5-C6-carbocyclic and 5-6-membered heterocyclyl replaced by Deputy selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In other such embodiments, the implementation5-C6-carbocyclic and 5-6-membered heterocyclyl substituted by two substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, KJand RK. In additional such embodiments, the implementation5-C6-carbocyclic and 5-6-membered heterocyclyl substituted with three substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In additional such embodiments, the implementation5-C6-carbocyclic and 5-6-membered heterocyclyl substituted one, two or three substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK.

[00187] In some embodiments, implementation, R6represents a C5-C6-carbocyclic, not battelino substituted by one or more substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In some such embodiments, the implementation5-C6-carbocyclic not replaced. In other such embodiments, the implementation5-C6-carbocyclic replaced by Deputy selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In other such embodiments, the implementation5-C6-carbocyclic substituted by two substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In additional such embodiments, the implementation5-C6-carbocycle substituted with three substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In additional such embodiments, the implementation5-C6-carbocycle substituted one, two or three substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK.

[00188] In some embodiments, implementation, R6is a 5-6-membered heterocyclyl, optionally substituted by one or more substituents independently selected from the group consisting of RE, RF, RG, RH, RI , RJand RK. In some such embodiments, implementation, 5-6-membered heterocyclyl not replaced. In other such embodiments, implementation, 5-6-membered heterocyclyl replaced by Deputy selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In other such embodiments, implementation, 5-6-membered heterocyclyl substituted by two substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In additional such embodiments, implementation, 5-6-membered heterocyclyl substituted with three substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In additional such embodiments, implementation, 5-6-membered heterocyclyl substituted one, two or three substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK.

[00189] In some embodiments, implementation, R6selected from the group consisting of condensed 2-ring carbocycle and condensed 2-ring heterocyclyl, where each such Deputy optionally substituted by one or more substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK/sup> . In some such embodiments, the implementation of the fused 2-ring carbocyclic and condensed 2-ring heterocyclyl not replaced. In other such embodiments, the implementation of the fused 2-ring carbocyclic and condensed 2-ring heterocyclyl replaced by Deputy selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In other such embodiments, the implementation of the fused 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted by two substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In additional such embodiments, the implementation of the fused 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted with three substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In additional such embodiments, the implementation of condensed 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted one, two or three substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK.

[00190] In some embodiments, implementation, R6is the th condensed 2-ring carbocyclic, optionally substituted by one or more substituents independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In some such embodiments, the implementation of the fused 2-ring carbocyclic not replaced. In other such embodiments, the implementation of the fused 2-ring carbocyclic replaced by Deputy selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In other such embodiments, the implementation of condensed 2-ring carbocyclic substituted by two substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In additional such embodiments, the implementation of the fused 2-ring carbocycle substituted with three substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In additional such embodiments, the implementation of the fused 2-ring carbocycle substituted one, two or three substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK.

[00191] In some embodiments, implementation, R6represents a condensed 2-ring heterocyclyl, neobyazatel is substituted by one or more substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In some such embodiments, the implementation of the fused 2-ring heterocyclyl not replaced. In other such embodiments, the implementation of the fused 2-ring heterocyclyl replaced by Deputy selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In other such embodiments, the implementation of the fused 2-ring heterocyclyl substituted by two substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In additional such embodiments, the implementation of the fused 2-ring heterocyclyl substituted with three substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In additional such embodiments, the implementation of the fused 2-ring heterocyclyl substituted one, two or three substituents, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK.

[00192] In some of these embodiments, optionally substituted C5-C6-carbocycle selected from the group consisting of cyclopentyl, cyclopenten is a, of cyclopentadienyl, cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl. In some such embodiments, implementation, optionally substituted C5-C6-carbocyclic represents phenyl.

[00193] In some of these embodiments, optionally substituted C5-C6-carbocyclic represents a C5-carbocyclic. Examples5-carbocyclic include cyclopentyl, cyclopentenyl and cyclopentadienyl.

[00194] In another of the above embodiments, optionally substituted C5-C6-carbocyclic represents a C6-carbocyclic. Examples6-carbocyclic include cyclohexyl, cyclohexenyl, cyclohexadienyl and phenyl.

[00195] In some of these embodiments, optionally substituted 5-6-membered-heterocyclyl selected from the group consisting of furanyl, dihydrofurane, tetrahydrofuranyl, thiophenyl (thiopurine), dihydrothiophene, tetrahydrothiophene, pyrrolyl, pyrrolidyl, pyrrolidinyl, oxazolyl, dihydrooxazolo, isoxazolyl, dihydroisoxazole, oxazolidinyl, isoxazolidine, thiazolyl, isothiazoline, thiazoline, isothiazoline, thiazolidine, isothiazolinone, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolyl, pyrazolidine, oxathiolane, oxathiolan the sludge, triazolyl, oxadiazolyl, furazane, tetrazolyl, oxadiazolyl, dioxazine, oxadiazolyl, oxadiazolidine, dihydroimidazole, deoxythymidine, pyranyl, dihydropyrrole, tetrahydropyranyl, pyridinyl, dihydropyridine, tetrahydropyridine, piperidine, diazine, pyrazinyl, pyridazinyl, pyrimidinyl, dihydropyrazine, tetrahydropyranyl, piperazinil, triazinyl, dihydrotriazine, tetrahydrothiophene, triazinyl, oxazinyl, dihydrooxazolo, morpholinyl, oxadiazolyl, dihydroartemisinin, oxathiazine, oxadiazine, Dihydrocodeine, oxadiazine, dipiradol, dihydrothiophene and tetrahydrothiopyrano.

[00196] In some of these embodiments, optionally substituted 5-6-membered-heterocyclyl represents a 5-membered heterocyclyl. Examples of such 5-membered heterocyclyl include furanyl, dihydrofurane, tetrahydrofuranyl, thiophenyl (thiopurines), dihydrothiophene, tetrahydrothiophene, pyrrolyl, pyrrolidyl, pyrrolidinyl, oxazolyl, dihydrooxazolo, isoxazolyl, dihydroisoxazole, oxazolidinyl, isoxazolidine, thiazolyl, isothiazolin, thiazolyl, isothiazolines, diazolidinyl, isothiazolinones, imidazolyl, imidazolidinyl, pyrazolyl, pyrazolyl, pyrazolidine, oxacillin, oxathiolane, triazolyl, Arcadia is alil, furutani, tetrazolyl, oxadiazolyl, doxazosin, oxadiazolyl, oxadiazolidine, dihydroimidazole and dioxanelignin.

[00197] In other above options, implementation, optionally substituted 5-6-membered heterocyclyl represents a 6-membered heterocyclyl. Examples of 6-membered heterocyclyl include pyranyl, dihydropyran, tetrahydropyranyl, pyridinyl, dihydropyridines, tetrahydropyridine, piperidine, diazines, pyrazinyl, pyridazinyl, pyrimidinyl, dihydropyrazine, tetrahydropyranyl, piperazinil, triazinyl, dihydrotriazine, tetrahydrocanabinol, triazinyl, oxazinyl, dihydroxyphenyl, morpholinyl, oxadiazolyl, dihydroartemisinin, oxathiazine, oxadiazine, dihydroartemisinin, oxadiazine, tiopronin, dihydrothiophene and tetrahydrothiopyran.

[00198] In some of these embodiments, the optionally substituted condensed 2-ring carbocycle selected from the group consisting of naphthalenyl, dihydronaphthalene, tetrahydronaphthalene, hexahydronaphthalen, octahydronaphthalene, decahydronaphthalene, indenyl, dihydroindole, hexahydrobenzene, octahedrite, pentalene, octahydrophenanthrene and hexahydrophthalate. In some such embodiments, implementation, optionally substituted condensed-ring carbocycle selected from the group consisting of naphthalenyl and dihydroindole. In some such embodiments, implementation, optionally substituted condensed 2-ring carbocycles is naphthalenyl. In other such embodiments, implementation, optionally substituted condensed 2-ring carbocycles is dihydroindeno. In additional such embodiments, implementation, optionally substituted condensed 2-ring carbocycles is indenyl.

[00199] In some of these embodiments, the optionally substituted condensed 2-ring heterocyclyl selected from the group consisting of

,,,,,,,,,,,,,,,,,,,,and;

X1X2and X3independently in the gap group, consisting of N and C(N);

X4selected from the group consisting of N(H), O and S;

X5X6and X7independently selected from the group consisting of N and C(N);

X8selected from the group consisting of N(H), O and S;

X9selected from the group consisting of N(H), O and S;

X10X11X12and X13independently selected from the group consisting of N and C(N);

X14selected from the group consisting of N(H), O and S;

X15X16X17and X18independently selected from the group consisting of N and C(N);

one or more of the X19X20and X21represents N, and the rest (the rest) is/are C(H);

one or more of the X22X23X24and X25represents N, and the rest (the rest) is/are C(H);

one or more of the X26X27and X28represents N, and the rest (the rest) is/are C(H);

one or more of the X29X30X31and X32represents N, and the rest (the rest) is/are C(H);

one or more of the X33X34and X35represents N, and the rest (the rest) is/are C(H);

one or more of the X36X37X38and X39represents N, and the rest of (rest of) the submitted is/are C(H);

X40X41and X42independently selected from the group consisting of N and C(N);

one of X43X44and X45selected from the group consisting of N(H), O and S, and the remaining two represent C(H)2;

one of X46and X47selected from the group consisting of N(H), O and S, and the other represents C(H)2;

X48X49X50and X51independently selected from the group consisting of N and C(N);

X52X53and X54independently selected from the group consisting of N and C(N);

X55selected from the group consisting of N(H), O and S;

X56X57and X58independently selected from the group consisting of N and C(N);

X59selected from the group consisting of N(H), O and S;

X60selected from the group consisting of N(H), O and S;

X61X62X63and X64independently selected from the group consisting of N and C(N);

X65selected from the group consisting of N(H), O and S;

X66X67X68and X69independently selected from the group consisting of N and C(N);

one or more of the X70X71and X72represents N, and the rest (the rest) is/are C(H);

one or more of the X73X74X75and X76represents N, and the rest (the rest) is/are C(H); and

one of X77and X78the submitted is an N(H), and the rest is a(N)2.

[00200] In some of these embodiments, the optionally substituted condensed 2-ring heterocyclyl selected from the group consisting of,,,,,,,,,,,,,,,and.

[00201] In some of these embodiments, the optionally substituted condensed 2-ring heterocyclyl selected from the group consisting of:

,,,,,,,,,and.

[00202] In some of these embodiments, X1X2and X3represent C(H).

[00203] In some of p is iudenich above embodiments, X5X6and X7represent C(H).

[00204] In some of these embodiments, X10X11X12and X13represent C(H).

[00205] In some of these embodiments, X15X16X17and X18represent C(H).

[00206] In some of these embodiments, one of X19X20and X21represents N.

[00207] In some of these embodiments, one of X22X23X24and X25represents N.

[00208] In some of these embodiments, one of X26X27and X28represents N and one of X29X30X31and X32represents N.

[00209] In some of these embodiments, X40X41and X42represent C(H).

[00210] In some of these embodiments, X48X49X50and X51represent C(H).

[00211] In some of these embodiments, X52X53and X54represent C(H).

[00212] In some of these embodiments, X56X57and X58represent C(H).

[00213] In some of the above, VA is Ianto implementation X61X62X63and X64represent C(H).

[00214] In some of these embodiments, X66X67X68and X69represent C(H).

[00215] In some of these embodiments, one or more of the X70X71and X72represents N, and the rest (the rest) is/are C(H).

[00216] In some of these embodiments, one or more of the X73X74X75and X76represents N, and the rest (the rest) is/are C(H).

B9. Deputy RE.

[00217] Each REindependently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido, and aldehydo, where amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil.

[00218] In some embodiments, implementation, each REindependently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, amino, imino, aldehyde, where amino optionally substituted with one or two independently selected alkilani.

[00219] In some embodiments, implementation, each REindependently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, amino, imino,aldehyde, alkylamino.

[00220] In some embodiments, implementation, each REindependently selected from the group consisting of chlorine, fluorine, nitro, hydroxy, oxo, carboxy, amino, imino, aldehyde, alkylamino.

[00221] In some embodiments, implementation, each REindependently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino, imino, azido. In some such embodiments, implementation, each RErepresents halo. In other such embodiments, implementation, each RErepresents nitro. In other such embodiments, implementation, each RErepresents hydroxy. In other such embodiments, implementation, each RErepresents oxo. In other such embodiments, implementation, each RErepresents carboxy. In other such embodiments, implementation, each RErepresents cyano. In other such embodiments, implementation, each RErepresents amino. In additional such embodiments, implementation, each RErepresents imino. In additional embodiments, implementation, each RErepresents azido.

[00222] In some embodiments, implementation, each REindependently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino and imino.

10. Deputy RF.

[00223] Each RFindependently selected from the group consisting of alkyl, alkenyl and quinil where:

each such Deputy optionally substituted by one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, allyloxycarbonyl, alkenylboronic, alkyloxyaryl, alkylcarboxylic, alkenylboronic, alkylcarboxylic, alkyloxy, alkenylacyl, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl where:

amino, imino, aminosulfonyl, aminocarbonyl, carbocyclic and heterocyclyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, quinil, alkylsulfonyl, alkanesulfonyl, alkylsulfonyl, alkylsulfonyl, hydroxy, alkyloxy,

where:

amino part of alkylsulfonyl optionally substituted Deputy selected from the group consisting of alkyl, alkenyl and quinil.

[00224] In some embodiments, implementation, each RFindependently selected from the group consisting of alkyl, alkenyl and quinil where:

each such Deputy optionally substituted by one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, is sido, oxo, aminosulfonyl, alkylsulfonyl, allyloxycarbonyl, alkenylboronic, alkyloxyaryl, alkylcarboxylic, alkenylboronic, alkylcarboxylic, alkyloxy, alkenylacyl, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl where:

amino, imino, aminosulfonyl and aminocarbonyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, quinil, alkylsulfonyl, alkanesulfonyl, alkylsulfonyl, alkylsulfonyl,

where:

amino part of alkylsulfonyl optionally substituted Deputy selected from the group consisting of alkyl, alkenyl and quinil.

[00225] In some of these embodiments, each RFindependently selected from the group consisting of alkyl, quinil and quinil, where such substituents are unsubstituted.

[00226] In some embodiments, implementation, each RFindependently selected from the group consisting of alkyl, alkenyl and quinil where:

each such Deputy optionally substituted by one or two substituents, independently selected from the group consisting of carboxy, herokee, halo, amino, imino, nitro, oxo, aminosulfonyl, alkylsulfonyl, allyloxycarbonyl, alkylcarboxylic, alkyloxy, carbocycle, heterocyclyl, cyano what aminocarbonyl, where:

amino, imino, aminosulfonyl and aminocarbonyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkylsulfonyl, alkylsulfonyl,

where:

amino part of alkylsulfonyl optionally substituted alkyl.

[00227] In some embodiments, implementation, each RFis an independently selected alkyl, optionally substituted Deputy selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, oxo, aminosulfonyl, alkylsulfonyl, allyloxycarbonyl, alkylcarboxylic, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl where:

amino, imino, aminosulfonyl and aminocarbonyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkylsulfonyl, alkylsulfonyl where:

amino part of alkylsulfonyl optionally substituted alkyl.

[00228] In some embodiments, implementation, each RFis an independently selected alkyl, optionally substituted Deputy selected from the group consisting of carboxy, halo, amino, imino and aminosulfonyl where:

amino, imino and aminosulfonyl optionally substituted by one or more substituents independently selected from the group consisting of al the sludge, alkylsulfonyl, alkylsulfonyl.

[00229] In some embodiments, implementation, each RFis an independently selected alkyl, optionally substituted amino, where the amino optionally substituted by alkylsulfonyl.

[00230] In some embodiments, implementation, each RFis an independently selected alkyl, substituted amino, where the amino substituted by alkylsulfonyl. In some such embodiments, implementation, each RFis methylsulfonylamino.

[00231] In some embodiments, implementation, each RFindependently selected from the group consisting of alkyl, alkenyl and quinil where:

each such Deputy optionally substituted one, two or three substituents, independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, allyloxycarbonyl, alkenylboronic, alkyloxyaryl, alkylcarboxylic, alkenylboronic, alkylcarboxylic, alkyloxy, alkenylacyl, alkenylacyl, carbocycle, heterocyclyl, cyano and aminocarbonyl.

[00232] In some embodiments, implementation, each RFis an independently selected alkyl, substituted by one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, imino, nitro, azido, oxo, aminosulfonyl, alkylsulfonyl, allyloxycarbonyl, alkenylboronic, alkyloxyaryl, alkylcarboxylic, alkenylboronic, alkylcarboxylic, alkyloxy, alkenylacyl, alkenylacyl, carbocycle, heterocyclyl, cyano and aminocarbonyl.

B11. Deputy RG.

[00233] Each RGindependently selected from the group consisting of carbocyclic and heterocyclyl where:

each such Deputy optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, quinil, carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, allyloxycarbonyl, alkenylboronic, alkyloxyaryl, alkylcarboxylic, alkenylboronic, alkylcarboxylic, alkyloxy, alkenylacyl, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl where:

amino, aminosulfonyl and aminocarbonyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, quinil, alkylsulfonyl, alkanesulfonyl and alkylsulfonyl.

[00234] In some of these embodiments, each RGindependently selected from the group consisting of carbocyclic and heterocyclyl, where such substituents are unsubstituted.

[00235] in Some embodiments, implementation, each RGindependently selected from the group consisting of carbocyclic and heterocyclyl where:

each such Deputy optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, allyloxycarbonyl, alkylcarboxylic, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl where:

amino, aminosulfonyl and aminocarbonyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl and alkylsulfonyl.

[00236] In some of these embodiments, carbocycle represents a C3-C6-carbocyclic.

[00237] In some of these embodiments, heterocyclyl is a 5-6-membered heterocyclyl.

B12. Deputy RH.

[00238] Each RHindependently selected from the group consisting of alkyloxy, alkenylacyl, alkyloxy, alkylsulfonate, alkanesulfonyl, alkylsulfonate where:

each such Deputy optionally substituted by one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, allyloxycarbonyl, alkenylboronic, alkyloxyaryl, alkylborane is hydroxy, alkenylboronic, alkylcarboxylic, alkyloxy, alkenylacyl, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl where:

amino, aminosulfonyl and aminocarbonyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, quinil, alkylsulfonyl, alkanesulfonyl and alkylsulfonyl.

[00239] In some of these embodiments, each RHindependently selected from the group consisting of alkyloxy, alkenylacyl, alkyloxy, alkylsulfonate, alkanesulfonyl, alkylsulfonate, where such substituents are unsubstituted.

[00240] In some embodiments, implementation, each RHindependently selected from the group consisting of alkyloxy, alkylsulfonate where:

each such Deputy optionally substituted by one or two substituents, independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, allyloxycarbonyl, alkylcarboxylic, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl where:

amino, aminosulfonyl and aminocarbonyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl and alkylsulfonyl.

[00241] In some embodiments, implementation, each is R Hindependently selected from the group consisting of alkyloxy, alkylsulfonate where:

each such Deputy optionally substituted by one or two substituents, independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, allyloxycarbonyl, alkylcarboxylic, alkyloxy, cyano and aminocarbonyl where:

amino, aminosulfonyl and aminocarbonyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl and alkylsulfonyl.

[00242] In some embodiments, implementation, each RHindependently selected from the group consisting of alkyloxy, alkylsulfonate where:

each such Deputy optionally substituted by one or two substituents, independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, allyloxycarbonyl, alkylcarboxylic, alkyloxy, cyano and aminocarbonyl.

[00243] In some embodiments, implementation, each RHis an independently selected alkyloxy.

[00244] In some embodiments, implementation, each RHis an independently selected alkylsulfonate.

B13. Deputy RI.

[00245] Each RIindependently selected from the group consisting of alkylcarboxylic, alkenylamine, alkyne is carbonyl, aminocarbonyl, allyloxycarbonyl, carbocisteine and geterotsiklicheskikh where:

(a) alkylsulphonyl, alkenylboronic and alkenylboronic optionally substituted by one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, allyloxycarbonyl, alkenylboronic, alkyloxyaryl, alkylcarboxylic, alkenylboronic, alkylcarboxylic, alkyloxy, alkenylacyl, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl, and

(b) aminocarbonyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, alkyloxyalkyl, carbocycle, heterocyclyl, alkylsulfonyl, alkylsulfonyl where:

carbocyclic and heterocyclyl optionally substituted by one or more substituents independently selected from the group consisting of halo, alkyl and oxo.

[00246] In some embodiments, implementation, each RIindependently selected from the group consisting of alkylcarboxylic, alkenylamine, alkynylaryl, aminocarbonyl, allyloxycarbonyl, carbocisteine and geterotsiklicheskikh, where such substituents are unsubstituted.

[00247] In some embodiments, implementation, each RIindependently selected from the group is s, consisting of alkylcarboxylic, aminocarbonyl, allyloxycarbonyl, carbocisteine and geterotsiklicheskikh where:

(a) alkylsulphonyl optionally substituted Deputy selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, allyloxycarbonyl, alkylcarboxylic, alkyloxy and aminocarbonyl, and

(b) aminocarbonyl optionally substituted Deputy selected from the group consisting of alkyl, alkyloxyalkyl, alkylsulfonyl, alkylsulfonyl.

[00248] In some embodiments, implementation, each RIindependently selected from the group consisting of alkylcarboxylic and aminocarbonyl where:

aminocarbonyl optionally substituted Deputy selected from the group consisting of alkyl, alkyloxyalkyl, alkylsulfonyl, alkylsulfonyl.

[00249] In some embodiments, implementation, each RIindependently selected from the group consisting of alkylcarboxylic, alkenylamine, alkynylaryl and aminocarbonyl where:

(a) alkylsulphonyl, alkenylboronic and alkenylboronic optionally substituted by one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, allyloxycarbonyl, alkenylboronic, alkyloxyaryl, alkylcarboxylic, alkenylboronic and, alkylcarboxylic, alkyloxy, alkenylacyl, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl, and

(b) aminocarbonyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, alkylsulfonamides.

[00250] In some of these embodiments, each RIindependently selected from the group consisting of alkylcarboxylic, alkenylamine, alkynylaryl and aminocarbonyl, where such substituents are unsubstituted.

[00251] In some embodiments, implementation, each RIindependently selected from the group consisting of alkylcarboxylic and aminocarbonyl where:

(a) alkylsulphonyl optionally substituted by one or two substituents, independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, allyloxycarbonyl, alkylcarboxylic, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl, and

(b) aminocarbonyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkylsulfonate.

[00252] In some embodiments, implementation, each RIindependently selected from the group consisting of alkylcarboxylic and aminocarbonyl where:

(a) alkylsulphonyl optionally substituted by one the m or two substituents, independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, allyloxycarbonyl, alkylcarboxylic, alkyloxy, cyano and aminocarbonyl, and

(b) aminocarbonyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkylsulfonate.

[00253] In some embodiments, implementation, each RIindependently selected from the group consisting of alkylcarboxylic and aminocarbonyl where:

alkylsulphonyl optionally substituted by one or two substituents, independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, allyloxycarbonyl, alkylcarboxylic, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl.

[00254] In some embodiments, implementation, each RIis an independently selected alkylsulphonyl.

[00255] In some embodiments, implementation, each RIis an independently selected aminocarbonyl.

B14. Deputy RJ.

[00256] Each RJindependently selected from the group consisting of carbocyclization, heterocyclization, alkylcarboxylic, alkenylamine, alkylcarboxylic, allyloxycarbonyl, alkenylcarbazoles, alkyloxycarboxylic, is alkylsulfonamides, alkanesulfonyl, alkylsulfonyl, aminocarbonyl, allyloxycarbonyl, alkylsulfonamides, alkanesulfonyl, alkylsulfonamides where:

(a) the amino portion of such substituents optionally is substituted by the Deputy, is independently selected from the group consisting of carbocyclic, geterotsiklicheskikh, alkylcarboxylic, aminocarbonylmethyl, alkyl, alkenyl, quinil, alkylcarboxylic, alkenylamine, alkynylaryl, allyloxycarbonyl, alkyloxyaryl, alkylcarboxylic and alkylsulfonyl where:

(1) carbonilla part of carbocyclic and heterocyclyl part of geterotsiklicheskikh optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, quinil, carboxy, hydroxy, alkyloxy, alkenylacyl, alkyloxy, halo, nitro, cyano, azido, oxo and amino, and

(2) the amino portion of aminocarbonylmethyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil,

(b) alkyl, Alchemilla and Alchemilla portion of such substituents optionally is substituted by one or more substituents independently selected from the group consisting of carboxy, halo, oxo, amino, allyloxycarbonyl, alkylcarboxylic, hydro is si, alkyloxy, carbocycle, heterocyclyl and cyano, where:

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, alkyloxy, alkenylacyl, alkyloxy where:

alkyl optionally substituted by one or more hydroxy;

(C) carballeira and heterocyclyl portions of such substituents optionally is substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, quinil, carboxy, hydroxy, alkyloxy, alkenylacyl, alkyloxy, halo, nitro, cyano, azido and amino, where:

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil.

[00257] In some embodiments, implementation, each RJindependently selected from the group consisting of carbocyclization, heterocyclization, alkylcarboxylic, alkenylamine, alkylcarboxylic, allyloxycarbonyl, alkenylcarbazoles, alkyloxycarboxylic, alkylsulfonyl, alkanesulfonyl, alkylsulfonyl, aminocarbonyl, alkylsulfonamides, alkanesulfonyl, alkylsulfonamides where:

(a) the amino portion of such substituents optionally is substituted by the Deputy, independently of wybrand the m group, consisting of carbocyclic, geterotsiklicheskikh, alkylcarboxylic, aminocarbonylmethyl, alkyl, alkenyl, quinil, alkylcarboxylic, alkenylamine, alkynylaryl, allyloxycarbonyl, allyloxycarbonyl, alkylcarboxylic and alkylsulfonyl where:

(1) carbonilla part of carbocyclic and heterocyclyl part of geterotsiklicheskikh optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl, quinil, carboxy, hydroxy, alkyloxy, alkenylacyl, alkyloxy, halo, nitro, cyano, azido, oxo and amino, and

(2) the amino portion of aminocarbonylmethyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil,

(b) alkyl, Alchemilla and Alchemilla portion of such substituents optionally is substituted by one or more substituents independently selected from the group consisting of carboxy, halo, oxo, amino, allyloxycarbonyl, alkylcarboxylic, hydroxy, alkyloxy, carbocycle, heterocyclyl and cyano, where:

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl, quinil, alkyloxy, alkenylacyl, alkyloxy where:

alkyl optionally substituted by one or more hydroxy;

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil; and

[00258] In some of these embodiments, each RJindependently selected from the group consisting of carbocyclization, heterocyclization, alkylcarboxylic, alkenylamine, alkylcarboxylic, allyloxycarbonyl, alkenylcarbazoles, alkyloxycarboxylic, alkylsulfonyl, alkanesulfonyl, alkylsulfonyl, aminocarbonyl, alkylsulfonamides, alkanesulfonyl, alkylsulfonamides, where such substituents are unsubstituted.

[00259] In some embodiments, implementation, each RJindependently selected from the group consisting of carbocyclization, heterocyclization, alkylcarboxylic, allyloxycarbonyl, alkylsulfonyl, aminocarbonyl, alkylsulfonamides where:

(a) the amino portion of such substituents optionally is substituted by the Deputy, is independently selected from the group consisting of carbocyclic, geterotsiklicheskikh, al is ylcarbonyl, aminocarbonylmethyl, alkyl, alkylsulphonyl, allyloxycarbonyl, allyloxycarbonyl, alkylcarboxylic and alkylsulfonyl where:

(1) carbonilla part of carbocyclic and heterocyclyl part of geterotsiklicheskikh optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2) the amino portion of aminocarbonylmethyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil,

(b) the alkyl portion of such substituents optionally is substituted by one or two substituents, independently selected from the group consisting of carboxy, halo, oxo, amino, allyloxycarbonyl, alkylcarboxylic, hydroxy, alkyloxy, carbocycle, heterocyclyl and cyano, where:

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkyloxy where:

alkyl optionally substituted by one or more hydroxy;

(c) carballeira and heterocyclyl part of such zamestitel optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, amino, where:

amino long is Ino substituted with one or two independently selected alkyl substituents.

[00260] In some embodiments, implementation, each RJindependently selected from the group consisting of carbocyclization, heterocyclization, alkylsulfonyl, alkylsulfonamides where:

(a) the amino portion of such substituents optionally is substituted by the Deputy, is independently selected from the group consisting of carbocyclic, geterotsiklicheskikh, alkylcarboxylic, aminocarbonylmethyl, alkyl, alkylsulphonyl, allyloxycarbonyl, allyloxycarbonyl, alkylcarboxylic and alkylsulfonyl where:

(1) carbonilla part of carbocyclic and heterocyclyl part of geterotsiklicheskikh optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2) the amino portion of aminocarbonylmethyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil,

(b) the alkyl portion of such substituents optionally is substituted by one or two substituents, independently selected from the group consisting of carboxy, halo, oxo, amino, allyloxycarbonyl, alkylcarboxylic, hydroxy, alkyloxy, carbocycle, heterocyclyl and cyano, where:

amino optionally substituted with one or two mixing what italiani, independently selected from the group consisting of alkyl, alkyloxy where:

alkyl optionally substituted by one or more hydroxy;

(c) carballeira and heterocyclyl portions of such substituents optionally is substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, amino, where:

amino optionally substituted with one or two independently selected alkyl substituents.

[00261] In some embodiments, implementation, each RJindependently selected from the group consisting of carbocyclization, heterocyclization, alkylsulfonyl, alkylsulfonamides where:

the amino portion of such substituents optionally is substituted by the Deputy, is independently selected from the group consisting of carbocyclic, geterotsiklicheskikh, alkylcarboxylic, aminocarbonylmethyl, alkyl, alkylsulphonyl, allyloxycarbonyl, allyloxycarbonyl, alkylcarboxylic and alkylsulfonyl where:

(1) carbonilla part of carbocyclic and heterocyclyl part of geterotsiklicheskikh optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2) the amino portion of aminocarbonyl is Lila optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil.

[00262] In some embodiments, implementation, each RJindependently selected from the group consisting of carbocyclization, heterocyclization, alkylsulfonyl, alkylsulfonamides where:

the alkyl part of alkylsulfonamides, alkylsulfonamides optionally substituted by one or two substituents, independently selected from the group consisting of carboxy, halo, oxo, amino, allyloxycarbonyl, alkylcarboxylic, hydroxy, alkyloxy, carbocycle, heterocyclyl and cyano, where:

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkyloxy where:

alkyl optionally substituted by one or more hydroxy.

[00263] In some embodiments, implementation, each RJindependently selected from the group consisting of carbocyclization, heterocyclization, alkylsulfonyl, alkylsulfonamides where:

carballeira and heterocyclyl portions of such substituents optionally is substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano and amino.

[00264] In some embodiments, implementation, each RJregardless of the pre-selected from the group consisting of carbocyclization, geterotsiklicheskikh where:

carballeira and heterocyclyl portions of such substituents optionally is substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano and amino.

[00265] In some embodiments, implementation, each RJindependently selected from the group consisting of alkylsulfonyl, alkanesulfonyl, alkylsulfonyl, alkylsulfonamides where:

(a) the amino portion of such substituents optionally is substituted by the Deputy, is independently selected from the group consisting of carbocyclic, geterotsiklicheskikh, alkylcarboxylic, aminocarbonylmethyl, alkyl, alkylsulphonyl, allyloxycarbonyl, allyloxycarbonyl, alkylcarboxylic and alkylsulfonyl where:

(1) carbonilla part of carbocyclic and heterocyclyl part of geterotsiklicheskikh optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2) the amino portion of aminocarbonylmethyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil,

(b) alkyl, Alchemilla and Alchemilla portion of such substituents optionally is substituted by one or two substituents, independently selected from the group consisting of carboxy, halo, oxo, amino, allyloxycarbonyl, alkylcarboxylic, hydroxy, alkyloxy, carbocycle, heterocyclyl and cyano, where:

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkyloxy where:

alkyl optionally substituted by one or more hydroxy.

[00266] In some embodiments, implementation, each RJis an independently selected alkylsulfonamides where:

(a) the amino portion of alkylsulfonyl optionally substituted by the Deputy, is independently selected from the group consisting of carbocyclic, geterotsiklicheskikh, alkylcarboxylic, aminocarbonylmethyl, alkyl, alkylsulphonyl, allyloxycarbonyl, allyloxycarbonyl, alkylcarboxylic and alkylsulfonyl where:

(1) carbonilla part of carbocyclic and heterocyclyl part of geterotsiklicheskikh optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2) the amino portion of aminocarbonylmethyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil,

(b) the alkyl part of alkylsulfonates is optionally substituted by one or two substituents, independently selected from the group consisting of carboxy, halo, oxo, amino, allyloxycarbonyl, alkylcarboxylic, hydroxy, alkyloxy, carbocycle, heterocyclyl and cyano, where:

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkyloxy where:

alkyl optionally substituted by one or more hydroxy.

[00267] In some embodiments, implementation, each RJis an independently selected alkylsulfonamides where:

amino part of alkylsulfonyl optionally substituted by the Deputy, is independently selected from the group consisting of carbocyclic, geterotsiklicheskikh, alkylcarboxylic, aminocarbonylmethyl, alkyl, alkylsulphonyl, allyloxycarbonyl, allyloxycarbonyl, alkylcarboxylic and alkylsulfonyl where:

(1) carbonilla part of carbocyclic and heterocyclyl part of geterotsiklicheskikh optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2) the amino portion of aminocarbonylmethyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil.

[00268] In some embodiments, the implementation of each R Jis an independently selected alkylsulfonamides where:

amino part of alkylsulfonyl optionally substituted by the Deputy, is independently selected from the group consisting of carbocyclic, geterotsiklicheskikh, alkylcarboxylic, aminocarbonylmethyl, alkyl, alkylsulphonyl, allyloxycarbonyl, allyloxycarbonyl, alkylcarboxylic and alkylsulfonyl.

[00269] In some embodiments, implementation, each RJis an independently selected alkylsulfonamides where:

the alkyl part of alkylsulfonyl optionally substituted by one or two substituents, independently selected from the group consisting of carboxy, halo, oxo, amino, allyloxycarbonyl, alkylcarboxylic, hydroxy, alkyloxy, carbocycle, heterocyclyl and cyano, where:

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkyloxy where:

alkyl optionally substituted by one or more hydroxy.

[00270] In some embodiments, implementation, each RJis an independently selected alkylsulfonamides where:

the alkyl part of alkylsulfonyl optionally substituted by one or two substituents, independently selected from the group consisting of carboxy, halo, oxo, amino, allyloxycarbonyl the La, alkylcarboxylic, hydroxy, alkyloxy, carbocycle, heterocyclyl and cyano.

[00271] In some embodiments, implementation, each RJis an independently selected alkylsulfonamides. In some such embodiments, implementation, each RJrepresents methylsulfonylamino.

[00272] In some embodiments, implementation, each RJis an independently selected alkylsulfonamides where:

(a) the amino portion of alkylsulfonamides optionally substituted by the Deputy, is independently selected from the group consisting of carbocyclic, geterotsiklicheskikh, alkylcarboxylic, aminocarbonylmethyl, alkyl, alkylsulphonyl, allyloxycarbonyl, allyloxycarbonyl, alkylcarboxylic and alkylsulfonyl where:

(1) carbonilla part of carbocyclic and heterocyclyl part of geterotsiklicheskikh optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2) the amino portion of aminocarbonylmethyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil,

(b) the alkyl part of alkylsulfonamides optionally substituted by one or two will replace the guides and independently selected from the group consisting of carboxy, halo, oxo, amino, allyloxycarbonyl, alkylcarboxylic, hydroxy, alkyloxy, carbocycle, heterocyclyl and cyano, where:

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkyloxy where:

alkyl optionally substituted by one or more hydroxy.

[00273] In some embodiments, implementation, each RJis an independently selected alkylsulfonamides where:

amino part of alkylsulfonamides optionally substituted by the Deputy, is independently selected from the group consisting of carbocyclic, geterotsiklicheskikh, alkylcarboxylic, aminocarbonylmethyl, alkyl, alkylsulphonyl, allyloxycarbonyl, allyloxycarbonyl, alkylcarboxylic and alkylsulfonyl where:

(1) carbonilla part of carbocyclic and heterocyclyl part of geterotsiklicheskikh optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2) the amino portion of aminocarbonylmethyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil.

[00274] In some embodiments, the wasp is estline, each RJis an independently selected alkylsulfonamides where:

amino part of alkylsulfonamides optionally substituted by the Deputy, is independently selected from the group consisting of carbocyclic, geterotsiklicheskikh, alkylcarboxylic, aminocarbonylmethyl, alkyl, alkylsulphonyl, allyloxycarbonyl, allyloxycarbonyl, alkylcarboxylic and alkylsulfonyl.

[00275] In some embodiments, implementation, each RJis an independently selected alkylsulfonamides where:

the alkyl part of alkylsulfonamides optionally substituted by one or two substituents, independently selected from the group consisting of carboxy, halo, oxo, amino, allyloxycarbonyl, alkylcarboxylic, hydroxy, alkyloxy, carbocycle, heterocyclyl and cyano, where:

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkyloxy where:

alkyl optionally substituted by one or more hydroxy.

[00276] In some embodiments, implementation, each RJis an independently selected alkylsulfonamides where:

the alkyl part of alkylsulfonamides optionally substituted by one or two substituents, independently selected from the group consisting of the arbaki, halo, oxo, amino, allyloxycarbonyl, alkylcarboxylic, hydroxy, alkyloxy, carbocycle, heterocyclyl and cyano.

[00277] In some embodiments, implementation, each RJis an independently selected alkylsulfonamides. In some such embodiments, implementation, each RJrepresents methylsulfonylamino.

[00278] In some embodiments, implementation, each RJindependently selected from the group consisting of alkylcarboxylic, allyloxycarbonyl where:

the alkyl portion of such substituents optionally is substituted by one or two substituents, independently selected from the group consisting of carboxy, halo, oxo, amino, allyloxycarbonyl, alkylcarboxylic, hydroxy, alkyloxy, carbocycle, heterocyclyl and cyano.

15. Deputy RK.

[00279] Each RKindependently selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkanesulfonyl and alkylsulfonyl where:

(a) alkylsulfonyl, alkanesulfonyl and alkylsulfonyl optionally substituted by one or more substituents independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, allyloxycarbonyl, alkenylboronic, alkyloxyaryl, alkylcarboxylic, alkenylboronic, alkylcarboxylic alkyloxy, alkenylacyl, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl where:

amino, aminosulfonyl and aminocarbonyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alkenyl and quinil; and

(b) aminosulfonyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil.

[00280] In some of these embodiments, each RKindependently selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkanesulfonyl and alkylsulfonyl, where such substituents are unsubstituted.

[00281] In some embodiments, implementation, each RKindependently selected from the group consisting of aminosulfonyl and alkylsulfonyl where:

(a) alkylsulfonyl optionally substituted with one or two substituents, independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, oxo, aminosulfonyl, allyloxycarbonyl, alkylcarboxylic, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl; and

(b) aminosulfonyl optionally substituted with one or two independently selected alkylsalicylate.

[00282] In some embodiments, implementation, each RKindependently selected from the group consisting of AMI is sulfonyl and alkylsulfonyl.

C. modifications of the compounds of formula I.

[00283] Various modifications of the substituents R1, R2, R3, R4, R5, L, RA, RB, RC, RD, R6, RE, RF, RG, RH, RI, RJand RKwere discussed above. These modifications of the substituents may be combined to produce different variants of embodiment of compounds of formula I. All variants of embodiments of compounds of formula I formed by combining modifications of the substituents discussed above, included in the scope of Applicants invention, some illustrative options embodiments of compounds of formula I are presented below.

[00284] In some embodiments, the implementation, the compounds of the formula I:

selected from the group consisting of single carbon-carbon links and double carbon-carbon linkages;

R1selected from the group consisting of hydrogen and methyl;

R2selected from the group consisting of hydrogen and halogen;

R3selected from the group consisting of hydrogen and halogen;

R4selected from the group consisting of C1-C4-alkyl, C3-C6-carbocycle and 5-6-membered heterocyclyl where:

(a) C1-C4-alkyl optionally substituted by substituents with up to three independently selected and from the group consisting of halo, oxo, hydroxy, alkyloxy and trimethylsilyl, and

(b) (C3-C6-carbocyclic and 5-6-membered heterocyclyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl, halo, alkylsulfonyl;

R5selected from the group consisting of hydrogen, hydroxy, alkyloxy and halo;

L is selected from the group consisting of C(RA)=C(RB), ethylene and cyclopropyl-1,2-ene;

one of RAand RBrepresents hydrogen and the other is selected from the group consisting of hydrogen, methyl, methoxy, and halo;

R6selected from the group consisting of C5-C6-carbocycle and 5-6-membered heterocyclyl, where each such Deputy substituted one, two or three substituents, independently selected from the group consisting of RE, RFand RJ;

each REindependently selected from the group consisting of chlorine, fluorine, nitro, hydroxy, oxo, carboxy, amino, imino, aldehyde, alkylamino;

each RFis an independently selected alkyl, optionally substituted Deputy selected from the group consisting of carboxy, halo, amino, imino and aminosulfonyl where:

amino, imino and aminosulfonyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl, alcalali the onila, alkylsulfonamides;

each RIindependently selected from the group consisting of alkylcarboxylic and aminocarbonyl where:

aminocarbonyl optionally substituted Deputy selected from the group consisting of alkyl, alkyloxyalkyl, alkylsulfonyl, alkylsulfonyl; and

each RJindependently selected from the group consisting of alkylsulfonyl, alkanesulfonyl, alkylsulfonyl, alkylsulfonamides where:

(a) the amino portion of such substituents optionally is substituted by the Deputy, is independently selected from the group consisting of carbocyclic, geterotsiklicheskikh, alkylcarboxylic, aminocarbonylmethyl, alkyl, alkylsulphonyl, allyloxycarbonyl, allyloxycarbonyl, alkylcarboxylic and alkylsulfonyl where:

(1) carbonilla part of carbocyclic and heterocyclyl part of geterotsiklicheskikh optionally substituted by one or more substituents independently selected from the group consisting of alkyl, carboxy, hydroxy, alkyloxy, halo, nitro, cyano, oxo and amino, and

(2) the amino portion of aminocarbonylmethyl optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkenyl and quinil,

(b) alkyl, Alchemilla and Alchemilla portion of such substituents optionally is substituted by one or two Deputy is mi, independently selected from the group consisting of carboxy, halo, oxo, amino, allyloxycarbonyl, alkylcarboxylic, hydroxy, alkyloxy, carbocycle, heterocyclyl and cyano, where:

amino optionally substituted by one or two substituents, independently selected from the group consisting of alkyl, alkyloxy, where alkyl optionally substituted by one or more hydroxy.

[00285] Examples of compounds of formula I (and their salts) are given in Tables 1-7 below. Examples of synthesis described below provide step-by-step instructions on how to obtain some of these compounds. Other compounds obtained using General review of the production method, specific examples of synthesis described below, and/or discussion throughout the text of this application.

TABLE 1
connectionR5RBDeputy(s)
IA-L1-1.3-Och3-Cl-4-N(H)S(O)2CH3[Z]
IA-L1-1.4-Och3 -F-4-N(H)S(O)2CH3[Z]
IA-L1-1.5-Och3-F-4-N(H)S(O)2CH3[E]
IA-L1-1.6-Och3-CH3-4-N(H)S(O)2CH3[E]
IA-L1-1.9-Och3-N-4-N(H)S(O)2CH3[E]
IA-L1-1.10-Och3-N-4-N(H)S(O)2CH3[Z]
IA-L1-1.11-Och3-N-4-N[C(O)CH3]S(O)2CH3[E]
IA-L1-1.12-Och3-N-4-F [E]
IA-L1-1.13-Och3-N-4-NH2[E]
IA-L1-1.14-Och3-N-4-och3[E]
IA-L1-1.16 -N-N-4-N(H)S(O)2CH3[E]
IA-L1-1.17-Och3-Och3-4-N(H)S(O)2CH3[Z]
IA-L1-1.18-Och3-N- [E]
IA-L1-1.20-Och3-N-4-N(H)S(O)2CH3[Z]
IA-L1-1.21-Och3-F-4-N(H)S(O)2CH3[Z]:[E](1:1)
IA-L1-1.22-Och3-N-4-NO2[E]
IA-L1-1.23-Och3-Cl-4-NO2[Z]
IA-L1-1.24-Och3-CH3-4-NO2[E]
IA-L1-1.25-N-N-4-NO2[E]
IA-L1-1.26-N-3-F-4-N(H)S(O)2CH3[E]
IA-L1-1.27-Och3-N-2-och3and-4-N(H)S(O)2CH3[E]

TABLE 2
connectionDeputy(s)
IB-L1-1.1-4-N(H)S(O)2CH3[E]
IB-L1-1.4-2-C(O)HE-4-N(H)S(O)2CH3[E]
IB-L1-1.5-3-F-4-N(H)S(O)2CH3[E]
IB-L1-1.6-2-C(O)H and-4-N(H)S(O)2CH3[E]
IB-L1-1.7-2-C(O)och3and-4-N(H)S(O)2CH3[E]
IB-L1-1.8-2-C(H)=N(OH) and-4-N(H)S(O)2CH3[E]
IB-L1-1.9-2-C(O)N(H)CH2CH2OCH3and-4-N(H)S(O)2CH3[E]
IB-L1-1.10-2-CH2OH and-4-N(H)S(O)2CH3[E]
IB-L1-1.11-2-S(O)OS(H)2CH3and-4-N(H)S(O)2CH3[E]
IB-L1-1.13-2-C(H)2OCH3and-4-N(H)S(O)2CH3[E]
IB-L1-1.14-2-C(O)N(CH3)2 and-4-N(H)S(O)2CH3[E]
IB-L1-1.15-2-CH3and-4-N(H)S(O)2CH3and-5-F [E]
IB-L1-1.16imidazol-2-yl-4-N(H)S(O)2CH3[E]
IB-L1-1.17-2-C(O)N(H)CH3and-4-N(H)S(O)2CH3[E]
IB-L1-1.18-2and-4-N(H)S(O)2CH3[E]
IB-L1-1.19-2-C(H)=NOCH3and-4-N(H)S(O)2CH3[E]
IB-L1-1.21-2-C(O)NH2and-4-N(H)S(O)2CH3[E]
IB-L1-1.22-2and-4-N(H)S(O)2CH3[E]
IB-L1-1.23-2and-4-N(H)S(O)2CH3[E]
IB-L1-1.24-2-C(O)N(CH3)C(H)2C(H)2OCH3and-4-N(H)S(O)2CH3[E]

connectionDeputy(s)
IB-L1-1.25-2-C(H)2OC(N)(SN3)2and-4-N(H)S(O)2CH3[E]
IB-L1-1.26-2and-4-N(H)S(O)2CH3[E]
IB-L1-1.27-2and-4-N(H)S(O)2CH3[E]
IB-L1-1.28-2-NH2and-4-N(H)S(O)2CH3[E]
IB-L1-1.29-2and-4-N(H)S(O)2CH3[E]
IB-L1-1.31-2-C(H)2N(H)C(H)2C(H)2C(H)(CH3)2 and-4-N(H)S(O)2CH3[E]
IB-L1-1.32-2-N(H)C(O)OC(CH3)3and-4-N(H)S(O)2CH3[E]
IB-L1-1.33-2and-4-N(H)S(O)2 CH3[E]
IB-L1-1.34-4-N(H)S(O)2CH3[Z]
TABLE 3
connectionR4
IB-L1-1.45- (CH3)2C(H)2OH [F]
IB-L1-1.46furan-2-yl [E]
IB-L1-1.47[E]
IB-L1-1.48[E]
IB-L1-1.49-S(O)2CH3[E]
IB-L1-1.50furan-3-yl [E]
IB-L1-1.51-I [E]
IB-L1-1.52-Br [E]
IB-L1-1.53pyridine-3-yl [E]
IB-L1-1.55pyridine-4-yl [E]

TABLE 4
connectionR2R5
IB-L1-1.2-F-Och3[E]
IB-L1-1.12-N-Cl [E]
IB-L1-1.20-Cl-Och3[E]
IB-L1-1.30-N-Och2CH3[E]
TABLE 5
connectionR5
IA-L5-2-1.1-Och3
IA-L5-2-1.2-N
TABLE 6
connectionDeputy(s)
IB-L5-2-1.1-2-C(O)och3and-4-N(H)S(O)2CH3
IB-L5-2-1.2-4-N(H)S(O)2CH3

TABLE 7

D. Isomers.

[00286] the Present invention partially applies to all isomers of the compounds of formula I (and their salts) (i.e., structural and stereoisomers). Structural isomers include the chain and position isomers. Stereoisomers include E/Z isomers (i.e., isomers relative to one or more double bonds), the enantiomers (i.e., stereoisomers, which have the opposite configuration at all stereogenic centers), and diastereoisomer (i.e., stereoisomers, which have the same configuration at one or more stereogenic centers, but great at other stereogenic centers).

Or Salt.

[00287] the Present invention also relates, in part, to all salts of the compounds of formula I. Salt compounds may be site is titelnoj due to one or more properties of salt, for example, such as enhanced pharmaceutical stability at different temperatures and humidity, or a desirable solubility in water or other solvents. In cases where salt is intended for introduction to the patient (unlike, for example, from the use in the context of in vitro), salt preferably is pharmaceutically acceptable and/or physiologically compatible. The term "pharmaceutically acceptable" is used as an adjective in this patent application to indicate that the defined noun suitable for use as a pharmaceutical product or as part of a pharmaceutical product. Pharmaceutically acceptable salts include the salts commonly used for the formation of salts of alkali metals and for the formation of additive salts of free acids or free bases. Basically, these salts can be obtained by conventional methods, through interaction, for example, the appropriate acid or base with the compound according to the invention.

[00288] Pharmaceutically acceptable acid additive salts of compounds of formula I may be derived from inorganic or organic acids. Examples in many cases, suitable inorganic acids include hydrochloric, Hydrobromic, yodiewonderdog, nitric, carbonic, sulfuric and ostroy acid. Suitable organic acids generally include, for example, aliphatic, cycloaliphatic, aromatic, analiticheskie, heterocyclic, carboxylic and sulfonic classes of organic acids. Specific examples in many cases, 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, aminobenzoic acid, mesilate, stearate, salicylate, p-hydroxybenzoate, phenyl acetate, salt almond acid, embonate (pamoate), aconsultant, bansilalpet, Pantothenate, 2-hydroxyethanesulfonic, sulfanilic, cyclohexylsulfamate, alginic acid, beta-hydroxybutiric acid, galactarate, galacturonic, adipate, alginate, bisulfate, butyrate, comfort, camphorsulfonate, cyclopentanepropionate, dodecyl sulphate, glucoheptonate, glycyrrhizinate, heptanoate, hexanoate, nicotinate, oxalate, palmoate, pectinate, 2-naphthalenesulfonate, 3-phenylpropionate, picrate, pivalate, thiocyanate, tosylate, undecanoate.

[00289] Pharmaceutically acceptable basic salt additive compounds of formula I include, for example, metal salts and organic salts. Preferred metal salts include salts of alkali metals (group Ia) salts, Melo rosemaling metals (group IIa) and other physiologically acceptable metal salts. Such salts can be obtained with aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be obtained with amines, such as tromethamine, diethylamine, N,N'-dibenziletilendiaminom, chloroprocaine, choline, diethanolamine, Ethylenediamine, meglumine (N-methylglucamine), and procaine. The basic nitrogen-containing groups can be stereoselectivity of such agents as lower alkyl (C1-C6) halide {e.g., methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), diallylsulfide (e.g., dimethyl, diethyl, dibutil and dimycolate), halide long chain (e.g., decyl, lauryl, miratel and stearyl chlorides, bromides and iodides), arylalkyl halide (for example, benzyl and phenethyl bromides), and others.

[00290] In some embodiments, implementation, salt is a sodium salt of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-pyrimidine-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00291] In some embodiments, implementation, salt is a disodium salt of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00292] In some embodiments, implementation, salt is a potassium salt of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00293] In some embodiments, implementing the tvline, salt is Moncalieri salt (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

F. Clean.

[00294] the compounds of formula I (and their salts) of any purity level (including pure and essentially pure) are included in the scope of the present invention. The term "essentially pure" in relation to the compound/salt/isomer, means that the product/composition containing the compound/salt/isomer contains more than about 85% by weight of the compound/salt/isomer, preferably more than about 90% by weight of the compound/salt/isomer, preferably more than about 95% by weight of the compound/salt/isomer, preferably more than about 97% by weight of the compound/salt/isomer, and preferably more than about 99% by weight of the compound/salt/isomer.

G. Crystalline forms of some specific compounds and salts according to the present invention.

G1. Crystalline forms of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide, disodium salt.

[00295] the Present invention also relates, in part, to crystalline forms of disodium salt of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide, namely deviationism and chetyrekhtomnym crystalline forms, discussed below.

[00296] This is the invention relates, partly, to deviational crystalline disodium salt. The crystallographic unit cell parameters deviations crystalline disodium salt were identified as the following: as of 8.9 Å, b is equal to 9.4 Å and equal to 20.7 Å (more accurately, as well as 8,926(2)Å, b is 9,415(2)Å, and C is 20,674(5)Å); the corners of the cell are: α - 94,8°, β - 93,3°, and γ - 107,0° (more precisely, α is equal to 94,796(4)°, β is equal to 93,345(4)0and γ equal 107,013(4)°); and the cell volume is 1649Å3(more precisely, 1649,3(7)Å3). This salt crystallizes in the space group P-1.

[00297] In some embodiments, implementation, deviationa disodium salt has a powder x-ray containing one or more peaks selected from the group consisting of 4,3±0,2, 10,4±0,2, 10,9±0,2, 11,6±0,2, 12,9±0,2, 14,7±0,2, 16,4±0,2, 17,8±0,2, 19,4±0,2, 19,8±0,2, 20,8±0,2, 21,9±0,2 and 23.5±0.2 degrees 2θ. In some such embodiments, implementation, deviationa disodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 4,3±0,2, 10,4±0,2, 10,9±0,2, 11,6±0,2, 12,9±0,2, 14,7±0,2, 16,4±0,2, 17,8±0,2, 19,4±0,2, 19,8±0,2, 20,8±0,2, 21,9±0,2 and 23.5±0.2 degrees 2θ. In other such embodiments, implementation, deviationa disodium salt has a powder x-ray that contains five or more peaks selected from the group consisting of 4,3±0,2, 10,4±0,2, 10,9±0,2, 11,6±0,2, 12,9±0,2, 14,7±0,2, 16,4±0,2, 17,8±0,2, 19,4±0,2, 19,8±0,2, 20,8±0,2, 21,9±0,2 and 23.5±0.2 degrees is in 2θ.

[00298] In some embodiments, implementation, deviationa disodium salt has a powder x-ray containing one or more peaks selected from the group consisting of 4,3±0,2, 10,4±0,2, 10,9±0,2, 11,6±0,2, 12,9±0,2, 14,7±0,2, 14,9±0,2, 16,4±0,2, 17,8±0,2, 19,4±0,2, 19,7±0,2, 19,8±0,2, 20,8±0,2, 20,9±0,2, 21,9±0,2, 22,1±0,2 and 23.5±0.2 degrees 2θ. In some such embodiments, implementation, deviationa disodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 4,3±0,2, 10,4±0,2, 10,9±0,2, 11,6±0,2, 12,9±0,2, 14,7±0,2, 14,9±0,2, 16,4±0,2, 17,8±0,2, 19,4±0,2, 19,7±0,2, 19,8±0,2, 20,8±0,2, 20,9±0,2, 21,9±0,2, 22,1±0,2 and 23.5±0.2 degrees 2θ. In other such embodiments, implementation, deviationa disodium salt has a powder x-ray that contains five or more peaks selected from the group consisting of 4,3±0,2, 10,4±0,2, 10,9±0,2, 11,6±0,2, 12,9±0,2, 14,7±0,2, 14,9±0,2, 16,4±0,2, 17,8±0,2, 19,4±0,2, 19,7±0,2, 19,8±0,2, 20,8±0,2, 20,9±0,2, 21,9±0,2, 22,1±0,2 and 23.5±0.2 degrees 2θ.

[00299] In some embodiments, implementation, deviationa disodium salt has a powder x-ray are, essentially, as shown in Figure 1. Size 29 for peaks in Figure 1 (and their intensities) are the following: 4,31 (100), 10,36 (12), 10,91 (23), 11,61 (52), 12,93 (24), 14,73 (65), 14,89 (20), 16,44 (41), 17,80 (38), 19,44 (26), 19,67 (37), 19,83 (59), 20,75 (69), 20,89 (21), 21,92 (43), 22,13 (40) and are 22.42 (24).

[00300] the Present invention also relates, in part, to a method for deviations Dimitriev the th of salt. It was received in the aquatic environment. Aqueous NaOH (1M, of 1.18 ml) was added to (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide (compound IB-L1-1.1) (27,82 mg) (molar ratio of 1:20 acid:base). The resulting suspension was balanced in ambient conditions. Deviationa disodium salt formed after seven days in the process, mediated dissolution. Alternatively, desativado disodium salt was obtained by suspension much as 278.8 mg of compound IB-L1-1.1 1.25 ml of THF by heating to approximately 50°C. was Added aqueous NaOH (1 n, 1.5 ml and 2.2 molar equivalent). The solid was dissolved completely with the formation of a clear solution, which naturally cooled to ambient temperature. This salt crystallized spontaneously. The molecular structure was determined using single crystal diffraction.

[00301] the Present invention relates, in part, to chetyrehbalnoy crystalline disodium salt.

[00302] In some embodiments, implementation, cetarehwodie disodium salt has a powder x-ray containing one or more peaks selected from the group consisting of 4,8±0,2, 12,1±0,2, 14,0±0,2, 17,0±0,2, 17,5±0,2, 20,9±0,2, 21,6±0,2, 25,0±0,2 and 29.5±0.2 degrees 2θ. In some such embodiments, implementation, cetarehwodie disodium salt has a powder x is the programs containing three or more peaks selected from the group consisting of 4,8±0,2, 12,1±0,2, 14,0±0,2, 17,0±0,2, 17,5±0,2, 20,9±0,2, 21,6±0,2, 25,0±0,2 and 29.5±0.2 degrees 2θ. In other such embodiments, implementation, cetarehwodie disodium salt has a powder x-ray that contains five or more peaks selected from the group consisting of 4,8±0,2, 12,1±0,2, 14,0±0,2, 17,0±0,2, 17,5±0,2, 20,9±0,2, 21,6±0,2, 25,0±0,2 and 29.5±0.2 degrees 2θ.

[00303] In some embodiments, implementation, cetarehwodie disodium salt has a powder x-ray containing one or more peaks selected from the group consisting of 4,8±0,2, 12,1±0,2, 14,0±0,2, 14,4±0,2, 17,0±0,2, 17,5±0,2, 20,9±0,2, 21,6±0,2, 25,0±0,2, 29,5±0,2 and 34.2±0.2 degrees 2θ. In some such embodiments, implementation, cetarehwodie disodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 4,8±0,2, 12,1±0,2, 14,0±0,2, 14,4±0,2, 17,0±0,2, 17,5±0,2, 20,9±0,2, 21,6±0,2, 25,0±0,2, 29,5±0,2 and 34.2±0.2 degrees 2θ. In other such embodiments, implementation, cetarehwodie disodium salt has a powder x-ray that contains five or more peaks selected from the group consisting of 4,8±0,2, 12,1±0,2, 14,0±0,2, 14,4±0,2, 17,0±0,2, 17,5±0,2, 20,9±0,2, 21,6±0,2, 25,0±0,2, 29,5±0,2 and 34.2±0.2 degrees 2θ.

[00304] In some embodiments, implementation, cetarehwodie disodium salt has a powder x-ray are, essentially, as shown in Figure 2. The 2θ values for the peaks on the Figo is e 2 (and their intensities) are the following: 4,81 (100), 12,07 (7), 14,01 (27), 14,41 (8), 16,96 (18), 17,53 (11), 20,87 (18), 21,58 (22), 24,99 (11), 29,47 (9) and 34,20 (9).

[00305] the Present invention also relates, in part, to a method for chetyrehbalnoy disodium salt by suspension deviational disodium salt in an organic solvent (e.g. ethanol, 1-propanol or 2-propanol).

G2. The crystalline form of Pikalevo salt (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00306] the Present invention also relates, in part, to the crystalline chetyrehbalnoy Pikalevo salt (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00307] Crystallographic unit cell parameters chetyrehbalnoy Pikalevo salt were determined as follows: a is equal to 14.5 Å, b is about 10.8 Å and equal to 35.8 Å (more accurately, as well as 14,454(14)Å, b is 10,763(14)Å, and C is 35,75(4)Å); the angle of the cell is: β is 98.8° (more precisely, β is 98,82(3)°); and the cell volume is 5499Å3(more precisely, 5499(11)Å3). This salt crystallizes in the space group C2/C.

[00308] In some embodiments, implementation, cetarehwodie dikalova salt has a powder x-ray containing one or more peaks selected from the group consisting of 5,0±0,2, 11,9±0,2, 12,4±0,2, 13,7±0,2, 15,0±0,2, 16,5±0,2, 17,1±0,2, 20,8±0,2, 21,3±0,2, 22,2±0,2, 24,0±0,2, 26,4±0,2 and of 29.3±0.2 g is adosow 2θ. In some such embodiments, implementation, cetarehwodie dikalova salt has a powder x-ray that contains three or more peaks selected from the group consisting of 5,0±0,2, 11,9±0,2, 12,4±0,2, 13,7±0,2, 15,0±0,2, 16,5±0,2, 17,1±0,2, 20,8±0,2, 21,3±0,2, 22,2±0,2, 24,0±0,2, 26,4±0,2 and of 29.3±0.2 degrees 2θ. In other such embodiments, implementation, cetarehwodie dikalova salt has a powder x-ray that contains five or more peaks selected from the group consisting of 5,0±0,2, 11,9±0,2, 12,4±0,2, 13,7±0,2, 15,0±0,2, 16,5±0,2, 17,1±0,2, 20,8±0,2, 21,3±0,2, 22,2±0,2, 24,0±0,2, 26,4±0,2 and of 29.3±0.2 degrees 2θ.

[00309] In some embodiments, implementation, cetarehwodie dikalova salt has a powder x-ray containing one or more peaks selected from the group consisting of 5,0±0,2, 11,9±0,2, 12,4±0,2, 12,6±0,2, 13,7±0,2, 15,0±0,2, 16,5±0,2, 16,7±0,2, 17,1±0,2, 20,7±0,2, 20,8±0,2, 21,3±0,2, 22,2±0,2, 22,4±0,2, 24,0±0,2, 26,4±0,2 and of 29.3±0.2 degrees 2θ. In some such embodiments, implementation, cetarehwodie dikalova salt has a powder x-ray that contains three or more peaks selected from the group consisting of 5,9±0,2, 11,9±0,2, 12,4±0,2, 12,6±0,2, 13,7±0,2, 15,0±0,2, 16,5±0,2, 16,7±0,2, 17,1±0,2, 20,7±0,2, 20,8±0,2, 21,3±0,2, 22,2±0,2, 22,4±0,2, 24,0±0,2, 26,4±0,2 and of 29.3±0.2 degrees 2θ. In other such embodiments, implementation, cetarehwodie dikalova salt has a powder x-ray that contains five or more peaks selected from the group consisting of 5,0±0,2, 11,9±0,2, 12,4±0,2, 12,6±0,2, 13,7±0,2, 15,0�0,2, 16,5±0,2, 16,7±0,2, 17,1±0,2, 20,7±0,2, 29,8±0,2, 21,3±0,2, 22,2±0,2, 22,4±0,2, 24,9±0,2, 26,4±0,2 and of 29.3±0.2 degrees 2θ.

[00310] In some embodiments, implementation, cetarehwodie dikalova salt has a powder x-ray are, essentially, as shown in Figure 4. The 2θ values for the peaks in Figure 4 (and their intensities) are the following: 5,99 (199), 11,86 (34), 12,39 (32), 12,64 (19), 13,79 (23), 15,93 (21), 16,47 (24), 16,66 (24), 17,12 (28), 29,75 (29), 29,81 (33), 21,34 (22), 22,15 (46), 22,38 (31), 24,92 (24), 26,44 (24) and 29,32 (21).

[00311] the Present invention also relates, in part, to a method for chetyrehbalnoy Pikalevo salt by suspension of compound IB-L1-1.1 (261,13 mg) in 1.25 ml THF by heating to about 59°C. was Added KOH (1 n, 1.3 ml, of 2.2 molar equivalent). The solid is completely dissolved with the formation of a clear solution, which naturally cooled to ambient temperature. Crystallization occurred during the slow evaporation process.

G3. Crystalline forms of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide montalieu salt.

[00312] the Present invention also relates, in part, to crystalline forms of montalieu salt (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide, namely trihydrate and dowolnym crystalline forms, discussed below.

[0313] the Present invention relates, partly, to trihydrate montalieu salt. The crystallographic unit cell parameters trihydrate crystal montalieu salts were determined by the following: A. equal to 9.0 Å, b is equal to 8.3 Å and equal to 18.6 Å (more accurately, as well as 9,9393(16)Å, b is 8,3332(15)Å, and C is 18,582(3)Å); the corners of the cell are: α - 89,5°, β - 85,1°, and γ - 80.5° (more precisely, α is equal to 80,511(2)°, β is equal to 85,134(3)°, and equal 89,531(2)°); and the cell volume is 1359Å3(more precisely, 1359,3(4)Å3). This salt crystallizes in the space group P-1.

[00314] In some embodiments, implementation, trihydrate monogalia salt has a powder x-ray containing one or more peaks selected from the group consisting of 4,8±0,2, 19,8±0,2, 11,3±0,2, 13,4±0,2, 15,3±0,2, 16,9±0,2, 21,2±0,2, 21,7±0,2, 22,1±0,2, 22,5±0,2 and 23.0±0.2 degrees 2θ. In some such embodiments, implementation, trihydrate monogalia salt has a powder x-ray that contains three or more peaks selected from the group consisting of 4,8±0,2, 10,8±0,2, 11,3±0,2, 13,4±0,2, 15,3±0,2, 16,9±0,2, 21,2±0,2, 21,7±0,2, 22,1±0,2, 22,5±0,2 and 23.0±0.2 degrees 2θ. In other such embodiments, implementation, trihydrate monogalia salt has a powder x-ray that contains five or more peaks selected from the group consisting of 4,8±0,2, 10,8±0,2, 11,3±0,2, 13,4±0,2, 15,3±0,2, 16,9±0,2, 21,2±0,2, 21,7±0,2, 22,1±0,2, 22,5±0,2 and 23.0±0.2 degrees 2θ.

[00315] In some embodiments, implementation, trihydrate mon the potassium salt has a powder x-ray, containing one or more peaks selected from the group consisting of 4,8±0,2, 10,8±0,2, 11,3±0,2, 13,4±0,2, 13,6±0,2, 15,3±0,2, 16,9±0,2, 21,2±0,2, 21,7±0,2, 21,7±0,2, 22,1±0,2, 22,5±0,2, 22,6±0,2 and 23.0±0.2 degrees 2θ. In some such embodiments, implementation, trihydrate monogalia salt has a powder x-ray that contains three or more peaks selected from the group consisting of 4,8±0,2, 10,8±0,2, 11,3±0,2, 13,4±0,2, 13,6±0,2, 15,3±0,2, 16,9±0,2, 21,2±0,2, 21,7±0,2, 21,7±0,2, 22,1±0,2, 22,5±0,2, 22,6±0,2 and 23.0±0.2 degrees 2θ. In other such embodiments, implementation, trihydrate monogalia salt has a powder x-ray that contains five or more peaks selected from the group consisting of 4,8±0,2, 10,8±0,2, 11,3±0,2, 13,4±0,2, 13,6±0,2, 15,3±0,2, 16,9±0,2, 21,2±0,2, 21,7±0,2, 21,7±0,2, 22,1±0,2, 22,5±0,2, 22,6±0,2 and 23.0±0.2 degrees 2θ.

[00316] In some embodiments, implementation, trihydrate monogalia salt has a powder x-ray containing one or more peaks selected from the group consisting of 4,8±0,2, 10,8±0,2, 11,3±0,2, 13,4±0,2, 13,6±0,2, 15,3±0,2, 16,9±0,2, 21,2±0,2, 21,7±0,2, 21,7±0,2, 22,1±0,2, 22,5±0,2, 22,6±0,2 and 23.0±0.2 degrees 2θ. In some such embodiments, implementation, trihydrate monogalia salt has a powder x-ray that contains three or more peaks selected from the group consisting of 4,8±0,2, 10,8±0,2, 11,3±0,2, 13,4±0,2, 15,3±0,2, 16,9±0,2, 21,2±0,2, 21,7±0,2, 22,1±0,2, 22,5±0,2 and 23.0±0.2 degrees 2θ. In other such embodiments, implementation, trihydrate monogalia salt has oroscopogratisonline, containing five or more peaks selected from the group consisting of 4,8±0,2, 10,8±0,2, 11,3±0,2, 13,4±0,2, 15,3±0,2, 16,9±0,2, 21,2±0,2, 21,7±0,2, 22,1±0,2, 22,5±0,2 and 23.0±0.2 degrees 2θ.

[00317] In some embodiments, implementation, trihydrate monogalia salt has a powder x-ray are, essentially, as shown in Figure 5. The 2θ values for the peaks in Figure 5 (and their intensities) are the following: 4,83 (60), 10,79 (100), 11,31 (22), 13,42 (41), 13,59 (18), 15,32 (21), 16,90 (38), 21,24 (22), 21,68 (20), 21,68 (21), 22,15 (22), 22,55 (29), 22,63 (23) and 23,02 (27).

[00318] the Present invention also relates, in part, to a method for the trihydrate montalieu salt. It is obtained by suspension of compound IB-L1-1.1 (108,81 mg) in 0.4 ml of THF by heating to approximately 50°C. was Added an aqueous solution of KOH (1 n, 0,278 ml of 1.2 molar equivalent). The solid was dissolved completely with formation of a transparent solution. To the solution was added addition of 1.6 ml of THF, which is then naturally cooled to ambient temperature, and watched the crystallization. Alternatively, trihydrate Moncalieri salt was obtained by suspension of compound IB-L1-1.1 (343,89 mg) in 1.0 ml THF by heating to 50°C. was Added aqueous KOH (1 n, of 0.878 ml, and 1.2 molar equivalent). The solid was dissolved completely with formation of a transparent solution. To the solution was added dropwise ethanol to a total volume of 4.0 ml of This solution then is was gladly naturally to ambient temperature and was observed crystallization.

[00319] the Present invention relates, in part, to dowdney montalieu salt.

[00320] In some embodiments, implementation, dvuvodny monogalia salt has a powder x-ray containing one or more peaks selected from the group consisting of 7,7±0,2, 8,8±0,2, 16,1±0,2 and 19.7±0.2 degrees 2θ. In some such embodiments, implementation, dvuvodny monogalia salt has a powder x-ray that contains three or more peaks selected from the group consisting of degrees 2θ.

[00321] In some embodiments, implementation, dvuvodny monogalia salt has a powder x-ray containing one or more peaks selected from the group consisting of 7,7±0,2, 8,8±0,2, 12,4±0,2, 14,0±0,2, 16,1±0,2, 17,7±0,2, 19,2±0,2, 19,7±0,2, 23,1±0,2 and 29.2±0.2 degrees 2θ. In some such embodiments, implementation, dvuvodny monogalia salt has a powder x-ray that contains three or more peaks selected from the group consisting of 7,7±0,2, 8,8±0,2, 12,4±0,2, 14,0±0,2, 16,1±0,2, 17,7±0,2, 19,2±0,2, 19,7±0,2, 23,1±0,2 and 29.2±0.2 degrees 2θ. In other such embodiments, implementation, dvuvodny monogalia salt has a powder x-ray that contains five or more peaks selected from the group consisting of 7,7±0,2, 8,8±0,2, 12,4±0,2, 14,0±0,2, 16,1±0,2, 17,7±0,2, 19,2±0,2, 19,7±0,2, 23,1±0,2 and 29.2±0.2 degrees 2θ.

[00322] In some embodiments, implementation, dvuvodny monogalia salt has a powder x-ray of the gram, essentially, as shown in Figure 6. The 2θ values for the peaks in Figure 6 (and their intensities) are the following: 7,68 (19), 8,83 (100), 12,40 (7), 13,97 (10), 16,12 (25), 17,75 (9), 19,22 (12), 19,73 (40), 23,05 (9) and 29,21 (7).

[00323] the Present invention also relates, in part, to a method for dowdney montalieu salt. It was prepared by suspension trihydrate montalieu salt in a medium with low water activity, such as a mixture of ethanol/N2On (50/1 V/V). Alternatively, duvignau Moncalieri salt was obtained by dissolving solid trihydrate potassium (1.8 g) in 36 ml of IPA and 4 ml of water at 80°C. the resulting solution was cooled to 55°C for 1 h, This solution was then led to the use of 7.5 mg of crystals of the dihydrate at 55°C and maintained at 55°C for 1 h and Then was added heptane (36 ml) for 3 hours, the Reaction mixture was cooled to 0°C., and filtering gave substance containing crystals as di-, and three-hydrate. The solid is then resuspendable in 20 ml of 10:1 V/V EtOH/H2O at 50°C for 3 h and cooled to 25°C for 5 hours, the Suspension is then stirred at 25°C for an additional 3 days and cooled to 0°C for 3 h and kept at this temperature for 2 hours the resulting crystals were filtered and dried in the air in a separating funnel for 1 h with getting dihydrate. Duvignau of montalieu the Yu salt was also obtained by suspension of a mixture of dihydrate crystals and three-hydrate in 10:1 V/V EtOH/H 2O at 80°C for 2 days. The potassium content was confirmed using ion chromatography.

G4. Crystalline form 1/7 potassium salt (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00324] the Present invention also relates, in part, to the crystalline form 1/7 potassium salt (E)-N-(4-(3-tert-butyl-5 -(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00325] In some embodiments, implementation, 1/7 potassium salt has a powder x-ray containing one or more peaks selected from the group consisting of 7,7±0,2, 8,3±0,2, 10,1±0,2, 10,6±0,2, 11,4±0,2, 12,0±0,2, 13,4±0,2, 15,6±0,2, 16,3±0,2, 16,7±0,2, 17,2±0,2, 18,3±0,2, 18,8±0,2, 19,4±0,2, 19,9±0,2, 20,2±0,2, 20,5±0,2, 21,2±0,2, 22,1±0,2 and 22.9±0.2 degrees 2θ. In some such embodiments, implementation, 1/7 potassium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 7,7±0,2, 8,3±0,2, 10,1±0,2, 10,6±0,2, 11,4±0,2, 12,0±0,2, 13,4±0,2, 15,6±0,2, 16,3±0,2, 16,7±0,2, 17,2±0,2, 18,3±0,2, 18,8±0,2, 19,4±0,2, 19,9±0,2, 20,2±0,2, 20,5±0,2, 21,2±0,2, 22,1±0,2 and 22.9±0.2 degrees 2θ. In other such embodiments, implementation, 1/7 potassium salt has a powder x-ray that contains five or more peaks selected from the group consisting of 7,7±0,2, 8,3±0,2, 10,1±0,2, 10,6±0,2, 11,4±0,2, 12,0±0,2, 13,4±0,2, 15,6±0,2, 16,3±0,2, 16,7±0,2, 17,2±0,2, 18,3±0,2, 18,8±0,2, 19,4±0,2, 19,9±0,2, 20,2±0,2, 20,5±0,2, 21,2±0,2, 22,1±0,2 and 22.9±0.2 degrees 2θ.

[00326] In some embodiments, implementation, 1/7 potassium salt has a powder x-ray containing one or more peaks selected from the group consisting of 7,7±0,2, 8,3±0,2, 10,1±0,2, 10,6±0,2, 11,4±0,2, 12,0±0,2, 13,4±0,2, 15,6±0,2, 16,3±0,2, 16,7±0,2, 17,2±0,2, 18,3±0,2, 18,8±0,2, 19,4±0,2, 19,9±0,2, 20,2±0,2, 20,5±0,2, 20,8±0,2, 21,2±0,2, 22,1±0,2, 22,9±0,2, 24,3±0,2, 24,9±0,2 and 25.1±0.2 degrees 2θ. In some such embodiments, implementation, 1/7 potassium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 7,7±0,2, 8,3±0,2, 10,1±0,2, 10,6±0,2, 11,4±0,2, 12,0±0,2, 13,4±0,2, 15,6±0,2, 16,3±0,2, 16,7±0,2, 17,2±0,2, 18,3±0,2, 18,8±0,2, 19,4±0,2, 19,9±0,2, 20,2±0,2, 20,5±0,2, 20,8±0,2, 21,2±0,2, 22,1±0,2, 22,9±0,2, 24,3±0,2, 24,9±0,2 and 25.1±0.2 degrees 2θ. In other such embodiments, implementation, 1/7 potassium salt has a powder x-ray that contains five or more peaks selected from the group consisting of 7,7±0,2, 8,3±0,2, 10,1±0,2, 10,6±0,2, 11,4±0,2, 12,0±0,2, 13,4±0,2, 15,6±0,2, 16,3±0,2, 16,7±0,2, 17,2±0,2, 18,3±0,2, 18,8±0,2, 19,4±0,2, 19,9±0,2, 20,2±0,2, 20,5±0,2, 20,8±0,2, 21,2±0,2, 22,1±0,2, 22,9±0,2, 24,3±0,2, 24,9±0,2 and 25.1±0.2 degrees 2θ.

[00327] In some embodiments, implementation, 1/7 potassium salt has a powder x-ray are, essentially, as shown in Figure 8. Size 29 for the peaks in Figure 8 (and their intensities) are the following: 7,71 (19), 8,33 (34), 10,10 (100), 10,66 (29), 11,39 (27), 12,04 (22), 13,39 (39), 15,56 (41), 16,27 (62), 16,69 (70), 17,22 (59), 18,31 (18), 18,78 (47), 19,44 (36), 19,89 (28), 20,19 (33), 20,54 (87), 20,80 (33), 21,15 (47), 22,05 (24), 22,82 (67), 24,32 (22), 24,87 (22) and 5,07 (33).

[00328] the Present invention also relates, in part, to a method for 1/7 potassium salt. It was prepared by suspension of compound IB-L1-1.1 (2 g) in 6 ml THF at 50°C. was Added one molar equivalent of KOH, dissolved in 4.3 ml of water, and the reaction mixture was heated to 65°C. to dissolve all solids. Then the solution was cooled to ambient temperature over 2 h and was spontaneous crystallization. Then the suspension was cooled to 5°C. and kept at this temperature for 2 h Pale yellow crystals were filtered and air-dried for 24 h at ambient conditions. The potassium content was determined using ion chromatography.

G5. Crystalline form chetyrehbalnoy monomethylamine salt (E)-N-(4-(2-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00329] the Present invention also relates, in part, to the crystalline chetyrehbalnoy monomethylamine salt (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00330] In some embodiments, implementation, cetarehwodie monomethylamine salt has a powder x-ray containing one or more peaks selected from the group consisting of 9,5±0,2, 10,0±0,2, 11,8±0,2, 12,1±0,2, 14,4±0,2, 16,8±0,2, 17,6±0,2, 19,8±0,2, 20,8±0,2, 21,4±0,2, 21,8±0,2 and 29.8±0.2 degrees 2θ. In some such embodiments implement the program, cetarehwodie monomethylamine salt has a powder x-ray that contains three or more peaks selected from the group consisting of 9,5±0,2, 10,0±0,2, 11,8±0,2, 12,1±0,2, 14,4±0,2, 16,8±0,2, 17,6±0,2, 19,8±0,2, 20,8±0,2, 21,4±0,2, 21,8±0,2 and 29.8±0.2 degrees 2θ. In other such embodiments, implementation, cetarehwodie monomethylamine salt has a powder x-ray that contains five or more peaks selected from the group consisting of 9,5±0,2, 10,0±0,2, 11,8±0,2, 12,1±0,2, 14,4±0,2, 16,8±0,2, 17,6±0,2, 19,8±0,2, 20,8±0,2, 21,4±0,2, 21,8±0,2 and 29.8±0.2 degrees 2θ.

[00331] In some embodiments, implementation, cetarehwodie monomethylamine salt has a powder x-ray containing one or more peaks selected from the group consisting of 9,5±0,2, 10,0±0,2, 11,8±0,2, 12,1±0,2, 14,4±0,2, 16,8±0,2, 17,6±0,2, 19,4±0,2, 19,8±0,2, 20,8±0,2, 21,4±0,2, 21,8±0,2, 21,9±0,2 and 29.8±0.2 degrees 2θ. In some such embodiments, implementation, cetarehwodie monomethylamine salt has a powder x-ray that contains three or more peaks selected from the group consisting of 9,5±0,2, 10,0±0,2, 11,8±0,2, 12,1±0,2, 14,4±0,2, 16,8±0,2, 17,6±0,2, 19,4±0,2, 19,8±0,2, 20,8±0,2, 21,4±0,2, 21,8±0,2, 21,9±0,2 and 29.8±0.2 degrees 2θ. In other such embodiments, implementation, cetarehwodie monomethylamine salt has a powder x-ray that contains five or more peaks selected from the group consisting of 9,5±0,2, 10,0±0,2, 11,8±0,2, 12,1±0,2, 14,4±0,2, 16,8±0,2, 17,6±0,2, 19,4±0,2, 19,8±0,2, 20,8±0,2, 21,4±0,2, 21,8±0,2, 21,9±0,2 and 29.8±0.2 g is adosow 2θ.

[00332] In some embodiments, implementation, cetarehwodie monomethylamine salt has a powder x-ray are, essentially, as shown in Figure 9. The 2θ values for the peaks in Figure 9 (and their intensities) are the following: 9,45 (100), 9,97 (31), 11,85 (67), 12,09 (16), 14,38 (22), 16,80 (9), 17,59 (10), 19,39 (8), 19,83 (21), 20,85 (25), 21,37 (12), 21,75 (34), 21,87 (8) and 29,78 (7).

[00333] the Present invention also relates, in part, to a method for chetyrehbalnoy monomethylamine salt. It was received in the aquatic environment. Compound IB-L1-1.1 was slowly added to 500 ál of 1 M diethylamine, up until the solid can be dissolved in the solution. Then the solution was slowly evaporated at ambient temperature, and salt crystallized 2 days later. Alternatively, chetyrehbalnoy monomethylamine salt was obtained by suspension 64,15 mg of compound IB-L1-1.1 400 μl of 1M Diethyleneamine when heated to 50°C. was Added about 5 drops of THF (~20 µl). The solid is completely dissolved after adding with the formation of a transparent solution. This solution is then evaporated at ambient temperature, and salt crystallized after 4 days. The stoichiometry of this salt was confirmed using1H NMR in solution.

G6. Crystalline forms of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide (compound IB-L1-1.1).

[00334] Us Aasee the invention also relates, partly, to crystalline forms of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide (compound IB-L1-1.1), namely to these polymorphs (sample A, sample B, sample C and sample D) and hydrated (sample an, sample NR, sample SN, and the sample DH) crystalline forms, discussed below.

G6A. These polymorphs IB-L1-1.1.

[00335] the Present invention relates, in part, to sample And crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00336] In some embodiments, implementation, sample And polymorph has a powder x-ray containing one or more peaks selected from the group consisting of 5,8±0,2, 9,9±0,2, 11,8±0,2, 12,4±0,2, 14,5±0,2, 18,8±0,2, 22,7±0,2 and 29.2±0.2 degrees 2θ. In some such embodiments, implementation, sample And polymorph has a powder x-ray that contains three or more peaks selected from the group consisting of 5,8±0,2, 9,9±0,2, 11,8±0,2, 12,4±0,2, 14,5±0,2, 18,8±0,2, 22,7±0,2 and 29.2±0.2 degrees 2θ. In other such embodiments, implementation, sample And polymorph has a powder x-ray that contains five or more peaks selected from the group consisting of 5,8±0,2, 9,9±0,2, 11,8±0,2, 12,4±0,2, 14,5±0,2, 18,8±0,2, 22,7±0,2 and 29.2±0.2 degrees 2θ.

[00337] In some embodiments, implementation, sample And polymorph has a powder x-ray containing one or more peaks, selected from the group consisting of 5,8±0,2, 9,9±0,2, 11,8±0,2, 12,4±0,2, 14,0±0,2, 14,5±0,2, 15,3±0,2, 18,5±0,2, 18,8±0,2, 22,2±0,2, 22,7±0,2, 23,8±0,2, 26,0±0,2 and 29.2±0.2 degrees 2θ. In some such embodiments, implementation, sample And polymorph has a powder x-ray that contains three or more peaks selected from the group consisting of 5,8±0,2, 9,9±0,2, 11,8±0,2, 12,4±0,2, 14,0±0,2, 14,5±0,2, 15,3±0,2, 18,5±0,2, 18,8±0,2, 22,2±0,2, 22,7±0,2, 23,8±0,2, 26,0±0,2 and 29.2±0.2 degrees 2θ. In other such embodiments, implementation, sample And polymorph has a powder x-ray that contains five or more peaks selected from the group consisting of 5,8±0,2, 9,9±0,2, 11,8±0,2, 12,4±0,2, 14,9±0,2, 14,5±0,2, 15,3±0,2, 18,5±0,2, 18,8±0,2, 22,2±0,2, 22,7±0,2, 23,8±0,2, 26,9±0,2 and 29.2±0.2 degrees 2θ.

[00338] In some embodiments, implementation, sample And polymorph has a powder x-ray are, essentially, as shown in Figure 11. The 2θ values for the peaks in Figure 11 (and their intensities) are the following: 5,85 (28), 9,88 (51), 11,79 (73), 12,38 (56), 14,93 (38), 14,45 (199), 15,27 (29), 18,52 (39), 18,89 (47), 22,24 (49), 22,72 (77), 23,76 (39), 25,98 (22) and 29,21 (64).

[00339] the Present invention also relates, in part, to a method for sample And polymorph. Sample And polymorph received as described below in Example E.

[00340] the Present invention relates, in part, the pattern of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00341] In some the older versions of the implementation, sample of polymorph has a powder x-ray containing one or more peaks selected from the group consisting of 11,5±0,2, 13,3±0,2, 15,4±0,2, 16,4±0,2, 17,1±0,2, 18,6±0,2, 19,4±0,2, 29,4±0,2, 21,6±0,2, 22,4±0,2, 24,9±0,2, 26,8±0,2 and 29.9±0.2 degrees 2θ. In some such embodiments, implementation, sample polymorpha has a powder x-ray that contains three or more peaks selected from the group consisting of 11,5±0,2, 13,3±0,2, 15,4±0,2, 16,4±0,2, 17,1±0,2, 18,6±0,2, 19,4±0,2, 29,4±0,2, 21,6±0,2, 22,4±0,2, 24,9±0,2, 26,8±0,2 and 29.9±0.2 degrees 2θ. In other such embodiments, implementation, sample polymorpha has a powder x-ray that contains five or more peaks selected from the group consisting of 11,5±0,2, 13,3±0,2, 15,4±0,2, 16,4±0,2, 17,1±0,2, 18,6±0,2, 19,4±0,2, 29,4±0,2, 21,6±0,2, 22,4±0,2, 24,9±0,2, 26,8±0,2 and 29.9±0.2 degrees 2θ.

[00342] In some embodiments, implementation, sample polymorpha has a powder x-ray are, essentially, as shown in Figure 13. The 2θ values for the peaks in Figure 13 (and their intensities) are the following: 11,52 (71), 13,39 (87), 15,37 (199), 16,42 (69), 17,13 (69), 18,69 (97), 19,37 (56), 29,49 (62), 21,55 (55), 22,41 (39), 23,99 (33), 26,81 (31) and 28.98 (59).

[00343] the Present invention relates, in part, the pattern of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00344] In some embodiments, implementation, sample From polymorpha has a powder x-ray photograph, the content is the relevant one or more peaks, selected from the group consisting of 7,7±0,2, 19,1±0,2, 19,6±0,2, 12,9±0,2, 13,4±0,2, 16,2±0,2, 19,4±0,2, 29,5±0,2, 21,4±0,2, 22,9±0,2, 22,6±0,2, 24,3±0,2 and 27.6±0.2 degrees 2θ. In some such embodiments, implementation, sample From polymorpha has a powder x-ray that contains three or more peaks selected from the group consisting of 7,7±0,2, 19,1±0,2, 19,6±0,2, 12,9±0,2, 13,4±0,2, 16,2±0,2, 19,4±0,2, 29,5±0,2, 21,4±0,2, 22,9±0,2, 22,6±0,2, 24,3±0,2 and 27.6±0.2 degrees 2θ. In other such embodiments, implementation, sample From polymorpha has a powder x-ray that contains five or more peaks selected from the group consisting of 7,7±0,2, 19,1±0,2, 19,6±0,2, 12,9±0,2, 13,4±0,2, 16,2±0,2, 19,4±0,2, 29,5±0,2, 21,4±0,2, 22,0±0,2, 22,6±0,2, 24,3±0,2 and 27.6±0.2 degrees 2θ.

[00345] In some embodiments, implementation, sample From polymorpha has a powder x-ray are, essentially, as shown in Figure 14. The 2θ values for the peaks in Figure 14 (and their intensities) are the following: 7,69 (27), 10,13 (27), 10,64 (49), 12,01 (31), 13,39 (33), 16,25 (91), 19,44 (46), 20,49 (100), 21,40 (35), 22,03 (37), 22,60 (30), 24,32 (23) and 27,55 (27).

[00346] the Present invention relates, in part, to the sample D crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00347] In some embodiments, implementation, sample D polymorpha has a powder x-ray containing one or more peaks selected from the group consisting of 5,8±0,2, 10,7±0,2, 11,2±0,2, 15,2±0,2, 16,1±0,2 16,9±0,2, 19,9±0,2, 22,1±0,2, 24,7±0,2 and to 26.0±0.2 degrees 2θ. In some such embodiments, implementation, sample D polymorpha has a powder x-ray that contains three or more peaks selected from the group consisting of 5,8±0,2, 10,7±0,2, 11,2±0,2, 15,2±0,2, 16,1±0,2, 16,9±0,2, 19,9±0,2, 22,1±0,2, 24,7±0,2 and to 26.0±0.2 degrees 2θ. In other such embodiments, implementation, sample D polymorpha has a powder x-ray that contains five or more peaks selected from the group consisting of 5,8±0,2, 10,7±0,2, 11,2±0,2, 15,2±0,2, 16,1±0,2, 16,9±0,2, 19,9±0,2, 22,1±0,2, 24,7±0,2 and to 26.0±0.2 degrees 2θ.

[00348] In some embodiments, implementation, sample D polymorpha has a powder x-ray containing one or more peaks selected from the group consisting of 5,8±0,2, 10,7±0,2, 11,2±0,2, 15,2±0,2, 16,1±0,2, 16,9±0,2, 17,1±0,2, 19,9±0,2, 20,1±0,2, 22,1±0,2, 24,7±0,2 and to 26.0±0.2 degrees 2θ. In some such embodiments, implementation, sample D polymorpha has a powder x-ray that contains three or more peaks selected from the group consisting of 5,8±0,2, 10,7±0,2, 11,2±0,2, 15,2±0,2, 16,1±0,2, 16,9±0,2, 17,1±0,2, 19,9±0,2, 20,1±0,2, 22,1±0,2, 24,7±0,2 and to 26.0±0.2 degrees 2θ. In other such embodiments, implementation, sample D polymorpha has a powder x-ray that contains five or more peaks selected from the group consisting of 5,8±0,2, 10,7±0,2, 11,2±0,2, 15,2±0,2, 16,1±0,2, 16,9±0,2, 17,1±0,2, 19,9±0,2, 20,1±0,2, 22,1±0,2, 24,7±0,2 and to 26.0±0.2 degrees 2θ.

[00349] In some embodiments, implementation, sample D polymorph which has powder x-ray, essentially, as shown in Figure 15. The 2θ values for the peaks in Figure 15 (and their intensities) are the following: 5,81 (24), 10,70 (91), 11,23 (60), 15,17 (28), 16,10 (48), 16,89 (100), 17,10 (42), 19,88 (81), 20,12 (100), 22,12 (59), 24,72 (37) and 25,91 (24).

[00350] the Present invention also relates, in part, to a method for sample b, C and D of polymorphs, by heating the sample And polymorph to about 160, about 225 and about to 268°C, respectively, using DSC.

G6B. Hydrates IB-L1-1.1.

[00351] the Present invention also relates, in part, to the hydrate of compound IB-L1-1.1, namely, to hydrate a, b, C, D, and E, are discussed below.

[00352] the Present invention relates, in part, to the sample And hydrate (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro - pyrimidine - 1(2H)-yl)-2-methoxyethyl)phenyl)methanesulfonamide.

[00353] In some embodiments, implementation, sample And hydrate has a powder x-ray containing one or more peaks selected from the group consisting of 5,1±0,2, 7,9±0,2, 9,5±0,2, 10,3±0,2, 13,7±0,2, 16,5±0,2, 17,1±0,2, 17,5±0,2, 18,8±0,2, 19,2±0,2, 20,7±0,2, 21,3±0,2, 21,6±0,2, 25,8±0,2, 26,8±0,2 and 28,4±0.2 degrees 2θ. In some such embodiments, implementation, sample And hydrate has a powder x-ray that contains three or more peaks selected from the group consisting of 5,1±0,2, 7,9±0,2, 9,5±0,2, 10,3±0,2, 13,7±0,2, 16,5±0,2, 17,1±0,2, 17,5±0,2, 18,8±0,2, 19,2±0,2, 20,7±0,2, 21,3±0,2, 21,6±0,2, 25,8±0,2, 26,8±0,2 and 28,4±0.2 degrees 2θ. In other such options is the ants implementation sample And hydrate has a powder x-ray that contains five or more peaks selected from the group consisting of 5,1±0,2, 7,9±0,2, 9,5±0,2, 10,3±0,2, 13,7±0,2, 16,5±0,2, 17,1±0,2, 17,5±0,2, 18,8±0,2, 19,2±0,2, 20,7±0,2, 21,3±0,2, 21,6±0,2, 25,8±0,2, 26,8±0,2 and 28,4±0.2 degrees 2θ.

[00354] In some embodiments, implementation, sample And hydrate has a powder x-ray are, essentially, as shown in Figure 16. The 2θ values for the peaks in Figure 16 (and their intensities) are the following: 5,13 (13), 7,87 (80), 9,45 (100), 10,29 (60), 13,7 (28), 16,54 (30), 17,07 (17), 17,51 (40), 18,80 (99), 19,18 (74), 20,69 (21), 21,25 (21), 21,63 (23), 25,85 (32), 26,81 (20) and 28,35 (27).

[00355] the Present invention also relates, in part, to a method for sample And hydrate by suspension of the sample And polymorpha (discussed above) in ethyl acetate. The recovered sample And hydrate contains ~1 molecule of water per molecule of compound IB-L1-1.1.

[00356] the Present invention also relates, in part, to the sample In the hydrate (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro - pyrimidine-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00357] In some embodiments, implementation, sample hydrate has a powder x-ray containing one or more peaks selected from the group consisting of 6,3±0,2, 7,7±0,2, 10,4±0,2, 12,7±0,2, 13,3±0,2, 14,9±0,2, 15,4±0,2, 16,4±0,2, 18,6±0,2, 18,9±0,2, 19,4±0,2, 22,5±0,2, 23,5±0,2, 24,0±0,2, 26,8±0,2 and 29.0±0.2 degrees 2θ. In some such embodiments, implementation, about ASEC In hydrate has a powder x-ray, containing three or more peaks selected from the group consisting of 6,3±0,2, 7,7±0,2, 10,4±0,2, 12,7±0,2, 13,3±0,2, 14,9±0,2, 15,4±0,2, 16,4±0,2, 18,6±0,2, 18,9±0,2, 19,4±0,2, 22,5±0,2, 23,5±0,2, 24,0±0,2, 26,8±0,2 and 29.0±0.2 degrees 2θ. In other such embodiments, implementation, sample hydrate has a powder x-ray that contains five or more peaks selected from the group consisting of 6,3±0,2, 7,7±0,2, 10,4±0,2, 12,7±0,2, 13,3±0,2, 14,9±0,2, 15,4±0,2, 16,4±0,2, 18,6±0,2, 18,9±0,2, 19,4±0,2, 22,5±0,2, 23,5±0,2, 24,0±0,2, 26,8±0,2 and 29.0±0.2 degrees 2θ.

[00358] In some embodiments, implementation, sample hydrate has a powder x-ray containing one or more peaks selected from the group consisting of 6,3±0,2, 7,7±0,2, 10,4±0,2, 12,7±0,2, 13,3±0,2, 13,5±0,2, 14,9±0,2, 15,4±0,2, 16,4±0,2, 18,5±0,2, 18,6±0,2, 18,9±0,2, 19,4±0,2, 22,5±0,2, 23,5±0,2, 24,0±0,2, 26,8±0,2 and 29.0±0.2 degrees 2θ. In some such embodiments, implementation, sample hydrate has a powder x-ray that contains three or more peaks selected from the group consisting of 6,3±0,2, 7,7±0,2, 10,4±0,2, 12,7±0,2, 13,3±0,2, 13,5±0,2, 14,9±0,2, 15,4±0,2, 16,4±0,2, 18,5±0,2, 18,6±0,2, 18,9±0,2, 19,4±0,2, 22,5±0,2, 23,5±0,2, 24,0±0,2, 26,8±0,2 and 29.0±0.2 degrees 2θ. In other such embodiments, implementation, sample hydrate has a powder x-ray that contains five or more peaks selected from the group consisting of 6,3±0,2, 7,7±0,2, 10,4±0,2, 12,7±0,2, 13,3±0,2, 13,5±0,2, 14,9±0,2, 15,4±0,2, 16,4±0,2, 18,5±0,2, 18,6±0,2, 18,9±0,2, 19,4±0,2, 22,5±0,2, 23,5±0,2, 24,0±0,2, 26,8±0,2 and 29.0±0.2 degrees 2θ.

[00359] In some variants of the Ah implementation sample hydrate has a powder x-ray are, essentially, as shown in Figure 18. The 2θ values for the peaks in Figure 18 (and their intensities) are the following: 6,31 (7), 7,72 (14), 19,45 (24), 12,67 (26), 13,30 (88), 13,50 (44), 14,89 (70), 15,40 (100), 16,43 (43), 18,46 (47), 18,63 (86), 18,91 (26), 19,42 (33), 22,52 (47), 23,52 (44), 24,02 (20), 26,82 (40) and 28,97 (49).

[00360] the Present invention also relates, in part, to a method of obtaining a sample of the hydrate by suspension of the sample And polymorpha (discussed above) in acetonitrile/water (9/1 V/V). The recovered sample hydrate contains ~0.7 molecules of water per molecule of compound IB-L1-1.1.

[00361] the Present invention also relates, in part, to the sample hydrate (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00362] In some embodiments, implementation, sample hydrate has a powder x-ray containing one or more peaks selected from the group consisting of 10,5±0,2, 13,3±0,2, 14,9±0,2, 15,4±0,2, 16,4±0,2, 18,6±0,2, 19,0±0,2, 19,4±0,2, 22,5±0,2, 23,5±0,2, 26,9±0,2 and 29.0±0.2 degrees 2θ. In some such embodiments, implementation, sample hydrate has a powder x-ray that contains three or more peaks selected from the group consisting of 10,5±0,2, 13,3±0,2, 14,9±0,2, 15,4±0,2, 16,4±0,2, 18,6±0,2, 19,0±0,2, 19,4±0,2, 22,5±0,2, 23,5±0,2, 26,9±0,2 and 29.0±0.2 degrees 2θ. In other such embodiments, implementation, sample hydrate has been skovby x-rays, containing five or more peaks selected from the group consisting of 10,5±0,2, 13,3±0,2, 14,9±0,2, 15,4±0,2, 16,4±0,2, 18,6±0,2, 19,0±0,2, 19,4±0,2, 22,5±0,2, 23,5±0,2, 26,9±0,2 and 29.0±0.2 degrees 2θ.

[00363] In some embodiments, implementation, sample hydrate has a powder x-ray containing one or more peaks selected from the group consisting of 10,5±0,2, 13,3±0,2, 13,5±0,2, 14,9±0,2, 15,4±0,2, 16,4±0,2, 18,6±0,2, 19,0±0,2, 19,4±0,2, 22,5±0,2, 23,5±0,2, 26,9±0,2 and 29.0±0.2 degrees 2θ. In some such embodiments, implementation, sample hydrate has a powder x-ray that contains three or more peaks selected from the group consisting of 10,5±0,2, 13,3±0,2, 13,5±0,2, 14,9±0,2, 15,4±0,2, 16,4±0,2, 18,6±0,2, 19,0±0,2, 19,4±0,2, 22,5±0,2, 23,5±0,2, 26,9±0,2 and 29.0±0.2 degrees 2θ. In other such embodiments, implementation, sample hydrate has a powder x-ray that contains five or more peaks selected from the group consisting of 10,5±0,2, 13,3±0,2, 13,5±0,2, 14,9±0,2, 15,4±0,2, 16,4±0,2, 18,6±0,2, 19,0±0,2, 19,4±0,2, 22,5±0,2, 23,5±0,2, 26,9±0,2 and 29.0±0.2 degrees 2θ.

[00364] In some embodiments, implementation, sample hydrate has a powder x-ray are, essentially, as shown in Figure 20. The 2θ values for the peaks in Figure 20 (and their intensities) are the following: 10,47 (21), 13,31 (56), 13,49 (31), 14,91 (28), 15,40 (86), 16,43 (48), 18,61 (100), 18,96 (20), 19,44 (19), 22,55 (26), 23,54 (39), 26,84 (29) and 28,99 (54).

[00365] the Present invention also relates, in part, to a method of obtaining a sample With hidrocapital the suspension of the sample And polymorpha (discussed above) in the water. The recovered sample hydrate contains ~1 molecule of water per molecule of compound IB-L1-1.1.

[00366] the Present invention also relates, in part, to the pattern D hydrate (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00367] the Crystallographic unit cell parameters of the sample D of hydrated salts were determined as follows: a is equal to 17.8 Å, b is equal to 9.6 Å and equal to 27.0 Å (more accurately, as well as 17,783(2)Å, b is 9,5651(12)Å, and C is 27,014(4)Å); the angle of the cell is: β - 93,3° (more precisely, β is equal to 93,256(2)°); and the cell volume is 4588Å3(more precisely, 4587,5(10)Å3). This salt crystallizes in the space group C2/C.

[00368] In some embodiments, implementation, pattern D hydrate has a powder x-ray containing one or more peaks selected from the group consisting of 6,6±0,2, 10,0±0,2, 10,5±0,2, 11,1±0,2, 11,6±0,2, 12,2±0,2, 14,2±0,2, 16,6±0,2, 17,1±0,2, 17,7±0,2, 18,5±0,2, 18,8±0,2, 19,3±0,2, 21,4±0,2, 22,7±0,2, 23,1±0,2, 23,6±0,2, 24,6±0,2, 25,2±0,2, 27,2±0,2, 29,1±0,2 and 31.0±0.2 degrees 2θ. In some such embodiments, implementation, pattern D hydrate has a powder x-ray that contains three or more peaks selected from the group consisting of 6,6±0,2, 10,0±0,2, 10,5±0,2, 11,1±0,2, 11,6±0,2, 12,2±0,2, 14,2±0,2, 16,6±0,2, 17,1±0,2, 17,7±0,2, 18,5±0,2, 18,8±0,2, 19,3±0,2, 21,4±0,2, 22,7±0,2, 23,1±0,2, 23,6±0,2, 24,6±0,2, 25,2±0,2, 27,2±0,2, 29,1±0,2 and 31.0±0.2 degrees 2θ. In other such embodiments, implementation,pattern D hydrate has a powder x-ray, containing five or more peaks selected from the group consisting of 6,6±0,2, 10,0±0,2, 10,5±0,2, 11,1±0,2, 11,6±0,2, 12,2±0,2, 14,2±0,2, 16,6±0,2, 17,1±0,2, 17,7±0,2, 18,5±0,2, 18,8±0,2, 19,3±0,2, 21,4±0,2, 22,7±0,2, 23,1±0,2, 23,6±0,2, 24,6±0,2, 25,2±0,2, 27,2±0,2, 29,1±0,2 and 31.0±0.2 degrees 2θ.

[00369] In some embodiments, implementation, pattern D hydrate has a powder x-ray containing one or more peaks selected from the group consisting of 6,6±9,2, 10,0±0,2, 10,5±0,2, 11,1±0,2, 11,6±0,2, 12,2±0,2, 12,5±0,2, 14,2±0,2, 16,6±0,2, 17,1±0,2, 17,7±0,2, 18,5±0,2, 18,8±0,2, 19,3±0,2, 21,4±0,2, 22,7±0,2, 22,8±0,2, 23,1±0,2, 23,6±0,2, 24,6±0,2, 24,9±0,2, 25,2±0,2, 27,2±0,2, 29,1±0,2 and 31.0±0.2 degrees 2θ. In some such embodiments, implementation, pattern D hydrate has a powder x-ray that contains three or more peaks selected from the group consisting of 6,6±0,2, 10,0±0,2, 10,5±0,2, 11,1±0,2, 11,6±0,2, 12,2±0,2, 12,5±0,2, 14,2±0,2, 16,6±0,2, 17,1±0,2, 17,7±0,2, 18,5±0,2, 18,8±0,2, 19,3±0,2, 21,4±0,2, 22,7±0,2, 22,8±0,2, 23,1±0,2, 23,6±0,2, 24,6±0,2, 24,9±0,2, 25,2±0,2, 27,2±0,2, 29,1±0,2 and 31.0±0.2 degrees 2θ. In other such embodiments, implementation, pattern D hydrate has a powder x-ray that contains five or more peaks selected from the group consisting of 6,6±0,2, 10,0±0,2, 10,5±0,2, 11,1±0,2, 11,6±0,2, 12,2±0,2, 12,5±0,2, 14,2±0,2, 16,6±0,2, 17,1±0,2, 17,7±0,2, 18,5±0,2, 18,8±0,2, 19,3±0,2, 21,4±0,2, 22,7±0,2, 22,8±0,2, 23,1±0,2, 23,6±0,2, 24,6±0,2, 24,9±0,2, 25,2±0,2, 27,2±0,2, 29,1±0,2 and 31.0±0.2 degrees 2θ.

[00370] In some embodiments, implementation, pattern D hydrate has a powder x-ray are essentially as shown in Fig is re 22. The 2θ values for the peaks in Figure 22 (and their intensities) are the following: 6,55 (10), 9,96 (12), 10,51 (37), 11,09 (31), 11,62 (100), 12,24 (44), 12,54 (40), 14,22 (15), 16,62 (68), 17,07 (22), 17,77 (21), 18,52 (82), 18,84 (47), 19,30 (63), 21,45 (34), 22,67 (30), 22,80 (34), 23,08 (20), 23,57 (58), 24,63 (73), 24,88 (26), 25,24 (21), 27,23 (36), 29,06 (41) and 31,04 (21).

[00371] the Present invention also relates, in part, to a method for pattern D hydrate. It can be obtained by suspension of the sample And polymorpha (discussed above) in ethanol. Alternatively, it can be obtained by suspension of compound IB-L1-1.1 (103,03 mg) in 400 μl of THF by heating to about 55°C. was Added aqueous NaOH (1M, 264 μl, of 1.2 molar equivalent). The solid was dissolved completely with formation of a transparent solution. To this solution was added ethanol (1.6 ml). The solution was left to cool naturally to ambient temperature. The crystals formed during the slow evaporation process. Although, apparently, the crystal lattice can accommodate up to 0.5 molecules of water per molecule of compound IB-L1-1.1, restored the pattern D hydrate contained ~0.2 molecules of water per molecule of compound IB-L1-1.1.

[00372] the Present invention also relates, in part, to the sample E hydrate (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00373] the Crystallographic parameters of lementarnoj cell sample E, hydrate, crystalline disodium salt were determined as follows: a is equal to 9.5 Å, b is equal to 14.5 Å and equal to 17.3 Å (more accurately, as well as 9,462(2)Å, b is 14,462(3)Å and C is 17,281(4)Å); the corners of the cell are: α - 84,9°, β - 80,8° and γ - 81,8° (more precisely, α is equal to 84,863(4)°, β is equal to 80,760(4)° and γ equal 81,751(4)°); and the cell volume is 2304Å3(more precisely, 2304,4(9)Å3). This salt crystallizes in the space group P-1.

[00374] In some embodiments, implementation, sample E hydrate has a powder x-ray containing one or more peaks selected from the group consisting of 6,2±0,2, 7,8±0,2, 10,2±0,2, 10,7±0,2, 12,1±0,2, 16,3±0,2, 19,7±0,2, 20,9±0,2, 21,8±0,2, 24,5±0,2 and 28.0±0.2 degrees 2θ. In some such embodiments, implementation, sample E hydrate has a powder x-ray that contains three or more peaks selected from the group consisting of 6,2±0,2, 7,8±0,2, 10,2±0,2, 10,7±0,2, 12,1±0,2, 16,3±0,2, 19,7±0,2, 20,9±0,2, 21,8±0,2, 24,5±0,2 and 28.0±0.2 degrees 2θ. In other such embodiments, implementation, sample E hydrate has a powder x-ray that contains five or more peaks selected from the group consisting of 6,2±0,2, 7,8±0,2, 10,2±0,2, 10,7±0,2, 12,1±0,2, 16,3±0,2, 19,7±0,2, 20,9±0,2, 21,8±0,2, 24,5±0,2 and 28.0±0.2 degrees 2θ.

[00375] In some embodiments, implementation, sample E hydrate has a powder x-ray containing one or more peaks selected from the group consisting of 6,2±0,2, 7,8±0,2, 10,2±0,2, 10,4±0,2, 10,7±0,2, 12,1±0,2, 16,3±0,2, 19,7±0,2, 20,9±0,2, 21,8±0,2, 24,5±0,2 and 28.0±0.2 degrees 2θ. In some such embodiments, the implementation of the population, sample E hydrate has a powder x-ray that contains three or more peaks selected from the group consisting of 6,2±0,2, 7,8±0,2, 10,2±0,2, 10,4±0,2, 10,7±0,2, 12,1±0,2, 16,3±0,2, 19,7±0,2, 20,9±0,2, 21,8±0,2, 24,5±0,2 and 28.0±0.2 degrees 2θ. In other such embodiments, implementation, sample E hydrate has a powder x-ray that contains five or more peaks selected from the group consisting of 6,2±0,2, 7,8±0,2, 10,2±0,2, 10,4±0,2, 10,7±0,2, 12,1±0,2, 16,3±0,2, 19,7±0,2, 20,9±0,2, 21,8±0,2, 24,5±0,2 and 28.0±0.2 degrees 2θ.

[00376] In some embodiments, implementation, sample E hydrate has a powder x-ray are, essentially, as shown in Figure 23. The 2θ values for the peaks in Figure 23 (and their intensities) are the following: 6,19 (6), 7,81 (18), 19,17 (13), 10,49 (14), 10,68 (39), 12,06 (20), 16,29 (78), 19,72 (32), 20,88 (100), 21,77 (27), 24,52 (25) and 28,01 (27).

[00377] the Present invention also relates, in part, to a method for sample E hydrate. It is produced by suspension of compound IB-L1-1.1 (56,76 mg) in 200 μl of THF by heating. Was added aqueous NaOH (1M, 146 μl, of 1.2 molar equivalent), which gave a clear solution. To this solution was added ethanol (800 ml). This solution was left to cool naturally to ambient temperature. The crystals formed during the slow process of evaporation. Although, apparently, the crystal lattice can accommodate up to one molecule of water per molecule with the organisations IB-L1-1.1, the recovered sample E hydrate contained ~0.25 molecules of water per molecule of compound IB-L1-1.1.

N. Song.

[00378] the Present invention also relates, in part, to compositions containing one or more compounds and/or salts of the invention (including crystalline compounds and salts described above in section G). In some embodiments, the implementation, the compositions contain one or more essentially phase-pure crystalline forms (connections/salt/solvate/hydrate) discussed above in section G. These composition can be a pharmaceutical composition.

[00379] In some embodiments, implementation, compositions optionally contain one or more additional therapeutic agents. Such therapeutic agents may, but need not be, additional inhibitors of HCV.

[00380] the Preferred composition depends on the method of administration and usually contains one or more conventional pharmaceutically acceptable carriers, adjuvants and/or excipients (collectively referred to as "excipients"). The technology of reception of medicines mainly considered, for example, Hoover, J., Remington's Pharmaceutical Sciences (Mack Publishing Co., 1975) and Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems (Lippincott Williams & Wilkins, 2005).

[00381] Solid dosage forms for oral administration include, for example,capsules, tablets, pills, powders and granules. In such solid dosage forms, the compounds or salts combine with one or more excipients. With the introduction of per os, the compounds or salts can be mixed, for example, lactose, sucrose, powdered starch esters of cellulose and alkanovykh acids, complex alcelaphinae cellulose, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinylpyrrolidone and/or polyvinyl alcohol, and then tableted or encapsulated for convenient use. Such capsules or tablets may contain formulations of controlled release, which can be achieved, for example, dispersion of the compound or salt in the hypromellose. In the case of capsules, tablets and pills, the dosage forms may also contain buffering agents such as sodium citrate or carbonate or bicarbonate of magnesium or calcium. Tablets and pills can additionally be obtained with enteric coatings.

[00382] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions (including as emulsion, oil-in-water, emulsion water-in-oil), solutions (including, as water rastv the market, and nonaqueous solutions), suspensions (including both aqueous and non-aqueous suspensions, syrups and elixirs containing inert diluents commonly used in this field (e.g., water). Such compositions may also contain, for example, moisturizing, emulsifying, suspendida, aromatic (e.g., podslastiteli) and/or flavouring agents.

[00383] Parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, vnutrigrudne injection and infusion. Injectable drugs (for example, sterile injectable aqueous or oily suspension) can be obtained in accordance with the prior art, using suitable dispersing, moisturizing agents and/or suspendresume agents. Suitable fillers and solvents include, for example, water, 1,3-butanediol, ringer's solution, isotonic sodium chloride, light non-volatile oils (e.g., synthetic mono - or diglycerides), fatty acids (e.g. oleic acid), dimethylacetamide, surfactants (for example, ionic and non-ionic detergents), and/or glycols.

[00384] the Compositions for parenteral administration, for example, can be obtained from sterile powders or granules, containing one or more of these excipients for use in the compositions of the La oral administration. The compound or salt of the present invention can be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride and/or various buffers. If necessary, the pH can be set using an appropriate acid, base or buffer.

[00385] Suppositories for rectal injection can be obtained, for example, by mixing the compound or salt of the present invention with suitable non-irritating by excipients, which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Suitable excipients include, for example, cocoa butter, synthetic mono-, di-, or triglycerides, fatty acids and/or glycols.

[00386] the Local application includes the use of percutaneous administration, such as transdermal patches or device for iontophoresis.

[00387] can Also be used with other excipients and methods of administration known in the pharmaceutical field.

[00388] Applicants found that some compounds I-L1, in which R6and eniluracil are in TRANS-position to the double bond, when in solution, have tendenz the Yu to be converted into the corresponding CIS-isomer under the influence of light; therefore, it may be desirable to store such solutions in the conditions under which decreases exposure to light (e.g., in a vessel of yellow glass or in a dark place).

[00389] the Preferred total daily dose of a compound or salt (introduced in single or fractional doses) is typically from about 0.001 to about 100 mg/kg, more preferably about 0.001 to about 30 mg/kg, and even more preferably from about 0.01 to about 10 mg/kg (i.e., mg of the compound or salt per kg of body weight). Single dose compositions may contain such amounts or shares to get a daily dose. In many cases, the introduction of the compound or salt will be repeated many times. Multiple daily doses can usually be used to increase the total daily dose, if necessary.

[00390] the Factors affecting the preferred dosage regimen include the type, age, weight, sex, diet, and condition of the patient; the severity of the pathological condition; the route of administration; pharmacological considerations such as the activity, efficacy, pharmacokinetic and toxicology profiles of the particular applied compounds or salts; whether the delivery system of the medicinal product; and if you enter the compound or salt as part of combination drug environments the TV. Thus, in fact, used the dosage can vary within wide limits, and, therefore, can be obtained from the preferred dosage regimen set forth above.

I. Sets.

[00391] the Present invention also relates, in part, to the set containing one or more compounds and/or salts according to the invention. The kit optionally can contain one or more additional therapeutic agents and/or instructions, for example, on the application of this set.

J. Methods of application.

[00392] the Present invention also relates, in part, to a method of inhibiting replication of an RNA virus. This method involves exposure to a virus one or more compounds and/or salts of the present invention. In some embodiments, implementation, replication of RNA virus inhibit in vitro. In other embodiments, implementation, replication of the RNA of the virus is inhibited in vivo. In some embodiments, implementation, RNA virus replication which inhibit represents a single positive polar RNA virus. In some such embodiments, implementation, RNA virus replication which inhibit, is a virus of the family Flaviviridae. In some such embodiments, implementation, RNA virus replication which inhibit represents HCV.

[00393] the Present invention is that the same applies, in part, to a method of inhibiting RNA polymerase of HCV. This method includes the impact on polymerase, one or more compounds and/or salts of the present invention. In some embodiments, the implementation, the activity of RNA polymerase inhibit HCV in vitro. In other embodiments, the implementation, the activity of RNA polymerase inhibit HCV in vivo.

[00394] the Term "inhibition" means reducing the level of replication of RNA-virus/activity of HCV polymerase, either in vitro or in vivo. For example, if the compound/salt of the present invention reduces the level of replication of the RNA virus of at least about 10% compared with the level of replication of the RNA virus before exposure to the virus compound/salt, then the compound/salt inhibits the replication of RNA virus. In some embodiments, implementation, connection/salt can inhibit the replication of RNA virus of at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%.

[00395] the Present invention relates, in part, to a method of treatment of diseases which can be treated by inhibiting RNA polymerase of HCV. Thus, the present invention also relates in part, the method of treatment of hepatitis C in an animal in need of such treatment. These methods include the introduction of the animal one or more compounds and/or salts of the present invention, and, optionally, one or more additional pharmaceutical agents. In some embodiments, the implementation, the animal is administered a therapeutically effective amount of the compound(s) and/or salts(salts). "Treatment" means relief, suppression, eradication, prevention, risk reduction and/or delay the occurrence of the disease under treatment. Applicants especially mean that the term "treatment" includes the introduction of compounds and/or salts of the present invention, HCV-negative patient who is a candidate for organ transplantation. The treatment methods are particularly suitable for use in humans, but can be used in other animals, particularly mammals. "Therapeutically effective amount" or "effective amount" is the amount by which it will achieve the purpose of treatment of the target state.

[00396] In some embodiments, implementation, these methods include a combination therapy, where the compound(I) and/or salt(s) according to the invention is administered together with a second (or even third, fourth, and so on) connection, such as another therapeutic agent, the COI is ltheme for the treatment of hepatitis C (e.g., interferon or combination interferon/ribavirin, or an inhibitor of HCV, such as an inhibitor of HCV polymerase or an inhibitor of HCV protease). The compound(I) and/or salt(s) of the present invention can also be introduced together with therapies other than therapeutic agents used to treat hepatitis C (e.g., anti-HIV). In these embodiments, the implementation of joint injection, the compound(I) and/or salt(s) of the present invention and the second, and so on, therapeutic agent(a) can be entered on the merits at the same time (for example, within about 5 minutes from each other), sequentially, or in any other way. It is assumed that such combined methods of treatment may include the introduction of a single therapeutic agent, a large amount of time between the introduction of another. The period of time between the introduction of each tool may be in the range from a few seconds (or less) to several hours or days, and will depend, for example, from the properties of each composition and the active ingredient (e.g., efficiency, solubility, bioavailability, half-life and kinetic profile), as well as the patient's condition. The compound(I) and/or salt(s) of the present invention and the second, and so on, a therapeutic agent can also be entered in a single composition

[00397] the Present invention also relates, in part, to the use of one or more compounds and/or salts of the present invention, and, optionally, one or more additional therapeutic agents to obtain drugs. In some embodiments, the implementation, the drug is intended for joint injection with one or more additional therapeutic agents.

[00398] In some embodiments, the implementation, the drug is intended for the inhibition of the replication of the RNA virus.

[00399] In some embodiments, the implementation, the drug is intended to treat hepatitis C.

[00400] the Present invention also relates, in part, to one or more compounds and/or salts of the present invention, and, optionally, one or more additional therapeutic means, for use as a drug. In some embodiments, the implementation, the drug is intended for the inhibition of the replication of the RNA virus. In other embodiments, implementation, drug is intended to treat hepatitis C.

K. Intermediate connection.

[00401] the Present invention also relates, in part, to intermediate compounds that correspond in structure to formula II, which can b shall be used to obtain compounds of formula I (and their salts), (although some intermediate compounds can also be used, as well as the compounds of formula I as inhibitors of HCV, and the person skilled in the art can determine the ability of compounds of the formula II by using, for example, methods, discussed below):

.

[00402] In the formula II:

, R1, R2, R3, R4and R5above for compounds of formula I; and

X2is a halo.

[00403] Different ways embodiment for, R1, R2, R3, R4and R5(and their combinations) above, applicable to compounds of formula II. As for the X2in some embodiments, implementation, X2selected from the group consisting of chlorine, bromine and iodine. In other embodiments, implementation, X2selected from the group consisting of chlorine and bromine. In some embodiments, implementation, X2selected from the group consisting of chlorine and iodine. In some embodiments, implementation, X2selected from the group consisting of iodine and bromine. In additional embodiments, implementation, X2represents fluorine. In additional embodiments, implementation, X2represents chlorine. In additional embodiments, implementation of the X2is a b is om. And in some cases implement, X2represents iodine.

[00404] Different ways embodiment for, R1, R2, R3, R4, R5and X2the above can be combined to produce different variants of embodiment of compounds of formula II, and all variants of the embodiment of the compounds of formula II thus obtained compounds are included in the scope proposed by the Applicants of the invention. Some of the variants of embodiment of the compounds (and their salts) of formula II, cited as an example, discussed below.

[00405] In some embodiments, implementation of the compounds of formula II correspond to the structure of formula IIA:

.

[00406] In other embodiments, implementation of the compounds of formula II correspond to the structure of formula IIB:

.

[00407] In some embodiments, embodiments of compounds of formula II:

R41selected from the group consisting of hydrogen, methyl and nitrogen-protecting group;

R2selected from the group consisting of hydrogen and halogen;

R3selected from the group consisting of hydrogen and halogen;

R4selected from the group consisting of C1-C4-alkyl, C3-C6-carbocycle and 5-6-membered heterocyclyl where:

(a)1-C4-alkyl optionally substituted at what estately, up to three independently selected from the group consisting of halo, oxo, herokee, alkyloxy and trimethylsilyl, and

(b) (C3-C6-carbocyclic and 5-6-membered heterocyclyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl, halo, alkylsulfonyl;

R5selected from the group consisting of hydrogen, herokee, alkyloxy and halo; and

X2selected from the group consisting of chlorine, bromine and iodine.

[00408] In some embodiments, embodiments of compounds of formula II:

is a double carbon-carbon bond;

R1represents hydrogen;

R2selected from the group consisting of hydrogen and halogen;

R3represents hydrogen;

R4represents tert-butyl;

R5selected from the group consisting of hydrogen, herokee and methoxy; and

X2selected from the group consisting of bromine and iodine.

[00409] In some embodiments, embodiments of compounds of formula II:

R1selected from the group consisting of hydrogen and methyl;

R2selected from the group consisting of hydrogen and methyl;

R3selected from the group consisting of hydrogen and methyl;

R4represents tert-butyl;

R5selected from the group consisting of hydroxy and methoxy; and

X2select the n group, consisting of chlorine, bromine and iodine.

[00410] In some embodiments, embodiments of compounds of formula II:

is a double carbon-carbon bond;

R1represents hydrogen;

R2represents hydrogen;

R3represents hydrogen;

R4represents tert-butyl;

R5selected from the group consisting of hydroxy and methoxy; and

X2selected from the group consisting of chlorine, bromine and iodine.

[00411] In some embodiments, the implementation, the compound of formula II selected from the group consisting of

,,.

[00412] the following description provides instructions for obtaining the intermediate compounds of formula II (and their salts).

L. the Original connection.

[00413] the Present invention also relates, in part, to the original compounds that correspond in structure to formula III, which can be used to obtain the compounds of formulas II and I (and their salts):

.

[00414] In formula III,, R1, R2and R3above for compounds of formulas I and II. Different ways embodiment for, R1, R2and R3(and their combinations) rassmotren the e above, applicable to compounds of formula III. Different ways embodiment for, R1, R2and R3the above and can be combined to produce different variants of embodiment of compounds of formula III, and all variants of embodiments of compounds of formula III thus obtained, enter the amount submitted by the Applicants invention. Some of the variants of embodiment of the compounds (and their salts) of formula III, shown in the example below.

[00415] In some embodiments, embodiments of compounds of formula III:

R1selected from the group consisting of hydrogen, methyl and nitrogen-protecting group;

R2selected from the group consisting of hydrogen and halogen; and

R3selected from the group consisting of hydrogen and halogen.

[00416] In some embodiments, embodiments of compounds of formula III:

is a double carbon-carbon bond;

R1selected from the group consisting of hydrogen;

R2selected from the group consisting of hydrogen and halogen; and

R3selected from the group consisting of hydrogen.

[00417] In some embodiments, embodiments of compounds of formula III:

R1selected from the group consisting of hydrogen and methyl;

R2selected from the group consisting of hydrogen and methyl; and

R3selected from the group, with the standing of hydrogen and methyl.

[00418] In some embodiments, the implementation, the compound of formula III represents a uracil.

[00419] the Present invention also relates, in part, to the original compounds that correspond in structure to formula IV, which can be used to obtain the compounds of formulas II and I (and their salts):

.

[00420] In the formula IV:

R4, R5and X2above for compounds of formulas I and II; and

X1is a halo.

[00421] Different ways embodiment for R4, R5and X2(and their combinations), discussed above, applies to compounds of the formula IV. As for the X1in some embodiments, implementation, X1selected from the group consisting of chlorine, bromine and iodine. In other embodiments, implementation, X1selected from the group consisting of chlorine and bromine. In some embodiments, implementation, X1selected from the group consisting of chlorine and iodine. In other embodiments, implementation, X1selected from the group consisting of iodine and bromine. In additional embodiments, implementation, X1represents fluorine. In additional embodiments, implementation, X1represents chlorine. In additional embodiments, implementation, X1represents bromine. And in additional embodiments, implementation, X1PR is dstanley an iodine. As for the X1and X2in some embodiments, implementation, X1and X2are identical.

[00422] Different ways embodiment for R4, R5X1and X2the above can be combined to produce different variants of embodiment of compounds of formula IV, and all variants of embodiments of compounds of formula III thus obtained, enter the amount submitted by the Applicants invention. Some of the variants of embodiment of the compounds of formula IV (and their salts), are given by way of example, discussed below.

[00423] In some embodiments, embodiments of compounds of formula IV:

R4selected from the group consisting of C1-C4-alkyl, C3-C6-carbocycle and 5-6-membered heterocyclyl where:

(a)1-C4-alkyl optionally substituted by substituents with up to three independently selected from the group consisting of halo, oxo, hydroxy, alkyloxy and trimethylsilyl, and

(b) (C3-C6-carbocyclic and 5-6-membered heterocyclyl optionally substituted by one or more substituents independently selected from the group consisting of alkyl, halo, alkylenediamine;

R5selected from the group consisting of hydrogen, hydroxy, alkyloxy;

X1selected from the group consisting of chlorine, bromine and iodine; and

X2selected from the group sotoyama is from chlorine, bromine and iodine.

[00424] In some embodiments, embodiments of compounds of formula IV:

R4selected from the group consisting of tert-butyl;

R5selected from the group consisting of hydrogen, hydroxy and methoxy;

X1selected from the group consisting of bromine and iodine; and

X2selected from the group consisting of bromine and iodine.

[00425] In some embodiments, embodiments of compounds of formula IV:

R4selected from the group consisting of tert-butyl;

R5selected from the group consisting of hydroxy and methoxy;

X1selected from the group consisting of chlorine, bromine and iodine; and

X2selected from the group consisting of chlorine, bromine and iodine.

[00426] In some embodiments, embodiments of compounds of formula IV:

R4represents tert-butyl;

R5selected from the group consisting of hydroxy and methoxy;

X1selected from the group consisting of chlorine, bromine and iodine; and

X2selected from the group consisting of chlorine, bromine and iodine.

[00427] In some embodiments, the implementation, the compound of formula IV selected from the group consisting of

,and.

[00428] the following description provides instructions for obtaining the source compounds of the formula IV (and their salts).

L. Methods of obtaining.

[00429] the Present invention also relative to the tsya, in particular, to a method for producing compounds of formula II. The method involves the reaction of the compound of formula III with the compound of the formula IV in the presence of (i) as catalyst salt of copper (1) and (ii) nitrogen-containing heteroaryl ligand:

[00430] In the above process R1, R2, R3, R4, R5X1and X2have the above values.

[00431] Applicants have found that the process basically consists in the substitution of hydrogen at the nitrogen atom N1 Aracinovo derivative III with obtaining an intermediate compound (II). When X2the intermediate compound II represents a chlorine, bromine or iodine, then the connection II is suitable for subsequent reactions (for example, reaction of a combination of Suzuki with the appropriate Bronevoy acid or boronate ether) to give the compounds of formula I. in Other words, when X2in the intermediate compound II represents a chlorine, bromine or iodine, then the above process is suitable for preparing compounds of formula I.

[00432] In some embodiments of the invention, the compound III is a uracil and compound IV corresponds to the structure of the compound selected from the group consisting of compound IV-I, IV-Br and IV-Cl, in the case of compounds IV-I and IV-Br exit is usually better than in the case of compound IV-Cl.

[00433] Suitable copper rolled atory Cu(1) include, for example, CuI, CuBr, CuCl, Cu2O and CH3C(O)OCu. In some embodiments of the invention the catalyst is chosen from the group consisting of CuI and CuBr. In one of such embodiments of the invention the catalyst is a CuI. In another of these embodiments of the invention the catalyst is a CuBr.

[00434] In some embodiments of the invention the process is conducted in the presence of a base. In one of such embodiments of the invention the base is an inorganic base. Suitable inorganic bases include, for example, salts of sodium, potassium and cesium (e.g., K2CO3, K3PO4Cs2CO3, Na2CO3). In some embodiments of the invention the base is selected from the group consisting of salts of potassium or cesium salt. In one of such embodiments of the invention the salt is selected from the group consisting of K3PO4and Cs2CO3. In some embodiments of the invention, the base includes potassium salt. In one of such embodiments of the invention the salt of potassium is K2CO3. In another of these embodiments, the potassium salt is a K3PO4. In some embodiments of the invention, the base includes a salt of cesium. In one of these embodiments salt of cesium represents Cs2CO3.

[00435] Typically, the process is conducted in the presence of a solvent. Suitable solvents include, for example, dimetilan foxed (DMSO), dimethylformamide (DFA) and acetonitrile (MeCN). In some embodiments of the invention the solvent is DMSO.

[00436] Typically, the process is conducted at a temperature of from about 40 to about 130°C.

[00437] In some embodiments of the invention, nitrogen-containing heteroaryl ligand includes 8-hydroxyquinolin. In other embodiments of the invention, the ligand comprises 2-(2-pyridyl)-benzimidazole. In other embodiments of the invention, the ligand includes picolinamides compound corresponding in structure to the formula V:

.

[00438] In the formula V R11, R12, R13, R14, R15, R16and R17independently selected from the group consisting of hydrogen, C1-4-perfluoroalkyl, C1-4-alkoxy, C1-4-haloalkyl, chlorine or cyano. In some embodiments of the invention R11, R12, R13, R14, R15, R16and R17independently selected from the group consisting of hydrogen, methyl, methoxy, trifloromethyl, chlorine or cyano. In some embodiments of the invention, the ligand fomula V include N-(4-cyanophenyl)picolinate. In other embodiments of the invention, the ligand fomula V include N-(2-cyanophenyl)picolinate.

[00439] In some embodiments of the invention the method comprises (a) obtaining a compound of formula IV; and (b) reaction of compounds of formula III with a compound of formula IV in the presence of (i) the catalyst salt of copper (1) and (ii) nitrogen-containing heteroaryl ligand optionally in the presence of inorganic bases.

[00440] the Compound of formula IV-I can be obtained, for example, the conversion of 2-tert-butylphenol 2-tert-butyl-4,6-deadpool (for example, through its interaction with NaI and NaOCl), and then the conversion of 2-tert-butyl-4,6-deiodinase 1-tert-butyl-3,5-dead-2-anisole (for example, the processing of CH3I in the presence of a base, such as NaOH).

[00441] the Compound of formula IV-Br can be obtained, for example, the conversion of 2-tert-butylphenol 2,4-dibromo-6-tert-butylphenol (for example, through its interaction with 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione) and then the transformation of 2,4-dibromo-6-tert-butylphenol 1,5-dibromo-3-tert-butyl-2-anisole (for example, its processing SNS in the presence of KOtBu).

[00442] for More information about how to obtain the compounds of formulas I and II (and their salts) has the following General notes and/or the following specific examples of the synthesis. The following General comments R1, R2, R3, R4, R5, L, RA, RB, RC, RD, R6, RE, RF, RG, RH, RI, RJ, RKX1and X2have, unless otherwise stated, the above values.

Scheme 1

[00443] the Compound (1-1), where R7is, for example, hydrogen or-CO2Me and R8is, for example, in Gorod or t-butyl, can be treated with nitric acid in a solvent such as, for example, acetic acid or water, at a temperature of from about 0 to about 35°C for about 1 to about 5 hours to obtain the compound (1-2). Then, the compound (1-2) can be recovered in known for specialist conditions to obtain the corresponding aniline (1-3). Typical conditions for this recovery include the use of hydrogen at a pressure of from about 1 to about 5 atmospheres in the presence of a catalyst, such as palladium or platinum on charcoal, in a solvent such as, for example, tetrahydrofuran, ethyl acetate, ethanol or hexane at ambient temperature or about her for about 1-12 hours. Depending on the presence of functional groups, more optimum may be different recovery procedure, for example, using iron filings in the presence of weak acids, such as, for example, ammonium chloride or dilute hydrochloric acid at a temperature of reflux distilled in a mixture of solvents containing, for example, methanol, water and/or tetrahydrofuran, for about 1-12 hours. Other terms of recovery include the use of sodium borohydride in a mixture of solvents, such as, for example, water and tetrahydrofuran. Still other terms of recovery include the use of the s of tin chloride (II) in the presence of hydrochloric acid in solvents such as, for example, water and methanol or a mixture.

[00444] the Compound (1-2) before recovery can be modified. For example, treatment of compound (1-2), where R7represents hydrogen, chlorine iodine in a mixture of methanol - water at ambient temperature for about 8-24 hours gives compound (1-4), where X1represents iodine. Alternatively, the compound (1-2) can be processed by perbromide of pyridinediamine in a solvent such as, for example, acetic acid at ambient temperature or near it for about 2-16 hours to obtain the compound (1-4), where X1is bromine. Modifications can be made by phenolic fragment of compound (1-4). For example, phenol can be alkylated halide alkilani (e.g., methyl iodide), alkyl sulphates (for example, methyl sulfate), metal-halide alkenylamine (for example, allylbromide), halide akinyemi (for example, propylbromide) in the presence of a base, such as potassium carbonate in acetone, sodium hydride in dimethylformamide or t-butyl potassium in tetrahydrofuran, at a temperature of from about 0 to about 35°C. for about 1-24 hours to obtain the compound (1-5), where R9is, for example, alkyl, alkenyl or quinil. Alternatively, the alkylation can be carried out using thiriart, (trimethylsilyl) diazomethane in a solvent such as, for example, methanol or t-butyl methyl ether or a mixture thereof, in a sealed tube at room temperature or around it for about 8-24 hours. The compound (1-5) can be subsequently restored to the compounds (1-6), using iron filings or tin chloride (II) in the above-described conditions. Alternative recovery process uses the hydrogenation at a pressure of approximately 1 atmosphere in the presence of a catalyst such as 5% platinum on sulfide carbon, in a solvent such as methanol. Protection obtained aniline compounds (1-6), for example, t-BUTYLCARBAMATE can be carried out by treatment with di-tert-BUTYLCARBAMATE in a solvent such as, for example, tetrahydrofuran or dioxane at a temperature of from approximately 50 to approximately 65°C for about 1-8 hours to obtain the compound (1-7).

[00445] Modifications can be made by phenolic fragment of compound (1-2). The person skilled in the art can carry out the alkylation of phenolic part of the compound (1-2) using, for example, the above-described conditions to obtain compounds (1-8). The compound (1-8) into a compound (1-9) using, for example, one or more of the above conditions.

[00446] Another modification of phenolic groups in the compounds is AI (1-2) is sulfonylamine to the final compounds (1-8), where R9represents alkylsulfonyl, carbocyclization or haloalkylthio. This connection can be obtained by treating compound (1-2) sulfochloride, such as, for example, methanesulfonate, cyclohexanesulfamic, benzosulphochloride or 3-chloropropanesulfonyl in the presence of a base, such as, for example, triethylamine, diisopropylethylamine or pyridine, in a solvent such as, for example, dichloromethane at ambient temperature or about her for about 1 to 24 hours. The person skilled in the art can carry out the conversion of the compound (1-8) in the compound (1-9), using appropriate terms of recovery.

Scheme 2

[00447] Aniline (2-4) can be obtained using the rearrangement of kurzius. To this end, compound (2-1), where R4is not amino, treated with a catalytic amount of dimethylformamide at reflux in thionyl chloride for about 1 to about 4 hours to obtain the acid chloride (2-2). The compound (2-2) can also be obtained by treating at a temperature of phlegmy with thionyl chloride in solvents such as, for example, chloroform or toluene. The compound (2-2) can also be subjected to contact with an aqueous solution of sodium azide in the environment of a solvent, such as acetone, in accordance with what their about 1-8 hours with obtaining utilised (2-3). Then, the compound (2-3) can be subjected to rearrangement of kurzius in solvents such as dioxane or toluene, at reflux. The intermediate isocyanate is subjected to hydrolysis in aqueous acid, such as dilute hydrochloric acid in a solvent environment, such as dimethoxyethane, to obtain the compound (2-4).

Scheme 3

[00448] the Compound (3-1) where R10is, for example, hydrogen, bromine, iodine or-CO2Me, can be treated with acrylic acid at ambient temperature or about her environment solvent, such as toluene, followed by heating under reflux for from about 15 to about 48 hours to obtain the compound (3-2). When an excess of acrylic acid to obtain the compound (3-3). The compound (3-2) or (3-3) can be treated with urea in a solvent such as, for example, acetic acid at approximately 100-120°C for from about 2 to about 48 hours to obtain the compound (3-4).

Scheme 4

[00449] the Compound (4-2) can be obtained from the compounds (3-1) by dissolving in solvents, such as, for example, dimethylformamide or dimethylacetamide, followed by the addition of the benzene solution of (E)-3-methoxycarbonylamino (obtained as described the ANO in Santana, L.; et al. J. Heterocyclic Chem. 1999, 36, 293-295.) at a temperature of from about -40 to about -15°C in an inert atmosphere, and then heated to ambient temperature for from about 30 minutes to about 4 hours. The compound (4-2) can be treated with acid, such as sulfuric acid, in a mixture of ethanol-water at temperatures from about 90 to about 110°C for about 1-8 hours to obtain the compound (4-3). Alternatively, it is possible to carry out the cyclization of the compound (4-2) to uracil (4-3) in a basic environment, as described Ueno, Y.; et al. J. Org. Chem. 70:7925-7935 (2005).

Scheme 5

[00450] the Compound (9-1) can be treated with thionyl chloride at reflux for from about 1 to about 4 hours to obtain the acid chloride (9-2). Treatment with thionyl chloride at a temperature of phlegmy in solvents, such as chloroform or toluene leads to the formation of compound (9-2). The compound (2) is transformed into the corresponding aldehyde (9-3) recovery using lithium tri-t-butoxyaniline hydride in a solvent such as, for example, tetrahydrofuran, at about -78°C for about 1-8 hours. Recovery can also be performed using processing chloride India and anti-hydride in the presence of triphenylphosphine in a solvent such as tetrahydrofuran is h or toluene at a temperature of from about - approximately 40 to 0°C. Compound (9-3) can be processed by the connection (9-4) in the presence of a base, such as t-butyl potassium, in a solvent such as dichloromethane, at room temperature near or within about 1 to about 8 hours to obtain compound (9-5).

Scheme 6

[00451] the Compound (10-1), where X1represents a halogen (e.g. bromine, iodine) can be subjected to reaction combinations Suzuki with vinylboronic acid (10-2) to obtain the compound (10-3). The reaction usually requires the use of base and catalyst. Examples of bases include, for example, potassium carbonate, potassium phosphate, t-butyl potassium, sodium carbonate, cesium carbonate, and cesium fluoride. Examples of catalysts include, for example, Tris(dibenzylidineacetone)dipalladium (0), palladium acetate, bis(triphenylphosphine)palladium (II) chloride, tetrakis(triphenylphosphine)palladium, dichloro[1,1'-bis(di-tert-butylphosphino)ferrocene] palladium (II) or adduct dichloro[1,1'-bis(diphenylphosphino)ferrocene] palladium (II)/dichloromethane. The reaction can be carried out in a solvent such as, for example, water, dioxane, dimethoxyethane, dimethylformamide, toluene, ethanol, tetrahydrofuran, etc. or a mixture thereof. The reaction can be conducted at ambient temperature or above.

Scheme 7

[00452] the Compound (11-1), you can turn soedinenii (11-2) by treatment with diazomethane in a solvent, such as, for example, tetrahydrofuran, in the presence of palladium acetate at room temperature or around it for about 30 min to about 4 hours.

Scheme 8

[00453] the Compound (11-1) is subjected to grafting with obtaining the compound (14-2). Typical conditions for recovery include the use of hydrogen at a pressure of from about 1 to about 5 atmospheres in the presence of a catalyst, such as palladium or platinum on charcoal, in a solvent such as, for example, tetrahydrofuran, ethyl acetate, ethanol or hexane at ambient temperature is near or within about 1 to about 12 hours.

Scheme 9

[00454] the Compound (15-1) can be converted into compound (15-2) in two stages. The initial phase includes the recovery of aromatic nitro iron filings in the presence of weak acids, such as, for example, ammonium chloride or dilute hydrochloric acid at a temperature of from about 60 to about 80°C in a mixture of solvents containing, for example, methanol, water and tetrahydrofuran, for about from 1 to about 12 hours. The second stage represents the curing obtained in the first stage of aniline with methanesulfonamide in the presence of a base, such as pyridine, in a solvent such to the to dichloromethane, when the ambient temperature or around it.

Scheme 10

[00455] the Compound (17-1) can be processed by methanesulfonamido in the presence of a base, such as pyridine, in a solvent such as, for example, dichloromethane, obtaining mutilator connection (17-2). The ageing of the compound (17-3) with a complex of borane-dimethyl sulfide in a solvent such as, for example, tetrahydrofuran, at about 0-10°C results in compounds (17-4). Connection (17-2) and (17-4) can be associated with acetaldehyde in tetrahydrofuran at reflux. Subsequent treatment with water at room temperature leads to the production of compounds (17-5).

Scheme 11

[00456] Carboxylic acid (18-1) may be restored borane-tetrahydrofuranyl complex when heated with obtaining alcohol (18-2). Connection (18-2) may be converted to the corresponding bromide (18-3) using N-bromosuccinimide and triphenylphosphine in a solvent environment, such as, for example, dichloromethane, at room temperature for several hours. The process of joining (18-3) triethylphosphite approximately at 120°C for about 1 to about 3 hours gives compound (18-4). Connection (18-4) can be used, for example, to obtain compounds (9-5) as description is about in Scheme 5.

Scheme 12

[00457] Benzaldehyde (19-1) can be processed by diethylphosphonate in the presence of a base, such as, for example, sodium methylate, in a solvent such as, for example, methanol, at room temperature to obtain compounds (19-2). Connection (19-2) can be treated with N-chlorosuccinimide and triphenylphosphine in dichloromethane at room temperature to obtain compounds (19-3). Connection (19-2) you can also enter into reaction with (diethylamino)sulfur TRIFLUORIDE (DAST) to give the compound (19-4).

[00458] Connection (19-1) can also be processed p-toluensulfonate acid and triethylorthoformate in methanol at about 50°C to obtain the acetal (19-5). Connection (19-5) can also be converted into the compound (19-6) keeping with triethylphosphite and vetilation boron TRIFLUORIDE at a temperature of from about -20°C. to about ambient temperature.

[00459] Connection (19-3), (19-4) and (19-6) can be used, for example, to obtain compounds (9-5), as described in Scheme 5.

Scheme 13

[00460] Phenol (20-1), where R4is other than amino, is treated with a source of electrophilic halide, such as, for example, monochloride iodine, obtaining dehalogenating compound (20-2), where X1and X2independently represent bromo is whether iodine. The compound (20-2) is converted into a compound (20-3) interaction alkylating agent, such as, for example, methyl sulfate, with a base, such as, for example, potassium carbonate, when heated under reflux in acetone. Alternatively, methyliodide in the presence of a base, such as, for example, t-butyl potassium, in a solvent such as, for example, tetrahydrofuran or dimethylformamide, and also gives compound (20-3). In another alternative, the compound (20-2) can be prometherion (trimethylsilyl)diazomethane in a solvent such as, for example, t-butyl methyl ether. The compound (20-3), you can enter into reaction with uracil, ligand (20-4), copper iodide (I) and potassium phosphate in dimethylsulfoxide at a temperature of from about 40°to about 100°C to obtain compound (20-5).

[00461] for Example, when the compound (20-3) R4represents tert-butyl, X1represents iodine and X2represents iodine or bromine, the compound (20-3) can mix with uracil and connection (20-4) in the presence of CuI and K2PO4in DMSO for about 15-24 hours at about 60°C to obtain compound (20-5). Instead ligand (20-4) for manufacturing (20-5), you can use 8-hydroxyquinoline and 2-(2-pyridyl)-benzimidazole.

Scheme 14

[00462] it is Possible to carry out the nitration of the compound (21-1) nitric acid is in the acetic acid at a temperature of from about 10 to about 15°C to obtain compound (21-2). Phenolic connection part (21-2) can be protected sillavan ether, for example, t-butyldimethylsilyl ester, by treatment with similiarites, such as, for example, t-butyldimethylsilyloxy, and imidazole in a solvent such as, for example, dimethylformamide at ambient temperature to obtain compounds (21-3). Then the connection (21-3) can be recovered in known for specialist conditions to obtain the corresponding aniline (21-4).

[00463] Typical conditions for such recovery include the use of hydrogen at a pressure of about 1 to 5 atmospheres in the presence of a catalyst, such as palladium or platinum on coal in a solvent such as, for example, tetrahydrofuran, ethyl acetate, ethanol, methanol, or hexane at ambient temperature, or near it, for about 1-12 hours. Depending on the presence of functional groups, may be more suitable for other terms of recovery, such as, for example, using iron filings in the presence of weak acids, such as, for example, ammonium chloride or dilute hydrochloric acid, when heated under reflux in a mixture of solvents containing, for example, methanol, water and tetrahydrofuran, for about 1-12 hours.

[00464] Then you can sulfonylamine aniline (21-4) methanesulfonanilide is in the presence of pyridine in a solvent, such as, for example, dichloromethane. Starting materials and reagents are mixed at about 0°C. and then slowly heated to ambient temperature to obtain compounds (21-5). Protective silylating group is removed in a well known specialist conditions. For example, tetrabutylammonium in tetrahydrofuran at room temperature makes the connection (21-5) in the connection (21-6). Phenolic group of the compound (21-6) can be sulfonylureas anhydride triftormetilfullerenov acid in the presence of a base, such as pyridine, in a solvent such as, for example, dichloromethane, at room temperature to obtain compounds (21-7). Connection (21-7) can be used as described in Scheme 12, to obtain the compound (12-3).

Scheme 15

[00465] the Compound (22-1) can be converted into compound (22-2) in two stages. First, it is possible to carry out the hydrolysis of the compound (22-1) using a base such as, for example, sodium hydroxide, lithium hydroxide or potassium hydroxide, in a solvent such as, for example, methanol, ethanol or tetrahydrofuran, or a mixture thereof. The resulting reaction mixture is stirred for approximately onset 6 to 48 hours at ambient temperature. Then, the obtained carboxylic acid is heated under reflux in thionyl chloride with catalytic is Kim quantity of dimethylformamide, or without, from about 1 to about 4 hours to obtain the acid chloride (22-2). Treatment with thionyl chloride at reflux in a solvent such as, for example, chloroform or toluene, also leads to the production of compounds (22-2). Treatment of carboxylic acid oxaliplatin in dichloromethane with a catalytic amount of dimethylformamide also gives compound (22-2).

[00466] the Compound (22-2) may be treated with an amine or the corresponding salt in a solvent such as, for example, dioxane, dimethylformamide, dimethylacetamide or dichloromethane, optionally in the presence of a base, such as pyridine, triethylamine or diisopropylethylamine at a temperature of from ambient temperature, or close to it, up to about 100°C. for about 1-24 hours to obtain compound (22-4), where R11and R12independently represent hydrogen or R17or taken together with the nitrogen to which they are attached, form a 5-6-membered heterocyclic or condensed from 2 rings heterocyclyl.

[00467] Connection (22-2) may be converted into the corresponding aldehyde (22-3) by restoring using lithium tri-t-butoxyaniline hydride in a solvent such as, for example, tetrahydrofuran, at about temperatures from -60°C. to about -78°C.

Scheme 16

[00468] Connection (22-3) can be converted into compound (23-2), where R11and R12independently predstavlyaet a hydrogen or RFor taken together with the nitrogen to which they are attached, form a 5-6-membered heterocyclic or condensed from 2 rings heterocyclyl, processing Amin, N(R11)(R12), in the presence of a reducing agent, such as, for example, triacetoxyborohydride sodium or cyanoborohydride sodium in a solvent such as, for example, methanol, ethanol, dichloromethane, dimethylacetamide or dimethylformamide, for from about 1 to about 24 hours. Often better reaction proceeds at an acidic pH value, which can be supported by adding acetic acid or hydrochloric acid.

[00469] Connection (22-3) can also be converted into the compound (23-3) recovery using lithium tri-t-butoxyaniline hydride in a solvent such as tetrahydrofuran, at room temperature.

Scheme 17

[00470] Connection (23-3) can be converted into a compound of formula (24-2) by treatment with thionyl chloride in dichloromethane at room temperature. Connection (24-2) can be treated with sodium alkoxide R13ONa in a hot solution of the corresponding alcohol with obtaining the compound (24-3), where R13represents hydrogen or RF.

Scheme 18

p>

[00471] it is Possible to carry out the bromination of the compound (25-1) processing, for example, perbromide of pyridinediamine in a solvent such as, for example, acetic acid at ambient temperature, or close to it, for about 1-8 hours to obtain compound (25-2). The amino group of compound (25-2) can be removed keeping with t-butylnitrite in a solvent such as, for example, dimethylformamide, at ambient temperature followed by an increase of temperature up to about 50-65°C to obtain compound (25-3). You can add additional aliquots of t-butylnitrite at ambient temperature followed by heating to complete the transformation. Connection (25-3) can be restored to the connection (25-4), for example, processing of iron and chloride ammonia.

EXAMPLES

[00472] the Following examples are merely explanatory and not limiting this description in any way.

[00473] Example A. Obtaining (E)-N-(3-tert-butyl-5-iodine-4-methoxyphenylacetyl)-3-methoxy acrylamide.

[00474] Part A. Obtain 2-tert-butyl-4-NITROPHENOL.

[00475] To intensively stirred solution of 2-tert-butylphenol (10 g, of 66.6 mmol) in heptane (67 ml) was added quick drops of a solution of 70% nitric acid (4,25 ml 66,6 mmol) diluted with water (4,25 is l). The resulting dark red/brown mixture was intensively stirred for 2 hours Suspended solid was collected by filtration, washed with hexane (300 ml), water (200 ml) and again with hexane (200 ml) to obtain the powder color of cocoa, which was dried to constant weight (4,65 g, 35.6 percent).

[00476] part of the Century, Obtaining 2-tert-butyl-6-iodine-4-NITROPHENOL.

[00477] To the product from part a (4.5 g, 23,05 mmol) dissolved in Meon (120 ml) and water (30 ml), was added dropwise monochloride iodine (1,155 ml, 23,05 mmol) over a period of time of 10 minutes and the Mixture was stirred for 2 h and was diluted in 1 l of water, and left to stand over night. The solid is collected by filtration and washed with 3×50 ml water, and dried under vacuum overnight to obtain a solid substance, yellowish-brown (7,14 g, 96%).

[00478] Part C. Obtain 1-tert-butyl-3-iodine-2-methoxy-5-nitrobenzene. It chilled in an ice bath to a solution of the product from Part b (5.5 g, 17,13 mmol) in MTBE (15 ml) in a 50 ml pressure vessel was added 2.0 M TMS diazomethane (12,85 ml of 25.7 mmol), followed by adding dropwise methanol (1.0 ml), resulting in the peaceful liberation of gas bubbles. The vessel was tightly closed and stirred at room temperature for 16 h, cooled and the pressure dropped. The solution was distributed between EtOAc and water. The organic layer was washed with 1.0 M HC, saturated potassium carbonate solution and saturated NaCl. The organic layer was dried over sodium sulfate, filtered and concentrated to obtain a red oil which was used without purification (5,4 g, 84%).

[00479] Part D. Obtain 3-tert-butyl-5-iodine-4-methoxyaniline

[00480] a Mixture of the product from Part C (5,80 g, 17,31 mmol), ammonium chloride (1.389 g, 26.0 mmol), and iron (4.83 g, 87 mmol) in THF/MeOH/water (200 ml, 2/2/1) was heated under reflux for 2 h, cooled and filtered through celite. The filtrate was evaporated, and the residue was separated between water and EtOAc. The organic layer was washed with saturated saline solution, dried with sodium sulfate, filtered and evaporated to obtain a brown oil (5,28 g, 100% yield).

[00481] Part E. Obtaining (E)-N-(3-tert-butyl-5-iodine-4-metacommunicative)-3-methoxy acrylamide.

[00482] To a solution of the product from Part D (3,05 g, 10 mmol) in DMF (50 ml) at -20°C in an atmosphere of N2added quick drops 0.4 M solution in benzene (E)-3-methoxycarbonylamino (50,0 ml, 20.00 mmol, obtained by the method Santana et al., J. Heterocyclic Chem. 36:293 (1999). The solution was stirred for 15 min at -20°C, heated up to room temperature for 45 min and was diluted in EtOAc. The EtOAc layer was washed 4×300 ml water, 2×100 ml brine, dried (Na2SO4) and concentrated to a solid brown color. The residue is triturated in Orasac in Et 2O/hexane to obtain fine powder, which was collected by filtration and dried to obtain a yellowish-brown powder (2,46 g, 57%).

[00483] Example Century. Obtain 1-(3-tert-butyl-5-iodine-4-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[00484] To a suspension of the product from Example A (2,46 g, 5,69 mmol) in ethanol (50 ml) was added a solution of 5.5 ml of H2SO4in 50 ml of water, and the mixture was heated at 110°C for 2.5 hours to obtain a transparent solution. The solution was cooled and diluted with 50 ml of water under stirring, obtaining a whitish solid, which was collected by filtration, washed with water and dried (to 2.06 g, 90%).

[00485] Example C. Obtain 1-(3-tert-butyl-5-iodine-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00486] Part A. Obtain 2-tert-butyl-4,6-deadpool.

[00487] a Solution of 2-tert-butylphenol (20,0 g, 133 mmol) in methanol (266 ml) was treated with granules of sodium hydroxide (6,39 g, 160 mmol). The mixture was stirred to dissolve all of the sodium hydroxide and then cooled in a bath of ice and salt to -2°C. was Added sodium iodide (15.0 g, 100 mmol) and then dropwise added 10% sodium hypochlorite solution (45 ml, 73,3 mmol) with such speed, that the solution temperature did not rise above 1,3°C. This sequence of events was repeated (3x) until you add all 60 g (400 mmol) jodidamente, and the sodium hypochlorite solution was added to until the color of solution changed from light yellow-green color to the color of weak tea with ice. This requires almost 16 ml 180 ml total measured sodium hypochlorite solution. Continuing the cooling at about 2°C, the solution pativedha sodium thiosulfate (20 g) in water (100 ml) was added dropwise over 20 minutes After the addition, the solution was acidified to pH 3 by adding dropwise concentrated hydrochloric acid (about 35 ml was required of 40 ml, placed in the additional funnel). The precipitate was collected by filtration and washed with the use of >1 liter of water. Solid orange-yellow color was aspirated to dryness, and dried in a vacuum oven at 50°C for 18 hours These procedures gave the product (49,61 g, 93%) as a solid, yellowish-brown.

[00488] part of the Century, Obtaining 1-tert-butyl-3,5-dead-2-methoxybenzene.

[00489] a solution of the product from part a (20,0 g, 49.7 mmol) in acetone (140 ml) was treated with methyliodide (3.9 ml, 8,83 g, 62,2 mmol) and 50% (mass/mass) solution of sodium hydroxide (to 3.02 ml, 4,58 g, 57,2 mmol) followed by stirring at ambient temperature for 48 hours the Mixture was concentrated in vacuo to a volume of approximately 50-60 ml, followed by dilution with heptane (80 ml) and water (50 ml). The layers were separated, and the organic layer extras is listed as a saturated solution of sodium chloride. Drying (Na2SO4) and concentration in vacuo gave the product (20,59 g, 99%) as a pale yellow oil.

[00490] Part C. Obtain 1-(3-tert-butyl-5-iodine-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00491] a Suspension of the product from Part b (12,04 g of 28.9 mmol), uracil (to 3.89 g of 34.7 mmol), N-(2-cyanophenyl)picolinamides (1.29 g, 5,79 mmol) and trehosnovnogo potassium phosphate (12.9 g, of 60.8 mmol) in DMSO (181 ml) was degirolami by ozonation of nitrogen for 1 h Then the mixture was treated with copper iodide (I) (551 mg, 2.89 mmol) and degassing was continued for another 10 minutes Then the mixture was heated at 60°C for 18 h Then the mixture was poured into water (600 ml) and acidified to pH 3 by adding 4 n hydrochloric acid. The mixture was diluted with ethyl acetate, and the organic layer was extracted with water (3x), saturated solution of ammonium chloride (1x) and a saturated solution of sodium chloride. The solution was dried and treated with (3-mercaptopropyl) silica gel, followed by stirring for 2 hours the Mixture was filtered and concentrated in vacuum. The obtained solid was ground into powder with ether-ethyl acetate (>10:1) and collected by filtration and washed with ether. After drying in a vacuum oven at 50°C for 2 h, these procedures gave the product (2,75 g) as a solid white color. The mother solution was concentrated in vacuum to obtain a solid ve is esta amber-yellow color. This substance was chromatographically on the cartridge with silica gel Flash 65, elwira 20-100% ethyl acetate in hexane. These procedures gave an almost white solid, which was ground into powder with ether-hexane and collected by filtration. After drying in a vacuum oven for 3 h, these procedures were made more or 4.31 g of the product in the form of a solid white color. Total output: 7,06 g (61%).

[00492] Example D. Obtain 1-(3-tert-Butyl-5-iodine-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00493] Part A. Obtain 2-tert-butyl-4,6-deadpool.

[00494] 2-threat-butylphenol (99,95 g, 665,36 mmol) was dissolved in 1250 ml of methanol and converted into the corresponding phenoxide using 31,96 g (799,0 mmol, 1.2 EQ.) sodium hydroxide by mixing pellets of sodium hydroxide at room temperature, and then cooling the reaction mixture in a bath of ice/salt. Sodium iodide (299,34 g, 1997,07 mmol, 3.0 EQ.) and 8.3% solution of sodium hypochlorite (1265,83 g, 1411,39 mmol, 2.1 EQ.) was added to the cold reaction solution in four equal parts, the sodium hypochlorite solution was added, maintaining the reaction mixture at <0°C. 500 ml of 20% (mass/mass) of sodium thiosulfate solution was added over a period of time of 18 minutes, with increasing temperature from minus 0.6°C to 2.5°C. the pH of the reaction mixture is brought to approximately 3, by adding 197,5 ml to the TS. HCl over a period of time 97 min with reaction temperature, going from 1.2°C to 4.1°C. the resulting thick suspension was filtered and the filter cake washed with about 2 l of water. The filtered precipitate was left on a Buechner funnel under vacuum overnight (about 15 h) to obtain the output 289,33 g (potentially adjusted output =254,61 g) of the named product.

[00495] part of the Century, Obtaining 1-tert-butyl-3,5-dead-2-methoxybenzene.

[00496] the Product from part a (93% of the sample, 21,6 g, 50 mmol) was dissolved in 140 ml of acetone. Added methyliodide (4,2 ml of 67.5 mmol, of 1.35 equiv.) with the subsequent addition of 50% aqueous sodium hydroxide (5.0 g, 62.5 mmol, 1.25 EQ.). The reaction mixture was stirred overnight, then concentrated to approximately 50-60 ml) was Added 80 ml of heptane, followed by adding 50 ml of water, and the layers were shaken and separated, and the aqueous layer was subjected to back extraction with 20 ml of heptane. The organic layers were combined and washed twice with 50 ml each, 10% aqueous NaCl with getting to 91.1 grams of a solution of heptane, the analysis of which gave to 19.1 g of the named compound.

[00497] Part C. Obtain 1-(3-treat-butyl-5-iodine-4-methoxyphenyl)pyrimidine-2,4(1H,3H)- dione.

[00498] Uracil (33,3 g, 297 mmol, 1.2 equiv.) K3PO4(106 g, 500 mmol, 2.1 equiv.) CuI (4.6 g, and 24.2 mmol, 0.1 EQ.), and N-(2-cyanophenyl)picolinate (6.4 g, 28.7 mmol, 0,12 EQ.) was placed in a flask with a trade is essential argon. Dissolved in MeCN 1-tert-butyl-3,5-diiodo-2-methoxybenzoyl dissolved in 1 l of DMSO while bubbling with argon and added to the solid residue. The reaction mixture was heated to 60°C for 16 hours After cooling, the reaction mixture was diluted with 2 l of EtOAc and washed 2.6 liters of water (reverse extraction 3×1 l of EtOAc). The combined organic layers were washed 2×1 l of 0.25 M (CuOAc)2then 2×830 ml of 15% NH4Cl then 800 ml of saline solution. The organic layer was then concentrated and washed with 1 l of heptane, and then was ground into powder by heating under reflux 85:15 (V/V) heptane:iPrOAc within 4 hours After cooling, the product was collected by filtration and washed with additional 330 ml of 85:15 V/V heptane:EtOAc to yield after drying of 66.9 g (70% yield) of product as a solid white color.

[00499] Example E. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00500] In a three-necked round bottom flask was loaded Bronevoy acid (96% concentration) (3.75 g, 15.6 mmol, 1.2 equiv.) the product from Example D (5.0 g, 12.5 mmol), Cytec ligand (175 mg, 5 mol%), Pd2(dba)3(46 mg, and 0.4 mol%) and potassium phosphate (5,25 g 25,0 mmol, 2 EQ.). Solid for 10 min was purged with nitrogen and loaded into the flask. In 75 ml of 4:1 THF: water for 10 min was barbotirovany nitrogen and loaded into Kolb is. The reaction mixture was stirred to dissolve the solids, followed by heating the mixture at 50°C in the dark during the night. The HPLC results showed that after stirring overnight the reaction was not complete (~2% unreacted iodouracil). The reaction mixture was diluted with 375 ml of dichloromethane (DCM) and 250 ml of 10% citric acid. The mixture was shaken in a separating funnel and the layers were separated. The dichloromethane layer was washed with a solution of 0.6 g of L-cysteine in 250 ml of 5% NaHCO330 min, during which time the dichloromethane layer was changing color from orange to yellow. Repeated processing dichloromethane layer of 0.6 g of L-cysteine in 250 ml of 5% NaHCO3for 30 min followed by washing with 250 ml of 5% NaHCO3and 250 ml of 10% NaCl. The dichloromethane layer was treated with 2 g of kremnezemistye for 30 minutes was Added 1 g of charcoal, stirred 5 min before bleaching and filtered through filter hy-flo. The filter cake is washed with DCM. DCM solution was then otparyvali obtaining 6,74 g light yellow solid residue. The solid residue had a purity of ~92%. The solid residue was heated in a mixture of 192 ml DCM and 9 ml of the Meon. He was never fully dissolved. Was cooled to room temperature under stirring. Added 80 ml of heptane, and more product began to crystallize. The suspension is stirred from Saturday until Monday. Portions p is 50 ml) was added a total of 230 ml of heptane. The product was filtered. The filtrate was measured when to 1.21 mg/ml at 210 nm and 1.35 at 220 nm, which is equal to the loss 522-582 mg fluid or loss of 9-10% compared with theoretical predictions. The filter cake was washed with 50 ml of a mixture of 27 ml of heptane: 22 ml DCM: 1 ml Meon. The wash solution contained 0.5 mg/ml of the product or 25 mg (0.4% compared with theoretical). The product yield was 5.22 g (88,9%) with a purity of 99.2%RA. Crystallization occurs remove iodouracil. Samples were presented in the solid state for analysis and analysis to determine the Pd. NMR showed no evidence of any residual solvent.

[00501] Example 1. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide (compound IA-L1-1.9).

[00502] Part A. Obtain methyl 3-tert-butyl-2-hydroxy-5-nitrobenzoate.

[00503] Methyl 3,5-di-tert-butyl-2-hydroxybenzoate (28,66 g, 108,4 mmol) was dissolved with stirring in 430 ml of glacial acetic acid and the resulting mixture was treated dropwise fuming nitric acid (90%, 179,26 ml). After complete addition, the resulting mixture was stirred for 2.5 hours, the Reaction mixture was poured into 2.0 l of crushed ice and left to stand for 30 minutes then added to 1.0 l of water and the mixture of water and ice left to melt. The mixture is then filtered, about ivali water and dried to obtain the above compound (a 24.57 g, 89%).

[00504] Part C. Obtain methyl 3-tert-butyl-2-methoxy-5-nitrobenzoate.

[00505] was Added along methyl 3-tert-butyl-2-hydroxy-5-nitrobenzoate (11,41 g, 45,0 mmol), potassium carbonate (9,34 g of 67.6 mmol), acetone (200 ml), and dimethylsulfate (6,46 g of 67.6 mmol). The resulting mixture was then heated under reflux for 16 hours the Mixture is then filtered and the solid washed with ethyl acetate. The resulting organic liquid was then concentrated under vacuum to oil and pererestorani in ethyl acetate (600 ml). The organic solution is then washed with water, dried, filtered and concentrated under vacuum to an oil, which was then subjected to purification by column chromatography (gradient 5% to 40% EtOAc/hexane)to obtain at the output of these compounds in the form of oil (10,42, 87%).

[00506] Part C. Obtain methyl 5-amino-3-tert-butyl-2-methoxybenzoate.

[00507] was Added along methyl 3-tert-butyl-2-methoxy-5-nitrobenzoate (10,42 g of 39.0 mmol), iron filings (325 mesh, 10,89 g, 195 mmol), ammonium chloride (3.13 g, 58,5 mmol), water (30 ml), and methanol (150 ml). The resulting mixture was then heated under reflux for 1 h the Mixture was then cooled to room temperature, filtered through celite, and the celite was washed with methanol. The filtrate is then concentrated under vacuum and dissolved in ethyl acetate (600 ml). the received resulting solution is then washed with water and brine. The organic extract was then dried, filtered and concentrated under vacuum to obtain at the output of these compounds in the form of oil (9,25 g, 100%).

[00508] Part D. Obtain 3-(3-tert-butyl-4-methoxy-5-(methoxycarbonyl)phenylamino) propanoic acid.

[00509] the Product from Part C (16,44 g and 69.3 mmol) was dissolved in toluene (200 ml). This mixture was heated under reflux was added to acrylic acid over a period of time (1 ml of acrylic acid was added every 3 hours, just 5,23 ml, 76,2 mmol). The mixture then was heated under reflux for 24 hours the Mixture was then cooled and concentrated under vacuum to dryness to obtain at the output of the oil as the crude titled compound which was used directly in the next reaction.

[00510] Part E. Obtain methyl 3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxybenzoate.

[00511] was Added together the product from Part D (21,43 g and 69.3 mmol), urea (10.4 g, 173 mmol) and acetic acid (ice, 200 ml). The mixture then was heated to 120°C for 18.5 hours, followed by concentration under vacuum to obtain oil. To this oil was added methanol (13 ml) and ethyl acetate (350 ml). The resulting mixture was left to stand for 24 to 48 h, which was formed precipitate. The resulting solid was filtered and washed and a small amount of methanol (10 ml) and then dried in air to obtain at the output of these compounds in the form of solids (15,26 g, 66%).

[00512] Part F. Obtain 3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxy benzoic acid.

[00513] was Added together the product from Part D (4.52 g, 13,52 mmol), methanol (70 ml), and tetrahydrofuran (70 ml). The mixture was then intensively stirred to produce a homogeneous solution. After achieving a homogeneous solution was added aqueous sodium hydroxide (1.0 M, 68 ml). The mixture then was stirred for 12 h, the mixture was then concentrated under vacuum to remove the organic solvent, followed by addition of an aqueous solution of hydrochloric acid (1.0 M, 80 ml), which in result led to the formation of solids. The mixture was then concentrated under vacuum. This substance was added hydrochloric acid (12 M, 100 ml) and the resulting substance was heated to 100°C. for 1.5 hours, the Reaction mixture was then cooled and added to water. The resulting solid was filtered, washed with water, and dried to obtain at the output of the named compound as a solid (3.55 g, 82%).

[00514] Part G. Obtain 3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxy-benzaldehyde.

[00515] the Product obtained in Part F (4,07 g 12,71 mmol) and thionyl chloride (40,82 ml, 559 mmol) were combined, and the mixture was heated under reflux for 2 h, followed by concentration under vacuum is obtaining the solid product is a light yellow color. The solid was dissolved in tetrahydrofuran (125 ml), the solution was cooled to -78°C. and slowly added LiAlH(OtBu)3(1M, 14 ml) over 10 min, maintaining the temperature of -78°C. the Mixture was stirred at -78°C for 2 h, and the reaction was suppressed hydrochloric acid (aq., 1M, 25 ml) at -78°C. the Mixture was heated to room temperature and was added ethyl acetate. The layers were separated and the aqueous layer washed with ethyl acetate. The organic extracts were combined and washed with semi-saturated sodium bicarbonate solution. The organic layer was dried, filtered and concentrated under vacuum to obtain at the output of these compounds in the form of a solid substance (of 3.73 g, 96%).

[00516] Part N. Obtain 1-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)dihydro-pyrimidine-2,4(1H,3H)-dione.

[00517] the Product obtained in Part G (1,00 g, 3,29 mmol) and diethyl 4-nitrobenzyl-phosphonate (0,853 g of 3.12 mmol) was dissolved in dichloromethane (50 ml). Solid tert-piperonyl potassium (0,737 g, to 6.57 mmol) was added by portions at room temperature. The resulting dark red solution was stirred for 1.5 h at room temperature. Solution was added 1 n aqueous HCl (50 ml) and the mixture was stirred 30 min, and then was diluted with dichloromethane (50 ml). The resulting organic layer was separated and dried. This substance was purified by column chromatography on silica gel, ISOE is isua 99/1 dichloromethane/methanol as eluent to obtain these compounds in the form of a solid (1.12 g, 80%).

[00518] Part I. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-pyrimidine-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00519] the Product obtained in Part N (1.1 g, 2.60 mmol), iron (0,725 g 12,99 mmol) and ammonium chloride (0,208 g, 3.90 mmol) was added to a mixture of tetrahydrofuran (40 ml), ethanol (40 ml) and water (12 ml). The suspension was heated to 90°C for 45 min, and then cooled to ambient temperature. This solution was filtered through a layer of celite (10 g), washed with ethanol (20 ml) and the filtrate was concentrated under vacuum to a solid. The resulting solid was dissolved in ethyl acetate (100 ml) and this solution was washed with water (50 ml) and dried over Na2SO4. Drying substance was filtered, and the solvent was removed under vacuum to obtain the aniline adduct in the form of a solid yellow (830 mg).

[00520] Solid (830 mg, 2,109 mmol) was dissolved in dichloromethane (50 ml), was added pyridine (0,512 ml, 6,33 mmol) and methanesulfonamide (0,181 ml, 2.32 mmol) and the resulting solution was stirred at room temperature for 16 hours was Added dichloromethane (100 ml) followed by extraction with a solution of 1 n aq. HCl (2×50 ml). The organic layer was dried, concentrated under vacuum and was purified by column chromatography on silica gel using 98/2 CH2Cl2/MeOH with getting on the cell connection in the form of a solid (480 mg, 39%, two stages). Melting point = 260-261°C (TRANS-isomer)1H NMR (500 MHz, DMSO-d6): δ ppm 1.37 (s, 9H), 2.71 (t, J=6.7 Hz, 2H), 3.01 (s, 3H), 3.75 (s, 3H), 3.79 (t, J=6.6 Hz, 2H), 7.13 (d, J=16.5 Hz, 1H), 7.15 (d, J=2.4 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.25 (d, J=16.5 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 9.80 (bs, 1H), 10.30 (s, 1H). (TRANS-isomer).

[00521] Example 2. Receive (2)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)-1-chloride)phenyl)methanesulfonamide (compound IA-L1-1.3).

[00522] Part A. Obtaining diethylketone(4-nitrophenyl)methylphosphonate.

[00523] the Named compound was obtained as described by Taylor, WP, et. AI, Bioorg. Med. Chem. 4:1515-1520 (1996). 4-Nitrobenzaldehyde (3.0 g, 19,85 mmol) and diethyl phosphonate (2,74 g, 19,85 mmol) were combined and treated with 0.5 n solution of sodium methoxide in methanol (0,993 ml, 0,496 mmol). The resulting red-orange solution was stirred for 12 h at room temperature. The reaction mixture was extracted with dichloromethane (20 ml), then polysystem ammonium chloride (20 ml). The organic layer was separated, dried and concentrated under vacuum to obtain these compounds in the form of semi-solid substances (5,1 g, 89%).

[00524] part of the Century, Obtaining ditillo(4-nitrophenyl)methylphosphonate.

[00525] the Product obtained in part a (500 mg shipped 1,729 mmol) was dissolved in dichloromethane (10 ml) and treated with triphenylphosphine (998 mg, of 3.80 mmol), then N is loratidine (462 mg, 3.46 mmol). The mixture was stirred at room temperature for 18 hours the Solution was concentrated under vacuum and the residue was purified by column chromatography using silica gel, elwira mixture 1/1 hexane/ethyl acetate to obtain these compounds in the form of oil (262 mg, 49%).

[00526] Part C. Obtaining (2)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)-1-chloride)phenyl)methanesulfonamide.

[00527] the Product obtained in Example 1, Part G (100 mg, 0,329 mmol) was treated with the product obtained from Part b using the procedure described in Example 1, Part H and Example 1, Parts I to obtain 39 mg of the named compound.1H NMR (300 MHz, DMSO-d6): δ ppm 1.36 (s, 9H), 2.71 (t, J=6.8 Hz, 2H), 3.06 (s, 3H), 3.71 (s, 3H), 3.78 (t, J=6.8 Hz, 2H), 7.23 (d, J=2.6 Hz, 1H), 7.27 (s, 1H), 7.28 (d, J=8.6 Hz, 2H), 7.48 (d, J=2.6 Hz, 1H), 7.78 (d, J=8.8 Hz, 1H), 10.05 (s, 1H), 10.34 (s, 1H).

[00528] Example 3. Obtaining (E)-1-(3-tert-butyl-5-(4-forsteri)-4-methoxyphenyl) dihydropyrimidine-2,4(1H,3H)-dione (compound IA-L1-1.12).

[00529] the Named compound was obtained in accordance with the procedures described in Example 1, Part H and Example 1, Part I, using the product obtained in Example 1, Part G (50 mg, 0,164 mmol) and diethyl 4-forbindelsen (40.5 mg, 0,164 mmol). The named compound was obtained as a solid (30 mg, 46%).1H NMR (300 MHz, DMSO-d6): δ ppm 1.37 (s, 9H), 2.72 (t, J=6.6 Hz, 2H), 3.76 (s, 3H, 3.79 (t=6.6 Hz, 2H), 7.21 (m, 4H), 7.30 (d, J=16.3 Hz, 1H), 7.53 (d, J=2.6 Hz, 1H), 7.73 (m, 2H), 10.35 (s, 1H).

[00530] Example 4. Obtain (Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)-1-Porvenir)phenyl)methanesulfonamide (compound IA-L1-1.4).

[00531] Part A. Obtaining diethylether(4-nitrophenyl)methylphosphonate.

[00532] the Named compound was obtained as described by Taylor, WP, et. Al, Bioorg. Med. Chem. 4:1515-1520 (1996). The product from Example 2, part a (500 mg shipped 1,729 mmol) was dissolved in dichloromethane (10 ml) and was treated by adding dropwise TRIFLUORIDE (diethylamino)sulfur (DAST) (2.5 ml, of 18.9 mmol). The mixture was stirred at room temperature for 18 h solution was Added Polynesians monobasic phosphate (20 ml), followed by addition of dichloromethane (20 ml) and separation of the resulting organic phase. This organic solution was dried and concentrated under vacuum, and then subjected to column chromatography using silica gel, elwira 1/1 mixture of hexane/ethyl acetate to obtain these compounds in the form of oil (215 mg, 43%).

[00533] Part C. Obtain (Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)-1-Porvenir)phenyl)methanesulfonamide.

[00534] the Product obtained as described in part a (100 mg, 0,329 mmol) was treated with the product obtained in Example 1, Part G (96 mg, 0,329 mmol) in soo is according with the procedures described in Example 1, Part H and Example 1, Parts I to obtain 53 mg of the above compound in the form of a 1/1 mixture of CIS/TRANS isomers. Chromatographic separation by HPLC with reversed phase, using 40-100% gradient of acetonitrile in 0.1% aqueous triperoxonane acid gave the titled compound as a solid (20 mg).1H NMR (300 MHz, DMSO-d6): δ ppm 1.37 (s, 9H), 2.71 (t, J=6.8 Hz, 2H), 3.06 (s, 3H), 3.77 (s, 3H), 3.78 (m, 2H), 6.62 (d, J=40.4 Hz, 1H), 7.18 (d, J=2.6 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.55 (d, J=2.6 Hz, 1H), 7.75 (d, J=8.8 Hz, 2H), 10.08 (s, 1H), 10.33 (s, 1H).

[00535] Example 5. Obtaining (E)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)-1-Porvenir)phenyl)methanesulfonamide (compound IA-L1-1.5).

[00536] Chromatographic separation by HPLC with reversed phase 1/1 mixture of CIS/TRANS isomeric substances (53 mg) from Example 4, part a, using 40-100% gradient of acetonitrile in 0.1% aqueous triperoxonane acid, gave the titled compound as a solid (16.5 mg).1H NMR (300 MHz, DMSO-d6): δ ppm 1.33 (s, 9H), 2.60 (t, J=6.6 Hz, 2H), 3.01 (s, 3H), 3.57 (t, J=6.6 Hz, 2H) 3.79 (s, 3H), 6.46 (d, J=21.3 Hz, 1H), 6.87 (d, J=2.2 Hz, 1H), 7.14 (m, 3H), 7.36 (d, J=8.8 Hz, 2H), 10.02 (s, 1H), 10.24 (s, 1H).

[00537] Example 6. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxytrityl)-2-forfinal)methanesulfonamide (compound IA-L1-1.26)

[00538] Part A. Obtain 4-(b shall ammeter)-2-fluoro-1-nitrobenzene.

[00539] (3-fluoro-4-NITROPHENOL)methanol (1.24 g, of 7.25 mmol) was dissolved in dichloromethane (25 ml) and treated with triphenylphosphine (2,281 g to 8.70 mmol) then N-bromosuccinimide (1,548 g to 8.70 mmol). The mixture was stirred at room temperature for 2 hours was Added water (50 ml) and dichloromethane (40 ml) and the organic layer was separated and dried. This solution was concentrated under vacuum and was purified by column chromatography using silica gel, elwira 5/1 mixture of hexane/ethyl acetate to obtain these compounds in the form of a solid (1.27 g, 75%).

[00540] part of the Century, Obtaining diethyl-3-fluoro-4-nitrobenzaldehyde.

[00541] the Product obtained in part a (1.27 g, 5.43 mmol) was added to triethylphosphine (8 ml, to 54.3 mmol), and the solution was heated to 120°C for 1 h, After cooling, the excess triethylphosphite was removed by heating under vacuum and the residue was subjected to column chromatography on silica gel using 99/1 dichloromethane/methanol as eluent to obtain the crude titled compound as an oil (800 mg).

[00542] Part C. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxytrityl)-2-forfinal)methanesulfonamide.

[00543] the Product described in Example 1, Part G (533 mg, 1,751 mmol) was treated with the product described in Part (510 mg, 1,751 mmol) according to the procedures described in Example 1, Cha is t H and Example 1 Part I to obtain 80 mg of the named compound. 'H NMR (300 MHz, DMSO-d6): δ ppm 1.37 (s, 9H), 2.71 (t, J=6.5 Hz, 2H), 3.05 (s, 3H), 3.76 (s, 3H), 3.79 (t, J=6.6 Hz, 2H), 7.18 (m, 2H), 7.36 (d, J=16.5 Hz, 1H), 7.39 (m, 1H), 7.44 (m, 1H), 7.52 (d, J=2.6 Hz, 1H), 7.63 (m, 1H). 9.65 (s, 1H), 10.35 (s, 1H).

[00544] Example 7. Obtaining N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)cyclopropyl)phenyl)methanesulfonamide (compound IA-L8-1.1).

[00545] the Product obtained as described in Example 1, Part I (30 mg, 0,064 mmol) was dissolved in tetrahydrofuran (2 ml) and was treated with 0.95 ml of 0.67 M ethereal solution diazomethane (0,636 mmol), followed by palladium acetate (0.7 mg, 0,0031 mmol). The mixture was stirred for 30 min at room temperature followed by removal of solids by filtration and concentration of the filtrate. The filtrate was purified by column chromatography on silica gel using 98/2 dichloromethane/methanol as eluent to obtain these compounds in the form of solids (to 21.6 mg, 70%). Melting point 265-266°C.1H NMR (300 MHz, DMSO-d6): δ ppm 1.33 (s, 9H) 1.50 (m, 2H), 2.13 (m, 1H), 2.27 (m, 1H), 2.69 (t, J=6.6 Hz, 2H), 2.94 (s, 3H), 3.63 (s, 3H), 3.74 (t, J=6.6 Hz, 2H),6.84 (d, J=2.6 Hz, 1H), 7.04 (d, J=2.6 Hz, 1H), 7.14 (d, J=8.8 Hz, 2H), 7.20 (d, J=8.8 Hz, 2H), 9.60 (s, 1H),10.29 (s, 1H).

[00546] Example 8. Obtaining N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenethyl)phenyl)methanesulfonamide (compound IA-L5-2-1.1).

[00547] the Product obtained as described in Example 1, Part I (415 mg, 0.88 mmol) was dissolved in methanol (30 ml) and was treated with 50 mg of 10% palladium on coal. The suspension was stirred for 48 h at room temperature under a pressure of 1 ATM of hydrogen. The reaction mixture was filtered through celite and concentrated in vacuum to obtain these compounds in the form of a solid (230 mg, 55%). Melting point 233-234°C.1H NMR (300 MHz, DMSO-d6): δ ppm 1.34 (s, 9H), 2.68 (t, J=6.8 Hz, 2H), 2.86 (s, 4H), 2.93 (s, 3H), 3.70 (m, 2H), 3.74 (s, 3H), 7.11 (m, 4H), 7.23 (m, 2H),9.59(s, 1H), 10.29 (s).

[00548] Example 9. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)styryl)phenyl)methanesulfonamide (compound IA-L1-1.16)

[00549] Part A. Obtain methyl 3-tert-butyl-5-(chlorocarbonyl)benzoate.

[00550] a Mixture of 3-tert-butyl-5-(methoxycarbonyl)benzoic acid (9,18 g of 38.9 mmol, obtained by the method of Carter et. al., WO2005021500A1), thionyl chloride (75 ml) and 1 drop of DMF in toluene (200 ml) was heated under reflux for 2 h, cooled and concentrated. The residue was azeotropically toluene (3×50 ml) and dried under high vacuum to obtain these compounds in the form of a whitish waxy solids (9,9 g, quantitative yield).

[00551] Part C. Obtain methyl 3-(azidocarbonyl)-5-tert-butylbenzoate.

[00552] To the product of Part a (9,9 g of 38.9 mmol) in Aceto is e (200 ml) was added quick drops of a solution of sodium azide (10,12 g, 156 mmol) dissolved in water (20 ml). The mixture was stirred for 2 h and diluted with EtOAc. The organic layer was washed H2O, saturated salt solution, dried (Na2SO4), filtered and concentrated to obtain these compounds in a solid white color (9,9 g, 97%).

[00553] Part C. Obtain methyl 3-amino-5-tert-butylbenzoate.

[00554] the Product from Part b (9,9 g of 37.9 mmol) in toluene (100 ml) was heated under reflux for 1 h and then concentrated to obtain an intermediate isocyanate, which was dissolved in DME (60 ml) was treated with 8% HCl (150 ml) and was stirred for 16 hours the Mixture was concentrated and the residue was dissolved in water, neutralized with solid sodium bicarbonate and was extracted with 3×100 ml EtOAc. The organic phases were combined, washed with saturated NaCl, dried (Na2SO4), filtered and concentrated. The crude product was chromatographically on silica gel, elwira 2:1 hexane/EtOAc to obtain these compounds in the form of an oil (2.7 g, 35%).

[00555] Part D. Obtain methyl 3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxybenzoate.

[00556] a Mixture of the product of Part C (2,34 g of 11.29 mmol) and acrylic acid (2,32 ml, to 33.9 mmol) in toluene (60 ml) was heated under reflux in nitrogen atmosphere for 24 h, cooled and concentrated. The resulting residue is then clicks sativali urea (2,03 g, to 33.9 mmol) in acetic acid (35 ml) and heated at 120°C for 24 h, cooled and concentrated. The residue was azeotropically 3×50 ml of toluene and dissolved in 100 ml EtOAc. The organic layer is washed with dilute aqueous NaHCO3H2O, saturated salt solution, dried (Na2SO4), filtered and concentrated to obtain these compounds in a solid white color (2.1 g, 61%).

[00557] Part E. Obtain 3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)benzoic acid.

[00558] a Mixture of the product from Part D (1.8 g, 5,91 mmol) and 1M NaOH (up 29.6 ml, 29.6 mmol) in Meon (15 ml) and THF (15 ml) was stirred for 24 h and concentrated. The residue was treated with 50 ml of 1M HCl and was extracted in EtOAc. The EtOAc layer was washed N2Oh, saturated salt solution, dried (Na2SO4), filtered and concentrated to obtain a solid substance of white color. This intermediate urea was combined with 20 ml of concentrated HCl and heated at 100°C for 1 h, cooled and diluted with 75 ml of ice water to obtain a white powder, which was collected by filtration and dried to constant weight to obtain the above compound (1.6 g, 93%).

[00559] Part F. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl) styryl)phenyl)methanesulfonamide.

[00560] the Product described in Part E was treated with thionyl chloride is lithium tri-tert - butoxyaniline hydride in accordance with the procedures described in Example 1, Part G, to obtain 3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)benzaldehyde. This aldehyde was treated with diethyl-4-nitrobenzenesulfonate in accordance with the procedures described in Example 1, Part H and Example 1, Parts I to obtain the above compound (85 mg).1H NMR (300 MHz, DMSO-d6): δ ppm 1.32 (s, 9 H) 2.72 (t, J=6.43 Hz, 2 H) 3.01 (s, 3 H) 3.82 (t, J=6.62 Hz, 2 H) 7.18-7.25 (m, 5 H) 7.39 (s, 1 H) 7.46 (s, 1 H) 7.58 (d, J=8.46 Hz, 2 H) 9.84 (s, 1 H) 10.37 (s, 1 H).

[00561] Example 10. Obtain (Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)-1-methoxyphenyl)phenyl)methanesulfonamide (compound IA-L1-1.17).

[00562] Part A. Obtaining 1-(dimethoxymethyl)-4-nitrobenzene.

[00563] In a flask equipped with a magnetic stirrer and a Vigreux column was placed 4-nitro-benzaldehyde (5.0 g, up 33.1 mmol), pyridine p-toluolsulfonic (1.66 g, 6.62 mmol), trimethoxymethane (3.51 g, up 33.1 mmol) and methanol (100 ml). The mixture was heated at 50°C for 12 h and concentrated in vacuum. The remainder of pererestorani in EtOAc and washed with aq. NaOH (1M), H2O and brine. The mixture was dried (Na2SO4), filtered and concentrated in vacuum to obtain at the output of these compounds in the form of a transparent light-Zelenogo oil product (6,36 g, 97%).

[00564] part of the Century, Obtaining diethylketone(4-nitrophenyl)methylphosphonate.

[00565] the Product from part a (3, g, of 15.2 mmol) and triethylphosphite (2,53 g of 15.2 mmol) was dissolved in dichloromethane (30 ml) under nitrogen atmosphere, was cooled to -20°C and treated dropwise addition of epirate boron TRIFLUORIDE (2,27 g, 16 mmol). The mixture was left to slowly warm to room temperature overnight with stirring. Added water and the resulting mixture was stirred 5 min, separated, and the organic layer was dried (Na2SO4), filtered and concentrated in vacuum to obtain a solid residue. This residue was purified on silica gel (100% EtOAc to 3% SN3HE/EtOAc)to obtain the output of the named compound as a light yellow oil product (of 3.78 g, 82%).

[00566] Part C. Obtain (Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)-1-methoxyphenyl)phenyl)methanesulfonamide.

[00567] the Product obtained in accordance with the procedure described in Example 1, Part G (400 mg, 1.314 GC mmol) was treated with the product obtained in Part b (399 mg, 1.314 GC mmol) according to the procedures described in Example 1, Part H and Example 1, Parts I to obtain the above compound (17 mg, 6%).1H NMR (300 MHz, DMSO-d6): δ ppm 1.36 (s, 9 H), 2.71 (t, J=6.62 Hz, 2 H) 3.05 (s, 3 H), 3.58 (s, 3 H) 3.75 (s, 3 H) 3.76-3.81 (m, 2 H) 6.25 (s, 1 H) 7.11 (d, J=2.57 Hz, 1 H) 7.27 (d, J=8.46 Hz, 2 H) 7.60 (d, J=8.82 Hz, 2 H) 7.67 (d, J=2.57 Hz, 1 H), 9.96 (s, 1 H), 10.32 (s, 1 H).

[00568] Example 11. Obtaining (E)-1-(3-tert-butyl-4-methoxy-5-stillfeel)digid the on-pyrimidine-2,4(1H,3H)-dione (compound IA-L1-1.18).

[00569] the Product obtained in accordance with the procedure described in Example 1, Part G (50 mg, 0,164 mmol) was treated with determenirovana (0,034 ml, 0,164 mmole) in accordance with the procedure described in Example 1, Part H to obtain the above compound (13 mg, 19%).1H NMR (300 MHz, DMSO-d6): δ ppm 1.37 (s, 9 H), 2.72 (t, J=6.62 Hz, 2 H) 3.76 (s, 3 H) 3.80 (t, J=6.80 Hz, 2 H) 7.16-7.18 (m, 1 H) 7.21-7.23 (m, 1 H) 7.29-7.33 (m, 2 H) 7.36-7.43 (m, 2 H) 7.54 (d, J=2.57 Hz, 1 H) 7.64 (d, J=7.35 Hz, 2 H), 10.35 (s, 1 H).

[00570] Example 12. Obtaining (E)-1-(3-tert-butyl-4-methoxy-5-(4-methoxystyrene)phenyl) dihydropyrimidine-2,4(1H,3H)-dione (compound IA-L1-1.14).

[00571] the Product obtained in accordance with the procedure described in Example 1, Part G (50 mg, 0,164 mmol) was treated with diethyl-4-methoxybenzophenone (0,028 ml, 0,164 mmol) according to the procedure described in Example 1, Part H to obtain the above compound (4 mg, 4%).1H NMR (300 MHz, DMSO-d6): δ ppm 1.37 (s, 9 H), 2.71 (t, J=6.62 Hz, 2 H) 3.70-3.81 (m, 8 H) 6.96 (d, J=8.82 Hz, 2 H) 7.13 (d, J=2.21 Hz, 1 H) 7.15 (d, J=2.57 Hz, 2 H) 7.50 (d, J=2.57 Hz, 1 H) 7.58 (d, J=8.46 Hz, 2 H), 10.34 (s, 1 H).

[00572] Example 13A. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide (compound IB-L1-1.1).

[00573] Part A. Obtaining (E)-methyl 3-tert-butyl-2-methoxy-5-(3-(3-methoxyacetyl)oreid) benzoate.

[00574] the Product p is obtained as described in Example 1, Part C (2.0 g, 8,43 mmol) was dissolved in 30 ml of N,N-dimethylacetamide and cooled to -25°C. was Added dropwise a 0.5 molar solution of E-3-methoxycarbonylamino in benzene (of 21.9 ml, 10,96 mmol) and the resulting solution was stirred at ambient temperature for 4 h, and then poured into water. This product was extracted into dichloromethane, washed with saline, dried over sodium sulfate, filtered and evaporated under vacuum to obtain these compounds.

[00575] Part C. Obtain methyl 3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxybenzoate.

[00576] the Product from part a (3.1 g, 8,51 mmol) was dissolved in ethanol (60 ml). To this solution was added a mixture of concentrated sulfuric acid (6 ml) and water (60 ml). The heterogeneous mixture was heated at 100°C for 3 hours, the Ethanol was removed under vacuum, and then the aqueous solution was extracted with dichloromethane and evaporated to dryness. This residue was purified by column chromatography on silica gel, elwira 1% methanol/dichloromethane to obtain at the output of the above compound (1.23 g, 44%).

[00577] Part C. Obtain 3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy benzoic acid.

[00578] the Product from Part b (1.23 g, 3.7 mmol) was placed in ethanol (5 ml) and 1M sodium hydroxide solution (10 ml) and stirred at ambient temperature for 18 hours This races the thief was acidified using 1M HCl and the resulting solid was filtered and dried to obtain the above compound (0,945 g, 80%).

[00579] Part D. Obtain 3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy benzaldehyde.

[00580] the Product from Part C (0,945 g of 2.97 mmol) were placed in thionyl chloride (4.5 ml) and the mixture was heated at 80°C for 40 minutes After evaporation to dryness, the acid chloride was dissolved in dry THF (8 ml) and cooled to -78°C. was Added dropwise a 1 M solution of lithium tri-tert-butoxyaniline hydride in THF (3.0 ml, 3.0 mmol). After 45 min the cold reaction mixture is extinguished 1M HCl (5 ml), was extracted in ethyl acetate and was purified by column chromatography on silica gel, elwira dichloromethane and then 1% methanol/dichloromethane to obtain these compounds (0,635 g, 71%).

[00581] Part E. Obtaining (E)-1-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)pyrimidine-2,4(1H,3H)-dione.

[00582] the Product of Part D (0,634 g, 2.1 mmol) and diethyl 4-nitrobenzenesulfonate (0,573 g, 2.1 mmol) were combined in dichloromethane (25 ml) at ambient temperature. Added portions of tert-piperonyl potassium (0,494 g, 4.4 mmol) and the resulting red/brown heterogeneous mixture was stirred for 1.5 hours the mixture was suppressed 1M HCl (15 ml), poured into water and was extracted into ethyl acetate, and the crude product was purified by column chromatography on silica gel, elwira 1% methanol/dichloromethane to obtain these compounds (0,735 g, 83%).

[00583] Part F. Obtaining (E)-1-(3-(4-amino is tiril)-5-tert-butyl-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00584] the Product from Part E (0,735 g of 1.74 mmol), ammonium chloride (0.14 g, 2,62 mmol), and iron (0,487 g, 8,72 mmol) were combined in ethanol (10 ml), water (5 ml), and THF (10 ml) and heated at 75°C for 1 h the Mixture was filtered through diatomaceous earth, well washed with THF and concentrated to obtain these compounds.

[00585] Part G. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00586] the Product from Part F (0,683 g of 1.75 mmol) and pyridine (0,564 ml, 6,98 mmol) were combined in dichloromethane (15 ml) at ambient temperature. Methanesulfonanilide (0,163 ml, 2.1 mmol) was added dropwise, and the solution was stirred for 18 hours the Mixture was poured into 1M HCl and was extracted into dichloromethane, concentrated, and was purified by column chromatography on silica gel, elwira 1%, 2% methanol/dichloromethane. Rubbing with dichloromethane gave a solid, which was filtered and dried to obtain these compounds in the form of a colourless powder (0,465 g, 57%).1H NMR (300 MHz, DMSO-D6) δ ppm 1.38 (s, 9 H), 3.01 (s, 3 H), 3.79 (s, 3 H), 5.65 (d, J=7.72 Hz, 1 H), 7.17-7.28 (m, 5 H), 7.58-7.70 (m, 3 H), 7.75 (d, J=7.72 Hz, 1 H), 9.86 (s, 1 H), 11.42(s, 1 H).

[00587] Example 13 Century, Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide (compound IB-L1-1.1).

[00588] Part A. Obtain N-(4-eminelton the l)methanesulfonamide.

[00589] In a 2 l 3-neck round bottom flask equipped verhneprivodnaya stirrer, was added 4-itinerary (30 g, 256 mmol) and pyridine (42,5 ml, 525 mmol) in dichloromethane (512 ml) to give an orange solution. The mixture was cooled to 5°C was added dropwise methanesulfonanilide (19,96 ml, 256 mmol) for 15 min the Reaction solution was stirred at 5°C for 2 h and washed with 1M aqueous HCl (3×250 ml). The dichloromethane layer was then washed sequentially with saturated aqueous NaHCO3, water, and saturated aqueous NaCl. The dichloromethane layer was dried over sodium sulfate and treated simultaneously decolorizing charcoal for 30 min, this solution was then filtered through celite and the filtrate was concentrated. Pink/orange solid was dissolved in minimum amount of hot ethyl acetate (50-75 ml) and was slowly diluted with hexane (500-600 ml) to give orange crystals, which were collected by filtration and dried to obtain the above compound (40,0 g, 80%).

[00590] part of the Century, Obtaining (E)-4-(methylsulfonyl)styrylboronic acid.

[00591] (Reference: Org. Prep.Proc. Int., 2004, 36, 573-579) In a flask was added borane complex-metilsulfate (8,03 ml, 85 mmol), and then tetrahydrofuran (16 ml), and the mixture is then cooled to 0°C. Then cooled to ice the solution was added dropwise (1R)-(+)-alpha-pinene (26,2 ml, 169 mmol) (for 10 min). The mixture is then stirred at 0°C for 1 h, followed by stirring 2 h at room temperature. The resulting thick white suspension was cooled to -40°C and dried in a bath of ice/acetone, followed by adding dropwise during 30 min of the product from part a (15.0 g, 77 mmol), dissolved in 60 ml of THF. After complete addition, the mixture was stirred for an additional hour at -35°C., then 1 h at room temperature. Light yellow solution was then cooled to 0°C was added acetaldehyde (61,4 ml, 1088 mmol), then the mixture was heated under reflux at 50°C for 18 hours Then the solvent was removed under vacuum to obtain a concentrated solution of orange color, to which was added water (115 ml), and the heterogeneous mixture was stirred for 3 h at room temperature. The resulting light yellow solid was collected and washed with water (250 ml), then dried in a vacuum oven over night. The resulting substance is then dissolved in boiling acetone (190 ml), which gave the homogeneous yellow solution, followed by removal of heat of solution and the addition of hexane (365 ml) over a period of time of 5 minutes In a solution formed solid white, and the mixture was stirred until cooled to room temperature, then the white solid was collected and dried in a vacuum oven for 1 hour to obtain these compounds (12,1 who, 85%).

[00592] Part C. Obtain 2-tert-butyl-4-NITROPHENOL.

[00593] To intensively stirred solution of 2-tert-butylphenol (10 g, of 66.6 mmol) in heptane (67 ml) was added quick drops of a solution of 70% nitric acid (4,25 ml 66,6 mmol) diluted with water (4,25 ml). The resulting dark red/brown mixture was intensively stirred for 2 hours Suspended solid was collected by filtration, washed with hexane (300 ml), water (200 ml) and once with hexane (200 ml) to obtain the powder color of cocoa, which was dried to constant weight (4,65 g, 35.6 percent).

[00594] Part D. Obtain 2-bromo-6-tert-butyl-4-NITROPHENOL.

[00595] a solution of the product from Part C (1.0 g, 5,12 mmol) in glacial acetic acid (of 10.25 ml) was treated with portions of pyridine hydrobromide by perbromide (1.80 g, 5,63 mmol) followed by stirring at room temperature for 2 hours an Additional amount of pyridinium hydrobromide of perbromide (3.6 g) was added in two portions and after another 3 h of stirring the reaction was completed. The mixture was poured into ice water, and this mixture was treated with a small amount of sodium sulfite. The resulting solid was filtered and dried under vacuum to obtain these compounds in a solid brown color (1.40 g, 100%).

[00596] Part E. Obtain 1-bromo-3-tert-butyl-2-methoxy-5-nitrobenzene.

[0057] a solution of the product from Part D (1.40 g, 5,11 mmol) in 10:1 t-butyllithium ether-methanol (25,5 ml) was treated with a 2.0 M trimethylsilyldiazomethane in ether (5,1 ml of 10.21 mmol), followed by stirring at room temperature for 18 hours the Mixture was concentrated under vacuum to obtain a yellow oil, which was purified by column chromatography on silica gel, elwira EtOAc/hexane to obtain the above compound as a yellow oil (1,36 g, 92%).

[00598] Part F. Obtain tert-butyl 3-bromo-5-tert-butyl-4-methoxyphenylalanine.

[00599] a solution of the product from Part E (960 mg, of 3.33 mmol) in methanol (17 ml) was treated with 5% platinum on solifidianism carbon (100 mg), followed by hydrogenation under pressure of balloon tires for 3 h, and then filtered through celite and concentrated under vacuum to obtain 3-bromo-5-tert-butyl-4-methoxyaniline in the form of a yellow oil (860 mg, of 3.33 mmol, 100%). The solution of this substance in THF (17 ml) was treated with di-tert-butyl dicarbonate (800 mg, 3,66 mmol) followed by heating under reflux for 2 hours Concentration under vacuum gave a solid beige color, which was purified by column chromatography on silica gel, elwira EtOAc/hexane. The solid was ground into powder with hexane, collected by filtration, and dried under vacuum to obtain these compounds in the form of almost white is th solid (890 mg, 75%).

[00600] Part G. Obtaining (E)-N-(3-bromo-5-tert-butyl-4-methoxyphenylacetyl)-3-ethoxyacrylate.

[00601] the Product from Part F (2.0 g, to 5.58 mmol) was dissolved in dichloromethane (10 ml) and added triperoxonane acid (5 ml). This solution was stirred at room temperature for 1 h followed by concentration under vacuum and addition of 10% aqueous sodium bicarbonate (50 ml), followed by extraction with ethyl acetate (3×50 ml). The combined organic extracts were dried and concentrated to obtain residue, which was dissolved in 10 ml of N,N - dimethylacetamide and cooled to -25°C. was Added dropwise a 0.5 molar solution of E-3-methoxycarbonylamino in benzene (20,3 ml, 11,16 mmol) and the resulting solution was stirred at ambient temperature for 4 h, and then poured into water. This product was extracted into dichloromethane, washed with saline, dried over sodium sulfate, filtered and evaporated under vacuum to obtain these compounds.

[00602] Part N. Obtain 1-(3-bromo-5-tert-butyl-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00603] the Product from Part G (2.15 g, to 5.58 mmol) was dissolved in ethanol (10 ml). To this solution was added a mixture of concentrated sulfuric acid (1 ml) and water (10 ml). This heterogeneous mixture was heated at 100°C for 2 hours, the Ethanol was removed under vacuum, and then an aqueous solution uh what was strayaway dichloromethane and evaporated to dryness. This residue was purified by column chromatography on silica gel, elwira 1% methanol/dichloromethane to obtain at the output of the above compound (1.35 g, 69%).

[00604] Part I. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00605] the Product from Part H (8.0 g, 22,65 mmol), the product from Part b (5,90 g, 24,46 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0,738 g, 1,132 mmol), and potassium phosphate (9,62 g of 45.3 mmol) was dissolved in a mixture of tetrahydrofuran (128 ml) and water (32 ml). Nitrogen gas was barbotirovany through the resulting mixture for 10 min followed by heating this solution at 50°C for 5 h in the dark. The reaction mixture was left to cool to room temperature followed by the addition of saturated aqueous ammonium chloride (50 ml), water (200 ml) and this solution was extracted with dichloromethane (600 ml). The organic extract was added magnesium sulfate and 3-mercaptopropyl-activated silica gel (20 g) and the resulting solution was stirred in the dark for 18 hours, the Solids were then removed by filtration and the filtrate was concentrated under vacuum and subjected to column chromatography on silica gel using a gradient 99/1 - 99/2 dichloromethane/methanol to obtain the above compound (7.4 g, 70%).1H NMR (300 MHz, DMSO-D6) δ pm 1.38 (s, 9 H), 3.01 (s, 3 H), 3.79 (s, 3 H) 5.65 (d, J=7.72 Hz, 1 H), 7.17-7.28 (m, 5 H), 7.58-7.70 (m, 3 H), 7.75 (d, J=7.72 Hz, 1 H), 9.86 (s, 1 H), 11.42(s, 1 H).

[00606] Example 14. Obtaining (E)-N-(4-(3-tert-butyl-5-(5-fluoro-2,4-dioxo-3,4-dihydro-pyrimidine-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide (compound IB-L1-1.2).

[00607] Part A. Obtain methyl 3-tert-butyl-5-(5-fluoro-6-methoxy-2,4-dioxotetrahydrofuran-pyrimidine-1(2H)-yl)-2-methoxybenzoate.

[00608] the Procedure for fluorination was performed as described by Lal, GS, et al. J. Org Chem., 60:7340-7342 (1995). The product from Example 13A, Part b (0,42 g of 1.26 mmol) and Selectfluor™ (0,672 g, 1.9 mmol) were combined in a mixture of acetonitrile (8 ml) and methanol (1 ml) and heated at 90°C in an atmosphere of N2within 5 hours the Solution was diluted with water, was extracted into ethyl acetate, washed with sodium bicarbonate solution, concentrated and was purified by column chromatography on silica gel to obtain the above compound (was 0.138 g, 29%).

[00609] Part C. Obtain methyl 3-tert-butyl-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxybenzoate.

[00610] the Product from part a (0,134 g, 0.35 mmol) and triethylamine (1 ml) were combined in methanol (4 ml) and stirred at ambient temperature for 18 hours the Solution was suppressed 1M HCl, extracted into dichloromethane and concentrated to obtain these compounds (0,113 g, 92%).

[00611] Part C. Obtain 3-tert-butyl-5-(5-fluoro-2,4-dioxo-3,4-dihydrospiro the one-1(2H)-yl)-2-methoxybenzoic acid.

[00612] the Product from Part b (0,113 g, 0.32 mmol) was treated as described in Example 13A, Part C with obtaining these compounds (0,088 g, 81%).

[00613] Part D. Obtain 3-tert-butyl-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxybenzaldehyde.

[00614] the Product from Part C (0,088 g, 0.26 mmol) was treated as described in Example 13A, Part D to obtain the above compound (0.075 g, 90%).

[00615] Part E. Obtaining (E)-1-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)-5-ftorpirimidinu-2,4(1H,3H)-dione.

[00616] the Product of Part D (0.075 g, 0.23 mmol) was treated as described in Example 13A, Part E with getting 0,077 g (75%).

[00617] Part F. Obtaining (E)-1-(3-(4-aminosterol)-5-tert-butyl-4-methoxyphenyl)-5 - ftorpirimidinu-2,4(1H,3H)-dione.

[00618] the Product of Part E (0,077 g, 0.18 mmol) was treated as described in Example 13A, Part F of obtaining these compounds (0,071 g, 94%).

[00619] Part G. Obtaining (E)-N-(4-(3-tert-butyl-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00620] the Product of Part F (0,071 g, 0,17 mmol) were processed as described in Example 13A, Part G of obtaining these compounds (0,048 g, 57%).1H NMR (300 MHz, DMSO-D6): δ ppm 1.38 (s, 9 H), 3.01 (s, 3 H), 3.79 (s, 3 H) 7.19-7.27 (m, 5 H), 7.62 (d, J=8.82 Hz, 2 H), 7.66 (d, J=2.57 Hz, 1 H), 8.25 (d, J=6.99 Hz, 1H).

[00621] Example 15. Obtaining (E)-N-(4-(3-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide(compound IB-L1-1.52).

[00622] Part A. Obtain 2-bromo-4,6-deadpool.

[00623] In a 1 l round bottom flask was placed 2-bromophenol (8.65 g, 50 mmol) and methanol (100 ml) to give a colorless solution. Was added sodium hydroxide (2,40 g, 60,0 mmol) and stirred until complete dissolution of the hydroxide pellets. The solution was cooled in an ice bath was added sodium iodide (5.6 g, or 37.4 mmol), followed by adding dropwise sodium hypochlorite (17 ml, 27.5 mmol) to obtain the transparent brown/red solution, and the gradual deposition of thick white solid. Adding sodium iodide and sodium hypochlorite solution was repeated 3 times with getting the orange mixture, which was stirred for 2 h, treated with sodium thiosulfate solution in water (20 g in 100 ml) was stirred for 15 min and treated dropwise with concentrated HCl until a constant pH 1. The mixture was stirred for 15 min and filtered to collect the solids in white, which was washed repeatedly with water and dried to constant weight (14,7 g, 69%).

[00624] part of the Century, Obtaining 1-bromo-3,5-dead-2-methoxybenzene.

[00625] In a 500 ml round bottom flask was placed the product from part a (14,7 g, 34.6 mmol), logmean (2,70 ml of 43.3 mmol), and sodium hydroxide (2,101 ml, 39.8 mmol) in acetone (96 ml) to give a yellowish-brown solution. The mixture was stirred for 24 hours and concentrated. The residue was dissolved in ethyl acetate, washed with water and saturated sodium chloride, dried over sodium sulfate, filtered and concentrated to obtain a solid substance of white color. The solid is recrystallized from hot hexane to obtain a solid substance is white, which was collected by filtration (12.3 g, 81%).

[00626] Part C. Obtain 1-(3-bromo-5-iodine-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00627] In a 250 ml round bottom flask was placed the product from Part b (of 8.09 g, 18,44 mmol), pyrimidine-2,4(1H,3H)-dione (2,273 g to 20.28 mmol), N-(2-cyanophenyl)picolinate (0,823 g of 3.69 mmol), copper iodide (I) (0,351 g, 1,844 mmol) and potassium phosphate (by 8.22 g of 38.7 mmol) in DMSO (70 ml). The mixture is hermetically closed, barbotirovany nitrogen for 15 min and heated at 60°C for 16 hours the Mixture was separated with ethyl acetate and water. The organic layer washed with 1M HCl, water, brine, dried with sodium sulfate, and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel (Aldrich catalog #538086), filtered through celite and evaporated to obtain a whitish solid (to 3.92 g, 50%).

[00628] Part D. Obtaining (E)-N-(4-(3-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00629] In a 100 ml round bottom flask was added the product from Part C (846 mg, 2.0 mmol), the product from Example 13, Part b (482 mg, 2,000 mmol), phosphate ka the Oia (892 mg, 4.20 mmol), 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-postadmin (PA-Ph) (CAS 97739-46-3) (comprised 17.54 mg, to 0.060 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (18,31 mg, at 0.020 mmol) in THF (12.0 ml) and water (4.0 ml). The flask was tightly closed and the mixture was barbotirovany nitrogen for 5 min and stirred at ambient temperature for 72 hours and the Mixture was separated with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel, filtered and evaporated. The residue is triturated with a minimal amount of methanol/CH2Cl2obtaining these compounds in a solid white color (595 mg, 60%).1H NMR (300 MHz, DMSO-d6) δ ppm 3.03 (s, 3 H) 3.82 (s, 3 H) 5.69 (dd, J=7.72, 1.50 Hz, 1 H) 7.24 (d, J=8.46 Hz, 2 H) 7.35 (m, 2 H) 7.61 (d, J=8.46 Hz, 2 H) 7.69 (d, J=2.21 Hz, 1 H) 7.78 (d, J=8.09 Hz, 1 H) 7.87 (d, J=2.21 Hz, 1 H) 9.90 (s, 1 H) 11.50 (s, 1 H). MS (ESI-) m/z 490,492 (M-H)+.

[00630] Example 16. Obtaining (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophene-2-yl)styryl)phenyl)methanesulfonamide (compound IB-L1-1.48).

[00631] a 5 ml microwave tube was added the product from Example 15, Part D (40 mg, of 0.081 mmol), thiophene-2-Voronovo acid (the 10.40 mg of 0.081 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (2.65 mg, 4,.06 mmol) and potassium phosphate (34,5 mg, rate £ 0.162 mm is l) in THF (3.0 ml) and water (1.0 ml). The vessel was tightly closed and the mixture was barbotirovany nitrogen for 5 min and heated at 50°C for 3 hours the Mixture was separated with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel, filtered through celite and evaporated. The residue was purified using chromatography with reversed phase with obtaining these compounds in a solid white color (20 mg, 50%).1H NMR (300 MHz, DMSO-d6) δ ppm 3.03 (s, 3 H) 3.70 (s, 3 H), 5.70 (dd, J=7.72, 2.21 Hz, 1 H) 7.18 (dd, J=5.43, 4.05 Hz, 1 H) 7.25 (d, J=8.82 Hz, 2 H) 7.35 (s, 2 H) 7.63 (d, J=8.82 Hz, 2 H) 7.68 (m, 2 H) 7.77 (m, 2 H) 7.83 (d, J=7.72 Hz, 1 H), 9.89 (s, 1 H) 11.49 (d, J=2.21 Hz, 1 H). MS (ESI+) m/z 496 (M+H)+.

[00632] Example 17. Obtaining (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-2-yl)-2-methoxystyrene)phenyl)methanesulfonamide (compound IB-L1-L46).

[00633] the Named compound was obtained in accordance with the procedure of Example 16 substituting furan-2-Voronovo acid on thiophene-2-Voronovo acid with getting solid white (22 mg, 56%).1H NMR (300 MHz, DMSO-d6) δ ppm 3.03 (s, 3 H) 3.76 (s, 3 H), 5.69 (d, J=7.72 Hz, 1 H) 6.69 (dd, J=3.31, 1.84 Hz, 1 H) 7.08 (d, J=2.57 Hz, 1 H) 7.25 (d, J=8.46 Hz, 2 H) 7.36 (m, 2 H) 7.63 (d, J=8.82 Hz, 2 H) 7.67 (d, J=2.57 Hz, 1 H) 7.77 (d, J=2.57 Hz, 1 H), 7.82 (m, J=7.72 Hz, 2 H), 9.88 (s, 1 H), 11.48 (s, 1 H). MS (ESI+) m/z 497 (M+NH4)+.

[00634] Example 18. Receiving (E-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-metakey-3-(pyridin-4-yl)styryl)phenyl)methanesulfonamide (compound IB-L1-1.55).

[00635] the Named compound was obtained in accordance with the procedure of Example 16, substituting 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine on thiophene-2-Voronovo acid with getting solid white (15 mg, 38%).1H NMR (300 MHz, DMSO-d6) δ ppm 3.03 (s, 3 H) 3.49 (s, 3 H), 5.72 (dd, J=7.72, 2.21 Hz, 1 H) 7.25 (d, J=8.46 Hz, 2 H) 7.38 (d, J=4.41 Hz, 2 H) 7.51 (d, J=2.57 Hz, 1 H) 7.63 (d, J=8.82 Hz, 2 H) 7.80 (d, J=5.88 Hz, 2 H) 7.85 (d, J=7.72 Hz, 1 H) 7.97 (d, J=2.57 Hz, 1 H), 8.77 (d, J=6.25 Hz, 2 H), 9.90 (s, 1 H) 11.51 (d, J=2.21 Hz, 1 H). MS (ESI+) m/z 491 (M+H)+.

[00636] Example 19. Obtaining (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(pyridin-3-yl)styryl)phenyl)methanesulfonamide (compound IB-L1-1.53).

[00637] the Named compound was obtained in accordance with the procedure of Example 16, substituting 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine on thiophene-2-Voronovo acid to obtain a solid substance, white (19 mg, 48%).1H NMR (300 MHz, DMSO-d6) δ ppm 3.02 (s, 3 H) 3.45 (s, 3 H), 5.71 (dd, J=8.09, 2.21 Hz, 1 H) 7.24 (d, J=8.46 Hz, 2 H) 7.37 (d, J=2.94 Hz, 2 H) 7.47 (d, J=2.57 Hz, 1 H) 7.63 (m, 3 H) 7.85 (d, J=7.72 Hz, 1 H) 7.93 (d, J=2.57 Hz, 1 H) 8.15 (m, 1 H) 8.68 (dd, J=4.80 Hz, 1.47 Hz, 1 H), 8.86 (d, J=1.84 Hz, 1 H), 9.89 (s, 1 H), 11.50 (d, J=2.21 Hz, 1 H). MS (ESI+) m/z 491 (M+H)+.

[00638] Example 20. Obtaining (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophene-3-yl)styryl)phenyl)methanesulfonamide (compound IB-L1-1.47).

[00639] the Named compound was obtained in accordance with the laws the AI with the procedure of Example 16, substituting thiophene-3-Voronovo acid on thiophene-2-Voronovo acid to obtain a solid substance, white (19 mg, 38%).1H NMR (300 MHz, DMSO-d6) δ ppm 3.02 (s, 3 H) 3.55 (s, 3 H), 5.69 (d, J=8.09 Hz, 1 H) 7.24 (d, J=8.46 Hz, 2 H) 7.36 (s, 2 H) 7.55 (m, 2 H) 7.61 (d, J=8.46 Hz, 2 H) 7.67 (dd, J=5.15, 2.94 Hz, 1 H) 7.78 (d, J=2.57 Hz, 1 H) 7.83 (d, J=7.72 Hz, 1 H) 7.93 (dd, J=2.57, 0.96 Hz, 1 H), 9.88 (s, 1 H), 11.48 (s, 1 H). MS (ESI-) m/z 494 (M-H)+.

[00640] Example 21. Obtaining (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-3-yl)-2-methoxystyrene)phenyl)methanesulfonamide (compound IB-L1-1.50).

[00641] the Named compound was obtained in accordance with the procedure of Example 16, substituting furan-3-Voronovo acid on thiophene-2-Voronovo acid with getting solid white (14 mg, 29%).1H NMR (300 MHz, DMSO-d6) δ ppm 3.02 (s, 3 H), 3.69 (s, 3 H), 5.69 (d, J=8.09 Hz, 1 H) 7.05 (dd, J=2.57, 0.90 Hz, 1 H) 7.24 (d, J=8.82 Hz, 2 H) 7.34 (s, 2 H) 7.61 (m, 3 H) 7.74 (d, J=2.57 Hz, 1 H), 7.80 (m, 2 H) 8.25 (s, 1 H), 9.88 (s, 1 H), 11.49 (s, 1 H). MS (ESI-) m/z 478 (M-H)+.

[00642] Example 22. Obtaining (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-methoxystyrene)phenyl)methanesulfonamide (compound IB-L1-1.45).

[00643] Part A. Obtaining 2-(2-hydroxy-3,5-goodfeel)acetic acid.

[00644] In a 250 ml round bottom flask was added 2-(2-hydroxyphenyl)acetic acid (Aldrich, totaling 3.04 g, 20 mmol) in acetonitrile (50 ml) to give a colorless solution. N-jodatime (9.00 g, 40,0 shall mol) was added in portions over a period of time of 15 min with getting the red/brown transparent solution, which was stirred for 16 hours the Mixture was concentrated, and the resulting solid is triturated in 75 ml of water and filtered to collect an orange solid, which was dried under vacuum. This crude solid was recrystallized from toluene to obtain a light orange powder (6.0 g, 74%).

[00645] Part C. Obtain methyl 2-(3,5-dead-2-methoxyphenyl)acetate.

[00646] In a 250 ml round bottom flask was added the product from part a (6 g, 14,85 mmol), potassium carbonate (6,16 g and 44.6 mmol), and dimethylsulfate (4.12 g, to 32.7 mmol) in acetone (49.5 ml) to give a brown suspension. This suspension was heated under reflux for 16 h, cooled, concentrated, and the residue was distributed between EtOAc and water. The EtOAc layer was washed with saline, dried (Na2SO4) and concentrated to a brown oil, which was chromatographically on the cartridge with silica 40 g, elwira 3:1 hexane/EtOAc to obtain a yellow oil (6.0 g, 94%).

[00647] Part C. Obtain methyl 2-(3,5-dead-2-methoxyphenyl)-2-methylpropanoate.

[00648] In a 100 ml round bottom flask under nitrogen atmosphere was added the product from Part b (1,728 g, 4 mmol) in anhydrous THF (20 ml) and NMRI (2 ml) to give a colorless solution. Added methyliodide (1,251 ml, 20.00 mmol), and the solution was cooled to -40°C. was Added dropwise t-piperonyl potassium (12,00 ml 12,00 mmol who), and the mixture was stirred at a temperature of from -40 to -20°C for 30 min and extinguished 1M HCl to pH 1. The mixture was extracted with 3×40 ml EtOAc. The extracts were combined, washed with brine, dried (Na2SO4) and concentrated. The crude product was subjected to flash chromatography on a cartridge with silica 40 g ISCO, elwira 9:1 hexane/EtOAc to obtain bis-methylated product as a yellow oil (1.63 g, 89%).

[00649] Part D. Getting 2-(3,5-dead-2-methoxyphenyl)-2-methylpropanoic acid.

[00650] a Suspension of the product from Part C (2,63 g, 5,72 mmol) in Meon (40 ml) and THF (40 ml) was treated with 4.0 M sodium hydroxide (28 ml, 112 mmol) and was heated at 80°C for 48 hours the Organic solvent was evaporated and the remaining aqueous solution was acidified using 1M HCl, getting a solid, which was collected by filtration, washed with water and dried to obtain the desired carboxylic acid (2,46 g, 96%).

[00651] Part of that is Getting 2-(3,5-dead-2-methoxyphenyl)-2-methylpropan-1-ol.

[00652] a solution of the product from Part D (1,00 g 2,242 mmol) in THF (40 ml) was treated dropwise with borane complex THF 1.0 M (20 ml, 20 mmol) and then heated at 50°C for 24 h the Mixture was treated with methanol (20 ml) was heated under reflux for 30 min and concentrated. The resulting residue was washed with water, brine, dried sodium sulfate, filtered and evaporated. The mod is to have chromatographically on silica gel, elwira hexane/EtOAc (4:1) to give the desired product (810 mg, 84%).

[00653] Part F. Obtain tert-butyl(2-(3,5-dead-2-methoxyphenyl)-2-methylpropoxy)-dimethylsilane.

[00654] a solution of the product from Part E (432 mg, 1.000 mmol) in DMF (5 ml) was treated with tert-butyldimethylchlorosilane (301 mg, 2,000 mmol), and imidazole (204 mg, 3.00 mmol) and was stirred for 2 h the Mixture was distributed between 1M HCl and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried sodium sulfate, filtered and evaporated. The residue was chromatographically on silica gel, elwira hexane/EtOAc (9:1) to give the desired product (522 mg, 96%).

[00655] Part G. Obtain 1-(3-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5-iodine-4-methoxyphenyl)pyrimidine-2,4(1 H,ZN)-dione.

[00656] In a 50 ml round bottom flask was added the product from Part F (520 mg, 0,952 mmol), pyrimidine-2,4(1H,3H)-dione (117 mg, at 1,047 mmol), N-(2-cyanophenyl)picolinate (42,5 mg, 0,190 mmol), copper iodide (I) (18,13 mg, 0,095 mmol) and potassium phosphate (424 mg, 1,999 mmol) in DMSO (5 ml). The vessel was tightly closed, was barbotirovany nitrogen and then heated at 60°C for 24 h the Mixture was distributed between 1M HCl and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate, and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized, silicagel is m, filtered and evaporated. The residue was chromatographically on silica gel, elwira hexane/EtOAc (3:2) to give the product as a solid (285 mg, 65%).

[00657] Part N. Obtaining (E)-N-(4-(3-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00658] a 5 ml microwave tube was added the product from Part G (53 mg, 0.1 mmol), the product from Example 13, Part b (24 mg, 0.1 mmol), potassium phosphate (to 44.0 mg, 0.2 mmol), PA-Ph (CAS 97739-46-3) (0,87 mg, 3.0 mmol) and Tris(dibenzylideneacetone)palladium(0) (0.9 mg, 1 mmol) in THF (3.0 ml) and water (1.0 ml). The vessel was tightly closed and the mixture was barbotirovany nitrogen for 5 min and then was heated at 50°C for 2 hours the Mixture was distributed between 1M HCl and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel, filtered and evaporated. The residue was chromatographically on silica gel, elwira hexane/EtOAc (1:1) to give a solid (50 mg, 83%).

[00659] Part I. Obtaining (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

[00660] a solution of the product from Part H (120 mg, 0.20 mmol) in THF (5.0 ml) was treated with 1M TBAF (0.800 to ml HDI, 0.800 mmol) in THF and peremeci the Ali for 16 PM The mixture was separated by water and ethyl acetate. The organic layer was washed (3 × brine), dried sodium sulfate, filtered and evaporated. The residue was chromatographically on silica gel, elwira 4% methanol in CH2Cl2obtaining a solid (85 mg, 88%).1H NMR (300 MHz, DMSO-d6) δ ppm 1.30 (s, 6 H) 3.01 (s, 3 H) 3.62 (d, J=5.52 Hz, 2 H) 3.77 (s, 3 H) 4.67 (t, J=5.33 Hz, 1 H) 5.66 (d, J=8.09 Hz, 1 H) 7.21 (m, 5 H) 7.62 (m, 3 H) 7.72 (d, J=8.09 Hz, 1 H) 9.85 (s, 1 H) 11.42 (s, 1 H). MS (ESI+) m/z 503 (M+NH4)+.

[00661] Example 23. Obtaining (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-iodine-2-methoxystyrene)phenyl)methanesulfonamide (compound IB-L1-1.51).

[00662] Part A. Obtaining 1,3,5-triiodothyronine-2-methoxybenzene.

[00663] In a 250 ml pressure vessel was added 2,4,6-triiodophenol (5 g, or 10.60 mmol) in MTBE (60 ml) to give a yellow solution. The solution was cooled in an ice bath and added quickly drops 2.0 M trimethylsilyldiazomethane (7,95 ml, 15,90 mmol), followed by adding dropwise methanol (6 ml), resulting in the peaceful liberation of gas bubbles. The vessel was tightly closed and stirred at room temperature for 4 h the Reaction solution was distributed between EtOAc and water and the organic layer washed with 1M HCl, saturated NaHCO3and saturated NaCl. The EtOAc layer was dried (MgSO4), filtered and concentrated to obtain a solid substance yellowish-max is the first color, which was used without purification (4.8 g, 94%).

[00664] part of the Century, Obtaining 1-(3,5-dead-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00665] In a 100 ml round bottom flask in an atmosphere of N2was added the product from part a (3.5 g, 7.2 mmol), 1H-pyrimidine-2,4-dione (0.97 g, 8,64 mmol), and rejonowy potassium phosphate (3.2 g, 15.0 mmol) in DMSO (50 ml) to give a colorless suspension. Was added N-(2-cyanophenyl)picolinate (320 mg, 1.44 mmol) and the mixture was barbotirovany N2within 5 minutes was Added copper iodide (I) (137 mg, to 0.72 mmol) and the mixture was barbotirovany again for 10 min, placed in an atmosphere of N2and was heated at 60°C for 18 hours the Mixture was cooled and distributed between EtOAc and water, bringing the pH to 1 with HCl. The aqueous layer was extracted 2X EtOAc. The organic extracts were combined, washed with water, saturated NaHCO3and saturated NaCl, dried (Na2SO4), was treated with 3-mercaptopropyl-functionalized-silica, filtered and concentrated. The resulting solid is triturated in 2:1 hexane/EtOAc to obtain white powder (2.2 g, 62%).

[00666] Part C. Obtaining (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-iodine-2-methoxystyrene)phenyl)methanesulfonamide.

[00667] a 5 ml microwave tube was mixed product from Part b (141 mg, 0.30 mmol), the product from Example 13, Part b (to 72.3 mg, 0,300 mmol), the complex of 1,1'-bis(definites is Ino)ferrocene-palladium(II)dichloride CH 2Cl2(12,25 mg, 0.015 mmol) and potassium phosphate (70.0 mg, 0,330 mmol) in THF (3.0 ml) and water (1.0 ml). The mixture was barbotirovany nitrogen for 5 min and heated at 50°C for 2 hours the Mixture was separated with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel, filtered and evaporated. The residue was chromatographically on the silicon dioxide, elwira 5% methanol in CH2Cl2obtaining a solid (47 mg, 29%).1H NMR (300 MHz, DMSO-d6) δ ppm 3.02 (s, 3 H), 3.77 (s, 3 H), 5.67 (d, J=7.72 Hz, 1 H) 7.28 (m, 4 H) 7.60 (d, J=8.82 Hz, 2 H) 7.76 (d, J=8.09 Hz, 1 H) 7.81 (d, J=2.57 Hz, 1 H) 7.86 (d, J=2.21 Hz, 1 H), 9.90 (s, 1 H), 11.48 (s, 1 H). MS (ESI-) m/z 538 (M-H)+.

[00668] Example 24. Obtaining (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(methylsulphonyl)styryl)phenyl)methanesulfonamide (compound IB-L1-1.49).

[00669] Part A. Obtaining 4-nitrobenzene-2-diazo-1-oxide.

[00670] In a 250 ml round bottom flask was added 2-amino-4-NITROPHENOL (6,165 g, 40.0 mmol) in 48% terraforming acid (15 ml). Was added dropwise sodium nitrite (2.76 g, 40.0 mmol) in water (6 ml) at 0°C., and the mixture was stirred at room temperature for 30 minutes, the Solid was collected by filtration, washed terraforming acid and water. The solid is suspended in and is ethane (50 ml), was filtered and dried to obtain a solid substance (of 3.31 g, 50%).

[00671] part of the Century, Obtaining 2-(methylthio)-4-NITROPHENOL.

[00672] In a 1 l a beaker were added the product from part a (2.70 g, 16,35 mmol) in ice water (250 g) to give a brown suspension. Added copper (0,520 g, 8,18 mmol) followed by slow addition of timelocked sodium (2,292 g, to 32.7 mmol) in water (50 ml). The mixture was stirred at room temperature for 24 h the Mixture was filtered, and the filtrate was acidified using 1M HCl, getting a solid, which was collected by filtration, and dried (2,53 g, 84%).

[00673] Part C. Obtaining 2-(methylsulphonyl)-4-NITROPHENOL.

[00674] In a 250 ml round bottom flask was added the product from Part b (1,111 g, 6,00 mmol) in Meon (20 ml) to give a brown suspension. Was slowly added Oxon (7,746 g, 12,60 mmol) in water (20 ml) at 0°C. the Mixture was heated to room temperature, was stirred for 1 h and separated with ethyl acetate and 1M HCl. The organic layer was washed with saline, dried with sodium sulfate, filtered and evaporated. The residue was chromatographically on silica gel, elwira 1% - 5% methanol in CH2Cl2obtaining a solid substance (0,472 g, 36%).

[00675] Part D. Getting 2-iodine-6-(methylsulphonyl)-4-NITROPHENOL.

[00676] In a 50 ml round bottom flask was added the product from Part C (470 mg, 2,164 mmol) in Meon (10 ml) and water (2.5 ml). Was added dropwise m is nojorid iodine (0,130 ml, 2,60 mmol) in CH2Cl2(2.0 ml) and the mixture was stirred at room temperature, poured into water (200 ml) and was stirred for 10 minutes the resulting solid was collected by filtration and dried (636 mg, 86%).

[00677] Part of that is Getting 1-iodine-2-methoxy-3-(methylsulphonyl)-5-nitrobenzene.

[00678] In a 50 ml pressure vessel was added the product from Part D (630 mg, 1,836 mmol) in MTBE (6 ml) to give a yellow solution. The mixture was cooled in an ice bath and added quick drops of 2M (trimethylsilyl)-diazomethane (1,377 ml to 2.75 mmol), followed by adding dropwise the Meon (0.4 ml), resulting in the peaceful liberation of gas bubbles. The vessel was tightly closed and stirred at room temperature for 1 h the Mixture was separated with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried sodium sulfate, filtered and evaporated to obtain a whitish solid (655 mg, 100%).

[00679] Part F. 3 iodine-4-methoxy-5-(methylsulphonyl)aniline.

[00680] In a 250 ml round bottom flask was added the product from Part E (0,650 g, 1,820 mmol), ammonium chloride (0,146 g, 2,73 mmol), and iron (0,508 g, 9,10 mmol) in THF/MeOH/water (50 ml, 2/2/1). The mixture was heated under reflux for 2 h, cooled and filtered. The filtrate was evaporated, and the residue was separated with ethyl acetate and water. The organization is a mini layer was washed with saline, dried sodium sulfate, filtered and evaporated to obtain a solid (590 mg, 99%).

[00681] Part G. Obtaining (E)-N-(3-iodine-4-methoxy-5-(methylsulphonyl)phenylcarbamoyl)-3-ethoxyacrylate.

[00682] In a 100 ml round bottom flask was added the product from Part F (500 mg, 1,528 mmol) in DMF (15.0 ml). The solution was cooled in nitrogen atmosphere at -20°C and added dropwise (S)-3-methoxycoronaridine (15,28 ml, 6,11 mmol; obtained as described Santana, L.; et al. J. Heterocyclic Chem. 1999, 36, 293-295). The mixture was stirred at this temperature for 15 min, then was heated to room temperature and was stirred for 45 minutes the Mixture was diluted with ethyl acetate and washed with water (3×50 ml), brine (3×50 ml), dried sodium sulfate, filtered and evaporated. The residue is triturated with ethyl acetate/hexane to obtain a solid (425 mg, 61%).

[00683] Part N. Obtain 1-(3-iodine-4-methoxy-5-(methylsulphonyl)phenyl)pyrimidine-2,4(1H,3H)-dione.

[00684] In a 100 ml round bottom flask was added the product from Part G (420 mg, 0,925 mmol) in ethanol (10 ml) to give a suspension. Added concentrated sulfuric acid (1 ml, 18,76 mmol) in water (10 ml), and the mixture was heated at 110°C for 2 h, the Reaction mixture was cooled, diluted with water (50 ml) and was stirred for 10 minutes, the Solid was collected by filtration, washed with water and dried to obtain solid white(325 mg, 83%).

[00685] Part I. Obtaining (E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(methylsulphonyl)styryl)phenyl)methanesulfonamide.

[00686] a 5 ml microwave tube was added the product from Part H (63,3 mg, 0.15 mmol), the product from Example 13, Part b (36.2 mg, 0,150 mmol), potassium phosphate (66,9 mg, 0,315 mmol), PA-Ph (CAS 97739-46-3) (1,315 mg, 4,50 μmol) and Tris(dibenzylideneacetone)dipalladium(0) (1,374 mg, 1,500 µmol) in THF (3.0 ml) and water (1.0 ml). The vessel was tightly closed and the mixture was barbotirovany nitrogen for 5 min and heated at 50°C for 2 hours the Mixture was separated with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried with sodium sulfate and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel, filtered and evaporated. The residue is triturated with methanol/CH2Cl2obtaining a solid (62 mg, 84%).1H NMR (300 MHz, DMSO-d6) δ ppm 3.03 (s, 3 H) 3.37 (s, 3 H) 3.94 (s, 3 H) 5.72 (d, J=7.72 Hz, 1 H) 7.26 (m, 3 H) 7.45 (m, 1 H) 7.65 (d, J=8.46 Hz, 2 H) 7.77 (d, J=2.57 Hz, 1 H) 7.81 (d, J=8.09 Hz, 1 H) 8.21 (d, J=2.57 Hz, 1 H) 9.93 (s, 1 H) 11.52 (s, 1 H). MS (ESI+) m/z 509 (M+NH4)+.

[00687] Example 25. Obtaining (E)-methyl 2-(3-treat-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-5-(methylsulfonyl)benzoate (compound IB-L1-1.7).

[00688] Part A. Obtain methyl 2-((diethoxyphosphoryl)methyl)-5-nitrobenzoate.

[00689] To R is the target methyl 2-methyl-5-nitrobenzoate (0.40 g, 2.05 mmol) in CCl4(20 ml) was added N-bromosuccinimide (365 mg, 2.05 mmol) and 2,2'-azobisisobutyronitrile (34 mg, 0.21 mmol). The resulting mixture was stirred at reflux for 18 h, cooled to room temperature and distributed between EtOAc (50 ml) and N2About (50 ml). The organic layer was dried over Na2S04, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 1:3 EtOAc:hexane as eluent to obtain this bromide in the form of oil (345 mg, 61%). This oil was placed in triethylphosphite (5 ml) and was heated under stirring at 120°C for 3 hours the Mixture was left to cool to room temperature, and the crude product was purified by column chromatography on silica gel using 5% Meon in CH2Cl2as eluent. The named compound was obtained as oil (313 mg, 75%).

[00690] part of the Century, Obtaining (E)-methyl 2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-5-nitrobenzoate.

[00691] To a solution of the product from part a (360 mg, of 1.09 mmol) and the product from Example 13A, Part D (329 mg, of 1.09 mmol) in anhydrous CH2Cl2(10 ml) was added tert-piperonyl potassium (305 mg, of 2.72 mmol). The resulting dark red solution was stirred at room temperature for 1 h, and then poured into 1 n aq. HCl (10 ml). The floor is Chennai resulting mixture was extracted with CH 2Cl2(10 ml), dried over Na2SO4, filtered and concentrated in vacuum to obtain a solid substance. The solution of this solid in thionyl chloride (2.3 ml) was heated at 85°C for 30 min, and thionyl chloride was removed under vacuum. The residue was stirred in a mixture of 2:1 CH2Cl2and Meon (3 ml) for 30 min, and evaporated in vacuo to dryness. The crude product was purified by column chromatography on silica gel using 3% Meon in CH2Cl2as the eluent, to obtain the titled compound (350 mg, 69%).

[00692] Part C. Obtaining (E)-methyl 2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-5-(methylsulfonyl)benzoate.

[00693] To a solution of the product from Part b (465 mg, 0.97 mmol) in a mixture of 2:2:1 THF:MeOH:H2O (10 ml) was added iron filings (271 mg, is 4.85 mmol) and ammonium chloride (78 mg, of 1.46 mmol). The mixture was heated at 80°C for 45 min, filtered through celite, and concentrated to dryness in vacuum. The residue was combined with methanesulfonanilide (0.16 ml, 2.0 mmol) and triethylamine (0,392 ml, is 4.85 mmol) in anhydrous CH2Cl2(10 ml) and the resulting mixture was stirred at room temperature for 3 hours the Mixture was distributed between 1 n HCl (20 ml) and CH2Cl2(20 ml) and the organic layer was dried over Na2SO4, filtered and concentrated in vacuum. The crude product is ciali using column chromatography on silica gel, using 3% Meon in CH2Cl2as eluent to obtain the above compound (270 mg, 53%).1H NMR (300 MHz, DMSO-d6) δ 11.42 (s, 1 H) 10.07 (s, 1 H) 7.90 (d, J=8.82 Hz, 1 H) 7.66-7.79 (m, 3 H) 7.52 (d, J=2.57 Hz, 1 H) 7.44 (dd, J=8.64, 2.39 Hz, 1 H) 7.14-7.26 (m, 2 H) 5.65 (dd, J=7.72, 1.84 Hz, 1 H) 3.86 (s, 3 H) 3.79 (s, 3H) 3.04 (s, 3H) 1.38 (s, 9H).

[00694] Example 26. Obtaining (E)-2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-5-(methylsulfonyl)benzoic acid (compound IB-L1-1.4).

[00695] a solution of the product from Example 25 (55 mg, 0.104 g mmol) in THF (1 ml) and 1 n aq. NaOH (1 ml) was stirred in the dark at room temperature for 1.5 hours was Added 1 n aqueous HCl to pH 3, and the resulting mixture was extracted with EtOAc (2×2 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated to obtain the above compound (53 mg, 99%).1H NMR (300 MHz, DMSO-d6) δ 13.22 (br s, 1 H) 11.40 (d, J=2.21 Hz, 1 H) 10.02 (s, 1 H) 7.72-7.91 (m, 3 H) 7.68 (d, J=2.57 Hz, 1 H) 7.49 (d, J=2.57 Hz, 1 H) 7.42 (dd, J=8.64, 2.39 Hz, 1 H) 7.21 (d, J=2.57 Hz, 1 H) 7.16 (d, J=16.18 Hz, 1 H) 5.64 (dd, J=7.72, 2.21 Hz, 1 H) 3.79 (s, 3 H) 3.04 (s, 3H) 1.38 (s, 9H).

[00696] Example 27. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-(morpholine-4-carbonyl)phenyl)methanesulfonamide (compound IB-L1-1.23).

[00697] Part A. Obtaining (E)-2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-5-(m is tranformed)of benzoyl chloride.

[00698] a solution of the product from Example 26 (257 mg, 0.50 mmol) in thionyl chloride (1.5 ml) was heated at 85°C for 40 min and then concentrated and dried in vacuum to obtain these compounds in the form of a solid (0.27 g).

[00699] part of the Century, Obtaining (E)-N-(4-(3-theriot-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-(morpholine-4-carbonyl)phenyl)methanesulfonamide.

[00700] To a solution of the product from part a (24 mg, 0.045 mmol) in anhydrous CH2Cl2(1 ml) was added morpholine (0,02 ml, 0,226 mmol). The mixture was stirred at room temperature for 2 h, and then distributed between 1 n aq. HCl (5 ml) and EtOAc (2×5 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 4% Meon in CH2Cl2as the eluent, to obtain the titled compound (19 mg, 71%).1H NMR (300 MHz, DMSO-d6) δ 11.41 ppm (d, J=1.84 Hz, 1 H) 10.04 (s, 1 H) 7.85 (d, J=8.46 Hz, 1 H) 7.75 (d, J=8.09 Hz, 1 H) 7.52 (d, J=2.57 Hz, 1 H) 6.99-7.34 (m, 5 H) 5.65 (dd, J=7.72, 1.84 Hz, 1 H) 3.76 (s, 3 H) 3.56-3.71 (m, 4 H) 3.40-3.51 (m, 2H) 3.11-3.22 (m, 2 H) 3.06 (s, 3 H) 1.38 (s, 9 H).

[00701] Example 28. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-(hydroxymethyl)phenyl)methanesulfonamide (compound IB-L1-1.10).

[00702] To a solution of the product from Example 27, part of the (375 mg, 0,705 mmol) in anhydrous THF (5 ml) at 0°C in an atmosphere of gaseous N2was added dropwise 1.0 M solution of lithium tert-butoxyaniline hydride (1.8 ml, 1.8 mmol). The resulting mixture was stirred at 0°C for 30 min, and then left to warm to room temperature and was stirred for 1 h, the Mixture was distributed between 1 n aq. HCl (10 ml) and EtOAc (2×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 3% Meon in CH2Cl2as the eluent, to obtain the titled compound (220 mg, 63%).1H NMR (300 MHz, DMSO-d6) δ ppm 11.41 (s, 1 H) 9.82 (s, 1 H) 7.73 (t, J=8.27 Hz, 2 H) 7.66 (d, J=2.57 Hz, 1 H) 7.31-7.39 (m, 2 H) 7.20 (d, J=2.57 Hz, 1 H) 7.12-7.19 (m, 2 H) 5.65 (d, J=8.09 Hz, 1 H) 5.28 (t, J=5.52 Hz, 1 H), 4.65 (d, J=5.52 Hz, 2 H) 3.79 (s, 3 H) 3.00 (s, 3 H) 1.38 (s, 9 H).

[00703] Example 29. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-(methoxymethyl)phenyl)methanesulfonamide (compound IB-L1-1.13).

[00704] To a solution of the product from Example 28 (32 mg, 0,064 mmol) in anhydrous CH2Cl2(1 ml) was added thionyl chloride (23 μl, 0.32 mmol) and the resulting mixture was stirred at room temperature for 30 minutes the Mixture was distributed between saturated aq. NaHCO3(5 ml) and CH2Cl2(5ml), and the organic layer was dried over Na2SO4, filtered and concentrated. The residue was dissolved in Meon (1 ml) and the solution was added 25% NaOMe in Meon (58 μl, 0,254 mmol). The resulting mixture was stirred at 50°C for 2 hours the Mixture was distributed between 1 n aq. HCl (10 ml) and EtOAc (2×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 3% Meon in CH2Cl2as the eluent, to obtain the titled compound (15 mg, 46%).1H NMR (300 MHz, DMSO-d6) δ 11.43 (s, 1 H), 9.86 (s, 1 H) 7.62-7.87 (m, 3 H), 7.12-7.39 (m, 5 H), 5.66 (d, J=7.72 Hz, 1 H), 4.58 (s, 2 H) 3.78 (s, 3 H), 3.35 (s, 3 H) 3.00 (s, 3 H) 1.38 (s, 9H).

[00705] Example 30. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-((isobutylamino)methyl)phenyl)methanesulfonamide (compound IB-L1-1.31).

[00706] Part A. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-formylphenyl)methanesulfonamide.

[00707] To a solution of the product from Example 28 (0,60 g, 1.20 mmol) in anhydrous DMA (15 ml) was added 2-iodoxybenzoic acid (336 mg, 1.20 mmol). The mixture was stirred at room temperature for 1 h, and then was distributed between EtOAc (20 ml) and H2O (2×20 ml). The organic layer was dried over Na2SO4that filter is Ali and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 2% Meon in CH2Cl2as the eluent, to obtain the titled compound as a colourless solid (395 mg, 66%).1H NMR (300 MHz, DMSO-d6) δ 11.43 ppm (d, J=2.21 Hz, 1 H), 10.45 (s, 1 H), 10.15 (s, 1 H) 8.06 (d, J=16.18 Hz, 1 H) 7.97 (d, J=8.82 Hz, 1 H) 7.73-7.78 (m, 2 H) 7.69 (d, J=2.57 Hz, 1 H) 7.51 (dd, J=8.64, 2.39 Hz, 1 H) 7.30 (d, J=16.18 Hz, 1 H) 7.26 (d, J=2.57 Hz, 1 H), 5.66 (dd, J=7.72, 2.21 Hz, 1 H) 3.81 (s, 3 H) 3.07 (s, 3 H) 1.39 (s, 9 H).

[00708] part of the Century, Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-((isobutylamino)methyl)phenyl)methanesulfonamide.

[00709] To a solution of the product from part a (50 mg, 0.10 mmol) and 3-methylbutane-1-amine (12 μl, 0.10 mmol) in anhydrous THF (3 ml) was added triacetoxyborohydride sodium (32 mg, 0.15 mmol) and Asón (9 μl, 0.15 mmol). The resulting mixture was stirred at room temperature for 4 h, and then distributed between the H2O (10 ml) and EtOAc (2×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 3% Meon in CH2Cl2as eluent to obtain the above compound (37 mg, 65%).1H NMR (300 MHz, DMSO-d6) δ 11.45 (d, J=1.84 Hz, 1 H), 10.04 (s, 1 H), 8.80-8.87 (m, 1 H) 7.88 (d, J=8.46 Hz, 1 H), 7.71-7.77 (m, 2 H) 7.41-7.48 (m, 1 H) 7.37 (d, J=2.21 Hz, 1 H) 7.21-7.29 (m, 3 H), 5.67 (dd, J=7.91, 2.02 Hz, 1 H) 4.30-.38 (m, 2 H) 3.80 (s, 3 H) 3.10 (s, 3 H) 2.95-3.04 (m, 2 H) 1.49-1.67 (m, 3 H) 1.38 (s, 9 H), 0.86 (d, J=6.25 Hz, 6 H).

[00710] Example 31. Obtaining N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-((E)-(methoxyimino)methyl)phenyl)methanesulfonamide (compound IB-L1-1.19).

[00711] To a solution of the product from Example 30, part a (35 mg, 0,070 mmol) in EtOH (2 ml) was added 0-methoxylamine hydrochloride (29 mg, 0.35 mmol) and sodium bicarbonate (30 mg, 0.35 mmol). The resulting mixture was stirred at 70°C for 2 hours To the mixture was added 1 n aq. HCl (1 ml) to give a colorless precipitate, which was filtered and dried to obtain the above compound as a colourless solid (24 mg, 64%).1H NMR (300 MHz, DMSO-d6) δ 11.43 ppm (d, J=2.21 Hz, 1 H) 9.94 (s, 1 H) 8.74 (s, 1 H) 7.79-7.85 (m, 2 H) 7.76 (d, J=7.72 Hz, 1 H) 7.57-7.65 (m, 2 H) 7.32 (dd, J=8.64, 2.39 Hz, 1 H) 7.23 (d, J=2.57 Hz, 1 H) 7.18 (d, J=16.18 Hz, 1 H) 5.66 (dd, J=7.72, 2.21 Hz, 1 H) 3.93 (s, 3 H) 3.79 (s, 3 H) 3.03 (s, 3 H) 1.38 (s, 9 H).

[00712] Example 32. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-(oxazol-2-yl)phenyl)methanesulfonamide (compound IB-L1-1.26).

[00713] To a solution of the product from Example 27, part a (80 mg, 0.15 mmol) in tetramethylsilane (1.5 ml) was added 1H-1,2,3-triazole (10 μl, 0,17 mmol) and potassium carbonate (73 mg, of 0.53 mmol). The mixture was heated for 35 min at 130°C in a microwave reactor. After cooling to room is based temperature the mixture was distributed between 1 n aqueous HCl (10 ml) and EtOAc (2×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 3% Meon in CH2Cl2as eluent to obtain the above compound (37 mg, 46%).1H NMR (300 MHz, DMSO-d6) δ 11.41 (d, J=1.84 Hz, 1 H) 10.10 (s, 1 H) 8.29 (d, J=1.10 Hz, 1 H) 8.05 (d, J=16.18 Hz, 1 H) 7.95 (d, J=8.82 Hz, 1 H) 7.82 (d, J=2.21 Hz, 1 H) 7.74 (d, J=8.09 Hz, 1 H) 7.51 (d, J=2.57 Hz, 1 H) 7.46 (d, J=0.74 Hz, 1 H) 7.39 (dd, J=8.64, 2.39 Hz, 1 H) 7.20-7.30 (m, 2 H) 5.65 (dd, J=7.91, 2.02 Hz, 1 H) 3.80 (s, 3 H) 3.07 (s, 3H) 1.38 (s, 9H).

[00714] Example 33. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-(1H-imidazol-2-yl)phenyl)methanesulfonamide (compound IB-L1-1.16).

[00715] To a solution of the product from Example 30, part a (50 mg, 0.10 mmol) in EtOH (2 ml) was added glacial (57 μl, 0.50 mmol) and concentrated aqueous NH4OH (70 μl, 0.50 mmol). The resulting mixture was stirred at room temperature for 16 hours the mixture was added 1 n aq. HCl to pH=7, and the mixture was distributed between the H2O (10 ml) and EtOAc (2×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 5% Meon in CH2Cl2in quality the ve eluent, with obtaining the above compound (27 mg, 50%).1H NMR (300 MHz, DMSO-d6) δ 12.39 (s, 1 H) 11.40 (d, J=1.84 Hz, 1 H) 9.98 (s, 1 H) 7.89 (d, J=8.82 Hz, 1 H) 7.66-7.76 (m, 2 H) 7.38 (t, J=2.21 Hz, 2 H) 7.23-7.31 (m, 2 H) 7.06-7.21 (m, 3 H) 5.63 (dd, J=8.09, 1.84 Hz, 1 H) 3.78 (s, 3 H) 3.07 (s, 3 H) 1.37 (s, 9 H).

[00716] Example 34. Obtaining (E)-tert-butyl 2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-5-(methylsulfonyl)phenylcarbamate (compound IB-L1-1.32).

[00717] To a solution of the product from Example 26 (75 mg, 0,146 mmol) in tert-butanol (4 ml) was added diphenylphosphoryl (47 μl 0,219 mmol) and triethylamine (31 μl, 0,219 mmol). The resulting mixture was stirred at 80°C for 18 hours, the Cooled mixture was distributed between H2About (10 ml) and EtOAc (2×10 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 3% Meon in CH2Cl2as the eluent, to obtain the titled compound (16 mg, 19%).1H NMR (300 MHz, DMSO-d6) δ 11.45 (d, J=1.84 Hz, 1 H), 9.86 (s, 1 H) 9.03 (s, 1 H) 7.75 (d, J=7.72 Hz, 2 H) 7.55 (d, J=2.57 Hz, 1 H), 7.10-7.33 (m, 4 H) 7.04 (dd, J=8.64, 2.39 Hz, 1 H), 5.66 (dd, J=7.91, 2.02 Hz, 1 H) 3.78 (s, 3 H) 3.02 (s, 3 H), 1.45 (s, 9 H), 1.38 (s, 9 H).

[00718] Example 35. Obtaining (E)-N-(3-amino-4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide (compound IB-L1-1.28).

[00719] the Procedure described for an Example 34 gave the titled compound, which was purified by column chromatography on silica gel using 5% methanol in CH2Cl2as eluent (6 mg, 9%).1H NMR (300 MHz, DMSO-d6) δ 11.44 (d, J=2.21 Hz, 1 H), 9.55 (s, 1 H) 7.77 (d, J=2.57 Hz, 1 H) 7.75 (d, J=8.09 Hz, 1 H) 7.45 (d, J=8.46 Hz, 1 H) 7.33 (d, J=15.81 Hz, 1 H) 7.15 (d, J=2.57 Hz, 1 H) 7.00 (d, J=16.18 Hz, 1 H), 6.56 (d, J=2.21 Hz, 1 H), 6.44 (dd, J=8.46, 2.21 Hz, 1 H), 5.66 (dd, J=7.91, 2.02 Hz, 1 H), 5.56 (s, 2 H) 3.78 (s, 3 H) 2.97 (s, 3 H) 1.37 (s, 9 H).

[00720] Example 36. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxytrityl)-2-forfinal)methanesulfonamide (compound IB-L1-1.5).

[00721] Part A. Obtain (3-fluoro-4-nitrophenyl)methanol.

[00722] To a solution of 3-fluoro-4-nitrobenzoic acid (2.0 g, a 10.8 mmol) in THF (50 ml) at 0°C was added dropwise a complex NR3·Me2S (2,215 ml, 22,15 mmol). The mixture was stirred at 0°C for 3 h, and then stirred at 65°C for 18 h To a cooled mixture was added ice (50 g), followed by adding 1 n aq. HCl (100 ml) and the resulting mixture was extracted with EtOAc (200 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to obtain these compounds in a solid white color (1,79 g, 97%).

[00723] part of the Century, Obtaining 4-(methyl bromide)-2-fluoro-1-nitrobenzene.

[00724] a solution of the product from Frequent Is A (1,79 g, 10,46 mmol), N-bromosuccinimide (2,234 g, 12,55 mmol) and triphenylphosphine (3,29 g, 12,55 mmol) in CH2Cl2(100 ml) and THF (50 ml) was stirred at room temperature for 3 hours the Mixture was distributed between the H2O (200 ml) and EtOAc (400 ml) and the organic layer was dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 1:1 EtOAc:hexane as eluent to obtain these compounds (1,14 g, 47%).

[00725] Part C. Obtaining diethyl-3-fluoro-4-nitrobenzenesulfonate.

[00726] the Product from Part b (1,25 g of 5.34 mmol) was subjected to the conditions described for Example 6, Part In obtaining this product (0.75 g, 48%).

[00727] Part D. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxytrityl)-2-forfinal)methanesulfonamide.

[00728] the Product from Part C (rate of 0.193 g, to 0.662 mmol) was subjected to the conditions described for Example 13A, Part E, Part F and Part G of obtaining the named product as colorless solid (15 mg, 5%).1H NMR (300 MHz, DMSO-d6) δ 11.43 (s, 1H), 9.67 (s, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.62 (m, 2H), 7.41 (m, 2H), 7.38 (m, 1H), 7.23 (m, 2H), 5.66 (dd, J=8.0, 2.0 Hz, 1H), 3.80 (s, 3H), 3.05 (s, 3H), 1.38 (s, 9H).

[00729] Example 37. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxytrityl)-2-fluoro-5-were)methanesulfonamide (compound IB-L1-1.15).

[00730] Part A. Obtain N-(4-bromo-2-fluoro-5-were)methanesulfonamide.

[00731] To a solution of 4-bromo-2-fluoro-5-methylaniline (2,04 g, 10.0 mmol) in anhydrous CH2Cl2(20 ml) and pyridine (3,23 ml, 40.0 mmol) was added methanesulfonamide (0,86 ml, 11.0 mmol) and the resulting mixture was stirred at room temperature for 2 hours the Solvent was removed in vacuo, and the residue was distributed between EtOAc and 1M aq. HCl. The organic layer was washed with saturated aqueous NaHCO3, saline and then dried over Na2SO4. Drying substance was filtered, and the filtrate was concentrated to obtain these compounds in the form of solids (2,80 g, 99%).

[00732] part of the Century, Obtaining N-(4-ethinyl-2-fluoro-5-were)methanesulfonamide.

[00733] a Mixture of the product from part a (3.0 g, as 10.63 mmol), triphenylphosphine (0,279 g, 1.06 mmol), trimethylsilylacetamide (6,0 ml, 42,5 mmol) and palladium(II) acetate (0.12 g, of 0.53 mmol) in triethylamine (30 ml) and toluene (15 ml) in an atmosphere of N2was heated at 80°C for 5 hours the Mixture was left to cool to room temperature, and was distributed between EtOAc and 1M aq. HCl. The organic layer was washed with saturated NaHCOa and brine, dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using a gradient dissolve the oil 10% - 35% EtOAc in hexane to obtain oil (3.0 g, 94%). To a solution of this oil (3.0 g, 10.0 mmol) in Meon (50 ml) was added 1M aq. NaOH (21 ml, or 21.0 mmol) and the resulting mixture was stirred at room temperature for 45 minutes the Mixture was distributed between EtOAc and 1M aq. HCl, and the organic layer washed with brine and dried over Na2SO4. Drying substance was filtered, and the filtrate was concentrated in vacuum to obtain these compounds in the form of a solid (2.3 g, Quant.).

[00734] Part C. Obtaining (E)-5-fluoro-2-methyl-4-(methylsulfonyl)styrylboronic acid.

[00735] the Product from Part b (0.20 g, 0.88 mmol) was subjected to the conditions described for an Example 13, Part b to obtain the above compound (42 mg, 17%).

[00736] Part D. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxytrityl)-2-fluoro-5-were)methanesulfonamide.

[00737] the Product from Part C (40 mg, 0.15 mmol) was subjected to the conditions described for an Example 13, Parts I to obtain the above compound (51 mg, 83%).1H NMR (300 MHz, DMSO-d6) δ 11.42 (d, J=2.21 Hz, 1 H) 9.59 (s, 1 H) 7.70-7.78 (m, 2 H) 7.66 (d, J=11.77 Hz, 1 H) 7.20-7.32 (m, 3 H) 5.65 (dd, J=7.72, 2.21 Hz, 1 H) 3.79 (s, 3 H) 3.05 (s, 3 H) 2.38 (s, 3 H) 1.38 (s, 9 H).

[00738] Example 38. Obtain methyl 2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenethyl)-5-(methylsulfonyl)benzoate (compound IB-L5-2-L1)

[00739] To a solution of the product from Example 25(40 mg, 0,076 mmol) in Meon (2 ml) and THF (2 ml) was added 10% Pd/C (20 mg), and the resulting mixture was stirred at room temperature under a pressure of 1 ATM H2within 16 hours the Mixture was filtered through celite and concentrated in vacuum to obtain a solid (27.5 mg, 68%).1H NMR (300 MHz, DMSO-d6) δ 11.39 (s, 1 H) 9.88 (s, 1 H) 7.61-7.71 (m, 2 H) 7.28-7.36 (m, 2 H) 7.20 (d, J=2.57 Hz, 1 H) 7.13 (d, J=2.94 Hz, 1 H), 5.64 (d, J=7.72 Hz, 1 H) 3.83 (s, 3 H) 3.75 (s, 3 H), 3.14 (dd, J=10.30, 5.88 Hz, 2 H) 2.96 (s, 3 H) 2.83-2.92 (m, 2 H), 1.34 (s, 9 H).

[00740] Example 39. Obtaining N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenethyl)phenyl)methanesulfonamide (compound IB-L5-2-1.2).

[00741] the Product from Example 13B, Part M (200 mg, 0,426 mmol) was dissolved in Meon (10 ml) followed by addition of 10% palladium on charcoal (50 mg). The resulting mixture was evacuated and hydrogen attached to the bus, then stirred at room temperature for 48 hours the Mixture was then filtered through celite and the filtrate was concentrated under vacuum to an oil, which was dissolved in ethanol (4 ml), then was added a 1 n aqueous solution of sodium hydroxide (3.8 ml, 3.8 mmol), and the solution was stirred at room temperature for 18 hours the Ethanol was then removed under vacuum and added a 1 n aqueous solution of hydrochloric acid is you (4 ml) for acidification of the mixture, followed by extraction using EtOAc (2×10 ml). The organic extracts were combined, dried and purified by column chromatography on silica gel using 5% Meon in CH2Cl2as eluent to obtain these compounds in the form of a colorless solid (82 mg, 41%).1H NMR (300 MHz, DMSO-d6) δ 11.39 (s, 1H), 9.60 (s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.23 (m, 3H), 7.17 (m, 3H), 5.64 (d, J=7.7 Hz, 1H), 3.77 (s, 3H), 2.93 (s, 3H), 2.88 (br s, 4H), 1.35 (s, 9H).

[00742] Example 40. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-amoxicill)phenyl)methanesulfonamide (compound IB-L1-1.30).

[00743] Part A. Obtain 2-tert-butyl-4-itfinal.

[00744] In a 250 ml round bottom flask was added 2-tert-butylphenol (3,76 g, 25 mmol) in Meon (50,0 ml) to give a colorless solution. Was added sodium hydroxide (1,200 g, 30.0 mmol) and the mixture was stirred until complete dissolution of the hydroxide. The solution was cooled to 0°C and treated with sodium iodide (1.75 g, 11.6 mmol) followed by adding dropwise a 10% sodium hypochlorite solution (7.2 ml, 11.6 mmol). The addition of sodium iodide followed by the addition of sodium hypochlorite was repeated twice, and the mixture was stirred at 0°C for 30 minutes the Mixture was treated with 10% mass/mass solution of sodium thiosulfate, stirred for 30 min and treated dropwise with concentrated HCl until a constant pH 1. The mixture was extracted with 3 EtOAc. The extracts were combined, p is washed with saline, dried (MgSO4), filtered and concentrated. The crude oil was subjected to flash chromatography on a cartridge with silica Isco 80 g, elwira hexane to >4:1 hexane/EtOAc to obtain a yellow oil (5.2 g, 75%).

[00745] part of the Century, Obtaining 2-bromo-6-tert-butyl-4-itfinal.

[00746] In a 250 ml round bottom flask was added the product from part a (4.8 g, 17,38 mmol) and 1,3-dibromo-5,5-dimethylhydantoin (2,61 g, 9,13 mmol) in chloroform (87 ml) to give an orange solution. The reaction mixture was stirred for 2 h, resulting in the black solution, which is washed with water, brine, dried (Na2SO4) and concentrated. The black oil was subjected to flash chromatography on a cartridge with silicon dioxide 120 g Isco, getting a pinkish solid (4,84 g, 78%).

[00747] Part C. Obtain 1-bromo-3-tert-butyl-2-ethoxy-5-yogashala.

[00748] In a 50 ml round bottom flask was added the product from Part b (888 mg, 2.5 mmol), ethyliodide (409 mg, 2,63 mmol), and potassium carbonate (415 mg, 3.00 mmol) in acetone (12 ml) to give a green suspension. The mixture was heated under reflux for 16 h, cooled and concentrated. The residue was separated between water and EtOAc. The organic layer was washed twice with saline, dried over Na2S04, filtered and concentrated to a red oil. This oil was subjected to flash chromatography on a cartridge dioxide is m silicon Isco 40 g, elwira hexane to obtain a clear oil (820 mg, 86%).

[00749] Part D. Obtain 1-(3-bromo-5-tert-butyl-4-ethoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00750] a 20 ml microwave tube under a stream of nitrogen was added the product from Part C (0.4 g, 1,044 mmol), 1 H-pyrimidine-2,4-dione (0,140 g, 1,253 mmol), and rejonowy potassium phosphate (0,465 g 2,193 mmol) in DMSO (5 ml) to give a colorless suspension. Was added N-(2-cyanophenyl)picolinate (0,047 g, 0,209 mmol) and the mixture was barbotirovany nitrogen for 10 minutes was Added copper iodide (I) (0,020 g, 0.104 g mmol) and the mixture was barbotirovany again within 10 minutes, was placed in a nitrogen atmosphere and was heated at 60°C for 18 hours the Mixture was cooled and distributed between EtOAc and water, bringing the pH to 1 with HCl. The aqueous layer was extracted 2X EtOAc. The organic extracts were combined, washed with water, saturated NaHCO3and saturated NaCl. The organic layer was dried (Na2SO4), was stirred with 3-mercaptopropyl-functionalized dioxide Varenna for 1 h, filtered and concentrated. The crude product was purified by chromatography cartridge with silica Isco 12 g, elwira 2% Meon in CH2Cl2obtaining a white powder (266 mg, 69%).

[00751] Part E. Obtaining (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-amoxicill)phenyl)methanesulfonamide.

[00752] a Mixture of the product from Part D (55,1 mg, 0.15 mmol), is the product from Example 13, Part b (36.2 mg, 0,150 mmol), trehosnovnogo potassium phosphate (63.7 mg, 0,300 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (4,89 mg, 7,50 mmol) in THF (3 ml) and water (1 ml) was barbotirovany for 10 min with nitrogen, and then tightly closed and heated at 50°C for 4 h the Mixture was cooled to room temperature and was diluted in EtOAc. The EtOAc layer washed with 1M HCl, saturated NaHCO3, saturated NaCl, dried (Na2SO4) and simultaneously treated with mercaptopropionate, filtered and concentrated. The crude product was purified by column chromatography on silica gel using 2% Meon in CH2Cl2as eluent to obtain these compounds in the form of a solid (40 mg, 55%) melting point 265-266°C.1H NMR (300 MHz, DMSO-d6) δ 11.42 (s, 1 H), 9.87 (s, 1 H) 7.76 (d, J=8.09 Hz, 1 H), 7.55-7.66 (m, 3 H) 7.17-7.27 (m, 5 H), 5.65 (dd, J=7.72, 1.47 Hz, 1 H), 3.89 (q, J=6.74 Hz, 2 H) 3.02 (s, 3 H), 1.45 (t, J=6.99 Hz, 3 H) 1.39 (s, 9 H).

[00753] using the above descriptions were obtained the following compounds:

[00754] (E)-N-(4-(1-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)prop-1-EN-2-yl)phenyl)methanesulfonamide (compound IA-L1-1.6).1H NMR (300 MHz, DMSO-d6) δ 2.14 (s, 3 H) 2.70 (t, J=6.62 Hz, 2 H) 3.01 (s, 3 H), 3.68 (s, 3 H) 3.78 (t, J=6.62 Hz, 2 H) 6.82 (s, 1 H), 7.10-7.17 (m, 2 H) 7.23 (d, J=8.46 Hz, 2 H) 7.59 (d, J=8.46 Hz, 2 H), 9.78 (s, 1 H), 10.32 (s, 1 H). (Z)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-label Estoril)phenyl) methanesulfonamide (compound IA-L1-1.10). 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1 H), 9.74 (s, 1 H) 7.23 (d, J=8.46 Hz, 2 H) 7.13 (d, J=2.57 Hz, 1 H) 7.06 (d, J=8.82 Hz, 2 H) 6.92 (d, J=2.57 Hz, 1 H), 6.54-6.67 (m, 2 H) 3.78 (s, 3 H), 3.57 (t, J=6.62 Hz, 2 H) 2.96 (s, 3 H) 2.60 (t, J=6.80 Hz, 2 H), 1.34 (s, 9 H).

[00756] (E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxystyrene)phenyl)-N-(methylsulphonyl)ndimethylacetamide (compound IA-L1-1.11).1H NMR (300 MHz, DMSO-d6) δ 10.36 (s, 1 H) 7.77 (d, J=8.46 Hz, 2 H) 7.56 (d, J=2.21 Hz, 1 H) 7.39-7.50 (m, 3 H) 7.25 (d, J=16.55 Hz, 1 H) 7.19 (d, J=2.57 Hz, 1 H), 3.74-3.85 (m, 5 H), 3.54 (s, 3 H) 2.72 (t, J=6.62 Hz, 2 H) 1.94 (s, 3 H) 1.38 (s, 9 H).

[00757] (E)-1-(3-(4-aminosterol)-5-tert-butyl-4-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione (compound IA-L1-1.13).1H NMR (300 MHz, DMSO-d6) δ 1.36 (s, 9 H), 2.70 (t, J=6.62 Hz, 2 H) 3.74 (s, 3 H), 3.77 (t, J=6.62 Hz, 2 H), 5.34 (s, 1 H), 6.57 (d, J=8.46 Hz, 2 H) 6.98 (s, 1 H) 7.07 (d, J=2.21 Hz, 1 H) 7.17 (s, 2 H) 7.30 (d, J=8.09 Hz, 2 H) 7.45 (d, J=2.21 Hz, 1 H), 10.32 (s, 1 H).

[00758] (Z)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxystyrene)phenyl) methanesulfonamide (compound IA-L1-1.20).1H NMR (500 MHz, DMSO-d6): δ ppm 1.37 (s, 9H), 2.71 (t, J=6.7 Hz, 2H), 3.01 (s, 3H), 3.75 (s, 3H), 3.79 (t, J=6.6 Hz, 2H), 7.13 (d, J=16.5 Hz, 1H), 7.15 (d, J=2.4 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 7.25 (d, J=16.5 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 9.80(bs, 1H), 10.30 (s, 1H).

[00759] N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)-1-Porvenir)phenyl)methanesulfonamide (compound IA-L1-1.21). (racemic mixture (1:1) compounds IA-L1-1.4 and IA-L1-1.5).

[00760] (E)-1-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione (compound IA-L1-1.22).

[00761] 1-{3-the pet-butyl-5-[(Z)-2-chloro-2-(4-nitro-phenyl)-vinyl]-4-methoxy-phenyl}-dihydro-pyrimidine-2,4-dione (compound IA-L1-1.23).

[00762] 1-{3-tert-butyl-4-methoxy-5-[(E)-2-(4-nitro-phenyl)-propenyl]-phenyl}-dihydro-pyrimidine-2,4-dione (compound IA-L1-1.24).

[00763] 1-{3-tert-butyl-5-[(E)-2-(4-nitro-phenyl)-vinyl]-phenyl}-dihydro-pyrimidine-2,4-dione (compound IA-L1-1.25).1H NMR (300 MHz, DMSO-D6) δ ppm 1.33 (s, 9 H), 2.70-2.77 (m, 2 H) 3.84 (t, J=6.80 Hz, 2 H) 7.33 (s, 1 H) 7.49 (d, J=4.04 Hz, 2 H) 7.56 (d, J=5.88 Hz, 2 H) 7.89 (d, J=8.82 Hz, 2 H) 8.25 (d, J=8.82 Hz, 2 H), 10.40 (s, 1 (H)

[00764] N-(4-{(E)-2-[3-tert-butyl-5-(dioxo-tetrahydro-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-3-methoxy-phenyl)-methanesulfonamide (compound IA-L1-1.27).1H NMR (300 MHz, DMSO-D6) δ ppm 10.33 (s, 1 H), 9.86 (s, 1 H) 7.64 (d, J=8.46 Hz, 1 H) 7.45 (d, J=2.21 Hz, 1 H) 7.26 (s, 2 H) 7.12 (d, J=2.21 Hz, 1 H), 6.89 (s, 1 H) 6.85 (dd, J=8.46, 1.84 Hz, 1 H) 3.84 (s, 3 H) 3.78 (t, J=6.80 Hz, 2 H) 3.74 (s, 3 H) 3.04 (s, 3 H) 2.71 (t, J=6.62 Hz, 2 H) 1.37 (s, 9 H)

[00765] N-(4-{(E)-2-[3-tert-Butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-3-formyl-phenyl)-methanesulfonamide (compound IB-L1-1.6).1H NMR (300 MHz, DMSO-D6) δ ppm 1.39 (s, 9 H) 3.07 (s, 3 H) 3.81 (s, 3 H), 5.66 (dd, J=7.72, 2.21 Hz, 1 H) 7.26 (d, J=2.57 Hz, 1 H) 7.30 (d, J=16.18 Hz, 1 H) 7.51 (dd, J=8.64, 2.39 Hz, 1 H) 7.69 (d, J=2.57 Hz, 1 H) 7.73-7.78 (m, 2 H) 7.97 (d, J=8.82 Hz, 1 H) 8.06 (d, J=16.18 Hz, 1 H), 10.15 (s, 1 H), 10.45 (s, 1 H), 11.43 (d, J=2.21 Hz, 1 H)

[00766] N-[4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-3-(hydroxyimino-methyl)-phenyl]-methanesulfonamide (compound IB-L1-1.8).1H NMR (300 MHz, DMSO-d6) δ 1.38 (s, 9 H) 3.03 (s, 3 H), 3.79 (s, 3 H), 5.66 (dd, J=7.91, 2.02 Hz, 1 H) 7.16 (d, J=15.81 Hz, 1 H) 7.22 (d, J=2.57 Hz, 1 H) 7.26 (dd, J=8.64, 2.39 Hz, 1 H) 7.59 (d, J=16.18 Hz, 1 H) 7.63 (d, J=2.21 Hz, 1 H) 7.73-7.83 (m, 3 H), 8.64 (s, 1 H), 9.96 (s, 1H) 11.42 (d, J=2.21 Hz, 1 H), 11.50 (s, 1 H).

[00767] 2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonamido-N-(2-methoxy-ethyl)-benzamide (compound IB-L1-1.9).1H NMR (300 MHz, DMSO-D6) δ 1.38 (s, 9 H) 3.05 (s, 3 H) 3.20 (s, 3 H) 3.37-3.49 (m, 4 H), 3.78 (s, 3 H), 5.64 (d, J=7.72 Hz, 1 H) 7.15 (d, J=2.57 Hz, 1 H) 7.20 (d, J=2.57 Hz, 1 H) 7.24 (s, 2 H) 7.28 (dd, J=8.46, 2.21 Hz, 1 H) 7.42 (d, J=2.57 Hz, 1 H) 7.73 (d, J=7.72 Hz, 1 H) 7.87 (d, J=8.82 Hz, 1 H) 8.49 (t, J=5.15 Hz, 1 H), 9.99 (s, 1 H), 11.42 (s, 1 H).

[00768] Ethyl ester 2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonamido-benzoic acid (compound IB-L1-1.11).1H NMR (300 MHz, DMSO-d6) δ 1.31 (t, J=7.17 Hz, 3 H) 1.38 (s, 9 H) 3.05 (s, 3 H), 3.79 (s, 3 H), 4.33 (q, J=7.23 Hz, 2 H), 5.65 (dd, J=7.72, 2.21 Hz, 1 H) 7.15-7.25 (m, 2 H) 7.46 (dd, J=8.64, 2.39 Hz, 1 H) 7.52 (d, J=2.57 Hz, 1 H) 7.68 (d, J=2.57 Hz, 1 H), 7.71-7.81 (m, 2 H) 7.90 (d, J=8.46 Hz, 1 H), 10.06 (s, 1 H), 11.42 (d, J=1.84 Hz, 1 H).

[00769] N-(4-{(E)-2-[3-tert-butyl-2-chloro-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-phenyl]-vinyl}-phenyl)-methanesulfonamide (compound IB-L1-1.12).1H NMR (300 MHz, DMSO-d6) δ ppm 1.49 (s, 9 H), 3.02 (s, 3 H), 5.69 (d, J=7.72 Hz, 1 H) 7.22 (m, 3 H) 7.41 (d, J=2.21 Hz, 1 H) 7.51 (d, J=16.18 Hz, 1 H) 7.59 (d, J=8.82 Hz, 2 H) 7.78 (d, J=2.21 Hz, 1 H) 7.80 (d, J=8.09 Hz, 1 H), 9.90 (s, 1 H), 11.47 (s, 1 H).

[00770] 2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonamido-N,N-dimethyl-benzamide (compound IB-L1-1.14).1H NMR (300 MHz, DMSO-d6) δ 1.37 (s, 9 H) 2.76 (s, 3 H) 3.03 (s, 3 H) 3.05 (s, 3 H) 3.76 (s, 3 H), 5.64 (dd, J=7.91, 1.65 Hz, 1 H) 6.95 (d, J=16.55 Hz, 1 H) 7.02 (d, J=2.21 Hz, 1 H) 7.17-7.25 (m, 2 H) 7.27 (dd, J=8.64, 2.39 Hz, H) 7.48 (d, J=2.57 Hz, 1 H) 7.74 (d, J=8.09 Hz, 1 H) 7.82 (d, J=8.82 Hz, 1 H), 10.03 (s, 1 H) 11.39-11.43 (m, 1 H).

(00771] 2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonamido-N-methyl-benzamide (compound IB-L1-1.17).1H NMR (300 MHz, DMSO-d6) δ 1.38 (s, 9 H), 2.77 (d, J=4.41 Hz, 3 H) 3.06 (s, 3 H), 3.77 (s, 3 H), 5.64 (dd, J=7.72, 1.84 Hz, 1 H) 7.16-7.33 (m, 5 H), 7.43 (d, J=2.21 Hz, 1 H) 7.73 (d, J=7.72 Hz, 1 H) 7.84 (d, J=8.46 Hz, 1 H) 8.37 (q, J=4.41 Hz, 1 H), 10.00 (s, 1 H) 11.40 (d, J=1.84 Hz, 1 H).

[00772] 2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-N-(1,1-dioxo-tetrahydro-lambda*6*-thiophene-3-yl)-5-methanesulfonamido-N-methyl-benzamide (compound IB-L1-1.18).1H NMR (300 MHz, DMSO-d6) δ 1.37 (s, 9 H) 2.17-2.47 (m, 2 H) 2.70 (s, 3 H) 3.06 (s, 3 H) 3.15-3.31 (m, 2 H) 3.36-3.51 (m, 2 H) 3.77 (s, 3 H), 5.37 (dt, J=17.74, 8.96 Hz, 1 H), 5.65 (dd, J=7.91, 2.02 Hz, 1 H) 6.93 (d, J=16.18 Hz, 1 H) 7.05 (d, J=2.21 Hz, 1 H) 7.19-7.35 (m, 3 H) 7.50 (d, J=2.57 Hz, 1 H) 7.76 (d, J=8.09 Hz, 1 H) 7.87 (d, J=8.82 Hz, 1 H), 10.04 (s, 1 H) 11.38 (d, J=2.21 Hz, 1 H).

[00773] N-(4-{(E)-2-[3-tert-butyl-5-(5-chloro-2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-phenyl)-methanesulfonamide (compound IB-L1-1.20).1H NMR (300 MHz, DMSO-D6) δ ppm 11.31 (s, 1 H), 9.77 (s, 1 H) 7.53 (d, J=8.09 Hz, 1 H) 7.23 (d, J=8.46 Hz, 2 H) 7.17 (d, J=2.57 Hz, 1 H) 7.06 (d, J=8.82 Hz, 2 H) 7.01 (d, J=2.57 Hz, 1 H), 6.53-6.71 (m, 2 H), 5.56 (d, J=7.72 Hz, 1 H) 3.81 (s, 3 H) 2.96 (s, 3 H) 1.35 (s, 9 H)

[00774] 2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonamido-benzamide (compound IB-L1-1.21).1H NMR (300 MHz, DMSO-d6) δ 1.38 (s, 9 H) 3.07 (s, 3 H) 3.78 (s, 3 H), 5.64 (d, J=7.72 Hz, 1 H) 7.18-7.34 (m, 5 H), 7.43 (d, J=2.21 Hz, 1 H) 7.54 (s, 1 H) 7.73 (d, J=7.72 Hz, 1 H) 7.84 (d, J=8.46 Hz, 1 H) 7.93 (s, 1 H).

[00775] N-(3-(azetidin-1-carbonyl)-4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-phenyl)-methanesulfonamide (compound (compound IB-L1-1.22).1H NMR (300 MHz, DMSO-d6) δ 1.38 (s, 9 H) 3.07 (s, 3 H) 3.78 (s, 3 H), 5.64 (d, J=7.72 Hz, 1 H) 7.18-7.34 (m, 5 H), 7.43 (d, J=2.21 Hz, 1 H) 7.54 (s, 1 H) 7.73 (d, J=7.72 Hz, 1 H) 7.84 (d, J=8.46 Hz, 1 H) 7.93 (s, 1 H).

[00776] 2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonamido-N-(2-methoxy-ethyl)-N-methyl-benzamide (compound IB-L1-1.24).1H NMR (300 MHz, DMSO-d6) δ 1.40 (s, 9 H) 2.81 (s, 3 H) 3.07 (s, 3 H) 3.23 (s, 3 H) 3.29 (t, J=5.33 Hz, 1 H) 3.39 (t, J=4.96 Hz, 1 H) 3.62 (t, J=4.78 Hz, 2 H) 3.82 (s, 3 H) 5.68 (d, J=8.09 Hz, 1 H) 6.96-7.07 (m, 1 H) 7.09-7.17 (m, 1 H) 7.23-7.38 (m, 3 H) 7.49 (dd, J=16.55, 2.57 Hz, 1 H) 7.71-7.76 (m, 1 H) 7.83-7.94 (m, 1 H).

[00777] N-(4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-3-isopropoxyphenyl-phenyl)-methanesulfonamide (compound IB-L1-1.25).1H NMR (300 MHz, DMSO-d6) δ 1.16 (d, J=5.88 Hz, 6 H) 1.38 (s, 9 H) 3.01 (s, 3 H) 3.69 (dt, J=12.13, 6.07 Hz, 1 H) 3.79 (s, 3 H) 4.59 (s, 2 H) 5.65 (dd, J=7.91, 2.02 Hz, 1 H) 7.13-7.29 (m, 4 H) 7.32-7.40 (m, 1 H) 7.59 (d, J=2.57 Hz, 1 H) 7.75 (d, J=8.09 Hz, 2 H), 9.86 (s, 1 H), 11.43 (d, J=1.84 Hz, 1 H).

[00778] N-[4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-3-(pyrrolidin-1-carbonyl)-phenyl]-methanesulfonamide (compound IB-L1-1.27).1H NMR (300 MHz, DMSO-d6) δ 1.37 (s, 9 H), 1.73-1.89 (m, 4 H), 3.03-3.12 (m, 5 H), 3.51 (t, J=6.80 Hz, 2 H) 3.76 (s, 3 H), 5.64 (dd, J=7.91, 2.02 Hz, 1 H), 6.99-7.06(m, 1 H) 7.08 (d, J=2.21 Hz, 1 H) 7.19-7.31 (m, 3 H) 7.46 (d, J=2.57 Hz, 1 H) 7.75 (d, J=8.09 Hz, 1 H) 7.82 (d, J=8.82 Hz, 1 H), 10.01 (s, 1 H) 11.41 (d, J=2.21 Hz, 1 H).

[00779] N-[4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-3-(3-hydroxy-azetidin-1-ylmethyl)-phenyl]-methanesulfonamide (compound IB-L1-1.29).1H NMR (300 MHz, DMSO-d6) δ 1.38 (s, 9 H), 2.78-2.85 (m, 2 H) 2.99 (s, 3 H), 3.50-3.58 (m, 2 H) 3.71 (s, 2 H) 3.79 (s, 3 H), 4.19 (td, J=12.41, 6.07 Hz, 1 H), 5.29 (d, J=6.25 Hz, 1 H), 5.66 (d, J=8.09 Hz, 1 H), 7.10-7.18 (m, 2 H) 7.20 (t, J=2.21 Hz, 2 H) 7.35-7.42 (m, 1 H) 7.63 (d, J=2.57 Hz, 1 H) 7.69 (d, J=8.46 Hz, 1 H) 7.76 (d, J=7.72 Hz, 1 H), 9.78 (s, 1 H), 11.42 (s, 1 H).

[00780] N-(4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-3-pyrrolidin-1-ylmethyl-phenyl)-methanesulfonamide (compound IB-L1-1.33).1H NMR (500 MHz, DMSO-d6) δ 1.40 (s, 9 H), 1.72-1.95 (m, 4 H), 2.84 (s, 2 H) 2.88-2.98 (m, 2 H) 3.01 (s, 3 H) 3.81 (s, 3 H) 3.86-4.23 (m, 2 H), 5.63 (d, J=7.81 Hz, 1 H) 7.17 (d, J=15.63 Hz, 1 H) 7.21-7.28 (m, 2 H) 7.32-7.38 (m, 1 H) 7.47 (d, J=16.11 Hz, 1 H) 7.53-7.59 (m, 1 H) 7.61 (d, J=7.81 Hz, 1 H) 7.70 (d, J=6.35 Hz, 1 H), 9.42 (s, 1 H), 10.88 (s, 1 H).

[00781] N-(4-{(Z)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-phenyl)-methanesulfonamide (compound IB-L1-1.341H NMR (300 MHz, DMSO-D6) δ ppm 11.31 (s, 1 H), 9.77 (s, 1 H) 7.53 (d, J=8.09 Hz, 1 H) 7.23 (d, J=8.46 Hz, 2 H) 7.17 (d, J=2.57 Hz, 1 H) 7.06 (d, J=8.82 Hz, 2 H) 7.01 (d, J=2.57 Hz, 1 H), 6.53-6.71 (m, 2 H), 5.56 (d, J=7.72 Hz, 1 H) 3.81 (s, 3 H) 2.96 (s,3H) 1.35 (s, 9H)

[00782] N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)phenethyl)phenyl)methane sulfonamide (compound IA-L5-2-1.2).1H NMR (300 MHz, DMSO-d6) δ 1.25 (s, 9 H), 2.69 (t, J=6.62 Hz, 2 H) 2.83 (s, 4 H), 2.91 (s, 3 H), 3.7 (t, J=6.62 Hz, 2 H) 6.99-7.21 (m, 7 H), 9.60 (s, 1 H), 10.31 (s, 1 H).

[00783] methyl 2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenethyl)-5-(methylsulfonyl)benzoate (compound IB-L5-2-1.1).1H NMR (300 MHz, DMSO-d6) δ 1.34 (s, 9 H), 2.83-2.92 (m, 2 H) 2.96 (s, 3 H), 3.14 (dd, J=10.30, 5.88 Hz, 2 H) 3.75 (s, 3 H) 3.83 (s, 3 H), 5.64 (d, J=7.72 Hz, 1 H) 7.13 (d, J=2.94 Hz, 1 H) 7.20 (d, J=2.57 Hz, 1 H) 7.28-7.36 (m, 2 H) 7.61-7.71 (m, 2 H), 9.88 (s, 1 H), 11.39 (s, 1 H)

[00784] N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenethyl)phenyl) methanesulfonamide (compound IB-L5-2-1.2).1H NMR (300 MHz, DMSO-d6): δ 11.39 (s, 1H), 9.60 (s, 1H), 7.65 (d, J=8.1 Hz, 1H), 7.23 (m, 3H), 7.17 (m, 3H), 5.64 (d, J=7.7 Hz, 1H), 3.77 (s, 3H), 2.93 (s, 3H), 2.88 (bs, 4H), 1.35 (s, 9H)

[00785] the Following compounds can be obtained using the above descriptions:

Table a

[00786] Study of inhibiting HCV polymerase

[00787] Or twofold serial dilutions (the study of partial inhibition), or a narrower interval breeding, overlying the IC50inhibitor (study of the strength of binding of the inhibitors were incubated with 20 mm Tris-Cl pH 7.4, 2 mm MnCl2, 1 mm dicit what Eidolon, 1 mm ethylenediaminetetraacetic acid (EDTA), 60-125 μm GTP and 20-50 nm Δ21 NS5B (HCV strain 1 (VK, Genbank registration number M, or N, Genbank registration number AF011751)) for 15 min at room temperature. The reaction was initiated by addition of 20 µm P, 20 μm ATP, 1 μm3H-UTP (10 millicurie/mmol), 5 nm messenger RNA and 0.1 U/μl of inhibitor RNase (RNasin, Promega), and left for reaction for 2-4 h at room temperature. Reaction volume was 50 µl. The reaction was completed by adding 1 volume of 4 mm spermine in 10 mm Tris-Cl pH 8.0, 1 mm EDTA. After incubation for at least 15 min at room temperature, the precipitated RNA was collected by filtration through GF/B filter (Millipore) in a 96-hole format. The filter plate was washed three times with 200 μl each of 2 mm spermine, 10 mm Tris-Cl pH 8.0, 1 mm EDTA, and 2 times with ethanol. After air drying to each well was added 30 μl of scintillation mixture of Microscint 20 (Packard), and deducted the number of pulses per minute was determined using scintillation counting. The values of the IC50was calculated using nonlinear regression equation with two independent variables, using neighborly control sample and a fully-inhibited control sample to determine the minimum and maximum of this curve. Research the strength of bonding was carried out on those compounds that demonstrate the value of the IC 50less than 0,005 µm in the study of partial inhibition for a more accurate measurement values IC50. Withheld number of pulses per minute were plotted on the graph depending on the concentration of the inhibitor and approximiately to equation 1, using nonlinear regression (reference 1) to obtain the values for IC50:

Withheld number of pulses per minute=A[sqrt{(IC50+It-Et)^2+4*IC50*Et}-(IC50+It-Et)] (equation 1)

where A=Vmax[S]/2(Km+[S]); It=total concentration of inhibitor and E1=total active concentration of the enzyme.

[00788] Reference: Morrison, J. F. and S. R. Stone. 1985. Approaches to the study and analysis of the inhibition of enzymes by slow - and tight-binding inhibitors. Comments Mol. Cell. Biophys. 2: 347-368.

[00789] Sequence used messenger RNA were: 5'-GGGCGAAUUG GGCCCUCUAG AUGCAUGCUC GAGCGGCCGC CAGUGUGAUG GAUAUCUGCA GAAUUCGCCC UUGGUGGCUC CAUCUUAGCC CUAGUCACGG CUAGCUGUGA AAGGUCCGUG AGCCGCUUGA CUGCAGAGAG UGCUGAUACU GGCCUCUCUG CAGAUCAAGUC-3'

[00790] When testing the above method, the compounds of the present invention inhibit HCV polymerase 1A and/or 1B. Indicate in the Table below represent the following: -- IC50≤0,01 μm; 0.1 ám≥IC50>0.01 µm; C - 1 µm≥IC50>0.1 mm; and D -- IC50>1 μm; ND - not determined.

Table IC50
Connect the out 1A1bConnection1A1b
IA-L1-1.3AndAndIA-L1-1.4AndAnd
IA-L1-1.5AndInIA-L1-1.6AndIn
IA-L1-1.9AndInIA-L1-1.10InIn
IA-L1-1.11InInIA-L1-1.12
IA-L1-1.13IA-L1-1.14DD

Connection1a1bConnection1AIA-L1-1.16AAndIA-L1-1.17InIn
IA-L1-1.18IA-L1-1.20AndIn
IA-L1-1.21InInIA-L1-1.22
IA-L1-1.23IA-L1-1.24DD
IA-L1-1.25DDIA-L1-1.26InIn
IA-L1-1.27AInIB-L1-1.1AndAnd
IB-L1-1.2InInIB-L1-1.4AndAnd
AAndIB-L1-1.6AndIn
IB-L1-1.7AInIB-L1-1.8AndIn
IB-L1-1.9AInIB-L1-1.10AndIn
IB-L1-1.11AInIB-L1-1.12AndIn
IB-L1-1.13AInIB-L1-1.14AndIn
IB-L1-1.15AInIB-L1-1.16AndIn
IB-L1-1.17AInIB-L1-1.18AndIn
IB-L1-1.19 AInIB-L1-1.20AndIn
IB-L1-1.21AInIB-L1-1.22InIn
IB-L1-1.23InInIB-L1-1.24InIn
IB-L1-1.25InInIB-L1-1.26InIn
IB-L1-1.27InInIB-L1-1.28InIn
IB-L1-1.29InInIB-L1-1.30InIn
IB-L1-1.31InIB-L1-1.32
IB-L1-1.33 IB-L1-1.34DD
IB-L1-1.45AndInIB-L1-1.46InIn
IB-L1-1.47InInIB-L1-1.48InIn
IB-L1-1.49InIB-L1-1.50InIn
IB-L1-1.51InInIB-L1-1.52
IB-L1-1.53DDIB-L1-1.55DD
IA-L5-2-1.1InInIA-L5-2-1.2InIn
IB-L5-2-1.1AndIn IB-L5-2-1.2InIn
IA-L8-1.1

[00791] Study replicon HCV polymerase

[00792] To characterize compounds in cell culture used two stable cell lines carrying sebenarnya the replicons: one derived from genotype 1A-N and one derived from genotype Ib-Con1 (obtained from Apath, LLC, St. Louis, MO). All constructs replicon was bicistronic subgenomic the replicons, equivalent to those described Bartenschlager and co-authors (Lohmann et al., Replication of Subgenomic Hepatitis With Virus RNAs in a Hepatoma Cell Line, science 285:110-3(1999)). Construct replicon of genotype 1a contains the NS3-NS5B coding region, originating from N strain of HCV (1a-H77) (Blight et al., Efficient Replication of Hepatitis With Virus Genotype 1a RNAs in Cell Culture, J. virol. 77:3181-90 (2003)). This replicon also has repairnow the Firefly luciferase and breeding marker neomycin to phosphotransferase (Neo). These two coding region separated FMDV 2A protease, contain the first cistron bicistronic construct replicon with the second cistrana containing the NS3-NS5B coding region with additional adaptive mutations E G, K1691R, K2040R and S2204I. Ib-Con1 replicon construct is identical to 1a-the H77 replicon, except t the th, what NS3-NS5B coding region was obtained from strain Ib-Con1, and the adaptive mutations are E G, T1280I and S2204I. The replicon-containing cell lines were pokasivali modified by Dulbecco environment Needle (DMEM) containing 10% (V/V) fetal calf serum (FBS), 100 IU/ml penicillin, 100 mg/ml streptomycin (Invitrogen), and 200 mg/ml G418 (Invitrogen).

[00793] Inhibiting action of the compounds on the replication of HCV was determined by measuring the activity of the reporter gene luciferase. Briefly, the replicon-containing cells were planted in 96-well tablets with a density of 5000 cells per well in 100 μl DMEM containing 5% FBS. 16-24 h later, compounds were diluted in dimethyl sulfoxide (DMSO) to obtain a 200x stock solution in series of eight semi-log dilution. Series breeding then further diluted 100-fold in medium containing 5% FBS. Added Wednesday with inhibitor at night tablets for cell cultures, already containing 100 μl of DMEM with 5% FBS. In studies that measure the inhibitory activity in the presence of human plasma, Wednesday night from tablets to cell cultures was replaced with DMEM containing 40% human plasma and 5% FBS. Cells were incubated for three days in thermostats for cell cultures, and then subjected to lysis for RNA extraction. For luciferase research in each well was added 30 μl of passive puff the RA lysis (Passive Lysis buffer (Promega), and then the plates were incubated for 15 min with rocking for lysis of the cells. The solution luciferin (50-100 ál, Promega) was added to each well and the luciferase activity was measured using a luminometer Victor II (Perkin-Elmer). The percentage of inhibition of HCV RNA replication was calculated for each concentration of the compound and is EU50calculated using nonlinear regression curve, approximated to 4-parametric logarithmic equation and the software GraphPad Prism 4.

[00794] When testing the above method, the compounds of the present invention inhibit HCV polymerase 1A and/or 1B. Indicate in the below Table represent the following: a -- EU50≤0,01 μm; 0.1 ám≥EC50>0.01 µm; C - 1 µm≥EU50>0.1 mm; and D -- EU50>1 μm; ND - not determined.

Table EU50
Connection1a1bConnection1A1b
IA-L1-1.3InAndIA-L1-1.4AndAnd
IA-L1-1.5InAndIA-L1-1.6InIn
IA-L1-1.9InAndIA-L1-1.10InIn
IA-L1-1.11AAndIA-L1-1.12
IA-L1-1.13DIA-L1-1.14DD
IA-L1-1.16InInIA-L1-1.17InIn
IA-L1-1.18IA-L1-1.20InIn
IA-L1-1.21AAndIA-L1-1.22D
IA-L1-1.23 DDIA-L1-1.24DD
IA-L1-1.25NDNDIA-L1-1.26InIn
IA-L1-1.27InAndIB-L1-1.1AndAnd
IB-L1-1.2NDInIB-L1-1.4InAnd
IB-L1-1.5InAndIB-L1-1.6AndAnd
IB-L1-1.7AAndIB-L1-1.8InAnd
IB-L1-1.9InAndIB-L1-1.10AndAnd
IB-L1-1.11In AndIB-L1-1.12InIn
IB-L1-1.13InAndIB-L1-1.14InAnd
IB-L1-1.15AAndIB-L1-1.16In
IB-L1-1.17InAndIB-L1-1.18InIn
IB-L1-1.19InAndIB-L1-1.20InAnd
IB-L1-1.21InAndIB-L1-1.22InAnd
IB-L1-1.23AndIB-L1-1.24InAnd
IB-L1-1.25InAnd IB-L1-1.26InAnd
IB-L1-1.27InAndIB-L1-1.28AndAnd
IB-L1-1.29IB-L1-1.30In
IB-L1-1.31DDIB-L1-1.32In
IB-L1-1.33InIB-L1-1.34InAnd
IB-L1-1.45InAndIB-L1-1.46And
IB-L1-1.47InIB-L1-1.48And
IB-L1-1.49DDIB-L1-1.50 In
IB-L1-1.51DInIB-L1-1.52D
IB-L1-1.53NDNDIB-L1-1.55NDND
IA-L5-2-1.1InIA-L5-2-1.2
IB-L5-2-1.1InAndIB-L5-2-1.2In

Connection1a1bConnection1a1b
IA-L6-1.1InIA-L8-1.1C

***********

[00795] All references (antennae and non-patent), cited above, included in the quality of the ve reference into this patent application. The description of these links is intended only to summarize the claims made by their authors. Not recognized the fact that any link (or part of any link is relevant prior art (or art in General). Applicants retain the right to dispute the accuracy and relevance of the cited references.

1. The compound or its pharmaceutically acceptable salt, where
the compound corresponds in structure to formula I:

selected from the group consisting of single carbon-carbon links and double carbon-carbon linkages;
R1represents hydrogen;
R2selected from the group consisting of hydrogen and halo;
R3represents hydrogen;
R4selected from the group consisting of halo, C1-C6of alkyl, C1-C6alkylsulfonyl and 5-6-membered heteroaryl containing a heteroatom selected from N, O and S, where alkyl optionally substituted by one or more hydroxy;
R5selected from the group consisting of hydrogen, hydroxy, C1-C6alkyloxy and halo;
L is selected from the group consisting of C(RA)=C(RB), ethylene and cyclopropyl-1,2-ene;
RAand RBindependently selected from the group consisting of hydrogen, C1-C6of alkyl, C1-C6alkylic and and halo;
R6represents a C6aryl, optionally substituted by one or more substituents independently selected from the group consisting of RE, RF, RG, RH, RIand RJ;
each REindependently selected from the group consisting of halo, nitro, carboxy, amino, aldehyde;
each RFrepresents a C1-C6alkyl, optionally substituted by one or more substituents independently selected from the group consisting of carboxy, hydroxy, amino, imino, C1-C6alkyloxy and 4-5-membered heterocyclyl containing one N atom as the heteroatom, where:
amino, imino and heterocyclyl optionally substituted by one or two substituents, independently selected from the group consisting of C1-C6the alkyl, hydroxy and C1-C6alkyloxy;
each RGrepresents a 5-membered heteroaryl containing 1-2 heteroatoms, independently selected from the group consisting of N and O;
each RHrepresents a C1-C6alkyloxy;
each RIindependently selected from the group consisting of aminocarbonyl, C1-C6allyloxycarbonyl and 4-6-membered geterotsiklicheskikh containing 1-2 heteroatoms, independently selected from the group consisting of N and O, where:
aminocarbonyl optionally substituted with one or two mixing what italiani, independently selected from the group consisting of C1-C6of alkyl, C1-C6alkalosis1-C6the alkyl and 5-membered heterocyclyl containing S atom as heteroatom, where heterocyclyl optionally substituted by one or two oxo; and
each RJindependently selected from the group consisting of C1-C6allyloxycarbonyl and C1-C6alkylsulfonamides, where the amino portion of such substituents optionally substituted C1-C6alkylcarboxylic.

2. The compound or salt according to p. 1, whereis a double carbon-carbon bond.

3. The compound or salt according to p. 1, where R2represents hydrogen.

4. The compound or salt according to p. 1, where R4represents a C1-C6alkyl.

5. The compound or salt according to p. 1, where R4represents tert-butyl.

6. The compound or salt according to p. 1, where R5represents a C1-C6alkoxy.

7. The compound or salt according to p. 6, where R5represents methoxy.

8. The compound or salt according to p. 1, where L represents C(RA)=C(RB).

9. The compound or salt according to p. 1, where:
RArepresents hydrogen; and
RBrepresents hydrogen.

10. The compound or salt according to p. 1, where R6represents phenyl, substituted RJ.

11. The compound or salt according to p. 10, where each RJrepresents methylsulfonylamino.

12. The compound or salt according to p. 1, where:
is a double carbon-carbon bond
R2represents hydrogen;
R4represents a C1-C6alkyl; and
R5represents a C1-C6alkoxy.

13. The compound or salt according to p. 1, where:
is a double carbon-carbon bond
R2represents hydrogen;
R4represents tert-butyl; and
R5represents methoxy.

14. The compound or salt according to p. 1, where:
is a double carbon-carbon bond
R2represents hydrogen;
R4represents tert-butyl; and
R5represents methoxy;
R6represents phenyl, substituted RJwhere each RJrepresents methylsulfonylamino.

15. The compound or salt according to p. 1, where:
is a double carbon-carbon bond
R2represents hydrogen
R4represents tert-butyl; and
R5represents methoxy;
L represents C(RA)=C(RB);
RArepresents hydrogen; and
RB represents hydrogen, and
R6represents phenyl, substituted RJwhere RJrepresents methylsulfonylamino.

16. The compound or salt according to p. 1, where the compound is an (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

17. The compound or salt according to p. 1 wherein the salt compound is a potassium salt of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

18. The compound or salt according to p. 1 wherein the salt compound is Moncalieri salt (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

19. (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

20. Potassium salt of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

21. The compound or its pharmaceutically acceptable salt, where the compound is selected from the group of compounds consisting of
(E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide;
(Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)methoxyphenyl)-1-chloride)phenyl)methanesulfonamide;
(E)-1-(3-tert-butyl-5-(4-forsteri)-4-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione;br/> (Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)methoxyphenyl)-1-Porvenir)phenyl)methanesulfonamide;
(E)-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)-1-Porvenir)phenyl)methanesulfonamide;
(E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxytrityl)-2-forfinal)methanesulfonamide;
N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)cyclopropyl)phenyl)methanesulfonamide;
N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenethyl)phenyl)methanesulfonamide;
(E)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)styryl)phenyl)methanesulfonamide;
(Z)-N-(4-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)-1-methoxyphenyl)phenyl)methanesulfonamide;
(E)-1-(3-tert-butyl-4-methoxy-5-stillfeel)dihydropyrimidine-2,4(1H,3H)-dione;
(E)-1-(3-tert-butyl-4-methoxy-5-(4-methoxystyrene)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;
(E)-N-(4-(3-tert-butyl-5-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide;
(E)-N-(4-(3-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide;
(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophene-2-yl)styryl)phenyl)methanesulfonamide;
(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-2-yl)-2-methoxystyrene)phenyl)methanesulfonamide;
(E)-N-(4-(5-(2,4-diox is 3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(pyridin-4-yl)styryl)phenyl)methanesulfonamide;
(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(pyridin-3-yl)styryl)phenyl)methanesulfonamide;
(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophene-3-yl)styryl)phenyl)methanesulfonamide;
(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-3-yl)-2-methoxystyrene)phenyl)methanesulfonamide;
(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-methoxystyrene)phenyl)methanesulfonamide;
(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-iodine-2-methoxystyrene)phenyl)methanesulfonamide;
(E)-N-(4-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(methylsulphonyl)styryl)phenyl)methanesulfonamide;
(E)-methyl 2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-5-(methylsulfonyl)benzoate;
(E)-2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-5-(methylsulfonyl)benzoic acid;
(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-(morpholine-4-carbonyl)phenyl)methanesulfonamide;
(E)-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-(hydroxymethyl)phenyl)methanesulfonamide;
(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-(methoxymethyl)phenyl)methanesulfonamide;
(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-((isobutylamino)methyl)phenyl)methanesulfonamide;
N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-((E)-(methoxyimino)methyl)phenyl)methanesulfonamide;
(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-(oxazol-2-yl)phenyl)methanesulfonamide;
(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-3-(1H-imidazol-2-yl)phenyl)methanesulfonamide;
(E)-tert-butyl-2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)-5-(methylsulfonylamino)phenylcarbamate;
(E)-(3-amino-4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide;
(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxytrityl)-2-forefeel)methanesulfonamide;
(E)-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxytrityl)-2-fluorescent-5-were)methanesulfonamide;
methyl-2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenethyl)-5-(methylsulfonyl)benzoate;
N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenethyl)phenyl)methanesulfonamide;
(E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-amoxicill)phenyl)methanesulfonamide;
(E)-N-(4-(1-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)prop-1-EN-2-yl)phenyl)methanesulfonamide;
(Z)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide;
(E)-N-(4-(3-t the et-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxystyrene)phenyl)-N-(methylsulphonyl)ndimethylacetamide;
(E)-1-(3-(4-aminosterol)-5-tert-butyl-4-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione;
(Z)-N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide;
N-(4-(2-(3-tert-butyl-5-(2,4-dioxopyrimidine-1(2H)-yl)-2-methoxyphenyl)-1-fluoro-vinyl)phenyl)methanesulfonamide;
(E)-1-(3-tert-butyl-4-methoxy-5-(4-nitrostyryl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione;
1-{3-tert-butyl-5-[(Z)-2-chloro-(4-nitrophenyl)-vinyl]-4-methoxy-phenyl}-dihydropyrimidine-2,4-dione;
1-{3-tert-butyl-4-methoxy-5-[(E)-2-(4-nitrophenyl)-propenyl]-phenyl}-dihydropyrimidine-2,4-dione;
1-{3-tert-butyl-5-[(E)-2-(4-nitrophenyl)-vinyl]-phenyl}-dihydropyrimidine-2,4-dione;
N-(4-{(E)-2-[3-tert-butyl-5-(dioxotetrahydrofuran-1-yl)-2-methoxy-phenyl]-vinyl}-3-methoxyphenyl)methanesulfonamide;
N-(4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-3-formylphenyl)methanesulfonamide;
N-[4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxyphenyl]-vinyl}-3-(gidroksilaminami)-phenyl]methanesulfonamide;
2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonamido-N-(2-methoxy-ethyl)benzamide;
2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonamido-ethyl ester benzoic acid;
N-(4-{(E)-2-[3-tert-butyl-2-chloro-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-phenyl]vinyl}phenyl)methanesulfonamide;
2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonamido-N,N-dimethyl-benzamide;
2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonamido-N-methyl-benzamide;
2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-N-(1,1-dioxo-tetrahydrothiophene-3-yl)-5-methanesulfonamido-N-methyl-benzamide;
N-(4-{(E)-2-[3-tert-butyl-2-chloro-5-(5-chloro-2H-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}phenyl)methanesulfonamide;
2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonamido-benzamide;
N-(3-(azetidin-1-carbonyl)-4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}phenyl)methanesulfonamide;
2-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-5-methanesulfonamido-N-(2-methoxy-ethyl)-N-methyl-benzamide;
N-(4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-3-isopropoxyphenyl-phenyl)methanesulfonamide;
N-(4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-3-pyrrolidin-1-carbonyl)phenyl)methanesulfonamide;
N-(4-{(E)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-3-(3-hydroxy-azetidin-1-ylmethyl)phenyl)methanesulfonamide;
N-(4-{(E)-2-[3-tert-BU the Il-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}-3-pyrrolidin-1-ylmethyl-phenyl)methanesulfonamide;
N-(4-{(Z)-2-[3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidine-1-yl)-2-methoxy-phenyl]-vinyl}phenyl)methanesulfonamide; and
N-(4-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)phenethyl)phenyl)methanesulfonamide.

22. Crystalline form of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide selected from the group consisting of:
crystal deviational disodium salt of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide,
crystal chetyrehbalnoy disodium salt of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide,
crystal chetyrehbalnoy Pikalevo salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide,
crystalline trihydrate montalieu salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide,
crystal dowdney montalieu salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide,
crystal 1/7 potassium salt of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxide who yl)phenyl)methanesulfonamide,
crystal chetyrehbalnoy monomethylamine salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide and
the crystalline sample And hydrate (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide.

23. Crystalline form of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide selected from the group consisting of:
deviational disodium salt of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 4,3±0,2, 10,4±0,2, 10,9±0,2, 11,6±0,2, 12,9±0,2, 14,7±0,2, 16,4±0,2, 17,8±0,2, 19,4±0,2, 19,8±0,2, 20,8±0,2, 21,9±0,2 and 23.5±0.2 degrees 2θ;
deviational disodium salt of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 4,3±0,2, 10,4±0,2, 10,9±0,2, 11,6±0,2, 12,9±0,2, 14,7±0,2, 14,9±0,2, 16,4±0,2, 17,8±0,2, 19,4±0,2, 19,7±0,2, 19,8±0,2, 20,8±0,2, 20,9±0,2, 21,9±0,2, 22,1±0,2 and 23.5±0.2 degrees 2θ;
deviational disodium salt of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl) is econsultameri, having a powder x-ray are essentially presented on Figure 1;
deviational disodium salt of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide, having unit cell parameters, where a is equal to 8.9 Å, b is equal to 9.4 Å and equal to 20.7 Å;
chetyrehbalnoy disodium salt of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 4,8±0,2, 12,1±0,2, 14,0±0,2, 17,0±0,2, 17,5±0,2, 20,9±0,2, 21,6±0,2, 25,0±0,2 and 29.5±0.2 degrees 2θ;
chetyrehbalnoy disodium salt of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 4,8±0,2, 12,1±0,2, 14,0±0,2, 14,4±0,2, 17,0±0,2, 17,5±0,2, 20,9±0,2, 21,6±0,2, 25,0±0,2, 29,5±0,2 and 34.2±0.2 degrees 2θ;
chetyrehbalnoy disodium salt of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray are essentially presented on Figure 2;
chetyrehbalnoy Pikalevo salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenylmethanesulfonyl, having a powder x-ray containing one or more peaks selected from the group consisting of 5,0±0,2, 11,9±0,2, 12,4±0,2, 13,7±0,2, 15,0±0,2, 16,5±0,2, 17,1±0,2, 20,8±0,2, 21,3±0,2, 22,2±0,2, 24,0±0,2, 26,4±0,2 and of 29.3±0.2 degrees 2θ;
chetyrehbalnoy Pikalevo salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 5,0±0,2, 11,9±0,2, 12,4±0,2, 12,6±0,2, 13,7±0,2, 15,0±0,2, 16,5±0,2, 16,7±0,2, 17,1±0,2, 20,7±0,2, 20,8±0,2, 21,3±0,2, 22,2±0,2, 22,4±0,2, 24,0±0,2, 26,4±0,2 and of 29.3±0.2 degrees 2θ;
chetyrehbalnoy Pikalevo salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray are essentially presented on Figure 4;
chetyrehbalnoy Pikalevo salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide, having unit cell parameters, where a is equal to 14.5 Å, b is about 10.8 Å and equal to 35.8 Å;
trihydrate montalieu salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 4,8±0,2, 10,8±0,2, 11,3±0,2, 13,4±0,2, 15,3±0,2, 16,9±0,2, 21,2±0,2, 21,7±02, 22,1±0,2, 22,5±0,2 and 23.0±0.2 degrees 2θ;
trihydrate montalieu salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 4,8±0,2, 10,8±0,2, 11,3±0,2, 13,4±0,2, 13,6±0,2, 15,3±0,2, 16,9±0,2, 21,2±0,2, 21,7±0,2, 22,1±0,2, 22,5±0,2, 22,6±0,2, and 23.0±0.2 degrees 2θ;
trihydrate montalieu salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene) phenyl)methanesulfonamide having a powder x-ray that contains five or more peaks selected from the group consisting of 4,8±0,2, 10,8±0,2, 11,3±0,2, 13,4±0,2, 15,3±0,2, 16,9±0,2, 21,2±0,2, 21,7±0,2, 22,1±0,2, 22,5±0,2 and 23.0±0.2 degrees 2θ;
trihydrate montalieu salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide, having unit cell parameters, and where equal to 9.0 Å, b is equal to 8.3 Å and equal to 18.6 Å;
the two-water montalieu salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 7,7±0,2, 8,8±0,2, 16,1±0,2 and 19.7±0.2 degrees 2θ;
dowdney montalieu salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyran the DIN-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide, having a powder x-ray containing one or more peaks selected from the group consisting of 7,7±0,2, 8,8±0,2, 12,4±0,2, 14,0±0,2, 16,1±0,2, 17,7±0,2, 19,2±0,2, 19,7±0,2, 23,1±0,2 and 29.2±0.2 degrees 2θ;
dowdney montalieu salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray are essentially presented in Figure 6;
1/7 potassium salt of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 7,7±0,2, 8,3±0,2, 10,1±0,2, 10,6±0,2, 11,4±0,2, 12,0±0,2, 13,4±0,2, 15,6±0,2, 16,3±0,2, 16,7±0,2, 17,2±0,2, 18,3±0,2, 18,8±0,2, 19,4±0,2, 19,9±0,2, 20,2±0,2, 20,5±0,2, 21,2±0,2, 22,1±0,2 and 22.9±0.2 degrees 2θ;
1/7 potassium salt of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 7,7±0,2, 8,3±0,2, 10,1±0,2, 10,6±0,2, 11,4±0,2, 12,0±0,2, 13,4±0,2, 15,6±0,2, 16,3±0,2, 16,7±0,2, 17,2±0,2, 18,3±0,2, 18,8±0,2, 19,4±0,2, 19,9±0,2, 20,2±0,2, 20,5±0,2, 20,8±0,2, 21,2±0,2, 22,1±0,2, 22,9±0,2, 24,3±0,2, 24,9±0,2 and 25.1±0.2 degrees 2θ;
1/7 potassium salt of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide with powder the second radiograph, essentially presented on Figure 8;
chetyrehbalnoy monomethylamine salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 9,5±0,2, 10,0±0,2, 11,8±0,2, 12,1±0,2, 14,4±0,2, 16,8±0,2, 17,6±0,2, 19,8±0,2, 20,8±0,2, 21,4±0,2, 21,8±0,2 and 29.8±0.2 degrees 2θ;
chetyrehbalnoy monomethylamine salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 9,5±0,2, 10,0±0,2, 11,8±0,2, 12,1±0,2, 14,4±0,2, 16,8±0,2, 17,6±0,2, 19,4±0,2, 19,8±0,2, 20,8±0,2, 21,4±0,2, 21,8±0,2, 21,9±0,2 and 29.8±0.2 degrees 2θ;
chetyrehbalnoy monomethylamine salt crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray are essentially presented on Figure 9;
sample And crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 5,8±0,2, 9,9±0,2, 11,8±0,2, 12,4±0,2, 14,5±0,2, 18,8±0,2, 22,7±0,2 and 29.2±0.2 degrees 2θ;
sample And crystalline (E)-N-(4-(3-tert-Buti is-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide, having a powder x-ray containing one or more peaks selected from the group consisting of 5,8±0,2, 9,9±0,2, 11,8±0,2, 12,4±0,2, 14,0±0,2, 14,5±0,2, 15,3±0,2, 18,5±0,2, 18,8±0,2, 22,2±0,2, 22,7±0,2, 23,8±0,2, 26,0±0,2 and 29.2±0.2 degrees 2θ.
sample And crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray are essentially presented on Figure 11;
sample of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 11,5±0,2, 13,3±0,2, 15,4±0,2, 16,4±0,2, 17,1±0,2, 18,6±0,2, 19,4±0,2, 20,4±0,2, 21,6±0,2, 22,4±0,2, 24,0±0,2, 26,8±0,2 and 29.0±0.2 degrees 2θ;
sample of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray are essentially presented in Figure 13;
sample of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 7,7±0,2, 10,1±0,2, 10,6±0,2, 12,0±0,2, 13,4±0,2, 16,2±0,2, 19,4±0,2, 20,5±0,2, 21,4±0,2, 22,0±0,2, 22,6±0,2, 24,3±0,2 and 27.6±0.2 degrees 2θ;
sample of crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dio is co-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide, having a powder x-ray are essentially presented in Figure 14;
sample D crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 5,8±0,2, 10,7±0,2, 11,2±0,2, 15,2±0,2, 16,1±0,2, 16,9±0,2, 19,9±0,2, 22,1±0,2, 24,7±0,2 and to 26.0±0.2 degrees 2θ;
sample D crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 5,8±0,2, 10,7±0,2, 11,2±0,2, 15,2±0,2, 16,1±0,2, 16,9±0,2, 17,1±0,2, 19,9±0,2, 20,1±0,2, 22,1±0,2, 24,7±0,2 and to 26.0±0.2 degrees 2θ;
sample D crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray are essentially presented in Figure 15;
sample And hydrate crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 5,1±0,2, 7,9±0,2, 9,5±0,2, 10,3±0,2, 13,7±0,2, 16,5±0,2, 17,1±0,2, 17,5±0,2, 18,8±0,2, 19,2±0,2, 20,7±0,2, 21,3±0,2, 21,6±0,2, 25,8±0,2, 26,8±0,2 and 28,4±0.2 degrees 2θ;
sample And hydrate crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-D. the oxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide, having a powder x-ray are essentially presented in Figure 16;
sample And hydrate crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 6,3±0,2, 7,7±0,2, 10,4±0,2, 12,7±0,2, 13,3±0,2, 14,9±0,2, 15,4±0,2, 16,4±0,2, 18,6±0,2, 18,9±0,2, 19,4±0,2, 22,5±0,2, 23,5±0,2, 24,0±0,2, 26,8±0,2 and 29.0±0.2 degrees 2θ;
sample hydrate crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 6,3±0,2, 7,7±0,2, 10,4±0,2, 12,7±0,2, 13,3±0,2, 13,5±0,2, 14,9±0,2, 15,4±0,2, 16,4±0,2, 18,5±0,2, 18,6±0,2, 18,9±0,2, 19,4±0,2, 22,5±0,2, 23,5±0,2, 24,0±0,2, 26,8±0,2, and 29.0±0.2 degrees 2θ;
sample hydrate crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray are essentially as shown in Figure 18;
sample hydrate crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 10,5±0,2, 13,3±0,2, 13,5±0,2, 14,9±0,2, 15,4±0,2, 16,4±0,2, 18,6±0,2, 19,0±0,2, 19,4±0,2, 22,5±0,2, 23,5±0,2, 26,9±0,2 and 290±0.2 degrees 2θ;
sample hydrate crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 10,5±0,2, 13,3±0,2, 13,5±0,2, 14,9±0,2, 15,4±0,2, 16,4±0,2, 18,6±0,2, 19,0±0,2, 19,4±0,2, 22,5±0,2, 23,5±0,2, 26,9±0,2 and 29.0±0.2 degrees 2θ;
sample of the crystalline hydrate of (S)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray are essentially as shown in Figure 20;
pattern D hydrate crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 6,6±0,2, 10,0±0,2, 10,5±0,2, 11,1±0,2, 11,6±0,2, 12,2±0,2, 14,2±0,2, 16,6±0,2, 17,1±0,2, 17,7±0,2, 18,5±0,2, 18,8±0,2, 19,3±0,2, 21,4±0,2, 22,7±0,2, 23,1±0,2, 23,6±0,2, 24,6±0,2, 25,2±0,2, 27,2±0,2, 29,1±0,2 and 31.0±0.2 degrees 2θ;
pattern D hydrate crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 6,6±0,2, 10,0±0,2, 10,5±0,2, 11,1±0,2, 11,6±0,2, 12,2±0,2, 12,5±0,2, 14,2±0,2, 16,6±0,2, 17,1±0,2, 17,7±0,2, 18,5±0,2, 18,8±0,2, 19,3±0,2, 21,4±0,2, 22,7±0,2, 22,8±0,2, 23,1±0,2, 23,6±0,2, 24,6±0,2, 24,9±0,2, 25,2±0,2, 27,2±0,2, 29,1±0,2 and 1.0±0.2 degrees 2θ;
pattern D hydrate crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray are essentially presented in Figure 22;
sample D crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide, having unit cell parameters, where a is equal to 17.8 Å, b is equal to 9.6 Å and equal to 27.0 Å;
sample E, hydrate, crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 6,2±0,2, 7,8±0,2, 10,2±0,2, 10,7±0,2, 12,1±0,2, 16,3±0,2, 19,7±0,2, 20,9±0,2, 21,8±0,2, 24,5±0,2 and 28.0±0.2 degrees 2θ;
sample E, hydrate, crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 6,2±0,2, 7,8±0,2, 10,2±0,2, 10,4±0,2, 10,7±0,2, 12,1±0,2, 16,3±0,2, 19,7±0,2, 20,9±0,2, 21,8±0,2, 24,5±0,2 and 28.0±0.2 degrees 2θ;
sample E, hydrate, crystalline (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide having a powder x-ray are essentially presented in Figure 23; and
sample E hydrate crystallic the sky (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide, with the unit cell parameters, where a is equal to 9.5 Å, b is equal to 14.5 Å and equal to 17.3 Å.

24. Pharmaceutical composition having the properties of an inhibitor of HCV polymerase, containing a therapeutically effective amount of one or more compounds and/or their pharmaceutically acceptable salts according to any one of paragraphs.1-23;
and one or more fillers.

25. Pharmaceutical composition having the properties of an inhibitor of HCV polymerase, containing a therapeutically effective amount of one or more compounds and/or their pharmaceutically acceptable salts according to any one of paragraphs.1-23, optional therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of agent interferon, ribavirin and HCV inhibitor; and one or more fillers.

26. Pharmaceutical composition having the properties of an inhibitor of HCV polymerase, containing a therapeutically effective amount of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide or its pharmaceutically acceptable salt and one or more fillers.

27. Pharmaceutical composition having the properties of an inhibitor of HCV polymerase, containing a therapeutically effective amount of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenylmethanesulfonyl or its pharmaceutically acceptable salt, optional therapeutically effective amount of one or more additional therapeutic agents selected from the group consisting of agent interferon, ribavirin and HCV inhibitor; and one or more fillers.

28. The application of one or more compounds and/or their pharmaceutically acceptable salts according to any one of paragraphs.1-23 for the manufacture of a medicine for inhibiting RNA polymerase of HCV.

29. The application of one or more compounds and/or their pharmaceutically acceptable salts according to any one of paragraphs.1-23 for the manufacture of a medicinal product for the treatment of hepatitis C in a mammal in need of such treatment.

30. The application of one or more compounds and/or their pharmaceutically acceptable salts according to any one of paragraphs.1-23 for inhibition of RNA polymerase of HCV.

31. The application of one or more compounds and/or their pharmaceutically acceptable salts according to any one of paragraphs.1-23 for the treatment of hepatitis C in a mammal in need of such treatment.

32. The use of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide or its pharmaceutically acceptable salts for inhibiting RNA polymerase of HCV.

33. The use of (E)-N-(4-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxystyrene)phenyl)methanesulfonamide or its pharmaceutically acceptable salts for the treatment is of Apatite With mammals, those in need of such treatment.

34. One or more compounds and/or pharmaceutically acceptable salt according to any one of paragraphs.1-23 for the treatment of hepatitis C in a mammal in need of such treatment.

35. One or more compounds and/or pharmaceutically acceptable salt according to any one of paragraphs.1-23, and optionally, one or more additional therapeutic agents selected from the group consisting of agent interferon, ribavirin and HCV inhibitor, for the treatment of hepatitis C in a mammal in need of such treatment.

36. The method of obtaining the compound or its pharmaceutically acceptable salt according to p. 1, where the method includes the interaction of the compounds of formula III with the compound of the formula IV in the presence of (i) catalyst salt of copper (I) and (ii) nitrogen-containing heteroaryl ligand

with the subsequent receipt of the compounds of formula I from the compounds of formula II by replacing X2L-R6,
where R1, R2, R3, R4and R5defined in paragraph 1 and X1and X2each independently represents halo.

37. The method according to p. 36, where the method is carried out in the presence of a base.

38. The method according to p. 37, in which the base is selected from the group consisting of salts of potassium, sodium and cesium salt.

39. The method according to p. 36, in which nitrogen-containing heteroaryl ligand content is t picolinamides connection, corresponding in structure to formula V:
and
where R11, R12, R13, R14, R15, R16and R17independently selected from the group consisting of hydrogen, C1-4-perfluoroalkyl, C1-4-alkyloxy, C1-4-haloalkyl, chlorine and cyano.

40. The method according to p. 36, in which nitrogen-containing heteroaryl ligand selected from the group consisting of 8-hydroxyquinoline solution, 2-(2-pyridyl)-benzimidazole, N-(4-cyano-phenyl)picolinamides and N-(2-cyanophenyl)picolinamides.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (Ip1) or (Ip3) or its pharmaceutically acceptable salt, where G1 represents (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)halogenalkyl, (C1-C4)halogenalkoxy, halogen, cyano or nitro; n equals 0; G2a represents (C3-C4)cycloalkyl or (C3-C4)cycloalkyl(C1-C2)alkyl; G2b represents hydrogen; R1 represents methyl or ethyl; R2 represents phenyl or fluorophenyl; and R3 represents 2-hydroxy-2-methylpropyl or 2-methyl-2-cyanopropyl.

EFFECT: invention relates to application of compound of formula (Ip1 and Ip3) for manufacturing medication or pharmaceutical composition, intended for treating a person with disease or state, selected from type II diabetes mellitus, obesity, glucose intolerance, hyperglycemias, hyperlipidemis, insulin resistance, decrease of cognitive functions and dyslipidemia.

5 cl, 6 tbl, 107 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrimidine derivatives of structural formula (I-L0) and their crystalline forms possessing the inhibitory activity on the hepatitis C virus (HCV) polymerase. In formula is specified in a single or double carbon-carbon bond; R1, R2 and R3 represent hydrogen; R4 is specified in halo, C1-C6alkyl, C2-C6alkinyl, amino, C1-C6alkylsulphonyl, C3-C10carbocyclyl and 5-6-merous heterocyclyl having a heteroatom specified in a group consisting of O and S, wherein amino is optionally substituted by one or two C1-C6alkylsulphonyls, and C1-C6alkyl and C2-C6alkynyl are optionally substituted by one or more substitutes optionally specified in a group consisting of halo, oxo, hydroxy, C1-C6alkyloxy and trimethylsilyl, and C3-C10carbocyclyl and 5-6-merous heterocyclyl are optionally substituted by substitutes specified in C1-C6alkyl, halo and amino, wherein amino is optionally substituted by one or two C1-C6alkylsulphonyls; R5 is specified in a group consisting of hydrogen, hydroxy, C1-C6alkyloxy and halo; R6 represents a condensed 2-ring C3-C10carbocyclyl optionally substituted by substitutes specified in RE, RF, RG, RH, RI, RJ and RK, the values of which are specified in the patent claim.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, to using the compounds for producing a therapeutic agent for hepatitis C, to an intermediate compound for producing the compound of structural formula (I-L0) and to a method for preparing the above compounds and their crystalline forms.

70 cl, 23 dwg, 9 tbl, 83 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, namely to a new compound of formula or its pharmaceutically acceptable salt, wherein R1 represents (C1-C6)alkyl; an oxodihydropyridyl ring in the formula is optionally substituted by 1-3 groups optionally specified in fluorine, (C1-C6)alkyl, hydroxy(C1-C6)alkyl, (C3-C6)cycloalkyl, (C4-C7)cycloalkylalkyl, halo(C1-C6)alkyl and (C1-C6)alkoxy(C1-C6)alkoxy; R2 represents (C1-C6)alkyl, phenyl, or tetrahydropyranyl optionally substituted by a group in the number of up to 1 independently specified in fluorine, hydroxy(C1-C6)alkyl and (C3-C6)cycloalkyl; R3 is specified in (C1-C6)alkyl optionally substituted by groups in the number of up to 3 independently specified in fluorine, cyano, R4, R4O-, (R4)2N-, R4C(=O)NR4-, (R4)2NC(=O)-, R4OC(=O)NR4-, R4S(=O)2NR4- and oxadiazolyl optionally substituted by (C1-C6)alkyl; R4 independently represents H or (C1-C6)alkyl. Also, the invention refers to a method of treating an individual by using the above compound, a method of inhibiting 11β-HSD1, and a compound-based pharmaceutical composition.

EFFECT: there are prepared new compounds effective in treating the diseases related to 11β-HSD1 activity or expression.

15 cl, 6 tbl, 101 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to new phenylpyrimidone derivatives of formula I possessing the properties of a phosphodiesterase type 5 (PDE5) inhibitor. The compounds of formula I can be used for treating various vascular disorders, such as erectile dysfunction, pulmonary arterial hypertension, etc. In formula each R1 and R2 independently means H; C1-C10alkyl; halogen; CF3; CN; OR5; NR6R7; NHCOR8; aryl; or C1-C4alkyl optionally substituted by OR5; Z means OR3; R3 means C1-C6alkyl or C1-C3alkyl, substituted by C1-C3alkoxy group; R4 means SO2NR6R7; NR9R10, providing NR9R10 is other than NH2; COR11; OR12; or R4 means 5-6-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of OH and C1-C6 alkyl; or R4 means 5- or 6-merous cyclic monosaccharide group; R5 means C1-C6alkyl; C1-C4alkyl optionally substituted by C1-C4alkoxy group; each R6 and R7 independently means H, OH, C1-C6alkyl, C1-C6alkoxy group, C3-C6alkenyl, C3-C6cycloalkyl, adamantyl, C3-C8lactamyl, aryl, Het or (CH2CH2O)jH, wherein j is 1-3; or each R6 and R7 independently means C1-C6alkyl, optionally substituted by OH, C1-C4alkoxy group, SO3H, SO2NR13R14, SO2R16, NR13R14, aryl, Het or 5-6-merous heterocyclyl; or each R6 and R7 independently means 5-6-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of C1-C6 alkyl and C1-C6alkyl substituted by hydroxyl; or R6 and R7 together with a nitrogen atom attached whereto form 5-7-merous heterocyclyl optionally substituted by one or more substitutes specified in a group consisting of OH, COOR8, (CH2CH2O)jH, wherein j is 1-3, C1-C4alkoxy group, Het and C1-C6alkyl substituted by aryl; or R6 and R7 together with a nitrogen atom attached whereto form a glucosyl amino group, an amino acid residue, a residue of an amino acid ester or an amino amide residue. The other radical values are specified in the patent claim.

EFFECT: invention refers to pharmaceutical compositions based on the above compounds, using them, methods for preparing the compounds, and intermediate products.

18 cl, 2 tbl, 224 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel 4-substituted-N-phenyl-1,8-naphthalimides which contain in the N-aryl nucleus a crown ether residue (with a different combination of oxygen, nitrogen and sulphur atoms) of general formula (I) , where R1=NO2, Br, NH2, OCH3, NHCOCH3, Ia: Rl=NO2, X=S, n=1; Ib: R1=NO2, x=NCH3, n=1; Ic: R1=NO2, X=NCH3, n=2; Id: R1=Br, X=NCH3, n=2; Ie: R1=NH2, X=S, n=1; If: R1=NHCOCH3, X=S, n=1; Ig: R1=OMe, X=S, n=1; Ih: R1=OMe, X=NCH3, n=1; Ii: R1=OMe, X=NCH3, n=2, where compounds If-Ii exhibit properties of fluorescent sensors on cations of alkali-earth, transition and heavy metals, and compounds Ia-Ie are intermediate compounds in the process of synthesis of compounds If-Ii. The invention also relates to a method of producing a compound of formula (I) and intermediate compounds of formula (II)

EFFECT: obtaining novel sensors on cations of alkali-earth, transition and heavy metals, novel methods of producing compounds of the given formula.

7 cl, 3 tbl, 7 ex

Cetp inhibitors // 2513107

FIELD: chemistry.

SUBSTANCE: invention relates to compound of formula I, or its pharmaceutically acceptable salt where: X stands for -O-; Z stands for -C(=O)-; Y stands for -(CRR1)-, where R1 is selected from -C1-C2alkyl; R stands for H or -C1-C5alkyl; R5 stands for H; R2 and B each is selected from A1 and A2, where one of R2 and B stands for A1, and the other from R2 and B stands for A2; where A1 has structure (a); A2 is selected from the group, which includes phenyl, pyridyl, pyrazolyl, thienyl, 1,2,4-triazolyl and imodazolyl; A3 is selected from the group including phenyl, thiazolyl and pyrazolyl; A4 is selected from the group, including phenyl, pyridyl, thiazolyl, pyrazolyl, 1,2,4-triazolyl, pyrimidinyl, piperidinyl, pyrrolidinyl and asetidinyl; A2 is optionally substituted with 1-3 substituents, independently selected from halogen atom, -OCH3 and -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A3 is substituted with one A4 group and is optionally substituted with 1-2 substituents, independently selected from halogen atom, -OH, -OCH3, -OCF3 and -C1-C3alkyl, optionally substituted with 1-3 halogen atoms; A4 is optionally substituted with 1-3 substituents, independently selected from the group, which includes: (a) -C1-C5alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with group -OH, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) halogen atom, (j) -CN, (k) -NO2, (l) -C(=O)NR3R4, (m) -OC1-C2alkyleneOC1-C2alkyl, (n) -OC1-C3alkyl, optionally substituted with 1-3 halogen atoms, (o) -C(=O)OC1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (q) -NR3R4 and (r) -S(O)xNR3R4, on condition that A4 stands for heterocyclic group, attached to A3 by means of ring carbon atom in A4, at least, one substituent in A4 must be selected from Re, where Re is selected from the group including: (a) -C1-C5alkyl, substituted with -OH group and optionally substituted with 1-3 halogen atoms, (b) -C2-C4alkenyl, optionally substituted with 1-3 halogen atoms, (c) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group selected from -OH, -CO2CH3, -C(=O)CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (d) -C(=O)H, (e) -CO2H, (f) -CO2C1-C4alkyl, optionally substituted with one group, selected from -C(=O)C1-C2alkyl, -OH, -CO2CH3, -CO2H, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (g) -OH, (h) -S(O)xC1-C2alkyl, (i) -CN, (j) -NO2, (k) -C(=O)NR3R4, (l) -OC1-C2alkyleneOC1-C2alkyl, (m) -C(=O)C1-C2alkyl, optionally substituted with 1-3 halogen atoms and optionally substituted with one group, selected from -OH, -CO2CH3, -NR3R4 and -OC1-C2alkyleneOC1-C2alkyl, (n) -NR3R4(=O)OC1-C2alkyl, (o) -NR3R4 and (p) -S(O)xNR3R4; p equals 0, 1 or 2; and Ra is selected from halogen atom, -CH3, -CF3, -OCH3 and -OCF3; R3 and R4 each is independently selected from H and CH3; and x equals 0, 1 or 2.

EFFECT: formula (I) compound is applied for medication, which possesses properties of CETP inhibitor, for increase of HDL-C and for reduction of LDL-C Technical result is compounds, inhibiting cholesterol ether transferring protein (CETP).

10 cl, 140 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an amide derivative of formula (I), where A is benzene or pyridine, where the benzene or pyridine optionally contain 1 or 2 or 3 identical or different substitutes selected from an alkyl containing 1-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, an alkoxy containing 1-6 carbon atoms, a halogen atom, nitro, cyano, alkylsulphonyl containing1-6 carbon atoms, amino, cyclic amine selected from 1,1-di-oxoisothiazolidinyl, 2-oxooxazolidinyl, oxopyrrolidinyl, 1,1-dioxothiazinyl and 2-oxoimidazolidinyl optionally having a substitute selected from an alkyl containing 1-6 carbon atoms and an alkylcarbonyl containing a total of 2-7 carbon atoms, acylamino containing a total of 2-7 carbon atoms, and an alkylsulphonyl amino containing 1-6 carbon atoms, wherein the right-side bond is linked to the carbonyl and the left-side bond is linked to the nitrogen atom, R1 and R2 are identical or different and each is a hydrogen, an alkyl containing 1-6 carbon atoms and optionally containing 3 halogen atoms as substitutes, a cycloalkyl containing 3-6 carbon atoms, a phenyl, a halogen atom or a cyano group and R1 and R2 are not a hydrogen atom at the same time, R3 is a hydrogen atom, an alkyl containing 1-6 carbon atoms, an alkenyl containing 2-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, or a halogen, R4a, R4b and R4c are each independently a hydrogen atom, an alkyl containing 1-6 carbon atoms, or an oxo, R5a, R5b and R5c are identical or different and each is a hydrogen atom, an alkyl containing 1-6 carbon atoms and optionally containing substitute(s) selected from phenyl, an alkoxy group containing 1-6 carbon atoms, optionally substituted with an alkoxy group containing 1-6 carbon atoms, a phyenylcarbonyloxy group and a hydroxy group, or a phenyl, X is a carbon atom (any of R4a, R4b and R4c can be bonded to a carbon atom, but the carbon atom is not substituted with oxo) or a nitrogen atom (if Y is a single bond, the nitrogen atom can be oxidised to form an N oxide), Y is a single bond, a carbonyl or an oxygen atom, Z1 and Z2 are each independently a carbon atom (substitute R3 is optionally bonded to a carbon atom) or a nitrogen atom, and m equals 1 or 2, a pharmacologically acceptable salt thereof. The amide derivative is used as a preventive/therapeutic drug for treating autoimmune diseases, inflammatory bowel diseases or osteoarthritis.

EFFECT: amide derivative which suppresses production of inductive type MMP-9.

14 cl, 4 tbl, 581 ex

FIELD: chemistry.

SUBSTANCE: invention describes novel azabiphenylaminobenzoic acid derivatives, having the chemical formula: , where R1 is selected from a group consisting of hydrogen atoms, halogen atoms, C1-4-alkyl, C3-4-cycloalkyl and -CF3, R2 is selected from a group consisting of hydrogen atoms, halogen atoms and C1-4-alkyl group, R3 is -COOR5, where R5 is selected from a group consisting of a hydrogen atom and linear or branched C1-4-alkyl groups, R4 is selected from a group consisting of a hydrogen atom and C1-4-alkyl group; R9 is selected from a group consisting of a hydrogen atom and a phenyl group, G1 is a group selected from N and CR6, where R6 is selected from a group consisting of hydrogen atoms, halogen atoms, C1-4-alkyl, C3-4-cycloalkyl, -CP3 and C6-10-aryl group, G2 is a group selected from: - a hydrogen atom, hydroxy group, halogen atom, C3-4-cycloalkyl group, C1-4-alkoxy group and -NRaRb, where Ra is C1-4-alkyl group and Rb is selected from a group consisting of C1-4-alkyl group and C1-4-alkoxy-C1-4-alkyl group, or Ra and Rb together with the nitrogen atom with which they are bonded, form a saturated 6-8-member heterocyclic ring optionally containing one oxygen atom as an additional heteroatom, -monocyclic or bicyclic 5-10-member heteroatomatic ring containing one or more nitrogen atoms which are optionally substituted with one or more halogen atoms, and a phenyl group which is optionally substituted with one or more substitutes selected from halogen atoms, C1-4-alkyl, hydroxy group, C1-4-alkoxy group, C3-4-cycloalkyl, C3-4-cycloalkoxy group, cyano group, -CF3, -OCF3, -CONR7R8, oxadiazolyl, and where R7 and R8 are independently selected from a hydrogen atom, a linear or branched C1-4-alkyl group, C3-7-cycloalkyl group, or R7 and R8 together with a nitrogen atom with which they are bonded form a group of formula: , where n equals 0-3; or G2 together with R6 form a non-aromatic C5-10-carbocyclic group or a C6-10-aryl group, and pharmaceutically acceptable and N oxides thereof. Also described are pharmaceutical compositions containing said compounds and use thereof in treatment as dehydroorotate dehydrogenase (DHODH) inhibitors.

EFFECT: novel compounds which can be used as dehydroorotate dehydrogenase inhibitors are obtained and described.

30 cl, 118 ex

FIELD: chemistry.

SUBSTANCE: invention relates to bicyclosulphonyl acid (BCSA) compounds of formula: where: where each of -Rpw, -Rpx, -RPY, and -RPZ independently denotes H or -RRS1; each -RRS1 independently denotes -F, -Cl, -Br, -I, -RA1, -CF3, -OH, -OCF3 or -ORA1; where each RA1 independently denotes C1-4alkyl, phenyl or benzyl; and additionally, two neighbouring -RRS1 groups can together form -OCH2O-, -OCH2CH2O- or -OCH2CH2CH2O-; -RAK independently denotes a covalent bond, -(CH2)- or -(CH2)2-; -RN independently denotes -RNNN, or -LN-RNNN; the rest of the values of the radicals are given in claim 1, which act as inhibitors of inhibitors of tumor necrosis factor-α converting enzyme (TACE).

EFFECT: compounds are useful in treating TNF-α mediated conditions.

36 cl, 303 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrimidine derivatives of structural formula (I-L0) and their crystalline forms possessing the inhibitory activity on the hepatitis C virus (HCV) polymerase. In formula is specified in a single or double carbon-carbon bond; R1, R2 and R3 represent hydrogen; R4 is specified in halo, C1-C6alkyl, C2-C6alkinyl, amino, C1-C6alkylsulphonyl, C3-C10carbocyclyl and 5-6-merous heterocyclyl having a heteroatom specified in a group consisting of O and S, wherein amino is optionally substituted by one or two C1-C6alkylsulphonyls, and C1-C6alkyl and C2-C6alkynyl are optionally substituted by one or more substitutes optionally specified in a group consisting of halo, oxo, hydroxy, C1-C6alkyloxy and trimethylsilyl, and C3-C10carbocyclyl and 5-6-merous heterocyclyl are optionally substituted by substitutes specified in C1-C6alkyl, halo and amino, wherein amino is optionally substituted by one or two C1-C6alkylsulphonyls; R5 is specified in a group consisting of hydrogen, hydroxy, C1-C6alkyloxy and halo; R6 represents a condensed 2-ring C3-C10carbocyclyl optionally substituted by substitutes specified in RE, RF, RG, RH, RI, RJ and RK, the values of which are specified in the patent claim.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, to using the compounds for producing a therapeutic agent for hepatitis C, to an intermediate compound for producing the compound of structural formula (I-L0) and to a method for preparing the above compounds and their crystalline forms.

70 cl, 23 dwg, 9 tbl, 83 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing 5,5'-(2,3,7,8-bis-(9H,10H-anthracene-9,10-diiyl)pyrene-1,6-diiyl)bis(2-dodecylthiophene), which includes reacting 1,6-dibromopyrene with 2-dodecyl-5-tributylstannyl thiophene by a Stille method to obtain a first intermediate product 1,6-bis(5-dodecylthiophen-2-yl)pyrene, bromation of the latter to obtain a second intermediate product 5,5'-(3,8-dibromopyrene-1,6-diiyl)bis(2-dodecylthiophene), heating said product with anthracene and sodium amide in an argon atmosphere.

EFFECT: novel method for synthesis of a derivative of hexane-substituted pyrene using a Stille cross-coupling reaction and highly reactive arine intermediates, which ultimately results in synthetic availability of derivatives of hexane-substituted pyrene, which can be used in scientific research laboratories, as well at home and in agriculture as a monomolecular optical sensor for detecting nitroaromatic compounds.

2 dwg, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a method of controlling infection of useful plants with phytopathogenic microorganisms or prevention thereof, wherein a compound of formula I or a composition thereof, which contains said compound as an active ingredient, is deposited on plants, on a parts thereof or place where said plants grow, where the compound of formula I is substitutes are as defined in claim 1.

EFFECT: obtaining a compound for controlling infection of useful plants with phytopathogenic microorganisms.

26 cl, 2 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formulas I, II, III, IV, V, VIII or to their pharmaceutically acceptable salts, wherein: Z represents , or phenyl; D represents or ; X represents N(R9), O, S, S(=O) or S(O)2; each Y independently represents O or S; G represents or ; the other radical values are described in the patent claim. The invention also refers to pharmaceutical compositions based on the above compounds.

EFFECT: there are prepared new compounds and based compositions which can find application for treating malaria or eliminating or inhibiting the growth of Plasmodium species.

30 cl, 3 tbl, 23 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula (I) , where is a substituted 5-member heteroaryl ring selected from thienyl, thiazolyl, oxazolyl, pyrrolyl, imidazolyl or pyrazolyl, W is selected from a group comprising N and -C=; M is selected from a group comprising -C(O)N(R1)OR2, -CXCONR1R2 and -C(O)OR1, or M is -C1-C2alkyl-C(O)N(R1)OR2, wherein is , R1 and R2 are independently selected from a group comprising -H, C1-C3-alkyl, C6-aryl, and C1-C3-alkyl-C6-aryl; R is selected from a group comprising H, C1-C3alkyl, halogen, NR1R2, -OR1 and C6aryl; n is an integer from 0 to 1; L and Y are as indicated in the claim; and to compounds of formula (II) , where L2 is selected from a group comprising H, - C0-C3alkyl- C6aryl, -C0-C3alkyl-heteroaryl, where the heteroaryl is pyridyl; -C1-C6alkyl, Y and M are the same as for compounds of formula (I). The invention also relates to a pharmaceutical composition based on compounds (I) and (II), having inhibiting action on histone deacetylase (HDAC), a method of inhibiting and a method of treating a disease which is sensitive to the HDAC inhibitor.

EFFECT: compounds of formula I and II as histone deacetylase inhibitors.

18 cl, 18 dwg, 10 tbl, 19 ex

FIELD: chemistry.

SUBSTANCE: invention describes compounds of formula I , where R1 and R2 independently denote hydrogen, C3-C7cycloalkyl, C1-C6alkyl, C2-C6alkynyl, hydrogen or pyridine; or R1 and R2 together with a nitrogen atom which binds them form a pyrroline group; R3 denotes hydrogen, C1-C6halogenalkyl, C1-C6alkyl, halogen, cyano group, nitro group, C1-C4alkoxy group, phenyl, halogen-substituted phenyl, (R51)(R52)(R53)Si-(C2-C6alkynyl)-, where R51, R52, R53 independently denote halogen, cyano group, C1-C6alkyl, C2-C6alkenyl, C3-C8cycloalkyl, C5-C8cycloalkenyl, C2-C6alkynyl, C1-C6alkoxy group, benzyl or phenyl; R4 denotes hydrogen, halogen, phenyl, imidazolyl, amino group, C1-C6alkoxy group or C1-C6alkyl; R5 denotes C1-C12alkyl or a group A, where A denotes a 3-10-member monocyclic or condensed bicyclic ring system which can be aromatic, partially unsaturated or completely saturated, where said 3-10-member ring system can be mono- or polysubstituted with substitutes independently selected from a group comprising halogen, C1-C6alkyl, C1-C6halogenalkyl, C1-C6alkoxy group and C1-C6alkylthio group; R6 denotes hydrogen; and R7 denotes hydrogen or C1-C6alkyl and agronomically acceptable salts/metal complexes/metalloid complexes/isomers/structural isomers/stereoisomers. The invention also relates to methods of controlling infection of useful plants by phytopathogenic microorganisms by applying a compound of formula I onto the plants, a part thereof or place where said plants grow, as well as a composition for controlling infection by phytopathogenic microorganisms.

EFFECT: novel compounds which are suitable for use as microbiocides are obtained and described.

7 cl, 48 ex, 151 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula

and

possessing the protein kinase inhibitor property, their pharmaceutically acceptable salts, solvates and hydrates, as well as to the use thereof and a based pharmaceutical composition. In general formula (1) X1 represents N, CRt1; X2 represents N, CRt2, X3 represents N, CRt3, X4 represents N, CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H, halogen, -COOH, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, -CH3OH; Rt2 represents -H, halogen, -CH3, -CH2CH3, -OH, -OCH3, -OCH2CH3, -CN, CH2OH, -NH2; Rt3 represents -H, -S(O)rR4, halogen, -CN, -COOH, -CONH2, -COOCH3, -COOCH2CH3; the cycle A represents phenyl or a 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R'; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle, wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb; Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5, -NR4SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -O-, -S-, -NR3-; L1 represents NR3C(O) or C(O)NR3; R3, R4 and R5 are independently specified and represent H, C1-C6-alkyl, and also the group NR4 R5 may represent a 5- or 6-member saturated or aromatic cycle; in each case R6 is independently specified and represents C1-C6-alkyl optionally substituted by C1-C6- alkyl or 5-6 merous heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; In general formula (II) Z represents CH; X, represents CRt1; X2 represents CRt2, X3 represents CRt3 X4 represents CH and wherein X1, X2, X3 and X4 are independently specified; Rt1 represents -H; Rt2 represents -H, -F; Rt3 represents -H, -F; the cycle A represents phenyl or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N optionally substituted by 1-4 groups R3; the cycle B represents phenyl or a 5- or 6-member heteroaryl cycle wherein heteroaryl contains 1-2 heteroatoms specified in N, S optionally substituted by 1-5 groups Rb, Ra and Rb are independently specified and represent -H, halogen, -CN, -R6, -OR4, -NR4R5, -C(O)YR4, -S(O)rR4, -SO2NR4R5 wherein Y is independently specified and represents a chemical bond, -NR3-; L represents NR3C(O) or C(O)NR3; R4 and R5 are independently specified and represent H, C1-C6-alkyl, also the group NR4R3 may represent a 6-member saturated cycle; in each case R6 is independently specified and represents, C1-C6-alkyl optionally substituted by C1-C6-alkyl or 5-6 member heterocyclyl which may be substituted by C1-C6-alkyl; r is equal to 0; m is equal to 1; p is equal to 1.2.

EFFECT: preparing the compounds possessing the protein kinase inhibitor property.

16 cl, 5 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there are described new benzimidazole derivatives of general formula I wherein: R1 = CN, halogen or C(=O)CH3; R2 means methyl or H; R3=H or halogen; R4 and R5 independently mean methyl or ethyl, or R4 and R5 together with a carbon atom whereto attached form C3-6cycloalkyl or 5-6-member heterocycloalkyl; R6 and R7 independently mean H, halogen, methyl or ethyl; or their pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds, and their application in therapy.

EFFECT: compounds may be used in treating osteoarthritis, chronic tendinitis, pelvic pain and peripheral neuropathy, gastroesophageal reflux disease, irritable bowel syndrome and overactive bladder.

39 cl, 34 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel azoles of general formula 1A and 1B and pharmaceutically acceptable salts thereof, having activity on hepatitis C and hepatitis GBV-C virus. Said compounds have NS5A viral protein ligand properties and can be used as active components for a pharmaceutical composition and a medicinal agent for treating diseases caused by said viruses. In general formula 1A and 1B, the solid lines accompanied by dotted lines denote a single or double bond, wherein if one of them is a single bond, the other is a double bond; X and Y optionally assume different values and denote a nitrogen, oxygen or sulphur atom or a NH group; R1 and R2 optionally denote identical radicals 2.1-2.20, in which the asterisk (*) indicates site of the bond to azole fragments. Said fragments and values of A and B are given in the claim.

EFFECT: more value of the compounds.

10 cl, 1 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyrimidine derivatives of structural formula (I-L0) and their crystalline forms possessing the inhibitory activity on the hepatitis C virus (HCV) polymerase. In formula is specified in a single or double carbon-carbon bond; R1, R2 and R3 represent hydrogen; R4 is specified in halo, C1-C6alkyl, C2-C6alkinyl, amino, C1-C6alkylsulphonyl, C3-C10carbocyclyl and 5-6-merous heterocyclyl having a heteroatom specified in a group consisting of O and S, wherein amino is optionally substituted by one or two C1-C6alkylsulphonyls, and C1-C6alkyl and C2-C6alkynyl are optionally substituted by one or more substitutes optionally specified in a group consisting of halo, oxo, hydroxy, C1-C6alkyloxy and trimethylsilyl, and C3-C10carbocyclyl and 5-6-merous heterocyclyl are optionally substituted by substitutes specified in C1-C6alkyl, halo and amino, wherein amino is optionally substituted by one or two C1-C6alkylsulphonyls; R5 is specified in a group consisting of hydrogen, hydroxy, C1-C6alkyloxy and halo; R6 represents a condensed 2-ring C3-C10carbocyclyl optionally substituted by substitutes specified in RE, RF, RG, RH, RI, RJ and RK, the values of which are specified in the patent claim.

EFFECT: invention refers to a pharmaceutical composition containing the above compounds, to using the compounds for producing a therapeutic agent for hepatitis C, to an intermediate compound for producing the compound of structural formula (I-L0) and to a method for preparing the above compounds and their crystalline forms.

70 cl, 23 dwg, 9 tbl, 83 ex

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