Pyrimidines applicable as anti-infectious agents, and applications thereof

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

 

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

[0001] this patent application claims the priority of provisional patent application U.S. No. 60/972881 (filed September 17, 2007), and provisional patent application U.S. No. 61/096792 (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 I have are 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 not Sawada 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, indicating 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 formula I-L0:

.

[0010] In the formula (I-L0:

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 status is the present of 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;

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;

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 and the 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, alkenylcarbazoles, 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;

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, alkenylcarbazoles, 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 independently selected from the group consisting of carboxy, hydroxy, halo, amino, nitro, azido, oxo, aminosulfonyl, allyloxycarbonyl, alkenylcarbazoles, 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 R Iindependently 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, alkenylcarbazoles, 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;

each RJindependently selected from the group consisting of carbocyclization, heterocyclization, alkylcarboxylic, alkenylamine, alkylcarboxylic, allyloxycarbonyl, alkanolammonium, alkyloxycarboxylic, alcalali is ylamino, 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 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, Hydra is XI, 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 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, alkenylcarbazoles, alkyloxyaryl, alkylcarboxylic, alkenylboronic, alkylcarboxylic, alkyloxy, alkenylacyl, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarb the Nile, 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 also relates to kits that 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 image is eenie 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 ethanol MES compound IB-L0-2.3.

[0018] Figure 2 shows an illustrative TGA profile of ethanol MES compound IB-L0-2.3.

[0019] Figure 3 shows an illustrative x-ray powder diffraction for the combined acetonitrile MES compound IB-L0-2.3.

[0020] Figure 4 shows an illustrative x-ray powder diffraction for an ethyl acetate of MES compound IB-L0-2.3.

[0021] Figure 5 shows an illustrative x-ray powder diffraction 2-propanole of MES compound IB-L0-2.3.

[0022] Figure 6 shows an illustrative x-ray powder diffraction for methanol MES compound IB-L0-2.3.

[0023] Figure 7 shows an illustrative x-ray powder diffraction for 1-propanole of MES compound IB-L0-2.3.

[0024] Figure 8 on the show illustrative x-ray powder diffraction for crystalline compound IB-L0-2.3, free of solvent.

[0025] Figure 9 shows an illustrative x-ray powder diffraction for the hydrate of compound IB-L0-2.3.

[0026] Figure 10 shows an illustrative x-ray powder diffraction for the sample And the monosodium salt of compound IB-L0-2.3.

[0027] Figure 11 shows an illustrative TGA profile of the sample And the monosodium salt of compound IB-L0-2.3.

[0028] Figure 12 shows an illustrative x-ray powder diffraction for the sample In the monosodium salt of compound IB-L0-2.3.

[0029] Figure 13 shows an illustrative TGA profile of the sample In the monosodium salt of compound IB-L0-2.3.

[0030] Figure 14 shows an illustrative x-ray powder diffraction for the sample With the monosodium salt of compound IB-L0-2.3.

[0031] Figure 15 shows an illustrative x-ray powder diffraction for the disodium salt of compound IB-L0-2.3.

[0032] Figure 16 shows an illustrative TGA profile disodium salt of compound IB-L0-2.3.

[0033] Figure 17 shows an illustrative x-ray powder diffraction for montalieu salt of compound IB-L0-2.3.

[0034] Figure 18 shows an illustrative TGA profile montalieu salt of compound IB-L0-2.3.

[0035] Figure 19 shows an illustrative x-ray powder diffraction the sample And monjolinho salt of compound IB-L0-2.3.

[0036] Figure 20 shows an illustrative TGA profile of the sample And monjolinho salt of compound IB-L0-2.3.

[0037] Figure 21 shows an illustrative x-ray powder diffraction for the sample In monjolinho salt of compound IB-L0-2.3.

[0038] Figure 22 shows an illustrative TGA profile of the sample In monjolinho salt of compound IB-L0-2.3.

[0039] Figure 23 shows an illustrative x-ray powder diffraction for cihalikova salt of compound IB-L0-2.3.

DETAILED description of the INVENTION

[0040] the Present detailed description is intended only to familiarize the experts with Applicants invention, 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 from PR is my or branched chain, usually containing from 1 to 20 carbon atoms, more usually from about 1 to 8 carbon atoms, and still more usually from 1 to about 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" (alone or 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 still 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 usually from about 2 to 20 carbon atoms is kind, more usually from about 2 to about 8 carbon atoms, and still 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 usually contains 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 the AET 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 y is the 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 the N.

[0049] the Term is 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 (terms)) 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. Also what about the, the sulfur atom in 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 with two fluorine radicals. 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. Still the way 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 2 is not hydrogen radicals, whereas 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. Should be a paragraph is clear, what 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, replaced 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. PR is the measure of such a substituent include methoxy (-O-CH 3), ethoxy, n-propoxy, isopropoxy, n-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 "allocatable" (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 another term (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-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 another term (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 sludge is sulfur), the rest of the ring atoms is 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 significant 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, thiazolyl, 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,triazinyl (including 1,3,5-triazinyl, 1,2,4-Tr is azinil 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-oxadiazolyl, 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 condensed 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 courtesans who were cilil 2-condensed rings" (alone or in combination with another term (terms)) means a saturated, partially saturated or arylheteroacetic 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, benzothiazolyl, benzoxazolyl 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, benzothiazole, purines and antron is poured; 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 component. 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 others is Gogo, Deputy (deputies).

[0090] In cases where for describing Deputy 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, 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 mean that each the second 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" in relation to the connection relates 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. When conducting x-ray diffraction, non-crystalline compound does not have any characteristic crystalline peaks.

[0096] the Term "crystalline form" as applied to the connection relates to a solid state in which molecules connections are with the formation of distinguishable crystal lattice (i) containing distinct unit cell, and (ii) 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 "phase is pure" refers to a 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 partially refers to compounds, 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 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 embodiments, 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 implement the Oia, 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, bromide and iodine.

[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 bromide. 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, R3selected 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, R3pre is is a 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, 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 a heterocycle,

(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 Deputy and, 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 done what I 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 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 is, 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, alkenylacyl, 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 is a, and heterocyclyl, 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, alkyl, alkenyl, quinil, nitro, cyano, azido, alkyloxy, alkenylacyl, alkenylacyl, 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, alkenylacyl, amino, aminocarbonyl, aminosulfonyl, alkylsulfonyl, carbocycle and heterocycle where:

alkyl, alkenyl, quinil, alkyloxy, alkenylacyl, alkenylacyl, alkylsulfonyl, carbocyclic, and heterocyclic obazatelno substituted by substituents, 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.

[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 substituents, including the about 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-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.

[00138] In some the x variants of 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 substituents 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-C4of alkyl, C3-C6-carbocycle, and 5-6-membered heterocyclyl where:

(a)1-C4-alkyl optionally substituted by substituents, including the about 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-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.

[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 vari is ntah 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-C4-alkylsulfonyl,3-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 implementing the tvline, 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, phenyl, 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 implement the program, 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 such embodiments, 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, R4SEL is an 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, implementation, 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 the other is their exercise of such options, 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, 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, hydroxy, 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 of the s variants of implementation, R5represents methoxy.

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

B6. Deputy L.

[00166] L is a bond, and the structure of the compounds of formula I correspond to the formula I-L0:

.

[00167] In some such embodiments, the implementation, the structure of the compounds correspond to the following formula (i.e., formula IA-L0):

[00168] In other such embodiments, the implementation, the structure of the compounds correspond to the following formula (i.e., formula IB-L0):

.

V7. Deputy R6

[00169] In some embodiments, implementation, R6selected from the group consisting of 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.

[00170] In some such embodiments, the implementation of the fused 2-ring carbocyclic and condensed 2-ring heterocyclyl not substituted.

[00171] 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 Rsup> E, RF, RG, RH, RI, RJand RK. In some 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, RI, RJand RK. 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, RFand RJ. 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 RFand RJ. In other such embodiments, the implementation of the fused 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted RJ.

[00172] 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 some such embodiments, the implementation of the fused 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted by two substituents, independently researched the performance of selected from the group consisting of RE, RF, 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, RFand RJ. 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 RFand RJ.

[00173] 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 some 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, RI, RJand RK. In other 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, RFand RJ. In dopolnitelnich options implementation condensed 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted with three substituents, independently selected from the group consisting of RFand RJ.

[00174] In additional such embodiments, the implementation of the fused 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. In some such embodiments, the implementation of the 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 other such embodiments, the implementation of the fused 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted one, two or three substituents, independently selected from the group consisting of RE, RFand RK. In other such embodiments, the implementation of the fused 2-ring carbocyclic and condensed 2-ring heterocyclyl substituted one, two or three substituents, independently selected from the group consisting of RFand RJ.

[00175] In some embodiments, implementation, R6performance, which provides a 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 carbocycles is not substituted. 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 the fused 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.

[00176] In some embodiments, implementation, R6represents a condensed 2-ring heterocy is poured, 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 heterocyclyl is unsubstituted. In other such embodiments, the implementation of 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 condensed 2-ring heterocyclyl replaced two zamestitelyami, independently selected from the group consisting of RE, RF, RG, RH, RI, RJand RK. In additional such embodiments, the implementation of 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 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.

[00177] In some of these embodiments, the optionally substituted condensed-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 2-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.

[00178] In some of these embodiments, the optionally substituted condensed 2-ring heterocyclyl selected from the group consisting of

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

X1X2and X3independently selected from the 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 (is);

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 (the rest) 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 Is 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 X78represents N(H), and the remaining represents C(H)2.

[00179] In some of these embodiments, the optionally substituted condensed 2-ring heterocyclyl selected from the group consisting of,,,,,,,,,,,,,,,, and.

[00180] In some of these embodiments, the optionally substituted condensed 2-ring heterocyclyl selected from the group consisting of:

,,,,,,,,,and.

[00181] In some of these embodiments, X1X2and X3represent C(H).

[00182] In some of these embodiments, X5X6and X7represent C(H).

[00183] In some of these embodiments, X10X11X12and X13represent C(H).

[00184] In some of these embodiments, X15X16X17and X18represent C(H).

[00185] In some of these embodiments, one of X19X20and X21represents N.

[00186] In some of these embodiments, one of X22X23X24and X25represents N.

[00187] In some of these embodiments, one of X26X27and X28represents N and one of X29X30X31and X32represents N.

[00188] In some of these embodiments, X40/sup> X41and X42represent C(H).

[00189] In some of these embodiments, X48X49X50and X51represent C(H).

[00190] In some of these embodiments, X52X53and X54represent C(H).

[00191] In some of these embodiments, X56X57and X58represent C(H).

[00192] In some of these embodiments, X61X62X63and X64represent C(H).

[00193] In some of these embodiments, X66X67X68and X69represent C(H).

[00194] In some of these embodiments, one or more of the X70X71and X72represents N, and the rest (the rest) is/are C(H).

[00195] In some of these embodiments, one or more of the X73X74X75and X76represents N, and the rest (the rest) is/are C(H).

B8. Deputy RE.

[00196] 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 mandated what teli, independently selected from the group consisting of alkyl, alkenyl and quinil.

[00197] 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.

[00198] In some embodiments, implementation, each REindependently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, amino, imino, aldehyde, alkylamino.

[00199] In some embodiments, implementation, each RFindependently selected from the group consisting of chlorine, fluorine, nitro, hydroxy, oxo, carboxy, amino, imino, aldehyde, alkylamino.

[00200] 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, assests the tion, 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.

[00201] In some embodiments, implementation, each REindependently selected from the group consisting of halo, nitro, hydroxy, oxo, carboxy, cyano, amino and imino.

B9. Deputy RF.

[00202] 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, alkenylcarbazoles, 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, alkyl is of sulfonylamino, hydroxy, alkyloxy where:

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

[00203] 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, azido, oxo, aminosulfonyl, alkylsulfonyl, allyloxycarbonyl, alkenylcarbazoles, 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.

[00204] In some of these embodiments, each RFindependently selected from the group consisting of alkyl, quinil and quinil where did the substituents are unsubstituted.

[00205] 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, 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.

[00206] 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 and alkylsulfonyl is, where:

amino part of alkylsulfonyl optionally substituted alkyl.

[00207] 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 alkyl, alkylsulfonyl, alkylsulfonyl.

[00208] In some embodiments, implementation, each RFis an independently selected alkyl, optionally substituted amino, where the amino optionally substituted by alkylsulfonyl.

[00209] 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.

[00210] 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, and killalpaninna, allyloxycarbonyl, alkenylcarbazoles, alkyloxyaryl, alkylcarboxylic, alkenylboronic, alkylcarboxylic, alkyloxy, alkenylacyl, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl.

[00211] 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, alkenylcarbazoles, alkyloxyaryl, alkylcarboxylic, alkenylboronic, alkylcarboxylic, alkyloxy, alkenylacyl, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl.

10. Deputy RG.

[00212] 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, alkenylcarbazoles, alkyloxyaryl, alkylcarboxylic, alkenylboronic, alkylcarboxylic, alkyloxy, alkenylacyl, alkyloxy, carbocycle, heterocyclyl, cyano and aminocarbonyl, g is e:

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.

[00213] In some of these embodiments, each RGindependently selected from the group consisting of carbocyclic and heterocyclyl, where such substituents are unsubstituted.

[00214] 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.

[00215] In some of these embodiments, carbocycle represents a C3-C6-carbocyclic.

[00216] In some of these embodiments, heterocyclyl is a 5-6-membered heterocyclyl.

B11 substituent R H.

[00217] 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, alkenylcarbazoles, 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.

[00218] In some of these embodiments, each RHindependently selected from the group consisting of alkyloxy, alkenylacyl, alkyloxy, alkylsulfonate, alkanesulfonyl, alkylsulfonate, where such substituents are unsubstituted.

[00219] In some embodiments, implementation, each RHindependently selected from the group consisting of alkyloxy, alkylsulfonate where:

each such Deputy optionally substituted onemile two alternates, 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.

[00220] 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 where:

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

[00221] 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, alkyl is of sikabonyi, alkylcarboxylic, alkyloxy, cyano and aminocarbonyl.

[00222] In some embodiments, implementation, each RHis an independently selected alkyloxy.

[00223] In some embodiments, implementation, each RHis an independently selected alkylsulfonate.

B12. Deputy RI.

[00224] 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, alkenylcarbazoles, 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 researched the MoE selected from the group consisting of halo, alkyl and oxo.

[00225] 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.

[00226] In some embodiments, implementation, each RIindependently selected from the group 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.

[00227] 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.

[00228] In some embodiments, implementation, each RIindependently selected from the group consisting whom her from alkylcarboxylic, alkenylboronic, 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, alkenylcarbazoles, 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, alkylsulfonamides.

[00229] In some of these embodiments, each RIindependently selected from the group consisting of alkylcarboxylic, alkenylamine, alkynylaryl and aminocarbonyl, where such substituents are unsubstituted.

[00230] 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, carb which was tilila, heterocyclyl, cyano and aminocarbonyl, and

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

[00231] 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, 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.

[00232] 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.

[00233] In some embodiments, implementation, each RIis an independently selected alkylsulphonyl.

[00234]In some embodiments, implementation, each RIis an independently selected aminocarbonyl.

B13. Deputy RJ.

[00235] Each RJindependently selected from the group consisting of carbocyclization, heterocyclization, alkylcarboxylic, alkenylamine, alkylcarboxylic, allyloxycarbonyl, alkanolammonium, alkyloxycarboxylic, alkylsulfonyl, 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 the group consisting of alkyl, alkenyl, quinil, carboxy, hydroxy, alkyloxy, alkenylacyl, alkyloxy, halo, nitro, cyano, azido, oxo and amino, and

(2) the amino portion and is of indocarbocyanine 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.

[00236] In some embodiments, implementation, each RJindependently selected from the group consisting of carbocyclization, heterocyclization, alkylcarboxylic, alkenylamine, alkylcarboxylic, allyloxycarbonyl, alkenyl is starsonline, alkyloxycarboxylic, alkylsulfonyl, alkanesulfonyl, alkylsulfonyl, aminocarbonyl, 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 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, alkyls is bonelace, 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

[00237] In some of these embodiments, each RJindependently selected from the group consisting of carbocyclization, heterocyclization, alkylcarboxylic, alkenylamine, alkylcarboxylic, allyloxycarbonyl, alkanolammonium, alkyloxycarboxylic, alkylsulfonyl, alkanesulfonyl, alkylsulfonyl, aminocarbonyl, alkylsulfonamides, alkanesulfonyl, alkylsulfonamides, where such substituents are unsubstituted.

[00238] In some in the ways of 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, 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 by the ne 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 optionally substituted with one or two independently selected alkyl substituents.

[00239] In some embodiments, implementation, each RJindependently selected from the group consisting

from 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 Aminata is banyankole 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 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.

[00240] 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, ALK is of carbonyl, 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.

[00241] 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.

[00242] In some embodiments, implementation, each RJ independently 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.

[00243] In some embodiments, implementation, each RJindependently 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.

[00244] 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 alkyls who were radioactive, 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.

[00245] 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, alkyloxy the onila, alkylaminocarbonyl, 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 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.

[00246] 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, aminocarb is lalqila, of 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.

[00247] 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.

[00248] 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, and the Ino, 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.

[00249] 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.

[00250] In some embodiments, implementation, each RJis an independently selected alkylsulfonamides. In some such embodiments, implementation, each RJrepresents methylsulfonylamino.

[00251] 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 is a, alkylaminocarbonyl, 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 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.

[00252] 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 the si, 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.

[00253] 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.

[00254] 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 and is a 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.

[00255] 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.

[00256] In some embodiments, implementation, each RJis an independently selected alkylsulfonamides. In some such embodiments, implementation, each RJrepresents methylsulfonylamino.

[00257] 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, and is biloxicasino, alkylcarboxylic, hydroxy, alkyloxy, carbocycle, heterocyclyl and cyano.

B14. Deputy RK.

[00258] 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, alkenylcarbazoles, 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.

[00259] In some of these embodiments, each RKindependently selected from the group consisting of aminosulfonyl, alkylsulfonyl, alkanesulfonyl and alkylsulfonyl, where such substituents are unsubstituted.

[00260] In some variant of the x 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 alkyl substituents.

[00261] In some embodiments, implementation, each RKindependently selected from the group consisting of aminosulfonyl and alkylsulfonyl.

C. modifications of the compounds of formula I.

[00262] 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 represented the s below.

[00263] In some embodiments, implementation of the compounds of formula I correspond in structure to formula I-L0:

;

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)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, alkylsulfonyl;

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

R6selected from the group consisting of condensed 2-ring heterocyclyl and condensed 2-ring carbocycle, where each such Deputy substituted one, two or three substituents, independently selected from the group, with Toyama of R E, RF, RI, RJand RK;

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, alkylsulfonyl, alkylsulfonyl;

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;

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, the de:

(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, karokee, 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; and

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 s is noncarbonyl; and

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

[00264] In some embodiments, implementation of the compounds of formula I correspond in structure to formula I-L0:

;

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 halogen

R3represents hydrogen;

R4represents tert-butyl;

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

R6represents a condensed 2-ring carbocycle selected from the group consisting of naphthalenyl, dihydronaphthalene, tetrahydronaphthalene, hexahydronaphthalen, octahydronaphthalene, decahydronaphthalene, indenyl, dihydroindole, hexahydrobenzene, octahedrite, pentalene, octahydrophenanthrene and hexahydrophthalate, where each such Deputy substituted Deputy selected from the group consisting of RFand RJ;

RFis alkylsulfonamides; and

RJrepresents alkylsulfonamides.

[00265] Examples of compounds of formula I (and their salts) are listed in the Table is Zach 1-9, are presented below. Examples of the synthesis 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
connectionR6
The ring/the ring structureDeputy(s)
IA-L0-2.1the benzimidazole-2-yl-5-N(H)S(O)2CH3
IA-L0-2.2benzothiazol-2-yl-6-N(H)S(O)2CH3
IA-L0-2.3benzothiazol-2-yl---
IA-L0-2.4benzothiazol-2-yl-5-N(H)S(O)2CH3
IA-L0-2.5/td> benzoxazol-2-yl-6-N(H)S(O)2CH3
IA-L0-2.6benzoxazol-2-yl-6-NO2
IA-L0-2.7benzoxazol-2-yl-5-NO2
IA-L0-2.8benzoxazol-2-yl-5-N(H)S(O)2CH3
IA-L0-2.9naphthalen-2-yl-6-N(H)S(O)2CH3
IA-L0-2.10the benzimidazole-2-yl-5-N[S(O)2CH3]2

-N
table 2
connectionR4R5Deputy(s)
IB-L0-2.1- (CH3)3-Och3
IB-L0-2.2- (CH3)3-Och3-Och3
IB-L0-2.3- (CH3)3-Och3-N(H)S(O)2CH3
IB-L0-2.8- (CH3)3-N-N(H)S(O)2CH3
IB-L0-2.14- (CH3)3-Cl-N(H)S(O)2CH3
IB-L0-2.23- (CH3)3-OS(H)2CH3-N(H)S(O)2CH3
IB-L0-2.52- (CH3)2C(H)2C(H)3-Och3-N(H)S(O)2CH3

IB-L0-2.64
connectionR4R5Deputy(s)
IB-L0-2.53 -Och3-N(H)S(O)2CH3
IB-L0-2.54- (CH3)2C(H)2OH-Och3-N(H)S(O)2CH3
IB-L0-2.56-CF3-Och3-N(H)S(O)2CH3
IB-L0-2.57-I-Och3-N(H)S(O)2CH3
IB-L0-2.58-Och3-N(H)S(O)2CH3
IB-L0-2.59the Funan-2-yl-Och3-N(H)S(O)2CH3
IB-L0-2.60-C(F)2CF3-Och3-N(H)S(O)2CH3
IB-L0-2.61-Och3-N(H)S(O)2CH3
furan-3-yl-Och3-N(H)S(O)2CH3
IB-L0-2.66- (CH3)2C(H)2OCH3-Och3-N(H)S(O)2CH3
IB-L0-2.68-S(O)2CH3-Och3-N(H)S(O)2CH3
IB-L0-2.69-Br-Och3-N(H)S(O)2CH3
IB-L0-2.70- (CH3)2C(O)och3-Och3-N(H)S(O)2CH3
IB-L0-2.71phenyl-Och3-N(H)S(O)2CH3
IB-L0-2.72-C(O)och3-Och3-N(H)S(O)2CH3
IB-L0-2.73-Och3IB-L0-2.74-Och3-N(H)S(O)2CH3
IB-L0-2.75-N(H)S(O)2CH3-Och3-N(H)S(O)2CH3
IB-L0-2.76-Och3-N(H)S(O)2CH3
IB-L0-2.77- (CH3)2(O)HE-Och3-N(H)S(O)2CH3
IB-L0-2.78-C≡CSi(CH3)3-Och3-N(H)S(O)2CH3

table 3
connectionR5Deputy(s)
IB-L0-2.4-Och3 =NN(H)S(O)2CH3
IB-L0-2.7-H=NN(H)S(O)2CH3
IB-L0-2.9-Och3(S)-C(H)2N(H)S(O)2CH3
IB-L0-2.10-Och3(R)-F and-C(H)2N(H)S(O)2CH3
IB-L0-2.12-Och3-F and-C(H)2N(H)S(O)2CH3
IB-L0-2.15-Och3(R)-C(H)2N(H)S(O)2CH3
IB-L0-2.17-Och3-C(H)2N(H)S(O)2CH3
IB-L0-2.20-Och3(S)-F and-C(H)2N(H)S(O)2CH3
IB-L0-2.22-Och3(S)-C(CH3)2N(H)S(O)2CH3
IB-L0-2.24-Och3=NN(H)C(O)OCH3
IB-L0-2.25-Och3 -CH3and-C(H)2N(H)S(O)2CH3
IB-L0-2.29-Och3-C(CH3)2N(H)S(O)2CH3
IB-L0-2.31-Och3-N(H)N(H)S(O)2CH3
IB-L0-2.34-Och3-C(O)N(H)S(O)2CH3
IB-L0-2.36-Och3-OH
IB-L0-2.37-Och3(R)-C(CH3)2N(H)S(O)2CH3
IB-L0-2.44-Och3-N(H)S(O)2CH3
IB-L0-2.50-Och3=O

table 4
connectionR4R5Deputy(s)
IB-L0-2.51-Och3=NN(H)S(O)2CH3
IB-L0-2.55furan-2-yl-Och3=NN(H)S(O)2CH3

TABLE 5
connectionR5Deputy(s)
IB-L0-2.11-Och3C(H)2N(H)S(O)2CH3
IB-L0-2.21-Och3-C(H)2N(CH3)S(O)2CH3
IB-L0-2.35-Cl-C(H)2N(H)S(O)2CH3

table 6
connectionR4the Deputy(s)
IB-L0-2.13- (CH3)3-C(H)2N(H)S(O)2CH3
IB-L0-2.16- (CH3)3-C(H)2N(CH3)S(O)2CH3
IB-L0-2.41- (CH3)3-C(CH3)2N(H)S(O)2CH3
IB-L0-2.62-C(H)2N(H)S(O)2CH3
IB-L0-2.63-C(H)2N(H)S(O)2CH3
IB-L0-2.65furan-2-yl-C(H)2N(H)S(O)2CH3
IB-L0-2.67furan-3-yl-C(H)2N(H)S(O)2CH3

TABLE 7
connectionDeputy(s)
IB-L0-2.18-C(H)2N(H)S(O)2CH3
IB-L0-2.42-CH3

TABLE 8
connectionDeputy(s)
IB-L0-2.27-NH2
IB-L0-2.28-N(H)S(O)2CH3
IB-L0-2.33-N
IB-L0-2.38-Cl
IB-L0-2.39-NH2
IB-L0-2.46-N(H)C(H)2C(H)2Snz
IB-L0-2.47
IB-L0-2.49-N(H)C(O)CH3

TABLE 9

D. Isomers.

[00266] 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.

p> [00267] the Present invention also relates, in part, to all salts of the compounds of formula I. Salt compounds may be preferred due to one or more properties of salts, 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.

[00268] Pharmaceutically acceptable acid additive salts of compounds of formula I can be obtained from reorganise the coy or organic acids. Examples in many cases, suitable inorganic acids include hydrochloric, Hydrobromic, yodiewonderdog, nitric, carbonic, sulfuric and phosphoric 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, cyclohexanesulfonic, 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.

[00269] Pharmaceutically acceptable basic additive is Oli compounds of formula I include, for example, metal salts and organic salts. Preferred metal salts include salts of alkali metals (group Ia), salts of alkaline earth 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 (for example, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides), diallylsulfide (e.g., dimethyl, diethyl, dibutil and dimycolate), halide long chain (e.g., decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides), arylalkyl halide (for example, benzyl and phenethyl bromides), and others.

[00270] In some embodiments, the implementation, is a sodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-pyrimidine-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00271] In some embodiments, implementation, salt is a monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00272] In some embodiments, implementation, salt is a disodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-pyrimidine-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00273] In some embodiments, implementation, salt is a potassium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-pyrimidine-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00274] In some embodiments, implementation, salt is Moncalieri salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00275] In some embodiments, implementation, salt is Kalinovo salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydro-pyrimidine-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00276] In some embodiments, implementation, salt is mnogolinkovuyu salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

F. Clean.

[00277] 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" on the connection/salt/isomer, means that the product/composition containing the compound/salt/isomer, contains more than about 85% by weight of the compound/salt/isomer, prefer the Ino 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 N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.3),

[00278] the Present invention also relates, in part, to crystalline forms of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.3), namely, solvate, hydrate and solvent free crystalline forms, discussed below.

G1A. IB-L0-2.3 Solvate.

[00279] the Present invention also relates, in part, to the ethanol MES compound IB-L0-2.3.

[00280] In some embodiments, implementation, ethanol MES has a powder x-ray containing one or more peaks selected from the group consisting of 8,3±0,2, 9,7±0,2, 10,6±0,2, 13,6±0,2, 17,2±0,2, 19,2±0,2, 22,7±0,2, 26,9±0,2 and 29.4±0.2 degrees two theta (2θ). In some such embodiments, implementation, ethanol MES has a powder x-ray that contains three or more peaks selected from the group consisting of 8,3±0,2, 9,7±0,2, 10,6±0,2, 13,6±0,2 17,2±0,2, 19,2±0,2, 22,7±0,2, 26,9±0,2 and 29.4±0.2 degrees 2θ. In other such embodiments, implementation, ethanol MES has a powder x-ray that contains five or more peaks selected from the group consisting of 8,3±0,2, 9,7±0,2, 10,6±0,2, 13,6±0,2, 17,2±0,2, 19,2±0,2, 22,7±0,2, 26,9±0,2 and 29.4±0.2 degrees 2θ.

[00281] In some embodiments, implementation, ethanol MES has a powder x-ray containing one or more peaks selected from the group consisting of 8,3±0,2, 9,7±0,2, 10,0±0,2, 10,6±0,2, 13,6±0,2, 17,2±0,2, 17,5±0,2, 19,2±0,2, 19,4±0,2, 22,7±0,2, 26,9±0,2 and 29.4±0.2 degrees 2θ. In some such embodiments, implementation, ethanol MES has a powder x-ray that contains three or more peaks selected from the group consisting of 8,3±0,2, 9,7±0,2, 10,0±0,2, 10,6±0,2, 13,6±0,2, 17,2±0,2, 17,5±0,2, 19,2±0,2, 19,4±0,2, 22,7±0,2, 26,9±0,2 and 29.4±0.2 degrees 2θ. In other embodiments, implementation, ethanol MES has a powder x-ray that contains five or more peaks selected from the group consisting of 8,3±0,2, 9,7±0,2, 10,0±0,2, 10,6±0,2, 13,6±0,2, 17,2±0,2, 17,5±0,2, 19,2±0,2, 19,4±0,2, 22,7±0,2, 26,9±0,2 and 29.4±0.2 degrees 2θ.

[00282] In some embodiments, implementation, ethanol MES has a powder x-ray are, essentially, as shown in Figure 1. The 2θ values for the peaks in Figure 1 (and their intensities) are the following: 8,25 (54), 9,67 (74), 9,92 (63), 10,59 (21), 13,64 (49), 17,25 (40), 17,51 (20), 19,19 (66), 19,43 (100), 22,75 (19), 26,92 (25) and 29,39 (18).

[00283] This is total invention also relates, in part, to the combined acetonitrile MES compound IB-L0-2.3.

[00284] In some embodiments, the implementation, the combined acetonitrile MES has a powder x-ray containing one or more peaks selected from the group consisting of 5,3±0,2, 8,3±0,2, 9,7±0,2, 10,5±0,2, 13,8±0,2, 17,2±0,2, 19,1±0,2 and 19.5±0.2 degrees 2θ. In some such embodiments, the implementation, the combined acetonitrile MES has a powder x-ray that contains three or more peaks selected from the group consisting of 5,3±0,2, 8,3±0,2, 9,7±0,2, 10,5±0,2, 13,8±0,2, 17,2±0,2, 19,1±0,2 and 19.5±0.2 degrees 2θ. In other such embodiments, the implementation, the combined acetonitrile MES has a powder x-ray that contains five or more peaks selected from the group consisting of 5,3±0,2, 8,3±0,2, 9,7±0,2, 10,5±0,2, 13,8±0,2, 17,2±0,2, 19,1±0,2 and 19.5±0.2 degrees 2θ.

[00285] In some embodiments, the implementation, the combined acetonitrile MES has a powder x-ray containing one or more peaks selected from the group consisting of 5,3±0,2, 8,3±0,2, 9,7±0,2, 10,5±0,2, 13,8±0,2, 17,2±0,2, 17,7±0,2, 19,1±0,2, 19,5±0,2, 22,0±0,2, 22,8±0,2 and 27.2±0.2 degrees 2θ. In some such embodiments, the implementation, the combined acetonitrile MES has a powder x-ray that contains three or more peaks selected from the group consisting of 5,3±0,2, 8,3±0,2, 9,7±0,2, 10,5±0,2, 13,8±0,2, 17,2±0,2, 17,7±0,2, 19,1±0,2, 19,5±0,2, 22,0±0,2, 22,8±0,2 and 27.2±0.2 degrees 2θ. In other such embodiments, the implementation, the combined acetonitrile solvation powder x-ray, containing five or more peaks selected from the group consisting of 5,3±0,2, 8,3±0,2, 9,7±0,2, 10,5±0,2, 13,8±0,2, 17,2±0,2, 17,7±0,2, 19,1±0,2, 19,5±0,2, 22,0±0,2, 22,8±0,2 and 27.2±0.2 degrees 2θ.

[00286] In some embodiments, the implementation, the combined acetonitrile MES has a powder x-ray are, essentially, as shown in Figure 3. Size 29 for the peaks in Figure 3 (and their intensities) are the following: 5,27 (14), 8,29 (33), 9,72 (100), 10,53 (20), 13,77 (67), 17,25 (38), 17,69 (17), 19,05 (63), 19,47 (58), 22,05 (19), 22,75 (16) and 27,17 (21).

[00287] the Present invention also relates, in part, to an ethyl acetate the MES compound IB-L0-2.3.

[00288] In some embodiments, implementation, an ethyl acetate MES has a powder x-ray containing one or more peaks selected from the group consisting of 7,9±0,2, 9,3±0,2, 9,7±0,2, 10,6±0,2, 18,7±0,2, 38,5±0,2 and 44.7±0.2 degrees 2θ. In some such embodiments, implementation, an ethyl acetate MES has a powder x-ray that contains three or more peaks selected from the group consisting of 7,9±0,2, 9,3±0,2, 9,7±0,2, 10,6±0,2, 18,7±0,2, 38,5±0,2 and 44.7±0.2 degrees 2θ. In other such embodiments, implementation, an ethyl acetate MES has a powder x-ray that contains five or more peaks selected from the group consisting of 7,9±0,2, 9,3±0,2, 9,7±0,2, 10,6±0,2, 18,7±0,2, 38,5±0,2 and 44.7±0.2 degrees 2θ.

[00289] In some embodiments, implementation, an ethyl acetate MES has a powder x is the programs containing one or more peaks selected from the group consisting of 7,9±0,2, 9,3±0,2, 9,7±0,2, 10,6±0,2, 13,7±0,2, 17,4±0,2, 18,7±0,2, 21,7±0,2, 22,0±0,2, 28,2±0,2, 38,5±0,2 and 44.7±0.2 degrees 2θ. In some such embodiments, implementation, an ethyl acetate MES has a powder x-ray that contains three or more peaks selected from the group consisting of 7,9±0,2, 9,3±0,2, 9,7±0,2, 10,6±0,2, 13,7±0,2, 17,4±0,2, 18,7±0,2, 21,7±0,2, 22,0±0,2, 28,2±0,2, 38,5±0,2 and 44.7±0.2 degrees 2θ. In other such embodiments, implementation, an ethyl acetate MES has a powder x-ray that contains five or more peaks selected from the group consisting of 7,9±0,2, 9,3±0,2, 9,7±0,2, 10,6±0,2, 13,7±0,2, 17,4±0,2, 18,7±0,2, 21,7±0,2, 22,0±0,2, 28,2±0,2, 38,5±0,2 and 44.7±0.2 degrees 2θ.

[00290] In some embodiments, implementation, an ethyl acetate MES 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: 7,94 (24), 9,33 (26), 9,72 (13), 10,58 (23), 13,71 (19), 17,40 (28), 18,72 (44), 21,69 (8), 22,04 (10), 28,23 (8), 38,45 (100) and 44,66 (95).

[00291] the Present invention also relates, in part, to the 2-propanole the MES compound IB-L0-2.3.

[00292] In some embodiments, implementation, 2-profanely MES has a powder x-ray containing one or more peaks selected from the group consisting of 8,2±0,2, 9,3±0,2, 10,1±0,2, 16,3±0,2, 18,1±0,2, 18,6±0,2, 19,4±0,2, 21,6±0,2 and 22.5±0.2 degrees 2θ. In some such variant is x implementation 2-profanely MES has a powder x-ray that contains three or more peaks selected from the group consisting of 8,2±0,2, 9,3±0,2, 10,1±0,2, 16,3±0,2, 18,1±0,2, 18,6±0,2, 19,4±0,2, 21,6±0,2 and 22.5±0.2 degrees 2θ. In other such embodiments, implementation, 2-profanely MES has a powder x-ray that contains five or more peaks selected from the group consisting of 8,2±0,2, 9,3±0,2, 10,1±0,2, 16,3±0,2, 18,1±0,2, 18,6±0,2, 19,4±0,2, 21,6±0,2 and 22.5±0.2 degrees 2θ.

[00293] In some embodiments, implementation, 2-profanely MES has a powder x-ray containing one or more peaks selected from the group consisting of 8,2±0,2, 9,3±0,2, 10,1±0,2, 16,3±0,2, 18,1±0,2, 18,6±0,2, 19,4±0,2, 21,6±0,2, 22,5±0,2, 23,8±0,2, 26,0±0,2 and 28.0±0.2 degrees 2θ. In some such embodiments, implementation, 2-profanely MES has a powder x-ray that contains three or more peaks selected from the group consisting of 8,2±0,2, 9,3±0,2, 10,1±0,2, 16,3±0,2, 18,1±0,2, 18,6±0,2, 19,4±0,2, 21,6±0,2, 22,5±0,2, 23,8±0,2, 26,0±0,2 and 28.0±0.2 degrees 2θ. In other such embodiments, implementation, 2-profanely MES has a powder x-ray that contains five or more peaks selected from the group consisting of 8,2±0,2, 9,3±0,2, 10,1±0,2, 16,3±0,2, 18,1±0,2, 18,6±0,2, 19,4±0,2, 21,6±0,2, 22,5±0,2, 23,8±0,2, 26,0±0,2 and 28.0±0.2 degrees 2θ.

[00294] In some embodiments, implementation, 2-profanely MES has a powder x-ray are, essentially, as shown in Figure 5. Ve is icine 2θ for the peaks in Figure 5 (and their intensities) are the following: 8,18 (32), 9,26 (100), 10,12 (81), 16,28 (93), 18,11 (30), 18,59 (63), 19,40 (67), 21,57 (60), 22,51 (31), 23,82 (29), 25,94 (24) and to 28.05 (29).

[00295] the Present invention also relates, in part, to the methanol MES compound IB-L0-2.3.

[00296] In some embodiments, implementation, methanol MES has a powder x-ray containing one or more peaks selected from the group consisting of 8,4±0,2, 9,7±0,2, 10,1±0,2, 13,8±0,2, 17,4±0,2, 19,3±0,2 and of 19.6±0.2 degrees 2θ. In some such embodiments, implementation, methanol MES has a powder x-ray that contains three or more peaks selected from the group consisting of 8,4±0,2, 9,7±0,2, 10,1±0,2, 13,8±0,2, 17,4±0,2, 19,3±0,2 and of 19.6±0.2 degrees 2θ. In other such embodiments, implementation, methanol MES has a powder x-ray that contains five or more peaks selected from the group consisting of 8,4±0,2, 9,7±0,2, 10,1±0,2, 13,8±0,2, 17,4±0,2, 19,3±0,2 and of 19.6±0.2 degrees 2θ.

[00297] In some embodiments, implementation, methanol MES has a powder x-ray containing one or more peaks selected from the group consisting of 8,4±0,2, 9,7±0,2, 10,1±0,2, 13,5±0,2, 13,8±0,2, 17,4±0,2, 19,3±0,2, 19,6±0,2 and 27.1±0.2 degrees 2θ. In some such embodiments, implementation, methanol MES has a powder x-ray that contains three or more peaks selected from the group consisting of 8,4±0,2, 9,7±0,2, 10,1±0,2, 13,5±0,2, 13,8±0,2, 17,4±0,2, 19,3±0,2, 19,6±0,2 and 27.1±0.2 degrees 2θ. Other such variations is tah implementation methanol MES has a powder x-ray that contains five or more peaks selected from the group consisting of 8,4±0,2, 9,7±0,2, 10,1±0,2, 13,5±0,2, 13,8±0,2, 17,4±0,2, 19,3±0,2, 19,6±0,2 and 27.1±0.2 degrees 2θ.

[00298] In some embodiments, implementation, methanol MES has a powder x-ray are, essentially, as shown in Figure 6. The 2θ values for the peaks in Figure 6 (and their intensities) are the following: 8,36 (48), 9,74 (65), 10,05 (74), 13,55 (24), 13,79 (69), 17,40 (32), 19,30 (80), 19,58 (100) and 27,08 (24).

[00299] the Present invention also relates, in part, to the 1-propanole the MES compound IB-L0-2.3.

[00300] In some embodiments, implementation, 1-profanely MES has a powder x-ray containing one or more peaks selected from the group consisting of 8,2±0,2, 9,3±0,2, 10,1±0,2, 15,7±0,2, 16,2±0,2, 18,4±0,2, 19,3±0,2, 21,6±0,2 and 22.8±0.2 degrees 2θ. In some such embodiments, implementation, 1-profanely MES has a powder x-ray that contains three or more peaks selected from the group consisting of 8,2±0,2, 9,3±0,2, 10,1±0,2, 15,7±0,2, 16,2±0,2, 18,4±0,2, 19,3±0,2, 21,6±0,2 and 22.8±0.2 degrees 2θ. In other such embodiments, implementation, 1-profanely MES has a powder x-ray that contains five or more peaks selected from the group consisting of 8,2±0,2, 9,3±0,2, 10,1±0,2, 15,7±0,2, 16,2±0,2, 18,4±0,2, 19,3±0,2, 21,6±0,2 and 22.8±0.2 degrees 2θ.

[00301] In some embodiments, domestic the, 1-profanely MES has a powder x-ray containing one or more peaks selected from the group consisting of 8,2±0,2, 9,3±0,2, 10,1±0,2, 10,5±0,2, 15,7±0,2, 16,2±0,2, 18,4±0,2, 18,6±0,2, 19,3±0,2, 21,0±0,2, 21,6±0,2 and 22.8±0.2 degrees 2θ. In some such embodiments, implementation, 1-profanely MES has a powder x-ray that contains three or more peaks selected from the group consisting of 8,2±0,2, 9,3±0,2, 10,1±0,2, 10,5±0,2, 15,7±0,2, 16,2±0,2, 18,4±0,2, 18,6±0,2, 19,3±0,2, 21,0±0,2, 21,6±0,2 and 22.8±0.2 degrees 2θ. In other such embodiments, implementation, 1-profanely MES has a powder x-ray that contains five or more peaks selected from the group consisting of 8,2±0,2, 9,3±0,2, 10,1±0,2, 10,5±0,2, 15,7±0,2, 16,2±0,2, 18,4±0,2, 18,6±0,2, 19,3±0,2, 21,0±0,2, 21,6±0,2 and 22.8±0.2 degrees 2θ.

[00302] In some embodiments, implementation, 1-profanely MES has a powder x-ray are, essentially, as shown in Figure 7. The 2θ values for the peaks in Figure 7 (and their intensities) are the following: 8,15 (27), 9,26 (87), 10,08 (84), 10,47 (62), 15,73 (40), 16,24 (100), 18,37 (41), 18,59 (49), 19,33 (50), 20,97 (28), 21,65 (71) and 22,81 (44).

[00303] the Present invention also relates, in part, to a method for producing the above solvate by suspension of compound IB-L0-2.3 in an appropriate solvent.

G1B. IB-L0-2.3 solvent.

[00304] the Present invention also relates, in part, to the crystalline Faure is e compound IB-L0-2.3, solvent free.

[00305] In some embodiments, implementation, solvent free compound IB-L0-2.3 has a powder x-ray containing one or more peaks selected from the group consisting of 6,2±0,2, 7,9±0,2, 9,9±9,2, 16,2±0,2 and 18.3±0.2 degrees two theta (2θ). In some such embodiments, implementation, solvent free compound IB-L0-2.3 has a powder x-ray that contains three or more peaks selected from the group consisting of 6,2±0,2, 7,9±0,2, 9,9±0,2, 16,2±0,2 and 18.3±0.2 degrees 2θ. In other such embodiments, implementation, solvent free compound IB-L0-2.3 has a powder x-ray that contains five or more peaks selected from the group consisting of 6,2±0,2, 7,9±0,2, 9,9±0,2, 16,2±0,2 and 18.3±0.2 degrees 2θ.

[00306] In some embodiments, implementation, solvent free compound IB-L0-2.3 has a powder x-ray containing one or more peaks selected from the group consisting of 6,2±0,2, 7,9±9,2, 9,9±0,2, 10,1±0,2, 14,9±0,2, 16,2±0,2, 18,3±9,2, 19,8±0,2 and 26.5±0.2 degrees 2θ. In some such embodiments, implementation, solvent free compound IB-L0-2.3 has a powder x-ray that contains three or more peaks selected from the group consisting of 6,2±0,2, 7,9±0,2, 9,9±0,2, 10,1±0,2, 14,9±0,2, 16,2±0,2, 18,3±0,2, 19,8±0,2 and 26.5±0.2 degrees 2θ. In other such embodiments, the implementation of the solvent connect the tion IB-L0-2.3 has a powder x-ray, containing five or more peaks selected from the group consisting of 6,2±0,2, 7,9±0,2, 9,9±0,2, 10,1±0,2, 14,9±0,2, 16,2±0,2, 18,3±0,2, 19,8±0,2 and 26.5±9.2 degrees 2θ. In other such embodiments, implementation, solvent free compound IB-L0-2.3 has a powder x-ray containing eight or more peaks selected from the group consisting of 6,2±0,2, 7,9±0,2, 9,9±0,2, 10,1±0,2, 14,9±0,2, 16,2±0,2, 18,3±0,2, 19,8±0,2 and 26.5±9.2 degrees 2θ.

[00307] In some embodiments, implementation, solvent free compound IB-L0-2.3 has a powder x-ray are, essentially, as shown in Figure 8. The 2θ values for the peaks in Figure 8 (and their intensities) are the following: 6,29 (36), 7,85 (66), 9,89 (61), 19,12 (75), 14,87 (27), 16,19 (89), 18,32 (199), 19,82 (77) and 26,53 (34).

[00308] the Present invention also relates, in part, to a method for producing crystalline form of compound IB-L0-2.3, solvent free, by desolvation one of the solvate IB-L0-2.3, above. MES can be resolverian by heating of the MES in the solid state for approximately 19 minutes at ~125°C.

G1C. hydrate IB-L0-2.3.

[00309] the Present invention also relates, in part, to the hydrate of compound IB-L0-2.3.

[00310] In some embodiments, the implementation, the hydrate has a powder x-ray containing one or more peaks selected from the group consisting of 6,4±9,2, 12,9±9,2, 17,9±9,2 and 18.9±9.2 degrees 2θ.In some such embodiments, implementation, the hydrate has a powder x-ray that contains three or more peaks selected from the group consisting of 6,4±9,2, 12,9±0,2, 17,9±0,2 and 18.9±0.2 degrees 2θ.

[00311] In some embodiments, the implementation, the hydrate has a powder x-ray containing one or more peaks selected from the group consisting of 6,4±0,2, 12,9±0,2, 17,5±0,2, 17,9±0,2, 18,9±0,2 and 24.4±0.2 degrees 2θ. In some such embodiments, the implementation, the hydrate has a powder x-ray that contains three or more peaks selected from the group consisting of 6,4±0,2, 12,9±0,2, 17,5±0,2, 17,9±0,2, 18,9±0,2 and 24.4±0.2 degrees 2θ. In other such embodiments, the implementation, the hydrate has a powder x-ray that contains five or more peaks selected from the group consisting of 6,4±0,2, 12,9±0,2, 17,5±0,2, 17,9±0,2, 18,9±0,2 and 24.4±0.2 degrees 2θ.

[00312] In some embodiments, the implementation, the hydrate has a powder x-ray containing one or more peaks selected from the group consisting of 6,4±0,2, 12,7±0,2, 12,9±0,2, 14,1±0,2, 15,7±0,2, 17,2±0,2, 17,5±0,2, 17,9±0,2, 18,9±0,2, 21,2±0,2, 24,4±0,2 and 25.0±0.2 degrees 2θ. In some such embodiments, the implementation, the hydrate has a powder x-ray that contains three or more peaks selected from the group consisting of 6,4±0,2, 12,7±0,2, 12,9±0,2, 14,1±0,2, 15,7±0,2, 17,2±0,2, 17,5±0,2, 17,9±0,2, 18,9±0,2, 21,2±0,2, 24,4±0,2 and 25.0±0.2 degrees 2θ. In other such embodiments, the implementation, the hydrate has a powder x-ray containing five and and more peaks, selected from the group consisting of 6,4±0,2, 12,7±0,2, 12,9±0,2, 14,1±0,2, 15,7±0,2, 17,2±0,2, 17,5±0,2, 17,9±0,2, 18,9±0,2, 21,2±0,2, 24,4±0,2 and 25.0±0.2 degrees 2θ.

[00313] In some embodiments, the implementation, the hydrate has a powder x-ray are, essentially, as shown in Figure 9. Size 29 for the peaks in Figure 9 (and their intensities) are the following: 6,42 (60), 12,71 (33), 12,89 (58), 14,05 (17), 15,68 (18), 17,22 (44), 17,53 (100), 17,86 (51), 18,87 (77), 21,25 (17), 24,35 (28) and 24,95 (20).

[00314] the Present invention also relates, in part, to a method for hydrate by suspension in water of the above described crystalline compounds that do not contain solvent. The hydrate was obtained by suspension of 300 mg of crystalline compound, solvent free, 2 ml of water at 45°C for four days.

G2. Crystalline forms of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide, monosodium salt.

[00315] the Present invention also relates, in part, to crystalline forms of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide, monosodium salt, namely, sample A, sample b and sample C, crystalline forms, discussed below.

[00316] the Present invention relates, in part, to the sample And the crystalline monosodium salt.

[00317] In some vari is ntah implementation sample a monosodium salt has a powder x-ray containing one or more peaks selected from the group consisting of 4,6±0,2, 10,4±0,2, 12,0±0,2, 15,6±0,2, 18,6±0,2, 22,8±0,2 and 23.9±0.2 degrees 2θ. In some such embodiments, implementation, sample And monosodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 4,6±0,2, 10,4±0,2, 12,0±0,2, 15,6±0,2, 18,6±0,2, 22,8±0,2 and 23.9±0.2 degrees 2θ. In other such embodiments, implementation, sample And monosodium salt has a powder x-ray that contains five or more peaks selected from the group consisting of 4,6±0,2, 10,4±0,2, 12,0±0,2, 15,6±0,2, 18,6±0,2, 22,8±0,2 and 23.9±0.2 degrees 2θ.

[00318] In some embodiments, implementation, sample And monosodium salt has a powder x-ray containing one or more peaks selected from the group consisting of 4,6±0,2, 10,4±0,2, 12,0±0,2, 15,6±0,2, 18,6±0,2, 22,8±0,2, 23,3±0,2 and 23.9±0.2 degrees 2θ. In some such embodiments, implementation, sample And monosodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 4,6±0,2, 10,4±0,2, 12,0±0,2, 15,6±0,2, 18,6±0,2, 22,8±0,2, 23,3±0,2 and 23.9±0.2 degrees 2θ. In other such embodiments, implementation, sample And monosodium salt has a powder x-ray that contains five or more peaks selected from the group consisting of 4,6±0,2, 10,4±0,2, 12,0±0,2, 15,6±0,2, 18,6±0,2, 22,8±0,2, 2,3±0,2 and 23.9±0.2 degrees 2θ.

[00319] In some embodiments, implementation, sample And monosodium salt has a powder x-ray containing one or more peaks selected from the group consisting of 4,6±0,2, 10,4±0,2, 12,0±0,2, 15,6±0,2, 16,0±0,2, 18,6±0,2, 22,8±0,2, 23,3±0,2, 23,9±0,2 and 28.3±0.2 degrees 2θ. In some such embodiments, implementation, sample And monosodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 4,6±0,2, 10,4±0,2, 12,0±0,2, 15,6±0,2, 16,0±0,2, 18,6±0,2, 22,8±0,2, 23,3±0,2, 23,9±0,2 and 28.3±0.2 degrees 2θ. In other such embodiments, implementation, sample And monosodium salt has a powder x-ray that contains five or more peaks selected from the group consisting of 4,6±0,2, 10,4±0,2, 12,0±0,2, 15,6±0,2, 16,0±0,2, 18,6±0,2, 22,8±0,2, 23,3±0,2, 23,9±0,2 and 28.3±0.2 degrees 2θ. In other such embodiments, implementation, sample And monosodium salt has a powder x-ray containing eight or more peaks selected from the group consisting of 4,6±0,2, 10,4±0,2, 12,0±0,2, 15,6±0,2, 16,0±0,2, 18,6±0,2, 22,8±0,2, 23,3±0,2, 23,9±0,2 and 28.3±0.2 degrees 2θ.

[00320] In some embodiments, implementation, sample And monosodium salt has a powder x-ray are, essentially, as shown in Figure 10. The 2θ values for the peaks in Figure 10 (and their intensities) are the following: 4,64 (62), 10,41 (38), 12,04 (38), 15,62 (44), 15,99 (44), 18,63 (49), 22,77 (60), 23,29 (40), 23,93 (100) and 28,31 (56).

[00321] the Present invention is that the same applies, in part, to a method for sample And monosodium salt. Sample And monosodium salt was obtained by addition of 1M aqueous NaOH (0,548 ml) to the compound IB-L0-2.3 (225,72 mg), crystallization of the resulting suspension of crystalline disodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide, (obtained as described below), and trim the resulting suspension in external conditions. Sample And monosodium salt was formed the next day by the way-mediated solution. The stoichiometry of the salt presumably is 1:1 on the basis of the crystallization process. The present invention also relates, in part, to the sample In the crystalline monosodium salt.

[00323] In some embodiments, implementation, sample monosodium salt has a powder x-ray containing one or more peaks selected from the group consisting of 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 21,6±0,2, 22,1±0,2 and 23.7±0.2 degrees 2θ. In some such embodiments, implementation, sample monosodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 21,6±0,2, 22,1±0,2 and 23.7±0.2 degrees 2θ. In other such embodiments, implementation, sample monosodium salt has a powder roentgenol is the Amma, containing five or more peaks selected from the group consisting of 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 21,6±0,2, 22,1±0,2 and 23.7±0.2 degrees 2θ.

[00324] In some embodiments, implementation, sample monosodium salt has a powder x-ray containing one or more peaks selected from the group consisting of 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 19,2±0,2, 19,6±0,2, 21,6±0,2, 22,1±0,2, 23,7±0,2, 28,8±0,2, 29,1±0,2 and 31.8±0.2 degrees 2θ. In some such embodiments, implementation, sample monosodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 19,2±0,2, 19,6±0,2, 21,6±0,2, 22,1±0,2, 23,7±0,2, 28,8±0,2, 29,1±0,2 and 31.8±0.2 degrees 2θ. In other such embodiments, implementation, sample monosodium salt has a powder x-ray that contains five or more peaks selected from the group consisting of 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 19,2±0,2, 19,6±0,2, 21,6±0,2, 22,1±0,2, 23,7±0,2, 28,8±0,2, 29,1±0,2 and 31.8±0.2 degrees 2θ. In other such embodiments, implementation, sample monosodium salt has a powder x-ray containing eight or more peaks selected from the group consisting of 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 19,2±0,2, 19,6±0,2, 21,6±0,2, 22,1±0,2, 23,7±0,2, 28,8±0,2, 29,1±0,2 and 31.8±0.2 degrees 2θ.

[00325] In some embodiments, implementation, sample monosodium salt has a powder x-ray is, containing one or more peaks selected from the group consisting of 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 19,2±0,2, 19,6±0,2, 21,6±0,2, 22,1±0,2, 23,7±0,2, 28,8±0,2, 29,1±0,2 and 31.8±0.2 degrees 2θ. In some such embodiments, implementation, sample monosodium salt has a powder x-ray containing two or more peaks selected from the group consisting of 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 19,2±0,2, 19,6±0,2, 21,6±0,2, 22,1±0,2, 23,7±0,2, 29,1±0,2 and 31.8±0.2 degrees 2θ. In other such embodiments, implementation, sample monosodium salt has a powder x-ray containing two or more peaks selected from the group consisting of 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 19,2±0,2, 19,6±0,2, 21,6±0,2, 22,1±0,2, 23,7±0,2, 28,8±0,2 and 31.8±0.2 degrees 2θ. In other such embodiments, implementation, sample monosodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 19,2±0,2, 19,6±0,2, 21,6±0,2, 22,1±0,2, 23,7±0,2 and 31.8±0.2 degrees 2θ. In other such embodiments, implementation, sample monosodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 19,2±0,2, 21,6±0,2, 22,1±0,2 and 23.7±0.2 degrees 2θ. In other such embodiments, implementation, sample monosodium salt has a powder x-ray that contains three or more PI is s, selected from the group consisting of 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 19,2±0,2, 21,6±0,2, 22,1±0,2 and 23.7±0.2 degrees 2θ. In other such embodiments, implementation, sample monosodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 21,6±0,2, 22,1±0,2 and 23.7±0.2 degrees 2θ. In other such embodiments, implementation, sample monosodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 21,6±0,2, 22,1±0,2 and 23.7±0.2 degrees 2θ. In other such embodiments, implementation, sample monosodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 5,4±0,2, 10,8±0,2, 16,3±0,2, 22,1±0,2 and 23.7±0.2 degrees 2θ.

[00326] In some embodiments, implementation, sample monosodium salt has a powder x-ray that contains peaks at 5.4±0,2, 10,8±0,2 16,3±0,2 degrees 2θ. In some such embodiments, implementation, sample monosodium salt has a powder x-ray that contains peaks at 5,4±0,2, 10,8±0,2, 16,3±0,2 and 22.1 ą 0.2 degrees 2θ. In other such embodiments, implementation, sample monosodium salt has a powder x-ray that contains peaks at 5,4±0,2, 10,8±0,2, 16,3±0,2, 22,1±0,2 and 23.7 ą 0.2 degrees 2θ. In other such embodiments, implementation, sample the monosodium salt has a powder x-ray, containing peaks at 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 21,6±0,2, 22,1±0,2 and 23.7 ą 0.2 degrees 2θ. In other such embodiments, implementation, sample monosodium salt has a powder x-ray that contains peaks at 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 21,6±0,2, 22,1±0,2 and 23.7 ą 0.2 degrees 2θ. In other such embodiments, implementation, sample monosodium salt has a powder x-ray that contains peaks at 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 19,2±0,2, 21,6±0,2, 22,1±0,2 and 23.7 ą 0.2 degrees 2θ. In other such embodiments, implementation, sample monosodium salt has a powder x-ray that contains peaks at 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 19,2±0,2, 21,6±0.2, 22,1±0,2 and 23.7 ą 0.2 degrees 2θ. In additional such embodiments, implementation, sample monosodium salt has a powder x-ray that contains peaks at 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 19,2±0,2, 19,6±0,2, 21,6±0,2, 22,1±0,2, 23,7±0,2 and 31.8 ą 0.2 degrees 2θ. In additional such embodiments, implementation, sample monosodium salt has a powder x-ray that contains peaks at 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 19,2±0,2, 19,6±9,2, 21,6±9,2, 22,1±9,2, 23,7±9,2, 28,8±9,2 and 31.8 ą 0.2 degrees 2θ. In additional such embodiments, implementation, sample monosodium salt has a powder x-ray that contains peaks at 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 19,2±0,2, 19,6±0,2, 21,6±0,2, 22,1±0,2, 23,7±9,2, 29,1±9,2 and 31.8±9,2 Gras the mustache 2θ. In additional such embodiments, implementation, sample monosodium salt has a powder x-ray that contains peaks at 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,9±9,2, 18,8±9,2, 19,2±0,2, 19,6±0,2, 21,6±9,2, 22,1±0,2, 23,7±0,2, 28,8±0,2, 29,1±0,2 and 31.8±9,2 degrees 2θ.

[00327] In some embodiments, implementation, sample monosodium salt has a powder x-ray are, essentially, as shown in Figure 12. The 2θ values for the peaks in Figure 12 (and their intensities) are the following: 5,36 (190), 19,75 (42), 14,43 (29), 16,34 (69), 17,99 (25), 18,83 (18), 19,24 (18), 19,66 (12), 21,64 (29), 22,12 (41), 23,73 (32), 28,83 (9), 29,19 (9) and 31.78 (19).

[00328] the Present invention also relates, in part, to the way the sample is received In the monosodium salt. Sample monosodium salt can be obtained by suspension of the sample And monosodium salt (for example, ~39 mg) in different organic solvents (for example, ~125 μl of acetonitrile, ethanol, 1-propanol or 2-propanol) at room temperature. A sample of the mono-sodium salt was obtained by crystallization of a solution of the sample In the monosodium salt. Compound IB-L0-2.3 (12.5 g) was dissolved in DMSO (37.5 ml) at ~68°C. was Added 1,94 g NaOH dissolved in 6.3 ml of water, 6.3 ml of 2-propanol and 12.5 ml of a mixture of 35.2:1 V/V 2-propanol/water. The solution was crystallizable using 125 mg of the seed sample, suspended in 12.5 ml of a mixture of 35.2:1 V/V 2-propanol/the odes, and crystallization, the suspension is incubated at ~68°C for ~1,5 hours 175 ml of a mixture of 35.2:1 V/V 2-propanol/water at ~68°C was added for ~7 h, and crystallization, the suspension was cooled to ~9°C for not less than 7 hours the Crystals were isolated by filtration and analyzed using PXRD. The crystals were then dried at ~59°C under vacuum (approximately 3 inches of mercury). The dried crystals were analyzed using PXRD, which did not show changes compared with the sample before drying. The stoichiometry of the sample In monosodium salt was confirmed using ion chromatography.

[00329] the Present invention also relates, in part, to the sample With crystalline monosodium salt.

[00330] In some embodiments, implementation, sample With a monosodium salt has a powder x-ray containing one or more peaks selected from the group consisting of 5,9±9,2, 12,9±9,2, 17,5±9,2, 18,8±9,2 and 22,7±9.2 degrees 2θ. In some such embodiments, implementation, sample With a monosodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 5,9±9,2, 12,9±9,2, 17,5±9,2, 18,8±9,2 and 22,7±9.2 degrees 2θ.

[00331] In some embodiments, implementation, sample With a monosodium salt has a powder x-ray containing one or more peaks selected from the group consisting of 5,9±9,2, 12,±0,2, 17,5±0,2, 17,8±0,2, 18,8±0,2 and an increase of 22.7±0.2 degrees 2θ. In some such embodiments, implementation, sample And monosodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 5,0±0,2, 12,0±0,2, 17,5±0,2, 17,8±0,2, 18,8±0,2 and an increase of 22.7±0.2 degrees 2θ. In other such embodiments, implementation, sample And monosodium salt has a powder x-ray that contains five or more peaks selected from the group consisting of 5,0±0,2, 12,0±0,2, 17,5±0,2, 17,8±0,2, 18,8±0,2 and an increase of 22.7±0.2 degrees 2θ.

[00332] In some embodiments, implementation, sample With a monosodium salt 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: 4,97 (100), 12,03 (24), 17,55 (32), 17,80 (77), 18,79 (23) and 22,74 (33).

[00333] the Present invention also relates, in part, to a method of obtaining a sample With monosodium salt. The sample With monosodium salt was prepared as follows. Sample monosodium salt (100 mg) was dissolved in 400 μl of DMSO and 2 ml of a mixture of 12:1 V/V 2-propanol/H2O at 70°C. the Crystals of the seed sample In monosodium salt was added to the solution, and this solution then was cooled to ambient temperature for 20 minutes Filtration gave crystals of the sample With monosodium salt.

G3. Crystalline form of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-ethoxyphenyl)naphthalen-2-yl)methanesulfonamide, disodium salt.

[00334] the Present invention also relates, in part, to the crystalline form of the disodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00335] In some embodiments, implementation, disodium salt has a powder x-ray containing one or more peaks selected from the group consisting of 4,8±0,2, 9,6±0,2, 10,5±0,2, 13,0±0,2, 14,6±0,2, 15,4±0,2, 16,8±0,2 and 23.0±0.2 degrees 2θ. In some such embodiments, implementation, disodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 4,8±0,2, 9,6±0,2, 10,5±0,2, 13,0±0,2, 14,6±0,2, 15,4±0,2, 16,8±0,2 and 23.0±0.2 degrees 2θ. In other such embodiments, implementation, disodium salt has a powder x-ray that contains five or more peaks selected from the group consisting of 4,8±0,2, 9,6±0,2, 10,5±0,2, 13,0±0,2, 14,6±0,2, 15,4±0,2, 16,8±0,2 and 23.0±0.2 degrees 2θ.

[00336] In some embodiments, implementation, disodium salt has a powder x-ray containing one or more peaks selected from the group consisting of 4,8±0,2, 9,6±0,2, 10,5±0,2, 13,0±0,2, 14,6±0,2, 15,4±0,2, 16,8±0,2, 22,7±0,2, 23,0±0,2 and 23.3±0.2 degrees 2θ. In some such embodiments, implementation, disodium salt has a powder x-ray that contains three or more peaks selected from the group consisting of 4,8±0,2, 9,6±0,2, 10,5±0,2, 13,0±0,2, 14,6±0,2, 15,4±02, 16,8±0,2, 22,7±0,2, 23,0±0,2 and 23.3±0.2 degrees 2θ. In other such embodiments, implementation, disodium salt has a powder x-ray that contains five or more peaks selected from the group consisting of 4,8±0,2, 9,6±0,2, 10,5±0,2, 13,0±0,2, 14,6±0,2, 15,4±0,2, 16,8±0,2, 22,7±0,2, 23,0±0,2 and 23.3±0.2 degrees 2θ.

[00337] In some embodiments, implementation, disodium salt has a powder x-ray are, essentially, as shown in Figure 15. The 2θ values for the peaks in Figure 15 (and their intensities) are the following: 4,89 (100), 9,59 (10), 10,51 (13), 12,98 (11), 14,56 (8), 15,38 (12), 16,84 (6), 22,68 (10), 23,04 (6) and 23,33 (4).

[00338] the Present invention also relates, in part, to the way to obtain the disodium salt. The disodium salt was obtained by suspension of compound IB-L0-2.3 (52,83 mg) in 1M aqueous NaOH (1.1 ml) (molar ratio connection: NaOH was 1:10). The solution was heated to 36°C, and the solid was completely dissolved with the formation of a transparent solution. This solution was naturally cooled to ambient temperature, and the salt crystallized in 24 hours Alternative, disodium salt was obtained by suspension of compound IB-L0-2.3 (51 mg) in EtOH (1 ml). Was added NaOH (1.2 ml of 5:1 V/V EtOH/H2O (2,1 molar equivalent). The reaction mixture was concentrated and 2 ml of acetonitrile was added to induce crystallization. The stoichiometry of this solid westwords using ion chromatography.

G4. Crystalline form of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide, monogalia salt.

[00339] the Present invention also relates, in part, to the crystalline form of montalieu salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00340] In some embodiments, implementation, monogalia salt has a powder x-ray containing one or more peaks selected from the group consisting of 5,0±0,2, 9,9±0,2, 11,3±0,2, 13,3±0,2, 16,9±0,2, 18,1±0,2, 19,1±0,2, 20,0±0,2, 21,1±0,2, 23,5±0,2, 24,8±0,2 and 25.7±0.2 degrees 2θ. In some such embodiments, implementation, monogalia salt has a powder x-ray that contains three or more peaks selected from the group consisting of 5,0±0,2, 9,9±0,2, 11,3±0,2, 13,3±0,2, 16,9±0,2, 18,1±0,2, 19,1±0,2, 20,0±0,2, 21,1±0,2, 23,5±0,2, 24,8±0,2 and 25.7±0.2 degrees 2θ. In other such embodiments, implementation, monogalia salt has a powder x-ray that contains five or more peaks selected from the group consisting of 5,0±0,2, 9,9±0,2, 11,3±0,2, 13,3±0,2, 16,9±0,2, 18,1±0,2, 19,1±0,2, 20,0±0,2, 21,1±0,2, 23,5±0,2, 24,8±0,2 and 25.7±0.2 degrees 2θ.

[00341] In some embodiments, implementation, monogalia salt has a powder x-ray containing one or more peaks selected from the group consisting of 5,0±0,2, 9,9±0,2, 11,3±0,2, 13,3±0,2, 16,9±0,2, 18,1±0,2, 19,1±0,2, 20,0±0,2, 21,1±0,2, 21,5±0,, 23,5±0,2, 24,8±0,2 and 25.7±0.2 degrees 2θ. In some such embodiments, implementation, monogalia salt has a powder x-ray that contains three or more peaks selected from the group consisting of 5,0±0,2, 9,9±0,2, 11,3±0,2, 13,3±0,2, 16,9±0,2, 18,1±0,2, 19,1±0,2, 20,0±0,2, 21,1±0,2, 21,5±0,2, 23,5±0,2, 24,8±0,2 and 25.7±0.2 degrees 2θ. In other such embodiments, implementation, monogalia salt has a powder x-ray that contains five or more peaks selected from the group consisting of 5,0±0,2, 9,9±0,2, 11,3±0,2, 13,3±0,2, 16,9±0,2, 18,1±0,2, 19,1±0,2, 20,0±0,2, 21,1±0,2, 21,5±0,2, 23,5±0,2, 24,8±0,2 and 25.7±0.2 degrees 2θ.

[00342] In some embodiments, implementation, monogalia salt has a powder x-ray are, essentially, as shown in Figure 17. The 2θ values for the peaks in Figure 17 (and their intensities) are the following: 4,97 (100), 9,94 (7), 11,33 (15), 13,28 (7), 16,91 (5), 18,13 (7), 19,14 (4), 20,00 (4), 21,13 (4), 21,45 (4), 23,54 (4), 24,84 (3) and 25,67 (6).

[00343] the Present invention also relates, in part, to a method for montalieu salt. Moncalieri salt was obtained in the aquatic environment. 0,366 ml of 1M aqueous KOH was added to 150,56 mg of compound IB-L0-2.3 (molar ratio 1:1,2). The resulting suspension was balanced in ambient conditions. Monogalia salt was formed the next day in the process, mediated dissolution. Alternatively, Moncalieri salt was obtained by suspension of compound IB-L0-2.3 (300 mg) is 3 ml of acetonitrile. Added KOH 1.3 ml of N2On (2,1 molar equivalent). Added an additional 1 ml of N2About to dissolve all solids. Then, 12 ml of acetonitrile was added to induce crystallization. The stoichiometry of the salt was confirmed using ion chromatography.

G5. Crystalline forms of N-(6-(2-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-PI)methanesulfonamide, monopoliova salt.

[00344] the Present invention also relates, in part, to crystalline forms monjolinho salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide, namely the sample and the sample of the crystalline forms described below.

[00345] the Present invention relates, in part, to the sample And kristallicheskij monjolinho salt.

[00346] In some embodiments, implementation, sample And monjolinho salt has a powder x-ray containing one or more peaks selected from the group consisting of 10,9±0,2, 12,1±0,2, 13,4±0,2, 15,5±0,2, 17,0±0,2, 17,8±0,2, 18,3±0,2, 19,5±0,2 and 21.9±0.2 degrees 2θ. In some such embodiments, implementation, sample And monjolinho salt has a powder x-ray that contains three or more peaks selected from the group consisting of 10,9±0,2, 12,1±0,2, 13,4±0,2, 15,5±0,2, 17,0±0,2, 17,8±0,2, 18,3±0,2, 19,5±0,2 and 21.9±0.2 degrees 2θ. In other such embodiments, Khujand the exercise of, sample And monjolinho salt has a powder x-ray that contains five or more peaks selected from the group consisting of 10,9±0,2, 12,1±0,2, 13,4±0,2, 15,5±0,2, 17,0±0,2, 17,8±0,2, 18,3±0,2, 19,5±0,2 and 21.9±0.2 degrees 2θ.

[00347] In some embodiments, implementation, sample And monjolinho salt has a powder x-ray containing one or more peaks selected from the group consisting of 10,9±0,2, 12,1±0,2, 13,0±0,2, 13,4±0,2, 13,6±0,2, 15,5±0,2, 17,0±0,2, 17,8±0,2, 18,3±0,2, 19,5±0,2, 19,7±0,2 and 21.9±0.2 degrees 2θ. In some such embodiments, implementation, sample And monjolinho salt has a powder x-ray that contains three or more peaks selected from the group consisting of degrees 2θ. In other such embodiments, implementation, sample And monjolinho salt has a powder x-ray that contains five or more peaks selected from the group consisting of degrees 2θ.

[00348] In some embodiments, implementation, sample And monjolinho salt has a powder x-ray are, essentially, as shown in Figure 19. The 2θ values for the peaks in Figure 19 (and their intensities) are the following: 19,94 (42), 12,06 (29), 12,96 (26), 13,42 (64), 13,64 (27), 15,51 (18), 16,98(78), 17,81 (26), 18,32(199), 19,49(48), 19,79 (33) and to 21.91 (22).

[00349] the Present invention also relates, in part, to a method for sample And monjolinho salt. He was received in a solvent mixture of tetrahydrofuran (THF) and methanol.Compound IB-L0-2.3 (56,79 mg) was dissolved in THF at 69°C, added 49,91 mg solution of choline hydroxide (45 mass% in methanol), resulting in the molar ratio 1:1,2. The crystals were formed by natural cooling to ambient temperature.

[00350] the Present invention also relates, in part, to the sample In the crystal monjolinho salt.

[00351] In some embodiments, implementation, sample monjolinho salt has a powder x-ray containing one or more peaks selected from the group consisting of 8,9±0,2, 9,4±9,2, 11,9±9,2, 13,9±9,2, 13,7±0,2, 15,9±9,2, 17,9±9,2, 18,3±9,2, 18,9±9,2, 19,8±9,2 and 22.1±9.2 degrees 2θ. In some such embodiments, implementation, sample monjolinho salt has a powder x-ray that contains three or more peaks selected from the group consisting of 8,9±9,2, 9,4±9,2, 11,9±9,2, 13,9±9,2, 13,7±9,2, 15,9±9,2, 17,9±9,2, 18,3±0,2, 18,9±9,2, 19,8±9,2 and 22.1±9.2 degrees 2θ. In other such embodiments, implementation, sample monjolinho salt has a powder x-ray that contains five or more peaks selected from the group consisting of 8,9±9,2, 9,4±9,2, 11,9±9,2, 13,9±9,2, 13,7±9,2, 15,9±9,2, 17,9±9,2, 18,3±9,2, 18,9±9,2, 19,8±9,2 and 22.1±9.2 degrees 2θ.

[00352] In some embodiments, implementation, sample monjolinho salt has a powder x-ray containing one or more peaks selected from the group consisting of 8,9±9,2, 9,4±0,2, 11,9±9,2, 13,9±9,2, 13,3±9,2, 13,7±9,2, 15,9±9,2, 17,9±9,2, 17,4±9,2, 18,3±9,2, 18,9±9,2, 19,8±9,2, 21,8±9,2 and 22.1±9.2 degrees 2θ. In some such embodiments, implementation, sample monjolinho salt has a powder x-ray that contains three or more peaks selected from the group consisting of 8,9±9,2, 9,4±9,2, 11,9±9,2, 13,9±9,2, 13,3±9,2, 13,7±9,2, 15,9±9,2, 17,9±9,2, 17,4±9,2, 18,3±0,2, 18,9±9,2, 19,8±9,2, 21,8±9,2 and 22.1±9.2 degrees 2θ. In other such embodiments, implementation, sample monjolinho salt has a powder x-ray that contains five or more peaks selected from the group consisting of 8,9±9,2, 9,4±9,2, 11,9±9,2, 13,9±9,2, 13,3±9,2, 13,7±9,2, 15,9±9,2, 17,9±9,2, 17,4±9,2, 18,3±9,2, 18,9±9,2, 19,8±9,2, 21,8±9,2 and 22.1±9.2 degrees 2θ.

[00353] In some embodiments, implementation, sample monjolinho salt has a powder x-ray are, essentially, as shown in Figure 21. The 2θ values for the peaks in Figure 21 (and their intensities) are the following: 7,96 (41), 9,38 (34), 10,96 (24), 12,98 (76), 13,34 (33), 13,72 (37), 15,90 (100), 17,03 (60), 17,42 (37), 18,30 (31), 18,85 (93), 19,82 (90), 21,76 (38) and representing 22.06 (46).

[00354] the Present invention also relates, in part, to the way the sample is received In monjolinho salt. It was obtained by suspension noncrystalline Kalinovo salt in ethyl acetate for seven days.

G6. Crystalline form of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide, cihalikova salt.

[00355] the Present invention also relates, in part, to the crystalline form daolin the howling salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00356] In some embodiments, implementation, cihalikova salt has a powder x-ray containing one or more peaks selected from the group consisting of 8,6±0,2, 11,0±0,2, 12,9±0,2, 17,0±0,2, 17,5±0,2, 18,9±0,2, 19,8±0,2 and 21.9±0.2 degrees 2θ. In some such embodiments, implementation, cihalikova salt has a powder x-ray that contains three or more peaks selected from the group consisting of 8,6±0,2, 11,0±0,2, 12,9±0,2, 17,0±0,2, 17,5±0,2, 18,9±0,2, 19,8±0,2 and 21.9±0.2 degrees 2θ. In other such embodiments, implementation, cihalikova salt has a powder x-ray that contains five or more peaks selected from the group consisting of 8,6±0,2, 11,0±0,2, 12,9±0,2, 17,0±0,2, 17,5±0,2, 18,9±0,2, 19,8±0,2 and 21.9±0.2 degrees 2θ.

[00357] In some embodiments, implementation, cihalikova salt has a powder x-ray containing one or more peaks selected from the group consisting of 8,6±0,2, 11,0±0,2, 12,9±0,2, 17,0±0,2, 17,5±0,2, 18,9±0,2, 19,8±0,2, 21,9±0,2 and 22.1±0.2 degrees 2θ. In some such embodiments, implementation, cihalikova salt has a powder x-ray that contains three or more peaks selected from the group consisting of 8,6±0,2, 11,0±0,2, 12,9±0,2, 17,0±0,2, 17,5±0,2, 18,9±0,2, 19,8±0,2, 21,9±0,2 and 22.1±0.2 degrees 2θ. In other such embodiments, implementation, cihalikova salt has a powder x-ray that contains five or more peaks selected from the group consisting of 8,6±0,2, 11,0±0,2, 12,9±0,2, 17,0±0,2, 17,5±0,2, 18,9±02, 19,8±0,2, 21,9±0,2 and 22.1±0.2 degrees 2θ.

[00358] In some embodiments, implementation, cihalikova salt 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: 8,62 (28), 10,98 (29), 12,93 (50), 15,88 (100), 17,03 (42), 17,47 (29), 18,88 (66), 19,82 (57), 21,89 (42), 2,07 (41).

[00359] the Present invention also relates, in part, to a method for cihalikova salt. It was prepared by suspension of compound IB-L0-2.3 (200 mg) in 0.75 ml of the Meon. Added choline hydroxide in the Meon (210 ml, 45 mass%, 2,10 molar equivalent). The reaction mixture was concentrated, and added to 4 ml of acetonitrile and 6 ml of isopropylacetate. The reaction mixture was then led trace quantities of seed crystals montalieu salt of compound IB-L0-2.3 (discussed above). Shortly thereafter, the reaction mixture began to crystallize. The stoichiometry of the salt was determined using the1H NMR in solution.

N. Song.

[00360] 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/Hydra is tov), discussed above in section G. These composition can be a pharmaceutical composition.

[00361] 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.

[00362] 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).

[00363] 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 is m, 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.

[00364] Liquid dosage forms for oral administration include, for example, pharmaceutically acceptable emulsions (including as emulsion, oil-in-water, emulsion water-in-oil), solutions (including both aqueous 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., sweeteners and/or flavouring agents.

[00365] Parenteral administration includes subcutaneous injection, intravenous injection, intramuscular injection, in triglycine 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.

[00366] 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 formulations for 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.

[00367] Suppositories for rectal injection can be obtained, for example, by mixing the compound or salt of the present is briteney with a 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.

[00368] the Local application includes the use of percutaneous administration, such as transdermal patches or device for iontophoresis.

[00369] can Also be used with other excipients and methods of administration known in the pharmaceutical field.

[00370] 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.

[00371] the Factors affecting the preferred dosage regimen include the type, against the t, body 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 medicines. 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.

[00372] 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.

[00373] 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 the variants of 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.

[00374] the Present invention also relates to 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.

[00375] 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 prima is but 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%.

[00376] 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, to a 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. Methods of treatment, particularly suitable for use in humans, but can be used in other animals, particularly mammals. "Therapeutically-effective amount of the om" or "effective amount" is the amount, which will achieve the purpose of treatment of the target state.

[00377] 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 used to treat 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 of several seconds is (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.

[00378] 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.

[00379] In some embodiments, the implementation, the drug is intended for the inhibition of the replication of the RNA virus.

[00380] In some embodiments, the implementation, the drug is intended to treat hepatitis C.

[00381] 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, implementation of drug is designed to inhibit the replication of the RNA virus. In other embodiments, implementation, drug is intended to treat hepatitis C.

K. Intermediate connection.

[00382] the Present invention also relates, in part, to intermediate compounds that correspond in structure to formula II, which can be used to obtain the 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):

.

[00383] In the formula II:

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

X2is a halo.

[00384] Different ways embodiment for, R1, R2, R3, R4and R5(and their combinations), discussed above, are applicable to the 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 status is the present 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 X2represents bromine. And in some cases implement, X2represents iodine.

[00385] Different ways embodiment for, R1, R2, R3, R4, R5and X2discussed 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.

[00386] In some embodiments, implementation of the compounds of formula II correspond to the structure of formula IIA:

.

[00387] In other embodiments, implementation of the compounds of formula II correspond to the structure of formula IIB:

.

[00388] In some embodiments, embodiments of compounds of formula II:

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

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

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

[00389] 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, hydroxy and methoxy; and

X2selected from the group consisting of bromine and iodine.

[00390] In some embodiments of the incarnation with the joining of the 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

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

[00391] 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.

[00392] In some embodiments, the implementation, the compound of formula II selected from the group consisting of

,,.

[00393] the following description provides instructions for obtaining the intermediate compounds of formula II (and their salts).

L. the Original connection.

[00394] the Present invention also relates, in part, to the original compounds that correspond in structure to formula III, which can be used for p which produce compounds of formulas II and I (and their salts):

.

[00395] In formula III,, R1, R2and R3above for compounds of formulas I and II. Different ways embodiment for, R1, R2and R3(and their combinations), discussed above, are applicable to the 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.

[00396] 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.

[00397] 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 is halogen; and

R3selected from the group consisting of hydrogen.

[00398] 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 consisting of hydrogen and methyl.

[00399] In some embodiments, the implementation, the compound of formula III represents a uracil.

[00400] 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):

.

[00401] In the formula IV:

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

X1is a halo.

[00402] 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 the ode 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, X* represents iodine. As for the X1and X2in some embodiments, implementation, X1and X2are identical.

[00403] 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.

[00404] 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 not battelino 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;

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

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

[00405] 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.

[00406] 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.

[00407] 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.

[00408] In some embodiments, the implementation, the compound of formula IV selected from the group consisting of

,and

[00409] the following description provides instructions for obtaining the source compounds of the formula IV (and their salts).

L. Methods of obtaining.

[00410] the Present invention also relates, 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:

[00411] In the above process R1, R2, R3, R4, R5X1and X2have the above values.

[00412] the 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.

[00413] In some embodiments of the invention the compound III made the focus of a uracil and compound IV corresponds to the structure of the connection, 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.

[00414] Suitable copper catalysts Cu(1) include, for example, CuI, CuBr, CuCl, CuzO 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.

[00415] 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 the bottom of these embodiments salt of cesium represents Cs 2CO3.

[00416] Typically, the process is conducted in the presence of a solvent. Suitable solvents include, for example, dimethylsulfoxide (DMSO), dimethylformamide (DFA) and acetonitrile (MeCN). In some embodiments of the invention the solvent is DMSO.

[00417] Typically, the process is conducted at a temperature of from about 40 to about 130°C.

[00418] 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:

[00419] In the formula V R11, R12, R13, R14, R15, R16and R17independently selected from the group consisting of hydrogen, C1-4-perfluoroalkyl, C1-4alkoxy, 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 of formula V include N-(4-cyanophenyl)picolinate. In other embodiments of the invention, the ligand of formula V include N-(2-cyanophenyl)picolinate.

[00420] In some embodied the Affairs of the invention the method comprises (a) obtaining a compound of formula IV; and

(b) reaction of compounds 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 optionally in the presence of inorganic bases.

[00421] 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).

[00422] 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, his treatment of CH3I in the presence of KOtBu).

[00423] 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 X 2have, unless otherwise stated, the above values.

Scheme 1

[00424] the Compound (1-1), where R7is, for example, hydrogen or-CO2Me and R8is, for example, hydrogen 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 those whom rehydrator, 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 tin chloride (II) in the presence of hydrochloric acid in solvents such as, for example, water and methanol or a mixture.

[00425] 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, guide the ID of sodium 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 such a reagent as (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 compound (1-7).

[00426] 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), COI is lsua, 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.

[00427] Another modification of phenolic groups in the compound (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

[00428] 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 from receipt of Florange the IDA (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, for 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

[00429] the Compound (3-1) where R10is, for example, hydrogen, bromine, iodine or-CO2IU can be processed 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 approximately 2 PR is approximately up to 48 hours to obtain the compound (3-4).

Scheme 4

[00430] 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 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 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

[00431] 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 bromine or 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, CT is ONAT potassium, 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 dimethyl sulfoxide at a temperature of from about 40°to about 100°C to obtain compound (20-5).

[00432] 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 6

[00433] 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, within primer is 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.

Scheme 7

[00434] Connection (26-1), where each Z independently represents N or CH, can be transformed into the ether Bronevoy acid for use in Suzuki reactions. For example, the compound of formula (26-1) can be converted into compound (26-2), where R14represents hydrogen or methanesulfonyl (using excess methanesulfonanilide), the processing methanesulfonamido in pyridine at about ambient temperature for about 1-8 hours.

[00435] the Compound (26-2) can be converted to compound (26-3) processing pinacol-borane in the presence of a catalyst, such as, for example, Tris(dibenzylidineacetone)dipalladium (0), ligand, such as tri-t-butylphosphine, and bases, such as triethylamine, in a solvent such to the to, for example, tetrahydrofuran, dioxane or toluene, at a temperature from ambient temperature to about 130°C.

[00436] you Can also interact compounds (26-2) with bis(pinacolato)diboron in the presence of a catalyst, such as, for example, Combiphos® Pd6, adduct dichloro[1,1'-bis(diphenylphosphino)ferrocene] palladium (II)/dichloromethane or palladium acetate, in the presence of ligand, such as, for example, 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (XPhos), and bases, such as potassium acetate, in a solvent, such as, for example, toluene, dioxane, tetrahydrofuran, dimethylformamide or dimethylsulfoxide, at a temperature of from about 60 to about 130°C to obtain compound (26-3).

[00437] Connection (26-3) can be converted into a protected connection (26-4) treatment benzylchloride at about 0°C in the presence of a saturated aqueous solution of sodium bicarbonate in a mixture of acetone and water. The mixture can be heated to ambient temperature and can be maintained at this temperature for about 12 to 24 hours. Then the connection (26-4) can be transformed into enconomy ether Bronevoy acid (26-5) using the above conditions.

Scheme 9

[00438] Connection (26-5), where each Z independently represents N or CH, can be connected with the connection (-7) under the reaction conditions combination Suzuki obtaining compounds (27-3). Such conditions include, for example, using a palladium catalyst, such as, for example, Tris(dibenzylidineacetone)palladium (0), palladium acetate, bis(triphenylphosphine)palladium (II) chloride, tetrakis(triphenylphosphine)palladium or adduct dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)/dichloromethane; bases, such as, for example, potassium carbonate, potassium phosphate, t-butyl potassium, sodium carbonate, cesium carbonate or cesium fluoride; and a solvent, such as toluene, ethanol, water or tetrahydrofuran or mixtures thereof, is heated to about 40-130°C.

[00439] Connection (27-3) can be converted to compound (27-4) in three stages. The first stage involves removal of the protective t-butoxycarbonyl group with acids such as, for example, triperoxonane acid, in a solvent such as, for example, dichloromethane or hydrochloric acid in dioxane at room temperature for about 1-24 hours. Then you can enter dihydropyrimidine as described in Scheme 3.

[00440] Connection (up 27-5) can be obtained from compound (27-4) in two stages. First, in terms of recovery naphtylamine remove the protective group. As a rule, it is rare (~1 atmosphere) in the presence of a catalyst, such as, for example, 10% palladium on charcoal, in a solvent such as, for example, ethylacetate, at a temperature of OCD the global environment or near it for about 8-24 hours. Then naphtylamine can be directly sulfonylurea treatment methanesulfonamido in the presence of a base, such as triethylamine, in a solvent (e.g. dichloromethane) at room temperature for from about 20 minutes to about 4 hours.

Scheme 10

[00441] Connection (28-1), where each Z independently represents N or CH and R15for example, hydrogen, -NHSO2Me, -N(SO2Me)2or methoxy, may be connected with the connection (1-7) under the reaction conditions combination Suzuki obtaining compounds (28-3). Such conditions include, for example, using a palladium catalyst, such as, for example, Tris(dibenzylidineacetone)palladium (0), palladium acetate, bis(triphenylphosphine)palladium (II) chloride, tetrakis(triphenylphosphine)palladium or adduct dichloro[1,1'-bis(diphenylphosphino)ferrocene] palladium (II)/dichloromethane; bases, such as, for example, potassium carbonate, potassium phosphate, t-butyl potassium, sodium carbonate, cesium carbonate or cesium fluoride; and a solvent, such as toluene, ethanol, water or tetrahydrofuran or mixtures thereof and heated to about 40-130°C. Before heating, as a rule, remove the oxygen with an inert gas, for example nitrogen. Heating can be accomplished in conventional glass sealed tube or in a microwave reactor for about 1-24 hours.

Scheme 11

[00443] Connection (28-1), where each Z independently represents N or CH and R15for example, hydrogen, -NHSO2Me, -N(SO2Me)2or methoxy, may be connected with the connection (29-2), where X1for example, bromine or iodine, the reaction conditions combination Suzuki obtaining the compounds of formula (28-3). Such conditions include, for example, using a palladium catalyst, such as, for example, Tris(dibenzylidineacetone)palladium (0), palladium acetate, bis(triphenylphosphine)palladium (II) chloride, tetrakis(triphenylphosphine)palladium, adduct dichloro[1,1'-bis(diphenylphosphino)ferrocene] palladium (II)/dichloromethane or bis(diphenylphosphino)ferrocene] palladium (II) dichloromethane; bases, such as, for example, potassium carbonate, potassium phosphate, t-butyl potassium, sodium carbonate, the cesium carbonate or cesium fluoride; and a solvent, such as, for example, toluene, ethanol, water or tetrahydrofuran or mixtures thereof, is heated to about 40-130°C. Before heating, as the government is about, remove the oxygen with an inert gas, for example nitrogen. Heating can be accomplished in conventional glass sealed tube or in a microwave reactor for about 1-24 hours.

Scheme 12

[00444] you Can interact compounds (30-1), where X1represents a bromine or iodine, n is 1 or 2 and Z represents CH or N, with bis(pinacolato)diboron in the presence of a catalyst, such as, for example, Combiphos® Pd6, adduct dichloro[1,1'- bis(diphenylphosphino)ferrocene] palladium (II)/dichloromethane or palladium acetate, in the presence of ligand, such as, for example, 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (XPhos), and bases, such as, for example, potassium acetate, in solvents such as, for example, toluene, dioxane, tetrahydrofuran, dimethylformamide or dimethylsulfoxide, at a temperature of from about 60 to about 130°C to obtain compound (30-2). Prior to heating, as a rule, remove the oxygen with an inert gas, for example nitrogen. Heating can be accomplished in conventional glass sealed tube or in a microwave reactor for about 1-24 hours. Connection (30-3), you can enter into reaction with the compound (30-2) to obtain the compound (30-4) using a described in Scheme 29 conditions.

[00445] Processing connection (30-4) methysulfonylmethane in a solvent such as, e.g. the measures tetrahydrofuran, methanol or ethanol or their mixture, at a temperature from ambient temperature to about 100°C. for 8-48 hours gives compound (30-5).

Scheme 13

[00446] the Compound (31-1) can be processed hexamethyldisilane or hexabutylditin in the presence of a catalyst, such as, for example, bis(triphenylphosphine)palladium (II) chloride, in a solvent such as, for example, toluene or dioxane at about 50 about 130°C to obtain compound (31-2). Connection (31-2) can be processed by the connection (31-3) in the presence of a catalyst, such as, for example, Tris(dibenzylidineacetone)palladium (0) and a ligand such as Tris(2-furyl)phosphine in a solvent such as, for example, toluene, dioxane or tetrahydrofuran, heated to about 40-130°C to obtain compound (31-4).

Scheme 14

[00447] you Can sulfonylamine dinitroaniline (34-1) methanesulfonanilide in the presence of a base, such as pyridine, in a solvent such as, for example, dichloromethane, at room temperature for about 8-36 hours to obtain compound (34-2). Connection (34-2) can be converted into compound (34-3), using iron filings in the presence of weak acids, such as, for example, ammonium chloride or dilute hydrochloric acid, when n is greaney under reflux in a mixture of solvents, such as, for example, methanol, water and tetrahydrofuran, for about 1-12 hours.

Scheme 15

[00448] Connection (35-1), you can enter into interaction with the compound (35-2), where Z1represents O, S or NH, and R16represents hydrogen, -NHSO2Me or NO2in the presence of being in contact with air charcoal in the environment of a solvent, such as toluene, by heating from about 90 to about 110°C for approximately 24 to 72 hours to obtain compound (35-3).

Scheme 16

[00449] Connection (36-1), where Z2represents O or S, can be restored to the connection (36-2), using 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 90°C. in solvents such as, for example, methanol, ethanol, water and tetrahydrofuran or mixtures thereof, for from about 30 minutes to about 12 hours. You can spend sulfonylamine connection (39-2) methanesulfonanilide in the presence of a base, such as pyridine in a solvent such as, for example, dichloromethane, at room temperature for about 8-36 hours.

Scheme 17

[00450] Connection (37-1) may be, for example, what does sulfonylamino methanesulfonamido in the presence of a base, for example, pyridine, in a solvent such as, for example, dichloromethane, at room temperature for about 8-36 hours to obtain compound (37-2). Connection (37-2) can be subjected to interaction with (4-methoxyphenyl)methanethiol in the presence of a base, such as potassium carbonate, in a solvent such as, for example, dimethylformamide, heated to about 90-110°C. for about 8-24 hours to obtain compound (37-3). Connection (37-3) can be restored to the connection (37-4), using 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 90°C., in a solvent such as, for example, methanol, ethanol, water and tetrahydrofuran or mixtures thereof, for from about 30 minutes to about 12 hours. Connection (37-4) can be converted into compound (37-5) in the presence of acetate mercury (II), anisole and triperoxonane acid at about 0°C for approximately 30 to 90 minutes, followed by bubbling hydrogen sulfide through the mixture. Connection (37-5) can be processed by the connection (37-6) in the presence of p-toluenesulfonic acid and triphenylphosphine in a solvent such as, for example, toluene, heated to a temperature phlegmy for about 2-16 hours to obtain compound (37-7).

Scheme 18

[00451] Connection (38-1), where X1represents a bromine or iodine and Z2represents O or S, you can enter into interaction with 2.5-hexanedione in the presence of p-toluenesulfonic acid and pyridine, which when heated in benzene to obtain the compounds of formula (38-2). Connection (38-2), you can enter into interaction bis(pinacolato)diboron in the presence of a catalyst, such as, for example, Combiphos® Pd6, adduct dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium (II)/dichloromethane or palladium acetate, in the presence of ligand, such as, for example, 2-dicyclohexylphosphino-2',4',6'-triisopropylphenyl (XPhos), and bases, such as potassium acetate, in a solvent such as, for example, toluene, dioxane, tetrahydrofuran, dimethylformamide or dimethylsulfoxide, at a temperature of from about 60 to about 130°C to obtain compound (38-3). Connection (38-3) can be entered into interaction with the compound (38-4) to obtain the compound (38-5) under the reaction conditions of a combination of Suzuki. Such conditions include, for example, the use of palladium catalyst, such as, for example, dihydro dichlorobis(di-t-butylphosphino-KP)palladate(2-), Tris(dibenzylidineacetone)palladium (0), palladium acetate, bis(triphenylphosphine)palladium (II) chloride, tetrakis (triphenylphosphine)palladium or adduct dichloro[1,1'-bis(diphenylphosphino)ferrocene] palladium (II)/dichloromethane; the base is, such as, for example, potassium acetate, potassium carbonate, potassium phosphate, t-butyl potassium, sodium carbonate, cesium carbonate or cesium fluoride; and a solvent, such as, for example, toluene, ethanol, water or tetrahydrofuran or mixtures thereof, is heated to about 40-130°C.

[00452] Connection (38-5) can be treated with hydroxylamine hydrochloride in hot ethanol to remove the protective pyrrole group. Then processing methanesulfonamido in the presence of a base, such as pyridine, in a solvent such as, for example, dichloromethane, at ambient temperature or close to it, gives compound (38-6).

EXAMPLES

[00453] the Following examples are merely explanatory and not limiting this description in any way.

[00454] Example A. Obtaining (E)-N-(3-tert-butyl-5-iodine-4-methoxyphenylacetyl)-3-methoxy acrylamide.

[00455] Part A. Obtain 2-tert-butyl-4-NITROPHENOL.

[00456] 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 of 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 R is h hexane (200 ml) to produce color powder cocoa, which was dried to constant weight (4,65 g, 35.6 percent).

[00457] part of the Century, Obtaining 2-tert-butyl-6-iodine-4-NITROPHENOL.

[00458] 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%).

[00459] Part C. Obtain 1-tert-butyl-3-iodine-2-methoxy-5-nitrobenzene.

[00460] To a cooled on 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 HCl, 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%).

[00461] Part D. Obtain 3-tert-butyl-iodine-4-methoxyaniline.

[00462] 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).

[00463] Part E. Obtaining (E)-N-(3-tert-butyl-5-iodine-4-methoxyphenylacetyl)-3-methoxy acrylamide.

[00464] 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 was ground into powder in Et2O/hexane to obtain fine powder, which was collected by filtration and dried to obtain a yellowish-brown powder (2,46 g, 57%).

[00465] Example Century. Obtain 1-(3-tert-butyl-5-iodine-4-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[00466] 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%).

[00467] Example C. Obtain 1-(3-tert-butyl-5-iodine-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00468] Part A. Obtain 2-tert-butyl-4,6-deadpool.

[00469] 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) of sodium iodide, and sodium hypochlorite solution was added until 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 cooling the s 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.

[00470] part of the Century, Obtaining 1-tert-butyl-3,5-dead-2-methoxybenzene.

[00471] 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 was extracted with a saturated solution of sodium chloride. Drying (Na2SO4) and concentration in vacuo gave the product (20,59 g, 99%) as a pale yellow oil.

[00472] Part C. Obtain 1-(3-tert-butyl-5-iodine-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00473] Suspension products Part In (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 solid amber 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 Phi is trevanian. 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%).

[00474] Example D. Obtain 1-(3-tert-Butyl-5-iodine-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00475] Part A. Obtain 2-tert-butyl-4,6-deadpool.

[00476] 2-tert-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 conc. 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 p is d vacuum overnight (about 15 h) to obtain the output 289,33 g (potentially adjusted output = 254,61 g) of the named product.

[00477] part of the Century, Obtaining 1-tert-butyl-3,5-dead-2-methoxybenzene.

[00478] 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.

[00479] Part C. Obtain 1-(3-tert-butyl-5-iodine-4-methoxyphenyl)pyrimidine-2,4(1H,3H)- dione.

[00480] 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 inert 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)2,then 2×830 ml of 15% NH4 Cl, 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.

[00481] Example E. Obtain N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00482] a Solution of 100 ml of water and 300 ml of THF was barbotirovany nitrogen, and then transferred via cannula under nitrogen pressure, into a flask containing 19,9965 g (49,96 mmol) of the product from Example D, 20,8234 g (59,97 mmol, 1.20 equivalents) of N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)methanesulfonamide and 21,8711 g (103,03 mmol, 2.06 to equivalents) of potassium phosphate, which had been purged with nitrogen. Through the resulting solution was again bubbled nitrogen.

[00483] THF (100 ml) was barbotirovany nitrogen, and then using a cannula transferred under nitrogen pressure, into a flask containing 462,8 mg (0.51 mmol, 0.01 equivalents) Pd2dba3and 735,8 mg (2,52 mmol, 0.05 equivalents) of 1,3,5,7-tetramethyl-6-phenyl-2,4,8-trioxa-6-phosphaadamantane, which had been purged with nitrogen. Through the resulting solution was again barbotin the Ute nitrogen.

[00484] the Original solution of THF/water transferred via cannula under nitrogen pressure in the flask containing the catalyst and ligand in THF. The reaction mixture was heated to 50°C. and stirred overnight under constant nitrogen pressure. The next morning took the reaction sample. The results of the HPLC sample showed 0,28 RA% source iodouracil, 76,8 RA% product and 5.2 RA% of boronate.

[00485] the Reaction mixture was cooled to room temperature and washed three portions, a solution of 5.84 g of L-cysteine and of 81.4 g of sodium chloride in 550 ml of water, which was barbotirovany nitrogen. The THF solution was filtered through a layer of celite. Layer was washed with 100 ml of THF, which was combined with the original solution of THF. The THF solution was concentrated on a rotary evaporator to 136, the white suspension was added 405 ml of ethyl acetate at a good shaking. The suspension was filtered after stirring over night. The filter residue was washed 2×50 ml of ethyl acetate. Solid, MES ethyl acetate, dried in a vacuum oven at 50°C. the Mass was 25,49,

[00486] Solid and 8.7 g of 3-mercaptopropyl-derived silica gel was stirred in 500 ml of THF, then filtered through a layer of cellite. The filtrate was concentrated on a rotary evaporator to obtain 13,08 g solid white. Solid, which was filtered on a layer of cellite, was extracted with 500 ml of TF at 60°C. The THF solution was concentrated to 66 g and processed 206 ml of ethyl acetate. The precipitated solid was filtered and dried, obtaining 9,13 g of the product. This solid was combined with the original solid and suspended in 100 ml of ethanol and 200-proof 3A. Was filtered and dried in a vacuum oven at 50°C with getting 20,74 g of the product.

[00487] Example 1. Obtaining N-(6-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IA-L0-2.9).

[00488] Part A. Obtain 6-bromo-2-naphthoic acid.

[00489] a Solution of methyl 6-bromo-2-naphthoate (of 7.70 g, 29,0 mmol) in a mixture of 2:1 THF: water (150 ml) was treated with hydrate of lithium hydroxide (2,44 g, to 58.1 mmol) followed by stirring at room temperature for 48 hours then Concentrated under vacuum, diluted with water and cooled to 0°C. was Acidified to pH 3 with 4 n HCl. The solids were collected by filtration, dissolved in toluene-EtOAc (approximately 2 l) and washed with saline. Dried over Na2SO4, filtered and concentrated under vacuum. Solid brown was ground into powder with ether, collected by filtration and dried under vacuum to obtain these compounds in the form of an almost white solid (5,07 g, 70%).

[00490] part of the Century, Obtaining 6-bromonaphthalene-2-amine.

[00491] R is the target product of Part a (5,07 g, 20,19 mmol) and triethylamine (4,22 ml of 3.07 g, 30.3 mmol) in dry DMF (155 ml) was treated with diphenylphosphonate (6,55 ml, 8.34 per g, 30.3 mmol), followed by stirring at room temperature for 3 hours Then the solution was treated with water (20 ml) followed by heating at 100°C for 1 h the Solution was cooled and the flask was supplied with the nozzle for molecular distillation, and DMF was removed by distillation under high vacuum. The solid residue was dissolved in EtOAc and washed with saturated sodium bicarbonate solution. Filtered through celite, and the filtrate was washed with water (3x), and then brine. Dried over Na2SO4, filtered and concentrated under vacuum to obtain these compounds in a solid beige color (4,48 g, 100%).

[00492] Part C. the Receipt of benzyl 6-bromonaphthalene-2-ylcarbamate.

[00493] a Mixture of the product from Part b (1,79 g of 8.06 mmol) and saturated sodium bicarbonate solution (18 ml) in acetone (40 ml) at 0°C was treated dropwise with benzylchloride. The mixture was stirred at 0°C for 1 h, and then left for gradual warming to room temperature for 18 hours the Mixture was diluted with EtOAc and water and the layers separated. The organic layer was extracted with water and washed with saline. Dried over Na2SO4, filtered and concentrated under vacuum. Purification using column chrome is adopted on silica gel with elution of EtOAc /hexane gave the titled compound in a solid pink color (1.5 g, 52%).

[00494] Part D. Getting benzyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl carbamate.

[00495] reseal the vessel Slanka containing a solution of the product from Part C (1.42 g, 3,99 mmol), bis(pinacolato)LIBOR (1,11 g, 4,39 mmol), and potassium acetate (1,17 g, 11,96 mmol) in DMF (28 ml) was degirolami through three cycles of freezing-thawing. The solution was treated with a complex of 1,1'-bis(diphenylphosphino)ferrocene palladium (II) Chlorodifluoromethane (98 mg, 0.12 mmol), followed by degassing by two additional cycles of freezing and thawing. Vessel Slanka then hermetically closed, and the mixture was heated at 80°C for 18 hours was Cooled and was diluted with ethyl acetate and water. The mixture was treated with Darco G-60, and then filtered through celite. The filtrate was extracted with water (4x) and a saturated solution of sodium chloride. Dried over Na2SO4, filtered and concentrated under vacuum to obtain a light brown oil. Purification using column chromatography on silica gel with elution of EtOAc/hexane gave the titled compound as a colourless oil (910 mg, 57%).

[00496] Part of that is Getting 2-tert-butyl-4-NITROPHENOL.

[00497] 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 of 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 once with hexane (200 ml) to obtain the powder color of cocoa, which was dried to constant weight (4,65 g, 35.6 percent).

[00498] Part F. Obtain 2-bromo-6-tert-butyl-4-NITROPHENOL.

[00499] a solution of the product from Part E (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 pyridine the 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 the 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%).

[00500] Part G. Obtain 1-bromo-3-tert-butyl-2-methoxy-5-nitrobenzene.

[00501] a solution of the product from Part F (1.40 g, 5,11 mmol) in a mixture of 10:1 t-butylmethylether-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 the 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%).

[00502] Part N. Obtain tert-butyl 3-bromo-5-tert-butyl-4-methoxyphenylalanine.

[00503] a solution of the product from Part G (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-BUTYLCARBAMATE (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 an almost white solid (890 m g, 75%).

[00504] Part I. Getting benzyl 6-(3-tert-butyl-5-(tert-butylcarbamoyl)-2-methoxyphenyl) naphthalen-2-yl carbamate.

[00505] Toluene (928 μl) and EtOH (928 μl) was combined with the product from Part H (133 mg, and 0.37 mmol), the product from Part D (299 mg, 0,74 mm is l) and 1M sodium carbonate (371 μl, of 0.37 mmol) and degirolami for 20 min with nitrogen. Added tetrakis(triphenylphosphine)palladium(0) (8.6 mg, 7.4 mmol) and degassing continued for 5-10 minutes was Heated at 85-90°C for 18 h, cooled and concentrated under vacuum. Purification using column chromatography on silica gel with elution of EtOAc/hexane gave the titled compound (102 mg, 49%).

[00506] Part J. the Receipt of benzyl 6-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-ylcarbamate.

[00507] a solution of the product from Part I (100 mg, 0.18 mmol) in CH2Cl2(1.0 ml) was treated triperoxonane acid (0.5 ml, 6.5 mmol) at room temperature for 1 h then Concentrated under vacuum. Was dissolved in ethyl acetate, washed with 10% NaHCO3, saline. Dried over Na2SO4, filtered and concentrated under vacuum. Was dissolved in toluene (1.0 ml) was added Et3N (25 μl, 0.18 mmol) and acrylic acid (13 μl, 0,19 mmol) and the mixture was heated under reflux for 16 hours then Concentrated under vacuum. Was dissolved in acetic acid (1.0 ml, 17.5 mmol) was added urea (to 11.9 mg, 0.20 mmol) and was heated under reflux for 72 hours was Cooled and poured into ice water, extracted three times with CHCl3the extracts were combined, dried over Na2SO4, filtered and concentrated under vacuum. Purification is by column chromatography on silica gel, with the elution of EtOAc/hexane gave the titled compound (of 57.5 mg, 58%).

[00508] K. Obtain N-(6-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00509] Combined product from Part J (56 mg, 0.10 mmol) and EtOAc (1.0 ml) was added 10% palladium on coal (10 mg). Was stirred under pressure gaseous H2from balloon tires for 16 hours was Filtered through celite and concentrated under vacuum. Was dissolved in CH2Cl2(1.0 ml) was added Et3N (16 μl, 0,115 mmol) and methanesulfonamide (8,7 μl, 0,112 mmol) and stirred at room temperature for 30 minutes then Concentrated under vacuum, and purification using column chromatography on silica gel with elution of EtOAc/hexane gave the titled compound (10 mg, 20%).1H NMR (300 MHz, DMSO-d6) δ 1.34-1.48 (m, 9 H), 2.71 (t, J=6.62 Hz, 2 H) 3.08 (s, 3 H), 3.21 (s, 3 H) 3.82 (t, J=6.62 Hz, 2 H) 7.26 (s, 2 H) 7.41 (dd, J=8.82, 1.84 Hz, 1 H) 7.59-7.76 (m, 2 H) 7.89-8.04 (m, 3 H) 10.03 (s, 1 H), 10.34 (s, 1 H); MS (ESI+) m/z 496 (M+H)+; (ESI-) m/z 494 (M-H)-.

[00510] Example 2A. Obtaining N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.3).

[00511] Part A. Obtain N-(6-bromonaphthalene-2-yl)methanesulfonamide.

[00512] a solution of the product from Example 1, Part (4,48 g, 20,17 mmol) in pyridine (100 ml) was treated dropwise with methanesulfonanilide (197 ml, 2,89 g of 25.2 mmol) followed by stirring at room temperature for 1 h was Diluted with toluene and twice concentrated under vacuum. The residue was extracted with EtOAc and washed with water, 1M citric acid and a salt solution. Processed Dareo G-60, dried over Na2SO4was filtered through celite and concentrated under vacuum. The solid was ground into powder with ether-hexane, collected by filtration and dried under vacuum to obtain these compounds in the form of a solid pale pink color (of 3.32 g, 55%).

[00513] part of the Century, Obtaining N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl) methanesulfonamide.

[00514] a Mixture of the product from part a (1,00 g of 3.33 mmol), bis(pinacolato)Debora (1.27 g, 5.00 mmol), potassium acetate (0,98 g of 9.99 mmol) and Combiphos Pd6 (84 mg, 0,17 mmol) in toluene (22 ml) was heated under reflux for 3 hours was Cooled and was diluted with ethyl acetate and water. The mixture was treated with Darco G-60 and filtered through celite. The filtrate was washed with water and brine. Dried over Na2SO4, filtered and concentrated under vacuum. The oil was dissolved in ether and precipitated by adding hexane. The product was collected by filtration and washed with hexane. Evaporation of the filtrate and purification using column chromatography on silica gel with elution of EtOAc/hexane. A named connection in resultattributelist and chromatography was obtained in the form of a solid white color (927 mg, 80%).

[00515] Part C. Obtain tert-butyl 3-tert-butyl-4-methoxy-5-(6-(methylsulfonyl) naphthalen-2-yl)phenylcarbamate.

[00516] Combined product from Example 1, Part H (87 mg, 0,243 mmol), the product from Part b (169 mg, 0,486 mmol), toluene (1.0 ml), ethanol (1.0 ml) and sodium carbonate (0,243 ml, 0,243 mmol) in a sealed tube and was degirolami gaseous N2within 20 minutes was Added tetrakis(triphenylphosphine)palladium(0) (5,61 mg, a 4.86 mmol) and degassing was continued for another 5 to 10 minutes) was Heated at 90-95°C for 16 hours was Cooled and concentrated under vacuum. Purification using column chromatography on silica gel with elution of EtOAc/hexane gave the titled compound (92,2 mg, 76%).

[00517] Part D. Obtain N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00518] a solution of the product from Part C (90 mg, 0,180 mmol) in CH2Cl2(2.0 ml) was treated triperoxonane acid (1.0 ml, 12,98 mmol) at room temperature for 1 h then Concentrated under vacuum, the residue was dissolved in EtOAc, washed with 10% NaHCO3and saline. Dried over Na2SO4, filtered and concentrated under vacuum. Was dissolved in DMF (1.4 ml) and cooled to -25°C and added (E)-3-methoxy-acrilonitrile (0,633 ml, 0,361 mmol) dropwise, keeping the temperature below -10°C. was Heated to room tempera is URS and was stirred for 2 hours Was poured into ether, washed with water and brine. Dried over Na2SO4, filtered and concentrated under vacuum. Was added a mixture of H2SO4(0.1 ml, 1,876 mmol), water (1.0 ml) and EtOH (1.0 ml), and stirred at 100°C. for 16 hours was Cooled and concentrated under vacuum. Was poured into water, extracted with EtOAc, the extracts were combined and washed with saline. Dried over Na2SO4, filtered and concentrated under vacuum. Purification using column chromatography on silica gel with elution of the Meon/CHCl3gave the titled compound (53 mg, 59%).1H NMR (300 MHz DMSO-d6) δ 1.42 (s, 9 H) 3.08 (s, 3 H) 3.25 (s, 3 H) 5.65 (d, J=7.72 Hz, 1 H) 7.34 (dd, J=15.81, 2.57 Hz, 2 H) 7.42 (dd, J=8.82, 1.84 Hz, 1 H) 7.65-7.76 (m, 2 H) 7.80 (d, J=8.09 Hz, 1 H) 7.96 (t, J=8.27 Hz, 2 H) 8.02 (s, 1 H) 10.04 (s, 1 H) 11.41 (s, 1H); MS (ESI+) m/z 494 (M+H)+; (ESI-) m/z 492 (M-H)-.

[00519] Example 2B. Obtaining N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.3).

[00520] Part A. Obtain 2-tert-butyl-6-iodine-4-NITROPHENOL.

[00521] To the product from Example 1, Part E (4.5 g, 23,05 mmol) dissolved in Meon (120 ml) and water (30 ml), was added monochloride iodine (1,155 ml, 23,05 mmol) dropwise 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 probyval×50 ml water and dried under vacuum overnight to obtain a solid substance, yellowish-brown (7,14 g, 96%).

[00522] part of the Century, Obtaining 1-tert-butyl-3-iodine-2-methoxy-5-nitrobenzene.

[00523] To a cooled on an ice bath to a solution of the product from part a (5.5 g, 17,13 mmol) in MTBE (15 ml) in a 50 ml pressure vessel was added 2.0 M trimethylsilyldiazomethane (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 separated between EtOAc and water. The organic layer was washed with 1.0 M HCl, 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%).

[00524] Part C. Obtain 3-tert-butyl-5-iodine-4-methoxyaniline.

[00525] a Mixture of the product from Part b (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).

[00526] Part D. Obtaining (E)-N-(3-tert-butyl-5-iodine-4-methoxyp ylcarbonyl)-3-methoxy acrylamide.

[00527] To a solution of the product from part C (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 according to the method of 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 diluted with EtOAc. The organic phase is washed with water and brine. Dried over Na2SO4, filtered and concentrated to a solid brown color. The residue was ground into powder in Et2O/hexane to obtain fine powder, which was collected by filtration and dried under vacuum to obtain these compounds in the form of a powder, yellowish-brown (2,46 g, 57%).

[00528] Part E. Obtain 1-(3-tert-butyl-5-iodine-4-methoxyphenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[00529] To a suspension of the product from Part D (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. Cooled and diluted with 50 ml of water under stirring to obtain a whitish solid, which was collected by filtration, washed with water and dried under vacuum to obtain these compounds from 2.06 g, 90%).

[00530] Part F. Obtain N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00531] In a microwave tube, the product from Part E (104 mg, 0.26 mmol), the product from Example 2A, Part b (108 mg, 0.31 mmol), and 1.0 M solution of sodium carbonate (312 μl, 0.31 mmol) in a mixture of 1:1 ethanol-toluene (1.7 ml) was degirolami by ozonation of nitrogen for 15 minutes were Added to the complex of 1,1'-bis(diphenylphosphino) ferrocene palladium (II) chloride dichloromethane (9 mg, to 0.011 mmol), and degassing was continued for another 5 minutes the tube was tightly closed and heated in a microwave oven at 100°C for 1 h was Diluted with dichloromethane and washed with 1M citric acid solution and brine. The organic layer was then mixed with (3-mercaptopropyl) silica gel for 1 h was Filtered through celite and concentrated under vacuum. Was ground into powder with ether, methanol and then with ether to obtain these compounds in the form of an almost white solid (32 mg, 25%).1H NMR (300 MHz, DMSO-d6): δ 11.41 (d, J=1.84 Hz, 1 H) 10.04 (s, 1 H) 8.03 (s, 1 H) 7.96 (t, J=8.09 Hz, 2 H) 7.80 (d, J=8.09 Hz, 1 H) 7.63-7.79 (m, 2 H) 7.35-7.45 (m, 1 H) 7.37 (d, J=2.57 Hz, 1 H) 7.32 (d, J=2.57 Hz, 1 H) 5.65 (dd, J=8.09, 2.21 Hz, 1 H) 3.25 (s, 3 H) 3.09 (s, 3 H) 1.43 (s, 9 H). MS (+ESI) m/z (relative prevalence): 494 (100, M+H), 511 (90, M+NH4), 987 (20, 2M+N), 1009 (8, 2M+Na).

[00532] Example 3. Obtaining N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)quinoline-2-yl)methanesulfonamide (compound IB-L0-2.5).

[00533] H is here A. Obtaining (E)-N-(4-bromophenyl)-3-ethoxyacrylate. [00534] United 4-bromaniline (285 mg, 1,659 mmol), CH2Cl2(2.0 ml) and pyridine (0.25 ml, to 3.09 mmol) and slowly added (E)-3-methoxyacetophenone (200 mg, 1,659 mmol) and stirred at room temperature for 2 hours the resulting solid yellow color was filtered and washed with water. The solid was dried under vacuum to obtain the above compound (406 mg, 96%).

[00535] part of the Century, Obtaining 6-bronchioles-2(1H)-it.

[00536] the Product from part a (395 mg, 1,542 mmol) was added in portions to H2SO4(4,5 ml). Was stirred for 3 h at room temperature, then poured into crushed ice. The solid was filtered, washed with water and dried under vacuum to obtain the above compound (203 mg, 59%).

[00537] Part C. Obtain 6-bromo-2-chlorhydrin.

[00538] the phosphorus oxychloride (2.5 ml, 26.8 mmol) was added, parts of the product from Part b (200 mg, 0,893 mmol). Was heated under reflux for 1 h, cooled to room temperature and poured on crushed ice. Was extracted with CHCl3the extracts were combined, dried over MgSO4, filtered and concentrated under vacuum to obtain the above compound (173 mg, 80%).

[00539] Part D. Obtain 6-bromo-2-aminoquinoline.

[00540] the Product from Part C (173 mg, 0,713 mmol), ndimethylacetamide (843 mg, 14,27 mmol) is potassium carbonate (493 mg, 3.57 mmol) were combined and heated at 200°C for 2 hours Cooled to room temperature, after which it froze. Was dissolved in a mixture of CHCl3and water. The aqueous layer was extracted two more times with CHCl3the extracts were combined, washed with brine, dried over Na2SO4, filtered and concentrated under vacuum. Purification using column chromatography on silica gel with elution of MeOH/CHCl3gave the titled compound (92 mg, 58%).

[00541] Part E. Obtain N-(6-bronchioles-2-yl)-N-(methylsulphonyl)methanesulfonamide.

[00542] Combined product from Part D (90 mg, 0,403 mmol) and CH2Cl2(2.0 ml) was added triethylamine (0,062 ml, 0,444 mmol) and methanesulfonamide (or 0.035 ml, 0,444 mmol). Was stirred at room temperature for 16 hours was Added triethylamine (0,062 ml, 0,444 mmol) and methanesulfonamide (or 0.035 ml, 0,444 mmol) and stirred at room temperature for 1 h was Diluted with EtOAc, washed with 10% citric acid, 10% NaHCO3and a salt solution. Dried over Na2SO4, filtered and concentrated under vacuum. Was dissolved in EtOAc and poured into an excess of hexane. The solid substance was collected by filtration to obtain the above compound (94 mg, 61%).

[00543] Part F. Obtaining N-(methylsulphonyl)-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline-2-yl)methanesulfonamide.

[00544] Combined product of H is STI E (94 mg, 0,248 mmol), bis(pinacolato)LIBOR (94 mg, 0,372 mmol), potassium acetate (73,0 mg, 0,744 mmol), Combi-Phos®PD6 (6,22 mg, 0.012 mmol) and toluene (1.5 ml) and heated under reflux for 18 hours was Cooled to room temperature, diluted with EtOAc and water, filtered through celite, separating phases, the organic phase is washed with salt solution. Dried over Na2SO4, filtered and concentrated under vacuum. Purification using column chromatography on silica gel with elution of EtOAc/hexane gave the titled compound (67 mg, 63%).

[00545] Part G. Obtain N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)quinoline-2-yl)methanesulfonamide.

[00546] were Combined in a microwave tube product from Example 2, Part E (27 mg, 0,067 mmol), the product from Part F (or 37.4 mg, 0,088 mmol), ethanol (1.0 ml), toluene (1.0 ml) and 1M sodium carbonate (0,067 ml 0,067 mmol) and the solution was degirolami using gaseous N2within 20 minutes was Added tetrakis-(triphenyl-phosphine)palladium(0) (1,559 mg, 1,349 mmol) and the solution was degirolami additional 5 minutes the Tube was tightly closed and heated in a microwave oven at 100°C for 45 minutes the Cooled solution was diluted 1:1 EtOAc and water and filtered through celite. The aqueous layer was extracted with another Yes times EtOAc, the combined organic extracts were washed with saline. Dried over Na2SO4was filtered and the have koncentrirebuli under vacuum. Purification using column chromatography on silica gel with elution of the Meon/CHCl3gave the titled compound (13,7 mg, 41%).1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9 H) 3.18 (s, 3 H), 3.30 (s, 3 H), 5.83 (dd, J=7.91, 2.02 Hz, 1 H) 6.99 (d, J=8.82 Hz, 1 H) 7.21 (d, J=2.57 Hz, 1 H) 7.36 (d, J=7.72 Hz, 1 H) 7.52 (d, J=8.46 Hz, 1 H), 7.82-7.91 (m, 2 H) 7.98 (d, J=9.19 Hz, 1 H) 8.29 (s, 1 H); MS (ESI+) m/z 495 (M+H)+; (ESI-) m/z 493 (M-H)-.

[00547] Example 4. Obtaining (E)-N'-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl-Eden)methanesulfonamide (compound IB-L0-2.4).

[00548] Part A. Obtaining 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-it.

[00549] a Mixture of 5-bromo-2,3-dihydro-1H-inden-1-it (2.50 g, 11,85 mmol), bis(pinacolato) Debora (3,61 g, 14,21 mmol), potassium acetate (3,49 g, 35.5 mmol) and Combiphos Pd6 (178 mg, 0.36 mmol) in toluene (60 ml) was heated under reflux for 8 hours was Cooled, diluted with EtOAc and extracted with water (2x) and washed with saline. Dried over Na2SO4and was stirred for 1 h with (3-mercaptopropyl)silica gel. Was filtered and concentrated under vacuum to obtain solid yellow color. Purification using column chromatography on silica gel with elution of EtOAc/hexane gave a solid yellow color. Was ground into powder with cold hexane, filtered and dried under vacuum obtaining's name is the first connection in the form of finely dispersed solids almost white (1,99 g, 65%). A second batch of crystals (140 mg) was obtained from the mother solution, receiving the output up to 70%.

[00550] part of the Century, Obtaining 1-(3-tert-butyl-4-methoxy-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)phenyl) pyrimidine-2,4(1H,3H)-dione.

[00551] In a microwave tube, a suspension of the product from Example 2, Part E (130 mg, 0.33 mmol), the product from part a (101 mg, 0,39 mmol), and 1.0 M solution of sodium carbonate (390 μl, 0,39 mmol) in a mixture of 1:1 ethanol-toluene (1.20 ml) was degirolami by ozonation of nitrogen for 15 minutes the Mixture was treated with a complex of 1,1'-bis(diphenylphosphino)ferrocene palladium (II) Chlorodifluoromethane (13 mg, to 0.016 mmol) and degassing was continued for another 5 min, and heated at 100°C. in microwave oven for 1 h was Cooled, diluted with EtOAc and was extracted with 1M citric acid solution and brine. The organic layer was then mixed with (3-mercaptopropyl)silica gel for 1 h was Filtered and concentrated under vacuum. Purification using column chromatography on silica gel with elution of EtOAc/hexane gave the titled compound in the form of a solid white (80 mg, 61%).

[00552] Part C. Obtaining (E)-N'-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl-Eden)methanesulfonamide.

[00553] a Suspension of the product from Part b (77 mg, 0,19 mmol) and methysulfonylmethane (22 mg, 0.20 mmol) in 3:1 THF:MeOH (1.9 ml) on revali at 60°C for 24 hours The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica gel, elwira EtOAc/hexane to obtain these compounds in a solid white (62 mg, 66%).1H NMR (300 MHz, DMSO-d6): δ 11.40 (d, J=1.84 Hz, 1 H), 9.94 (s, 1 H) 7.76 (dd, J=13.97, 8.09 Hz, 2 H) 7.52-7.59 (m, 1 H) 7.51 (d, J=8.46 Hz, 1 H), 7.11-7.40 (m, 2 H) 3.28 (s, 3 H) 2.96-3.19 (m, 5 H), 2.85 (m, 2 H), 1.40 (s, 9 H). MS (+ESI) m/z (relative prevalence): 497 (100, M+H), 1015 (5, 2M+Na).

[00554] Example 5. Obtaining N-(2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)benzo[d]oxazol-5-yl)methanesulfonamide (compound IB-L0-2.6).

[00555] Part A. Obtain methyl 3-tert-butyl-2-hydroxy-5-nitrobenzoate.

[00556] 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). When the addition was completed, 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 ice and water was left to melt. The mixture is then filtered, washed with water and dried to obtain the above compound (a 24.57 g, 89%).

[00557] Part C. Obtain methyl 3-tert-butyl-2-methoxy-5-nitrobenzoate.

[00558] EXT is ulali 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 is washed with ethyl acetate. The resulting organic liquid was then concentrated under vacuum to oil and repeated was dissolved 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%-40% EtOAc/hexane) to obtain at the output of these compounds in the form of oil (10,42, 87%).

[00559] Part C. Obtain methyl 5-amino-3-tert-butyl-2-methoxybenzoate.

[00560] 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 resulting solution is then washed with water and brine. The organic extract was then dried, filtered and concentrated p is d vacuum to obtain at the output of these compounds in the form of oil (9,25 g, 100%).

[00561] Part D. Obtaining (E)-methyl 3-tert-butyl-2-methoxy-5-(3-(3-methoxyacetyl)oreid)benzoate.

[00562] the Product obtained as described in Part C (2.0 g, 8,43 mmol), was dissolved in 30 ml of N,N-dimethylacetamide and cooled to -25°C. a 0.5 molar solution of E-3-methoxycarbonylamino in benzene (of 21.9 ml, 10,96 mmol) was added dropwise, and the resulting solution was stirred at ambient temperature for 4 h, and then poured into water. The product was extracted in dichloromethane, washed with saline, dried over sodium sulfate, filtered and evaporated under vacuum to obtain 100% of the output.

[00563] Part E. Obtain methyl 3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxybenzoate.

[00564] the Product from Part D (3.1 g, 8,51 mmol) was dissolved in ethanol (60 ml). Sulfuric acid (6 ml) was added water (60 ml), and then this solution was added in one portion to ethanol. 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 using flash chromatography elwira 1% methanol/dichloromethane to obtain at the output of 1.23 g (44%).

[00565] Part F. Obtain 3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2 - methoxybenzoic acid.

[00566] the Product from Part E (1,23 g, 3.7 mmol) was placed in ethanol (5 ml) and 1 mol of the hydrated sodium hydroxide solution (10 ml) and stirred at ambient temperature for 18 hours This solution was diluted with 1M HCl and the resulting solid was filtered and dried to obtain 0,945 g (80%).

[00567] Part G. Obtain 3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxybenzaldehyde.

[00568] the Product from Part F (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. 1 molar solution of lithium tri-tert-butoxyaniline hydride in THF (3.0 ml, 3.0 mmol) was added dropwise. After 45 min the cold reaction mixture is extinguished 1M HCl (5 ml), was extracted in ethyl acetate, and purified using the evaporative column, elwira dichloromethane, then 1% methanol/dichloromethane to obtain 0,635 g (71%).

[00569] Part N. Obtain 1-(3-tert-butyl-4-methoxy-5-(5-benzo[d]oxazol-2-yl)phenyl) pyrimidine-2,4(1H,3H)-dione.

[00570] the Product from Part G (400 mg, 1,323 mmol), 2-amino-4-NITROPHENOL (204 mg, 1,323 mmol), charcoal (Darco KB, 191 mg, 15,88 mmol) and toluene (50 ml) was added to the flask and the mixture was heated to 120°C., and stirred open to air for 48 hours was Filtered through celite and concentrated under vacuum. Purification using column chromatography on silica gel with elution of CH2Cl2/Meon gave the titled compound (300 mg, 52%).

[00571] Part I. Obtaining N-(2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyri midin-1(2H)-yl)-2-methoxyphenyl)benzo[d]oxazol-5-yl)methanesulfonamide.

[00572] To the product from Part H (300 mg, 0,687 mmol), iron (192 mg, 3,44 mmol) and ammonium chloride (55 mg, 1,031 mmol) was added to a mixture of THF (15 ml), EtOH (15 ml) and water (4.5 ml). The resulting solution was heated to 90°C for 45 min, and cooled. Filtered through celite, washed with ethanol and concentrated under vacuum. The solid was dissolved in ethyl acetate and washed with water. Dried over Na2SO4, filtered and concentrated under vacuum. Purification using column chromatography on silica gel with elution of CH2Cl2/MeOH gave aniline. Solid (75 mg, 0.185 mmol) was dissolved in CH2Cl2(5 ml) was added pyridine (0,045 ml, 0,554 mmol) and methanesulfonamide (0,025 ml, 0,323 mmol) and stirred at room temperature for 16 hours was Added CH2Cl2with subsequent washing with 1 n HCl. Dried over Na2SO4, filtered and concentrated under vacuum. Purification using column chromatography on silica gel with elution of CH2Cl2/MeOH gave the titled compound as a solid (9.8 mg, 3%, two stages). 1H NMR (300MHz, DMSO-d6): δ 11.46 (s,1H), 9.85 (s,1H), 7.91 (d, J=2.2 Hz, 1H), 7.81 (dd, J=9.9, 8.8 Hz, 2H), 7.68 (d, J=2.2 Hz, 1H), 7.56 (d, J=2.6 Hz, 1H), 7.33 (dd, J=8.8, 1.8 Hz, 1H), 5.68 (d, J=7.7 Hz, 1H), 3.64 (s, 3H), 3.00 (s, 3H), 1.42 (s, 9H). MS: m/z 485 (M+H)+.

[00573] Example 6. Obtain 1-(3-tert-butyl-4-methoxy-5-(6-nitrobenzo[d]oxazol-2-yl)phenyl) dihydropyrimidine-2,4(1H,3H)-Dion (with the unity IA-L0-2.6).

[00574] Part A. Obtaining 3-(3-tert-butyl-4-methoxy-5-(methoxycarbonyl)phenylamino) propanoic acid.

[00575] the Product from Example 5, Part (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). Then the mixture was heated under reflux for 24 hours Then the mixture was 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.

[00576] Part C. Obtain methyl 3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxybenzoate.

[00577] was Added together the product from part a (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 dryness 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 with a small amount of methanol (10 ml) and then dried in the air to receive output name is the first connection in the form of solids (15,26 g, 66%).

[00578] Part C. Obtain 3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxy benzoic acid.

[00579] was Added together the product from Part b (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 reaching homogeneity, the 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 and then adding 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%).

[00580] Part D. Obtain 3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxy benzaldehyde.

[00581] the Product obtained in Part (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 the m obtaining 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 LiAl(OtBu)3(1M, 14 ml) over 10 min, maintaining the temperature of -78°C. the Mixture was stirred at 78°C for 2 h 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 polysystem solution of sodium bicarbonate. The organic layer was dried, filtered and concentrated under vacuum to obtain at the output of a solid substance as a named connection (of 3.73 g, 96%).

[00582] Part E. Obtain 1-(3-tert-butyl-4-methoxy-5-(6-nitrobenzo[d]oxazol-2-yl)phenyl)dihydropyrimidine-2,4(1H,3H)-dione.

[00583] a Mixture of the product from Part D (75 mg, 0,246 mmol), 2-amino-5-NITROPHENOL (38 mg, 0,0246 mmol) and charcoal Darco KB (excess) was heated under reflux in toluene (10 ml) for 24 h under the influence of atmospheric oxygen. Was cooled, filtered and purified by HPLC with reversed phase, elwira 40-100% gradient of acetonitrile in water with 0.1% TFA) to give the titled compound as a solid (96 mg, 64%).1H NMR (300 MHz, DMSO-d6): δ 1.42 (s, 9 H), 2.74 (t, J=6.80 Hz, 2 H) 3.66 (s, 3 H) 3.82-3.88 (m, 2 H) 7.56 (d, J=2.57 Hz, 1 H) 7.91 (d, J=2.57 Hz, 1 H) 8.09 (d, J=8.82 Hz, 1 H) 8.37 (dd, J=8.82, 2.21 Hz, 1 H), 8.84 (d, J=2.21 Hz, 1 H) 1044 (s, 1 H). MS ESI+(439) (M+H)+.

[00584] Example 7. Obtaining N-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)benzo[d]oxazol-6-yl)methanesulfonamide (compound IA-L0-2.5).

[00585] the Product from Example 6 (96 mg, 0,219 mmol) interacted with iron (0,614 g, 1.10 mmol) and ammonium chloride (0,176 g, 0,329 mmol) in the presence of a mixture of tetrahydrofuran (5 ml), ethanol (5 ml) and water (3 ml). The suspension was heated to 90°C for 45 min, cooled to ambient temperature. 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 and washed with water. Dried over Na2SO4, filtered and concentrated under vacuum to a solid yellow color, getting the appropriate aniline. The solid was dissolved in dichloromethane (10 ml), was added pyridine (0,670 ml, 0,657 mmol) and methanesulfonamide (0,221 ml, 0,329 mmol) and the solution was stirred at room temperature for 16 hours was Added CH2Cl2with subsequent washing with 1 n aqueous HCl solution. Dried over Na2SO4, filtered and concentrated under vacuum. Purification using column chromatography on silica gel with elution with 98:2 CH2Cl2:Meon gave the titled compound as a solid (25 mg,21%, two stages).1H NMR (300 MHz, DMSO-d6): δ 1.41 (s, 9 H) 2.73 (t, J=6.62 Hz, 2 H) 3.06 (s, 3 H) 3.61 (s, 3 H) 3.83 (t, J=6.62 Hz, 2 H) 7.28 (dd, J=8.46, 1.84 Hz, 1 H) 7.48 (d, J=2.57 Hz, 1 H) 7.65 (d, J=1.84 Hz, 1 H) 7.80 (d, J=1.47 Hz, 1 H) 7.82 (d, J=4.04 Hz, 1 H) 10.03 (s, 1 H) 10.41 (s, 1 H). MS ESI+(487) (M+H)+.

[00586] Example 8. Obtain 1-(3-tert-butyl-4-methoxy-5-(5-nitrobenzo[d]oxazol-2-yl)phenyl) dihydropyrimidine-2,4(1H,3H)-dione (compound IA-L0-2.7).

[00587] the Product from Example 6, Part D (150 mg, 0,493 mmol) interacted with 2-amino-4-NITROPHENOL (76 mg, 0,493 mmol) in accordance with the procedures of Example 6, Part E of obtaining these compounds are in the form of a solid (70 mg, 32%).1H NMR (300 MHz, DMSO-d6): δ 1.42 (s, 9 H) 2.74 (t, J=6.80 Hz, 2 H) 3.65 (s, 3 H) 3.85 (t, J=6.62 Hz, 2 H) 7.55 (d, J=2.57 Hz, 1 H) 7.89 (d, J=2.94 Hz, 1 H) 8.12 (d, J=8.82 Hz, 1 H) 8.40 (dd, J=9.01, 2.39 Hz, 1 H) 8.76 (d, J=2.21 Hz, 1 H) 10.43 (s, 1 H). MS ESI+(439) (M+H)+.

[00588] Example 9. Obtaining N-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)benzo[d]oxazol-5-yl)methanesulfonamide (compound IA-L0-2.8).

[00589] the Product from Example 8 (65 mg, 0,148 mmol) reacts in accordance with the procedures of Example 7 with the formation of these compounds in the form of a solid (42 mg, 44%).1H NMR (300 MHz, DMSO-d6): δ 1.41 (s, 9 H), 2.73 (t, J=6.43 Hz, 2 H) 3.01 (s, 3 H), 3.60 (s, 3 H) 3.83 (t, J=6.43 Hz, 2 H) 7.31 (dd, J=8.64, 2.02 Hz, 1 H) 7.49 (d, J=2.94 Hz, 1 H) 7.56 (d, J=2.21 Hz, 1 H) 7.67 (d, J=2.21 Hz, 1 H) 7.81 (s, 1 H), 9.82 (s, 1 H), 10.41 (s, 1 H). MS ESI+(487) (M+H)+.

[00591] the Product from Example 6, Part D (75 mg, 0,246 mmol) interacted with 2-aminobenzamide (0,026 ml, 0,246 mmol) in accordance with the procedures of Example 6, Part E with the formation of these compounds in the form of a solid (25 mg, 25%).1H NMR (300 MHz, DMSO-d6): δ 1.44 (s, 9 H), 2.73 (t, J=6.43 Hz, 2 H) 3.62 (s, 3 H) 3.84 (t, J=6.62 Hz, 2 H) 7.46 (d, J=2.57 Hz, 1 H) 7.48-7.60 (m, 2 H) 7.86 (d, J=2.57 Hz, 1 H), 8.13 (dd, J=17.28, 7.72 Hz, 2 H), 10.40 (s, 1 H). MS ESI+(410)(M+H)+.

[00592] Example 11. Obtaining N-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)methanesulfonamide (compound IA-L0-2.1).

[00593] Part A. Obtaining N-(3,4-dinitrophenyl)methanesulfonamide.

[00594] a Mixture of 3,4-dinitroaniline (5,27 g, 28.8 mmol), methanesulfonamide (3,36 ml, to 43.1 mmol) and pyridine (of 5.82 ml, to 71.9 mmol) in CH2Cl2(100 ml) was stirred for 24 h the Mixture was concentrated under vacuum to obtain a crude semi-solid named compound that was used without further purification.

[00595] part of the Century, Obtaining N-(3,4-diaminophenyl)methanesulfonamide.

[00596] the Product from part a (7.51 g, 28.8 mmol) interacted with iron (16 g, 288 mmol) and NH4Cl (3.84 g, 71.9 mmol) in heated under reflux CH3HE(100 ml) and water (20 ml) for 2 hours Was filtered through celite and concentrated under vacuum. Purification using column chromatography on silica gel with elution of the Meon/CH2Cl2give the named compound as a dark semi-solid substance (0.5 g, 8%).

[00597] Part C. Obtain N-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)methanesulfonamide.

[00598] a Mixture of the product from Example 6, Part D (200 mg, 0,657 mmol) interacted with the product from Part b (132 mg, 0,657 mmol) in accordance with the procedures of Example 6, Part E with the formation of these compounds in the form of a solid (112 mg, 34%).1H NMR (300 MHz, DMSO-d6): δ 1.43 (s, 9 H) 2.72 (t, J=6.62 Hz, 2 H) 2.93 (s, 3 H) 3.44 (s, 3 H) 3.82 (t, J=6.43 Hz, 2 H) 7.07-7.14 (m, 1 H) 7.38 (d, J=2.57 Hz, 1 H) 7.48-7.64 (m, 2 H) 7.72 (d, J=2.57 Hz, 1 H) 9.57 (s, 1 H) 10.38 (s, 1 H) 12.55 (s, 1 H). MS ESI+(486) (M+H)+.

[00599] Example 12. Obtaining N-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)benzo[d]thiazol-6-yl)methanesulfonamide (compound IA-L0-2.2).

[00600] Part A. Obtain N-(3-chloro-4-nitrophenyl)methanesulfonamide.

[00601] a Mixture of 3-chloro-4-nitroaniline (4,85 g, 28.1 mmol), methanesulfonamide (3,29 ml, 42.2 per mmol) and pyridine (6,82 ml, 84 mmol) in THF (100 ml) was stirred for 24 hours was Poured into 1M HCl (500 ml). The resulting precipitate was filtered and dried in air to obtain these compounds in the form of a solid is the first substance (7,03 g, 100%).

[00602] part of the Century, Obtaining N-(3-(4-methoxybenzylthio)-4-nitrophenyl)methanesulfonamide.

[00603] a Mixture of the product from part a (7.0 g, and 27.9 mmol), (4-methoxyphenyl)methanethiol (3,89 ml of 27.9 mmol) and K2CO3(11,58 g, 84 mmol) in DMF was heated at 100°C for 12 h was Cooled and poured into 1M HCl (800 ml). The resulting precipitate was filtered and dried in air to obtain these compounds in a solid yellow color (6,98 g, 68%).

[00604] Part C. Obtain N-(4-amino-3-(4-methoxybenzylthio)phenyl)methanesulfonamide.

[00605] the Product from Part b (6,98 g, 19.0 mmol) cooperated in accordance with the procedures of Example 11, Part In obtaining the named compound as a yellow semi-solid substances (4.44 g, 69%).

[00606] Part D. Obtain N,N'-(3,3'-Desulfovibrio(4-amino-3,1-phenylene))demeton-sulfonamida.

[00607] the Product from Part C (708 mg, of 2.09 mmol) cooperated with acetate mercury (II) (667 mg, of 2.09 mmol), anisole (0,457 ml, 4,18 mmol) and TFA (10 ml) at 0°C for 45 minutes then Concentrated under vacuum and dissolved in the Meon. Gaseous hydrogen sulfide was barbotirovany in the solution for 1 h followed by filtration and concentration under vacuum. Purification via chromatography on silica gel with elution of EtOAc/hexane gave the titled compound as yellowish solid (340 mg, 75%).

[00608] Part E. Obtain N-(2-(3-tert-Buti is-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)benzo[d]thiazol-6-yl)methanesulfonamide.

[00609] the Product from Part D (100 mg, 0.23 mmol) interacted with the product from Example 6, Part D (140 mg, 0.46 mmol), triphenylphosphine (60,4 mg, 0.23 mmol) and 4-methylbenzenesulfonic acid (0,0054 ml, 0.046 mmol) in heated under reflux toluene for 3 hours then Concentrated under vacuum and purified by HPLC chromatography with reversed phase, elwira 40-100% gradient of acetonitrile in water with 0.1% TFA) to give the titled compound as a solid (99 mg, 43%).1H NMR (300 MHz, DMSO-d6): δ 1.43 (s, 9 H), 2.73 (t, 1=6.62 Hz, 2 H) 3.07 (s, 3 H), 3.63 (s, 3 H) 3.83 (t, J=6.62 Hz, 2 H) 7.39 (dd, J=8.82, 2.21 Hz, 1 H) 7.45 (d, J=2.57 Hz, 1 H) 7.83 (d, J=2.57 Hz, 1 H) 7.95 (d, J=2.21 Hz, 1 H) 8.05 (d, J=8.82 Hz, 1 H), 10.03 (s, 1 H), 10.39 (s, 1 H). MS ESI+(503) (M+H)+.

[00610] Example 13. Obtaining N-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)benzo[d]thiazol-5-yl)methanesulfonamide (compound IA-L0-2.4).

[00611] Part A. Obtain N-(4-chloro-3-nitrophenyl)methanesulfonamide.

[00612] a Mixture of 4-chloro-3-nitroaniline (5.0 g, 29 mmol), methanesulfonamide (2.37 ml, 30.4 mmol) and pyridine (5,9 ml, to 72.4 mmol) in THF (100 ml) was stirred for 24 hours was Poured into 1M HCl (500 ml). The resulting precipitate was filtered and dried in air to obtain these compounds in the form of a solid (6.7 g, 92%).

[00613] part of the Century, Obtaining N-(4-(4-methoxybenzylthio)-3-nitrophenyl)methanesulfonamide.

[00614] a Mixture cont the KTA from part a (3.0 g, 12 mmol), (4-methoxyphenyl)methanethiol (rate of 1.67 ml, 12 mmol) and K2CO3(4,96 g, 36 mmol) in DMF was heated at 100°C for 12 h was Cooled and poured into 1M HCl (800 ml). The resulting precipitate was filtered and dried in air to obtain these compounds in a solid yellow color (1,95 g, 44.2%).

[00615] Part C. Obtain N-(3-amino-4-(4-methoxybenzylthio)phenyl)methanesulfonamide.

[00616] the Product from Part b (1,43 g, 3.88 mmol) was entered in the reaction in accordance with the procedures of Example 11, Part b with the formation of these compounds in a solid white color (1.31 g, 100%).

[00617] Part D. Obtain N,N'-(4,4'-Desulfovibrio(3-amino-4,1-phenylene))demeton-sulfonamida.

[00618] the Product from Part C (75 mg, 0,222 mmol) cooperated with acetate mercury (II) (70,6 mg, 0,222 mmol), anisole (0,048 ml, 0,443 mmol) and TFA (10 ml) at 0°C for 45 minutes then Concentrated under vacuum and dissolved in the Meon. Gaseous hydrogen sulfide was barbotirovany in the solution for 1 h followed by filtration and concentration under vacuum. Purification using column chromatography on silica gel with elution of EtOAc/hexane gave the titled compound as yellowish solid (34 mg, 71%).

[00619] Part E. Obtain N-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxy phenyl)benzo[d]thiazol-5-yl)methanesulfonamide.

[00620] the Product and the Part D (50 mg, 0,115 mmol) interacted with the product from Example 6, Part D (70 mg, 0,230 mmol), triphenylphosphine (30,2 mg, 0,115 mmol) and 4-methylbenzenesulfonic acid (0,00267 ml, is 0.023 mmol) in heated under reflux toluene for 3 hours then Concentrated under vacuum and purified by HPLC chromatography with reversed phase, elwira 40-100% gradient of acetonitrile in water with 0.1% TFA) to give the titled compound as a solid (40 mg, 33%).1H NMR (300 MHz, DMSO-d6): δ 1.43 (s, 9 H) 2.73 (t, J=6.80 Hz, 2 H) 3.05 (s, 3 H) 3.63 (s, 3 H) 3.84 (t, J=6.62 Hz, 2 H) 7.35 (dd, J=8.64, 2.02 Hz, 1 H) 7.46 (d, J=2.94 Hz, 1 H) 7.86 (d, J=2.94 Hz, 1 H) 7.92 (d, J=1.84 Hz, 1 H) 8.10 (d, J=8.46 Hz, 1 H) 9.98 (s, 1 H) 10.40 (s, 1 H). MS ESI+(503) (M+H)+.

[00621] Example 14. Obtain 1-(3-tert-butyl-4-methoxy-5-(naphthalen-2-yl)phenyl) pyrimidine-2,4(1H,3H)-dione (compound IB-L0-2.1).

[00622] Part A. Obtain tert-butyl 3-tert-butyl-4-methoxy-5-(naphthalen-2-yl)phenyl carbamate.

[00623] reseal the vessel Slanka, a solution of the product from Example 1, Part H (200 mg, 0,56 mmol), naphthalen-2-Bronevoy acid (144 mg, 0.84 mmol), and 1.0 M solution of sodium carbonate (558 μl, of 0.56 mmol) in toluene (2.8 ml) was degirolami by ozonation of nitrogen for 10 minutes the mixture was treated with a complex of 1,1'-bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane (14 mg, of 0.017 mmol) and degassing was continued for another 5 minutes the Vessel Slanka ger is michno was closed and heated at 95°C for 18 hours Was cooled and was diluted with ethyl acetate and water. Was treated with Darco G-60 and filtered through celite. The filtrate was extracted with water (2x) and brine. Dried over Na2SO4, filtered and concentrated. Purification using column chromatography on silica gel with elution of 10-75% EtOAc in hexane gave the titled compound as oil (210 mg, 93%).

[00624] part of the Century, Obtaining 3-tert-butyl-4-methoxy-5-(naphthalen-2-yl)aniline.

[00625] the Product from part a (210 mg, 0.52 mmol) was dissolved in 4 n HCl in dioxane (4.0 ml) and stirred at room temperature for 1 h Concentration under vacuum gave a solid, which was suspended in ethyl acetate and stirred with a saturated solution of sodium bicarbonate. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to obtain these compounds, in the form of a brown oil (111 mg, 70%).

[00626] Part C. Obtaining (E)-N-(3-tert-butyl-4-methoxy-5-(naphthalen-2-yl)phenylcarbamoyl)-3 - ethoxyacrylate.

[00627] a solution of the product from Part b (111 mg, 0.36 mmol) in dry DMF (2.9 ml) at -20°C was treated with a solution of (E)-3-methoxycarbonylamino (0,66 ml, 0.55 M in benzene, 0.36 mmol) followed by gradual warming to room temperature. After stirring for 30 min the mixture was cooled again to -20°C was added a solution of (E)-3-methoxyacetanilide the Anata (1.0 ml, 0.55 mmol). After re-heating to room temperature for 30 min the reaction was completed. Was diluted with EtOAc and extracted with water and brine. Dried over Na2SO4, filtered and concentrated under vacuum. Purification using column chromatography on silica gel with elution of 10-100% EtOAc in hexane gave the titled compound as a pale yellow oil (144 mg, 92%).

[00628] Part D. Obtain 1-(3-tert-butyl-4-methoxy-5-(naphthalen-2-yl)phenyl)pyrimidine-2,4(1H,3H)-dione.

[00629] a Suspension of the product from Part C (144 mg, 0.33 mmol) in a mixture of 2:2:1 ethanol-water-THF (15 ml) was treated with a solution of 1 N. sulfuric acid (3.0 ml) followed by heating at 100°C for 24 h was Cooled and diluted with EtOAc and extracted with water and brine. Dried over Na2SO4, filtered and concentrated under vacuum. Purification using column chromatography on silica gel with elution of 10-100% EtOAc in hexane gave the titled compound in the form of a solid white (62 mg, 47%).1H NMR (300 MHz, DMSO-d6): δ 11.42 (s, 1 H), 8.08 (s, 1 H), 7.90-8.04 (m, 3 H), 7.81 (d, J=7.72 Hz, 1 H), 7.72 (d, J=8.46 Hz, 1 H), 7.56 (dd, J=6.25, 3.31 Hz, 2 H), 7.39 (d, J=2.57 Hz, 1 H), 7.33 (d, J=2.57 Hz, 1 H), 5.65 (d, J=7.72 Hz, 1 H), 3.24 (s, 3 H), 1.43 (s, 9 H). MS+ESI m/z (relative prevalence): 401 (100, M+H), 418 (30, M+NH4).

[00630] Example 15. Obtain 1-(3-tert-butyl-4-methoxy-5-(6-methoxynaphthalene-2-yl)phenyl)pyrimidine-2,4(1H,3H)-dione (connection of the group IB-L0-2.2).

[00631] Part A. Obtain tert-butyl 3-tert-butyl-4-methoxy-5-(6-methoxynaphthalene-2-yl)phenyl carbamate.

[00632] the Product from Example 1, Part H (158 mg, 0.44 mmol) interacted with 6-methoxy-naphthalen-2-Voronovo acid (107 mg, 0.52 mmol) in accordance with the procedures of Example 14, part a with the formation of these compounds in the form of a solid white (92 mg, 47 %).

[00633] part of the Century, Obtaining 3-tert-butyl-4-methoxy-5-(6-methoxynaphthalene-2-yl)aniline.

[00634] the Product from part a (92 mg, 0.21 mmol) was entered in the reaction in accordance with the procedures of Example 14, Part b with the formation of these compounds in a solid pink color (71 mg, 99%).

[00635] Part C. Obtaining (E)-N-(3-tert-butyl-4-methoxy-5-(6-methoxynaphthalene-2-yl)phenyl carbarnoyl)-3-ethoxyacrylate.

[00636] the Product from Part b (71 mg, 0.21 mmol) was entered in the reaction in accordance with the procedures of Example 14, Part C with the formation of these compounds in the form of a dark yellow solid (58 mg, 59%).

[00637] Part D. Obtain 1-(3-tert-butyl-4-methoxy-5-(6-methoxynaphthalene-2-yl)phenyl) pyrimidine-2,4(1H,3H)-dione.

[00638] a solution of the product from Part C (58 mg, 0.13 mmol) in a mixture of 2:1:1 ethanol-TNR-water (4.0 ml) was treated with 1.0 M solution of sulfuric acid (3.0 ml) followed by heating at 95°C for 24 h was Cooled and diluted with EtOAc. Was extracted with the water and salt solution. Dried over Na2SO4, filtered and concentrated under vacuum. Purification using column chromatography on silica gel with elution of 10-100% EtOAc in hexane gave the product as a pale pink solid (28 mg, 52%).1H NMR (300 MHz, DMSO-d6): δ 11.41 (s, 1 H), 8.00 (s, 1 H), 7.91 (dd, J=8.64, 4.60 Hz, 2 H), 7.80 (d, J=7.72 Hz, 1 H), 7.67 (d, J=8.82 Hz, 1 H), 7.34-7.47 (m, 2 H), 7.21-7.32 (m, 1 H), 7.20 (dd, J=9.01, 2.39 Hz, 1 H), 5.65 (d, J=7.72 Hz, 1 H), 3.90 (s, 3 H), 3.24 (s, 3 H), 1.42 (s, 9 H). MS+ESI m/z (relative prevalence): 431 (100, M+H), 448 (45, M+NH4).

[00639] Example 16. Obtaining N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl) phenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.8).

[00640] Part A. Obtain 2-bromo-4-tert-butyl-6-nitroaniline.

[00641] a Suspension of 4-tert-butyl-2-nitroaniline (1,033 g, 5,32 mmol) in glacial acetic acid (7.8 ml) was heated using a heat gun to dissolve all solids. The solution is then cooled and treated portions of pyridine the hydrobromide by perbromide (1,96 g, 6.12 mmol). After addition the solution was stirred at room temperature for 1 h the Mixture was added to water (50 ml) and treated with a small amount of sodium sulfite. After stirring for 30 min, the precipitate was collected by filtration. The obtained solid substance was washed with water and dissolved in EtOAc. Washed with water and brine. Dried over Na2SO4 , filtered and concentrated under vacuum to obtain the named compound as a yellow-orange solid (1,36 g, 94%).

[00642] part of the Century, Obtaining 1-bromo-3-tert-butyl-5-nitrobenzene.

[00643] a Solution of tert-butylnitrite (300 μl of 90%, 261 mg of 2.27 mmol) in dry DMF (4 ml) was heated at 50°C and treated with a solution of the product from part a (414 mg, of 1.52 mmol) in DMF (3.5 ml). After several minutes of stirring, the solution began intensively to allocate the gas bubbles.

After heating at 50°C for 1 h, was added advanced (300 ál) of tert-butylnitrite followed by heating at 50°C for 1 h After 18 h at room temperature, was added tert-butylnitrite (1.2 ml), and the mixture was heated at 50°C for 2 hours Cooled and diluted with EtOAc. Washed with water and brine. Dried over Na2SO4, filtered and concentrated under vacuum. Purification using column chromatography on silica gel with elution of 5-40% ethyl acetate in hexane gave the titled compound as a pale yellow oil (159 mg, 41%).

[00644] Part C. Obtain 3-bromo-5-tert-butylaniline.

[00645] a solution of the product from Part b (770 mg, 2,98 mmol) in a mixture of 3:3:1 methanol-water-THF (14.9 ml) was treated with ammonium chloride (239 mg, 4,47 mmol) and iron filings (833 mg, 14,92 mmol) followed by heating under reflux for 8 hours was Diluted with EtOAc and water and the Phi is trevali through celite. The filtrate was extracted with water and brine. Dried over Na2SO4, filtered and concentrated under vacuum to obtain these compounds in the form of a yellow oil.

[00646] Part D. Obtaining (E)-N-(3-bromo-5-tert-butylphenylmethyl)-3-methoxy acrylamide.

[00647] a solution of the product from Part C (681 mg, 2,99 mmol) in dry DMF (23 ml) at -30°C was treated dropwise 0.4 M solution of (E)-3-methoxycarbonylamino in benzene (14.9 ml, 5,96 mmol). The solution was stirred at -30°C for 30 min followed by gradual warming to room temperature, and then stirred for 18 hours was Diluted with EtOAc and washed with water and brine. Dried over Na2SO4, filtered and concentrated under vacuum to obtain solid yellow color, which was ground into powder with ether-hexane and collected by filtration. Dried under vacuum to obtain these compounds in the form of a light brown powder. (951 mg, 90%).

[00648] Part E. Obtain 1-(3-bromo-5-tert-butylphenyl)pyrimidine-2,4(1H,3H)-dione.

[00649] a Suspension of the product from Part D (951 mg, 2.68 mmol) in ethanol (25 ml) was treated with a solution of concentrated sulfuric acid (2,60 ml, 4,78 g, 18,22 mmol) in water (13.4 ml) followed by heating at 100°C for 1 h was Cooled and concentrated to remove ethanol. Was cooled to 0°C and the precipitate was collected on filter is on and washed with water. Dried under vacuum to obtain these compounds in a solid orange color (619 mg, 72%).

[00650] Part F. Obtain N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl) naphthalen-2-yl)methanesulfonamide.

[00651] In a microwave tube, a suspension of the product from Part E (104 mg, 0.32 mmol) of the product from Example 2A, Part b (134 mg, 0,39 mmol), and 1.0 M solution of sodium carbonate (386 μl, 0,39 mmol) in a mixture of 1:1 ethanol-toluene (2.1 ml) was degirolami by ozonation of nitrogen for 10 minutes the Solution was treated with 1,1'-bis(di-tert-butylphosphino)ferrocene-palladium (II) dichloride (20 mg, 0,031 mmol) and degassing was continued for another 5 minutes the Mixture was heated at 100°C in a microwave oven for 30 minutes, Diluted with EtOAc and washed with water and brine. Dried over Na2SO4and was treated with (3-mercaptopropyl) silica gel for 30 minutes was Filtered and concentrated under vacuum to obtain solid amber color, which was ground into powder with ether-hexane. The solid is collected by filtration and dried under vacuum to obtain the above compound (81 mg, 54%).1H NMR (300 MHz, DMSO-d6): δ 11.46 (s, 1 H) 10.05 (s, 1 H), 8.25 (s, 1 H) 7.98 (dd, J=11.58, 9.01 Hz, 1 H) 7.86-7.93 (m, 1 H) 7.78-7.85 (m, 2 H) 7.72 (s, 1 H) 7.67 (s, 1 H) 7.31-7.51 (m, 2 H) 5.70 (dd, J=7.72, 2.21 Hz, 1 H) 3.08 (s, 3 H) 1.39 (s, 9H).

[00652] Example 17. Obtaining (E)-N'-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihyd pyrimidin-1(2H)-yl)phenyl)-2,3-dihydro-1H-inden-1-ilidene)methanesulfonamide (compound IB-L0-2.7).

[00653] Part A. Obtain 1-(3-tert-butyl-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)phenyl) pyrimidine-2,4(1H,3H)-dione.

[00654] In a microwave tube, a suspension of the product from Example 16, Part E, of the product of Example 4, part a (144 mg, 0,56 mmol), 1.0 M solution of sodium carbonate (557 μl, of 0.56 mmol) in a mixture of 1:1 ethanol-toluene (3.0 ml) was degirolami by ozonation of nitrogen for 15 minutes were Added to the complex of 1,1'-bis(di-t-butylphosphino) ferrocene palladium (II) chloride (15 mg, is 0.023 mmol) and degassing was continued for another 5 minutes the Tube was tightly closed and the mixture was heated at 100°C in a microwave oven for 30 minutes, Diluted with EtOAc and water. Washed with 1M citric acid solution, water and brine. The organic phase was stirred with (3-mercaptopropyl)silica gel for 1 h was Dried over Na2SO4, filtered and concentrated under vacuum. Purification using column chromatography on silica gel with elution of 10-100% EtOAc in hexane gave the titled compound in the form of a whitish solid (86 mg, 50%).

[00655] part of the Century, Obtaining (E)-N'-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)-2,3-dihydro-1H-inden-1-ilidene)methanesulfonamide.

[00656] the Product from part a (80 mg, 0.21 mmol) was entered in the reaction in accordance with the procedures of Example 4, Part C with the formation of these compounds in the form of t is ejogo substance white (73 mg, 73%).1H NMR (300 MHz, DMSO-d6): δ 11.44 (s, 1 H) 9.92 (s, 1 H) 7.64-7.98 (m, 5 H) 7.57 (s, 1 H) 7.45 (s, 1 H) 5.68 (d, J=7.72 Hz, 1 H) 3.00-3.20 (m, 5 H) 2.85 (d, J=12.50 Hz, 2 H) 1.36 (s, 9 H). MS+ESI m/z (relative prevalence): 467 (100, M+H).

[00657] Example 18. Obtaining N-(6-(3-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.69).

[00658] Part A. Obtain 2-bromo-4,6-deadpool.

[00659] In a 1 l round bottom flask was placed 2-bromophenol (Aldrich, 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 was stirred to dissolve all of the hydroxide pellets. This solution was cooled in a bath of ice water was added sodium iodide (5.6 g, or 37.4 mmol) followed by the addition dropwise of hyrochloride sodium (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 three 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 value of 1. The mixture was stirred for 15 min and filtered to collect a white solid, which was washed mn is Socrate water and dried to constant weight (14,7 g, 69%).

[00660] part of the Century, Obtaining 1-bromo-3,5-dead-2-methoxybenzene.

[00661] 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 obtain the solution of a yellowish-brown color. The mixture was stirred for 24 h 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 white solid. This solid is recrystallized from hot hexane to obtain a white solid, which was collected by filtration (12.3 g, 81%).

[00662] Part C. Obtain 1-(3-bromo-5-iodine-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00663] In a 250 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 No. 538086), filtered through celite and upar is Wali of obtaining a whitish solid (to 3.92 g, 50%).

[00664] Part D. Obtain N-(6-(3-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00665] a 5 ml microwave tube was added the product from Part C (212 mg, 0.50 mmol), the product from Example 2A, Part b (17 mg, 0.50 mmol), potassium phosphate (223 mg, 1.05 mmol), PA-Ph (CAS 97739-46-3, to 4.38 mg, 0.015 mmol) and Tris (dibenzylideneacetone)dipalladium(0) (4,58 mg, 5.00 mmol) in tetrahydrofuran (3.0 ml) and water (1.0 ml). The tube was tightly closed and the mixture was barbotirovany nitrogen for 5 min, and then was stirred for 24 h the Reaction 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 (Aldrich catalog No. 538086), filtered through celite and evaporated. The residue is triturated with methanol/ CH2Cl2obtaining these compounds in a solid white color (256 mg, 51%).1H NMR (300 MHz, DMSO-D6) δ ppm 3.08 (s, 3 H), 3.43 (s, 3 H), 5.68 (d, J=8.09 Hz, 1 H) 7.43 (dd, J=8.82, 2.21 Hz, 1 H) 7.60 (d, J=2.57 Hz, 1 H) 7.72 (m, 2 H) 7.82 (d, J=3.31 Hz, 1 H) 7.84 (d, J=1.84 Hz, 1 H) 7.96 (m, 2 H) 8.09 (s, 1 H) 10.07 (s, 1 H), 11.49 (s, 1 H). MS (ESI-) m/z 513.9, 515.9 (M-H)+.

[00666] Example 19. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(5-methylfuran-2-yl)phenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.58).

[00667] a 5 ml microwave tube was added the product of Example 18 (52 mg, 0,101 mmol), 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolan (0,025 ml, 0,121 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (3.28 mg, 5,04 μmol) and potassium phosphate (42,8 mg, 0,201 mmol) in THF (3.0 ml) and water (1.0 ml). The tube was tightly closed and the mixture was barbotirovany nitrogen for 5 min and then was heated at 50°C for 3 hours, the Cooled mixture was separated with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried sodium sulfate, filtered and concentrated. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel, filtered and evaporated. The residue was purified using chromatography with reversed phase to give the desired product in the form of a solid white (23 mg, 44%, melting point 174-178°C).1H NMR (300 MHz, DMSO-D6) δ ppm 2.38 (s, 3 H) 3.09 (s, 3 H) 3.33 (s, 3 H), 5.69 (dd, J=7.72, 2.21 Hz, 1 H), 6.30 (d, J=3.31 Hz, 1 H) 7.00 (d, J=3.31 Hz, 1 H), 7.43 (m, 2 H) 7.74 (d, J=2.57 Hz, 2 H) 7.78 (dd, J=8.46, 1.84 Hz, 1 H) 7.85 (d, J=8.09 Hz, 1 H), 7.97 (t, J=8.82 Hz, 2 H) 8.12 (s, 1 H), 10.05 (s, 1 H) 11.46 (d, J=2.21 Hz, 1 H). MS (ESI+) m/z 518(M+N)+.

[00668] Example 20. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophene-3-yl)phenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.53).

[00669] the Named compound was obtained in accordance with the procedure of the example 19, substituting thiophene-3-Voronovo acid on 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolan obtaining a white solid (12 mg, 23%).1H NMR (300 MHz, DMSO-D6) δ ppm 3.07 (s, 3 H) 3.22 (s, 3 H), 5.69 (d, J=7.72 Hz, 1 H) 7.41 (dd, J=8.64, 2.02 Hz, 1 H) 7.50 (d, J=2.94 Hz, 1 H) 7.59 (dd, J=5.13, 1.08 Hz, 1 H) 7.69 (m, 3 H) 7.76 (dd, J=8.64, 1.65 Hz, 1 H) 7.89 (d, J=7.72 Hz, 1 H), 7.95 (m, 3 H) 8.09 (s, 1 H), 10.05 (s, 1 H), 11.47 (s, 1 H). MS (ESI+) m/z 520 (M+H)+.

[00670] Example 21. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophene-2-yl)phenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.61).

[00671] the Named compound was obtained in accordance with the procedure of Example 19, substituting thiophene-2-Voronovo acid on 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolan obtaining solid white (8 mg, 15%).1H NMR (300 MHz, DMSO-D6) δ ppm 3.08 (s, 3 H), 3.30 (s, 3 H), 5.70 (d, J=8.09 Hz, 1 H) 7.19 (dd, J=5.33, 3.86 Hz, 1 H) 7.42 (dd, J=8.82, 2.21 Hz, 1 H) 7.49 (d, J=2.57 Hz, 1 H) 7.69 (dd, J=5.15, 1.20 Hz, 1 H), 7.80 (m, 3 H) 7.88 (d, J=7.72 Hz, 1 H) 7.92 (d, J=2.57 Hz, 1 H) 7.98 (m, 2 H) 8.12 (s, 1 H), 10.06 (s, 1 H), 11.48 (s, 1 H). MS (ESI+) m/z 520 (M+H)+.

[00672] Example 22. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-2-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.59).

[00673] the Named compound was obtained in accordance with the procedure of Example 19, substituting furan-2-Voronovo acid on 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolan with receiving is receiving solid white color (16 mg, 32%).1H NMR (300 MHz, DMSO-D6) δ ppm 3.09 (s, 3 H) 3.35 (s, 3 H) 5.69 (d, J=7.72 Hz, 1 H) 6.69 (dd, J=3.31, 1.84 Hz, 1 H) 7.11 (d, J=3.31 Hz, 1 H) 7.43 (dd, J=8.82, 2.21 Hz, 1 H) 7.49 (d, J=2.94 Hz, 1 H) 7.80 (m, 5 H) 7.96 (m, 2 H) 8.13 (s, 1 H) 10.06 (s, 1 H), 11.47 (s, 1 H). MS (ESI-) m/z 502.1 (M-H)+.

[00674] Example 23. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-3-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.64).

[00675] the Named compound was obtained in accordance with the procedure of Example 19, substituting furan-3-Voronovo acid on 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolan obtaining solid white (6 mg, 12%).1H NMR (300 MHz, DMSO-D6) δ ppm 3.09 (s, 3 H), 3.30 (s, 3 H), 5.69 (dd, J=7.71, 1.83 Hz, 1 H) 7.10 (dd, J=1.74, 0.78 Hz, 1 H) 7.42 (dd, J=8.82, 2.21 Hz, 1 H) 7.46 (d, J=2.57 Hz, 1 H) 7.73 (d, J=2.21 Hz, 1 H) 7.76 (d, J=2.57 Hz, 1 H) 7.78 (d, J=1.84 Hz, 1 H), 7.81 (t, J=1.84 Hz, 1 H) 7.86 (d, J=7.72 Hz, 1 H), 7.96 (t, J=8.82 Hz, 2 H) 8.10 (s, 1 H) 8.28 (s, 1 H), 10.05 (s, 1 H), 11.48 (s, 1 H). MS (ESI-) m/z 502.1 (M-H)+.

[00676] Example 24. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-biphenyl-3-yl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.71).

[00677] the Named compound was obtained in accordance with the procedure of Example 19, replacing phenylboronic acid on 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolan. The crude product was purified by chromatography on silica gel, elwira 3% methanol/CH2Cl2obtaining solid white is one (10 mg, 8%).1H NMR (300 MHz, DMSO-D6) δ ppm 3.08 (s, 3 H), 3.12 (s, 3 H), 5.69 (dd, J=7.81, 1.47 Hz, 1 H) 7.36 (m, 5 H) 7.56 (d, J=2.57 Hz, 1 H) 7.64 (m, 2 H) 7.74 (d, J=2.21 Hz, 1 H) 7.78 (dd, J=8.46, 1.84 Hz, 1 H), 7.94 (m, 3 H) 8.11 (s, 1 H), 10.04 (s, 1 H), 11.47 (s, 1 H). MS (ESI-) m/z 512 (M-H)+.

[00678] Example 25. Obtaining N-(6-(3'-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxybiphenyl-3-yl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.74).

[00679] the Named compound was obtained in accordance with the procedure of Example 19, substituting 3-Chlorfenvinphos acid on 4,4,5,5-tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolan obtaining solid white (38 mg, 68%).1H NMR (300 MHz, DMSO-D6) δ ppm 3.09 (s, 3 H) 3.13 (s, 3 H), 5.70 (dd, J=8.09, 2.21 Hz, 1 H) 7.43 (dd, J=8.82, 2.21 Hz, 1 H) 7.52 (m, 3 H), 7.62 (m, 2 H) 7.72 (m, 2 H) 7.79 (dd, J=8.46, 1.47 Hz, 1 H), 7.95 (m, 3 H) 8.12 (s, 1 H), 10.05 (s, 1 H) 11.47 (d, J=2.21 Hz, 1 H). MS (ESI-) m/z 546 (M-H)+.

[00680] Example 26. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(5-methylthiophene-2-yl)phenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.73).

[00681] the Named compound was obtained in accordance with the procedure of Example 19, substituting 4,4,5,5-tetramethyl-2-(5-methylthiophene-2-yl)-1,3,2-dioxaborolan on 4,4,5,5-tetramethyl-2-(5-methyl-furan-2-yl)-1,3,2-dioxaborolan obtaining solid white (22 mg, 41%).1H NMR (300 MHz, DMSO-D6) δ ppm 2.49 (s, 3 H) 3.09 (s, 3 H), 3.29 (s, 3 H), 5.69 (dd, J=8.09, 2.21 Hz, 1 H) 6.87 (d, J=2.57 Hz, 1 H), 7.43 (m, 2 H) 7.54 (d, J=3.68 Hz, 1 H) 7.76 (m, 2 H) 7.85 (s, H) 7.87 (d, J=5.15 Hz, 1 H), 7.98 (t, J=9.01 Hz, 2 H) 8.11 (s, 1 H), 10.06 (s, 1 H) 11.47 (d, J=2.21 Hz, 1 H). MS (ESI+) m/z 534 (M+H)+.

[00682] Example 27. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.54).

[00683] Part A. Obtaining 2-(2-hydroxy-3,5-diiodophenyl)acetic acid.

[00684] 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 mmol) was added in portions over 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. The crude solid precrystallization of toluene to obtain a light orange powder (6.0 g, 74%).

[00685] Part C. Obtain methyl 2-(3,5-dead-2-methoxyphenyl)acetate.

[00686] 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. Was heated under reflux for 16 h, cooled, concentrated and the residue was separated between EtOAc and water. EtOAc clomipraminum salt solution, dried (Na2SO4) and concentrated to a brown oil, which was chromatographically 40 g cartridge with silica, elwira 3:1 hexane/EtOAc to obtain a yellow oil (6.0 g, 94%).

[00687] Part C. Obtain methyl 2-(3,5-dead-2-methoxyphenyl)-2-methylpropanoate.

[00688] 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) 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 40 g cartridge with silica ISCO, elwira 9:1 hexane/EtOAc to obtain bis-methylated product as a yellow oil (1.63 g, 89%).

[00689] Part D. Getting 2-(3,5-dead-2-methoxyphenyl)-2-methylpropanoic acid.

[00690] 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 f is litraly, washed with water and dried to obtain the desired carboxylic acid (2,46 g, 96%).

[00691] Part of that is Getting 2-(3,5-dead-2-methoxyphenyl)-2-methylpropan-1-ol.

[00692] 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 residue was chromatographically on silica gel, elwira hexane/EtOAc (4:1) to give the desired product (810 mg, 84%).

[00693] Part F. Obtain tert-butyl(2-(3,5-dead-2-methoxyphenyl)-2-methylpropoxy)-dimethylsilane.

[00694] 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%).

[00695] Part G. Obtain 1-(3-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5-iodine-4-methoxyphenyl)pyrimidine-24(1H,3H)-dione.

[00696] 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 silica gel, 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%).

[00697] Part N. Obtaining N-(6-(3-(1-(tert-butyldimethylsilyloxy)-2-methylpropan-2-yl)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00698] a 5 ml microwave tube was added the product from Part G (50 mg, 0,094 mmol), the product from Example 2A, Part b (32.7 mg, 0,094 mmol), potassium phosphate (42,0 mg, 0,198 mmol), PA-Ph (CAS 97739-46-3) (0,827 mg, and 2.83 mmol) and Tris(dibenzylideneacetone)palladium(0) (0,863 mg, 0,943 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 is the second layer was washed with saturated sodium bicarbonate, saline solution, 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 (3:7) to give a solid (32 mg, 54%).

[00699] Part I. Getting N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00700] the Product from Part H (31 mg, 0,050 mmol) in THF (2.0 ml) was treated with 1M TBAF (0.3 ml, 0.3 mmol) in THF and stirred overnight. The mixture was separated by water and ethyl acetate. The organic layer is washed with brine three times, dried with sodium sulfate, filtered and evaporated. The residue was chromatographically on silica gel, elwira 2% to 8% methanol in CH2Cl2obtaining a solid (21 mg, 83%). Melting point: 256-257°C.1H NMR (300 MHz, DMSO-D6) δ ppm 1.35 (s, 6 H) 3.08 (s, 3 H) 3.23 (s, 3 H) 3.67 (d, J=4.78 Hz, 2 H) 4.72 (t, J=4.78 Hz, 1 H) 5.65 (d, J=8.09 Hz, 1 H) 7.36 (m, 3 H) 7.74 (m, 3 H) 7.98 (m, 3 H) 10.04 (s, 1 H) 11.41 (s, 1 H). MS (ESI+) m/z 527 (M+NH4)+.

[00701] Example 28. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(1-methoxy-2-methylpropan-2-yl)phenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.66).

[00702] Part A. Obtaining 1,5-dead-2-methoxy-3-(1-methoxy-2-methylpropan-2-yl)benzene.

[00703] a 25 ml round bottom flask EXT is ulali the product from Example 27, Part E. (259 mg, 0.6 mmol) and sodium hydride (28.8 mg, 1,200 mmol) in THF (5 ml). The mixture was stirred for 30 min and was added logmean (0,045 1, determined as 0.720 mmol). The mixture was stirred for 16 h and was distributed between ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried sodium sulfate, filtered and evaporated to obtain an oil (235 mg, 88%).

[00704] part of the Century, Obtaining 1-(3-iodine-4-methoxy-5-(1-methoxy-2-methylpropan-2-yl)phenyl)pyrimidine-2,4(1H,3H)-dione.

[00705] a 25 ml round bottom flask was added the product from part a (230 mg, 0,516 mmol), pyrimidine-2,4(1H,3H)-dione (63,6 mg, 0,567 mmol), N-(2-cyanophenyl)picolinate (23,02 mg, 0,103 mmol), copper iodide (I) (9,82 mg, 0,052 mmol) and potassium phosphate (230 mg, 1,083 mmol) in DMSO (5 ml). The vessel was tightly closed, was barbotirovany nitrogen and was heated at 60°C for 16 hours the Mixture was cooled and distributed between ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried sodium sulfate, filtered and evaporated. The residue was chromatographically on silica gel, elwira 2% - 5% methanol in CH2Cl2obtaining a solid (140 mg, 63%).

[00706] Part C. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(1-methoxy-2-methylpropan-2-yl)phenyl)naphthalen-2-yl)methanesulfonamide.

[00707] a 5 ml microwave tube was added the product from Frequent Is In (43 mg, 0,100 mmol), the product from Example 2A, Part b (34.7 mg, 0,100 mmol), potassium phosphate (44,6 mg, 0,210 mmol), PA-Ph (CAS 97739-46-3) (0,876 mg, 3.00 mmol) and Tris(dibenzylideneacetone)palladium(0) (0,915 mg, 0,999 mmol) in THF (3.0 ml) and water (1.0 ml). The vessel was tightly closed, 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 sulphate, and filtered. The filtrate was treated with 3-mercaptopropyl-functionalized silica gel, filtered and evaporated. The residue is triturated with methanol/CH2Cl2(1:1) to give a solid (28 mg, 54%).1H NMR (300 MHz, DMSO-D6) δ ppm 1.39 (s, 6 H) 3.08 (s, 3 H) 3.23 (s, 3 H), 3.25 (s, 3 H) 3.61 (s, 2 H), 5.65 (d, J=7.72 Hz, 1 H) 7.27 (d, J=2.57 Hz, 1 H) 7.37 (d, J=2.57 Hz, 1 H) 7.42 (dd, J=8.64, 2.02 Hz, 1 H) 7.69 (dd, J=8.46, 1.84 Hz, 1 H) 7.73 (d, J=2.21 Hz, 1 H) 7.78 (d, J=7.72 Hz, 1 H), 7.95 (t, J=8.27 Hz, 2 H) 8.02 (s, 1 H), 10.04 (s, 1 H), 11.41 (s, 1 H). MS (ESI+) m/z 541 (M+NH4)+.

[00708] Example 29. Obtain methyl 2-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(6-(methylsulfonyl)naphthalen-2-yl)phenyl)-2-methylpropanoate (compound EB-L0-2.70).

[00709] Part A. Obtain methyl 2-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-iodine-2-methoxyphenyl)-2-methylpropanoate.

[00710] In a 100 ml round bottom flask in an atmosphere of N2was added the product from Example 27, Part (410 mg, 0,891 mmol), 1H-pyrimidine-2,4-dione (mg, 1,069 mmol), and rejonowy potassium phosphate (397 mg, 1,872 mmol) in DMSO (5 ml) to give a colorless suspension. Was added N-(2-cyanophenyl) picolinate or 39.8 mg, 0,178 mmol) and the mixture was barbotirovany N2within 5 minutes was Added copper iodide (I) (16,97 mg, 0,089 mmol) and the mixture again was barbotirovany 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, brought the pH to 1 with the use of HCl. The aqueous layers were extracted 2X EtOAc. The organic extracts were combined, washed with water, saturated NaHCO3and saturated NaCl. The organic layer was dried (Na2SO4), was treated with 3-mercaptopropyl-functionalized-silica, filtered and concentrated. The crude product was purified by chromatography on 40 g cartridge with silica ISCO, elwira 3% Meon in CH2Cl2obtaining a white foam (269 mg, 68%).

[00711] Part C. Obtain methyl 2-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(6-(methylsulfonyl)naphthalen-2-yl)phenyl)-2-methylpropanoate.

[00712] a 20 ml microwave tube was added the product from part a (0,444 g, 1.0 mmol), the product from Example 2A, Part b (0,365 g of 1.050 mmol) and rejonowy potassium phosphate (0,446 g, 2,100 mmol) in a mixture of 3:1 tetrahydrofuran-water (12 ml) and was degirolami by ozonation of nitrogen for 20 min Then the solution was treated with PA-Ph (CAS 97739-46-3) (,77 mg, 0,030 mmol) and Tris (dibenzylidene-acetone)palladium(0) (9,16 mg 10,00 mmol) followed by degassing for another 5 minutes This microwave tube is then tightly closed and heated at 50°C for 18 h, cooled and distributed between EtOAc and water, bringing the pH to 1 using 1M HCl. The EtOAc layer was washed with water, saturated NaHCO3and saturated NaCl. The organic layer was dried over sodium sulfate, stirred for 1 h, 3-mercaptopropyl - functionalized-silica, filtered and concentrated. The crude product was purified by chromatography on 12 g cartridge with silica ISCO, elwira 1-3% Meon in CH2Cl2obtaining a light yellowish-brown crystals (480 mg, 98%).1H NMR (300 MHz, DMSO-D6) δ ppm 1.52 (s, 6 H) 3.08 (s, 3 H) 3.14 (s, 3 H) 3.64 (s, 3 H) 5.67 (dd, J=8.09, 1.84 Hz, 1 H) 7.37-7.48 (m, 3 H) 7.65 (dd, J=8.46, 1.84 Hz, 1 H) 7.73 (d, J=2.21 Hz, 1 H) 7.83 (d, J=8.09 Hz, 1 H) 7.96 (dd, J=8.64, 5.70 Hz, 2 H) 8.01 (s, 1 H) 10.05 (s, 1 H) 11.45 (s, 1 H). MS (ESI-) m/z 536 (M-H)+.

[00713] Example 30. Getting 2-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(6-(methylsulfonyl)naphthalen-2-yl)phenyl)-2-methylpropanoic acid (compound IB-L0-2.77).

[00714] a Mixture of the product from Example 29 (108 mg, 0.2 mmol) and sodium hydroxide (1 ml, 4.00 mmol) in methanol, THF, water (3:3:1, 10 ml) was heated at 80°C for 18 h, cooled and carefully acidified to pH 1 with concentrated model HC1, receiving financial p is either the formation of a white precipitate. The solid is collected by filtration, washed with water and dried. The crude material was ground in 1 ml 1:1 EtOAc/MeOH, was treated with ultrasound for 5 min, and the solid substance was collected by filtration as a bright white solid (58 mg, 54% yield). Melting point >300°C.1H NMR (300 MHz, DMSO-D6) δ ppm 1.50 (s, 6 H) 3.08 (s, 3 H) 3.18 (s, 3 H) 5.66 (d, J=7.72 Hz, 1 H) 7.34-7.45 (m, 3 H) 7.67 (dd, J=8.64, 1.65 Hz, 1 H) 7.73 (d, J=1.84 Hz, 1 H) 7.82 (d, J=7.72 Hz, 1 H) 7.96 (dd, J=9.01, 4.60 Hz, 2 H) 8.02 (s. 1 H) 10.04 (s, 1 H) 11.43 (s, 1 H) 12.15 (s, 1 H). MS (ESI-) m/z 522 (M-H)+.

[00715] Example 31. Obtain methyl 5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(6-(methylsulfonyl)naphthalen-2-yl)benzoate (compound IB-L0-2.72).

[00716] Part A. Obtain methyl 3,5-dead-2-methoxybenzoate.

[00717] a Mixture of 2-hydroxy-3,5-diodontidae acid (3.9 g, 10.0 mmol), potassium carbonate (4.15 g, 30.0 mmol) and dimethylsulfate (2,77 g of 22.0 mmol) in acetone (33 ml) was heated under reflux for 16 h, cooled and concentrated. The residue was dissolved in EtOAc and washed with water, brine, dried (Na2SO4), filtered and concentrated to obtain a whitish solid (4,2 g, quantitative yield).

[00718] Part C. Obtain methyl 5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-iodine-2-methoxybenzoate.

[00719] In a 100 ml round bottom flask in an atmosphere of N2was added the product from part a (2,09 g, 5.0 mm is l), 1H-pyrimidine-2,4-dione (of 0.67 g, 6.0 mmol) and rejonowy potassium phosphate (2.2 g, 10.5 mmol) in DMSO (20 ml) to give a colorless suspension. Was added N-(2-cyanophenyl)picolinate (220 mg, 1.0 mmol) and the mixture was barbotirovany N2within 5 minutes was Added copper iodide (I) (95 mg, 0.5 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. The organic layer was dried (Na2SO4), was treated with 3-mercaptopropyl-functionalized-silica, filtered and concentrated. The crude product was purified by chromatography on 40 g cartridge with silica ISCO, elwira 3% Meon in CH2Cl2obtaining a white foam (1.0 g, 50%).

[00720] Part C. Obtain methyl 5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(6-(methylsulfonyl)naphthalen-2-yl)benzoate.

[00721] a Mixture of the product from Part b (101 mg, 0.25 mmol), the product from Example 2A, Part b (91 mg, to 0.263 mmol) and trehosnovnogo potassium phosphate (111 mg, 0,525 mmol) in a mixture of 3:1 tetrahydro-furan-water (12 ml) was degirolami by ozonation of nitrogen for 20 min Then the solution was treated with PA-Ph (CAS 97739-46-3) (2,192 mg, 7,50 μmol) and Tris(dibenzylidene the acetone)palladium (0) (2,289 mg, 2,500 μmol) followed by degassing for another 5 minutes Microwave tube is then hermetically closed, heated at 50°C for 18 h, cooled and distributed between EtOAc and water, bringing the pH to 1, using 1M HCl. The EtOAc layer was washed with water, saturated NaHCO3and saturated NaCl. The organic layer was dried Na2SO4was stirred for 1 h with 3-mercaptopropyl-functionalized-silica, filtered and concentrated. The crude product was purified by chromatography on 12 g cartridge with silica ISCO, elwira 3% Meon in CH2Cl2obtaining whitish foam (80 mg, 63%).1H NMR (300 MHz, DMSO-D6) δ ppm 3.09 (s, 3 H) 3.45 (s, 3 H) 3.89 (s, 3 H), 5.69 (d, J=7.72 Hz, 1 H) 7.43 (dd, J=8.82, 2.21 Hz, 1 H), 7.68-7.79 (m, 4 H) 7.84 (d, J=7.72 Hz, 1 H) 7.89-8.01 (m, 2 H) 8.09 (s, 1 H), 10.06 (s, 1 H), 11.49 (s, 1 H). MS (ESI-) m/z 494 (M-H)+.

[00722] Example 32. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-iodine-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.57).

[00723] Part A. Obtaining 1,3,5-triiodothyronine-2-methoxybenzene. [00724] 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. This solution was cooled in an ice bath and added quick drops of 1.0 M trimethylsilyldiazomethane (7,95 ml, 15,90 mmol), followed by adding dropwise methanol (6 ml), resulting in the calm part is the 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-brown, which was used without purification (4.8 g, 94%).

[00725] part of the Century, Obtaining 1-(3,5-dead-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00726] 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 using 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 substance rosterlive mixture 2:1 hexane/EtOAc to obtain white powder (2.2 g, 62%).

[00727] Part C. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-iodine-2-methoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00728] a Mixture of the product from Part 1-(3,5-dead-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (118 mg, 0.25 mmol), the product from Example 2A, Part b (87 mg, 0.25 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride CH2Cl2(of 10.21 mg of 0.013 mmol) and sodium carbonate (0,250 ml, 0.25 mmol) in toluene (1.0 ml) and ethanol (1.0 ml) was barbotirovany nitrogen for 5 min and heated in a microwave oven at 100°C for 30 minutes the Mixture was cooled and separated with ethyl acetate and 1M HCl. The organic layer was washed with saturated sodium bicarbonate, brine, dried sodium sulfate, filtered and evaporated. The residue was chromatographically on the silicon dioxide, elwira with ethyl acetate/hexane (2:3 to 4:1) to give the titled compound (16 mg, 11%).1H NMR (300 MHz, DMSO-D6) δ ppm 3.08 (s, 3 H), 3.35 (s, 3 H), 5.67 (d, J=8.09 Hz, 1 H) 7.42 (dd, J=8.82, 2.21 Hz, 1 H) 7.59 (d, J=2.57 Hz, 1 H) 7.73 (m, 2 H) 7.81 (d, J=8.09 Hz, 1 H), 7.95 (m, 3 H) 8.09 (s, 1 H) 10.06 (s, 1 H), 11.47 (s, 1 H). MS (ESI-) m/z 562 (M-H)+.

[00729] Example 33. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-((trimethylsilyl)ethinyl)phenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.78).

[00730] a 5 ml microwave tube was combined amenitieseven storage capacity (0.044 ml, 0.32 mmol), the product from Example 32 (45.1 mg, 0.08 mm is l), iodide copper (I) - (0,762 mg, 4.0 mmol), bis(triphenyl-phosphine)palladium(II) chloride (2,81 mg, 4.0 mmol) and triethylamine (0,056 ml, 0.40 mmol) in acetonitrile (2 ml). This mixture was barbotirovany nitrogen for 5 min, tightly closed and heated in a microwave oven at 80°C for 20 minutes the Reaction mixture was cooled and separated by ethyl acetate and water. The organic layer was washed with saline, dried with sodium sulfate, filtered and evaporated. The residue was chromatographically on the silicon dioxide, elwira 1-4% methanol in CH2Cl2obtaining solid (18 mg, 42%) melting point 175-178°C.1H NMR (300 MHz, DMSO-D6) δ ppm 0.25 (s, 9 H) 3.07 (s, 3 H), 3.65 (s, 3 H), 5.66 (dd, J=7.91, 2.02 Hz, 1 H) 7.41 (dd, J=8.82, 2.21 Hz, 1 H) 7.58 (m, 2 H) 7.69 (dd, J=8.46, 1.84 Hz, 1 H) 7.72 (d, J=2.21 Hz, 1 H) 7.81 (d, J=7.72 Hz, 1 H) 7.93 (m, 2 H) 8.05 (d, J=1.32 Hz, 1 H), 10.04 (s, 1 H) 11.45 (d, J=2.21 Hz, 1 H). MS (ESI+) m/z 534 (M+H)+.

[00731] Example 34. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(methylsulphonyl)phenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.68).

[00732] Part A. Obtaining 4-nitrobenzene-2-diazo-1-oxide.

[00733] 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). Sodium nitrite (2.76 g, 40.0 mmol) in water (6 ml) was added dropwise at 0°C., and the mixture was stirred at room temperature for 30 minutes, the Solid is collected on filter is on, washed terraforming acid and water. The solid is suspended in acetone (50 ml), filtered and dried to obtain a solid substance (of 3.31 g, 50%).

[00734] part of the Century, Obtaining 2-(methylthio)-4-NITROPHENOL.

[00735] 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%).

[00736] Part C. Obtaining 2-(methylsulphonyl)-4-NITROPHENOL.

[00737] 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%).

[00738] Part D. Getting 2-iodine-6-(methylsulphonyl)-4-NITROPHENOL.

[00739] In a 50 ml round bottom flask is obavljale the product from Part C (470 mg, 2,164 mmol) in Meon (10 ml) and water (2.5 ml). Was added dropwise to monochloride 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%).

[00740] Part of that is Getting 1-iodine-2-methoxy-3-(methylsulphonyl)-5-nitrobenzene.

[00741] 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 suspension. The mixture was cooled in an ice bath, was added 2M (trimethylsilyl)-diazomethane (1,377 ml to 2.75 mmol) quick drops and then 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%).

[00742] Part F. 3 iodine-4-methoxy-5-(methylsulphonyl)aniline.

[00743] 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 filtration is ovale. The filtrate was evaporated and the residue was separated with ethyl acetate and water. The organic layer was washed with saline, dried with sodium sulfate, filtered and evaporated to obtain a solid (590 mg, 99%).

[00744] Part G. Obtaining (E)-N-(3-iodine-4-methoxy-5-(methylsulphonyl)phenylcarbamoyl)-3-ethoxyacrylate.

[00745] In a 100 ml round bottom flask was added the product from Part F (500 mg, 1,528 mmol) in DMF (15.0 ml). This solution was cooled in nitrogen atmosphere at -20°C, was 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%).

[00746] Part N. Obtain 1-(3-iodine-4-methoxy-5-(methylsulphonyl)phenyl)pyrimidine-2,4(1H,3H)-dione.

[00747] 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 stirred during the 10 minutes The solid is collected by filtration, washed with water and dried to obtain solid white (325 mg, 83%).

[00748] Part I. Getting N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(methylsulphonyl)phenyl)naphthalen-2-yl)methanesulfonamide.

[00749] a 5 ml microwave tube was added the product from Part H (63,3 mg, 0.15 mmol), the product from Example 2A, Part b (52.1 mg, 0,150 mmol), the complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride (6,12 mg, 7,50 mmol) and 1M sodium carbonate (0,150 ml, 0,150 mmol) in the solvent toluene (1.0 ml) and ethanol (1.0 ml). The vessel was tightly closed and the mixture was barbotirovany nitrogen for 5 min and heated in a microwave oven at 100°C for 30 minutes 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. The residue was purified on silica gel, elwira 1% to 8% methanol in CH2Cl2obtaining a crude product. Final rubbing in a mixture of 1:1 methanol/ethyl acetate gave pure solid (26 mg, 34%).1H NMR (300 MHz, DMSO-D6) δ ppm 3.10 (s, 3 H) 3.44 (s, 3 H) 3.45 (s, 3 H) 5.71 (d, J=8.09 Hz, 1 H) 7.44 (dd, J=8.82, 2.21 Hz, 1 H) 7.75 (d, J=1.84 Hz, 1 H) 7.80 (dd, J=8.46, 1.84 Hz, 1 H) 7.86 (d, J=8.09 Hz, 1 H) 7.91 (d, J=2.57 Hz, 1 H) 7.96 (d, J=2.57 Hz, 1 H) 8.00 (m, 2 H) 8.16 (d, J=1.47 Hz, 1 H) 10.10 (s, 1 H) 11.51 (s, 1 H). MS (ESI+) m/z 533 (M+NH4)+.

[00750] Example 35. Obtaining N-(5-(2,4-dioxo-3,4-dihydropyri midin-1(2H)-yl)-2-methoxy-3-(6-(methylsulfonyl)naphthalen-2-yl)phenyl)methanesulfonamide (compound IB-L0-2.75).

[00751] Part A. Obtaining 2,4-dead-6-NITROPHENOL.

[00752] To a solution of 2-NITROPHENOL (2,78 g, 20 mmol) in Meon (120 ml) and water (30 ml) was added dropwise a solution of monochloride iodine (2,105 ml, 42.0 mmol) in 10 ml of CH2Cl2. The mixture was stirred for 2 h, poured into 600 ml of water, stirred and treated with ultrasound for 30 minutes the Mixture was filtered to collect the solid yellow color, which was washed 3x with water (50 ml each wash) and dried to constant weight (7,3 g, 93%).

[00753] part of the Century, Obtaining 1,5-dead-2-methoxy-3-nitrobenzene.

[00754] In a 50 ml pressure vessel was placed the product from part a and MTBE (10 ml) to obtain the solution yellow. This solution was cooled in an ice bath and quickly drops) was added 2M trimethylsilyldiazomethane (2,251 ml, 4,50 mmol), followed by adding dropwise the Meon (0.6 ml), resulting in the peaceful liberation of gas bubbles. The vessel was tightly closed and stirred, leaving to warm to room temperature over 4 h and 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 solid yellow (1.22 g, 100%).

[00755] Part C. Obtain 3,5-dead-2-methoxyaniline.

[00756] In a 250 ml round bottom to the forehead was added the product from Part b (0,98 g, 2,420 mmol), ammonium chloride (0,194 g, 3.63 mmol), and iron (0,676 g, 12,10 mmol) in a mixture of THF/methanol/water (20 ml/20 ml/10 ml). The mixture was heated under reflux for 16 h, cooled and filtered. The filtrate was evaporated, and the residue was separated by water and ethyl acetate. The organic layer was dried with sodium sulfate, filtered and evaporated to obtain an oil (780 mg, 86%).

[00757] Part D. Obtain 1-(3-amino-5-iodine-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00758] a 25 ml round bottom flask was added the product from Part C (650 mg, 1,734 mmol), pyrimidine-2,4(1H,3H)-dione (214 mg, 1,907 mmol), N-(2-cyanophenyl)picolinate (77 mg, 0,347 mmol), copper iodide (I) (33,0 mg, 0,173 mmol) and potassium phosphate (773 mg, of 3.64 mmol) in DMSO (5 ml). The vessel was tightly closed and the mixture was barbotirovany nitrogen for 15 min and heated at 60°C for 16 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 a mixture of 5:95 methanol/D CH2Cl2CM to obtain a solid (125 mg, 20%).

[00759] Part E. Obtain N-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-iodine-2-methoxy-phenyl)methanesulfonamide.

[00760] a solution of the product from Part D (110 mg, 0,306 the mol) in pyridine (2 ml) was treated with methanesulfonamide (0,048 ml, 0,612 mmol) and was stirred for 24 h the Solvent was evaporated and the residue was separated with ethyl acetate and 1M HCl. The organic layer was washed with saline, dried with sodium sulfate, filtered and evaporated. The residue was purified on silica gel, elwira 2% - 5% methanol in CH2Cl2obtaining a solid (20 mg, 15%).

[00761] Part F. Obtain N-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(6-(methylsulfonyl)naphthalen-2-yl)phenyl)methanesulfonamide.

[00762] a 5 ml microwave tube was added the product from Part E (18 mg, 0,041 mmol), Example 2A, Part b (14,30 mg, 0,041 mmol), potassium phosphate (18,35 mg, 0,086 mmol), PA-Ph (CAS 97739-46-3) (0,361 mg, 1,235 μmol) and Tris (dibenzylideneacetone)dipalladium(0) (0,377 mg, 0,412 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 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 sodium sulfate, filtered and evaporated. The residue was purified on silica gel, elwira 2% - 5% methanol in CH2Cl2obtaining a solid substance. Final rubbing in a mixture of 1:1 methanol/CH2Cl2gave the desired product (7 mg, 32%).1H NMR (300 MHz, DMSO-D6) δ ppm 3.09 (s, 3 H), 3.17 (s, 3 H) 3.37 (s, 3 H) 5.69 (dd, J=7.91, 2.02 Hz, 1 H) 7.34 (d, J=2.57 Hz, 1 H) 7.43 (dd, J=8.82, 2.21 Hz, 1 H) 7.47 (d, J=2.57 Hz, 1 H) 7.73 (m, 2 H) 7.81 (d, J=8.09 H, 1 H) 7.94 (d, J=6.25 Hz, 1 H) 7.97 (d, J=6.62 Hz, 1 H) 8.07 (s, 1 H), 9.45 (s, 1 H), 10.05 (s, 1 H) 11.45 (d, J=1.84 Hz, 1 H). MS (ESI-) m/z 529 (M-H).

[00763] Example 36. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(trifluoromethyl)phenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.56).

[00764] Part A. Obtaining 4-iodine-2-(trifluoromethyl)phenol.

[00765] To a solution of 2-(trifluoromethyl) phenol (3,24 g, 20 mmol) in Meon (40 ml) was added sodium hydroxide (0,960 g, 24,0 mmol) and was stirred to dissolve the hydroxide. The mixture was cooled to 0°C was added sodium iodide (3.0 g, 20 mmol), followed by adding dropwise a 10% aqueous sodium hypochlorite (9.0 ml, 14.6 mmol). The addition of sodium iodide followed by the addition of sodium hypochlorite was repeated twice more. The mixture was stirred at ambient temperature for 2 h and treated dropwise with concentrated HCl to pH 1. The mixture was extracted with 3 EtOAc. These extracts were combined, washed with saline, dried with sodium sulfate, filtered and evaporated. The residue was purified on silica gel, elwira EtOAc/hexane (1:9) to obtain monoiodo product (5.0 g, 87%).

[00766] part of the Century, Obtaining 2-bromo-4-iodine-6-(trifluoromethyl)phenol.

[00767] In a 250 ml round bottom flask was added the product from part a (5,00 g, 17,36 mmol) and 1,3-dibromo-5-dimethylhydantoin (2,73 g of 9.55 mmol) in CHCl3(80 ml) to give an orange solution. The mixture peremeci the Ali for 2 h, washed with water, brine, dried sodium sulfate, filtered and evaporated. The crude product was purified on silica gel, elwira with ethyl acetate/hexane (5:95) to give a solid (3.5 g, 54%).

[00768] Part C. Obtain 1-bromo-5-iodine-2-methoxy-3-(trifluoromethyl)benzene.

[00769] a Mixture of the product from Part b (3.2 g, 8,72 mmol), iodomethane (1,36 ml, and 21.8 mmol) and 50% sodium hydroxide (0,507 ml, 9,59 mmol) in acetone (20 ml) was stirred for 24 h the Solvent was evaporated, and the residue was separated with ethyl acetate and water. The organic layer was washed with saline, dried with sodium sulfate, filtered and evaporated. The crude material was purified on silica gel, elwira with ethyl acetate/hexane (5:95) to give a solid (2.67 g, 80%).

[00770] Part D. Obtain 1-(3-bromo-4-methoxy-5-(trifluoromethyl)phenyl)pyrimidine-2,4(1H,3H)-dione.

[00771] a 20 ml microwave tube was added the product from Part C (762 mg, 2.0 mmol), pyrimidine-2,4(1H,3H)-dione (247 mg, 2.2 mmol), N-(2-cyanophenyl)picolinate (89 mg, 0.4 mmol), copper iodide (I) (38,1 mg, 0.2 mmol) and potassium phosphate (892 mg, 4.2 mmol) in DMSO (10 ml). The vessel was tightly closed and the mixture was barbotirovany nitrogen for 15 min and heated at 60°C for 16 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-is mercaptopropyl-functionalized silica gel, filtered and evaporated. The residue was purified on silica gel, elwira with ethyl acetate/hexane (2:3) to give the desired product (63 mg, 9%).

[00772] Part E. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(trifluoromethyl)phenyl)naphthalen-2-yl)methanesulfonamide.

[00773] a 5 ml microwave tube was added the product from Part D (60 mg, 0,164 mmol), the product from Example 2A, Part b (of 62.8 mg, 0,181 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (are 5.36 mg, by 8.22 mmol) and potassium phosphate (69,8 mg, 0,329 mmol) in THF/water (3 ml/1 ml). The vessel was tightly closed and the mixture was barbotirovany nitrogen for 5 min and heated at 60°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 purified using chromatography with reversed phase with obtaining these compounds are in the form of a solid (26 mg, 31%).1H NMR (300 MHz, DMSO-D6) δ ppm 3.10 (s, 3 H) 3.37 (s, 3 H), 5.71 (dd, J=7.72, 2.21 Hz, 1 H) 7.44 (dd, J=8.82, 2.21 Hz, 1 H), 7.75 (s, 1 H) 7.78 (d, J=1.84 Hz, 1 H) 7.88 (m, 3 H) 7.98 (d, J=3.31 Hz, 1 H) 8.01 (d, J=3.68 Hz, 1 H) 8.15 (s, 1 H), 10.09 (s, 1 H) 11.51 (d, J=2.21 Hz, 1 H). MS (ESI-) m/z: 504.1 (M-H)+.

[00774] Example 37. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(perforated)phenyl)naphthalen-2-yl)methane is sulfonamide (compound IB-L0-2.60).

[00775] Part A. Obtaining 1-methoxy-4-nitro-2-(perforated)benzene.

[00776] In a 250 ml round bottom flask was added 2-bromo-1-methoxy-4-nitrobenzene (3.5 g, 15,08 mmol), copper iodide (I) (5.75 g, 30.2 mmol), and 2,2,3,3,3-pentafluoropropanol sodium (a 5.25 g of 28.2 mmol) in DMF (75 ml) and toluene (25 ml) to give a yellowish-brown suspension. The mixture was heated at 150°C., and the toluene was removed with the nozzle Dean-stark. The mixture was heated at 155°C for 6 h in nitrogen atmosphere, cooled and poured into 100 ml water and 100 ml of ether, filtered through a pad of celite 1 inch thick, and the pad was washed with ether. The layers of the filtrate were separated. The organic layer was washed with saline, dried (Na2SO4) filtered and concentrated. The dark oil was subjected to flash chromatography on a cartridge with silica Isco 40 g, elwira 4:1 hexane/EtOAc to obtain a yellow oil which was a mixture (3:1) of the desired substance and the source material (1.5 g, 37%).

[00777] part of the Century, Obtaining 4-nitro-2-(perforated)phenol.

[00778] In a 100 ml round bottom flask was added the product from part a (1.4 g, 5,16 mmol) and piridinkarboksamid (4 g, 34.6 mmol) pure. The mixture was heated at 210°C for 20 min, cooled, and distributed between EtOAc and water. The organic layer was washed with saline, dried (Na2SO4) and concentrated is. The crude product was subjected to flash chromatography on a cartridge with silica Isco 12 g, elwira 3:2 hexane/EtOAc to obtain a yellow oil (1.3 g, 98%).

[00779] Part C. Obtaining 2-iodine-4-nitro-6-(perforated)phenol.

[00780] In a 100 ml round bottom flask was added the product from Part b (1.3 g, of 5.06 mmol) and N-jodatime (1,251 g, to 5.56 mmol) in acetonitrile (16,85 ml) to give a yellow solution.

The solution was stirred for 16 h, diluted with 100 ml EtOAc and washed 2×50 ml 10% sodium thiosulfate, brine, dried (Na2SO4) and concentrated to a semi-solid substances orange. This semi-solid substance was subjected to flash chromatography on a cartridge with silica Isco 40 g, elwira 3:1 hexane EtOAc getting oil thick yellow/orange (1.3 g, 67%).

[00781] Part D. Getting 1-iodine-2-methoxy-5-nitro-3-(perforated)benzene.

[00782] In a 100 ml round bottom flask was added the product from Part C (1.04 g, of 2.72 mmol), potassium carbonate (0,563 g, 4.07 mmol) and dimethylsulfate (0,411 g, 3,26 mmol) in acetone (20 ml) to give a brown suspension. The mixture was carefully heated under reflux for 16 h, cooled, diluted in EtOAc, washed with water and brine. The organic layer was dried Na2SO4, filtered and concentrated to a yellow oil, which was purified using flash chromatography on a cartridge with dio is led by silicon Isco 40 g, elwira 9:1 hexane /EtOAc (600 mg, 56%).

[00783] Part E. Obtaining 3-iodine-4-methoxy-5-(perforated)aniline.

[00784] In a 250 ml round bottom flask was added the product from Part D (0.6 g, 1,511 mmol), iron (0,422 g, 7.56 mmol) and ammonium chloride (0,121 g of 2.267 mmol) in a solvent mixture of EtOH (9 ml), THF (9 ml) and water (3 ml) to give a brown suspension, which was heated at 95-100°C for 2 h, the Reaction mixture was filtered through a pad of celite, and the celite was washed repeatedly EtOH. The filtrate was concentrated, and the residue was dissolved in EtOAc, washed with water, brine, dried (Na2SO4), filtered and concentrated to obtain oil (560 mg, 99%).

[00785] Part F. Obtain 1,5-dead-2-methoxy-3-(perforated)benzene.

[00786] a 25 ml round bottom flask under nitrogen atmosphere was added the product from Part E (0.565 g, 1,539 mmol), tert-butylnitrite (0,293 ml, 2,463 mmol), copper iodide (I) (0,293 g, 1,539 mmol), sodium iodide (0,231 g, 1,539 mmol) and iodine (of € 0.195 g, 0,770 mmol) in DME (15,39 ml) to give a brown suspension. The mixture was heated at 60°C for 3 h, cooled and filtered through celite, rinsing well layer cellica EtOAc. The EtOAc filtrate was treated with 10% sodium thiosulfate, brine, dried (Na2SO4), filtered and concentrated to a dark oil. The crude material was purified using flash chromatography on a cartridge with silica Isco 40 g, elwira 95:5 hexane is m/EtOAc to obtain a yellow oil (360 mg, 49%).

[00787] Part G. Obtain 1-(3-iodine-4-methoxy-5-(perforated)phenyl)pyrimidine-2,4(1H,3H)-dione.

[00788] a 20 ml microwave tube was added the product from Part F (0.36 g, 0,753 mmol), 1H-pyrimidine-2,4-dione (0,101 g, 0,904 mmol), rejonowy potassium phosphate (0,336 g, 1,582 mmol) N-(2-cyanophenyl)picolinate (0,034 g, 0,151 mmol) and copper iodide (I) (0,014 g of 0.075 mmol in DMSO (7 ml). The vessel was tightly closed and the mixture was barbotirovany N2for 30 min, heated at 60°C for 24 h, cooled and diluted in EtOAc. The EtOAc layer washed with 1M HCl, saturated NaHCO3and saturated NaCl, dried (Na2SO4), filtered and concentrated. The residue was subjected to flash chromatography on a cartridge with silica Isco 40 g, elwira hexane --> 1:1 hexane/EtOAc to obtain a yellow foam (100 mg, 29%).

[00789] Part N. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(perforated)phenyl)naphthalen-2-yl)methanesulfonamide.

[00790] a 5 ml microwave tube was combined product from Part G (0.10 g, 0,216 mmol), Example 2A, Part b (0.075 g, 0,216 mmol), and rejonowy potassium phosphate (0,096 g, 0,454 mmol) in a mixture of 3:1 tetrahydrofuran-water (5 ml) and was degirolami by ozonation of nitrogen for 10 minutes the Mixture was then treated PA-Ph (CAS 97739-46-3) (1,898 mg of 6.49 mmol) and Tris(dibenzylideneacetone)dipalladium(0) (1,982 mg, 2,164 µmol) followed by degassing for another 5 minutes and Then the flask seal technics is about closed and stirred at 50°C for 16 h, and distributed between EtOAc and water. The EtOAc layer was washed with 0.1 M HCl, saturated NaHCO3and saturated NaCl. The organic phase was dried Na2SO4was stirred for 0.5 h with 3-mercaptopropyl-functionalized-silica for the removal of metals, filtered and concentrated. The crude product was purified by chromatography on a cartridge with silica Isco 12 g, elwira CH2Cl2--> 3% Meon in CH2Cl2obtaining a light yellow foam (84 mg, 99%). The melting point of 162 to 165°C.1H NMR (300 MHz, DMSO-D6) δ ppm 3.10 (s, 3 H) 3.33 (s, 3 H) 5.70 (d, J=7.72 Hz, 1 H) 7.44 (dd, J=8.82, 2.21 Hz, 1 H) 7.70-7.76 (m, 2 H) 7.80 (d, J=2.57 Hz, 1 H) 7.86 (d, J=8.09 Hz, 1 H) 7.91 (d, J=2.57 Hz, 1 H) 8.00 (dd, J=8.82, 2.94 Hz, 2 H) 8.12 (s, 1 H) 10.10 (s, 1 H) 11.50 (s, 1 H). MS (ESI-) m/z 554 (M-H)+.

[00791] Example 38. Obtaining (E)-N'-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophene-2-yl)phenyl)-2,3-dihydro-1H-inden-1-ilidene)methanesulfonamide (compound IB-L0-2.51).

[00792] Part A. Obtain 1-(3-bromo-4-methoxy-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)phenyl)-pyrimidine-2,4(1H,3H)-dione.

[00793] In a 100 ml round bottom flask was added the product from Example 18, Parts (846 mg, 2.00 mmol). Example 4, part a (516 mg, 2,000 mmol), potassium phosphate (892 mg, 4.20 mmol), 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 vessel was tightly closed and the mixture of barbatio is whether nitrogen for 5 min and stirred at ambient temperature for 72 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 silica gel, elwira 1-4% methanol in CH2Cl2obtaining a solid (690 mg, 81%).

[00794] part of the Century, Obtaining (E)-N'-(5-(3-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-ilidene)methanesulfonamide.

[00795] In a 50 ml round bottom flask was added the product from part a (685 mg, 1,603 mmol) and methanesulfonamide (194 mg, 1,764 mmol) in Meon (20 ml). The mixture was heated to 40°C. and was stirred for 24 h the Mixture was cooled, filtered and washed with methanol to obtain a solid (569 mg, 68%).

[00796] Part C. Obtaining (E)-N'-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophene-2-yl)phenyl)-2,3-dihydro-1H-inden-1-ilidene)methanesulfonamide.

[00797] a 5 ml microwave tube was added the product from Part b (52 mg, 0,100 mmol), thiophene-2-Voronovo acid (12,81 mg, 0,100 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (3,26 mg free 5.01 mmol) and potassium phosphate (42,5 mg, 0,200 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 3 hours the Mixture was divided uh what racedata 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 AA method of obtaining solid white (27 mg, 52%).1H NMR (300 MHz, DMSO-D6) δ ppm 2.86 (m, 2 H) 3.09 (s, 3 H), 3.14 (m, 2 H) 3.32 (s, 3 H), 5.69 (d, J=7.72 Hz, 1 H) 7.18 (dd, J=5.15, 3.68 Hz, 1 H) 7.41 (d, J=2.57 Hz, 1 H) 7.63 (m, 3 H), 7.75 (m, 2 H) 7.86 (d, J=8.09 Hz, 1 H) 7.91 (d, J=2.94 Hz, 1 H), 9.96 (s, 1 H), 11.48 (s, 1 H). MS (ESI+) m/z 523 (M+H)+.

[00798] Example 39. Obtaining (E)-N'-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-2-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-ilidene)methanesulfonamide (compound IB-L0-2.55).

[00799] a 5 ml microwave tube was added the product from Example 38, Part (52 mg, 0,100 mmol), furan-2-Voronovo acid (11,20 mg, 0,100 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (3,26 mg free 5.01 mmol) and potassium phosphate (42,5 mg, 0,200 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 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 silicagel who eat was filtered through celite and evaporated. The residue was purified using chromatography with reversed phase AA method of obtaining a solid (24 mg, 47%).1H NMR (300 MHz, DMSO-D6) δ ppm 2.86 (m, 2 H) 3.09 (s, 3 H) 3.14 (m, 2 H) 3.36 (s, 3 H) 5.68 (d, J=8.09 Hz, 1 H) 6.69 (dd, J=3.31, 1.84 Hz, 1 H) 7.09 (d, J=3.31 Hz, 1 H) 7.41 (d, J=2.57 Hz, 1 H) 7.62 (m, 2 H) 7.75 (d, J=8.09 Hz, 1 H) 7.80 (d, J=2.57 Hz, 1 H) 7.86 (m, 2 H) 9.97 (s, 1 H) 11.46 (s, 1 H). MS (ESI+) m/z 507 (M+H)+.

[00800] Example 40. Obtaining N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-ethoxyphenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.23).

[00801] Part A. Obtain 2-tert-butyl-4-itfinal.

[00802] 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 value of 1. The mixture was extracted with 3 EtOAc. The extracts were combined, amywali salt solution, dried (MgSO4), filtered and concentrated. The crude oil was subjected to flash chromatography on a cartridge with silica ISCO 80 g, elwira hexane --> 4:1 hexane/EtOAc to obtain a yellow oil (5.2 g, 75%).

[00803] part of the Century, Obtaining 2-bromo-6-tert-butyl-4-itfinal.

[00804] 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, elwira hexane, obtaining a pinkish solid (4,84 g, 78%).

[00805] Part C. Obtain 1-bromo-3-tert-butyl-2-ethoxy-5-yogashala.

[00806] 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 Na2SO4, filtered and concentrated to a red oil. The oil was subjected to flash chromatogra the AI on the cartridge with silica Isco 40 g, elwira hexane, obtaining a clear oil (820 mg, 86%).

[00807] Part D. Obtain 1-(3-bromo-5-tert-butyl-4-ethoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00808] a 20 ml microwave tube under a stream of nitrogen was added the product from Part C (0.4 g, 1,044 mmol), 1H-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-silica for 1 h, filtered and concentrated. The crude product was purified by chromatography on a cartridge with silica ISCO 12 g, elwira 2% Meon in CH2Cl2obtaining a white powder (266 mg, 69%).

[00809] Part E. Obtain N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-ethoxyphenyl)naphthalen-2-yl)methanesulfonamide.

[00810] a 5 ml microwave tube was added n is oduct from Part D (55,1 mg, 0.15 mmol), the product from Example 2A, Part b (52.1 mg, 0,150 mmol), rejonowy 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), water (1 ml). The mixture was barbotirovany for 10 min with nitrogen, was heated sealed at 50°C for 4 h, cooled and diluted in EtOAc. The EtOAc layer washed with 1M HCl, saturated NaHCO3, saturated NaCl, dried (Na2SO4) and simultaneously treated mercaptopropyl silica gel, filtered and concentrated. The residue was subjected to flash chromatography on a cartridge with silicon dioxide 12 g Isco, elwira 2% Meon in CH2Cl2obtaining a solid (16 mg, 21%). Melting point 196-202°C.1H NMR (300 MHz, DMSO-D6) δ ppm 1.00 (t, J=6.99 Hz, 3 H) 1.44 (s, 9 H) 3.09 (s, 3 H) 3.43 (q, J=7.11 Hz, 2 H) 5.64 (dd, J=7.91, 1.29 Hz, 1 H) 7.32 (d, J=2.94 Hz, 1 H) 7.36 (d, J=2.94 Hz, 1 H) 7.41 (dd, J=8.82, 2.21 Hz, 1 H) 7.72 (s, 1 H) 7.74 (d, J=1.47 Hz, 1 H) 7.80 (d, J=7.72 Hz, 1 H) 7.90-8.00 (m, 2 H) 8.05 (s, 1 H) 10.04 (s, 1 H), 11.41 (s, 1 H). MS (ESI.) m/z 506 (M-H)+.

[00811] Example 41. Obtaining N-(6-(3-tert-butyl-2-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.14).

[00812] Part A. Obtain 2-bromo-6-tert-butyl-4-itanyone.

[00813] In a 50 ml round bottom flask was added 2-bromo-6-tert-butylaniline [obtained by the method Onitsuka, et.al. Organometallics, 25(5), 2006, pp 1270-1278] (1.18 g, 5.17 mmol) and sodium bicarbonate (0,782 g, 931 mmol) in water (5 ml). The mixture was cooled in an ice bath was added iodine (1,444 g, 5,69 mmol) in several portions. The mixture was heated to ambient temperature and was stirred for 16 hours the Mixture was treated with aqueous sodium thiosulfate, extracted with ethyl acetate, dried with sodium sulfate, filtered and evaporated. The residue was purified on silica gel, elwira 5% ethyl acetate in hexane to obtain oil (1.2 g, 65%).

[00814] part of the Century, Obtaining 1-bromo-3-tert-butyl-2-chloro-5-yogashala.

[00815] To a mixture of tert-butylnitrite (0,198 ml, 1.5 mmol) and copper chloride (II) (161 mg, 1.2 mmol) in acetonitrile (5 ml) was added the product from part a (354 mg, 1.0 mmol) in solution in acetonitrile (5 ml). The mixture was heated at 60°C for 30 min, cooled, separated with ethyl acetate and 1M HCl. The organic layer was washed with saline, dried with sodium sulfate, filtered and evaporated. The residue was purified on silica gel, elwira 5% ethyl acetate in hexane to obtain this product (300 mg, 81%).

[00816] Part C. Obtain 1-(3-bromo-5-tert-butyl-4-chlorophenyl)pyrimidine-2,4(1H,3H)-dione.

[00817] a 20 ml microwave tube was added the product from Part b (300 mg, 0,803 mmol), pyrimidine-2,4(1H,3H)-dione (99 mg, 0,884 mmol), N-(2-cyanophenyl)picolinate (35,9 mg, 0,161 mmol), copper iodide (I) (15,30 mg, 0,080 mmol) and potassium phosphate (358 mg, 1,687 mmol) in DMSO (5 ml). The mixture is hermetically closed, purged with nitrogen and heated at 60°C for 4 h the Mixture p is sdelali 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 purified on silica gel, elwira 10% to 40% ethyl acetate in hexane to obtain a solid (175 mg, 61%).

[00818] Part D. Obtain N-(6-(3-tert-butyl-2-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)naphthalen-2-yl)methanesulfonamide.

[00819] a 5 ml microwave tube was added the product from Part (a 35.8 mg, 0.10 mmol), the product from Example 2A, Part b (38,2 mg, 0,110 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (3,26 mg, 5.00 mmol) and potassium phosphate (42,5 mg, 0,200 mmol) in THF/water (3 ml:1 ml). The mixture was purged with nitrogen for 5 min and heated at 60°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 purified on silica gel, elwira 1:1 ethyl acetate/hexane to obtain solid, which was washed with 1% methanol in CH2Cl2obtaining solid white color (29 mg, 55%), melting point: >280°C.1H NMR (300 MHz, DMSO-D6) δ ppm 1.53 (s, 9 H) 3.08 (s, 3 H), 5.6 (d, J=7.72 Hz, 1 H) 7.42 (m, 2 H) 7.52 (dd, J=8.46, 1.84 Hz, 1 H) 7.56 (d, J=2.57 Hz, 1 H) 7.74 (d, J=1.84 Hz, 1 H) 7.84 (d, J=7.72 Hz, 1 H) 7.88 (s, 1 H) 7.91 (d, J=8.82 Hz, 1 H) 7.95 (d, J=9.19 Hz, 1 H), 10.04 (s, 1 H), 11.46 (s, 1 H). MS (ESI-) m/z 496 (M-H)+.

[00820] Example 42. Obtaining N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)benzo[d]isoxazol-3-yl)methyl)methanesulfonamide (compound IB-L0-2.45).

[00821] Part A. Obtain N-((6-bromobenzo[d]isoxazol-3-yl)methyl)-N-(4-methoxybenzyl)-methanesulfonamide.

[00822] boiling under reflux a solution of 6-bromo-3-methylbenzo[d]isoxazol (1.0 g, 4,72 mmol) in CCl4(25 ml) was added 1-bromperidol-2,5-dione (0,923 g, 5,19 mmol) and the anhydride phenoxybenzoic acid (0,114 g, 0,472 mmol). The mixture was heated under reflux for 6 h, and then cooled to room temperature, filtered through celite, and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using CH2Cl2as the eluent, to obtain this dibromide in the form of a solid (0.84 g, 43%). To a solution of the dibromide (0.20 g, 0,687 mmol) and N-(4-methoxybenzyl)methanesulfonamide (0,148 g, 0,687 mmol) in EtOH (3 ml) was added 1 n aq. NaOH (0,722 ml, 0,722 mmol) and the resulting mixture was stirred at 80°C for 90 minutes the Mixture was distributed between 0.1 n aq. HCl (10 ml) and EtOAc (2×10 ml) and the combined organic layers were dried n the d Na 2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel, using 2:3 EtOAc:hexane as eluent to obtain these compounds in the form of an oil (65 mg, 22%).

[00823] part of the Century, Obtaining N-(4-methoxybenzyl)-N-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2 - yl)benzo[d]iso-3-yl)methyl)methanesulfonamide.

[00824] a solution of the product from part a (56 mg, 0,132 mmol), bis(pinacolato)Debora (37 mg, 0,145 mmol), and potassium acetate (39 mg, 0,395 mmol) in 1,4-dioxane (1.3 ml) was degirolami by ozonation gaseous N2within 15 minutes was Added to the complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (3 mg, 0.004 percent mmol) and the resulting mixture was stirred at 80°C for 16 h, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 1:2 EtOAc:hexane as eluent to obtain these compounds in the form of a colorless oil (49 mg, 79%).

[00825] Part C. Obtain N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)benzo[d]isoxazol-3-yl)methyl)-N-(4-methoxybenzyl)methanesulfonamide.

[00826] a Mixture of the product from Example C (31.8 mg, 0,079 mmol), the product from Part b (45 mg, 0,095 mmol) in EtOH (0.5 ml), toluene (0.5 ml) and 1M aq. Na2CO3(0,095 ml, 0,095 mmol) was degirolami by barbot is the formation of gaseous N 2within 10 minutes was Added to the complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane (2 mg, 2.4 mmol) and degassing using N2continued for 5 minutes, the Reaction mixture was tightly closed and heated at 100°C in a microwave reactor for 1 h the Mixture was concentrated in vacuo, and the crude product was purified by column chromatography on silica gel using 1:9 Meon:CHCl3as eluent. The named compound was obtained as a light brown oil (41 mg, 83%).

[00827] Part D. Obtaining N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)benzo[d]isoxazol-3-yl)methyl)methanesulfonamide.

[00828] a solution of the product from Part C (39 mg, 0,063 mmol) in TFA (0.5 ml) was stirred at 40°C for 6 hours TFA was removed in vacuo, and the crude product was purified by column chromatography on silica gel using 4% Meon in CHCl3as eluent to obtain the above compound (13 mg, 41%).1H NMR (300 MHz, CDCl3) δ 8.39 (s, 1 H), 7.74-7.82 (m, 2 H) 7.57 (dd, J=8.27, 1.65 Hz, 1 H) 7.36 (d, J=7.72 Hz, 1 H) 7.25 (d, 7=2.57 Hz, 1 H) 7.19 (d, 7=2.94 Hz, 1 H), 5.82 (dd, J=7.72, 2.21 Hz, 1 H), 5.25-5.33 (m, 1 H), 4.70 (d, J=6.25 Hz, 2 H) 3.29 (s, 3 H), 3.12 (s, 3 H), 1.45 (s, 9 H).

[00829] Example 43. Obtain methyl 2-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-ilidene)hydrazinecarboxamide (compound IB-L0-2.24).

[00830] To a solution of the product from Example 4, Part b (0.05 g, 0,124 mmol) in Meon (1 ml) was added methylcarbonate (17 mg, 0.185 mmol). The mixture was stirred at 60°C for 16 h, and then concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 5% Meon in CH2Cl2as eluent to obtain the above compound (44 mg, 74%).1H NMR (300 MHz, DMSO-d6) δ 11.40 (s, 1 H), 10.05 (s, 1 H) 7.78 (d, J=8.09 Hz, 1 H) 7.69 (d, J=7.72 Hz, 1 H), 7.45-7.57 (m, 2 H) 7.24-7.33 (m, 2 H), 5.64 (d, J=8.09 Hz, 1 H) 3.71 (s, 3 H), 3.28 (s, 3 H) 3.06-3.16 (m, 2 H) 2.78-2.88 (m, 2 H) 1.40 (s, 9 H).

[00831] Example 44. Obtain 1-(3-tert-butyl-4-methoxy-5-(1-occaisonaly-5-yl)phenyl)-pyrimidine-2,4(1H,3H)-dione (compound IB-L0-2.30).

[00832] Part A. Obtain 5-bromo-2-(2,4-dimethoxybenzyl)isoindoline-1-it.

[00833] To a solution of methyl 4-bromo-2-(methyl bromide)benzoate (1.0 g, 3.25 mmol) and (2,4-acid)methanamine (0.65 g, 3.90 mmol) in THF (16 ml) was added triethylamine (of 0.91 ml, 6.5 mmol) and the resulting mixture was stirred at room temperature for 16 hours the resulting solid was filtered, and the filtrate was concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 1:4 EtOA:hexane as eluent to obtain the above compound as a colourless solid (0.52 g, 44%).

[00834] Part C. the Floor is the group of 2-(2,4-dimethoxybenzyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline-1-it.

[00835] the Product from part a (100 mg, 0.276 mmol) was subjected to the conditions described for Example 42, Part In obtaining these compounds are in the form of an oil (107 mg, 95%).

[00836] Part C. Obtain 1-(3-tert-butyl-5-(2-(2,4-dimethoxybenzyl)-1-occaisonaly-5-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00837] the Product from Part C (44 mg, 0,111 mmol) was subjected to the conditions described for Example 42, Part C to obtain the above compound (50 mg, 81%).

[00838] Part D. Obtain 1-(3-tert-butyl-4-methoxy-5-(1-occaisonaly-5-yl)phenyl) pyrimidine-2,4(1H,3H)-dione.

[00839] a solution of the product from Part C (48 mg, 0,086 mmol) in CH2Cl2(0.3 ml) and TFA (0.6 ml, 7,79 mmol) was stirred at room temperature for 16 h, and then concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 5% Meon in CHCl3as the eluent, to obtain the titled compound as a colourless solid (22 mg, 63%).1H NMR (300 MHz, DMSO-d6) δ 11.41 (d, J=1.84 Hz, 1 H) 8.61 (s, 1 H), 7.72-7.83 (m, 3 H) 7.62-7.69 (m, 1 H) 7.29-7.36 (m, 2 H), 5.65 (dd, J=8.09, 2.21 Hz, 1 H), 4.44 (s, 2 H), 3.25 (s, 3 H) 1.41 (s, 9 H).

[00840] Example 45. Obtaining N-(2-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1H-inden-3-yl)propan-2-yl)methanesulfonamide (compound IB-L0-2.41).

[00841] Part A. Obtain 6-bromo-1H-inden-3-carbonitrile.

[00842] To a solution of 5-bromo-2,3-di is Idro-1H-inden-1-it (1 g, 4,74 mmol) in anhydrous THF (15 ml) at -10°C was added dropwise 2M diisopropylamide lithium in THF (0,242 ml, 0,483 mmol). The resulting mixture was stirred at -10°C for 15 min before adding dropwise diethylthiophosphate (0,791 ml, a total of 5.21 mmol). After the addition the mixture was left to warm to room temperature and was stirred at room temperature for 3 hours the Mixture was cooled to -78°C was added dropwise diethylether of boron TRIFLUORIDE (1,196 ml, 9,52 mmol). After the addition, the mixture was stirred at -78°C for 1 h and then left to warm to room temperature, and stirred at room temperature for 16 hours the Mixture was concentrated in vacuo and the residue was distributed between EtOAc (50 ml) and H2O (2×50 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo, and the crude product was purified by column chromatography on silica gel using 9:1 EtOAc:hexane as eluent. The named compound was obtained as a yellowish brown solid (0,72 g, 69%).

[00843] part of the Century, Obtaining N-(2-(6-bromo-1H-inden-3-yl)propan-2-yl)methanesulfonamide.

[00844] Anhydrous cerium chloride (III) (0,224 g, 0,909 mmol) was dried in vacuum flame and placed in an atmosphere of dry N2. Added anhydrous THF (1.5 ml) and the resulting mixture was stirred in an atmosphere of N2at 45° the period of 48 hours The mixture was cooled to room temperature, was added the product from part a (0.1 g, 0,454 mmol). The resulting mixture was cooled to -78°C, was added dropwise 1.5 M solution of the complex of methyl lithium-lithium bromide (0,757 ml, 1,136 mmol) in Et2O for a period of time of 15 minutes After the addition the mixture was left to warm to -20°C and was stirred for 24 h was Added dropwise concentrated aqueous NH4OH (0.3 ml) and the mixture was left to warm to room temperature, stirred for 30 min, and then filtered and washed with THF (2×5 ml). The filtrate was concentrated in vacuo, and the crude product was purified by column chromatography on silica gel using 5% Meon in CH2Cl2as elution solvent to obtain a solid (23 mg, 20%). To a solution of this solid (23 mg, 0,091 mmol) in CH2Cl2(1 ml) was added methanesulfonamide (to 0.011 ml, 0,137 mmol). The mixture was cooled to 0°C was added dropwise diisopropylethylamine (0,024 ml, 0,137 mmol). The resulting mixture was stirred at room temperature for 90 min, and then distributed between 0.1 n aq. HCl (2 ml) and CH2Cl2(3×2 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, and the crude product was purified by column chromatography on silica gel with getting called with the organisations (17 mg, 56%).

[00845] Part C. Obtaining N-(2-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-inden-3-yl)propan-2-yl)methanesulfonamide.

[00846] the Product from Part C (50 mg, 0,151 mmol) was subjected to the conditions described for Example 42, Part In obtaining these compounds are in the form of a colorless solid (37 mg, 65%).

[00847] Part D. Getting N-(2-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1H-inden-3-yl)propan-2-yl)methanesulfonamide.

[00848] the Product from Part C (35 mg, 0,093 mmol) was subjected to the conditions described for Example 42, Part C with obtaining these compounds are in the form of a colorless solid (41 mg, 84%).1H NMR (300 MHz, DMSO-d6) δ 11.40 (s, 1 H) 7.94 (d, J=8.09 Hz, 1 H) 7.78 (d, J=8.09 Hz, 1 H) 7.65 (d, J=1.50 Hz, 1 H) 7.56 (s, 1 H) 7.48 (dd, J=8.09, 1.47 Hz, 1 H) 7.27 (s, 2 H), 6.48 (s, 1 H), 5.63 (d, J=8.09 Hz, 1 H), 3.43 (s, 2 H) 3.25 (s, 3 H) 2.63 (s, 3 H) 1.68 (s, 6 H), 1.41 (s, 9 H).

[00849] Example 46. Obtaining N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)benzo[6]thiophene-3-yl)methyl)methanesulfonamide (compound IB-L0-2.11).

[00850] Part A. to Obtain ethyl 6-bromobenzo[b]thiophene-2-carboxylate.

[00851] a Solution of ethyldiglycol (0.65 g, 5,42 mmol), 4-bromo-2-forventelige (1.0 g, is 4.93 mmol) and triethylamine (1.25 ml, 12.3 mmol) in DMSO (5 ml) was heated at 75°C for 2 hours the Mixture was distributed between H2About (50 ml) and CH2Cl2(2×50 ml) and the combined organic layers with the sewed over Na 2SO4. Drying substance was filtered, and the solvent was removed in vacuum to obtain these compounds in the form of oil (1.29 g, 92%).

[00852] part of the Century, Obtaining 6-bromobenzo[b]thiophene-2-carboxylic acid.

[00853] To a solution of the product from part a (1,21 g, 4,24 mmol) in THF (10 ml) was added a solution of LiOH (0,305 g of 12.73 mmol) in H2O (4 ml) and the resulting mixture was stirred at 40°C for 2 hours the Mixture was distributed between H2About (50 ml) and CH2Cl2(50 ml). The aqueous layer was brought to pH=2 using 1 N. HCl, and was extracted with CH2Cl2(2×50 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to obtain these compounds in the form of an oil (1.04 g, 95%).

[00854] Part C. Obtaining 6-bromobenzo[b]thiophene.

[00855] the Product from Part b (0,70 g, 2,73 mmol) and DBU (1.35 ml, to 8.94 mmol) were combined in DMA (6 ml) in a sealed tube and heated at 200°C. in a microwave reactor for 70 minutes the resulting dark solution was diluted with 1 M HCl (20 ml) and was extracted with CH2Cl2(2×20 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo, and the crude product was purified by column chromatography on silica gel using CH2Cl2as eluent to obtain these compounds in the form of the of asle (0,484 g 83%).

[00856] Part D. Obtain 6-bromo-3-(chloromethyl)benzo[b]thiophene.

[00857] To a solution of the product from Part C (0,484 g of 2.27 mmol) in benzene (0,20 ml) was added 37% aq. formaldehyde solution (1 ml) and concentrated HCl (1 ml). The resulting mixture was heated at 70°C for 1 h, with gaseous HCl was barbotirovany through this mixture. The mixture was distributed between the H2O (20 ml) and CH2Cl2(2×20 ml) and 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 CH2Cl2obtaining these compounds are in the form of a waxy solid (0,49 g, 82%).

[00858] Part E. Obtain N-((6-bromobenzo[b]thiophene-3-yl)methyl)-N-(2,4-dimethoxybenzyl) methanesulfonamide.

[00859] To a solution of the product from Part D (275 mg, 1.05 mmol) and N-(2,4-dimethoxybenzyl)-methanesulfonamide (284 mg, 1.15 mmol) in DMA (6 ml) was added K2CO3(160 mg, 1.15 mmol) and the mixture was stirred at room temperature for 3 hours the Mixture was distributed between the H2O (20 ml) and Et2O (2×20 ml) and 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 2% EtOAc in CH2Cl2as eluent to obtain the titled compound in the form of a waxy solid (316 mg, 64%).

[00860] Part F. Obtaining N-(2,4-dimethoxybenzyl)-N-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-3-yl)methyl)methanesulfonamide.

[00861] the Product from Part E (300 mg, 0.64 mmol) was subjected to the conditions described for Example 42, Part In obtaining these compounds are in the form of a waxy solid (248 mg, 75%).

[00862] Part G. Obtaining N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)benzo[d]thiophene-3-yl)methyl)-1H-(2,4-dimethoxybenzyl)methanesulfonamide.

[00863] the Product from Part F (214 mg, 0,414 mmol) was subjected to the conditions described for Example 42, Part C with obtaining these compounds are in the form of a light yellow solid (238 mg, 87%).

[00864] Part N. Obtaining N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)benzo[b]thiophene-3-yl)methyl)methanesulfonamide.

[00865] To a solution of the product from Part G (230 mg, 0.34 mmol) in CH3Cl2(4 ml) was added triperoxonane acid (0.5 ml) and the mixture was stirred at room temperature for 30 minutes the Solution was diluted with CH2Cl2(10 ml) and was extracted with saturated aq. NaHCO3(2×10 ml). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo, and the crude product was purified by column chromatography on silica gel, elwira 3% Meon in CH2Cl2with obtaining the above connection is in the form of a whitish solid (149 mg, 84%).1H NMR (300 MHz, DMSO-d6) δ 11.41 (s, 1 H) 8.16 (d, J=1.10 Hz, 1 H) 8.02 (d, J=8.46 Hz, 1 H) 7.79 (d, J=7.72 Hz, 1 H) 7.71 (s, 1 H), 7.60-7.66 (m, 2 H) 7.29-7.38 (m, 2 H), 5.65 (d, J=7.72 Hz, 1 H), 4.44 (d, J=5.88 Hz, 2 H) 3.24 (s, 3 H) 2.95 (s, 3 H) 1.42 (s, 9 H).

[00866] Example 47. Obtaining N-(2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)methanesulfonamide (compound IB-L0-2.19).

[00867] Part A. Obtain 1-(3-amino-5-tert-butyl-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00868] To a solution of the product from Example 5, Part F (170 mg, 0,534 mmol) and triethylamine (223 μl, 1.6 mmol) in THF (5 ml) was added diphenylphosphoryl (173 μl, 0.80 mmol). The resulting mixture was stirred at room temperature for 1 h and then stirred at 45°C for 1 h was Added water (280 ml) and the resulting mixture was stirred at 50°C for 1 h, and then stirred at room temperature for 16 hours the Solution was diluted with N2About (10 ml) and the resulting solid was filtered. The solid is suspended in 1M aq. HCl and filtered to obtain amine product as HCl salt. This salt is suspended in aq. NaHCO3(20 ml) and was extracted with EtOAc (2×20 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum to obtain these compounds in the form of bescot the th solid (55 mg, 36%).

[00869] part of the Century, Obtaining 1-(3-tert-butyl-4-methoxy-5-(6-nitro-3,4-dihydroisoquinoline-2(1H)-yl)phenyl)pyrimidine-2,4(1H,3H)-dione.

[00870] a solution of the product from part a (100 mg, 0.28 mmol) and 2-(2-(methylsulfonylamino)-ethyl)-4-nitrobenzenesulfonate (196 mg, of 0.68 mmol) in anhydrous DMA (4 ml) was stirred at 80°C for 18 hours, the Cooled mixture was distributed between H2O (20 ml) and EtOAc (2×20 ml) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The residue is suspended in CH2Cl2and filtered to remove unreacted source aniline substances. The filtrate was concentrated in vacuo, and the crude product was purified by column chromatography on silica gel, elwira 1% Meon in CH2Cl2obtaining these compounds are in the form of a light yellow solid (39,3 mg, 31%).

[00871] Part C. Obtain N-(2-(3-tert-butyl-3-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)methanesulfonamide.

[00872] To a solution of the product from Part b (35 mg, 0,078 mmol) in THF (0.5 ml), Meon (0.5 ml) and H2O (0.25 ml) was added Fe powder (17,4 mg, 0.41 mmol) and NH4Cl (6.2 mg, 0.12 mmol) and the resulting mixture was stirred at 70°C for 1 h the Hot mixture was filtered through celite and washed using THF and Meon. The filtrate was concentrated and the sushi is whether in vacuum to obtain a solid substance. To a solution of this solid (32 mg, 0,076 mmol) and pyridine (26 μl, 0.32 mmol) in CH2Cl2(1.5 ml) was added methanesulfonamide (7,7 μl, 0,099 mmol). The mixture was stirred at room temperature for 1 h, then concentrated in vacuo. The crude product was purified by column chromatography on silica gel, elwira 5% Meon in CH2Cl2obtaining these compounds are in the form of a light yellow solid (7 mg, 19%).1H NMR (300 MHz, DMSO-d6) δ 7.71 (d, J=8.09 Hz, 1 H) 7.14-7.21 (m, 1 H) 7.05-7.12 (m, 3 H) 6.98 (d, J=2.57 Hz, 1 H), 5.65 (d, J=7.72 Hz, 1 H), 4.18 (s, 2 H) 3.86 (s, 3 H) 3.03 (t, J=4.23 Hz, 2 H) 2.99 (s, 3 H) 1.38 (s, 9 H).

[00873] Example 48. Obtaining N-(2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)isoindoline-5-yl)methanesulfonamide (compound IB-L0-2.79).

[00874] Part A. Obtain (4-nitro-1,2-phenylene)bis(methylene)dimethanesulfonate.

[00875] To a solution of 4-nitrophthalic acid (500 mg, is 2.37 mmol) in THF (24 ml) at room temperature was added dropwise 1M solution of complex NR3·THF (9,95 ml, for 9.95 mmol). This solution was stirred at 65°C for 1 h, and then left to cool to room temperature. To the mixture was added Meon (1 ml) and the mixture was stirred for 30 min and concentrated in vacuum. The residue was distributed between 1M aq. HCl (20 ml) and EtOAc (2×20 ml) and the combined organic layers were dried over Na2 4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel, elwira 3% Meon in CH2Cl2obtaining oil (253 mg, 58%). To a solution of this oil (250 mg, is 2.37 mmol) and triethylamine (438 μl, 3.14 mmol) in anhydrous CH2Cl2(30 ml) at 0°C was added dropwise methanesulfonanilide (234 μl, 3.0 mmol). The solution was stirred at room temperature for 18 h, and distributed between 1M aq. HCl (20 ml) and CH2Cl2(2×20 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, elwira CH2Cl2with obtaining the above compound (150 mg, 32%).

[00876] part of the Century, Obtaining 1-(3-tert-butyl-4-methoxy-5-(5-nitroisoquinoline-2-yl)phenyl) pyrimidine-2,4(1H,3H)-dione.

[00877] To a solution of the product of Part a (110 mg, 0,324 mmol) and the product of Example 47, part a (113 mg, 0,389 mmol) in anhydrous 1,4-dioxane (4 ml) was added sodium bicarbonate (60 mg, 0.71 mmol) and diisopropylethylamine (142 μl, 0.81 mmol) and the resulting mixture was stirred at 95°C for 16 hours the Mixture was distributed between 0.5 M aq. HCl (10 ml) and CH2Cl2(2×10 ml) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified with the aid of the rd column chromatography on silica gel, elwira 1% Meon in CH2Cl2obtaining these compounds are in the form of a light yellow solid (110 mg, 78%).

[00878] Part C. Obtain N-(2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)isoindoline-5-yl)methanesulfonamide.

[00879] the Product from Part b (100 mg, 0.25 mmol) was subjected to the conditions described for Example 47, Part C with obtaining these compounds are in the form of a whitish solid (53 mg, 45%).1H NMR (300 MHz, DMSO-d6) δ 11.37 (s, 1 H), 9.70 (s, 1 H) 7.71 (d, J=7.72 Hz, 1 H) 7.34 (d, J=8.09 Hz, 1 H) 7.23 (d, J=1.84 Hz, 1 H) 7.13 (dd, J=8.09, 1.84 Hz, 1 H) 6.98 (d, J=2.57 Hz, 1 H) 6.81 (d, J=2.21 Hz, 1 H), 5.62 (d, J=7.72 Hz, 1 H) 4.52 (s, 2 H) 4.50 (s, 2 H) 3.63 (s, 3 H) 2.98 (s, 3 H) 1.38 (s, 9 H).

[00880] Example 49. Obtaining N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1H-inden-3-yl)methyl)methanesulfonamide (compound IB-L0-2.13).

[00881] Part A. Obtain 5-bromo-1-(trimethylsilyloxy)-2,3-dihydro-1H-inden-1-carbonitrile.

[00882] To a solution of 5-bromo-2,3-dihydro-1H-inden-1-she (10.0 g, with 47.4 mmol) and N-methyl-morpholine N-oxide (1,67 g, 14,21 mmol) in CH2Cl2(50 ml) was added trimethylsilylacetamide (7,05 g, a 71.1 mmol) and the resulting solution was stirred at room temperature for 72 h, and then concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 5% EtOAc in hexane as eluent, according to the teachings of the named compound as a colourless liquid (12,65 g, 86%).

[00883] part of the Century, Obtaining 1-(aminomethyl)-5-bromo-2,3-dihydro-1H-inden-1-ol.

[00884] To a solution of the product from part a (18,44 g, to 59.4 mmol) in anhydrous Et2O (250 ml) in an atmosphere of gaseous N2at 0°C was added dropwise 1M solution of LiAlH4in Et2O (62,4 ml of 62.4 mmol) for 1 h After addition, the mixture was left to warm to room temp. and stirred at room temperature for 2 hours the Mixture was cooled in an ice bath while adding dropwise H2O (4,3 ml), followed by the addition of 15% aq. NH4OH (4.3 ml), and then H2About (13 ml). The mixture was stirred at room temperature for 15 min, and then filtered through celite and washed with EtOAc. The filtrate was concentrated in vacuo, and the residue suspended in Et2O (40 ml) to give the precipitate, which was filtered and dried, to obtain the titled compound as a colourless solid (10.0 g, 70%).

[00885] Part C. Obtaining salt (6-bromo-1H-inden-3-yl)methanimidamide.

[00886] To a solution of the product from Part b (10.0 g, a 41.3 mmol) in Meon (100 ml) was added 6 n aq. HCl (125 ml) and the mixture was stirred at 70°C for 3 h and then left to cool to room temperature. Meon was removed in vacuum to obtain a precipitate, which was collected by filtration, washed with N2Oh, and dried in vacuum to obtain these compounds in the form of colorless t is ejogo substances (of 9.89 g, 92%).

[00887] Part D. Obtaining N-((6-bromo-1H-inden-3-yl)methyl)methanesulfonamide.

[00888] To a suspension of the product from Part C (6,46 g of 24.8 mmol) in anhydrous CH2Cl2(260 ml) was added methanesulfonamide (3,86 ml of 49.6 mmol) and diisopropylethylamine (13,0 ml of 74.4 mmol) and the resulting mixture was stirred at room temperature for 10 hours, the Solution washed with 1 n aq. HCl (2×300 ml) and the organic layer was dried over Na2SO4, filtered and concentrated in vacuum. The residue is suspended in Et2O (100 ml) to give the precipitate, which was collected by filtration and dried to obtain the above compound as a colourless solid (6.25 g, 83%).

[00889] Part E. Obtain N-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-inden-3-yl)methyl)methanesulfonamide.

[00890] a solution of the product from Part D (2.0 g, 6.62 mmol), bis(pinacolato)Debora (1.85 g, 7,28 mmol), potassium acetate (1,95 g, 19,86 mmol) and complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (0.27 g, 0,331 mmol) in anhydrous 1,4-dioxane (80 ml) in an atmosphere of N2was stirred at 95°C for 8 hours, the Cooled mixture was filtered through celite, washed with EtOAc (2×20 ml) and then concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 1:2 EtOAc:hexane as eluent, to obtain the titled compound in sidebusting oil (2,02 g, 87%).

[00891] Part F. Obtaining N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1H-inden-3-yl)methyl)methanesulfonamide.

[00892] a Mixture of the product from Part E (3,14 g 8,99 mmol), the product from Example (of 3.78 g, 9,44 mmol), potassium triphosphate (3,82, 17,98 mmol), 1,3,5,7-tetramethyl-2,4,8-trioxa-6-FOSFA-6-phenyl-adamantane (Cytec [97739-46-3]) (105 mg, 0.36 mmol), and Tris(dibenzylideneacetone)-diplodia(0) (165 mg, 0.18 mmol) were placed in an atmosphere of gaseous N2. To the mixture was added, via cannula, a mixture of THF (45 ml) and N2About (15 ml), which was degassed by bubbling gaseous Ar for 10 minutes the resulting mixture was additionally degirolami by bubbling Ar for an additional 15 minutes and the Mixture was stirred at 50°C for 1.5 h under continuous bubbling Ar through the solution. Added additional amount of Tris(dibenzylideneacetone)diplegia(0) (55 mg, 0.6 mmol) in THF (2 ml) and the mixture was stirred at 50°C for 1 h the Mixture was left to cool to room temp., and distributed between CH2Cl2(300 ml) and 1 n aq. HCl (150 ml). Orange organic layer was added 3-mercaptopropyl-functionalized silica gel (10 g, Aldrich) and MgSO4and the mixture was stirred at room temperature for 16 h, filtered and concentrated in vacuum. The crude product was purified by column chromatography on when likehere, using 3:1 EtOAc:hexane as eluent to obtain the above compound as a colourless solid (2.7 g, 61%).1H NMR (300 MHz, DMSO-d6) δ 11.40 (s, 1H), 7.78 (d, J=7.4 Hz, 1H), 7.66 (s, 1H), 7.60 (d, J=7.7 Hz, 1H), 7.50 (m, 2H), 7.25 (m, 2H), 6.56 (m, 1H), 5.64 (dd, J=2.2, 7.7 Hz, 1H), 4.18 (d, J=5.1 Hz, 2H), 3.46 (s, 2H), 3.25 (s, 3H), 2.96 (s, 3H), 1.41 (s, 9H).

[00893] Example 50. Obtaining N'-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide (compound IB-L0-2.31).

[00894] To a solution of the product from Example 4, Part C (100 mg, 0,201 mmol) in THF (2 ml) and Meon (2 ml) was added 2 drops of 10% HCl in Meon, then added cyanoborohydride sodium (19 mg, 0,302 mmol). The mixture was brought to pH 4 by adding 10% HCl in Meon, and then stirred at room temperature for 1 h the resulting mixture was distributed between saturated aq. the sodium bicarbonate (5 ml) and CH2Cl2(20 ml) and the organic layer was dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography on silica gel using 3% Meon in CH2Cl2as eluent to obtain the above compound as a colourless solid (58 mg, 58%).1H NMR (300 MHz, DMSO-d6) δ. 11.39 (s, 1H), 8.18 (d, J=3.7 Hz, 1H), 7.77 (d, J=7.7 Hz, 1H), 7.51 (d, J=8.1 Hz, 1H), 7.38 (m, 2H), 7.27 (d, J=2.6 Hz, 1H), 7.21 (d, J=2.9 Hz, 1H), 5.63 (d, J=7.7 Hz, 1H), 5.25 (m, 1H), 4.39 (m, 1H), 3.27 (s, 3H), 2.98 (m, 1H) 2.83 (s, 3H), 2.78 (m, 1H), 2.22 (m, 1H), 2.07 (m, 1H), 1.40 (s, 9H).

[00895] Example 51. Obtain 1-(3-tert-butyl-5-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound IB-L0-2.36).

[00896] To a solution of the product from Example 4, Part b (150 mg, 0,371 mmol) in Meon (3 ml) and CH2Cl2(3 ml) was added sodium borohydride (28 mg, 0,742 mmol) and the mixture was stirred at room temperature for 1 h the Mixture was distributed between 1 n aq. HCl (10 ml) and CH2Cl2(20 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 5% Meon in CH2Cl2as the eluent, to obtain the titled compound as a colourless solid (90 mg, 60%).1H NMR (300 MHz, DMSO-d6): δ. 11.39 (s, 1H), 7.44 (d, J=4.0 Hz, 1H), 7.40 (m, 2H), 7.21 (d, J=2.6 Hz, 1H), 7.26 (d, J=2.6 Hz, 1H), 5.63 (d, J=8.1 Hz, 1H), 5.29 (d, J=5.9 Hz, 1H), 5.09 (m, 1H), 3.26 (s, 3H), 2.97 (m, 1H), 2.79 (m, 1H), 2.38 (m, 1H), 1.83 (m, 1H), 1.40 (s, 9H).

[00897] Example 52. Obtain 1-(3-tert-butyl-5-(2-(2,5-dimethyl-1H-pyrrol-1-yl)benzo[d]thiazol-6-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound IB-L0-2.47).

[00898] Part A. Obtain 6-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)benzo[d]thiazole.

[00899] a Solution of 6-bromobenzo[d]thiazol-2-amine (5.75 g of 25.1 mmol), hexane-2,5-dione (2,95 ml of 25.1 mmol), and PPTS (0.95 g, 3,76 mmol) in benzene (100 ml) is agrawala under reflux for 16 h, at the same time water was removed with the nozzle Dean-stark. The cooled mixture was poured into EtOAc (100 ml) and was extracted with saturated aq. NaHCO3(2×100 ml) and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 9:1 EtOAc:hexane as eluent to obtain the above compound as an orange oil (6,46 g, 84%).

[00900] part of the Century, Obtaining 2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiazole.

[00901] a Mixture of the product from part a (3,24 g, 10,54 mmol), bis(pinacolato)Debora (4,01 g, 15,81 mmol), bis(di-tert-butyl(hydroxy)phosphino)palladium(II)dichloride (0,264 g, 0,527 mmol), and potassium acetate (3,10 g of 31.6 mmol) in anhydrous toluene (25 ml) was degirolami by ozonation gaseous N2within 15 min, and then heated under reflux in an atmosphere of N2within 72 hours, the Cooled mixture was filtered through celite and washed with EtOAc, and the filtrate was concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 9:1 EtOAc:hexane as eluent, to obtain the titled compound (2,77 g, 74%).

[00902] Part C. Obtain 1-(3-tert-butyl-5-(2-(2,5-dimethyl-1H-pyrrol-1-yl)benzo[d]thiazol-6-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[00903] the product from Part b (405 mg, to 1.14 mmol) was subjected to the conditions described for Example 42, Part C to obtain the above compound (430 mg, 68%).1H NMR (300 MHz, DMSO-d6) δ 11.43 (d, J=2.21 Hz, 1 H) 8.32 (d, J=1.47 Hz, 1 H) 8.12 (d, J=8.46 Hz, 1 H) 7.80 (d, J=7.72 Hz, 1 H) 7.76 (dd, J=8.46, 1.84 Hz, 1 H), 7.35 (q, J=2.57 Hz, 2 H), 5.97 (s, 2 H), 5.66 (dd, J=7.72, 2.21 Hz, 1 H) 3.30 (s, 3 H) 2.30 (s, 6 H), 1.43 (s, 9 H).

[00904] Example 53. Obtain 1-(3-(2-aminobenzo[d]thiazol-6-yl)-5-tert-butyl-4-methoxy-phenyl)pyrimidine-2,4(1H,3H)-dione (compound IB-L0-2.27).

[00905] To a solution of the product from Example 52 (4.0 g, 8.0 mmol) in triperoxonane acid (50 ml) was added a few drops of N2Oh, and the resulting mixture was stirred at 80°C for 2.5 h, and then concentrated in vacuum. A solution of the residue in the Meon neutralized using conc. NH4OH, concentrated in vacuo, and the crude product was purified by column chromatography on silica gel using 9:1 CH2Cl2:MeOH as the eluent, to obtain the titled compound (3.3 g, 98%).1H NMR (300 MHz, DMSO-d6) δ 11.40 (s, 1 H) 7.81 (s, 1 H) 7.77 (d, J=8.09 Hz, 1 H) 7.57 (s, 1 H) 7.40 (s, 1 H) 7.33-7.38 (m, 1 H) 7.25 (s, 1 H), 5.60-5.69 (m, 1 H), 3.26 (s, 3 H) 1.40 (s, 9 H).

[00906] Example 54. Obtaining N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)benzo[d]thiazol-2-yl)methanesulfonamide (compound IB-L0-2.28).

[00907] To a solution of the product from Example 53 (0.35 g, 0.83 mmol) in anhydrous CH2Cl (50 ml) was added methanesulfonamide (194 μl, 2.49 mmol) and pyridine (1,34 ml of 16.6 mmol). The resulting mixture was stirred at room temperature for 16 h and concentrated in vacuum. The crude product was purified using C-18 HPLC with reversed phase, using a gradient of acetonitrile:H2O with 0.1% TFA), to obtain the titled compound (19 mg, 4%).1H NMR (300 MHz, DMSO-d6) δ 13.09 (s, 1 H) 11.41 (d, J=1.84 Hz, 1 H) 7.96 (d, J=1.47 Hz, 1 H) 7.77 (d, J=8.09 Hz, 1 H) 7.57 (dd, 1 H) 7.42 (d, J=8.09 Hz, 1 H) 7.25-7.32 (m, 2 H), 5.64 (dd, J=8.09, 2.21 Hz, 1 H), 3.25 (s, 3 H) 3.02 (s, 3 H) 1.40 (s, 9 H).

[00908] Example 55. Obtain 1-(3-(benzo[d]thiazol-6-yl)-5-tert-butyl-4-methoxyphenyl) pyrimidine-2,4(1H,3H)-dione (compound IB-L0-2.33).

[00909] To a solution of the product from Example 53 (30 mg, 0,071 mmol) in anhydrous 1,4-dioxane (3 ml) in an atmosphere of N2added soliditet (19 μl, 0,142 mmol). The resulting mixture was stirred at reflux for 1 h, and concentrated in vacuum. The crude product was purified using C-18 HPLC with reversed phase, using a gradient of acetonitrile:H2O with 0.1% TFA), to obtain the titled compound (14 mg, 48%).1H NMR (300 MHz, DMSO-d6) δ 11.42 (d, J=1.84 Hz, 1 H) 9.44 (s, 1 H) 8.34 (d, J=1.47 Hz, 1 H) 8.19 (d, J=8.46 Hz, 1 H) 7.79 (d, J=7.72 Hz, 1 H) 7.73 (dd, J=8.46, 1.84 Hz, 1 H) 7.32-7.37 (m, 2 H), 5.65 (dd, J=7.91, 2.39 Hz, 1 H), 3.24 (s, 3 H) 1.42 (s, 9 H).

[00910] Example 56. Obtaining N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimido is n-1(2H)-yl)-2-ethoxyphenyl)benzo[d]thiazol-2-yl)ndimethylacetamide (compound IB-L0-2.49).

[00911] a Mixture of the product from Example 53 (30 mg, 0,071 mmol) and acetic anhydride (3 ml) was stirred at 100°C for 2 h, and then left to cool to room temperature. The resulting solid was collected by filtration, washed with N2Oh, and dried to obtain these compounds in the form of a whitish solid (29 mg, 88%).1H NMR (300 MHz, DMSO-d6) δ 12.42 (s, 1 H) 11.41 (d, J=2.21 Hz, 1 H) 8.12 (d, J=1.47 Hz, 1 H) 7.82 (d, J=8.46 Hz, 1 H) 7.78 (d, J=8.09 Hz, 1 H) 7.61 (dd, J=8.46, 1.84 Hz, 1 H), 7.31 (q, J=2.70 Hz, 2 H), 5.64 (dd, J=8.09, 2.21 Hz, 1 H) 3.24 (s, 3 H) 2.22 (s, 3 H) 1.41 (s, 9 H).

[00912] Example 57. Obtain 1-(3-tert-butyl-4-methoxy-5-(2-(propylamino)benzo[d]thiazol-6-yl)phenyl)pyrimidine-2,4(1H,3H)-dione (compound IB-L0-2.46).

[00913] Part A. Obtain 1-(3-tert-butyl-5-(2-chlorobenzo[d]thiazol-6-yl)-4-methoxyphenyl) pyrimidine-2,4(1H,3H)-dione.

[00914] To a mixture of the product from Example 53 (50 mg, 0.118 the mmol) and copper chloride (II) (24 mg, 0,178 mmol) in acetonitrile (3 ml) at 0°C was added tert-butylnitrite (21 μl, 0,178 mmol). The mixture was stirred at 0°C for 1 h, and then was heated to 65°C and was stirred for 2 h the Mixture was concentrated in vacuo and was purified by column chromatography on silica gel using 5% Meon in CH2Cl2obtaining these compounds are in the form of a whitish solid (43 mg, 82%).

[00915] part of the Century, Obtaining 1-(3-tre the-butyl-4-methoxy-5-(2-(propylamino)benzo[d]thiazol-6-yl)phenyl)pyrimidine-2,4(1H,3H)-dione.

[00916] a Mixture of the product from part a (50 mg, 0.11 mmol), 1-aminopropane (9 μl, 0.11 mmol), and K2CO3(15.6 mg, 0.11 mmol) in anhydrous DMF (5 ml) was stirred at 100°C for 24 h the Mixture was concentrated in vacuo and was purified by column chromatography on silica gel using 2% Meon in EtOAc as eluent, to obtain the titled compound in the form of a whitish solid (21 mg, 40%).1H NMR (300 MHz, DMSO-d6) δ 11.39 (d, J=1.84 Hz, 1 H), 8.12 (t, J=5.52 Hz, 1 H) 7.82 (d, J=1.47 Hz, 1 H) 7.77 (d, J=7.72 Hz, 1 H) 7.44 (t, J=9.01 Hz, 1 H), 7.37-7.41 (m, 1 H) 7.25 (s, 2 H), 5.63 (dd, J=7.91, 2.02 Hz, 1 H), 3.33-3.38 (m, 2 H) 3.26 (s, 3 H), 1.56-1.69 (m, 2 H) 1.40 (s, 9 H), 0.94 (t, J=7.35 Hz, 3 H).

[00917] Example 58. Obtain 1-(3-tert-butyl-4-methoxy-5-(3-methylbenzofuran-6-yl)phenyl)-pyrimidine-2,4(1H,3H)-dione (compound IB-L0-2.42).

[00918] Part A. Obtain methyl 2-(2-acetyl-5-bromophenoxy)acetate.

[00919] a Solution of 1-(4-bromo-2-hydroxyphenyl)ethanone (1.35 g, 6,28 mmol) in anhydrous DMF (16 ml) was treated with several portions of sodium hydride (377 mg, 60% in oil, 226 mg, 9,42 mmol) followed by stirring at room temperature for 30 minutes the Mixture then was treated with methyl bromoacetate (871 μl, 1.45 g, 9,48 mmol) dropwise (after complete addition, the solution became warm) followed by stirring at room temperature for 18 hours the Mixture was diluted with ethyl acetate and was extracted with water (4x) and saturated dissolve the ohms of sodium chloride. Drying (Na2SO4) and concentration in vacuo gave a nearly colorless solid, which was purified by column chromatography on silica gel, elwira 20-100% ethyl acetate in hexane. These procedures give the named compound as a colourless solid (1.47 g, 82%).

[00920] part of the Century, Obtaining 2-(2-acetyl-5-bromophenoxy)acetic acid.

[00921] a solution of the product from part a (1.47 g, 5,12 mmol) in tetrahydrofuran (26 ml) was treated with 1.0 n sodium hydroxide solution (of 6.7 ml, 6.7 mmol), followed by stirring at room temperature for 3 h, the reaction was completed. The mixture was concentrated in vacuo to remove tetrahydrofuran and then diluted with water and cooled to 0°C. the Mixture was acidified to pH 3 by adding 1 n hydrochloric acid, and then the product was extracted with ethyl acetate. The organic layer was extracted with a saturated solution of sodium chloride and dried (Na2SO4). Concentration in vacuo gave the titled compound as a colourless solid (1,36 g, 97%).

[00922] Part C. Obtain 6-bromo-3-methylbenzofuran.

[00923] a solution of the product from Part b (500 mg, of 1.83 mmol) in acetic anhydride (9,2 ml) was treated with sodium acetate (300 mg, 3,66 mmol) followed by heating under reflux for 18 hours the Mixture was cooled to room Tempe is atory and was diluted with toluene and concentrated in vacuum for azeotropic removal of acetic anhydride. This process was repeated 3x. The mixture then was diluted with ethyl acetate and stirred with saturated sodium bicarbonate solution for 1 h, the Layers were separated and the organic layer was extracted with a saturated solution of sodium chloride. Drying (Na2SO4) and concentration in vacuo gave an oil of amber, which was purified by column chromatography on silica gel, elwira 8-50% ethyl acetate in hexane. These procedures give the named compound as a colourless liquid (316 mg, 82%).

[00924] Part D. Getting 4,4,5,5-tetramethyl-2-(3-methylbenzofuran-6-yl)-1,3,2-dioxaborolane.

[00925] In a microwave tube, a mixture of the product from Part C (303 mg, 1.44 mmol), bis(pinacolato)Debora (401 mg, was 1.58 mmol) and potassium acetate (423 mg, or 4.31 mmol) in anhydrous dioxane (5 ml) was degirolami by ozonation of nitrogen for 15 minutes the Mixture was treated with a complex of 1,1'-bis(diphenylphosphino)ferrocene palladium (II) chloride dichloromethane (24 mg, 0,029 mmol) followed by degassing for another 5 minutes Microwave tube was tightly closed, and the mixture was heated at 90°C for 18 hours the Mixture was cooled and was diluted with ethyl acetate and was extracted with water and saturated sodium chloride solution. The organic layer was dried (Na2SO4) and was stirred with (3-mercaptopropyl) silica gel for 1 h the Mixture was filtered and concentrated in vacuo to receive the receiving brown semi-solid substances, which was purified by column chromatography on silica gel, elwira 8-40% ethyl acetate in hexane. These procedures give the named compound as a colourless oil which slowly became solid upon standing (307 mg, 83%).

[00926] Part E. Obtain 1-(3-tert-butyl-4-methoxy-5-(3-methylbenzofuran-6-yl)phenyl)-pyrimidine-2,4(1H,3H)-dione.

[00927] In a microwave tube, a solution of the product from Part D (307 mg, 1,19 mmol), the product from Example (414 mg, of 1.03 mmol), 1,3,5,7-tetramethyl-2,4,8-trioxa-6-FOSFA-6-phenyl-adamantane (Cytec [97739-46-3]) (15 mg, 0,052 mmol), and trehosnovnogo potassium phosphate (439 mg, 2,07 mmol) in a mixture of 3:1 tetrahydrofuran-water (8 ml) was degirolami by ozonation of nitrogen for 20 minutes the Mixture was treated with Tris(dibenzylideneacetone)dipalladium (0) (12 mg, 0.012 mmol) followed by degassing for another 10 minutes During this time the solution turned from a source of deep maroon color greenish-brown color. The microwave tube was tightly closed, and the solution was heated at 50°C for 56 h, the Solution was cooled and was diluted with ethyl acetate and acidified using 1M citric acid solution. The organic layer was extracted with a saturated solution of sodium chloride, dried (Na2SO4), and then mixed with (3-mercaptopropyl) silica gel for 1 h After filtration and concentration in vacuo, the obtained residue is ciali using column chromatography on silica gel, elwira 4-20% acetone in dichloromethane, and then a second column chromatography on silica gel, elwira 20-100% ethyl acetate in hexane. These procedures give the named compound as a colourless solid (355 mg).1H NMR (300 MHz, DMSO-d6): δ 11.40 (d, J=1.84 Hz, 1 H) 7.74-7.92 (m, 2 H) 7.58-7.76 (m, 2 H) 7.46 (dd, J=8.09, 1.47 Hz, 1 H) 7.30 (q, J=2.82 Hz, 2 H), 5.64 (dd, J=8.09, 2.21 Hz, 1 H), 3.22 (s, 3 H) 2.25 (s, 3 H) 1.41 (s, 9 H).

[00928] Example 59. Obtaining N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)benzofuran-3-yl)methyl)methanesulfonamide (compound IB-L0-2.18).

[00929] Part A. Obtain 6-bromo-3-(methyl bromide)benzofuran.

[00930] a solution of the product from Example 58, Part C (1.0 g, 4,74 mmol) and dibenzoylperoxide (287 mg, 1,19 mmol) in chlorobenzene (24 ml) at reflux was treated with four portions of N-bromosuccinimide (843 mg, 4,74 mmol) over a period of time of 30 minutes the Mixture was then stirred at reflux for 2 hours the Mixture was cooled, filtered and concentrated and was purified by column chromatography on silica gel, elwira 7-30% chloroform in hexane. These procedures give the named compound as a pale yellow oil (438 mg, 32%).

[00931] part of the Century, Obtaining N-((6-bromobenzophenone-3-yl)methyl)-N-(4-methoxybenzyl)methane-sulfonamida.

[00932] a solution of the product from part a (515 mg, 1.78 mmol), N-(4-m is oxybenzyl)methane-sulfonamida (421 mg, 1,95 mmol), and potassium carbonate (260 mg, of 1.95 mmol) in anhydrous DMF (8,9 ml) was stirred at 70°C for 3 hours the Mixture was cooled and was diluted with ethyl acetate and was extracted with water (4x). The organic layer was then extracted with a saturated solution of sodium chloride and dried (Na2SO4). Concentration in vacuo gave a solid beige color. This substance was purified by column chromatography on silica gel, elwira 20-100% ethyl acetate in hexane. These procedures give the named compound as a colourless solid (224 mg, 35%).

[00933] Part C. Obtain N-(4-methoxybenzyl)-N-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-yl)methyl)methanesulfonamide.

[00934] the Product from Part b (186 mg, 0.44 mmol) was subjected to the conditions described for Example 58, Part D of obtaining these compounds as a colourless solid (177 mg, 86%).

[00935] Part D. Obtaining N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)benzofuran-3-yl)methyl)-N-(4-methoxybenzyl)methanesulfonamide.

[00936] In a microwave tube, a suspension of the product from Part C (169 mg, 0.36 mmol), the product from Example (143 mg, 0.36 mmol), and 1.0 M solution of sodium carbonate (0.5 ml, 0.50 mmol) in a mixture of 1:1 ethanol-toluene (3 ml) was degirolami by ozonation of nitrogen for 20 minutes the solution was treated with a complex of 1,1-bis(diphenylphosphino) is erroten-palladium(II) chloride dichloromethane (7 mg, 9 mmol) followed by degassing for another 5 minutes Microwave tube was tightly closed and the mixture was heated at 100°C. in microwave oven for 1 h the Mixture was diluted with ethyl acetate and water and acidified using 1M citric acid solution. The organic layer was extracted with a saturated solution of sodium chloride, dried (Na2SO4), and left to stand over night in (3-mercaptopropyl)silica gel. Filter and concentrate in vacuo gave a whitish foam, which was purified by column chromatography on silica gel, elwira 5-30% ethyl acetate in dichloromethane. These procedures give the named compound as a colourless solid (96 mg, 43%).

[00937] Part E. Obtain N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)benzofuran-3-yl)methyl)methanesulfonamide.

[00938] a solution of the product from Part D (88 mg, 0.14 mmol) in dichloromethane (1.4 ml) was treated triperoxonane acid (1.4 ml) followed by stirring at room temperature for 18 h, and then by stirring at 40°C for 2 hours the Mixture was concentrated in vacuum to obtain a dark purple-brown foam, which was subjected to column chromatography on silica gel, elwira 5-50% ethyl acetate in methylene chloride to obtain containing impurities of the substance, which was purified by chromatography the reversed-phase column (C-18, elwira 1% water-TFA/acetonitrile. These procedures give the named compound as a solid (3.9 mg).1H NMR (300 MHz, DMSO-d6): δ 11.31-11.48 (m, 1 H) 8.01 (s, 1 H) 7.68-7.94 (m, 2 H) 7.40-7.65 (m, 2 H) 7.10-7.38 (m, 2 H), 5.65 (dd, J=7.91, 2.02 Hz, 1 H) 4.33 (d, J=5.88 Hz, 2 H) 3.23 (s, 3 H) 2.95 (s, 3 H) 1.41 (s, 9 H).

[00939] Example 60. Obtaining N-((5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-methyl-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide (compound IB-L0-2.25).

[00940] Part A. Obtain 5-bromo-1-(1,3-dition-2-yl)-2,3-dihydro-1H-inden-1-ol.

[00941] a Solution of 1,3-dithiane (11,96 g, 99 mmol) in anhydrous tetrahydrofuran (100 ml) at -30°C was treated dropwise over 10 min n-butyllithium (2.5 M in hexane, to 38.4 ml, 96 mmol) followed by stirring at -15°C for 2 h Then the solution was treated with a solution of 5-bromo-2,3-dihydro-1H-inden-1-it (15 g, a 71.1 mmol) in anhydrous tetrahydrofuran (250 ml) for 1 h, maintaining the temperature between -9°C and 2°C. the Mixture is then left in the refrigerator at 2-8°C for 18 hours the Solution was concentrated in vacuum to obtain a dark red oil which was treated with 1 n hydrochloric acid and was extracted with ether. The ether layer was extracted with a saturated solution of sodium chloride, dried (Na2SO4) and concentrated in vacuo to obtain an oil of amber (23,55 g).

[00942] Part C. the Floor is the group of 2-(5-bromo-2,3-dihydro-1H-inden-1-ilidene)-1,3-dithiane.

[00943] a solution of the product from part a (23,55 g, a 71.1 mmol) in benzene (350 ml) was treated with monohydrate p-toluensulfonate acid (3.0 g), followed by stirring at reflux for 1 h, while removing the water by means of nozzles Dean-stark. The mixture was extracted with saturated sodium bicarbonate solution and then a saturated solution of sodium chloride. Drying (Na2SO4) and concentration in vacuo gave the product as oil is amber in color (22,27 g).

[00944] Part C. Obtain 5-bromo-2,3-dihydro-1H-inden-1-carboxylic acid.

[00945] a solution of the product from Part b (22,27 g, a 71.1 mmol) in glacial acetic acid (375 ml) was treated with concentrated hydrochloric acid (125 ml), followed by stirring under reflux for 3 hours the Mixture was cooled and concentrated in vacuo by azeotropic removal of acetic acid and water with toluene(3x). The obtained brown oil was filtered through a layer of silica gel 70-230 mesh in a 2 l sintered funnel glass (volume of silica gel OK. 1800 ml), elwira dichloromethane to remove non-polar impurities (1,3-propanedithiol, among other things) and then ethyl acetate for the elution these compounds, which were obtained in the form of a solid brown color (9,85 g, 58%).

[00946] Part D. Obtain methyl 5-bromo-2,3-dihydro-1H-inden-1-carbox elata.

[00947] a Suspension of the product from Part C (9,85 g of 40.9 mmol) in methanol (400 ml) was treated with 4 n chloride nitrogen in 1,4-dioxane (125 ml) and the mixture was stirred at reflux for 8 hours the Mixture was concentrated in vacuum to obtain a brown oil, which was purified by column chromatography on silica gel, elwira 0-30% methyl t-butyl ether in chloroform. These procedures gave the titled compound in the form of oil of amber (7,99 g, 77%).

[00948] Part E. Obtain methyl 5-bromo-1-methyl-2,3-dihydro-1H-inden-1-carboxylate.

[00949] a solution of the product from Part D (2,03 g of 7.96 mmol) in anhydrous tetrahydrofuran (40 ml) at -78°C in an atmosphere of N; was treated dropwise bis(trimethylsilyl)amidon lithium (1.0 M in tetrahydrofuran, of 9.55 ml, of 9.55 mmol) over 10 minutes the Solution was stirred at -78°C for 45 min and then treated with methyliodide (1.5 ml, previously dried by passing through a layer of alkaline aluminum oxide). The mixture is then left to slowly warm to room temp. and was stirred for 18 hours the Mixture was suppressed by adding a saturated solution of ammonium chloride (2 ml). The mixture was concentrated in vacuo to remove tetrahydrofuran, and the residue was diluted with ethyl acetate. The mixture was extracted with a saturated solution of ammonium chloride and a saturated solution of sodium chloride. Drying (Na2S 4) and concentration in vacuo gave the titled compound in the form of oil of amber (of 2.06 g, 96%).

[00950] Part F. Obtain 5-bromo-1-methyl-2,3-dihydro-1H-inden-1-carboxylic acid.

[00951] a solution of the product from Part E (of 2.06 g of 7.65 mmol) and trimethylsilanol potassium (5.5 g 90%, 4,91 g, to 38.3 mmol) in tetrahydrofuran (40 ml) was stirred at reflux for 3 hours the Mixture was cooled and concentrated in vacuo to remove tetrahydrofuran. Maroon precipitate was dissolved in water (about 175 ml) and was extracted with methyl t-butyl ether. The aqueous phase was cooled to 0°C and acidified to pH 3 by addition of concentrated hydrochloric acid. The mixture was extracted with ethyl acetate (2x) and then a saturated solution of sodium chloride. The solution was dried (Na2SO4and was treated with Darco G-60, followed by filtration through celite. The filtrate was concentrated in vacuum to obtain these compounds in the form of a light yellow solid (1,93 g, 99%).

[00952] Part G. Obtain 5-bromo-1-methyl-2,3-dihydro-1H-inden-1-carboxamide.

[00953] a solution of the product from Part F (1.56 g, 6.12 mmol) and DMF (473 μl, 447 mg, 6.12 mmol) in hexane (100 ml) was treated with oxalylamino (1,61 ml, 2,32 g, 18.4 mmol), followed by stirring at room temperature for 1 h the Mixture was treated with telicom and then filtered through celite. Phil the spending was concentrated in vacuo and dissolved in acetone (75 ml), and cooled to 0°C. This solution was treated with 28% aqueous ammonia solution (75 ml) followed by stirring at 0°C for 30 min and then heated to room temperature. The mixture was concentrated in vacuo and extracted with ethyl acetate. The organic layer was extracted with a saturated solution of sodium chloride and dried (Na2SO4). Concentration in vacuo gave the titled compound as oil (1.55 g, 100%).

[00954] Part N. Receive (5-bromo-1-methyl-2,3-dihydro-1H-inden-1-yl)methanimidamide.

[00955] In a flask equipped with a Vigreaux column and a nozzle for molecular distillation, a solution of the product from Part G (1,21 g, 4.76 mmol) in anhydrous tetrahydrofuran (8 ml) was heated to mild reflux distilled and treated dropwise borane-dimethylsulfide complex (904 μl, 723 mg, 9,52 mmol). The resulting mixture was stirred at reflux for 2 hours the Solution was cooled to room temp., and carefully treated with methanol until the termination of allocation of gas bubbles, followed by careful processing 4 N. was carried out in a solution of 1,4-dioxane (4 ml). The mixture was then concentrated in vacuum. The obtained colorless solid was ground into powder with ether and collected by filtration. After drying in a vacuum oven at 50°C for 2 h, the named compound was obtained in the form of bestv the private solids (893 mg, 68%).

[00956] Part I. Obtain tert-butyl (5-bromo-1-methyl-2,3-dihydro-1H-inden-1-yl)methyl-carbamate.

[00957] a Suspension of the product from Part H (893 mg, 3,23 mmol) in tetrahydrofuran (16 ml) was treated with di-tert-butyl dicarbonate (846 mg, a 3.87 mmol) and saturated sodium bicarbonate solution (7.2 ml, OK. 6,46 mmol) followed by stirring at room temperature for 18 hours the Mixture was diluted with ethyl acetate and was extracted with water and saturated sodium chloride solution. The solution was dried (Na2SO4) and concentrated in vacuum. The residue was purified using flash chromatography elwira 5-40% ethyl acetate in hexane. These procedures give the named compound as a colourless solid (1.03 g, 94%).

[00958] J. Obtain tert-butyl (1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)methylcarbamate.

[00959] the Product from Part I (1,03 g, 3.03 mmol) was subjected to the conditions described for Example 58, Part D of obtaining these compounds as colourless solids (977 mg, 83%).

[00960] they Obtain tert-butyl (5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-methyl-2,3-dihydro-1H-inden-1-yl)methylcarbamate.

[00961] the Product from Part J (965 mg, 2.49 mmol) was subjected to the conditions described for Example 59, Part D of obtaining these compounds are in the form of a colorless solid 618 mg, 47%).

[00962] Part L. Obtain N-((5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-methyl-2,3-dihydro - 1H-inden-1-yl)methyl)methanesulfonamide.

[00963] the Product from Part K (446 mg, 0.84 mmol) was dissolved in 4 BC hydrogen chloride in dioxane solution (12 ml), followed by stirring at room temperature for 18 hours, the Suspension obtained colorless solid was then concentrated in vacuum. This substance is suspended in dichloromethane (5 ml) and cooled to 0°C., followed by treatment with triethylamine (280 μl, 203 mg, a 2.01 mmol) and methanesulfonamide (81 μl, 120 mg, 1.05 mmol). The mixture was stirred at 0°C for 1 h and then was heated to room temperature and diluted with dichloromethane. The mixture was extracted with 1M citric acid solution and then dried (Na2SO4) and concentrated in vacuum. The residue was dissolved in 3:1 tetrahydrofuran-water (8 ml) and treated with potassium carbonate (231 mg, by 1.68 mmol) followed by stirring at room temperature for 1 h the Mixture was concentrated in vacuo, and the residue was diluted with water and then acidified to ca. pH 2 by addition of 1M citric acid. This product was extracted by ethyl acetate, and the organic layer was extracted with a saturated solution of sodium chloride. Drying (Na2SO4) and concentration in vacuo gave a colourless solid is emesto, which was purified by column chromatography on silica gel, elwira 30-100% ethyl acetate in hexane. These procedures give the named compound as a colourless solid (184 mg, 43%).1H NMR (300 MHz, DMSO-d6): δ 11.39 (s, 1 H) 7.77 (d, J=7.72 Hz, 1 H) 7.14-7.48 (m, 5 H) 7.06 (t, J=6.62 Hz, 1 H) 5.63 (d, J=7.72 Hz, 1 H) 3.18-3.33 (m, 3 H) 2.96-3.15 (m, 2 H) 2.85-3.00 (m, 2 H) 2.70-2.87 (m, 3 H) 2.10-2.34 (m, 1 H) 1.63-1.90 (m, 1 H) 1.40 (s, 9 H) 1.20-1.34 (m, 3 H).

[00964] Example 61. Obtaining N-((5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-fluoro-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide (compound IB-L0-2.12).

[00965] Part A. Obtain 5-(5-bromo-2,3-dihydro-1H-inden-1-ilidene)-2,2,3,3,7,7,8,8-octamethyl-4,6-dioxa-3,7-decylaniline.

[00966] To a solution of the product from Example 60, Part (1.2 g, to 4.98 mmol) in anhydrous THF (5 ml) was added TBSCl (cash consideration of USD 1,726 g of 11.45 mmol) and the resulting yellow solution was cooled to 0°C in an ice bath. Was added dropwise 1.0 M solution of LiHMDS in THF (11,95 ml, 11,95 mmol) over 5 min, and the resulting dark red solution was stirred at 0°C for 90 min and then at room temperature for 6 hours the Solvent was removed in vacuum and the oily semi-solid residue was treated with pentane (2×35 ml) to precipitate LiCl. The suspension was filtered, and the solvent was removed in vacuo to obtain the above compound as a brown oil (3 g).

[00967] part of the Century, Obtaining 5-bromo-1-fluoro-2,3-dihydro-1H-inden-1-carboxylic acid.

[00968] To a mixture of 1-chloromethyl-4-fluoro-1,1 - diazoniabicyclo[2.2.2.]octane bis(titrator-borate)(Selectfluor, and 2.26 g, 6,37 mmol in CH3CN (20 ml) was added the product from part a (2.3 g, of 4.90 mmol) in CH3CN (6 ml). The resulting yellow-orange solution was stirred at room temperature overnight. The reaction mixture was poured into 50 ml of 1 N. HCl (aqueous), extracted with EtOAc (2×35 ml). The combined organic extracts washed with 0.5 n NaOH (3×30 ml). The combined aqueous extracts washed with EtOAc (2×25 ml), then the pH of the mixture was adjusted to 1 using 5 N. HCl (10 ml). The resulting turbid brown solution was extracted with EtOAc (2×50 ml), the combined organic layers were washed with 10% NaCl and then was treated with decolorizing charcoal, and was stirred for 1 h, the Mixture was dried over anhydrous Na2SO4(s), filtered through celite and the solvent was removed in vacuum to obtain these compounds in the form of the remaining yellow oil (0.84 g).

[00969] Part C. Obtain 5-bromo-1-fluoro-2,3-dihydro-1H-inden-1-carbonylchloride.

[00970] To a solution of the product from Part b (0.95 g, to 3.67 mmol) in CH2Cl2added oxalicacid (of 0.96 ml, 11.00 mmol), followed by addition of DMF (0,28 ml). The resulting produce gas bubbles solution was stirred at room temperature for 2 h, filtered through celite, and the solvent was removed in vacuo to obtain the above compound as a brown oil (0,99 g).

[00971] Part D. Getting 5-bromo-1-fluoro-2,3-dihydro-1H-inden-1-carboxamide.

[00972] To a solution of the product from Part C (0,99 g of 3.57 mmol) in acetone (20 ml) and at 0°C was added aqueous NH4OH (28%, and 0.28 ml of 3.57 mmol) and the resulting dark brown mixture was stirred at 0°C for 1 h, the Reaction mixture was concentrated in vacuo, and the residue was separated between water and EtOAc (2×50 ml). The combined organic extracts were washed 1N H3PO4, 10% NaHCO3(aq.), 10% NaCl, and dried over anhydrous Na2SO4(s), filtered and concentrated in vacuum. Solid brown was purified by column chromatography on silica gel using a gradient solvent CH2Cl2/Meon (99/1-96/4). The named compound was obtained in a solid brown color (0,205 g, 22%).

[00973] Part E. Obtain tert-butyl (5-bromo-1-fluoro-2,3-dihydro-1H-inden-1-yl)methyl-carbamate.

[00974] To a solution of the product from Part D (0,234 g, 0,907 mmol) in anhydrous THF (5 ml) at 80°C was added dropwise a complex of borane-DMS (0,172 ml, 1,813 mmol). The reaction flask was supplied with condenser for molecular distillation, and the mixture was stirred at reflux for 2 h, collecting THF and DMS. Costatum was cooled to room temperature and added Meon (5 ml), then add 4 N. HCl in 1,4-dioxane (5 ml). The solvent was removed in vacuum to obtain a colorless solid (0.25 g, 98%). This solid was dissolved in THF (5 ml) and to this solution was added triethylamine (0,137 ml, 0,980 mmol), followed by addition of di-tert-butyl dicarbonate (0,214 g, 0,980 mmol). The cloudy mixture was stirred at room temperature for 30 min, and added 10% aq. NaHCO3(1 ml). The resulting mixture was stirred at room temperature for 18 h and then concentrated in vacuo to obtain an oily residue. The residue was dissolved in EtOAc (50 ml), washed with water, 1 N. H3PO4, 10% NaCl, and dried over anhydrous Na2SO4(s). Drying substance was filtered, and the solvent was removed in vacuum to obtain these compounds in the form of an oil (0.27 g, 88%).

[00975] Part F. Obtain tert-butyl (1-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)methylcarbamate.

[00976] the Product from Part E (0.27 g, 0,784 mmol) was subjected to the conditions described for Example 42, Part In obtaining these compounds are in the form of a solid, yellowish-brown (strength of 0.159 g, 52%).

[00977] Part G. Obtain tert-butyl (5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-fluoro-2,3-dihydro-1H-inden-1-yl)methylcarbamate.

[00978] To a solution of the product and the Part F (strength of 0.159 g, 0,405 mmol), the product from Example C (rate £ 0.162 g, 0,405 mol), 1,3,5,7 tetramethyl-2,4,8-trioxa-6-FOSFA-6-phenylalanine (PA-Ph, CAS 97739-46-3) (3.55 g, 0.012 mmol) in THF (3 ml) was added K3PO4(0,181 g, 0,851 mmol) and water (1 ml), followed by addition of the catalyst is Tris(dibenzylideneacetone)dipalladium(0) (3,71 mg, 0,00405 mmol). The resulting mixture was degirolami by bubbling N2within 20 min, and then stirred at room temperature for 12 hours the Reaction mixture was diluted with EtOAc (50 ml), washed with 1 N. H3PO4, 10% NaHCO3, 10% NaCl, and dried over anhydrous Na2SO4(s). The mixture was filtered, and the solvent was removed in vacuum to obtain a brown oil, which was purified by column chromatography on silica gel, elwira 98/2 CH2Cl2/Meon. The named compound was isolated as a colourless solid (amount of 0.118 g, 54%).

[00979] Part N. Obtaining N-((5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-fluoro-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide.

[00980] the Product from Part G (amount of 0.118 g, 0,219 mmol) was dissolved in 4 BC HCl in 1,4-dioxane (2 ml) and stirred at room temperature for 1 h the Solvent was removed in vacuo, and the residue suspended in CH2Cl2and evaporated (2×4 ml) to give a colorless solid (0.10 g, 96%). This solid was dissolved in CH2l 2(1 ml) and the resulting suspension was stirred in an ice bath. To this suspension was added triethylamine (0,059 ml, 0,422 mmol), receiving the resulting clear solution, and to this solution was added methanesulfonamide (0,02 ml, 0,253 mmol). The resulting mixture was stirred on an ice bath for 1 h, the Reaction mixture was diluted with CH2Cl250 ml, washed with 1 N. H3PO4, 10% NaHCO3, 10% NaCl, and dried over anhydrous Na2SO4(s). Drying substance was filtered, and the solvent was removed in vacuo, leaving the crude product, which was purified by column chromatography on silica gel, elwira gradient 1:1 to 3:7 hexane:EtOAc. The named compound was obtained as a colorless solid (64 mg, 62%).1H NMR (300 MHz, DMSO-d6) δ 11.39 (s, 1 H) 7.77 (d, J=7.72 Hz, 1 H), 7.30-7.48 (m, 3 H), 7.12-7.32 (m, 3 H), 5.63 (d, J=7.72 Hz, 1 H) 3.27 (s, 3 H) 2.94-3.08 (m, 4 H), 2.91 (s, 3 H) 2.17-2.38 (m, 1 H), 1.76-1.97 (m, 1 H), 1.40 (s, 9 H).

[00981] Example 62. Obtaining N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-yl)methanesulfonamide (compound IB-L0-2.43).

[00982] Part A. Obtain N-(3-brominated)-2,2,2-trifurcated.

[00983] To a solution of 2-(3-bromophenyl)ethanamine (10 g, 50.0 mmol) in dichloromethane (200 ml) at 0°C was added 2,6-lutidine (6,40 ml, 55,0 mmol) and then triptorelin (to 7.77 ml, 55,0 mmol dropwise, and the reaction mixture was stirred at room temperature overnight. Added water at 0°C, and the reaction mixture was washed with 1M HCl, H2O, and us. NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated to obtain these compounds in the form of a solid, yellowish-brown (14,7 g, 99%).

[00984] part of the Century, Obtaining 1-(6-bromo-3,4-dihydroisoquinoline-2(1H)-yl)-2,2,2-Cryptor-ethanone.

[00985] To the product from part a (14,70 g of 49.6 mmol) and paraformaldehyde (2,39 g, 80 mmol) was added a mixture of acetic acid (81 ml) and sulfuric acid (53,7 ml) at room temperature. The suspension was stirred for 60 h, during which she turned into a solution. The reaction mixture was poured into cold water. The reaction mixture was diluted with ethyl acetate and washed with water, us. NaHCO3and a salt solution. The organic layer was dried over MgSO4, filtered and concentrated to obtain these compounds, contaminated 8-bromo isomer as a colorless oil (10.5 g, 67%).

[00986] Part C. Obtain 6-bromo-1,2,3,4-tetrahydroisoquinoline.

[00987] To a solution of the product from Part b (9.5 g, 30,8 mmol) in methanol (231 ml) and water (77 ml) at room temperature was added potassium carbonate (charged 8.52 g of 61.7 mmol) and the reaction mixture was stirred at room temperature for 30 minutes, the Reaction mixture was diluted with water and 25% from what propanolol in chloroform and the pH was brought to 9, using 1 N. HCl. The mixture was extracted twice with 25% isopropanol in chloroform. The combined organic layers were dried over MgSO4, filtered and concentrated to obtain these compounds, contaminated 8-bromo isomer (6,55 g, quantitative).

[00988] Part D. Obtain 6-bromo-2-nitroso-1,2,3,4-tetrahydroisoquinoline.

[00989] To a solution of the product from Part C (6,55 g of 30.9 mmol) in acetic acid (61,8 ml) and 3 n aq. hydrochloric acid (10,29 ml of 30.9 mmol) at 0°C was added dropwise 1.9 M sodium nitrite (20,64 ml of 39.2 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the reaction mixture was diluted with 25% isopropanol in chloroform and us. NaHCO3. The aqueous layer was extracted twice with 25% isopropanol in chloroform. The combined organic layers were dried over MgSO4, filtered and concentrated to obtain these compounds, contaminated 8-bromo isomer (6,97 g, 94%).

[00990] Part E. Obtain 6-bromo-3,4-dihydroisoquinoline-2(1H)-amine.

[00991] To a solution of the product from Part D (0.5 g, 2,074 mmol) in methanol (4,15 ml) was added zinc (0,542 g, 8,30 mmol) and the reaction mixture was cooled to 0°C., followed by adding dropwise Asón (4,15 ml). The reaction mixture was heated up to room temp., and the reaction mixture was stirred for 2.5 hours, the Reaction mixture was filtered and the solid is about the Ali methanol. The filtrate was evaporated, and the residue was diluted with water and added 25% isopropanol in chloroform and saturated NaHCO3. Solid white color was removed by filtration, and the aqueous layer was extracted twice with 25% isopropanol in chloroform. The combined organic layers were dried over MgSO4, filtered and concentrated to obtain these compounds, contaminated 8-bromo isomer (0,472 g, quantitative).

[00992] Part F. Obtain tert-butyl 6-bromo-3,4-dihydroisoquinoline-2(1H)-ylcarbamate.

[00993] a solution of the product from Part E (0,472 g 2,078 mmol) in THF (20,78 ml) was cooled to 0°C followed by addition of di-tert-butyl dicarbonate (mean HDI of 0.531 ml, 2,286 mmol) and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo, and the crude product was purified by column chromatography on silica gel (selected low Rfproduct) using a gradient starting with dichloromethane and ending with 10% ethyl acetate in dichloromethane to obtain the above compound (49 mg, 73%).

[00994] Part G. Obtain tert-butyl 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroisoquinoline-2(1H)-ylcarbamate.

[00995 leather straps] a solution of the product from Part F (100 mg, 0,306 mmol), bis(pinacolato)Debora (85 mg, 0,336 mmol), and potassium acetate (57,3 μl, 0,917 mmol) in 1,4-dioxane (3.0 ml) was degirolami by ozonation gaseous N within 15 minutes was Added to the complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(11)dichloride dichloromethane (11,18 mg, 0.015 mmol) and the resulting mixture was stirred at 95°C for 16 hours, the Cooled solution was diluted with 25% isopropanol in chloroform and washed with water. The organic layer was dried over MgSO4, filtered and concentrated in vacuum. The product was purified by column chromatography on silica gel, elwira gradient starting with dichloromethane and ending with 25% ethyl acetate in dichloromethane to obtain the above compound (70 mg, 61%).

[00996] Part N. Obtain tert-butyl 6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-ylcarbamate.

[00997] a Mixture of the product from Example C (74,8 mg, 0,187 mmol), the product from Part G (70 mg, 0,187 mmol) in EtOH (1.0 ml), toluene (1.0 ml) and 1M aq. Na2CO3(281 μl, 0,281 mmol) was degirolami by ozonation gaseous N2within 10 minutes was Added to the complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane (6,84 mg, 9,35 mmol) and degassing using N2continued for 5 minutes, the Reaction mixture was tightly closed and heated at 78°C for 16 hours the Reaction mixture was cooled and diluted with 25% isopropanol in chloroform and washed with water. The organic layer was dried over MgSO4that was filtered concentrically. The crude product was purified by column chromatography on silica gel, elwira gradient starting with dichloromethane and ending with ethyl acetate to obtain the above compound (53 mg, 54%).

[00998] Part I. Obtaining N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-yl)methanesulfonamide.

[00999] To a solution of the product from Part H (25 mg, 0,048 mmol) in dichloromethane (0.5 ml) at room temperature was added TFA (0.5 ml) and the reaction mixture was stirred for 30 min, and then concentrated in vacuum. The residue was diluted with 25% isopropanol in chloroform and washed us. NaHCO3. The organic layer was dried over MgSO4, filtered and concentrated to obtain a solid substance (17,8 mg, 88%). To a solution of this solid in pyridine (0.5 ml) at 0°C was added methanesulfonamide (12,6 μl, rate £ 0.162 mmol) and the reaction mixture was stirred at room temperature for 90 minutes was Added methanol and the reaction mixture was stirred for 10 minutes, the Residue was diluted with 25% isopropanol in chloroform and washed us. NaHCO3. The organic layer was dried over MgSO4was filtered and concentrated, and the product was purified by column chromatography on silica gel, elwira gradient starting with dichloromethane and ending with ethyl acetate, to obtain the mentioned link is (11 mg, 52%).1H NMR (300 MHz, DMSO-d6) δ 11.39 (s, 1 H) 8.53 (s, 1 H) 7.76 (d, J=7.72 Hz, 1 H) 7.11-7.42 (m, 5 H) 5.63 (d, J=7.72 Hz, 1 H) 4.04 (s, 2 H) 3.28 (s, 3 H) 3.10 (d, J=5.52 Hz, 2 H) 2.98 (s, 3 H) 2.90-3.05 (m, 2 H) 1.40 (s, 9 H).

[001000] Example 63. Obtaining N-((6-(5-(2,4-Diageo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-2-yl)-2-methoxyphenyl)-1H-inden-3-yl)methyl)methanesulfonamide (compound IB-L0-2.65).

[001001] Part A. Obtain N-((6-(3-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1H-inden-3-yl)methyl)methanesulfonamide.

[001002] the Product from Example 18, Parts (0,242 g, 0,573 mmol) and the product from Example 49, Part E (0,200 g, or 0.57 mmol) was subjected to the conditions described for Example 49, Part F of obtaining these compounds are in the form of a whitish solid (0.104 g g, 35%).

[001003] part of the Century, Obtaining N-((6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-2-yl)-2-methoxyphenyl)-1H-inden-3-yl)methyl)methanesulfonamide.

[001004] a solution of the product from part a (to 25.2 mg, 0,049 mmol) in a mixture of 3:1 V/V THF-water (1.3 ml) were combined in a microwave tube at room temperature with furan-2-Voronovo acid (6,91 mg, holding 0.062 mmol) and potassium phosphate (at 16.84 mg, 0,097 mmol). To this solution was added 1,1'-bis(di-tert-butyl-phosphino)ferrocene palladium dichloride (1,65 mg of 2.53 mmol). The tube is hermetically closed, and the resulting mixture was purged with nitrogen for 4 min, and then heated in the course of 16.5 h at an oil bath at 50°C. the PE clonney the mixture was distributed between dilute HCl and ethyl acetate, and the organic phase was dried (MgSO4) and concentrated in vacuum. The residue was purified by chromatography on silica gel (ethyl acetate-hexane) to obtain the titled compound in the form of a whitish solid (11.4 mg, 46%).1H NMR (300 MHz, DMSO-d6) δ 11.45 (s, 1 H) 7.80-7.89 (m, 2 H) 7.73-7.79 (m, 2 H) 7.56-7.63 (m, 2 H) 7.50 (t, J=6.07 Hz, 1 H) 7.38 (d, J=2.94 Hz, 1 H) 7.09 (d, J=3.31 Hz, 1 H), 6.68 (dd, J=3.68, 1.84 Hz, 1 H), 6.58 (s, 1 H), 5.68 (d, J=7.72 Hz, 1 H), 4.19 (d, J=5.15 Hz, 2 H) 3.48 (s, 2 H) 3.34 (s, 3 H) 2.96 (s, 3 H).

[001005] Example 64. Obtaining N-((6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophene-2-yl)phenyl)-1H-inden-3-yl)methyl)methanesulfonamide (compound IB-L0-2.63).

[001006] the Product from Example 63, part a (26.5 mg, 0,051 mmol) interacted with thiophene-2-yl Bronevoy acid (8,3 mg 0,065 mmol) as described in Example 63, Part In obtaining these compounds are in the form of a whitish solid (8.6 mg, 32%).1H NMR (300 MHz, DMSO-d6) δ 11.47 (s, 1 H) 7.86 (d, J=7.72 Hz, 2 H) 7.55-7.78 (m, 5 H), 7.50 (t, J=6.25 Hz, 1 H) 7.38 (d, J=2.57 Hz, 1 H) 7.16-7.21 (m, 1 H), 6.58 (s, 1 H), 5.69 (d, J=7.72 Hz, 1 H), 4.19 (d, J=4.78 Hz, 2 H) 3.48 (s, 2 H) 3.30 (s, 3 H) 2.96 (s, 3 H).

[001007] Example 65. Obtaining N-((6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophene-3-yl)phenyl)-1H-inden-3-yl)methyl)methanesulfonamide (compound IB-L0-2.62).

[001008] the Product from Example 63, part a (25,9 mg, 0,050 mmol) interacted with thiophene-3-yl Bronevoy acid (8.1 mg, 0,063 mmol), as op is Sano in Example 63, Part In the formation of these compounds in the form of off-solid (8.6 mg, 33%).1H NMR (300 MHz, DMSO-d6) δ 11.45 (d, J=1.84 Hz, 1 H) 7.93 (d, J=2.94 Hz, 1 H) 7.87 (d, J=7.72 Hz, 1 H) 7.53-7.75 (m, 6 H) 7.49 (t, J=6.25 Hz, 1 H) 7.39 (d, J=2.57 Hz, 1 H), 6.57 (s, 1 H), 5.68 (dd, J=7.91, 2.02 Hz, 1 H), 4.19 (d, J=5.15 Hz, 2 H) 3.47 (s, 2 H) 3.21 (s, 3 H) 2.96 (s, 3 H).

[001009] Example 66. Obtaining N-((6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-3-yl)-2-methoxyphenyl)-1H-inden-3-yl)methyl)methanesulfonamide (compound IB-L0-2.67).

[001010] the Product from Example 63, part a (25,9 mg, 0,050 mmol) interacted with furan-3-yl Bronevoy acid (7.2 mg, 0,064 mmol) as described in Example 63, Part In obtaining these compounds are in the form of a whitish solid (10,6 mg, 45%).1H NMR (300 MHz, DMSO-d6) δ 11.46 (s, 1 H) 7.84 (d, J=8.09 Hz, 1 H), 7.80 (t, J=1.84 Hz, 1 H) 7.68-7.75 (m, 2 H) 7.54-7.64 (m, 2 H) 7.50 (t, J=6.07 Hz, 1 H) 7.35 (d, J=2.57 Hz, 1 H) 7.08 (d, J=1.47 Hz, 1 H), 6.57 (s, 1 H), 5.68 (d, J=8.09 Hz, 1 H), 3.47 (s, 2 H) 3.30 (s, 3 H) 2.96 (s, 3 H).

[001011] Example 67. Obtain 1-(3-tert-butyl-4-methoxy-5-(1-(methylsulphonyl)indolin-5-yl)phenyl)pyrimidine-2,4(1H,3H)-dione (compound IB-L0-2.32).

[001012] Part A. Obtain 5-bromo-1-(methylsulphonyl)indoline.

[001013] TO a DMF (5.0 ml) was added sodium hydride (53 mg, 1.3 mmol) and the solution was stirred at room temperature for 30 minutes was Added 5-bromoindoline (240 mg, 1.2 mmol), and the solution was stirred at room temperature for 30 minutes was Added methane is sulfonylurea (94 μl, 1.2 mmol), and the solution was stirred at room temperature overnight, then concentrated in vacuo. The crude product was purified by column chromatography on silica gel, elwira 2% CH3HE/CHCl3with obtaining the above compound (202 mg, 60%).

[001014] part of the Century, Obtaining 1-(methylsulphonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)indoline.

[001015] the Product from part a (192 mg, 0.70 mmol) was subjected to the conditions described for Example 42, Part b to obtain the above compound (114 mg, 51%).

[001016] Part C. Obtain 1-(3-tert-butyl-4-methoxy-5-(1-(methylsulphonyl)indolin-5-yl)phenyl)pyrimidine-2,4(1H,3H)-dione.

[001017] the Product from Example C (58 mg, 0,145 mmol) and the product from Part b (56,2 mg, 0,174 mmol) was subjected to the conditions described for Example 42, Part C with obtaining these compounds as a colourless solid (12 mg, 18%).1H NMR (300 MHz, DMSO-d6): δ 11.40 (d, J=1.84 Hz, 1 H) 7.76 (d, J=7.72 Hz, 1 H) 7.53-7.67 (m, 1 H) 7.45 (s, 1 H) 7.32-7.41 (m, 2 H) 7.23 (dd, J=13.60, 2.57 Hz, 2 H), 5.63 (dd, J=8.09, 2.21 Hz, 1 H), 3.99 (t, J=8.46 Hz, 2 H) 3.29 (s, 3 H) 3.18 (t, J=8.46 Hz, 2 H) 3.04 (s, 3 H).

[001018] Example 68. Obtaining N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)cinoxacin-2-yl)methanesulfonamide (compound IB-L0-2.26).

[001019] Part A. Obtain N-(4-bromo-2-nitrophenyl)-3-oxobutanamide.

[001020] a Solution of diketene (0,32 ml, 4,15 mmol) in toluene (2 ml) we use the and to 80°C to a solution of 4-bromo-2-nitroaniline (900 mg, to 4.15 mmol) in toluene (7 ml), and the solution was heated under reflux for 5 hours was Added triethylamine (of 0.58 ml, 4,15 mmol) in toluene (2 ml), and reflux was continued for 30 minutes, the Cooled solution was concentrated in vacuo, and the crude product was purified by column chromatography on silica gel, elwira 2:1 hexane/EtOAc to obtain these compounds in a solid yellow color (920 mg, 74%).

[001021] part of the Century, Obtaining 6-bromination-2(1H)-it.

[001022] To a solution of sodium hydroxide (337 mg, 8.4 mmol) in H2O (2.1 ml) was added the product from part a (423 mg, 1.4 mmol), and stirring continued at 65°C for 1 h, the Cooled solution was diluted with H2O (4 ml) was added sodium borohydride (31,9 mg, 0.84 mmol) and stirring continued at room temperature for 1.5 hours In this solution was added ice, followed by adding dropwise 6 N. HCl to acidification. The resulting solid was collected by filtration, washed with N2Oh, and dried in a vacuum oven to obtain the above compound (273 mg, 86%).

[001023] Part C. Obtain 6-bromo-2-chlorphenoxamine.

[001024] Into the flask containing the acid chloride phosphoric acid (3.4 ml, of 36.5 mmol) was added the product from Part b (255 mg, 1.1 mmol), and the solution was heated at 60°C over night. The solution was cooled to on the th temperature, poured into ice and the resulting solid was collected by filtration to obtain the above compound (239 mg, 87%).

[001025] Part D. Obtain 6-bromo-N-(4-methoxybenzyl)cinoxacin-2-amine.

[001026] To a solution of the product from Part C (2.8 g, 11.5 mmol) in ethanol (58 ml) was added (4-methoxyphenyl)methanamine (7.5 ml, 57.5 mmol), and the solution was stirred at room temperature for 1 h the Solvent was concentrated in vacuo, and the crude product was purified by column chromatography on silica gel, elwira 20% EtOAc/hexane to obtain the above compound (1.97 g, 50%).

[001027] Part E. Obtain N-(4-methoxybenzyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cinoxacin-2-amine.

[001028] the Product from Part D (500 mg, 1,45 mmol) was subjected to the conditions described for Example 42, Part b to obtain the above compound (378 mg, 66%).

[001029] Part F. Obtain 1-(3-tert-butyl-4-methoxy-5-(2-(4-methoxybenzylamine)cinoxacin-6-yl)phenyl)pyrimidine-2,4(1H,3H)-dione.

[001030] the Product from Part E (133 mg, 0.34 mmol) was subjected to the conditions described for Example 42, Part C to obtain the above compound (125 mg, 82%).

[001031] Part G. Obtain N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)cinoxacin-2-yl)methanesulfonamide.

[001032] To a solution of the product from Part F (87 mg, 0.16 mmol) in CH2Cl2(1.6 ml) and H2O (0,07 ml) add the Yali DDQ (40,4 mg, 0.18 mmol) and intensively stirred at room temperature for 1 h the Solution was filtered through celite, and the dark solid collected on celite, was dissolved in 5 ml of CH3HE. The methanol solution was filtered, the solvent was removed in vacuum and the crude intermediate compound was dissolved in pyridine (0.6 ml). Added methanesulfonamide (11 μl, 0.14 mmol) and the solution was heated at 60°C over night. The cooled solution was concentrated in vacuo, and the crude product was purified by column chromatography on silica gel, elwira 2% CH3HE/CHCl3with obtaining the above compound (7.7 mg, 12%).1H NMR (300 MHz, CDCl3) δ 8.42 (s, 1 H) 8.29 (s, 1 H) 8.13 (s, 1 H) 7.88 (d, 1 H) 7.54 (s, 1 H) 7.19-7.43 (m, 4 H), 5.83 (dd, J=7.91, 2.39 Hz, 1H) 3.32 (s, 3 H), 3.27 (s, 3 H) 1.46 (s, 9 H).

[001033] Example 69. Obtaining N-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide (compound IB-L0-2.44).

[001034] Part A. Obtain 5-bromo-2,3-dihydro-1H-inden-1-ol.

[001035] a Suspension of 5-bromo-2,3-dihydro-1H-inden-1-it (2,07 g, 9,81 mmol) in ethanol (49 ml) was treated with sodium borohydride (186 mg, of 4.90 mmol) at the same time. After several minutes, the solution was slightly heated, and all solids were dissolved. After stirring at room temperature for 1 h the mixture was concentrated in vacuo to-the Oia ethanol. The obtained resinous allocation was distributed between ethyl acetate and water. The organic layer was extracted with saturated sodium bicarbonate solution (2x) and saturated solution of sodium chloride. Drying (Na2SO4) and concentration in vacuo gave the titled compound (3,05 g, 98%) as a colorless oil, which crystallized when pumping under high vacuum over night.

[001036] part of the Century, Obtaining 1 azido-5-bromo-2,3-dihydro-1H-indene.

[001037] a solution of the product from part a (1.01 g, to 4.73 mmol) in toluene (8.1 ml) was treated with diphenylphosphonate (1.23 ml, 1.56 g, 5,67 mmol) then cooled to 0°C. the Solution was treated dropwise DBU (855 μl, 863 mg, 5,67 mmol) followed by stirring at 0°C for 2 h, and then heated to room temperature within 48 hours the Mixture was diluted with ethyl acetate and was extracted with water and 1 M citric acid solution and then a saturated solution of sodium chloride. Drying (Na2SO4) and concentration in vacuo gave a brown oil, which was purified using flash chromatography elwira 5-50% ethyl acetate in hexane. These procedures gave the titled compound (889 mg, 79%) as a pale yellow oil.

[001038] Part C. Obtain 5-bromo-2,3-dihydro-1H-inden-1-amine.

[001039] To -15°C. a solution of 1M lithium aluminum hydride in THF (from 0.84 ml, 0.84 mmol) in THF (0,88 ml) was added dropwise races is the thief of the product from Part b (200 mg, 0.84 mmol), and the solution was heated to room temperature and was stirred overnight. The solution was cooled to -10°C and 4:1 THF:H2O (0.5 ml) was added dropwise. The solution was stirred at room temperature for 4 h, filtered through celite, and the filtrate was concentrated in vacuo to obtain the above compound (151 mg, 85%).

[001040] Part D. Obtain N-(5-bromo-2,3-dihydro-1H-inden-1-yl)methanesulfonamide.

[001041] To a solution of the product from Part C (150 mg, 0.71 mmol) in pyridine (3.5 ml) was added methanesulfonamide (61 μl, 0.78 mmol), and the solution was stirred at room temperature overnight. The solution was concentrated in vacuo, and the crude product was purified by column chromatography on silica gel, elwira 20% EtOAc/hexane to obtain the above compound (111 mg, 54%).

[001042] Part E. Obtain N-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide.

[001043] the Product from Part D (109 mg, 0.38 mmol) was subjected to the conditions described for Example 42, Part b and Part C to obtain the above compound (39 mg, 60%).1H NMR (300 MHz, DMSO-d6) δ 11.39 (d, J=1.84 Hz, 1 H) 7.77 (d, J=7.72 Hz, 1 H) 7.58 (d, J=8.82 Hz, 1 H) 7.39-7.48 (m, 3 H) 7.27 (d, J=2.57 Hz, 1 H) 7.19-7.23 (m, 1 H) 5.63 (dd, J=8.09, 2.21 Hz, 1 H) 4.86 (q, J=7.97 Hz, 1 H) 3.27 (s, 3 H) 3.04 (s, 3 H) 2.90-3.01 (m, 1 H) 2.71-2.90 (m, 1 H) 2.52-2.62 (m, 1 H) 1.85-1.98 (m, 1 H) 1.40 (s, 9 H).

[001044] Example 70. Obtaining N-((5-(3-Tr is t-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide (compound IB-L0-2.17).

[001045] Part A. Obtaining (E)-5-bromo-1-(methoxymethyl)-2,3-dihydro-1H-indene.

[001046] To a suspension chloride (methoxymethyl)triphenylphosphine (and 39.7 g, 116 mmol) in THF (210 ml) at -20°C was added dropwise 1M t-piperonyl potassium (95 ml, 95 mmol), and the solution was stirred at -20°C for 20 minutes To this solution was added dropwise a solution of 5-bromo-2,3-dihydro-1H-inden-1-she (10.0 g, with 47.4 mmol) in THF (230 ml) and stirring was continued at -20°C for 30 min, then was heated to room temperature and was stirred for 2 h the Solution was filtered through celite, and the filtrate was concentrated in vacuum to obtain crude product, which was purified by chromatography on a cartridge of silica gel, elwira CH2Cl2/hexane, to obtain the titled compound (10,56 g, 93%).

[001047] part of the Century, Obtaining 5-bromo-2,3-dihydro-1H-inden-1-carbaldehyde.

[001048] To a solution of the product from part a (1.44 g, 6.0 mmol) in CH2Cl2(30 ml) at -78°C was added dropwise 1M trichromacy boron in CH2Cl2(13,8 ml of 13.8 mmol) and stirring continued at -78°C for 4 h the Solution was poured into a mixture of ice and saturated sodium bicarbonate and intensively stirred. The layers were separated, and the aqueous layer was extracted with CH2Cl2(2x), the organic extracts were combined, dried (Na2SO4), and concentrated in vacuo to obtain Iroha product, which was purified by column chromatography on silica gel, elwira 10% EtOAc/hexane to obtain the above compound (604 mg, 45%).

[001049] Part C. Obtain 1-(5-bromo-2,3-dihydro-1H-inden-1-yl)-N-(4-methoxybenzyl)-methanamine.

[001050] To a solution of the product from Part b (300 mg, 1.3 mmol) in CH3HE (18.5 ml) was added 4-methoxybenzylamine (0.17 ml, 1.3 mmol) and decaborane (49 mg, 0.4 mmol) and stirring continued at room temperature for 1 h, the solvent was concentrated in vacuo, and the crude product was purified by column chromatography on silica gel, elwira 3% CH3HE/CHCl3with obtaining the above compound (264 mg, 57%).

[001051] Part D. Obtaining N-((5-bromo-2,3-dihydro-1H-inden-1-yl)methyl)-N-(4-methoxy-benzyl)methanesulfonamide.

[001052] To a solution of the product from Part C (88 mg, 0.25 mmol) in CH2Cl2(1.0 ml) was added triethylamine (39 μl, 0.28 mmol) and methanesulfonamide (22 μl, 0.28 mmol) and stirring continued at room temperature for 1 h, the solvent was concentrated in vacuo, and the crude product was purified by column chromatography on silica gel, elwira EtOAc/hexane to obtain the above compound (55 mg, 51%).

[001053] Part E. Obtain N-(4-methoxybenzyl)-N-((5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide.

[001054] the Product from Part D (1,15 g ,71 mmol) was subjected to conditions described for Example 42, Part b to obtain the above compound (840 mg, 66%).

[001055] Part F. Obtaining N-((5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide.

[001056] the Product from Part E (840 mg, 2.1 mmol) was subjected to the conditions described for Example 42, Part C, and selected substance (1.28 g, 2,07 mmol) was dissolved in CH2Cl2(10 ml) and slowly added triperoxonane acid (10 ml). After stirring at room temperature for 1 h, the solvent was concentrated in vacuo, and the crude product is suspended in 10% NaHCO3, was extracted with CH2Cl2(3x), the organic extracts were combined, dried (Na2SO4), and the solvent was concentrated in vacuum to obtain crude product, which was purified by column chromatography on silica gel, elwira 2% CH3HE/CHCl3with obtaining the above compound (0.84 g, 81%).1H NMR (300 MHz, DMSO-d6) δ 11.39 (s, 1 H) 7.77 (d, J=8.09 Hz, 1 H) 7.29-7.59 (m, 3 H) 7.25 (d, J=2.94 Hz, 1 H), 7.10-7.22 (m, 2 H), 5.63 (dd, J=7.72, 1.84 Hz, 1 H) 3.93 (s, 3 H), 3.26 (s, 2 H) 3.23-3.40 (m, 1 H), 2.89 (s, 3 H) 2.71-3.09 (m, 2 H), 2.14-2.32 (m, 1 H), 1.75-1.95 (m, 1 H), 1.40 (s, 9 H).

[001057] Example 71. Getting 5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-N-(methylsulphonyl)-2,3-dihydro-1H-inden-1-carboxamide (compound IB-L0-2.34).

[001058] Part A. Receiving the s 5-bromo-2,3-dihydro-1H-inden-1-carboxylic acid.

[001059] To a solution of the product from Example 70, Part b (300 mg, 1.3 mmol) and 2-methyl-2-pentene (8 ml) in tert-butanol (32 ml) was added a solution of sodium chlorite (1,36 g, 0.12 mmol) in N2O (12 ml) containing one-deputizing phosphate sodium (1.07 g, 8.9 mmol) and the mixture was intensively stirred for 20 min at room temperature. The solvent was concentrated in vacuo, and the residue was diluted with H2O, was extracted with EtOAc (3x), the extracts were combined, dried (Na2SO4), and concentrated in vacuo to obtain the above compound (180 mg, 56%).

[001060] part of the Century, Obtaining 5-bromo-N-(methylsulphonyl)-2,3-dihydro-1H-inden-1-carboxamide.

[001061] To a solution of the product from part a (100 mg, 0.42 mmol) in CH2Cl2(1.7 ml) was added carbonyldiimidazole (67,3 mg, 0.42 mmol) and the reaction mixture was stirred for 2 h at room temperature. Added methanesulfonamide (39,5 mg, 0.42 mmol) and DBU (62.5 mg, 0.42 mmol) and stirring continued at room temperature for 2 hours the Solution was diluted with CH2Cl2off , washed with 1 N. HCl, brine, dried (Na2SO4), concentrated in vacuo, and the crude product was purified by column chromatography on silica gel, elwira 20% EtOAc/hexane to obtain the above compound (121 mg, 92%).

[001062] Part C. Obtain N-(methylsulphonyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-what ihydro-1H-inden-1-carboxamide.

[001063] the Product from Part b (159 mg, 0.5 mmol) was subjected to the conditions described for Example 42, Part b to obtain the above compound (144 mg, 79%).

[001064] Part D. Getting 5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-N-(methylsulphonyl)-2,3-dihydro-1H-inden-1-carboxamide.

[001065] the Product from Part C (134 mg, 0.34 mmol) was subjected to the conditions described for Example 42, Part C to obtain the above compound (14 mg, 8%).1H NMR (300 MHz, CDCl3) δ 8.11 (m, 1 H) 7.08-7.57 (m, 7 H), 5.80 (dd, J=7.91, 2.39 Hz, 1 H), 4.07 (dd, J=9.01, 6.07 Hz, 1 H) 3.33 (s, 3 H) 3.08 (s, 3H) 2.91-3.22 (m, 1 H) 2.35-2.74 (m, 1 H) 1.44 (s, 9H) 1.17-1.34 (m, 1 H), 0.60-1.00 (m, 1 H).

[001066] Example 72. Obtain 1-(3-(2-aminobenzo[d]thiazol-6-yl)-5-tert-butyl-4-methoxy-phenyl)pyrimidine-2,4(1H,3H)-dione (compound IB-L0-2.39).

[001067] the Named compound was obtained using the procedure described for an Example 53, substituting 5-bromo[d]thiazol-2-amine 6-bromobenzo[d]thiazol-2-amine.1H NMR (300 MHz, DMSO-d6) δ 11.40 (d, J=1.84 Hz, 1 H) 8.40 (s, 2 H) 7.84 (d, J=8.09 Hz, 1 H) 7.78 (d, J=7.72 Hz, 1 H) 7.54 (d, J=1.47 Hz, 1 H) 7.27-7.32 (m, 3 H) 5.64 (dd, J=8.09, 2.21 Hz, 1 H) 3.27 (s, 3 H) 1.41 (s, 9 H).

[001068] Example 73. Obtaining N-(2-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)propan-2-yl)methanesulfonamide (compound IB-L0-2.29).

[001069] To a solution of the product from Example 45, Part D (20 mg, of 0.038 mmol) in a mixture 1:1 benzo is: Meon (0.6 ml) was added platinum oxide (IV) (1 mg). The resulting mixture was stirred under a pressure of 1 ATM H2at room temperature for 1 h, and then filtered through celite, and concentrated in vacuum. The crude product was purified by column chromatography on silica gel using 3% Meon in CHCl3as the eluent, to obtain the titled compound as a solid (14 mg, 70%).1H NMR (300 MHz, DMSO-d6) δ 11.39 (s, 1 H) 7.77 (d, J=7.72 Hz, 1 H) 7.58 (d, J=8.09 Hz, 1 H) 7.28-7.38 (m, 2 H) 7.21-7.26 (m, 2 H) 7.07 (s, 1 H) 5.63 (d, J=7.72 Hz, 1 H) 3.61 (dd, J=8.64, 5.33 Hz, 1 H) 3.25 (s, 3 H) 3.00 (s, 3 H) 2.75-2.98 (m, 2 H) 1.97-2.21 (m, 2 H) 1.40 (s, 9 H) 1.24 (d, J=8.46 Hz, 6 H).

[001070] Example 74. Obtain (S)-N-(2-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)propan-2-yl)methanesulfonamide (compound IB-L0-2.22).

[001071] the Product from Example 73 (10 mg) was subjected to chiral chromatography (column Chiralpak AD-H; elwira 1:3 2-D:hexane (0.1% of TFA)). The selection component of the early elution gave the titled compound (4.4 mg).1H NMR was identical with the product from Example 73.

[001072] Example 75. Obtaining (R)-N-(2-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)propan-2-yl)methanesulfonamide (compound IB-L0-2.37).

[001073] the Product from Example 73 (10 mg) was subjected to chiral chromatography (column Chiralpak AD-H; elwira 1:3 2-D:Huck is an (0,1% TFA)). The selection component of late elution gave the titled compound (4.2 mg).1H NMR was identical with the product from Example 73.

[001074] Example 76. Obtain (S)-N-((5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide (compound IB-L0-2.9).

[001075] the Product from Example 70, Part F (20 mg) was subjected to chiral chromatography (column Chiralpak AD-H; elwira 1:4 2-D:hexane (0.1% of TFA)). The selection component of the early elution gave the titled compound (5.3 mg).1H NMR was identical with the product from Example A-70, Part F.

[001076] Example 77. Obtaining (R)-N-((5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide (compound IB-L0-2.15).

[001077] the Product from Example 70, Part F (20 mg) was subjected to chiral chromatography (column Chiralpak AD-H; elwira 1:4 2-D:hexane (0.1% of TFA)). The selection component of late elution gave the titled compound (5.7 mg).1H NMR was identical with the product from Example 70, Part F.

[001078] Example 78. Obtain (S)-N-((5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-fluoro-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide (compound IB-L0-2.20).

[001079] the Product from Example 61, Part H was subjected to the conditions described in Example 74 with the teachings of the above compounds. 1H NMR was identical with the product from Example 61, Part N.

[001080] Example 79. Obtaining (R)-N-((5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-fluoro-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide (compound IB-L0-2.10).

[001081] the Product from Example 61, Part H was subjected to the conditions described in Example 74 with obtaining these compounds.1H NMR was identical with the product from Example 61, Part N.

[001082] Example 80. Obtaining N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-tert-pentylphenol)naphthalen-2-yl)methanesulfonamide (compound IB-L0-2.52).

[001083] Part A. Obtain 1-(3-tert-butyl-5-iodine-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione.

[001084] 2-tert-amalfino (5.0 g, 30 mmol) reacts in accordance with the procedure of Example C, part a, Part b, and Part C with the formation of the named product as colorless solid (6.7 g, 56% of the total yield for 3 stages).

[001085] part of the Century, Obtaining N-(6-(5-(2,4-Diageo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-tert-pentylphenol)naphthalen-2-yl)methanesulfonamide.

[001086] the Product from part a (100 mg, 0,241 mmol), the product from Example 2A, Part b (92 mg, 0,266 mmol), sodium carbonate (38,4 mg, 0,362 mmol) and the complex of 1,1'-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane (9,9 mg, 0.012 mmol) was dissolved in a solvent mixture of toluene (4ml) and ethanol (4 ml), which was barbotirovany nitrogen for 10 min, then the mixture was heated to 85°C for 18 h To this solution is then added CH2Cl2(20 ml) followed by addition of 1 N. aqueous HCl (10 ml), the organic layer was separated by a 3-mercaptopropyl silica gel (100 mg) was added magnesium sulfate. The solution was concentrated and was purified by column chromatography on silica gel using 3% Meon in CH2Cl2as the eluent, to obtain the titled compound as a colorless solid (71 mg, 58%).1H NMR (300 MHz, DMSO-d6): δ 11.41 (s, 1H), 10.04 (s, 1H), 8.03 (s, 1H), 7.95 (t, J=8.7 Hz, 2H), 7.79 (d, J=7.7 Hz, 1H), 7.73 (d, J=1.8 Hz, 1H), 7.69(dd, J=8.8, 1.6 Hz. 1H), 7.42 (dd, J=8.8.2.2 Hz, 1H), 7.37 (d, 7=2.6 Hz, 1H), 7.25 (d, 7=2.6 Hz, 1H), 5.65 (dd, J=8.1, 1.6 Hz, 1H), 3.22 (s, 3H), 3.08 (s, 3H), 1.84 (m, 2H), 1.38 (s, 6H), 0.73 (t, J=7.5 Hz, 3H).

[001087] Example 81. Obtaining N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1H-inden-3-yl)methyl)-N-methylmethanesulfonamide (compound IB-L0-2.16).

[001088] Part A. Obtaining N-methyl-N-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-inden-3-yl)methyl)methanesulfonamide.

[001089] To a solution of the product from Example 49, Part E (210 mg, of 0.60 mmol) in anhydrous THF (5 ml) was added a 1.0 M solution of lithium bis(trimethylsilyl)amide in toluene (0,60 ml of 0.60 mmol) and the resulting mixture was stirred at room temperature for 5 minutes was Added logmean (0.075 ml, 1.20 mmol), the mixture was stirred at room temperature for 2 h, and distributed between ethyl acetate and water. The organic layer was washed with saline, dried with sodium sulfate, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel, elwira gradient of ethyl acetate/hexane (10% - 25%) to give the titled compound as a solid (125 mg, 57%).

[001090] part of the Century, Obtaining N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1H-inden-3-yl)methyl)-N-methylmethanesulfonamide.

[001091] a Mixture of the product from Example C (60,0 mg, 0.15 mmol), the product of Part a (to 54.5 mg, 0.15 mmol), potassium phosphate (66,9 mg, 0,315 mmol), PA-Ph (CAS 97739-46-3, 1,32 mg, 4.5 μmol) and Tris(dibenzylideneacetone)diplegia(0) (1,37 mg, 1.5 mmol) in tetrahydrofuran (3.0 ml) and water (1.0 ml) was purged with N2within 30 minutes the Mixture was stirred at 50°C for 2 h, and then was distributed between 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 concentrated in vacuum. The crude product was purified column chromatography with reversed-phase silica gel C-18, using a gradient solvent 10-100% acetonitrile in water with 0.1% TFA) to obtain the titled compound in the form of solid substances is a (19 mg, 24%).1H NMR (300 MHz, DMSO-d6) δ 11.40 (d, J=1.84 Hz, 1 H) 7.78 (d, J=7.72 Hz, 1 H) 7.65 (m, 2 H) 7.49 (dd, J=7.72, 1.47 Hz, 1 H) 7.26 (m, 2.57 Hz, 2 H) 6.63 (s, 1 H) 5.64 (dd, J=7.72, 2.21 Hz, 1 H) 4.26 (s, 2 H) 3.51 (s, 2 H) 3.26 (s, 3 H) 3.01 (s, 3 H) 2.72 (s, 3 H) 1.41 (s, 9 H).

[001092] Example 82. Obtaining N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)benzo[d]thiophene-2-yl)methyl)methanesulfonamide (compound IB-L0-2.40).

[001093] Part A. to Obtain ethyl 6-bromobenzo[d]thiophene-2-carboxylate.

[001094] To a solution of 4-bromo-2-forventelige (1,02 g of 4.83 mmol) in DMSO (4 ml), was added ethyl 2-mercaptoacetate (of 0.58 ml, 5,31 mmol), followed by addition of Et3N (1.35 ml, 9,65 mmol) and the mixture was heated at 80°C for 3 hours the resulting dark mixture was poured into water (50 ml) and was extracted with EtOAc (2×50 ml). The combined organic extracts were washed with 10% NaCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuum to obtain these compounds in the form of a light yellow waxy solid (1.29 g, 94%).

[001095] part of the Century, Obtaining (6 bromobenzo[b]thiophene-2-yl)methanol.

[001096] To a solution of the product from part a (0,82 g is 2.88 mmol) in Et2O (20 ml) at 0°C was added dropwise 1M solution of lithium aluminum hydride in Et2O (3,16 ml, and 3.16 mmol) and the resulting suspension was stirred between 5 and 10°C for 1 h the suspension was treated with 0.3 ml of N2/sub> Oh, 0.3 ml of 15% aq. NaOH, 0.7 ml H2O, stirred 30 min, filtered and concentrated in vacuo to obtain the above compound as a colourless solid (of 0.58 g, 83%).

[001097] Part C. Obtain 6-bromo-2-(methyl bromide)benzo[d]thiophene.

[001098] a Mixture of the product from Part b (85 mg, 0.35 mmol), N-bromosuccinimide (74 mg, 0,413 mmol) and triphenylphosphine (106 mg, 0,403 mmol) in CH2Cl2(2 ml) was stirred at room temperature for 2 hours the Reaction mixture was diluted with 50 ml of CH2Cl2, washed with water, 10% NaHCO3and 10% NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuum. The residue was purified by column chromatography on silica gel, elwira 9:1 hexane:EtOAc to obtain at the output of these compounds in a solid white color (96 mg, 89%).

[001099] Part D. Obtain N-(4-methoxybenzyl)methanesulfonamide.

[001100] To a solution of (4-methoxyphenyl)methanamine (1,317 g, 9,60 mmol) in CH2Cl2(10 ml) was added dropwise methanesulfonanilide (0,34 ml, 4,36 mmol). The mixture was stirred at room temperature for 2 hours the Reaction mixture was diluted with 50 ml of CH2Cl2off , washed with 1 N. H3PO4, 10% NaCl, dried over anhydrous MgSO4, filtered and concentrated in vacuum to obtain these compounds in a solid white color (0.84 g, 89%).

[001101] Frequent The E. Obtaining N-((6-bromobenzo[b]thiophene-2-yl)methyl)-N-(4-methoxybenzyl)-methanesulfonamide.

[001102] a solution of the product from Part D (0,223 g 1,037 mmol) in EtOH (2 ml) and 1.0 M NaOH (1.1 ml, 1.1 mmol) was added to the suspension containing the product from Part C (MX 0.317 g, 1,037 mmol) in EtOH (4 ml). The resulting suspension was heated under reflux for 1 h, and then concentrated in vacuum to obtain a pasty solid. The residue was distributed between 40 ml of water and 40 ml of EtOAc. The organic layer was washed 1 N. H3PO4, 10% NaHCO3, 10% NaCl, dried over anhydrous Na2SO4, filtered and concentrated in vacuum to obtain a yellow oil. The crude product was purified by column chromatography on silica gel, elwira CH2Cl2obtaining these compounds are in the form of a colorless solid (0.15 g, 33%).

[001103] Part F. Obtain N-(4-methoxybenzyl)-N-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[b]thiophene-2-yl)methyl)methanesulfonamide.

[001104] the Product from Part E (0.15 g, 0.34 mmol) was subjected to the conditions described for an Example 42, Part In obtaining these compounds as colourless solids (0,121 g, 73%).

[001105] Part G. Obtaining N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)- 2-methoxyphenyl)benzo[b]thiophene-2-yl)methyl)-N-(4-methoxybenzyl)methanesulfonamide.

[001106] the Product is from Part F (24 mg, 0,049 mmol) was subjected to the conditions described for an Example 42, Part C with obtaining these compounds as a colourless solid (20 mg, 65%).

[001107] Part N. Obtaining N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)benzo[b]thiophene-2-yl)methyl)methanesulfonamide.

[001108] a solution of the product from Part G (14 mg, of 0.022 mmol) in CH2Cl2(0.3 ml) and TFA (0.3 ml) was stirred at room temperature for 4 h and then concentrated in vacuum. The residue was distributed between 10 ml of CH2Cl2and 2 ml of 10% aq. NaHCO3and the organic layer was concentrated in vacuum. The crude product was purified by column chromatography on silica gel, elwira a mixture of 99:1 CH2Cl2:MeOH with obtaining these compounds as a colourless solid (5 mg, 44%).1H NMR (300 MHz, DMSO-d6) δ 11.40 (s, 1 H) 8.09 (s, 1 H) 7.82-7.97 (m, 3 H) 7.79 (d, J=7.72 Hz, 1 H) 7.47-7.63 (m, 1 H) 7.40 (s, 1 H) 7.26-7.34 (m, 1 H), 5.64 (d, J=7.72 Hz, 1 H), 4.48 (d, J=5.88 Hz, 2 H) 3.23 (s, 3 H) 2.95 (s, 3 H) 1.41 (s, 9 H).

[001109] Example 83. Obtaining N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)benzo[d]thiophene-3-yl)methyl)-N-methylmethanesulfonamide (compound IB-L0-2.21).

[001110] Part A. Obtain N-((6-bromobenzo[b]thiophene-3-yl)methyl)-N-methylmethanesulfonamide.

[001111] a Mixture of the product from Example 46, Part D (0,100 g, 0,382 mmol), N-methylmethane-sulfonamida (5.9 mg, 0,421 mmol) and potassium carbonate (to 0.127 g, 0,918 mmol) in N,N-dimethylacetamide (5 ml) was stirred at 80°C for 11 h, cooled to room temperature and distributed between diethyl ether and water (3x), dried over MgSO4, filtered and concentrated in vacuo to obtain the above compound as a colourless waxy solid (0,128 g, Quant.). was stirred at 80°C for 11 h, cooled to room temperature and distributed between diethyl ether and water (3x), dried over MgSO4, filtered and concentrated in vacuo to obtain the above compound as a colourless waxy solid (0,128 g, Quant.).

[001112] part of the Century, Obtaining N-methyl-N-((6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]thiophene-3-yl)methyl)methanesulfonamide.

[001113] the Product from part a (0,128 g, 0,382 mmol) was subjected to the conditions described for an Example 42, Part In obtaining these compounds are in the form of a colorless crystalline solid (0,120 g, 82%).

[001114] Part C. Obtain N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)benzo[b]thiophene-3-yl)methyl)-N-methylmethanesulfonamide.

[001115] the Product from Part b (50,6 mg, 0.133 mmol) was subjected to the conditions described for an Example 49, Part F of obtaining these compounds as colourless solids (61,5 mg, 8%). 1H NMR (300 MHz, DMSO-d6) δ 11.41 (s, 1 H) 8.17 (d, J=1.47 Hz, 1 H) 8.09 (d, J=8.09 Hz, 1 H), 7.74-7.85 (m, 2 H) 7.63 (dd, J=8.46, 1.47 Hz, 1 H) 7.29-7.36 (m, 2 H), 5.65 (d, J=7.72 Hz, 1 H) 4.52 (s, 2 H) 3.24 (s, 3 H) 3.03 (s, 3 H) 2.70 (s, 3 H) 1.42 (s, 9 H).

[001116] using the above descriptions were obtained the following compounds:

[001117] N-(2-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)-1H-benzo[d]imidazol-5-yl)-N-(methylsulphonyl)methanesulfonamide (compound IA-L0-2.10)1H NMR (300 MHz, DMSO-D6) δ ppm 1.45 (s, 9 H), 2.73 (t, J=6.62 Hz, 2 H) 3.48 (s, 3 H) 3.56 (s, 6 H), 3.83 (t, J=6.80 Hz, 2 H) 4.05 (s, 1 H) 7.38 (dd, J=8.46, 1.84 Hz, 1 H) 7.46 (d, J=2.57 Hz, 1 H) 7.71 (d, J=8.46 Hz, 1 H) 7.76 (d, J=2.57 Hz, 1 H) 7.82 (d, J=1.84 Hz, 1 H), 10.41 (s, 1 H)

[001118] N-((6-(3-tert-butyl-2-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)benzo[b]thiophene-3-yl)methyl)methanesulfonamide (compound IB-L0-2.35).1H NMR (300 MHz, DMSO-d6) δ ppm 1.52 (s, 9 H), 2.95 (s, 3 H) 4.44 (d, J=5.88 Hz, 2 H), 5.68 (d, J=8.09 Hz, 1 H) 7.40 (d, J=2.57 Hz, 1 H) 7.46 (dd, J=8.09, 1.47 Hz, 1 H) 7.56 (d, J=2.57 Hz, 1 H), 7.62 (t, J=6.07 Hz, 1 H) 7.72 (s, 1 H) 7.83 (d, J=8.09 Hz, 1 H) 8.01 (m, 2 H) 11.46 (s, 1 H).

[001119] 1-(3-tert-butyl-5-(2-chlorobenzo[d]thiazol-6-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione (compound IB-L0-2.38).1H NMR (300 MHz, DMSO-D6) δ ppm 1.41 (s, 9 H), 3.24 (s, 3 H), 5.65 (dd, J=8.09, 2.21 Hz, 1 H) 7.34 (s, 2 H) 7.73 (dd, J=8.64, 1.65 Hz, 1 H) 7.79 (d, J=8.09 Hz, 1 H) 8.07 (d, J=8.46 Hz, 1 H) 8.30 (d, J=1.84 Hz, 1 H) 11.42 (d, J=1.84 Hz, 1 H)

[001120] N-(2-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)quinoline-6-yl)methanesulfonamide (compound IB-L0-2.48).

[001121] 1-(3-tert-butyl-4-methoxy-5-(1-oxo-2,3-dihydro-1H-inden-5-is)phenyl)pyrimidine-2,4(1H,3H)-dione (compound IB-L0-2.50).

[001122] N,N'-(6,6'-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-1,3-phenylene)bis(naphthalen-6,2-diyl))dimethanesulfonate (compound IB-L0-2.76).1H NMR (300 MHz, DMSO-d6) δ ppm 3.08 (s, 6 H) 3.13 (s, 3 H), 5.72 (d, J=8.18 Hz, 1 H) 7.43 (dd, J=8.46, 1.84 Hz, 2 H) 7.59 (s, 2 H) 7.79 (m, 4 H), 7.96 (m, 5 H) 8.14 (s, 2 H), 10.05 (s, 2 H) 11.48 (s, 1 H).

[001123]

[001124] Study of inhibiting HCV polymerase

[001125] Or twofold serial dilutions (the study of partial inhibition), or a more narrow range of dilutions, 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 dithiothreitol, 1 mm ethylenediaminetetraacetic acid (EDTA), 60-125 μm GTP and 20-50 nm Δ21 NS5B (HCV strain 1 (BK, 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 96 - well format. Filter PL is stinky 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 neighbourly 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 IC50less than 0,005 µm in the study of partial inhibition for a more accurate measurement values IC50. Withheld number of pulses per minute was applied 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 Et = the total active concentration of the enzyme.

[001126] 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.

[001127] Sequence used matrichnoi were: 5'-GGGCGAAUUG GGCCCUCUAG AUGCAUGCUC GAGCGGCCGC CAGUGUGAUG GAUAUCUGCA GAAUUCGCCC UUGGUGGCUC CAUCUUAGCC CUAGUCACGG CUAGCUGUGA AAGGUCCGUG AGCCGCUUGA CUGCAGAGAG UGCUGAUACU GGCCUCUCUG CAGAUCAAGUC-3'

[001128] 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: A - IC50≤0,01 μm; 0.1 ám≥IC50>0.01 µm; C - 1 µm≥IC50>0.1 ám; and (D - IC50>1 μm; ND - not determined.

Table IC50
Connection1A1bConnection1a1b

IA-L0-2.1
IA-L0-2.2InInIA-L0-2.3
IA-L0-2.4InInIA-L0-2.5
IA-L0-2.6 IA-L0-2.7
IA-L0-2.8InInIA-L0-2.9AndAnd
IA-L0-2.10DDIB-L0-2.1
IB-L0-2.2IB-L0-2.3AndAnd
IB-L0-2.4AndAndIB-L0-2.5InIn
IB-L0-2.6InInIB-L0-2.7InIn
IB-L0-2.8InInIB-L0-2.9AndAnd
IB-L0-2.10AndInIB-L0-2.11 AndAnd
IB-L0-2.12AndInIB-L0-2.13AndIn
IB-L0-2.14AndAndIB-L0-2.15AndIn
IB-L0-2.16AndInIB-L0-2.17AndIn
IB-L0-2.18AndInIB-L0-2.19AndIn
IB-L0-2.20AndInIB-L0-2.21InIn
IB-L0-2.22InInIB-L0-2.23InAnd
IB-L0-2.24InInIB-L0-2.25In In
IB-L0-2.26InInIB-L0-2.27InIn
IB-L0-2.28InInIB-L0-2.29InIn
IB-L0-2.30InInIB-L0-2.31InIn
IB-L0-2.32InInIB-L0-2.33InIn
IB-L0-2.34InInIB-L0-2.35InIn
IB-L0-2.36InIB-L0-2.37
IB-L0-2.38InIB-L0-2.39
IB-L0-2.40IB-L0-2.41
IB-L0-2.42IB-L0-2.43
IB-L0-2.44IB-L0-2.45
IB-L0-2.46IB-L0-2.47DD
IB-L0-2.48DDIB-L0-2.49DD
IB-L0-2.50InInIB-L0-2.51AndIn
IB-L0-2.52AndInIB-L0-2.53AndIn
IB-L0-2.54InIB-L0-2.55AndIn
IB-L0-2.56AndInIB-L0-2.57AndIn
IB-L0-2.58AndInIB-L0-2.59AndIn

Connection1a1bConnection1A1b
IB-L0-2.60AInIB-L0-2.61AndIn
IB-L0-2.62InInIB-L0-2.63InIn
IB-L0-2.64InInIB-L0-2.65InAnd
InInIB-L0-2.67InIn
IB-L0-2.68InInIB-L0-2.69InIn
IB-L0-2.70InIB-L0-2.71
IB-L0-2.72IB-L0-2.73
IB-L0-2.74IB-L0-2.75D
IB-L0-2.76DIB-L0-2.77DD
IB-L0-2.78DDIB-L0-2.79InIn

[001129] the Study of HCV replicon floor is meraz

[001130] 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 1b-Con1 (obtained from Apath, LLC, St. Louis, MO). All constructs replicon was bicistronic subgenomic the replicons, similar 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 genotype la contains the NS3-NS5B coding region, originating from N strain of HCV (1A-N) (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 restroom containing the NS3-NS5B coding region with additional adaptive mutations E G, K1691R, K2040R and S2204I. 1b-Con1 replicon construct is identical to 1A-N the replicon, except that the NS3-NS5B coding region was obtained from strain Ib-ConI, and the adaptive mutations are E G, T 12801 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 of art is atomizing (Invitrogen), and 200 mg/ml G418 (Invitrogen).

[001131] 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 dilutions. A series of dilutions 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 buffer for 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 Konz is Tracii connection and electrical conductivity (EC) 50calculated using nonlinear regression curve, approximated to 4-parametric logarithmic equation and the software GraphPad Prism 4.

[001132] 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 - EC50≤0,01 μm; 0.1 ám≥EU50>0.01 µm; C - 1 µm≥EU50>0.1 ám; and (D - EU50>1 μm; ND - not determined.

Table EC50
Connection1A1bConnection1a1b
IA-L0-2.1DD
IA-L0-2.2InIA-L0-2.3
IA-L0-2.4DIA-L0-2.5D D
IA-L0-2.6DDIA-L0-2.7D
IA-L0-2.8InIA-L0-2.9AAnd
IA-L0-2.10NDNDIB-L0-2.1D
IB-L0-2.2DDIB-L0-2.3AAnd
IB-L0-2.4NDAndIB-L0-2.5InAnd
IB-L0-2.6InIB-L0-2.7In
IB-L0-2.8NDInIB-L0-2.9AAnd
IB-L0-2.10AndAndIB-L0-2.11InAnd
IB-L0-2.12InAndIB-L0-2.13InAnd
IB-L0-2.14InIB-L0-2.15In
IB-L0-2.16AndIB-L0-2.17InAnd
IB-L0-2.18InIB-L0-2.19InIn
IB-L0-2.20InIB-L0-2.21In
IB-L0-2.22InIB-L0-2.23In
IB-L0-2.24 InInIB-L0-2.25In

Connection1a1bConnection1A1b
IB-L0-2.26DIB-L0-2.27In
IB-L0-2.28DIB-L0-2.29In
IB-L0-2.30InIB-L0-2.31In
IB-L0-2.32InIB-L0-2.33
IB-L0-2.34DIB-L0-2.35D
IB-L0-2.36InIB-L0-2.37D
IB-L0-2.38DDIB-L0-2.39D
IB-L0-2.40DIB-L0-2.41
IB-L0-2.42IB-L0-2.43D
IB-L0-2.44DDIB-L0-2.45D
IB-L0-2.46NDNDIB-L0-2.47NDND
IB-L0-2.48NDNDIB-L0-2.49NDND
IB-L0-2.50 IB-L0-2.51InAnd
IB-L0-2.52InAndIB-L0-2.53InIn
IB-L0-2.54InInIB-L0-2.55InAnd
IB-L0-2.56AndIB-L0-2.57In
IB-L0-2.58InAndIB-L0-2.59In
IB-L0-2.60InIB-L0-2.61In
IB-L0-2.62InIB-L0-2.63In
IB-L0-2.64 AndIB-L0-2.65In
IB-L0-2.66InIB-L0-2.67In
IB-L0-2.68DIB-L0-2.69In
IB-L0-2.70DIB-L0-2.71In
IB-L0-2.72DIB-L0-2.73
IB-L0-2.74DIB-L0-2.75DD
IB-L0-2.76NDNDIB-L0-2.77NDND
IB-L0-2.78NDND IB-L0-2.79

***********

[001133] All references (patent and non-patent), cited above, incorporated by reference into the present 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-L0:

selected from the group consisting of single carbon-carbon links and double carbon-carbon linkages;
R1represents hydrogen;
R2represents hydrogen;
R3represents hydrogen;
R4selected from the group consisting of halo, C1-C6of alkyl, C2-C6the quinil, amino, C1-C6alkylsulfonyl, C3-C10carbocycle and 5-6-membered heterocyclyl having a heteroatom selected from the group consisting of oxygen and sulfur, where:
(a) amino optionally substituted by one or two C1-C6Ala is sulfonium, and
(b) C1-C6alkyl and C2-C6quinil optionally substituted by one or more substituents independently selected from the group consisting of halo, oxo, hydroxy, C1-C6alkyloxy and trimethylsilyl, and
(c) C3-C10carbocyclic and 5-6-membered heterocyclyl optionally substituted by substituents with up to three independently selected from the group consisting of C1-C6of alkyl, halo, amino, where the amino optionally substituted by one or two C1-C6alkylsulfonyl;
R5selected from the group consisting of hydrogen, hydroxy, C1-C6alkyloxy and halo;
R6represents a condensed 2-ring C3-C10carbocyclic, 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 and amino, where the amino optionally substituted by one or two C1-C6alkilani;
each RFrepresents a C1-C6alkyl, optionally substituted by one or more amino, where:
amino optionally substituted by one or more substituents independently selected from the group consisting of C1-C6the alkyl and C1-C6alkyls Livonia;
each RGindependently selected from 5-membered heterocyclyl containing N atom as the heteroatom, optionally substituted by one or more C1-C6alkilani;
each RHrepresents a C1-C6alkyloxy;
each RIis aminocarbonyl, optionally substituted by one or two C1-C6alkylsulfonyl;
each RJindependently selected from the group consisting of C1-C6alkylsulfonyl, C1-C6allyloxycarbonyl, C1-C6alkylsulfonamides; and each RKrepresents a C1-C6alkylsulfonyl.

2. The compound or pharmaceutically acceptable salt p. 1, whereis a double carbon-carbon bond.

3. The compound or pharmaceutically acceptable salt p. 1, where R4represents a C1-C6alkyl.

4. The compound or pharmaceutically acceptable salt according to p. 3, where R4represents tert-butyl.

5. The compound or pharmaceutically acceptable salt p. 1, where R5represents a C1-C6alkyloxy.

6. The compound or pharmaceutically acceptable salt p. 5, where R5represents methoxy.

7. The compound or pharmaceutically acceptable salt p. 1, where R6represents the t naphthalenyl.

8. The compound or pharmaceutically acceptable salt p. 1, where R6is naphthalenyl, substituted RJ.

9. The compound or pharmaceutically acceptable salt p. 8, where each RJrepresents methylsulfonylamino.

10. The compound or pharmaceutically acceptable salt p. 1, where:
is a double carbon-carbon bond;
R4represents a C1-C6alkyl; and
R5represents a C1-C6alkyloxy.

11. The compound or pharmaceutically acceptable salt p. 1, where:
is a double carbon-carbon bond;
R4represents tert-butyl; and R5represents methoxy.

12. The compound or pharmaceutically acceptable salt p. 1, where:
is a double carbon-carbon bond;
R4represents tert-butyl;
R5represents methoxy; and
R6is naphthalenyl.

13. The compound or pharmaceutically acceptable salt p. 1, where:
is a double carbon-carbon bond;
R4represents tert-butyl;
R5represents methoxy; and
R6is naphthalenyl, substituted R and RJrepresents methylsulfonylamino.

14. The compound or pharmaceutically acceptable salt p. 1, where the compound is selected from the group consisting of:
N-(6-(3-tert-butyl-5-(2,4-dioxotetrahydrofuran-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide;
N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide;
(E)-N'-(5(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)2,3-dihydro-1H-inden-1-ilidene)methanesulfonamide;
1-(3-tert-butyl-4-methoxy-5-(naphthalene-2-yl)phenyl)pyrimidine-2,4(1H,3H)-dione;
1-(3-tert-butyl-4-methoxy-5-(6-methoxynaphthalene-2-yl)phenyl)pyrimidine-2,4(1H,3H)-dione;
N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-phenyl)naphthalene-2-yl)methanesulfonamide;
(E)-N'-(5(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)-2,3-dihydro-1H-inden-1-ilidene) methanesulfonamide;
N-(6-(3-bromo-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide;
N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(5-methylfuran-2-yl)phenyl)naphthalene-2-yl)methanesulfonamide;
N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophene-3-yl)phenyl)naphthalene-2-yl)methanesulfonamide;
N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophene-2-yl)phenyl)naphthalene-2-yl)methanesulfonamide;
N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2N-yl)-3-(furan-2-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide;
N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-3-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide;
N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-biphenyl-3-yl)naphthalene-2-yl) methanesulfonamide;
N-(6-(3'-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxybiphenyl-3-yl)naphthalene-2-yl)methanesulfonamide;
N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(5-methylthiophene-2-yl)phenyl)naphthalene-2-yl)methanesulfonamide;
N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(1-hydroxy-2-methylpropan-2-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide;
N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(1-methoxy-2-methylpropan-2-yl)phenyl)naphthalene-2-yl)methanesulfonamide;
methyl-2-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(6-(methylsulfonylamino)naphthalene-2-yl)phenyl)-2-methylpropanoate;
2-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(6-(methylsulfonylamino)naphthalene-2-yl)phenyl)-2-methylpropanoate acid;
methyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(6-(methylsulfonylamino)naphthalene-2-yl)benzoate;
N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-iodine-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide;
N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-((trimethylsilyl)ethinyl)phenyl)naphthalene-2-yl)methanesulfonamide;
N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(methylsulphonyl) phenyl)naphthalene-2-yl)methanesulfonyl is d;
N-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(6-(methylsulfonylamino)naphthalene-2-yl)phenyl)methanesulfonamide;
N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(trifluoromethyl)phenyl)naphthalene-2-yl)methanesulfonamide;
N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(perforated)phenyl)naphthalene-2-yl)methanesulfonamide;
(E)-N'-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)phenyl)-2-methoxy-3-(thiophene-2-yl)phenyl)-2,3-dihydro-1H-inden-1-ilidene)methanesulfonamide;
(E)-N'-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-2-yl)-2-methoxyphenyl)-2,3-digdia-1H-inden-1-ilidene)methanesulfonamide;
N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-ethoxyphenyl)naphthalene-2-yl)methanesulfonamide;
N-(6-(3-tert-butyl-2-chloro-5-(2,4-dioxo-3,4-dihydropyrimidin-l(2H)-yl)phenyl)naphthalene-2-yl)methanesulfonamide;
methyl-2-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-ilidene)hydrazinecarboxamide;
N-(2-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1H-inden-3-yl)propan-2-yl) methanesulfonamide;
N'-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide;
1-(3-tert-butyl-5-(1-hydroxy-2,3-dihydro-1H-inden-5-yl)-4-methoxyphenyl)pyrimidine-2,4(1H,3H)-dione;
N-((5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-meth is l-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide;
N-((5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-fluoro-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide;
N-((6(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-2-yl)-2-methoxyphenyl)-1H-inden-3-yl)methyl)methanesulfonamide;
N-((6(5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-2-methoxy-3-(thiophene-2-yl)phenyl)-1H-inden-3-yl)methyl)methanesulfonamide;
N-((6(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-(thiophene-3-yl)phenyl)-1H-inden-3-yl)methyl)methanesulfonamide;
N-((6(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-3-(furan-3-yl)-2-methoxyphenyl)-1H-inden-3-yl)methyl)methanesulfonamide;
N-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)methanesulfonamide;
N-((5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide;
(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-N-(methylsulphonyl)-2,3-dihydro-1H-inden-1-carboxamide;
N-(2-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)propan-2-yl)methanesulfonamide;
(S)-N-(2-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)propan-2-yl)methanesulfonamide;
(R)-N-(2-(5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)propan-2-yl)methanesulfonamide;
(S)-N-((5-(3-tert-BU the Il-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide;
(R)-N-((5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide;
(S)-N-((5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-fluoro-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide;
(R)-N-((5-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1-fluoro-2,3-dihydro-1H-inden-1-yl)methyl)methanesulfonamide;
N-(6-(5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-3-tert-pentylphenol)naphthalene-2-yl)methanesulfonamide;
N-((6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)-1H-inden-3-yl)methyl)-N-methylmethanesulfonamide;
1-(3-tert-butyl-4-methoxy-5-(1-oxo-2,3-dihydro-1H-inden-5-yl)phenyl) pyrimidine-2,4(1H,3H)-dione; and
N,N'-(6,6'-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-1,3-phenylene)bis(naphthalene-6,2-diyl) dimethanesulfonate.

15. The compound or pharmaceutically acceptable salt p. 1, where the compound is a N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide.

16. Pharmaceutically acceptable salt p. 1, which is N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide sodium salt.

17. Pharmaceutically acceptable salt p. 1, which is N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-meth is xifei)naphthalene-2-yl)methanesulfonamide monosodium salt.

18. N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide.

19. N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide monosodium salt.

20. Pharmaceutical composition having inhibitory activity against polymerase of hepatitis C virus (HCV), containing a therapeutically effective amount of one or more compounds and/or their pharmaceutically acceptable salts under item 1 and one or more excipients.

21. Pharmaceutical composition having inhibitory activity against polymerase of hepatitis C virus (HCV), containing a therapeutically effective amount of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide and one or more excipients.

22. Pharmaceutical composition having inhibitory activity against polymerase of hepatitis C virus (HCV), containing a therapeutically effective amount of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide monosodium salt and one or more excipients.

23. The application of one or more compounds and/or their salts under item 1 for the production of pharmaceuticals for inhibition of RNA polymerase of HCV.

24. The use of N-(6-(3-tert-butyl--(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide for the production of pharmaceuticals for inhibition of RNA polymerase of HCV.

25. The application of one or more compounds and/or their salts under item 1 for the manufacture of a medicinal product for the treatment of hepatitis C in a mammal in need of such treatment.

26. The use of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide for the manufacture of a medicinal product for the treatment of hepatitis C in a mammal in need of such treatment.

27. The use according to any one of paragraphs.25-26, where the mammal is a human.

28. The compound or its pharmaceutically acceptable salt, where the compound corresponds in structure to formula II:

selected from the group consisting of single carbon-carbon links and double carbon-carbon linkages;
R1represents hydrogen
R2represents hydrogen;
R3represents hydrogen;
R4selected from the group consisting of C1-C6of alkyl, C2-C6the quinil, amino, C1-C6alkylsulfonyl, C3-C10carbocycle and 5-6-membered heterocyclyl having a heteroatom selected from the group consisting of oxygen and sulfur, where:
(a) amino optionally substituted by one or two C1-C6alkylsulfonyl, and
(b) C1-C6alkyl and C2-C6quinil neoba is consequently substituted by one or more substituents, independently selected from the group consisting of halo, oxo, hydroxy, C1-C6alkyloxy, and
(c) C3-C10carbocyclic and 5-6-membered heterocyclyl optionally substituted by substituents with up to three independently selected from the group consisting of C1-C6of alkyl, halo, amino, where the amino optionally substituted by one or two C1-C6alkylsulfonyl;
R5selected from the group consisting of hydrogen, hydroxy, C1-C6alkyloxy and halo; and X2is a halo.

29. The compound or pharmaceutically acceptable salt p. 28, whereis a double carbon-carbon bond.

30. The compound or pharmaceutically acceptable salt p. 28, where R4represents a C1-C6alkyl.

31. The compound or pharmaceutically acceptable salt p. 28, where R5represents a C1-C6alkyloxy.

32. The compound or pharmaceutically acceptable salt p. 28, where R4represents tert-butyl.

33. The compound or pharmaceutically acceptable salt p. 28, where R5represents methoxy.

34. The compound or pharmaceutically acceptable salt p. 28, where X2represents I.

35. The compound or pharmaceutically acceptable salt p. 28 where:
the submitted is a double carbon-carbon bond;
R4represents a C1-C6alkyl;
R5represents a C1-C6alkyloxy;
and X2represents I.

36. The compound or pharmaceutically acceptable salt p. 28 where:
is a double carbon-carbon bond;
R4represents tert-butyl;
R5represents methoxy; and
X2represents I.

37. The compound or pharmaceutically acceptable salt p. 28, where the compound corresponds in structure to a formula selected from the group consisting of:
and

38. The use of compounds on p. 28 for connection under item 1.

39. Application on p. 38, where a connection on p. 1 represents N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide.

40. The use according to any one of paragraphs.38-39, where a connection on p. 28 has a structure corresponding to formula (II-I):

41. The use of compounds on p. 28 for connection on p. 1 for the treatment of hepatitis C in a mammal in need of such treatment.

42. The application of p. 41, where the mammal is a human.

43. The method of obtaining the compound or its pharmaceutically acceptable salt under item 1, kiuchumi in yourself
the interaction of the compounds of formula III with the compound of the formula IV in the presence of (i) based catalyst salt of copper (I) and (ii) nitrogen-containing heteroaryl ligand

catalyst - catalyst; nitrogenous heteroaryl ligand is a nitrogen - containing heteroaryl ligand, where R1, R2, R3, R4, R5and X2such, as defined in paragraph 28, and X1represents halo; and the substitution of X2for R6in the formula (II) obtaining the compounds of formula I-L0.

44. The method according to p. 43, where X1selected from the group consisting of chlorine, bromine and iodine.

45. The method according to any of paragraphs.43 and 44, which is carried out in the presence of a base.

46. The method according to p. 45, in which the base is selected from the group consisting of salts of potassium, sodium and cesium salt.

47. The method according to p. 43, in which nitrogen-containing heteroaryl ligand contains picolinamides compound corresponding in structure to formula V:
and
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.

48. The method according to p. 47, 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-what anafanil)picolinamides.

49. The method according to p. 43, where the copper catalyst selected from the group consisting of CuI, CuBr, CuCl, Cu2O and CH3C(O)OCu.

50. Crystalline sample In the monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray containing peaks 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 21,6±0,2, 22,1±0,2 and 23.7±0.2 degrees 2θ.

51. Crystalline form of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide selected from the group consisting of:
crystalline ethanol MES N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 8,3±0,2, 9,7±0,2, 10,0±0,2, 10,6±0,2, 13,6±0,2, 17,2±0,2, 17,5±0,2, 19,2±0,2, 19,4±0,2, 22,7±0,2, 26,9±0,2 and 29.4±0.2 degrees 2θ;
crystalline ethanol MES N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray are essentially presented on Figure 1;
crystal combined acetonitrile MES N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray containing one or more peaks is selected from the group consisting of 5,3±0,2, 8,3±0,2, 9,7±0,2, 10,5±0,2, 13,8±0,2, 17,2±0,2, 17,7±0,2, 19,1±0,2, 19,5±0,2, 22,0±0,2, 22,8±0,2 and 27.2±0.2 degrees 2θ;
crystal combined acetonitrile MES N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray are essentially presented on Figure 3;
crystal of an ethyl acetate MES N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 7,9±0,2, 9,3±0,2, 9,7±0,2, 10,6±0,2, 13,7±0,2, 17,4±0,2, 18,7±0,2, 21,7±0,2, 22,0±0,2, 28,2±0,2, 38,5±0,2 and 44.7±0.2 degrees 2θ.
crystal of an ethyl acetate MES N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray are essentially presented on Figure 4;
crystalline 2-propanole of MES N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 8,2±0,2, 9,3±0,2, 10,1±0,2, 16,3±0,2, 18,1±0,2, 18,6±0,2, 19,4±0,2, 21,6±0,2, 22,5±0,2, 23,8±0,2, 26,0±0,2 and 28.0±0.2 degrees 2θ;
crystalline 2-propanole of MES N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-is)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide, having a powder x-ray are essentially presented in Figure 5;
crystalline methanol MES N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 8,4±0,2, 9,7±0,2, 10,1±0,2, 13,5±0,2, 13,8±0,2, 17,4±0,2, 19,3±0,2, 19,6±0,2 and 27.1±0.2 degrees 2θ;
crystalline methanol MES N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray are essentially presented in Figure 6;
crystalline 1-propanole of MES N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 8,2±0,2, 9,3±0,2, 10,1±0,2, 10,5±0,2, 15,7±0,2, 16,2±0,2, 18,4±0,2, 18,6±0,2, 19,3±0,2, 21,0±0,2, 21,6±0,2 and 22.8±0.2 degrees 2θ;
crystalline 1-propanole of MES N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray are essentially presented in Figure 7,
solvent free crystalline N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanol is Onamia, having a powder x-ray containing one or more peaks selected from the group consisting of 6,2±0,2, 7,9±0,2, 9,9±0,2, 10,1±0,2, 14,9±0,2, 16,2±0,2, 18,3±0,2, 19,8±0,2 and 26.5±0.2 degrees 2θ;
solvent free crystalline N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray are essentially presented on Figure 8;
hydrate crystalline N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 6,4±0,2, 12,9±0,2, 17,5±0,2, 17,9±0,2, 18,9±0,2 and 24.4±0.2 degrees 2θ;
crystal, hydrate, N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 6,4±0,2, 12,7±0,2, 12,9±0,2, 14,1±0,2, 15,7±0,2, 17,2±0,2, 17,5±0,2, 17,9±0,2, 18,9±0,2, 21,2±0,2, 24,4±0,2 and 25.0±0.2 degrees 2θ;
crystal, hydrate, N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray are essentially presented on Figure 9;
the crystalline sample And the monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-meth is XI-phenyl)naphthalene-2-yl)methanesulfonamide, having a powder x-ray containing one or more peaks selected from the group consisting of 4,6±0,2, 10,4±0,2, 12,0±0,2, 15,6±0,2, 16,0±0,2, 18,6±0,2, 22,8±0,2, 23,3±0,2, 23,9±0,2 and 28.3±0.2 degrees 2θ;
the crystalline sample And the monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray are essentially presented on Figure 10;
crystalline sample In the monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 19,2±0,2, 19,6±0,2, 21,6±0,2, 22,1±0,2, 23,7±0,2, 28,8±0,2, 29,1±0,2 and 31.8±0.2 degrees 2θ;
crystalline sample With monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 5,0±0,2, 12,0±0,2, 17,5±0,2, 17,8±0,2, 18,8±0,2 and an increase of 22.7±0.2 degrees 2θ;
crystalline sample With monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray are, essentially, as shown in Figure 14;
crystal Dean is ravoi salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide, having a powder x-ray containing one or more peaks selected from the group consisting of 4,8±0,2, 9,6±0,2, 10,5±0,2, 13,0±0,2, 14,6±0,2, 15,4±0,2, 16,8±0,2, 22,7±0,2, 23,0±0,2 and 23.3±0.2 degrees 2θ;
the crystalline disodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray are, essentially, as shown in Figure 15;
the crystalline montalieu salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 5,0±0,2, 9,9±0,2, 11,3±0,2, 13,3±0,2, 16,9±0,2, 18,1±0,2, 19,1±0,2, 20,0±0,2, 21,1±0,2, 21,5±0,2, 23,5±0,2, 24,8±0,2 and 25.7±0.2 degrees 2θ;
the crystalline montalieu salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray are essentially presented in Figure 17;
the crystalline sample And monjolinho salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 10,9±0,2, 12,1±0,2, 13,0±0,2, 13,4±0,2, 13,6±0,2, 15,5±0,2, 17,0±0,2, 17,8±0,2, 18,3±0,2, 19,5±0,2, 19,7±0,2 and 21.9±0.2 degrees 2θ;
the crystalline sample And monoko inovas salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy - phenyl)naphthalene-2-yl)methanesulfonamide, having a powder x-ray are essentially presented in Figure 19;
crystalline sample In monjolinho salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl) naphthalene-2-yl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 8,0±0,2, 9,4±0,2, 11,0±0,2, 13,0±0,2, 13,3±0,2, 13,7±0,2, 15,9±0,2, 17,0±0,2, 17,4±0,2, 18,3±0,2, 18,9±0,2, 19,8±0,2, 21,8±0,2 and 22.1±0.2 degrees 2θ;
crystalline sample In monjolinho salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray are essentially presented in Figure 21;
crystal cihalikova salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxyphenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray containing one or more peaks selected from the group consisting of 8,6±0,2, 11,0±0,2, 12,9±0,2, 17,0±0,2, 17,5±0,2, 18,9±0,2, 19,8±0,2, 21,9±0,2 and 22.1±0.2 degrees 2θ;
and crystal cihalikova salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide having a powder x-ray are essentially presented in Figure 23.

52. Crystalline form on p. 51, where the crystal sample In the monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimido is n-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide has a powder x-ray, containing peaks 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 21,6±0,2, 22,1±0,2 and 23.7±0.2 degrees 2θ.

53. Pharmaceutical composition having inhibitory activity against polymerase of hepatitis C virus (HCV), containing a therapeutically effective amount of one or more crystalline forms described in any of paragraphs.50-52, and one or more excipients.

54. The pharmaceutical composition according to p. 53, containing a crystalline form selected from the group consisting of:
the crystalline sample And the monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide;
crystalline sample In the monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide; and the crystalline sample With monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide.

55. The pharmaceutical composition according to p. 54, containing crystalline sample In the monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide.

56. Pharmaceutical composition having inhibitory activity against polymerase of hepatitis C virus (HCV), containing a therapeutically effective amount of the crystal of which were acquired In the monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide.

57. The use of one or more crystalline forms described in any of paragraphs.50-52, for inhibition of RNA polymerase of HCV.

58. The use of one or more crystalline forms described in any of paragraphs.50-52, for the treatment of hepatitis C in a mammal in need of such treatment.

59. The application of p. 58, where the mammal is a human.

60. The use of the crystal sample In the monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide for the treatment of hepatitis C in a mammal in need of such treatment.

61. A method of obtaining a crystalline form of the monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide, which includes the interaction of sodium base and N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide with the formation of the mixture, and the crystal form selected from the group consisting of a crystalline sample And the monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide, crystalline sample In the monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide the crystalline sample With monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide.

62. The method according to p. 61, in which the crystalline form is a crystalline sample In the monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide.

63. The method according to p. 62, in which the crystalline sample In the monosodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide has a powder x-ray containing peaks 5,4±0,2, 10,8±0,2, 14,4±0,2, 16,3±0,2, 17,0±0,2, 18,8±0,2, 19,2±0,2, 19,6±0,2, 21,6±0,2, 22,1±0,2, 23,7±0,2, 28,8±0,2, 29,1±0,2 and 31.8±0.2 degrees 2θ.

64. The method according to p. 61, in which the sodium base is a hydroxide of sodium.

65. The method according to p. 61, further comprising the bringing into contact of the solvent and N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide.

66. The method according to p. 65, in which the solvent is selected from the group consisting of acetonitrile, dimethyl sulfoxide, ethanol, 1-propanol, 2-propanol, water, and combinations thereof.

67. The method according to any of paragraphs.65-66, in which the sodium base is dissolved in a solvent.

68. The method according to p. 61, further including placing a seed in the mixture in the form of the seed crystalline form of the sodium salt of N-(6-(3-tert-butyl-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-2-methoxy-phenyl)naphthalene-2-yl)methanesulfonamide.

69. the manual by p. 68, in which the seed crystal form is a disodium salt.

70. The method according to any of paragraphs.68-69, in which the seed crystalline form is a crystalline sample of the mono-sodium salt.



 

Same patents:

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to phenol derivatives of formula (1), wherein R1 represents C1-C6 alkyl group, C1-C6 alkynyl group, C1-C6 halogen alkyl group, C1-C6 alkyl sulphanyl group or a halogen atom, R2 represents a cyano group or a halogen atom, R3 represents a hydrogen atom, and X represents -S(=O)2. Besides, the invention refers to a drug preparation containing a compound of formula (I) as an active ingredient.

EFFECT: phenol derivatives of formula (1) characterised by the high urine concentration of the permanent compound, and possess the uricosuric action.

11 cl, 1 dwg, 2 tbl, 42 ex

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: chemistry.

SUBSTANCE: invention relates to organic chemistry and a method of producing 3,3'-[bis-(1,4-phenylene)]bis-1,3,5-dithiazinanes of formula (1): wherein diphenylenediamine (diaminodiphenylmethane, diaminodiphenyl oxide) reacts with N-tert-butyl-1,3,5-dithiazinane in the presence of a Sm(NO3)3·6H2O catalyst in an argon atmosphere in molar ratio diphenylenediamine: N-tert-butyl-1,3,5-dithiazinane:Sm(NO3)3·6H2O=1:2:(0.03-0.07) at about 20°C in an ethanol-chloroform solvent system (1:1, by volume) for 2.5-3.5 hours.

EFFECT: method of obtaining novel compounds which can be used as antimicrobial and antifungual agents, selective sorbents and extractants of precious metals, special reagents for inhibiting bacterial activity in different process media.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and specifically to a method for selective production of 3,3'-[bis-(1,4-phenylene)]bis-1,5,3-dithiazepinanes of formula (1) where R = 4-C6H4-CH2-C6H4-4', 4-C6H4-O-C6H4-4', 4-H3COC6H3-C6H3OCH3-4', where diphenylenediamines (diaminodiphenylmethane, diaminodiphenyl oxide, dimethoxybenzidine) react with 1-oxa-3,6-dithiacycloheptane in the presence of a Sm(NO3)3·6H2O catalyst in an argon atmosphere in molar ratio diphenylenediamine:1-oxa-3,6-dithiacycloheptane:Sm(NO3)3·6H2O=1:2:(0.03-0.07) at about 20°C in an ethanol-chloroform solvent system for 2.5-3.5 hours.

EFFECT: novel method of producing 3,3'-[bis-(1,4-phenylene)]bis-1,5,3-dithiazepinanes, which can be used as antimicrobial, antifungal and anti-inflammatory agents, sorbents and extractants of precious metals and selective complexing agents.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to benzothiazine derivatives represented by general formula (I): 0, where R1 is a hydrogen atom; C1-C6 alkyl; COR5; SO2R5; CO(CH2)mOR6; (CH2)mR6; (CH2)mCONR7R8; (CH2)nNR7R8; (CH2)nOR6; CHR7OR9; (CH2)mR10; m assumes values from 1 to 6; n assumes values from 2 to 6; R2 is phenyl; naphthyl, 1,2,3,4-tetrahydro-naphthalene, biphenyl, phenylpyridine or a benzene ring condensed with a saturated or unsaturated monocyclic heterocycle containing 5-7 atoms and consisting of carbon atoms and 1-4 heteroatoms selected from N, O or S, other than indole, R3 is methyl or ethyl; R4 and R′4 are identical or different and denote a hydrogen atom; a halogen atom; C1-C6 alkyl; NR7R8; SO2Me; as well as stereoisomers, salts and solvates thereof, for therapeutic use and which are capable of inhibiting 11β-HSD1 on an enzymatic and cellular level.

EFFECT: obtaining benzothiazine derivatives.

17 cl, 197 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry, namely to method of obtaining 3,3'-[methylenebis(1,4-phenylene)]-, 3,3'-[oxybis(1,4-phenylene)]- and 3,3'-(3,3'-dimethoxybiphenyl-4, 4'-diyl)-bis-1,5,3-dithiazepinanes of general formula (1): R=4-C6H4-CH2-C6H4-4/, 4-C6H4-O-C6H4-4/, 4-H3COC6H3-C6H3OCH3-4/ which consists in the following: arylamines [diaminodiphenylmethane, diaminodiphenyloxide, dimethoxybenzidine] undergo interaction with N-tert-butyl-1,5,3-dithiazepinane in presence of catalyst Sm(NO3)3·6H2O in argon atmosphere with molar ratio arylamine:N-tert-butyl-1,5,3-dithiazeoinane: Sm(NO3)3·6H2O = 10 : 20 : (0.3-0.7) at temperature ~20°C in system of solvents ethanol-chloroform for 2.5-3.5 h.

EFFECT: increased efficiency of applying compound as antibacterial, antifungal and antiviral agents, biologically active complexants, selective sorbents and extractants of precious metals, special reagents for suppressing bacterial vital activity in different technical media.

1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of general formula I , where R1 is a hydrogen atom, a lower alkyl, CD3, -(CH2)n-CHO, -(CH2)n-O-lower alkyl, -(CH2)n-OH, -(CH2)n-cycloalkyl or is a heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O); R2 is a hydrogen atom, a halogen atom, hydroxy, lower alkyl, di-lower alkyl, -OCH2-O-lower alkyl or lower alkoxy; or the piperidine ring along with R2 forms a spiro-ring selected from 4-aza-spiro[2,5]oct-6-yl; Ar is an aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), optionally having one, two or three substitutes selected from a halogen atom, lower alkyl, lower alkyl having as substitutes, a halogen atom, a lower alkoxy having as substitutes, a halogen atom, cycloalkyl, lower alkoxy, S-lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with N), or optionally having as substitutes, phenyl, optionally having R' as substitutes, and R' is a halogen atom, CF3, lower alkyl, lower alkoxy or a lower alkoxy having as substitutes, a halogen atom, or is a heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N and S); R is a lower alkyl, heterocycloalkyl (where the heterocycloalkyl is a partially unsaturated ring containing up to 6 carbon atoms, at least one of which is substituted with O), aryl or heteroaryl (where the heteroaryl is a cyclic aromatic hydrocarbon radical consisting of one ring and containing 6 ring atoms, and which contains at least one heteroatom selected from N), Where the aryl and heteroaryl optionally have as substitutes, one or two R'; n equals 0, 1, 2 or 3; or to a pharmaceutically acceptable acid addition salt, a racemic mixture or a corresponding enantiomer and/or optical isomer of said compound. The invention also relates to pharmaceutical compositions based on a glycine reuptake inhibitor of a compound of formula I.

EFFECT: obtaining novel compounds and a pharmaceutical composition based thereon, which can be used in medicine to treat neurological and psychoneurological disorders.

22 cl, 1 tbl, 128 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 triazole compounds which are represented by specific chemical formulae and which can be used for preventing or treating diseases in which 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) participates, particularly dementia. It was found that the triazole derivative, in which one of 3rd and 5th positions of the triazole ring accommodates a (di)alkyl methyl or cycloalkyl, each substituted, -O-aryl or heterocyclic group, each of which can be substituted, or (lower alkylene)cycloalkyl, and the other position accommodates an aryl, heterocyclic or cycloalkyl group, each of which can be substituted, or a pharmaceutically acceptable salt thereof, has powerful inhibiting action on 11β-HSD1.

EFFECT: improved properties of the derivatives.

8 cl, 141 tbl, 89 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: 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.

SUBSTANCE: in claimed invention described is compound of general formula 1, or its pharmaceutically acceptable salt, where in each case independently on each other m equals 0, 1; p equals 1 or 2; R1 is selected from group, including -OH, -OC(O)NHMe, -OC(O)NMe2, -OC(O)NH(CH2)2Ph and OC(O)NH(CH2)2NMe2; R2 stands for -OH, -OC(O)Me, -OCH2CO2H, -OCH2CO2Et, -N3, -N=C(NMe2)2, -NH2, -NMe2, -NHC(O)Me, -NHC(O)CF3, - NHC(O)Ph, -NHC(O)NHPh, -NHC(O)CH2CH2CO2H, -NHC(O)CH2CH2CO2Me, - NHCH2Ph, -NHCH2(4-pyridyl), -NHCH2(2-pyridyl), -NHCH2(4-(CO2H)Ph), - NHCH2(3-(CO2H)Ph), -NHEt, -NHCHMe2, -NHCH2CHMe2, -N(CH2CHMe2)2, - NHCH2(cyclopropyl) or -NHC(O)CH2CH2NMe2; R3 stands for -OMe, -OEt, - OCH2(cyclopropyl), F, -O(CH2)2NMe2 or -O(CH2)2(4-morpholino); R4 stands for -NMe2, -NEt2, -NHEt, -NHCH2CHMe2, -N(Me)CH2CHMe2, - N(Me)CH2CH2NHS(O)2Me, -N(Me)CH2CH2NHS(O)2CF3, -NHCH2CH2OH, - N(Me)CH2CH2OH, -N(Me)CH2CO2H, -N(Me)CH2C(O)NH2, N(Me)CH2C(O)NHMe, -N(Me)CH2C(O)NMe2, -NHC(O)Me, 1-piperidinyl, 4-morpholino, (R)-2-(hydroxymethyl)-1-pyrrolidinyl, -NH2, -NO2, Br, CI, F, -C(O)Me or -CH2NH2; R5 stands for -OH or -N(R17)(R18); R17 and R18 independently in each case stand for H, (C1-C6)-alkyl, (C5-C7)-aryl-(C1-C6)-alkyl, where said aryl contains from zero to two heteroatoms, (C1-C6)-alkoxy or -[C(R19)(R20)]P-R21 R19 and R20 independently in each case represent H, (C1-C6)-alkyl, (C1-C6)-alkoxy, amino-(C1-C6)-alkyl, acylamino, sulfonylamino, (C5-C7)-aryl, (C5-C7)-aryl-(C1-C6)-alkyl or 3-10-membered heterocyclyl-(C1-C6)-alkyl, containing in ring from one to two heteroatoms; R21 independently in each case represents H, 3-10-membered heterocyclyl, containing in ring one heteroatom, (C1-C6)-alkylsulfonyl, (C1-C6)-alkylsulfonamido or amido; R22 stands for halogen; R23 stands for methyl; R24 stands for methyl and R25 stands for methyl, where said aryl stands for 5-7-membered ring, containing from zero to two heteroatoms, and said aryl or said heterocyclyl can be non-substituted or substituted halogen, (C1-C6)-alkyl or amino. Also described is pharmaceutical composition, possessing inhibiting activity with respect to Bcl-2 and/or Bcl-XL proteins, which includes said compound, also described is method of treating disorder, mediated by Bcl-2 and/or Bcl-XL proteins, which lies in introduction of said compound to patient, who needs such treatment, in therapeutically efficient amount.

EFFECT: increased efficiency of compound application.

41 cl, 6 dwg, 125 ex

New compounds // 2456273

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula: wherein B is specified in a group consisting of pyridine, pyridazine, pyrimidine and oxazole which can be optionally substituted by halogen, C1-7-alkyl or a C1-7-alkoxy group; L1 is specified in a group consisting of -NH-, -C(O)NH- and -NHC(O)-, A means C3-C12-cycloalkyl, C6-C12-aryl, a 4-7-member monocyclic heterocyclic group consisting of 1-3 heteroatoms optionally specified in O N and S, or a bicyclic heterocyclyl specified in a group consisting of benzimidazolyl, benzoxazolyl, benzothiazolyl, wherein cycloalkyl, aryl, mono- or bicyclic heterocyclyl can be optionally substituted by one or more substitutes optionally specified in a group consisting of a cyano group, halogen, an oxo group, C1-7-alkyl, C1-7-halogenalkyl, a C1-7-alkoxy group, C1-7-halogenalkoxy group, an amino group, a di-C1-7-alkylamino group, a C1-7-alkylthio group and C3-8-cycloalkyl, 1-2- means a bivalent residue specified in a group consisting of: - a bivalent alkyl group consisting of 1 to 4 carbon atoms, a bivalent alkenyl group consisting of 2 to 3 carbon atoms, - -C(O)-, - -C(O)-[R4]c-R5- wherein c is equal to 0, and R5 is specified in a group consisting of a bivalent C1-C4-alkyl group optionally substituted by another C1-4-alkyl, a C4-C8-cycloalkyl group, a phenyl group and a 5- or 6-member heterocyclyl group consisting of N heteroatoms, - -C(O)-NH-, - -(CH2)1-3-C(O)-NH-(CH2)1-3-, - -C(O)-NH-R4- wherein R4 is specified in a group consisting of a bivalent C1-C7-alkyl group optionally substituted by another C1-4-alkyl, a cyclohexyl group and a cyclopentyl group, and E is specified in a group consisting of: - COOH, - a ester group of carboxylic acid, or to its pharmaceutically acceptable salts. What is also described is a pharmaceutical composition exhibiting DGAT1 modulatory activity, on the basis of the presented compounds, and also a method of treating pathological conditions or disorders associated with DGAT1 activity.

EFFECT: there are prepared and described new compounds applicable for treating or preventing the pathological conditions or disorders associated with DGAT1 activity.

22 cl, 8 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

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