Heterocyclic mek inhibitors and methods of using thereof

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to a compound of formula IV: , where: R1 represents Cl or F; R3 represents H, Me, Et, OH, MeO-, EtO-, HOCH2CH2O-, HOCH2C(Me)2O-, (S)-MeCH(OH)CH2O-, (R)-HOCH2CH(OH)CH2O-, cyclopropyl-CH2O-, HOCH2CH2-, , , , , or , R7 represents methyl or ethyl which are optionally substituted with one or more F; R8 represents Br, I or SMe; and R9 represents H, C1-C4alkyl, Cl or CN where said alkyl it optionally substituted with one or more groups independently chosen from F or CN provided when a) R1 represents F, R8 represents Br, R9 represents H, and R7 represents either Me, or Et, then R3 cannot represent HOCH2CH2O; b) R1 represents F, R8 represents I, R9 represents H, and R3 represents MeO then R7 cannot represent Me; c) R1 represents F, R8 represents Me, R9 represents H, and R3 represents HOCH2CH2O then R7 cannot represent Me; and d) R1 represents F, R8 represents Br, R9 represents H, and R3 represents cyclopropyl-CH2O then R7 cannot represent Me, as well as to the use of said compound in preparing a drug for treating hyperproliferative disorder or an inflammatory state and to a pharmaceutical composition which inhibits MEK.

EFFECT: there are prepared and described new compounds effective in treating hyperproliferative diseases, such as cancer and inflammation.

17 cl, 25 ex, 8 tbl, 15 dwg

 

PRIOR art

The scope of the invention

This invention relates to a series of new heterocyclic compounds that are useful in the treatment of hyperproliferative diseases such as cancer and inflammation, in mammals. This invention also relates to a method for using such compounds in the treatment of hyperproliferative diseases in mammals, in particular humans, and to pharmaceutical compositions containing such compounds.

Description of the prior art

Signaling in cells via receptors of growth factors and protein kinase is an important regulator of growth, proliferation and differentiation of cells. During normal cell growth factors growth through activation of receptors (i.e. PDGF (platelet growth factor, or EGF (epidermal growth factor) and other) triggers MAR-kinase pathways (MAP - mitogen-activated protein). One of the most important and most well-studied MAR-kinase pathways involved in normal and uncontrolled cell growth is a Ras/Raf-kinase pathway. Active G (GTP-independent)-associated Ras leads to activation and indirect phosphorylation of Raf-kinase. Then Raf phosphorylates MEK 1 and 2 (kinase mitogen-activated ERK (kinases regulated by extracellular signals)on two serine residues (S218 and S222 for MAC and S222 and S226 for M is K2) (Ahn et al., Methods in Enzymology, 2001, 332, 417-431). Then activated MEK phosphorylates the only known substrates for her, MAR-kinases, ERK1 and 2. Phosphorylation of ERK by MEK occurs Y204 and T for ERK1 and Y185 and T for ERK2 (Ahn et al., Methods in Enzymology, 2001, 332, 417-431). Phosphorylated ERK dimerizes and then translocases into the nucleus, where its accumulation (Khokhlatchev et al., ll, 1998, 93, 605-615). In the nucleus ERK is involved in several important cellular functions, including, without limitation, nuclear transport, signaling, DNA repair, Assembly, and translocation of nucleosomes, processing and translation of mRNA (hn et al., Molecular Cell, 2000, 6, 1343-1354). In General, the effects of growth factors on cells leads to activation of ERK1 and 2, which causes proliferation and, in some cases, differentiation (Lewis et al., Adv. Cancer Res., 1998, 74, 49-139).

When proliferative diseases, genetic mutations and/or overexpression of the receptors of growth factors further downstream signaling proteins or protein kinases involved in ERK kinase path that leads to uncontrolled cell proliferation and eventually to the formation of tumors. For example, in some malignant tumors have mutations that cause continuous activation of this pathway due to the continuous production of growth factors. Other mutations can lead to defects in the deactivation of the activated complex of GTP-bound Ras, the Nova leading to activation of map-kinase pathway. Mutant oncogenic forms of Ras was detected in 50% of cases of colon cancer and more than 90% of cancers of the pancreas, but also in many other types of cancer (Kohl et al., Science, 1993, 260, 1834-1837). Recently skin disease mutations were found in more than 60% of cases of malignant melanoma (Davies, H. et al., Nature, 2002, 417, 949-954). These mutations in skin disease lead to constitutive active MAR-kinase cascade. Samples of primary tumors and cell lines also showed constitutive or overactivation MAR-kinase path with pancreas cancer, colon cancer, lung cancer, ovarian cancer and renal cancer (Hoshino, R. et al., Oncogene, 1999, 18, 813-822). Therefore, there is a strong correlation between cancer and overactive MAR-kinase by the result of genetic mutations.

Because as constitutive or overactivate MAR-kinase cascade plays a crucial role in cell proliferation, differentiation, inhibition of this cascade is considered favorable when hyperproliferative diseases. MEK plays a key role in this path, because it is located below Ras and Raf. Moreover it is an attractive therapeutic target because of the known substrates for MEK-phosphorylation are only MAR-kinases, ERK1 and 2. In several studies it was shown that inhibition of MEK has potential the optimum therapeutic benefit. For example, it has been shown that inhibitors of MEK with small molecules that inhibit the growth of human tumors in xenografts "Nude" mice (Sebolt-Leopold et al., Nature Medicine 1999, 5 (7), 810-816; Trachet et al., AACR April 6-10, 2002 Poster No. 5426; Tecle, H. IBC 2ndInternational Conference of Protein Kinases, September 9-10, 2002), block static allodynia in animals (WO 01/05390) and inhibit the growth of cells in acute myeloid leukemia (Milella et al., J. Clin. Invest. 2001, 108 (6), 851-859).

Inhibitors of MEK with small molecules have been disclosed, including publications, U.S. patent No. 2003/0232869, 2004/0116710 and 2003/0216460 and in applications for U.S. patent No. 10/654580 and 10/929295, each of which is incorporated in this description by reference. Over the past few years there have been at least fifteen additional patent applications (see, for example, U.S. patent 5525625; WO 98/43960; WO 99/01421; WO 99/01426; WO 00/41505; WO 00/42002; WO 00/42003; WO 00/41994; WO 00/42022; WO 00/42029; WO 00/68201; WO 01/68619; WO 02/06213; WO 03/077914; and WO 03/077855.

The INVENTION

This invention provides a new heterocyclic compounds and their pharmaceutically acceptable salts and prodrugs, which are useful in the treatment of hyperproliferative diseases. Found that 6-oxo-1,6-dihydropiridine and 6-oxo-1,6-dihydropyridine compounds having specific substituents, which are specified in this description, are potent inhibitors of the enzyme MEK.

More to ncrete in one aspect of the present invention proposed connection, including tautomers, metabolites, separated the enantiomers, the diastereomers, the solvate and their pharmaceutically acceptable salts, having the formula I:

where R1represents Cl or F;

R3represents H, Me, Et, HE, MeO-, tO, NON2CH2O-, NON2With(Me)2O-, (S)-MeCH(OH)CH2O-, (R)-HOCH2CH(OH)CH2O-, cyclopropyl-CH2O-, NON2CH2-,

,,,,or;

R7is cyclopropyl-CH2- or1-C4alkyl, where the specified alkyl possibly substituted by one or more F;

R8represents Br, I or SMe; and

R9represents CH3CH2F, CHF2, CF3, F or Cl.

In another aspect of this invention offered compounds, including the tautomers, metabolites, separated the enantiomers, the diastereomers, the solvate and their pharmaceutically acceptable salts, having the formula IV:

where R1represents Cl or F;

R3represents H, Me, Et, HE, MeO-, tO, NON2CH2Oh, NON2With(Me)2O-, (S)-MeCH(OH)CH2O-, (R)-HOCH2CH(OH)CH2O-, cyclopropyl-CH2Oh, the NOSE is 2CH2-,

,,,,or;

R7represents methyl or ethyl, where mentioned methyl and ethyl possibly substituted by one or more F;

R8represents Br, I or SMe; and

R9represents H, C1-C4alkyl, Cl or CN, where the specified alkyl possibly substituted by one or more groups independently selected from F, or CN, provided that:

a) when R1represents F, R8represents Br, R9represents N, and R3represents NON2CH2O, then R7can't represent Me or Et;

b) when R1represents F, R8is a I, R9represents N, and R3represents MeO, then R7can't represent Me;

b) when R1represents F, R8represents Me, R9represents N, and R3represents NON2CH2O, then R7can't represent Me; and

g) when R1represents F, R8represents Br, R9represents N, and R3is cyclopropyl-CH2Oh, then R7cannot p is establet a Me.

In another aspect of the present invention proposed two crystalline forms of the compounds of formula XI:

which is designated as Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide and Form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide.

Proposed methods for the Form 1 and Form 2 of compound of formula XI.

In another aspect of the present invention proposed compositions which inhibit MEK containing one or more compounds of the present invention.

According to the invention is also suggested methods for obtaining the compounds of the present invention.

In another aspect of the present invention, a method of using compounds according to this invention as a drug for the treatment of diseases or medical conditions mediated by MEK. For example, according to this invention proposed a connection according to this invention as a drug for the treatment of hyperproliferative disorders, or inflammatory conditions in a mammal, comprising an introduction to the specified mammal one or more compounds of the present invention or their pharmaceutically acceptable salts or prodrugs in Koli is este, effective for the treatment of this hyperproliferative disorders. In another aspect of the present invention proposed a connection according to this invention in the manufacture of medicinal products for the treatment of hyperproliferative disorders, or inflammatory conditions.

In another aspect of the present invention, a method for producing the effect of inhibiting MEK in a warm-blooded animal, such as man, in need of such treatment, comprising the introduction of a specified animal an effective amount of the compounds according to this invention.

In another aspect of the present invention proposed treatment or prevention of a condition mediated MEK, including the introduction of a human or animal in need of this, pharmaceutical compositions containing the compound of the present invention or its pharmaceutically acceptable salt or in vivo split the prodrug in a quantity effective to treat or prevent this condition, mediated by MEK.

Compounds according to the invention can be also preferably used in combination with other known therapeutic agents.

The invention also relates to pharmaceutical compositions which inhibit MEK containing an effective amount of compounds selected from compounds really to the invention or their pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, or pharmaceutically acceptable salts.

In an additional aspect of the invention the application of the compounds of the present invention in the manufacture of a medicine for treating or preventing the disease or medical condition mediated MEK, in a warm-blooded animal, preferably a mammal, more preferably a person suffering from this disorder. More specifically, the invention includes the use of compounds according to the invention in the manufacture of a medicinal product for treating or preventing hyperproliferative disorders, or inflammatory conditions in a mammal.

Additional advantages and new features of the present invention partially set forth in the following description and will be obvious to experts in the field of technology as the study of the following description or may be learned by carrying out the invention in practice. Advantages of the invention may be realized and attained by means of the combinations, compositions and methods, in particular, as indicated in the attached claims.

A BRIEF DESCRIPTION of GRAPHIC MATERIALS

Accompanying graphics that are included in this description and be part of it, illustrate neoprene ewusie embodiment of the present invention and together with the description serve to explain the principles of the invention.

In graphics:

Figure 1 shows the reaction scheme for the synthesis of compound 96.

Figure 2 presents the reaction scheme for the synthesis of compounds 96, 100, 101 and 102.

3 shows the reaction scheme for the synthesis of compounds 109, 110 and 111.

4 shows an alternative reaction scheme for the synthesis of compounds 109, 110 and 111.

Figure 5 presents the reaction scheme for the synthesis of compounds 119, 120 and 121.

Figure 6 presents the reaction scheme for the synthesis of compounds 124 and 125.

Figure 7 presents the reaction scheme for the synthesis of compounds 128, 129 and 130.

On Fig represented by the reaction scheme for the synthesis of compounds 145 and 146.

Figure 9 presents an alternative reaction scheme for the synthesis of compound 145.

Figure 10 shows the picture of the x-ray diffraction on the powder to Form 2, 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide, obtained according to Example 16A, step 3.

Figure 11 presents a picture of the x-ray diffraction on the powder to Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide, obtained according to Example 16A, step 4.

On Fig presents a picture of the x-ray diffraction on the powder to Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide, obtained according to Example 16B.

On Fig presents a picture of the x-ray diffraction on the powder to Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide, obtained according to Example 16G.

On Fig presents DSC-thermogram (DSC - differential scanning calorimetry) to the Form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide.

On Fig presents the DSC thermogram for Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide.

DETAILED description of the INVENTION

Compounds of the present invention and the tautomers, metabolites, separated the enantiomers, the diastereomers, the solvate and their pharmaceutically acceptable salts and prodrugs useful in the treatment of hyperproliferative diseases. In General, one aspect of the present invention relates to compounds of the present invention, which act as inhibitors of MEK.

More specifically, according to one aspect of the present invention proposed connection, including the tautomers, metabolites, separated the enantiomers, the diastereomers, the solvate and their pharmaceutically acceptable salts, having the formula I:

where R1represents Cl or F;

R3depict is to place a N, Me, Et, HE, MeO-, tO-, HOCH2CH2O-, HOCH2C(Me)2O-, (S)-MeCH(OH)CH2O-, (R)-HOCH2CH(OH)CH2O-, cyclopropyl-CH2O-, NON2CH2-,

,,,,or;

R7is cyclopropyl-CH2- or1-C4alkyl, where the specified alkyl possibly substituted by one or more F;

R8represents Br, I or SMe; and

R9represents CH3CH2F, CHF2, CF3, F or Cl.

In one of the embodiments of the invention proposed connection, including the tautomers, metabolites, separated enantiomers, diastereomers, solvate, and their pharmaceutically acceptable salts, having the formula IA:

where R1represents Cl or F;

R3represents H, Me, HE, MeO, tO, HOCH2CH2O, MeOCH2CH2O HOCH2CH2CH2,,,,,,or;

R7is cyclopropyl-CH2- or1-C4alkyl, where the specified alkyl may for the of Eden one or more F;

R8represents Br, I or SMe; and

R9represents CH3CH2F, CHF2, CF3, F or Cl.

In one of the embodiments in the compounds of the formula I or IA R7is cyclopropyl-CH2- or Me. In another embodiment R9represents CH3, F or Cl.

In another embodiment of the proposed compound of formula II

or its pharmaceutically acceptable salt,

where R3represents H, MeO, NON2CH2O, Meon2CH2O, NON2CH2CH2,,or; and

R9represents N, CH3, F or Cl.

The compounds of formula II, with the methyl substituent in position N1 and a specific group, R3and R9are potent inhibitors of MEK.

The particular new compounds according to the invention include any of the following connections:

4-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

4-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

N-(cyclopropylmethoxy)-4-(2-fluoro-4-(methylthio)phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

4-(2-fluoro-4-(methylthio)phenylamino)-N-(2-meth is xiaoxi)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

4-(2-fluoro-4-(methylthio)phenylamino)-N-methoxy-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

(S)-4-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

4-(2-fluoro-4-(methylthio)phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

5-fluoro-4-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

(S)-5-fluoro-4-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

5-chloro-4-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

(S)-5-chloro-4-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

4-(2-fluoro-4-(methylthio)phenylamino)-N-(3-hydroxypropyl)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide; and

(S)-N-(2,3-dihydroxypropyl)-4-(2-fluoro-4-(methylthio)phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide.

In another embodiment of the proposed compound of formula III:

or its pharmaceutically acceptable salt,

where R1represents Cl or F;

R3represents H, Me, MeO, HOCH2CH2O HOCH2CH2CH2NON2CH2,

,, ,,,or;

R8represents Br or I; and

R9represents CH3, F, Cl or Br.

The compounds of formula III, with the methyl substituent in position N1 and a specific group, R1, R3R8and R9are potent inhibitors of MEK.

The particular new compounds according to the invention include any of the following connections:

5-bromo-4-(4-bromo-2-forgenerating)-N-(cyclopropylmethoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

4-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

(R)-N-(2,3-dihydroxypropane)-4-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

4-(2-fluoro-4-itfinally)-N-methoxy-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

N-(cyclopropylmethoxy)-4-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

(S)-4-(2-fluoro-4-itfinally)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

4-(2-chloro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

(S)-4-(2-chloro-4-itfinally)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

4-(4-bromo-2-chlorpheniramine)-N(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

(S)-4-(4-bromo-2-chlorpheniramine)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

4-(4-bromo-2-forgenerating)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

(R)-4-(4-bromo-2-forgenerating)-N-(2,3-dihydroxypropane)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

4-(4-bromo-2-forgenerating)-N-(1-hydroxy-2-methylpropan-2-yloxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

4-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

4-(4-bromo-2-forgenerating)-5-fluoro-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

4-(2-fluoro-4-itfinally)-N,1,5-trimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

N-(cyclopropylmethyl)-4-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

4-(2-fluoro-4-itfinally)-N-(3-hydroxypropyl)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

5-fluoro-4-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

4-(2-fluoro-4-itfinally)-N-(2-hydroxyethyl)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

N-(2,3-dihydroxypropyl)-4-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

5-chloro-4-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

(S)-5-chloro-4-(2-fluoro-4-itfinally)-N-(2-HYDR is ciprodex)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

5-chloro-4-(2-fluoro-4-itfinally)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

5-chloro-N-(2,3-dihydroxypropyl)-4-(2-fluoro-4-itfinally)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide;

(S)-N-(2,3-dihydroxypropyl)-4-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide; and

(S)-5-chloro-N-(2,3-dihydroxypropyl)-4-(2-fluoro-4-itfinally)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide.

The particular new compounds according to the invention also include the following compounds:

4-(4-bromo-2-forgenerating)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide; and

(S)-4-(4-bromo-2-forgenerating)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide.

In another aspect of the present invention proposed connection, including the tautomers, metabolites, separated enantiomers, diastereomers, solvate, and their pharmaceutically acceptable salts, having the formula IV:

where R1represents Cl or F;

R3represents H, Me, Et, HE, MeO-, tO, NON2CH2O-, HOCH2C(Me)2O-, (S)-MeCH(OH)CH2O-, (R)-HOCH2CH(OH)CH2O-, cyclopropyl-CH2O-, NON2CH2-,,,,,or ;

R7represents methyl or ethyl, which may be substituted by one or more F;

R8represents Br, I or SMe; and

R9represents H, C1-C4alkyl, Cl or CN, where the specified alkyl possibly substituted by one or more groups independently selected from F, or CN, provided that when

a) R1represents F, R8represents Br, R9represents N, and R7is either Me, or Et, then R3can't imagine NON2CH2O;

b) R1represents F, R8is a I, R9represents N, and R3represents MeO, then R7can't represent Me;

in R1represents F, R8represents Me, R9represents N, and R3represents HOCH2CH2O, then R7can't represent Me; and

g) R1represents F, R8represents Br, R9represents N, and R3is cyclopropyl-CH2Oh, then R7can't represent Me.

In one of the embodiments in the compounds of formula IV, R9represents H, Me, Et, Cl or CN.

In one embodiments of the compounds according to the invention or their pharmaceutically acceptable salts are of the form is at V:

where R3represents NON2CH2O or (S)-MeCH(OH)CH2O; and

R9represents N, CH3, F or Cl, provided that when R1represents F, R8is a SMe, R9represents Cl, and R7represents Me, then R3may not be a HOCH2CH2O.

The compounds of formula V, where R3represents HOCH2CH2O or (S)-MeCH(OH)CH2O, are potent inhibitors of MEK.

The particular new compounds according to the invention include any of the following connections:

2-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

(S)-2-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

2-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

(S)-2-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

(S)-5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide; and

(S)-5-chloro-2-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)-1-methyl-oxo-1,6-dihydropyridines-3-carboxamide.

In one embodiment of the compounds according to the invention or their pharmaceutically acceptable salts have the formula VI:

where R1represents Cl or F;

R3represents H, HOCH2CH2O or (S)-MeCN(OH)CH2O; and

R9represents H, Me, F or Cl.

The compounds of formula VI, where R1represents Cl, R3represents NON2CH2O or (S)-MeCN(OH)CH2O, and R9represents H, are potent inhibitors of MEK.

The compounds of formula VI, where R1represents F, R3represents N, and R9represents Me, are potent inhibitors of MEK.

The compounds of formula VI, where R3represents HOCH2CH2O or (S)-MeCH(OH)CH2O, are potent inhibitors of MEK.

The compound of formula VI, where R1represents F, R3represents NON2CH2Oh, and R9represents Me, is a potent inhibitor of MEK, and also has good solubility. Used herein, the term "good solubility" refers to a compound that has a solubility of more than 50 µg/ml, for example the solubility of approximately 50-270 µg/ml, which is defined by way of Example C.

Specific new joint is of the formula VI according to the invention include any of the following connections:

2-(2-chloro-4-itfinally)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

(S)-2-(2-chloro-4-itfinally)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

(S)-2-(2-fluoro-4-itfinally)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

(S)-2-(2-fluoro-4-itfinally)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

2-(2-chloro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

5-chloro-2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

(S)-2-(2-chloro-4-itfinally)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

(S)-5-chloro-2-(2-fluoro-4-itfinally)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

5-fluoro-2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide; and

(S)-5-fluoro-2-(2-fluoro-4-itfinally)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide.

In another embodiment of the proposed compound of formula VI, where R1represents F, R3represents HOCH2CH2O, and R9PR is dstanley a methyl, or its pharmaceutically acceptable salt.

It was found that the compound of formula XI:

can exist in two crystalline forms, hereinafter designated as Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide and Form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide, and that the Form 2 can be transformed to the Form 1.

Samples of specific crystalline forms of the compounds of formula XI were analyzed using a combination of analysis of x-ray diffraction on the powder (XRPD) and differential scanning calorimetry as described in the Examples 16D and E.

If it is determined that the present invention relates to a crystalline form of the compound of formula XI, usually the degree of crystallinity according to x-ray diffraction on the powder is more than about 60%, preferably more than about 80%, preferably more than about 90% and even more preferably more than about 95%.

According to another aspect of the invention proposed crystalline form of the compound of formula XI is essentially in the Form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide.

According to another aspect of the invention proposed to istoricheskaya form the compounds of formula XI are essentially in the Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide.

The compound of formula XI in the Form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide has a picture of the x-ray diffraction with characteristic peaks on scale 2 theta (θ) at about a 9.5 and 12.6. According to another aspect of the invention proposed compound of formula XI in the Form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide, which has a picture of the x-ray diffraction with characteristic peaks on scale 2 theta (θ) with approximately 9,5; 12,6; and 14,7 19,6.

The form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide has the diffraction pattern of x-rays by being such, as shown in Figure 10, with the characteristic peaks [on a scale of 2 theta (θ)] about the provisions specified in Table A.

The compound of formula XI in the Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide has a picture of the x-ray diffraction with characteristic peaks on scale 2 theta (θ) at approximately 9.2 and 13.0. According to another aspect of the invention proposed compound of formula XI in the Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide, which has a picture on the fraction of x-rays with characteristic peaks on scale 2 theta (θ) at approximately 9.2; 13,0; 18,3; 21,0 and 21.7.

Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide has a picture of the x-ray diffraction essentially such as shown at 11 or 12, with characteristic peaks [on a scale of 2 theta (θ)] about the provisions specified in Table B.

As mentioned above, the intensity peaks in the XRPD of the diffraction pattern may exhibit some variability depending on the use conditions of the measurements. Respectively in Tables a and B, the numerical values of the relative intensities are not listed. More precisely the following definitions are used for the intensity:

The relative intensity in %Definition
25-100VS (very strong)
10-25S (strong)
3-10M (medium)
1-3W (weak)

where the relative intensity obtained from the paintings of the x-ray diffraction is measured with use of the variable slits.

On Fig presents a picture of the x-ray diffraction the rays on the powder to Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide, obtained according to Example 16G.

It is seen that some of the more minor peaks present in the film x-ray diffraction figure 10-13, not shown in Tables a and B.

The compound of formula XI in the Form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide has a picture of the x-ray diffraction is essentially the same as shown in Figure 10.

The compound of formula XI in the Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide has a picture of the x-ray diffraction is essentially the same, as shown in figure 11 or 12.

In the previous text, which identifies the peaks of x-ray powder diffraction for crystalline forms of 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide, the term "at approximately" used in the phrase "...on a scale of 2 theta (θ) at about..."to indicate that the precise position of peaks (i.e. the values of angle 2-theta) should not be interpreted as absolute values because, as is obvious to experts in this area, the exact position of the peaks may vary slightly from device to device, from sample to sample or as a result of small variations in the measurement conditions. In addition, previous AB is the AC installed, what is the crystal form of 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide give a picture of the x-ray diffraction on powder "essentially" the same as picture x-ray diffraction on the powder presented on Figure 10-13, and have essentially the most distinct peaks (angle 2-theta), are shown in Tables a and B, respectively. Clearly, that is used in this context, the term "essentially" is also intended to indicate that the values of the angles 2-theta at the pictures of the x-ray diffraction on the powder may slightly vary from device to device, from sample to sample or as a result of slight variations in the measurement conditions, therefore, the position of the peaks shown in the Figures or stated in the Tables a and B, should not be interpreted as absolute values.

In this description are disclosed methods for obtaining the compounds of formula XI in either Form 1 or Form 2.

In one aspect, a method for obtaining compounds of formula XI are essentially in the Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide, including:

a) cast (2 vinyloxyethoxy)-amide 2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylic acid in contact with the acid mixture for lying is neither, sufficient for the conversion of this compound to 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

b) an extract substance from step (a) until crystallization from an organic solvent containing a seed crystal of the Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide; and

in the selection of the Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide.

In one aspect, the acid mixture in stage (a) can be an inorganic or organic acid. In another aspect of stage (a) can be carried out in the two-phase solvent system water acid - ethyl acetate. In one aspect, the organic solvent at the stage (b) is ethyl acetate.

In another aspect, a method for obtaining compounds of formula XI are essentially in the Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide, including:

a) stirring of Form 2, 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide with a small number of the Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide in an organic solvent; and

b) the selection of the Form 1 2-(2-fluoro-4-itfinally)-N-(2-guide is acetoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide.

In one aspect, the amount of substance of the Form 1, used in stage (a)is approximately 5% wt./wt.

In another aspect of stage (a) is carried out in ethyl acetate at a temperature slightly above ambient temperature, for example approximately 50-60°C.

In another aspect of the invention, a method for obtaining compounds of formula XI are essentially in the Form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide according to claim 1 claims, including:

a) bringing into contact (2-vinyloxyethoxy)-amide 2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylic acid with an acid mixture for a time sufficient to convert the compound 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide;

b) an extract substance from step (a) until crystallization from an organic solvent; and

in the selection of the Form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide.

In one aspect, the organic solvent at the stage (b) contains the seed of the Form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide. The acid mixture in stage (a) can be an inorganic or organic acid, and stage (a) can be conducted in organic the immediate vicinity of the solvent, such as THF (tetrahydrofuran). In one aspect, the organic solvent at the stage (b) may be selected from ethyl acetate and isobutyl ketone, both possibly in the presence of isohexane.

Some compounds in this invention can exist in two or more tautomeric forms. "Tautomer" represents one of the two or more structural isomers that exist in equilibrium and are readily converted from one isomeric form to another, such as structures formed by displacement of hydrogen from one place to another within the same molecule. Other tautomeric forms of the compounds can be mutually exchanged, for example, by enolizatsii/detalization and the like. Accordingly, the present invention comprises obtaining all tautomeric forms of the compounds according to this invention.

Compounds according to this invention can have one or more asymmetric centers, therefore, such compounds can be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. If not stated otherwise, the description or the name of a particular compound in the specification and in the claims includes both individual enantiomer, it diastereomer mixture, racemic or otherwise. Accordingly, the invention also covers all such isome is s, including diastereomeric mixture and the separated enantiomers of the compounds according to this invention. Diastereomer mixture can be separated into their individual diastereomers on the basis of their physical chemical differences by methods known to experts in the art, such as chromatography or fractional crystallization. Enantiomers can be separated by turning the enantiomeric mixture in diastereomer mixture as a result of interaction with an appropriate optically active compound (for example, alcohol), separating the diastereomers and converting (for example by hydrolysis) the individual diastereomers to the corresponding pure enantiomers. Methods for the determination of stereochemistry and the separation of stereoisomers are well known in this area (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition, J. March, John Wiley and Sons, New York, 1992).

This invention also encompasses pharmaceutical compositions containing a compound of the present invention, and methods of treating proliferative disorders, or abnormal cell growth by introducing compounds of the present invention. Compounds of the present invention, having free amino, amido, hydroxy or carboxylic groups can be converted into pharmaceutically acceptable prodrugs.

"Prodrug" is a compound, which is passed under physiological conditions or by solvolysis can turn into a specific compound or pharmaceutically acceptable salt of such compounds. Prodrugs include compounds where the amino acid residue or a polypeptide chain of two or more (e.g. two, three or four) amino acid residues, covalently joined through an amide or ether bond to a free amino, hydroxy or carboxyl group of the compounds of the present invention. Amino acid residues include the 20 existing in nature, amino acids, usually indicated by three letter symbols and also includes 4-hydroxyproline, hydroxylysine, demazin, isodesmosine, 3-methylhistidine, Norvaline, beta-alanine, gamma-aminobutyric acid, Citroen, homocysteine, homoserine, ornithine and methanesulfonic, but not limited to. One preferred prodrug according to this invention is a compound of the present invention, covalently linked to a valine residue.

Also covered additional types of prodrugs. For example, can be obtained from derivatives of free carboxyl groups to form amides or alilovic esters. As another example, in the form of prodrugs derivatives of the compounds of this invention containing free hydroxyl groups can be obtained by conversion of the hydroxyl group of the phosphate ester, hemisuccinate, dimethylaminoacetyl or phosphorylethanolamine, as described in Advanced Dug Delivery Reviews, 1996, 19, 115. Also covered urethane prodrugs of hydroxy and amino groups, as representing the carbonate prodrugs, sulfate esters and sulfate esters of hydroxyl groups. Also involved in the preparation of derivatives of hydroxyl groups in the form (acyloxy)methyl and (acyloxy)ethyl ethers, where the acyl group can be alkilany ether complex, possibly substituted by groups including, without limitation, ether, amine or carbonisation functional group, or where the acyl group is a complex ester of the amino acids as described above. Prodrugs of this type is described in J. Med. Chem., 1996, 39, 10. More specific examples include replacement of the hydrogen atom of the alcohol group, this group, as With1-C6)alkanoyloxy, 1-((C1-C6)alkanoyloxy)ethyl, 1-methyl-1-((C1-C6)alkanoyloxy)ethyl, (C1-C6)alkoxycarbonylmethyl, N-(C1-C6)alkoxycarbonylmethyl, succinoyl, (C1-C6)alkanoyl, α-amino(C1-C4)alkanoyl, ariell and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoaniline group independently selected from the natural L-amino acids, group P(O)(OH)2, -P(O)(O(C1-C6)alkyl)2or glycosyl (the radical resulting from the removal of hydroxyl gr is PPI polyacetylenes form of carbohydrate).

Can also be obtained derivatives of free amines in the form of amides, sulfonamides or phosphoramidon. For example, a prodrug can be formed by replacing a hydrogen atom in the amine group, such a group as R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' each independently is a (C1-C10)alkyl, (C3-C7)cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α-aminoacyl)-(natural α-aminoacyl), -C(OH)C(O)OY where Y is H, (C1-C6)alkyl or benzyl, -C(OY0)Y1where Y0is a (C1-C4)alkyl, and Y1is a (C1-C6)alkyl, carboxy(C1-C6)alkyl, amino(C1-C4)alkyl or mono-N - or di-N,N-(C1-C6)acylaminoalkyl- (Y2)Y3where Y2represents H or methyl, and Y3is a mono-N - or di-N,N-(C1-C6)alkylamino, morpholino, piperidine-1-yl or pyrrolidin-1-yl.

All these proletarienne groups can be incorporated groups, including ether, amine or carbonisation functional group, but not limited to.

Prodrugs of the compounds of the present invention can be identified using routine techniques known in this field. In this about the Asti known various forms of prodrugs. Examples of such proletarienne derivatives, see, for example, in a) Design of Prodrugs, edited by .Bundgaard (Elsevier, 1985) and Methods in Enzymology, Vol.42, p.309-396, edited by K.Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H.Bundgaard, Chapter 5 "Design and Application of Prodrugs" by H.Bundgaard, p.113-191 (1991); C) H.Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77: 285 (1988); and d) N.Kakeya, et al., Chem. Pharm. Bull., 32: 692 (1984), which are all included in this description by reference.

The invention also covers a solvate, metabolites and pharmaceutically acceptable salts of the compounds of the present invention.

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

"Metabolite" is a pharmacologically active product produced during in vivo metabolism of a particular compound or its salts in the body. Such products can be formed, for example, oxidation, recovery, hydrolysis, amidation, deliciouse, esterification, deesterification, enzymatic degradation, etc. entered the compound. Accordingly, the invention encompasses metabolites of the compounds of the present invention, including the compounds obtained by the process comprising bringing a compound according to this invention in contact with a mammal for a period of time sufficient to obtain its metabolic what about the product.

Usually the metabolites identified by obtaining a radiolabelled (e.g.,14With or3H) compounds according to the invention, the introduction of it parenterally in a detectable dose (e.g. greater than about 0.5 mg/kg) to an animal such as rat, mouse, Guinea pig, monkey, or human, holding it in a period of time sufficient for the implementation of metabolism (typically from about 30 seconds to 30 hours) and excretion products of its transformation from urine, blood or other biological samples. These products distinguish without difficulty, as they are labeled (other produce through the use of antibodies capable of binding epitopes remaining in the metabolite). Patterns of metabolites determined by standard methods, for example MS (mass spectrometry), LC/MS (liquid chromatography/mass spectrometry (MS) or NMR (nuclear magnetic resonance). Typically, the analysis of metabolites perform as well as traditional studies of the metabolism of drugs, known to experts in this field. Metabolites, unless otherwise they are not found in vivo, are useful in diagnostic tests for therapeutic dosing of the compounds according to the invention.

Used herein, the term "pharmaceutically acceptable salt", unless otherwise stated, covers salts which retain the biological effect is aktivnosti free acids and bases of specific compounds and which are not biologically or otherwise undesirable. The connection according to the invention may have a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly can interact with any of a number of inorganic or organic bases, and inorganic and organic acids with the formation of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include salts obtained by the interaction of the compounds according to the present invention with a mineral or organic acid or inorganic base, such salts include the sulfates, pyrosulfite, bisulfate, sulfites, bisulfite, phosphates, monohydrogenphosphate, dihydrophosphate, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, oxalates, malonate, succinate, suberate, sebacate, fumarate, maleate, Butin-1,4-dioate, hexyne-1,6-dioate benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalates, sulfonates, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartratami, methansulfonate, propanesulfonate, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelate. Because one connection of the present invention m which may contain more than one acidic or basic group, compounds of the present invention may include mono-, di - or tri-salts in the same connection.

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

If the connection according to the invention is an acid, the desired pharmaceutically acceptable salt may be obtained by any appropriate is a procedure, for example, by treating the free acid with an inorganic or organic base. Preferred inorganic salts are salts formed with alkali and alkaline earth metals such as lithium, sodium, potassium, barium and calcium. Preferred salts of organic bases include, for example, ammonium salts of dibenzylamine, benzylamine, 2-hydroxyethylamine, bis(2-hydroxyethyl)ammonium, phenylethylenediamine, dibenziletilendiaminom and the like salts. Other salts of acid groups may include, for example, salts formed with procaine, quinine and N-methylglucamine, plus salts formed with basic amino acids such as glycine, ornithine, histidine, phenylglycine, lysine and arginine.

Methods for obtaining compounds of the present invention proposed as additional features of the invention. Compounds according to the invention can be obtained according to the reaction routes and synthesis schemes as described below, using methods known in this field, using the original substances that are available or can be synthesized by methods known in this field.

Illustrations obtain the compounds of the present invention are presented in figure 1-7.

The connection 96 is depicted in figure 1. Substituted hydrazine 28 may be pravr the puppy in hydrazinophenyl 29 on the two-stage method. In the first stage hydrazine 28 is subjected to condensation with atilpirina under standard conditions degidrirovaniya, for example in the presence of MgSO4in a suitable organic solvent such as chloroform or methylene chloride, at a temperature in the range from 0°C to ambient temperature. In the second stage, the acylation is achieved by treatment with base at low temperature in a suitable organic solvent, such as THF, DMF (dimethylformamide), dioxane or N, followed by the addition of methylmaleimide. In one embodiment of the hydrazone is treated with LiH in THF at 0°C, then add methylmalonate and warmed to room temperature. Hydroxypyridine 31 is obtained from hydrazinopyridazine 29 by cyclization in strongly basic conditions, followed by decarboxylation. The cyclization may be effected by treatment of hydrazinopyridazine 29 strong base, such as DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), LDA (diisopropylamide lithium) or NaH, in a suitable organic solvent, such as THF or N at room temperature. In one embodiment, the cyclization is achieved using DBU in MeCN at room temperature. Decarboxylation with the formation of hydroxypyridinone 31 can be achieved by heating the complex grouping methyl ether feast is Zinon in a suitable organic solvent, such as dioxane or decalin or a mixture of dioxane/decalin to elevated temperatures in the presence of concentrated HCl. Carboxylic acid 94 can be obtained from hydroxypyridinone 31 in the two-stage process, i.e. by chlorination and subsequent oxidation. Stage chlorination can be carried out by processing l3, thionyl chloride, oxalylamino or PCl5. In one embodiment of this transformation is achieved using pure l3at elevated temperature (about 85°). After stage chlorination of carboxylic acid 94 can be obtained by oxidation under standard conditions, including, without limitation, KMPO4in water, SeO2in an organic solvent, such as dioxane, xylene, or pyridine, NaOCl/RuCl3, SGAs3in water N2SO4, K2Cr2O7and Na2Cr2O7in the water. In one embodiment of this transformation is achieved using K2CR2O7-N2SO4. Carboxylic acid 94 can be converted into an ester of pyridazinone 95 a two-step process involving the esterification of pyridazinones acid 94 and subsequent palladium mediated reaction of cross-linking. The etherification can be carried out under standard conditions, including, without limitation, concentrated Hcl in Meon, MSCl in the Meon or TMSCHN 2in suitable organic solvents such as a mixture of ether/Meon, THF/MeOH or h/Meon. Mediated by palladium reaction of cross-linking may be effected by standard means, including, without limitation, processing ether of chloropyridazine aniline, palladium catalyst such as Pd(OAc)2, PdCl2(dppf), Pd(Ph3P)4or Pd2dba3, phosphine ligand and a base in a suitable organic solvent, such as THF, DMF, PhMe, DME (dimethyl ether) or MeCN at elevated temperatures. In one embodiment the reaction of cross-linking involves the manipulation of ester 94 Pd(OAc)2, racemic 2,2-bis(diphenylphosphino)-1,1'-binaphtyl and Cs2CO3in toluene at 70 to 100°C. In embodiments of the compounds 95, where it is desirable that R9represented VG, Deputy bromine can be introduced after the reaction of cross-linking. Bromination of pyridazinone can be carried out using NBS (N-bromosuccinimide) in a suitable organic solvent, such as DMF, MeCN or mixed solvent system at room temperature. In one embodiment of the bromination is carried out in DMF. Hydroxamate 96 can be obtained by treating the ester of pyridazinone 95 corresponding hydroxylamine and amide base such as LDA, LiHMDS (hexamethyldisilazide lithium) or NHMDS (hexamethyldisilazide sodium), in a suitable organic solvent, such as THF, at low temperature. In one embodiment a solution of LiHMDS added to a solution of the ester of pyridazinone 95 and hydroxylamine in THF at 0°C. the Reaction mixture was then warmed to room temperature to obtain the desired hydroxamate 96. In some cases, the hydroxylamine used in the reaction mix contains a standard protective group. In such cases, the protective group can be removed under standard conditions known in the art.

Figure 2 presents the synthesis of compounds 96, 100, 101 and 102. Substituted hydrazine 28 can be turned into hydrazinomethane 97 by one of two methods. In one embodiment, the condensation of the substituted hydrazine 28 with subsequent acylation is particularly suitable for analogues, where R9represents alkyl or halogen. In this embodiment, the hydrazine 28 may be subjected to condensation with diethyl-2-oxomalonate under standard conditions degidrirovaniya using traps Dean-stark in a suitable organic solvent such as benzene or toluene, at a temperature in the range from 80 to 120°C. the Acylation reagent that delivers acyl group, obtaining hydrazinomethane 97 is achieved by processing the base at the corresponding temperature in a suitable organic solvent, such the AK THF, DMF, dioxane or MeCN, followed by the addition Alliluyeva reagent. Examples alleluya reagents well known to specialists in this field and include, without limitation, the anhydrides of the acids, anhydrides of carboxylic acids and activated esters. In one embodiment of the hydrazone is treated with LiH in THF at 0°C, then add the acid chloride acid and stirred at 25-60°C With connection 97. An alternative method of synthesis of compound 97, where R9is not halogen, involves the acylation of hydrazine 28 reagent that delivers an acyl group, and then condensation with diethyl-2-oxomalonate with getting hydrazinomethane 97. In accordance with this method, the substituted hydrazine 28 can be converted into the hydrazide standard methods of acylation. In one embodiment of this transformation is achieved by using an appropriate carboxylic acid in methylene chloride at a temperature from 0°C to ambient temperature. The resulting hydrazide is subjected to condensation with diethylmalonate under standard conditions degidrirovaniya using the trap Dean-stark, in a suitable organic solvent such as benzene or toluene, at a temperature of from 80 to 130°C. Pyridazine 99 obtained from hydrazinomethane 97 by cyclization under alkaline conditions to obtain an intermediate acid and intermediate of ester 98, then by chlorination with obtaining pyridazinone 99. The cyclization can be carried out by processing hydrazinomethane 97 amide base, such as LiHMDS, NaHMDS, KHMDS, or LDA in a suitable organic solvent, such as THF or ether, at low temperatures. In one embodiment, the cyclization can be achieved with LiHMDS in THF at low temperature (-78 to -40°C) followed by treatment with concentrated Hcl to obtain ester derivative 98 (R=Et). In another embodiment the acid derivative 98 (R=H) is obtained by saponification in situ ester derivative of pyridazinone 98. Upon completion of the cyclization, the reaction mixture was quenched with water at low temperature (-78 to -40°C, then heated to ambient temperature with stirring, and then acidified. Pyridazine 99 then derived from the acid or ester derivative of pyridazinone 98 by processing l3, thionyl chloride, oxalylamino or PCl5. In one embodiment of this transformation is achieved using pure l3at elevated temperature (about 85°). When R9does not represent F, acid derived pyridazinone 99 (when R=H) can then be transformed into pyridazine 101. The introduction of aniline grouping is achieved by SNAG reaction in a suitable organic is kOhm solvent, such as THF, using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS at appropriate temperatures (-78°C to room temperature). In one embodiment of the aniline is added to LDA or LiHMDS in THF at low temperature (-20 to -80°C). Then add acid derivative of pyridazinone 99 (R=N), and the reaction mixture is heated to room temperature before the formation of carboxylic acid 101. Hydroxamate 96 and amides 102 can then be obtained from the acid 101 using standard reagent combinations, such as, without limitation, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole-6-sulfonamide hydrochloride (HOBt) or benzotriazol-1-yl-oxytropidoceras (Rumor)and the appropriate amine or hydroxylamine in a suitable organic solvent, such as DMF, THF or methylene chloride. In some cases, amine or hydroxylamine contains the standard protective group. In such cases, the protective group can be removed under standard conditions known in the art. Alternatively, the ether derivative of pyridazinone 99 (R=Et) can be transformed into hydroxamate 96 through the ether derivative of pyridazinone 100 standard methods are presented in figure 1. When you want to R8was a Br or I, the desired halogen may be in the Eden using NBS or NIS (N-jodatime) in a suitable organic solvent or mixed solvent system, such as DMF, THF-MeOH or AcOH-THF, in the presence of a suitable acid catalyst.

Figure 3 presents the synthesis of compounds 109, 110 and 111, where as the original substances using 2,6-dichloronicotinic acid. Nicotinic acid 103 in turn monochloromethyl acid 104 by boiling under reflux in 2 N. aqueous NaOH according to the method described in U.S. patent No. 3682932. Alkylation of compound 104 with obtaining connection 105 can be achieved under standard conditions the primary alkylation, including the use of alkylhalogenide, using two equivalents of the corresponding alkylhalogenide and the bottom with a mixture of the ester derivative of N-alkylpyridine 105 and ester derived regioisomeric O-alkylpyridine, which are easily separated column chromatography. These conditions include, without limitation, To2CO3in acetone or DMF at room or elevated temperature or NaH in THF at ambient temperature or elevated temperature and then add alkylhalogenide. In some embodiments of this alkylation is achieved with the use of LiH in DMF at 0°C followed by the addition of allylbromide or alkylated and heated to room temperature. Bromination ester derived pyridone 105 can be carried out and the use of either VG 2and acetic acid or NBS in a suitable organic solvent, such as DMF. In some embodiments of NBS are added to a solution of the ester derived pyridone 105 in DMF to obtain compound 106. Conversion of bromide 106 in connection 107 may be achieved using the conditions of the Pd-mediated cross-linking. When R9represents alkenyl or quinil, then you can restore using a suitable reducing agent, to obtain the alkyl substituents on-R9. Typically, this chemical reaction can be carried out using different Pd catalysts and ligands, with the addition of a base or without addition of base, in a suitable organic solvent, such as DMF, PhMe, DME, THF, CH3SP, at elevated temperature. Partner of the combination will depend on the nature of R9. For example, if it is desirable that R9represented CN, partner combination is Zn(CN)2. This reaction can be carried out using Pd2dba3and dppf in NMP (N-organic) at 120°C. the reactions palladium-mediated cross-linking are well documented in the literature and well known to the person skilled in the art. The introduction of an appropriately substituted aniline group in a compound 108 d is attained S NAR reaction. It can be carried out in a suitable organic solvent, such as THF, using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS at appropriate temperatures (-78°C to room temperature). In some embodiments of the aniline is added to LDA or LiHMDS in THF at low temperature (-20 to -80°C). Then add pyridone 105, and the mixture is stirred at low temperature before the formation of ester 108. Can then be obtained carboxylic acid 109 in standard saponification conditions such as LiOH or NaOH in a standard mixed water/organic solvents. Hydroxamate 110 and amide 111 can be obtained by standard methods of combination, including, without limitation, EDCI, HOBt, or Rumor and the appropriate amine or hydroxylamine in a suitable organic solvent, such as DMF, THF or methylene chloride. In some embodiments, the combination is performed with the use of HOBt and EDCI in DMF. In some cases, amine or hydroxylamine used in the reaction mix contains a standard protective group. In such cases, the protective group can be removed under standard conditions known in the art.

4 shows an alternative reaction scheme for the synthesis of compounds 109, 110 and 111. This path is particularly suitable for analogues, where R7not submitted the a Me or Et. Nicotinic acid 103 can be converted into a methyl ester of N-alkylpyridine 114 after conducting simistatin procedure, where first 2,6-dichloro-nicotinic acid 103 in turn methoxypyridine acid, which atrificial to the formation of the methyl ester, and then remove the protection with getting monochloromethyl ether 112. In some embodiments, the transformation in methoxypyridine acid is carried out by adding tert-butoxide potassium to the acid solution 103 in the Meon, and the mixture is then heated to a temperature of reflux distilled in a few days. Etherification with obtaining methyl ester can be carried out under standard conditions, including, without limitation, the Fisher esterification (Meon, H2SO4), TMSCI in the Meon or TMSCHN2in suitable organic solvents, such as h/Meon. Can then be implemented demethylation of methoxypyridine in standard conditions, including, without limitation, HCl at elevated temperature, p-TsOH (p-toluensulfonate acid in acetic acid at elevated temperature and water Nug in the Meon at elevated temperatures. Preferably demethylation with getting pyridone 112 is achieved by processing methoxypyridine water Nug in acetic acid at elevated temperature (80-120°C). Alkylation of compound 112 can be achieved is about standard basic conditions of alkylation, including the use of alkylhalogenide, using one equivalent of the corresponding alkylhalogenide and the bottom with a mixture of ether derivative N-alkylpyridine 113 and ether derivative regioisomeric O-alkylpyridine, which are easily separated column chromatography. These conditions include, without limitation, To2CO3in acetone or DMF at room or elevated temperature or NaH in THF at ambient temperature or elevated temperature and then add alkylhalogenide. In some embodiments of this alkylation is achieved with the use of LiH in DMF at 0°C followed by the addition of allylbromide or alkylated and heated to room temperature. Bromination ester derived pyridone 113 can be performed using either Br2and acetic acid or NBS in a suitable organic solvent, such as DMF. In some embodiments of NBS are added to a solution of the ester derived pyridone 113 in DMF to obtain compound 114. Conversion of bromide 114 115 connection can be achieved using conditions of palladium-mediated cross-linking. When R9represents alkenyl or quinil, then you can restore using a suitable reducing agent to obtain Alki is lnyh substituents for R 9. Typically, this chemical reaction can be carried out using different Pd catalysts and ligands, with the addition of a base or without addition of base, in a suitable organic solvent, such as DMF, h, DME, THF, CH3SP, at elevated temperature. Partner of the combination will depend on the nature of R9. Such reactions Pd-mediated cross-linking are well documented in the literature and well known to the person skilled in the art. The introduction of an appropriately substituted aniline group connection 116 is achieved SNAR reaction. It can be carried out in a suitable organic solvent, such as THF, using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS at appropriate temperatures (-78°C to room temperature). In some embodiments of the aniline is added to LDA or LiHMDS in THF at low temperature (-20 to -80°C). Then add pyridone 115, and the mixture is stirred at low temperature before the formation of ester 116. Transformation connection 116 to carboxylic acid 109, and hydroxamate 110 and amide 111 may be implemented as described for Figure 3. Alternative hydroxamate 110 can be obtained directly from the methyl ester 116 in a suitable organic solvent, such as THF, used with the eating of the corresponding hydroxylamine and amide base, such as LDA, LiHMDS, NaHMDS or KHMDS at appropriate temperatures (-78°C to room temperature). In some embodiments, the solution of LiHMDS added to a solution of ester 116 and hydroxylamine in THF at 0°C. the Reaction mixture was then warmed to room temperature to obtain the desired hydroxamate 110. In some cases, the hydroxylamine used in the reaction mix contains a standard protective group. In such cases, the protective group can be removed under standard conditions known in the art.

Figure 5 presents the reaction scheme for the synthesis of compounds 119, 120 and 121, where as the initial substance use methyl ether N-alkylpyridine 112. The formation of compound 117 can be made as a result of the introduction of appropriately substituted aniline group SNAR reaction. It can be carried out in a suitable organic solvent, such as THF, using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS at appropriate temperatures (-78°C to room temperature). In some embodiments of the aniline is added to LDA or LiHMDS in THF at low temperature (-20 to -80°C). Then add pyridone 112, and the mixture is stirred at low temperature with the receipt of ester 117. This can be accomplished in a suitable organic solvent, such as THF,using an amide base, such as LDA, LiHMDS, NaHMDS or KHMDS at appropriate temperatures (-78°C to room temperature). Chlorination of pyridone 117 with getting pyridone 118 may be carried out using standard conditions, such as NCS (N-chlorosuccinimide) in a suitable organic solvent, such as DMF. Transformation connection 118 to carboxylic acid 119, and hydroxamate 120 and amide 121 may be implemented as described for Figure 3 and 4.

Figure 6 presents the reaction scheme for the synthesis of compounds 124 and 125. 4-Perpiration 123 can be obtained from 4-chloropyridazine 122 by processing KF or HF in the presence or in the absence of a base such as Et3N or Me3N, in suitable organic solvents such as CH3CN, THF, DMF, NMP or DMSO (dimethylsulfoxide). In one embodiment of this transformation is achieved using KF in DMSO at elevated temperature (for example, 160°C). Ester derivative of pyridazinone 123 (when R=Et) can be transformed into pyridazine 124, and the introduction of aniline grouping is achieved by holding the SNAR reaction. It can be carried out in a suitable organic solvent, such as DMF, EtOH, iPrOH, CH3CN or THF, with a base, such as Cs2CO3, Panso3To2CO3or PA2CO3at a temperature of from 80 to 160 is C. In one embodiment of aniline and Cs2CO3added to a solution of pyridazinone 123 in DMF, and the reaction mixture is heated to 80°C. Alternative acid derivative of pyridazinone 123 (R=H) can be transformed into pyridazine 125 standard methods, for example, as shown in figure 2. Pyridazine 124 or 125 can be turned into hydroxamate or amides, as shown in figure 1 or 2.

Figure 7 presents the reaction scheme for the synthesis of compounds 128, 129 and 130, where as the initial substance use methylamine derived pyridone 117. Bromination essential pyridone derivative 117 may be implemented using either Br2and acetic acid or NBS in a suitable organic solvent, such as DMF. Preferably NBS are added to a solution of the ether derivative of pyridone 117 in DMF with getting 126. Conversion of bromide 126 in connection 127, where R9represents cyano, can be achieved using the conditions of the Pd-mediated cross-linking. Typically, this chemical reaction can be carried out using different Pd catalysts and ligands, with the addition of a base or without addition of base, in a suitable organic solvent, such as DMF, h, DME, THF, CH3CN or NMP, at elevated temperature. Preferably this reaction is carried out with and the use of Zn(CN) 2and PD2dba3and dppf in DMF at 120°C. the Conversion of compound 127 in carboxylic acid 128, as well as in hydroxamate 129 and amide 130 may be implemented as described for Figure 3 and 4.

On Fig presents the synthesis of compounds of formula V, where R9represents H or F, where as the original substances using 2,6-dichloro-nicotinic acid or 2,6-dichloro-6-fluoro-nicotinic acid. This path is particularly suitable for analogues, where R7represents Me. Nicotinic acid 140 in turn monochloromethyl acid 141 by boiling under reflux in 2 N. aqueous NaOH according to the method described in U.S. patent 3682932 (1972). Alkylation of compound 141 can be achieved under standard conditions the primary alkylation, including the use of alkylhalogenide, using two equivalents of the corresponding alkylhalogenide and the bottom with a mixture of the ester derivative of N-alkylpyridine and ester derived regioisomeric O-alkylpyridine, which are easily separated column chromatography. These conditions include, without limitation, To2CO3in acetone or DMF at room or elevated temperature or NaH in THF at ambient temperature or elevated temperature and then add alkylhalogenide. Preferably this alkalinemanganese using LiH in DMF at 0°C followed by the addition of allylbromide or alkylated and heated to room temperature. The introduction of an appropriately substituted aniline group connection 143 is achieved by SNAR reaction. It can be carried out in a suitable organic solvent, such as THF, using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS at appropriate temperatures (-78°C to room temperature). Preferably aniline is added to LDA or LiHMDS in THF at low temperature (-20 to -80°C). Then add pyridone, and the mixture is stirred at low temperature with the receipt of ester 143. Carboxylic acid 144 can then be obtained in the standard saponification conditions such as LiOH or NaOH in a standard mixed water/organic solvents. Hydroxamate 145 and amide 146 can be obtained using standard methods of combinations, including, without limitation, EDCI, HOBt, or Rumor and the appropriate amine or hydroxylamine in a suitable organic solvent, such as DMF, THF or methylene chloride. Preferably the combination is performed with the use of HOBt and EDCI in DMF. In some cases, amine or hydroxylamine used in the reaction mix contains a standard protective group. In such cases, the protective group can be removed under standard conditions known in the art.

Figure 9 presents an alternative synthesis connect the developments of the formula V, where R9represents H or F, where as the original substances using 2,6-dichloro-nicotinic acid or 2,6-dichloro-5-fornicating acid. Nicotinic acid 140 can be turned into methylamine derived N-alkylpyridine 149 after conducting platitudinous procedure, where first 2,6-dichloronicotinic acid 140 in turn methoxypyridine acid, which atrificial obtaining methyl ester, and then remove the protection with getting monochloromethyl ether 147. The transformation in methoxypyridine acid is preferably carried out by adding tert-butoxide potassium to a solution of acid 140 in the Meon, and the mixture is then heated to a temperature of reflux distilled in a few days. Etherification with obtaining methyl ester can be carried out under standard conditions, including, without limitation, the Fisher esterification (Meon, H2SO4), TMSCI in the Meon or TMSCHN2in suitable organic solvents, such as h/Meon. Can then be conducted demethylation of methoxypyridine in standard conditions, including, without limitation, HCl at elevated temperature, p-TsOH in acetic acid at elevated temperature and water Nug in the Meon at elevated temperatures. Preferably demethylation with getting pyridone 147 is achieved by processing the methoxy is iridine water Nug in acetic acid at elevated temperature (80-120°C). Alkylation of compound 147 obtaining connection 148 may be achieved under standard conditions the primary alkylation, including the use of alkylhalogenide, using one equivalent of the corresponding alkylhalogenide and the bottom with a mixture of the ester derivative of N-alkylpyridine and ester derived regioisomeric O-alkylpyridine, which are easily separated column chromatography. These conditions include, without limitation, To2CO3in acetone or DMF at room or elevated temperature or NaH in THF at ambient temperature or elevated temperature and then add alkylhalogenide. Preferably this alkylation is achieved with the use of LiH in DMF at 0°C followed by the addition of allylbromide or alkylated and heated to room temperature. The introduction of an appropriately substituted aniline group is achieved by SNAR reaction. It can be carried out in a suitable organic solvent, such as THF, using an amide base such as LDA, LiHMDS, NaHMDS or KHMDS at appropriate temperatures (-78°C to room temperature). Preferably aniline is added to LDA or LiHMDS in THF at low temperature (-20 to -80°C). Then add pyridone, and the mixture is stirred at n is scoi temperature with the receipt of ester 149. Hydroxamate 145 can be obtained directly from the methyl ester 149 in a suitable organic solvent, such as THF, using the appropriate hydroxylamine and amide base such as LDA, LiHMDS, NaHMDS or KHMDS at appropriate temperatures (-78°C to room temperature). Preferably a solution of LiHMDS added to a solution of methyl ester 149 and hydroxylamine in THF at 0°Sreaction the mixture was then warmed to room temperature to obtain the desired hydroxamate 145. In some cases, the hydroxylamine used in the reaction mix contains a standard protective group. In such cases, the protective group can be removed under standard conditions known in the art.

In another aspect of the present invention, a method for obtaining compounds of formula IA, including:

the interaction of the compounds of formula 100 or 101

with R3NH2in the presence of either (1) a reagent combinations when R3the same as defined in formula IA, or (2) amide base, when R3the same as defined in formula IA, except that R3does not represent H or Me, with receipt of the compounds of formula IA.

In another aspect of the present invention, a method for obtaining compounds of formula IV, on the make:

the interaction of the compounds of formula 108 or 109

with R3NH2where R3such as defined in the formula IV, in the presence of either (1) a reagent combination, or (2) amide base, when R3the same as defined in formula IV, except that R3does not represent H or Me.

In another aspect of this invention, a method for obtaining compounds of formula VI, including:

(a) bromination of compounds having the formula 105,

where R represents alkyl, with the connection 106

;

(b) interaction connection 106 with Zn(Me)2 in the presence of palladium catalyst and ligand and possibly in the presence of a base to obtain compound 107

;

(C) interaction connection 107 with aniline having the formula

,

in the presence of a palladium catalyst, a phosphine ligand and amide base with connection 108

;

(g) hydrolysis of compound 108 in alkaline conditions to obtain compound 109

; and

(d) interaction or connection 108 or connection 109 with R3NH2or in the presence (1) of the reagent with Etania, when R3the same as defined in formula VI, or (2) amide base, when R3the same as defined in formula VI, except that R3is not H, to obtain the compounds of formula VI.

In one of the embodiments, connection 105 receiving method including:

(a) the interaction of compounds 103

with aqueous sodium hydroxide to obtain connection 104

; and

(b) interaction connection 104 with RX, where R represents Me, and X is a halide, in the presence of a base to obtain compound 105.

In another aspect of the present invention, a method for obtaining compounds of formula II, including:

(a) interaction of hydrazine having the formula Me-NH-NH2with:

(1) diethyl-2-oxomalonate with subsequent processing allermuir reagent that delivers an acyl group having the formula C(=O)CH2R9where R9such as defined in the formula II, or

(2) allermuir reagent that delivers an acyl group having the formula C(=O)CH2R9where R9the same as defined in formula II, with subsequent treatment with diethylmalonate getting connection 97

;

(b) treating compound 97 amide base when power is re below -40°C followed by treatment with concentrated HCl to obtain the compounds of formula 98

;

(b) chlorination of compound 98 connection 99

;

(g) communicating connection 99 with aniline having the formula

,

in the presence of a palladium catalyst, ligand and amide base with connection 100

; and

(d) the interaction of the compounds of formula 100 with R3NH2or in the presence of (1) reagent combinations when R3such as defined in the formula II, or (2) amide base, when R3the same as defined in formula II, except that R3is not H, to obtain the compounds of formula II.

In another aspect of the present invention, a method for obtaining compounds of formula II, where R9represents H, Me or Cl, including:

(a) interaction of hydrazine having the formula Me-NH-NH2with:

(1) diethyl-2-oxomalonate with subsequent processing allermuir reagent that delivers an acyl group having the formula C(=O)CH2R9where R9represents H, Me, or Cl; or

(2) allermuir reagent that delivers an acyl group having the formula C(=O)CH2R9where R9represents H, Me or Cl, with subsequent treatment with diethylmalonate with poluchenierazreshenija 97

;

(b) treating compound 97 amide base at a temperature below -40°C To produce the compounds of formula 98

;

(b) chlorination of compound 98 connection 99

;

(g) communicating connection 99 with aniline having the formula

,

in the presence of the amide base to obtain compound 101

; and

(d) communicating connection 101 with R3NH2or in the presence of (1) reagent combinations when R3such as defined in the formula II, or (2) amide base, when R3the same as defined in formula II, except that R3is not H, to obtain the compounds of formula II.

In another aspect of the present invention, a method for obtaining compounds of formula V, where R9represents Me, including:

(a) bromination of compounds having the formula 105,

where R represents alkyl, with the connection 106

;

(b) interaction connection 106 with Zn(Me)2in the presence of palladium catalyst and ligand and possibly in the presence of a base to obtain compound 107

;

(the) interaction connection 107 with aniline, those having the formula : F

,

in the presence of the amide base with connection 108

;

(g) hydrolysis of compound 108 in alkaline conditions to obtain compound 109

; and

(d) interaction or connection 108 or connection 109 with R3NH2where R3the same as defined in formula V, in the presence of reagent combinations or amide base to obtain the compounds of formula V.

In another aspect of this invention, a method for obtaining compounds of formula V, where R9represents Cl, including:

(a) interactions of the compounds of formula 112

with aniline having the formula

,

in the presence of the amide base to obtain compound 117

;

(b) chlorination of compound 117 getting connection 118

; and

(C) possible hydrolysis connection 118 with getting connections 118A

;

(g) interaction or connection 118 or connections 118A with (S)-MeCH(OH)CH2ONH2or HOCH2CH2ONH2in the presence of reagent combinations or amide base to obtain the compounds of formula V.

Another is the SPECTA of the present invention, a method for obtaining compounds of formula V, where R9represents H or F, including:

(a) treatment of compounds of formula 140,

where R9represents H or F, water NaOH getting connection 141

;

(b) interaction of compound 141 with CH3X, where X is a halide, in the presence of a base to obtain compound 142

;

(C) interaction connection 142 with aniline having the formula

,

in the presence of the amide base to obtain compound 143

;

(g) hydrolysis of compound 143 getting connection 144

; and

(d) interaction or connection 143 or connection 144 with R3NH2where R3the same as defined in formula V, in the presence of reagent combinations or amide base to obtain the compounds of formula V.

In one embodiment of the above methods agent combination is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 1-hydroxybenzotriazole-6-sulfonamidophenylhydrazine or benzotriazol-1-yl-oxytropidoceras.

In another aspect of the present invention, a method of using compounds according to this invention as Les is artenova tools for the treatment of diseases or medical conditions, mediated by MEK. For example, according to this invention proposed a connection according to this invention as a drug for the treatment of hyperproliferative disorders, or inflammatory conditions in a mammal, comprising an introduction to the specified mammal one or more compounds of the present invention or their pharmaceutically acceptable salts or prodrugs in amounts effective for the treatment of this hyperproliferative disorders. In another aspect of the present invention proposed a connection according to this invention in the manufacture of medicinal products for the treatment of hyperproliferative disorders, or inflammatory conditions.

In another aspect of the present invention, a method for production of MEK inhibition effect in a warm-blooded animal, such as man, in need of such treatment, comprising the introduction of a specified animal an effective amount of the compounds according to this invention.

In another aspect of the present invention proposed treatment or prevention of a condition mediated MEK, including the introduction of a human or animal in need of this, pharmaceutical compositions containing the compound of the present invention or its pharmaceutically acceptable salt or in vivo split prole the arstvo in number, effective for the treatment or prevention of this condition, mediated by MEK.

The invention also relates to pharmaceutical compositions which inhibit MEK containing an effective amount of a compound selected from the compounds of the present invention or their pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, or pharmaceutically acceptable salts.

The invention also relates to pharmaceutical compositions for the treatment of hyperproliferative disorders in a mammal, soderjashie therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate and a pharmaceutically acceptable carrier. In one embodiment of specified pharmaceutical composition intended for the treatment of cancer such as brain cancer, lung cancer, squamous cell cancer, bladder cancer, stomach cancer, pancreatic cancer, breast cancer, cancer of the head and neck, kidney cancer, ovarian cancer, prostate cancer, cancer of the colon and rectum, cancer of the esophagus, cancer of the testis, gynecological cancer, or thyroid cancer. In another embodiment of specified pharmaceutical composition intended for the treatment of hyperproliferative disorders, noncancerous nature, such as dobrogicus the public hyperplasia of the skin (for example, psoriasis), restenosis, or disorder of the prostate (e.g., benign prostatic hypertrophy (national Department of standardization)).

The invention also relates to pharmaceutical compositions for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephritis and induced diabetes renal disease) or treatment of pain in a mammal containing a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate and a pharmaceutically acceptable carrier.

The invention also relates to pharmaceutical compositions for the prevention of implantation of blastocytes the mammal containing a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate and a pharmaceutically acceptable carrier.

The invention also relates to pharmaceutical compositions for the treatment of diseases associated with vasculogenesis or angiogenesis in a mammal containing a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate and a pharmaceutically acceptable carrier. In one embodiment of specified pharmaceutical composition purpose is to cure the disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease or other inflammatory condition such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retrolental fibroplasia, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, cancer of the colon and epidermoid cancer.

The invention also relates to a method of treatment of hyperproliferative disorders in a mammal, comprising an introduction to the specified mammal therapeutically effective amounts of compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate. In one embodiment of this method relates to the treatment of cancer such as brain cancer, lung cancer, squamous cell cancer, bladder cancer, stomach cancer, pancreatic cancer, breast cancer, cancer of the head and neck, kidney cancer, ovarian cancer, prostate cancer, cancer of the colon and rectum, cancer of the esophagus, cancer of the testis, gynecological cancer, or thyroid cancer. In another embodiment of this method relates the I to the treatment of hyperproliferative disorders, noncancerous nature, such as benign hyperplasia of the skin (e.g. psoriasis), restenosis, or disorder of the prostate (e.g., benign prostatic hypertrophy (national Department of standardization)).

The invention also relates to a method of treatment of hyperproliferative disorders in a mammal, comprising an introduction to the specified mammal therapeutically effective amounts of compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate in combination with an antitumor agent selected from the group consisting of inhibitors of mitosis, alkylating agents, antimetabolites, intercalating antibiotics, inhibitors of growth factors, inhibitors of cell cycle enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors and anti-androgens.

The invention also relates to a method of treating pancreatitis or kidney disease in a mammal, comprising an introduction to the specified mammal therapeutically effective amounts of compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate.

The invention also relates to a method of preventing implantation of blastocytes in a mammal, comprising an introduction to the specified mlekovita is it therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate.

The invention also relates to a method for treatment of diseases associated with vasculogenesis or angiogenesis in a mammal, comprising an introduction to the specified mammal therapeutically effective amounts of compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate. In one embodiment the method is for treatment of a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory diseases, such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes, diabetic retinopathy, retrolental fibroplasia, age-related macular degeneration, hemangioma, glioma, melanoma, sarcoma Galoshes and of ovarian cancer, breast cancer, lung cancer, pancreatic cancer, prostate cancer, cancer of the colon and epidermoid cancer.

The invention also relates to pharmaceutical compositions for the treatment of a disease or condition associated with an inflammatory disease, autoimmune disease, destructive bone disorders, proliferative disorders, infectious disease, viral disease, fibrotic disease or neurod the generative disease in a mammal, containing a therapeutically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, prodrug or hydrate and a pharmaceutically acceptable carrier. Examples of the above-mentioned diseases and/or conditions include, but are limited to, rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, eczema and scleroderma, diabetes and diabetic complications, diabetic retinopathy, retrolental fibroplasia, age-related macular degeneration, hemangioma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, allergic reactions, including asthma, allergic rhinitis and atopic dermatitis, renal disease and renal failure, polycystic renal disease, acute coronary syndrome, congestive heart failure, osteoarthritis, neurofibromatosis, rejection of organ transplants, cachexia and pain.

In addition, the compound of the present invention is proposed for use as drugs in treating above-described diseases and conditions in a warm-blooded animal, preferably a mammal, more preferably a person suffering from this disorder. Also proposed the use of compounds according to the present from which briteney in the manufacture of drugs for the treatment of the above diseases and conditions in a warm-blooded animal, preferably a mammal, more preferably a person suffering from this disorder.

Patients who can be treated by the compounds of the present invention or pharmaceutically acceptable salts, prodrugs and hydrates of these compounds in accordance with the methods according to this invention include, for example, patients diagnosed with psoriasis, restenosis, atherosclerosis, national Department of standardization, lung cancer, bone cancer, chronic myelomonocytic leukemia (CMML), pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer cancer, tumors of the testicles, gynecologic tumors (e.g., sarcoma of the uterus, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, esophageal cancer, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid glands or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumor in children, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis) or tumor in the Central the main system (for example, primary Central nervous system lymphoma, tumors of the spine, gliomas of the brainstem or pituitary adenomas).

The invention also relates to a pharmaceutical composition for inhibiting abnormal cell growth in a mammal containing a certain number of compounds of the present invention or its pharmaceutically acceptable salt or MES or prodrug in combination with a number of chemotherapeutic drugs, and the number of connections, salt, MES or prodrugs and chemotherapeutic are together effective in inhibiting abnormal cell growth. Currently in the art will know of many chemotherapeutic agents. In one embodiment of the chemotherapeutic agent selected from the group consisting of inhibitors of mitosis, alkylating agents, antimetabolites, intercalating antibiotics, inhibitors of growth factors, inhibitors of the cell cycle, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors and anti-androgens.

In another aspect of the present invention proposed pharmaceutical compositions which inhibit MEK containing one or more compounds of the present invention.

In addition, the invention relates to a method of inhibiting an the high cell growth in a mammal or treating a proliferative disorder, includes introduction to the mammal a number of compounds of the present invention or its pharmaceutically acceptable salt or MES or prodrug in combination with radiation therapy, where the number of connections, salt, MES or prodrug in combination with the radiation therapy effective in inhibiting abnormal cell growth or treating a proliferative disorder in a mammal. Techniques of radiation therapy known in the art, and these techniques can be used in this combination therapy. Introduction compounds according to the invention in such combination therapy can be determined, as described in this specification.

It is expected that the compounds of the present invention can make abnormal cells more sensitive to treatment with radiation for purposes of cell lysis and/or inhibiting the growth of such cells. Accordingly, the invention also relates to a method of sensitizing abnormal cells in a mammal to treatment with radiation, including introduction this mammal the compounds of the present invention or its pharmaceutically acceptable salt or MES or prodrug in an amount which is effective in sensitizing abnormal cells to treatment with radiation. The number of compounds, salts resolute in this way can be determined according to techniques of identifying effective amounts of such compounds, described in this specification.

Compounds according to the invention can be mostly used in combination with other known therapeutic agents. For example, the invention also relates to a method and pharmaceutical composition for inhibiting abnormal cell growth in a mammal, which contains a number of compounds of the present invention or its pharmaceutically acceptable salt or MES, its prodrugs or its isotope-labeled derivative and a number of one or more substances selected from antiangiogenetic agents, inhibitors of signal transduction and antiproliferative agents.

Antiangiogenesis agents, such as inhibitors of MMP-2 (matrix metalloproteinase 2)inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors SOH-11 (cyclooxygenase II), can be used together with the compound of the present invention and pharmaceutical compositions described herein. Examples of useful inhibitors SOH-II include CELEBREX™ (elecoxib), valdecoxib and rofecoksib. Examples of useful inhibitors of matrix metalloproteinases described in WO 96/33172, WO 96/27583, EP 818442, EP 1004578, WO 98/07697, WO 98/03516, WO 98/34918, WO 98/34915, WO 98/33768, WO 98/30566, EP 606046, EP 931788, WO 90/05719, WO 99/52910, WO 99/52889, WO 99/29667, WO 99/07675, EP 945864, U.S. patent No. 5863949, U.S. patent No. 5861510 and E is 780386, which in their entirety are included in this description by reference. Preferred inhibitors of MMP-2 and MMP-9 are inhibitors possessing insignificant activity inhibition of MMP-1 or no such activity. More preferred are the inhibitors that selectively inhibit MMP-2 and/or MMP-9 compared to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13).

The term "abnormal cell growth" and "hyperproliferative disorder" are used in this application interchangeably.

"Abnormal cell growth", as used herein and unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (e.g., loss of contact inhibition). It includes, for example, an abnormal growth of: (1) tumor cells (tumors)that have proliferated in the result of ekspressirovali mutant tyrosine kinase or overexpression of the receptor tyrosine kinase; (2) benign or malignant cells of other proliferative diseases in which aberrant activation of tyrosine kinase; (3) any tumors that proliferate under the action of the receptor tyrosinekinase; (4) any tumors that proliferate in aberrante the activation of the serine/trainingin; and (5) benign and malignant cells of other proliferative diseases in which there is aberrant activation of the serine/trainingin.

The term "treatment"as used herein and unless otherwise indicated, means reversing, alleviating, inhibition of the development or prevention of a disorder or condition to which to apply such a term, or one or more symptoms of such disorder or condition. The term "treatment"as used herein and unless otherwise indicated, also refers to the act of treating, as "treating", which is defined directly above.

The number of times a given agent that will correspond to such an amount will vary depending on such factors as the particular compound, disease state and its severity, the identity (e.g., weight) of the mammal in need of treatment, but may nevertheless be routinely determined by a person skilled in the art. It is assumed that the "treatment" means at least the relief of painful conditions in a mammal, such as man, which is exposed to, at least partially, the activity of MEK, and includes, without limitation, the prevention of a pathological state in a mammal, in particular when found that ml is kopituse has a predisposition to morbid state, but the diagnosis that he has not yet delivered; modulating and/or inhibiting the disease condition; and/or weakening of the painful condition.

To use the compound of the present invention or its pharmaceutically acceptable salt or a prodrug for therapeutic treatment (including prophylactic treatment) of mammals including humans, it is usually administered in the form of pharmaceutical compositions in accordance with standard pharmaceutical practice. According to this aspect of the invention proposed pharmaceutical composition which contains a compound of the present invention or its pharmaceutically acceptable salt or prodrug, as defined above, together with a pharmaceutically acceptable diluent or carrier.

To prepare the pharmaceutical compositions according to one embodiment of the present invention is a therapeutically or prophylactically effective amount of the compounds of the present invention or its pharmaceutically acceptable salt, MES, metabolite or prodrug (alone or together with an additional therapeutic agent) is first mixed with a pharmaceutically acceptable carrier according to conventional pharmaceutical techniques of mixing to obtain the dose. The carrier may take various forms depending on army drug desired for administration, e.g. oral, or parenteral. Examples of suitable carriers include any and all solvents, dispersion media, adjuvants, coatings, antibacterial and antifungal agents, isotonic agents, and agents that slow down the absorption, sweeteners, stabilizers (for long-term storage), emulsifiers, binding agents, thickening agents, salts, preservatives, solvents, corrigentov and mixed substances, such as buffers and absorbents that may be required to prepare a particular therapeutic composition. The use of such media and agents with pharmaceutically active substances is well known in this field. Their use in therapeutic compositions and preparations assumes, except in cases where any conventional medium or agent is incompatible with the compound of the present invention. In the compositions and preparations described in this description can also include additional active ingredients.

The composition of the invention can be in a form suitable for oral use (for example, in the form of tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example, in videorama, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example in the form of fine powder or a liquid aerosol), for administration by insufflating (for example, in the form of a fine powder) or for parenteral administration (for example, in the form of a sterile aqueous or oily solution for intravenous, subcutaneous or intramuscular injection or as a suppository for rectal administration). For example, compositions intended for oral use may contain, for example, one or more coloring agents, sweeteners, corrigentov and/or preservatives.

Suitable pharmaceutically acceptable excipients for a tablet of the drug include, for example, inert diluents, such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulating agents and disintegrating agents such as corn starch or alginic acid; binding agents such as starch; lubricating agents such as magnesium stearate, stearic acid or talc; preservative agents such as ethyl - or propyl-p-hydroxybenzoate; and antioxidants, such as ascorbic acid. Tablet drugs may not be coated or can be coated or to modify their raspadaemosti and subsequent absorption of the active ingredient in the stomach and ASECNA tract, or to improve their stability and/or appearance, in both cases using conventional coating agents and techniques, well known in this field.

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

Typically, aqueous suspensions contain the active ingredient in finely powdered form together with one or more suspendresume agents such as sodium carboxymethyl cellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and Arabic gum; dispersing or wetting agents such as lecithin or condensation products of accelerated with fatty acids (for example, polyoxyethylenated), or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with partial esters derived from fatty acids and exit, such as Policia resolutionaries, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides of exit, such as polyethylenterephthalat. Aqueous suspensions may also contain one or more preservatives (such as ethyl - or propyl-p-hydroxybenzoate), antioxidants (such as ascorbic acid), colorants, corrigentov and/or sweeteners (such as sucrose, saccharin or aspartame).

Oil suspensions can be prepared by suspension of the active ingredient in a vegetable oil (such as peanut butter, olive oil, sesame oil or coconut oil) or mineral oil such as liquid paraffin). Oily suspensions may also contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. To impart a pleasant taste to oral compositions can be added sweeteners, such as sweeteners mentioned above, and corrigentov. To save these compositions can be added such antioxidant like ascorbic acid.

Dispersible powders and granules suitable for preparation of the aqueous slurry by adding water, usually contain the active ingredient together with a dispersing or wetting agent, suspenders agent and one or more preservatives. Examples of suitable disingenuous the x or wetting agents and suspendida agents listed above. There may be additional excipients, such as sweeteners, corrigentov and dyes.

The pharmaceutical compositions according to the invention can also be in the form of emulsions of the type oil-in-water. The oil phase may be a vegetable oil, such as olive oil or peanut oil, or mineral oil, such as, for example, liquid paraffin, or a mixture of any of them. Suitable emulsifying agents may be, for example, gums of natural origin, such as the Arabian gum or tragacanth gum, phosphatides of natural origin, for example soy bean, lecithin, esters or partial esters derived from fatty acids and anhydrides of exit (for example, servicemanual), and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweeteners, corrigentov and preservatives.

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

Pharmaceutical compositions can also be in the form of sterile injectable aqueous or oily suspension which can be prepared according to known the m methods using one or more appropriate dispersing or wetting agents and suspendida agents, which are mentioned above. Sterile injectable composition may also be a sterile(th) injection(th) a solution or suspension in a non-toxic, suitable for injecting diluent or solvent, for example a solution in 1,3-butanediol.

Suppozitornyj compositions can be prepared by mixing the active ingredient with a suitable, not causing irritation excipient, 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 and polyethylene glycols.

Compositions for topical application such as creams, ointments, gels, and aqueous or oil solutions or suspensions, in the General case can be obtained by combining the active ingredient with a traditional, suitable for local use filler or diluent using standard techniques, well known in this field.

Compositions for administration by insufflating can be in the form of a fine powder containing particles of average diameter of, for example, 30 μm or much less, the powder contains the active ingredient either alone or diluted with one or more physiologically acceptable carriers, t is Kimi as lactose. Conveniently then powder for insufflation placed in a capsule containing, for example, 1-50 mg of active ingredient, for use in turbomaschinen device, such as a device that is used for insufflation known agent sodium cromoglycate.

Compositions for administration by inhalation may be in the form of a traditional aerosol under pressure, adapted for dispensing active ingredient or in the form of an aerosol containing fine solid or in the form of liquid droplets. Can be used conventional aerosol propellants such as volatile fluorinated hydrocarbons or hydrocarbons, and comfortable, if a spray device adapted for dispensing a measured amount of the active ingredient.

For more information on the technology of preparation of compositions can be found in Chapter 25.2 in volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press, 1990, which is incorporated in this description by reference.

The number of compounds according to this invention, which combine with one or more excipients for the manufacture of a single dosage form will necessarily vary depending on the exposed treatment of the subject, the severity of the disorder or condition, rate of administration, the nature of the connection and choice of physician. Nevertheless the, the effective dosage is in the range from about 0.001 to about 100 mg per kg of body weight per day, preferably from about 1 to about 35 mg/kg/day, in single or divided doses. For a person weighing 70 kg, this amount will be from about 0.07 to 2,45 g/day, preferably from about 0.05 to about 1.0 g/day. In some cases, the levels of dosages lower than the lower limit of the above range may be more than adequate, while in other cases, there may be used higher doses, causing no harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day. For more information on routes of administration and dosing schedules refer to Chapter 25.3 in volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press, 1990, which is incorporated in this description by reference.

The magnitude of the dose of the compounds of the present invention for therapeutic or prophylactic purposes will naturally vary depending on the nature and severity of the condition, age and sex of the animal or patient and the route of administration, according to well known principles of medicine.

Compounds according to this invention can be used alone or in combination with other uses is suspended in the treatment of painful conditions medicines and therapies, when are useful in the inhibition of the MEK. Such treatment may include, in addition to the compounds according to the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anticancer agents:

(1) antiproliferative/antineoplastic drugs and their combinations, which are used in medical Oncology, such as alkylating agents (for example, cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen analogue of mustard, melphalan, chlorambucil, busulfan, temozolomide and nitrosoanatabine); antimetabolites (for example gemcitabine, antifolates, such as ftorpirimidinu like 5-fluorouracil and tegafur, raltitrexed, methotrexate, citizenoriented, hydroxyurea, or one of the preferred antimetabolites disclosed in European patent application No. 239362 such as N-(5-[N-(3,4-dihydro-2-methyl-4-oxoindole-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamic acid); antitumor antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubitsina, mitomycin-C, dactinomycin and mithramycin); antimitoticescoe agents (for example Vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine, and taxaide like Taxol and taxes is Theroux, and inhibitors of polo-kinase); and topoisomerase inhibitors (for example, epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);

(2) cytostatic agents such as antiestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and idoxifene), step-down regulators of estrogen receptors (for example fulvestrant), antiandrogens (for example, bikalutamid, flutamide, nilutamide, cyproterone acetate and Casodex™ (4'-cyano-3-(4-perpenicular)-2-hydroxy-2-methyl-3'-(trifluoromethyl)propionanilide)), LHRH antagonists (releasing factor, luteinizing hormone or LHRH agonists (for example goserelin, laporan and buserelin), POCs (for example, megestrol acetate), aromatase inhibitors (for example, aseanstats, letrozole, varsol and exemestane) and inhibitors of 5α-reductase such as finasteride;

(3) antiinvasive agents (for example, inhibitors of c-Src kinase family and inhibitors of metalloproteinases, such marimastat, and inhibitors of the functioning of the receptor plasminogen activator urokinase or antibodies to heparanase);

(4) inhibitors of the function of growth factors, such antibodies to growth factors, antibodies to receptors of growth factors (e.g., anti-erb2-antibody tristanusa [Herceptin™], anti-GFR(the receptor for epidermal growth factor)-antibody panitumumab and the anti-erbb1-EN is Italo cetuximab [Erbitux C225]and any antibodies to growth factors or receptors of growth factors, revealed in Stern et al. Critical Reviews in Oncology/Haematology, 2005, vol.54, pp.11-29): such inhibitors include inhibitors tyrosinekinase (for example, inhibitors tyrosinekinase family of epidermal growth factors, such as N-(3-chloro-4-forfinal)-7-methoxy-6-(3-morpholinopropan)hinzelin-4-amine (gefitinib, AZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)hinzelin-4-amine (erlotinib, OSI-774) and 6-acrylamide-N-(3-chloro-4-forfinal)-7-(3-morpholinopropan)-hinzelin-4-amine (CI 1033)), inhibitors erb2-tyrosinekinase, such as lapatinib inhibitors family of growth factors hepatocyte inhibitors family of growth factors from platelets, such as imatinib, inhibitors of serine/trainingin (for example, inhibitors of Ras/Raf signalling pathway, such as inhibitors farnesyltransferase, for example sorafenib (BAY 43-9006)), inhibitors of cell signaling through kinase MEK and/or ACT (protein kinase C)inhibitors of the family growth factors hepatocyte, inhibitors of C-kit kinase inhibitors bl, inhibitors of receptor kinase IGF (insulin-like growth factor); inhibitors of kinases of the Aurora family (for example AZD1152, RN, VX-680, MLN8054, R763, MR, MR, VX-528 and AH) and inhibitors of cyclin-dependent kinases (cdks), such as inhibitors of CDK2 and/or CDK4;

(5) antiangiogenic agents, such as agents that inhibit the effects of vascular endothelial growth factor (VEGF) (e.g., an antibody against growth factor VA is circular endothelial cells bevacizumab [Avastin™], and inhibitors of the receptor tyrosinekinase to VEGF, such as 4-(4-bromo-2-foronline)-6-methoxy-7-(1-methylpiperidin-4-ylethoxy)hinzelin (ZD6474; Example 2 within WO 01/32651), 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-pyrrolidin-1 ipropose)hinzelin (AZD2171; Example 240 within WO 00/47212), vatalanib (RTK; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), connection as, for example, disclosed in publications of international applications No. WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354)and compounds acting via other mechanisms (for example, linomide inhibitors function αγβ3-integrins, MMP inhibitors, inhibitors SOH-2 and angiostatin);

(6) agents that damage the blood vessels, such as combretastatin A4 and compounds disclosed in the publications of international applications No. WO 99/02166, WO 0/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213;

(7) antisense therapy (e.g., therapies that are aimed at targets listed above, such as ISIS 2503, an anti-ras antisense);

(8) gene therapeutic approaches, including, for example, GVAX™, approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT approaches (gene-directed enzyme proletarienne therapy), such as approaches using sitoindosides, timedancing or bacterial enzyme nitroreductase, and approaches to improve tolerance patients chemotherapy or radiotherapy, such as gene therapy multilocational sustainability;

(9) and terferon; and

(10) immunotherapy approaches, including for example ex vivo and in vivo approaches to increase the immunogenicity of tumor cells, such as transfection with cytokines, such as interleukin-2, interleukin 4 or granulocyte-macrophage colony-stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as transfected cytokines dendritic cells, approaches using transfected cytokines tumor cell lines and approaches using antiidiotypic antibodies.

This combined treatment can be achieved by simultaneous, sequential or separate introduction of individual components of the treatment. In such combination products employ the compounds of this invention within the dosage range described above, and the other pharmaceutically active agent within its prescribed dose range.

According to this aspect of the invention proposed pharmaceutical product containing the compound of the present invention, as defined herein, and an additional anticancer agent, as defined above, for the combined treatment of cancer.

Despite the fact that the compounds of the present invention is primarily useful as a therapist is ical agents for use in warm-blooded animals (including humans), they are also useful wherever it is necessary to inhibit the effects of MEK. Thus, they are useful as pharmacological standards for use in the development of new biological tests and the search for new pharmacological agents.

Representative compounds of the present invention, which are covered by the present invention include, without limitation, compounds, examples of which are shown, and their pharmaceutically acceptable salts accession acid or base or their prodrugs. The examples below are intended to illustrate specific embodiments of the invention and are in no way intended to limit the scope of the invention.

Describe all publications cited herein, including patents, are included in this description by reference.

In another embodiment of the proposed invention the product of manufacture or "set"containing substances useful for the treatment of the disorders described above. In one embodiment the kit includes a container containing the compound of the present invention or its containing composition. The kit can also include a label or leaflet in the package. The term "insert" is used to refer to the instructions, usually invest in industrial packaging of therapeutic products, that contain information the s on indications, use, dosage, introduction, contraindications and/or warnings concerning the use of such therapeutic products. Suitable containers include, for example, bottles, vials, syringes, blister packing, etc. of the Container may be formed from various materials, such as glass or plastic. The container contains a compound of the present invention or its containing composition, which is effective for treating the condition and may have a sterile inlet (for example, the container may be a bag for intravenous solutions or vial having a stopper which can be punctured by a needle for subcutaneous injection). The label or leaflet may contain an indication that the composition is used for treating the condition of choice, such as cancer. In one embodiment of the labels or leaflets contain indications that the compound of the present invention or its containing composition can be used to treat diseases or medical conditions mediated by MEK. In addition, the label or package insert may indicate that the patient should be treated, is patient with such a disease or medical condition mediated MEK as a hyperproliferative disorder or an inflammatory condition. tiketti or flyer insert may also contain instructions on the composition may be used to treat other disorders. Alternative or in addition, the product may further include a second container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution and dextrose. It may optionally contain other substances which from the point of view of the seller and the consumer is desirable, including other buffers, diluents, filters, needles and syringes.

According to another embodiment, the kit may include a first container placed in him by the connection of the present invention or its containing composition, and possibly (b) a second container placed in a second pharmaceutical composition, the second pharmaceutical composition comprises a second compound with anti-proliferative or anti-inflammatory activity. Alternative or in addition, the product may additionally include a third container containing a pharmaceutically acceptable buffer, such as bacteriostatic water for injection (BWFI), phosphate buffered saline, ringer's solution and dextrose. It may additionally include other substances, which is desirable from the point of view of the seller and the consumer, including other buffers, diluents, filters, needles and syringes.

The kit may optionally include instructions for administering the compounds of the present invention or its containing composition and, if present, the second pharmaceutical composition. For example, if the set includes the connection of the present invention or its containing composition (first composition and the second pharmaceutical composition, the kit may optionally include instructions for simultaneous, sequential or separate maintenance of the first and second pharmaceutical compositions to the needy in this patient.

In another embodiment, the kits are suitable for the delivery of solid oral forms of the compounds of the present invention, such as tablets or capsules. Such a kit preferably includes a lot of standard dosages. Such kits can include a card with dosages oriented in the order of their intended use. An example of such a set is a "blister pack". Blister packs are well known in the packaging industry and are widely used for packing standard pharmaceutical dosage forms. If this is desirable, it may be provided with a checklist, for example, in the form of numbers, letters, or other characters, or calendar-liner, which shows the days of the regimen, which may be the administered dose.

In some other embodiments, where the set includes a compound of the present invention or its containing composition and the second therapeutic agent, the kit may include a container to be placed in a separate component, such as sectional vial or sectional foil bag, however, the separate compositions may also be in a single, undivided container. Typically, the kit includes instructions for the introduction of individual components. The form kit is especially useful in cases where separate components are preferably administered in different dosage forms (e.g., oral and parenteral), injected with different dosing intervals, or when prescribed by a doctor, preferably titration of the individual components of the combination.

Biological assays

To measure the effects of compounds of the present invention as inhibitors of MEK can be used in the following tests.

Example

Analysis of enzyme MEK (test 1A)

The activity of the compounds of the present invention can be determined by the following method. 6His-tagged N-end constitutive active MEK-1 (2-393) Express in E.li, and proteins purified by standard methods (Ahn et al., Science, 1994, 265, 966-970). Activity MEK appreciate through out erenia inclusion γ 33P-phosphate from γ-33P-ATP in the His-tagged N-end ERK2, which is expressed in E.li and purified by standard methods, in the presence of MEK-1. The analysis is performed in 96-well polypropylene plate. The incubation mixture (100 μl) consisting of 25 mm Hepes, pH of 7.4, 10 mm MgCl2, 5 mm β-glycerol, 100 μm Na-orthovanadate, 5 mm DTT (dithiotreitol), 5 nm MEK and 1 μm ERK2. Inhibitors suspended in DMSO, and all of the reaction mixture, including controls, are prepared at a final concentration of 1% DMSO. The reaction initiated by addition of 10 μm ATP (0.5 µci γ-33P-ATP/well), and the reaction mixture is incubated at ambient temperature for 45 minutes. To stop the reaction and precipitate proteins add an equal volume of 25%TCA (trichloroacetic acid). Precipitated precipitated proteins catch on the filter plates In fiberglass, and excess labeled ATP washed using harvester Tomtec MACH III. Tablets leave to air dry, then add the Packard Microscint 20 at the rate of 30 ál/well, and tablets read using a Packard TopCount.

Example B

Cellular analysis of the phosphorylation of ERK 1/2 (test 1B)

The properties of the compounds according to the invention in relation to inhibition of MEK 1/2 can be defined as cellular in vitro assays. The background inhibition of the phosphorylation of ERK1/2 was determined by incubation of the cells with compound for 1 hour and quantitative measurement of fluorescent signal pERK on fixed cells and bring to the signal and total ERK.

Materials and methods: cells Malme-3M received from ATS (American type culture collection) and were grown in RPMI-1640, supplemented with 10% serum fetal cows. Cells were planted in 96-well tablets at 15,000 cells/well and gave them the opportunity to attach within 1-2 hours. Then add the diluted compounds at a final concentration of 1% DMSO. After 1 hour, cells were washed in PBS and fixed in 3.7% formaldehyde in PBS for 15 minutes. Then washed in a mixture of PBS/0.2% Triton X-100 and subjected to permeabilization 100% Meon within 15 minutes. Cells were blocked in blocking buffer Odyssey (LI-COR Biosciences) for at least 1 hour. To the cells was added antibodies against phosphorylated ERK 1/2 (Cell Signaling, No. 9106, monoclonal) and total ERK 12 (Santa Cruz Biotechnology, No. sc-94, polyclonal) and incubated for at least 1 hour. After washing with a mixture of PBS/0.2% Triton X-100, cells were incubated with labeled fluorescent-labeled secondary antibodies (anti-rabbit IgG-IRDye800 goat, Rockland, and anti-mouse IgG-Alexa Fluor 680 goat, Molecular Probes) for one hour. Then cells were washed and analyzed for fluorescence at both wavelengths, using the visualization system in the infrared region of the Odyssey (LI-COR Biosciences). The signal of phosphorylated ERK led to signal total ERK.

The example In

Analysis of solubility in water

Thermodynamic rastvorimo the ü in water of the compounds measured, using a modified method of shaking the flask. The crystallinity of each of the compounds were confirmed using a polarizing optical microscope (Olympus BX51). For each test compound in a vial was weighed approximately 0.5 mg of dry compounds for use in the preparation of the standard solutions. Approximately 0.5 mg was weighed in a few vials for measurement of water of unknown parameters, one bottle for each pH that you are testing.

To measure each water required parameter to 0.5 mg of dry compounds were added to 0.5 ml aqueous buffer (10 mm potassium phosphate) at the desired pH (pH of 1.2 was used HCl 0.1 N.). Thus, the upper limit of concentration for this assay was 1 mg/ml of Each sample for measurement of water of the desired option then centrifuged at 350 rpm at room temperature for 24 hours for equilibration. After centrifugation, the final pH value of each sample was checked and confirmed. Then, taking aliquots and filtered into vials for HPLC analysis (HPLC - high performance liquid chromatography).

The original solution for each compound were prepared by dissolving 0.5 mg of the compound in a total volume of 1 ml of methanol to the initial concentration of 500 μg/ml of the Original solution, then the sequence is correctly bred to construct a calibration curve from 5 to 250 μg/ml

Samples and standards were immediately analyzed by the method LC/UV (liquid chromatography with UV detection). For each of the water samples on two different volume was injected in three repetitions. For each of the standards on two different volumes were injected once. Samples giving peaks outside the calibration range, serially diluted and analyzed again.

System HPLC/PDA (high performance liquid chromatography/detector diode matrix) consisted of the separation system Alliance 2795 (Waters) or the separation system Acquity UPLC (Waters), combined with a photodiode array detector 2996 Photodiode Array Detector (Waters). The system Alliance chromatographic separation of the analyte was achieved using column YMC ODS-Aq C18 (3,0×50 mm, particle size 3 μm, 120Ǻ, Waters) coupled with gradient conditions using mobile phases A (water, 0.01% of heptacosanoic acid (HFBA), 1% isopropyl alcohol) and B (0,01% HFBA and 1% isopropyl alcohol in acetonitrile). The total run time, including time for re-balancing for a single injection was 5 minutes. Characteristics of the analytes were measured by monitoring the absorption at 220 nm and 254 nm. The limit of detection for most connections on this system was approximately 1 mg/ml

The system Acquity chromatographic RA the division of the analyte was achieved, using column Acquity UPLC VEINS C18 (of 2.1×50 mm, particle size of 1.7 μm, Waters) coupled with gradient conditions using mobile phases A (water with 0.1% formic acid (FA), 1% isopropyl alcohol) and B (0.1% FA and 1% isopropyl alcohol in acetonitrile). The total run time, including time for re-balancing for a single injection was 3 minutes. Characteristics of the analytes were measured by monitoring the absorption at 220 nm and 254 nm. The limit of detection for most connections on this system was approximately 1 μg/ml At the output of the system Acquity is single quadrupole mass spectrometer ZQ-2000 (Waters). To identify the mass of the parent compound is used in positive ESI (electrospray ionization registration of positive ions).

Data were acquired and processed using software Waters Empower. Calibration was carried out by constructing a graph of the dependence of the peak area of the analyte from the nominal concentrations of the standard samples. The calibration model was created in the result of the linear regression of the calibration curve. This model was used to calculate concentrations in all water samples.

Although the pharmacological properties of the compounds of formulas I-V vary with structural change as expected, in common with the learn the activity and/or solubility, which are compounds can be demonstrated in the following concentrations or doses:

The compounds of formula II

Test 1A (enzyme assay): IC50≤250 nm, for example ≤100 nm, in another example, ≤30 nm.

Test 1B: (cell analysis): IC50≤180 nm, for example ≤80 nm, in another example, ≤10 nm.

The compounds of formula III

Test 1A (enzyme assay): IC50≤250 nm, e.g. ≤50 nm, in another example, the <20 nm; and

Test 1B: (cell analysis): IC50≤600 nm, for example ≤30 nm, in another example, ≤10 nm.

The compounds of formula V

Test 1A (enzyme assay): IC50≤40 nm, for example ≤20 nm; and

Test 1B: (cell analysis): IC50≤10 nm.

The compounds of formula VI

Test 1A (enzyme assay): IC50≤35 nm, in another example, ≤15 nm, and in another example, ≤10 nm.

Test 1B: (cell analysis): IC50≤5 nm, in another example, ≤1 nm.

EXAMPLES

To illustrate the invention are the following examples. However, it should be borne in mind that these examples do not limit the invention only and are intended to offer a practical application of the invention. Specialists in the art it is known that chemical reactions can easily be adapted for some other is inhibitorof MEK according to the invention, and it is believed that alternative means of obtaining compounds of this invention are included in the scope of this invention. For example, the synthesis is not illustrated by examples of compounds according to the invention can be successfully carried out using modifications, obvious to experts in the art, for example by appropriate protection of interfering ones of the groups, through the use of other suitable reagents known in the field that differ from those described and/or by routine modifications of reaction conditions. An alternative would be known by other reactions disclosed herein or known in this area, as which are used to obtain other compounds according to the invention.

In the following examples, unless otherwise indicated, all temperatures are given in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Lancaster, TCI or Maybridge, and used without further purification unless otherwise stated. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF), dichloromethane, toluene, dioxane and 1,2-differetn were purchased from Aldrich in sealed bottles and used as received.

The following reaction is usually conducted at a positive pressure of nitrogen or argon or with the use of drainage tubes (if not specified and the OU) in anhydrous solvents, and the reaction flask was usually closed fit the size of the rubber membranes for the introduction of substances and reagents via syringe. Glassware was dried in a drying Cabinet and/or dried by heating.

Column chromatography was carried out on a Biotage system (manufacturer: Dyax Corporation) silikagelevye column or cartridge with silica SepPak (Waters).

Spectra1H-NMR were recorded on a Varian instrument operating at 400 MHz. Spectra1H-NMR were obtained for solutions in CDCl3(expressed in million-1), using chloroform as the standard of comparison (7,25 million-1). Optionally used other solvents for NMR. If the multiple peaks, we used the following abbreviations: s (singlet), d (doublet), t (triplet), m (multiplet), br (broadened), dd (doublet of doublets), dt (doublet of triplets). The binding constants, if they are given in Hertz (Hz).

4-(2-Fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide

Stage A: Getting ethyl-2-(2-methylhydrazono)propanoate

To a suspension of atilirovanie (37,8 ml, 338 mmol) and MgSO4(40,8 g, 339 mmol) in l3(500 ml) solution was added methylhydrazine in (18.0 ml, 332 mmol) in l3(100 ml) at 0°C. the Reaction mixture was heated to room temperature. After p is remesiana for 24 hours at room temperature the reaction mixture was filtered. The filtrate was concentrated under reduced pressure to obtain 44 g (94%) of the desired product which was used directly without further purification.

Stage B: Obtaining methyl-3-(2-(1-ethoxy-1-oxoprop-2-ilidene)-1-methylhydrazino)-3-oxopropanoic

To a solution of ethyl-2-(2-methylhydrazono)propanoate (25,0 ml, 186 mmol) in THF (500 ml) at 0°C was added LiH (2,02 g, 241 mmol). The resulting mixture was stirred for 10 minutes at 0°C., was heated to room temperature and was stirred for 6 hours. Added methylmalonate (26,7 ml, 242 mmol) in THF (20 ml) at 0°C. the Reaction mixture was heated to room temperature and was stirred for 16 hours. The reaction was carefully marked 1 N. aqueous HCl at 0°C., concentrated under reduced pressure and diluted tO. The organic layer was dried over gSO4, filtered and concentrated under reduced pressure to obtain 46 g (99%) of the desired product which was used directly without further purification.

Stage: Obtaining methyl-5-hydroxy-2,6-dimethyl-3-oxo-2,3-dihydropyridin-4-carboxylate

To a solution of ethyl-2-(2-methyl-2-(methyl-3-oxopropanoic)hydrazono)-propanoate (1,02 g; 4.09 to mmol) in MeCN (10 ml) at 0°C was added DBU (2.0 ml; 13 mmol). The reaction mixture was heated to room temperature and was stirred for 3 hours. The reaction mixture was concentrated in bonigen the m pressure and diluted with EtOAc. The organic layer was washed with 10% aqueous HCl, dried over gSO4, filtered and concentrated under reduced pressure to obtain 0.39 g (48%) of the crude product, which was used directly without further purification.

Stage G: Obtain 5-hydroxy-2,6-dimethylpyridin-3(2H)-it

A mixture of methyl-5-hydroxy-2,6-dimethyl-3-oxo-2,3-dihydropyridin-4-carboxylate (3.00 g; 15.1 mmol) and 6 N. aqueous HCl (25 ml, 150 mmol) in dioxane (25 ml) was boiled under reflux for 48 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to get crude substance that has been diluted with EtOAc. The organic layer was washed with water and brine, dried over MgSO4, filtered and concentrated under reduced pressure to obtain 0.74 g (35%) of the desired product. The aqueous layer was concentrated under reduced pressure. The obtained solid was diluted with water and EtOAc-THF. The organic layer was separated. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to get 0,80 g (37%) of target product. Total received 1.54 g (72%) of the desired product which was used directly without further purification.

Stage D: Obtain 5-chloro-2,6-dimethylpyridin-3(2H)-on the Sabbath.

A mixture of 5-hydroxy-2,6-dimethylpyridin-3(2H)-she (736 mg; the 5.25 mmol) and l3(4,5 ml) was stirred at 85°C for 2 hours. The reaction mixture was concentrated under reduced pressure to get crude substance, which extinguished saturated aqueous PA2CO3. The resulting mixture was stirred for 2 hours and was extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to obtain 587 mg (70%) of the desired product which was used directly without further purification.

Stage E: Obtain 4-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxylic acid

To a solution of 5-chloro-2,6-dimethylpyridin-3(2H)-she (780 mg; of 4.67 mmol) in fuming H2SO4(25 ml) at 0°C was slowly added K2Cr2O7(3.33 g; and 11.2 mmol) under stirring. When I add2CR2O7the ice bath was removed and the reaction mixture was left to warm to room temperature. When the reaction began to occur too quickly, the ice bath was returned and added the remainder To2CR2O7. The reaction mixture was stirred at 60°C for 16 hours. The reaction mixture was cooled to room temperature, poured into ice and extracted tO (3×). The combined organic layers were dried over MgSO4was filtered and to the have centriole under reduced pressure to obtain 649 mg (74%) of the target product, which was used directly without further purification.

Stage G: Obtaining methyl-4-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxylate

A solution of 4-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxylic acid (390 mg; 2,07 mmol) and concentrated HCl (0.10 ml) in the Meon (6 ml) was boiled under reflux for 8 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to get crude substances, which pererestorani in tO. The organic layer was washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to get crude material, which was purified column flash chromatography on silica gel (100% hexanol to 10, to 20, to 30, up to 50% tO in hexano), which allowed us to obtain 72 mg (17%) of the target product.

Stage 3: Obtaining methyl-4-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxylate

The mixed solution of methyl 4-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxylate (72 mg; 0.35 mmol), 2-fluoro-4-methylthioinosine (69 mg; 0.44 mmol), Pd(OAc)2(10 mg; 0,044 mmol), BINAP (2,2'-bis(diphenylphosphino)-1,1'-binaphthyl) (40 mg; 0,064 mmol) and Cs2CO3(197 mg; a 0.60 mmol) in toluene (1.5 ml) was placed in a vessel in an atmosphere of N2. Was stirred for 10 minutes at room temperature and then heating and at 80°C for 16 hours with stirring. The reaction mixture was cooled to room temperature and was diluted tO. The precipitate was filtered and washed tO. The filtrate was washed with water. The organic layer was separated, and the aqueous layer was extracted with tO. The combined organic layers were dried over gSO4was filtered , concentrated to obtain crude material, which was purified column flash chromatography on silica gel (100% CH2Cl2up to 1% of the Meon in CH2Cl2with the subsequent column flash chromatography on silica gel (10 to 15 to 20% tO in CH2Cl2), which allowed us to obtain 48 mg (42%) of the target product.

Phase I: Obtain 4-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridin-3-carboxamide

To a solution of methyl-4-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-carboxylate (25 mg; 0,077 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (24 mg; 0.23 mmol) in THF (2 ml) at 0°C was added LiHMDS (of 0.54 ml, 0.54 mmol, 1 M in THF). The reaction mixture was heated to room temperature and was stirred for 1 hour. The reaction mixture was extinguished saturated water Panso3and diluted tO. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to get crude material, which was purified column flash chromatogr is via on silica gel (100% CH 2Cl2up to 1.5% Meon in CH2CL2), which allowed us to obtain 30 mg (99%) of the target product.

Stage To Obtain 4-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide

To a solution of 4-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridin-3-carboxamide (30 mg; 0,077 mmol) in tO/THF (2 ml/2 ml) was added 1 N. aqueous HCl (0.15 ml; 0.15 mmol, 1 N. aqueous solution) at room temperature. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was neutralized to pH 7, diluted tO (3×), washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to get crude material, which was purified column flash chromatography on silica gel (100% tO to 100% CH2CL2up to 2.5, to 3, to 5% Meon in CH2CL2), which allowed us to obtain 6 mg (22%) of the desired product. MS ARC (-) (mass spectrometry, chemical ionization at atmospheric pressure, check negative ions) m/z 367 (M-1);1H NMR (400 MHz, CD3OD) δ 7.35 (t, 1H), 7.18 (dd, 1H), 7.14 (dd, 1H), 5.92 (s, 1H), 4.06 (t, 2H), 3.79 (t, 2H), 3.74 (s, 3H), 2.51 (s, 3H).

5-Bromo-4-(4-bromo-2-forgenerating)-N-(cyclopropylmethoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide

Stage A: Obtaining methyl-4-(2-forgenerating)-methyl-6-oxo-1,6-dihydropyridin-3-carboxylate

Specified in the title compound was obtained with a yield of 61% according to the method described above in Example 1 (stage 3), using methyl-4-chloro-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxylate (109 mg; 0.54 mmol; obtained as described above in Example 1 (Stage a, W)) and 2-ftoranila (0,053 ml, 0.54 mmol).

Stage B: Obtain methyl 5-bromo-4-(4-bromo-2-forgenerating)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxylate

A mixture of methyl-4-(2-forgenerating)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxylate (88 mg; 0.32 mmol) and NBS (59 mg; 0.33 mmol) in DMF (1.5 ml) was stirred for 2 hours at room temperature. The reaction mixture was diluted tO and washed with water (2×). The organic layer was dried over gSO4, filtered and concentrated under reduced pressure to get crude material, which was purified column flash chromatography on silica gel (100% CH2Cl2up to 0.5% Meon in CH2Cl2with the subsequent column flash chromatography on silica gel (30% tO in CH2Cl2) to obtain 80 mg of the mixture of methyl 5-bromo-4-(2-forgenerating)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxylate and methyl 5-bromo-4-(4-bromo-2-forgenerating)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxylate. This mixture was subjected to re-bromirovanii. To this mixture was added DMF (1.5 ml), then NBS (29 mg; 0.22 mmol) at room temperature. The reaction to shift the ü was stirred for 2.5 hours at room temperature. Added additional 15 mg of NBS, and the reaction mixture was stirred for another 20 hours at room temperature. The reaction mixture was diluted tO and washed with water (2×). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to get crude material, which was purified column flash chromatography on silica gel (30% tO in CH2Cl2), which allowed us to obtain 62 mg (64%) of the target product.

Stage: Obtain 5-bromo-4-(4-bromo-2-forgenerating)-N-(cyclopropylmethoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide

Specified in the title compound was obtained with a yield of 40% according to the method described in Example 1 (stage I), using methyl 5-bromo-4-(4-bromo-2-forgenerating)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxylate (31 mg; 0,071 mmol) and O-cyclopropylmethyl-hydroxylamine (20 mg; 0.23 mmol). MS APCI (-) m/z 487, 489, 491 (M-1, the sample with VG);1H NMR (400 MHz, CD3OD) δ 7.38 (dd, 1H), 7.31 (dd, 1H), 7.05 (t, 1H), 3.82 (s, 3H), 3.65 (d, 2H), 1.13 (m, 1H), 0.58 (q, 2H), 0.31 (q, 2H).

4-(2-Fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

Stage a: Obtaining N-methylpropionitrile

To a solution of methylhydrazine (27,6 ml; 508 mmol) and catalytic amount of DMAP (4-(N,N-dimethylamino)pyridine) in CH2Cl2(130 ml) at 0°C was added a solution of ACE is inflorida (15.0 ml; 169 mmol) in CH2Cl2(30 ml). The reaction mixture was heated to room temperature and was stirred for 16 hours. White solid was filtered, and the filtrate was concentrated under reduced pressure to get crude material, which was purified by vacuum distillation, which allowed us to get to 8.25 g (48%) of the target product (63-66°C at 0.14 mm Od (18.7 PA)).

Stage B: Getting diethyl-2-(2-methyl-2-propenylidene)malonate

A solution of N-methylpropionitrile (18,78 g; 183,9 mmol) and diethylmalonate (56,1 ml, 368 mmol) in toluene (136 ml) was boiled under reflux using traps Dean-stark for 4 hours. The reaction mixture was concentrated under reduced pressure to get crude material, which was purified column flash chromatography on silica gel (100% hexanol up to 5, up to 10% tO in hexano), which allowed us to obtain 23 g (49%) of the target product.

Stage: Getting ethyl-4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylate

To a solution of LiHMDS (to 0.78 ml, 0.78 mmol, 1M solution in THF) in THF (1 ml) at -78°C was added a solution of diethyl-2-(2-methyl-2-propenylidene)-malonate (50 mg; 0,19 mmol) in THF (1 ml). The resulting mixture was slowly warmed to -40°C and was stirred for 1.5 hours at -40°C. the Reaction mixture was extinguished 10% aqueous HCl and diluted with water. The resulting mixture was extracted with tO the C (2×). The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to get crude material, which was purified column flash chromatography on silica gel (100% hexanol to 20% tO in hexano), which allowed us to obtain 25 mg (61%) of the target product.

Stage G: Getting ethyl-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylate

A mixture of ethyl-4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylate (1.85 g; 8,72 mmol) and l3(9 ml) was heated for 16 hours at 85°C. l3was removed under reduced pressure. Then the crude substance is extinguished by water with ice. The mixture was neutralized with saturated aqueous Panso3(approximately pH 6-7) and was extracted with tO (3×). The combined organic layers were dried over gSO4, filtered and concentrated under reduced pressure to get crude material, which was purified column flash chromatography on silica gel (100% hexanol to 5, to 10, to 20% tO in hexano), which allowed us to obtain 1,72 g (86%) of the target product.

Stage D: Getting ethyl-4-(2-fluoro-4-(methylthio)phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylate

Specified in the title compound was obtained with a yield of 81% by the method described in Example 1 (stage 3), using ethyl-4-chloro-1,5-dimethyl-6-oxo-1,6-digit pyridazin-3-carboxylate (500 mg; 2,17 mmol) and 2-fluoro-4-methylthioinosine (375 mg; of 2.38 mmol).

Stage E: Obtain 4-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

Specified in the title compound was obtained with the yield 78% (stage 2) according to the methods described in Example 1 (Stage), using ethyl-4-(2-fluoro-4-(methylthio)phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylate (50 mg; 0.14 mmol) and O-(2-vinyloxy-ethyl)-hydroxylamine (44 mg; 0.43 mmol). MS APCI (-) m/z 381 (M-1);1H NMR (400 MHz, CD3OD) δ 7.10 (dd, 1H), 7.03 (dd, 1H), 6.87 (t, 1H), 3.99 (t, 2H), 3.79 (s, 3H), 3.74 (t, 2H), 2.47 (s, 3H), 1.74 (s, 3H).

The following compounds were obtained according to the method described in Example 1 (stage I), using ethyl-4-(2-fluoro-4-(methylthio)phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylate and the corresponding hydroxylamine.

N-(Cyclopropylmethoxy)-4-(2-fluoro-4-(methylthio)phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 391 (M-1);1H NMR (400 MHz, CD3OD) δ 7.09 (dd, 1H), 7.03 (dd, 1H), 6.86 (t, 1H), 3.78 (s, 3H), 3.71 (d, 2H), 2.47 (s, 3H), 1.75 (s, 3H) 1.16 (m, 1H), 0.58 (m, 2H), 0.31 (m, 2H).

4-(2-Fluoro-4-(methylthio)phenylamino)-N-(2-methoxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 395 (M-1);1H NMR (400 MHz, CD3OD) δ 7.10 (dd, 1H), 7.03 (d, 1H), 6.87 (t, 1H), 4.05 (t, 2H), 3.78 (s, 3H), 3.64 (t, 2H), 3.37 (s, 3H), 2.47 (s, 3H, 1.74 (s, 3H).

4-(2-Fluoro-4-(methylthio)phenylamino)-N-methoxy-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 351 (M-1);1H NMR (400 MHz, CD3OD) δ 7.10 (d, 1H), 7.04 (d, 1H), 6.87 (t, 1H), 3.78 (s, 3H), 3.76 (s, 3H), 2.47 (s, 3H), 1.74 (s, 3H).

4-(2-Fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

Stage A: Obtain 4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylic acid

To a solution of LiHMDS (331 ml, 331 mmol, 1 M solution in THF) in THF (430 ml) at -78°C was added a solution of diethyl-2-(2-methyl-2-propenylidene)-malonate (21,40 g; 82,86 mmol), obtained according to the method described in Example 3 (stage B), in THF (10 ml). The resulting mixture was slowly warmed to -40°C for 1 hour and was stirred for 1.5 hours at -40°C. To the reaction mixture at -40°C was added water (500 ml). The reaction mixture was heated to room temperature and was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure to remove THF. The resulting aqueous mixture was suppressed 6 N. aqueous Hcl at 0°C and acidified to pH 1-2. The resulting mixture was stirred for 16 hours at room temperature. The precipitate was filtered and triturated with CH2Cl2that allowed us to obtain 7,21 g (47%) of the desired product. The filtrate was extracted with tO (3×). The combined organic layer is washed with water, dried over gSO4, filtered and concentrated under reduced pressure to get crude material, which was washed with CH2CL2that allows to get to 3.56 g (23%) of the desired product. The aqueous layer was extracted again tO (3×). The combined organic layers were washed with water, dried over gSO4, filtered and concentrated under reduced pressure to get crude material, which was washed with CH2Cl2that allows to get 1,32 g (9%) of the desired product. Total received 12,09 g (79%) of the target product.

Stage B: Obtain 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylic acid

A mixture of 4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylic acid (876 mg, 4.76 mmol) and l3(4,5 ml) was heated for 24 hours at 85°C. l3was removed under reduced pressure. The crude substance was switched off the ice. The reaction mixture was stirred for 1 hour at room temperature. After removing the solids by filtration the aqueous filtrate was extracted with tO (3×). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The extracted substance was combined with the solids, allotted, and triturated with ether, which allowed us to obtain 577 mg (60%) of the target product is A.

Stage: Obtain 4-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylic acid

To a suspension of 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylic acid (200 mg; 0,99 mmol) and 2-fluoro-4-joanina (478 mg; 1.97 mmol) in THF (6.5 ml) at -78°C was slowly added a solution of LiHMDS (to 3.00 ml, 3.00 mmol, 1 M solution in THF). After complete addition, the mixture was slowly heated to room temperature and was stirred for 4 hours. The reaction mixture was extinguished 6 N. aqueous HCl (8 ml) at 0°C., was heated to room temperature and was stirred for 1.5 hours. The precipitate was filtered, washed with water and ether and triturated with ether, which allowed us to obtain 158 mg (38%) of the target product.

Stage G: Obtain 4-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

To a suspension of 4-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylic acid (41 mg, 0.10 mmol) and HOBt (28 mg, 0.21 mmol) in DMF (1.5 ml) was added EDCI (40 mg, 0.21 mmol) at room temperature. The resulting mixture was stirred for 1.5 hours. To activated complex ether at room temperature was added O-(2-vinyloxy-ethyl)-hydroxylamine (21 mg; 0.20 mmol) and TEA (triethylamine) (0,030 ml; 0.22 mmol). After stirring for 1.5 hours the reaction mixture was diluted tO and washed with saturated aqueous NH4l, brine, saturated aqueous NaHCO3(2×) and brine. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to obtain 4-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridin-3-carboxamide, which was used directly without further purification. Specified in the title compound was obtained following the procedure described above in Example 1 (stage K), using crude 4-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridin-3-carboxamide (exit 40% over two stages). MS APCI (-) m/z 461 (M-1);1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (d, 1H), 6.63 (t, 1H), 3.98 (t, 2H), 3.80 (s, 3H), 3.74 (t, 2H), 1.78 (s, 3H).

The following compounds were obtained according to the methods described previously in Example 7 (Stages C and D) using the appropriate anilines and hydroxylamine. In some cases, at the end of may need to stage the removal of protection. Such removal protection can be performed by standard, well-known literature methods.

(R)-N-(2,3-Dihydroxypropane)-4-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 491 (M-1);1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (d, 1H), 6.63 (t, 1H), 4.02 (m, 1H), 3.88 (m, 2H), 3.80 (s, 3H), 3.59 (m, 2H), 1.77 (s, 3H).

4-(2-Fluoro-4-iodinium the but)-N-methoxy-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 431 (M-1);1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (d, 1H), 6.63 (t, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 1.77 (s, 3H).

N-(Cyclopropylmethoxy)-4-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 471 (M-1);1H NMR (400 MHz, CD3OD) δ 7.51 (dd, 1H), 7.44 (d, 1H), 6.62 (t, 1H), 3.79 (s, 3H), 3.70 (d, 2H), 1.78 (s, 3H), 1.15 (m, 1H), 0.57 (q, 2H), 0.30 (q, 2H).

4-(4-Bromo-2-forgenerating)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

Stage A: Getting diethyl-2-(2-methylhydrazono)malonate

To a solution of diethylmalonate (95 g, 546 mmol) in tO (600 ml) (3-necked flask with a capacity of 2 l, equipped with a thermocouple, a pipeline for supplying N2, a refrigerator and a mechanical stirrer) was added MeNHNH2(32 ml, 600 mmol) in one portion at room temperature. The reaction mixture was heated to 60°C (internal temperature, was heated using a heating grid) and was stirred for 6 hours. The reaction mixture was cooled to room temperature and was stirred overnight. The reaction mixture was concentrated under reduced pressure to get crude substances together with a solid precipitated substances, which was purified via silica gel gasket (3:2, hexane:tO), which allowed us to obtain 81 g (74%) of the target product.

Stage B: Getting diethyl-2-2-methyl-2-propenylidene)malonate

To a solution of 2-(2-methylhydrazono)malonate (100 g, 494 mmol) in THF (1 l) at 0°C via an addition funnel was added LiHMDS (643 ml; 643 mmol) for 45 minutes. The reaction mixture was stirred for 45 minutes at 0°C. was Added propionate (51,6 ml; 593 mmol) in one portion. The resulting mixture was heated to room temperature and was stirred for 20 hours. The reaction mixture was extinguished saturated aqueous NH4Cl (85 ml) and water (85 ml). The reaction mixture was concentrated under reduced pressure and optionally added water (300 ml). The resulting mixture was extracted with tO (3×250 ml). The combined organic layers were washed with saturated aqueous Panso3(2×250 ml), then brine (250 ml), dried over gSO4, filtered and concentrated under reduced pressure to obtain 112 g (88%) of the crude product, which was used directly in the next stage without additional purification.

Stage: Obtain 4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylic acid

To a solution of LiHMDS (331 ml, 331 mmol, 1 M solution in THF) in THF (430 ml) at -78°C was added a solution of 2-(2-methyl-2-propenylidene)malonate (21,40 g; 82,86 mmol) in THF (10 ml). The resulting mixture was slowly warmed to -40°C for 1 hour and was stirred for 1.5 hours at -40°C. To the reaction mixture were added water (500 ml) at -40°C. the Reaction mixture was heated to room is temperature and was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure, extinguished 6 N. aqueous HCl at 0°C and acidified to pH 1-2. The resulting mixture was stirred for 16 hours at room temperature. The precipitate was filtered and triturated with CH2Cl2that allowed us to obtain 7,21 g (47%) of the desired product. The filtrate was extracted with tO (3×). The combined organic layers were washed with water, dried over gSO4, filtered and concentrated under reduced pressure to get crude material, which was washed with CH2Cl2that allows to get to 3.56 g (23%) of the desired product. The aqueous layer was extracted again tO (3×). The combined organic layers were washed with water, dried over MgSO4, filtered and concentrated under reduced pressure to get crude material, which was washed with CH2Cl2that allows to get 1,32 g (9%) of the desired product. Total received 12,09 g (79%) of the target product.

Stage G: Obtain 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylic acid

A mixture of 4-hydroxy-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylic acid (35,4 g, 192 mmol), catalytic amount of DMF (3 drops) and l3(178 ml, 1.92 mol) was heated for 2 days at 90°C, and then l3was removed under reduced pressure. The crude substance extinguished the ice, and the reaction mixture was stirred for 2 hours at room temperature. Precipitate out of solution, was filtered and was washed with ether. The collected precipitate was washed with ether, which allowed us to obtain 11.7 g (30%) of the desired product. The filtrate was extracted with tO (2×). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to get crude product, which was triturated with ether and dried under reduced pressure, which allows to obtain of 9.56 g (24%) of the desired product. Total received 21,29 g (55%) of the target product.

Stage D: Obtain 4-(4-bromo-2-forgenerating)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylic acid

To a solution of 4-bromo-2-foronline (22,6 g, 116 mmol) in THF (165 ml) at -78°C was slowly added a solution of LiHMDS (174 ml, 174 mmol, 1M solution in THF). The resulting mixture was stirred for 1 hour at -78°C. To this mixture was added 4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylic acid (11,0 g; 54,4 mmol) as a solid substance at -78°C. the Reaction mixture was slowly heated to room temperature and was stirred for 21 hours. The reaction mixture was extinguished and acidified with 10% aqueous HCl (250 ml) at 0°C. To this mixture was added water (100 ml), tO (350 ml) and brine (50 ml). The reaction mixture was heated to room temperature and was stirred for 30 minutes. The organic layer was separated and the acidic aqueous layer was extracted with tO (2×300 ml). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to get crude material, which was washed with ether (5×), filtered, washed with ether and dried under reduced pressure, which allowed us to obtain 14,51 g (75%) of the target product.

Stage E: Obtain 4-(4-bromo-2-forgenerating)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridin-3-carboxamide

To a suspension of 4-(4-bromo-2-forgenerating)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxylic acid (14,51 g; 40,74 mmol) and HOBt (br11.01 g; 81,48 mmol) in DMF (165 ml) was added EDCI (15.62 wide g; 81,48 mmol) at room temperature. The resulting mixture was stirred for 1.5 hours. To activated complex ether at room temperature was added O-(2-(vinyloxy)ethyl)hydroxylamine (at 8.36 ml; 81,48 mmol) and TEA (11,36 ml; 81,48 mmol). After stirring for 1.5 hours the reaction mixture was diluted tO and washed with saturated aqueous NH4Cl, brine, saturated aqueous Panso3(2×) and brine. The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to get crude product which was used directly without further purification.

Stage G: Obtain 4-(4-bromo-2-forfinal the Mino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

A mixture of 4-(4-bromo-2-forgenerating)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridin-3-carboxamide (17,98 g; 40,75 mol) and 6 N. aqueous HCl (of 13.58 ml; 81,50 mmol) in tO/THF (50 ml/50 ml) was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure and diluted with water (50 ml). The resulting mixture was extracted with tO (2×). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure to get crude material, which was purified column flash chromatography on silica gel (100% CH2Cl2up to 2.5% of the Meon in CH2Cl2), which allowed us to obtain 9,41 g (56% in two stages) of the target product. MS APCI (-) m/z 413, 415 (M-1, the sample with VG);1H NMR (400 MHz, CD3OD) δ 7.38 (dd, 1H), 7.27 (d, 1H), 6.79 (t, 1H), 3.99 (t, 2H), 3.80 (s, 3H), 3.74 (t, 2H), 1.77 (s, 3H).

(S)-4-(4-Bromo-2-forgenerating)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 427, 429 (M-1, the sample with VG);1H NMR (400 MHz, CD3OD) δ 7.39 (dd, 1H), 7.27 (dd, 1H), 6.79 (t, 1H), 3.98 (m, 1H), 3.84 (dd, 1H), 3.80 (s, 3H), 3.72 (dd, 1H), 1.78 (s, 3H), 1.15 (d, 3H).

Methyl-2-(4-bromo-2-forgenerating)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylate

Stage A: Getting 2-chloro-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid

2-Chloro-6-oxo-1,6-dihydro-pyridine-3-carbonophobia received from dichloronicotinic acid (3.00 g; 15.6 mmol, Aldrich) by the method described in U.S. patent No. 3682932, to obtain 1.31 g (48%) of the target product.

Stage B: obtain the methyl ester of 2-chloro-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid

To a solution of 2-chloro-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (0,644 g; 3,71 mmol) in DMF (20 ml) was added lithium hydride (95%; 0,078 g; 9.28 are mmol)and the reaction mixture was stirred for 40 minutes in an atmosphere of N2. Then add methyliodide (0,508 ml of 1.16 g, 8.16 mmol)and the reaction mixture was stirred for an additional 45 minutes. The reaction mixture was extinguished 2M HCl up until the pH reached 6-7. The reaction mixture was diluted tO and saturated NaCl, and the layers were separated. The aqueous layer was extracted again tO (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to get crude yellow solid. HPLC analysis showed two products in a ratio of 4:1, which was separated by column flash chromatography (methylene chloride/tO, from 15:1 to 10:1) to obtain the 0,466 g (62%) of pure desired product as a white crystalline solid. Also identified a minor product in the form of a pale yellow crystalline solid and identified it as regioisomer methyl ester 2-chloro-6-methoxy-nicotinic acid.

Stage: Obtain methyl 5-bromo-2-chloro-1-m is Teal-6-oxo-1,6-dihydropyridines-3-carboxylate

To a solution of methyl 2-chloro-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate (0,100 g; 0,496 mmol) in DMF (5 ml) was added N-bromosuccinimide (0,177 g; 0,992 mmol)and the reaction mixture was stirred for 4 hours at room temperature in an atmosphere of N2. The reaction mixture was extinguished with saturated sodium bisulfite, then diluted tO and H2O and the layers were separated. The aqueous layer was extracted again tO (2×). The combined organic layers were dried (PA2SO4) and concentrated under reduced pressure to obtain yellow solid in quantitative yield.

Stage G: Obtain methyl 2-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylate

To a suspension of methyl 5-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate (0.400 g; 1,43 mmol) and 1,1'-bis(diphenylphosphino)-periodically(II) (0,0587 g; 0,0713 mmol) in dioxane (8 ml) at 0°C in an atmosphere of N2added dimethylzinc (0,713 ml; 1,43 mmol, 2M solution in toluene). The reaction mixture is immediately heated to 100°C for 30 minutes. The reaction mixture was cooled to 0°C and extinguished the Meon (0.800 to ml). The reaction mixture was diluted tO and washed with 1M HCl. The aqueous layer was extracted again tO (1×). The combined organic layers were washed with saturated NaCl, dried (Na2SO4) and concentrated under reduced pressure to a dark yellow resin. Purification column flash chromatographie the (methylene chloride/tO, 15:1) gave 0,164 g (53%) of pure desired product as a yellow crystalline solid.

Stage D: Obtaining methyl-2-(4-bromo-2-forgenerating)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylate

To a solution of 4-bromo-2-forbindelsen (0,058 g; 0.31 mmol) in THF (2 ml) at -78°C in an atmosphere of N2was added dropwise bis(trimethylsilyl)amide lithium high (0.56 ml; 0,56 mmol, 1M solution in hexano). The reaction mixture was stirred for one hour at -78°C. Then was added dropwise methyl-2-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylate (to 0.060 g, 0.28 mmol) in solution in THF (1 ml)and the reaction mixture was stirred for 25 minutes at -78°C. the Reaction mixture was suppressed by the addition of H2O, the pH was adjusted using 0.1 m HCl, then diluted tO and saturated NaCl, and the layers were separated. The aqueous layer was extracted again tO (1×). United tO layers were dried (PA2SO4) and concentrated under reduced pressure. Purification column flash chromatography (methylene chloride/tO, 20:1) gave 0,086 g (84%) of pure desired product as a white crystalline solid. MS ESI (+) m/z 371, 373 (M+, the sample with VG);1H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 7.79 (s, 1H), 7.32 (d, 1H), 7.18 (d, 1H), 6.58 (t, 1H), 3.85 (s, 3H), 3.29 (s, 3H), 2.14 (s, 3H).

2-(4-Bromo-2-forgenerating)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

Stage A: Obtaining 2-(4-bromo-2-forgenerating)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridines-3-carboxamide

To a solution of methyl 2-(4-bromo-2-forgenerating)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylate (to 0.060 g, 0.16 mmol) in THF (2 ml) was added O-(2-vinyloxy-ethyl)-hydroxylamine (0,042 ml; 0.41 mmol). The solution was cooled to 0°C. and was added dropwise bis(trimethylsilyl)amide lithium (0,81 ml, 0.81 mmol, 1M solution in hexano). The reaction mixture was heated to room temperature. After stirring for 35 minutes, the reaction mixture was suppressed by the addition of saturated Panso3and distributed between tO and saturated NaCl. The layers were separated, the organic layer was dried (Na2SO4) and concentrated under reduced pressure. Purification column flash chromatography (methylene chloride/Meon, 20:1) gave 0,067 g (94%) of pure desired product in the form of not-quite-white crystalline solid.

Stage B: Obtaining 2-(4-bromo-2-forgenerating)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

To a solution of 2-(4-bromo-2-forgenerating)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)-ethoxy)-1,6-dihydropyridines-3-carboxamide (0,067 g; 0,150 mmol) in ethanol (2 ml) was added aqueous 2M HCl (0,380 ml; 0,760 mmol). The reaction mixture was stirred for 16 hours at room temperature. the pH of the reaction mixture was adjusted using 1M NaOH. The reaction is ionic mixture was diluted tO and H 2O. the Organic layer was separated and washed with saturated NaCl. The combined aqueous layers was extracted again tO (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to get to 0.060 g (94%) of pure desired product in the form of not-quite-white crystalline solid. MS ESI (+) m/z 414, 416 (M+, sample Br);1H NMR (400 MHz, CDCl3) δ 9.80 (s, 1H), 8.44 (s, 1H), 7.31 (d, 1H), 7.19 (d, 1H), 6.59 (t, 1H), 4.05 (m, 2H), 3.85 (m, 1H), 3.75 (m, 2H), 3.29 (s, 3H), 2.15 (s, 3H).

The following compounds were obtained using the methods described in Examples 13 and 14. In some cases, such as in Example 14, the end may need to stage the removal of protection. Such removal protection can be performed by standard, well-known literature methods.

Methyl-2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylate

Methyl 2-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylate was converted to methyl 2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylate by the procedure described in Stage D of Example 13, using 2-fluoro-4-identally, to obtain the target product as a white crystalline solid. MS ESI (+) m/z 417 (M+1);1H NMR (400 MHz, CDCl3) δ 9.56 (s, 1H), 7.79 (s, 1H), 7.49 (d, 1H), 7.36 (d, 1H), 6.43 (t, 1H), 3.85 (s, 3H), 3.30 (s, 3H), 2.15 (s, 3H).

2-(2-f the PR-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

Stage A: Obtaining 2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridines-3-carboxamide

To a solution of methyl 2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylate (0,500 g; 1.20 mmol) in THF (60 ml) was added O-(2-vinyloxy-ethyl)-hydroxylamine (0,149 g; 1.44 mmol). The solution was cooled to 0°C. and was added dropwise bis(trimethylsilyl)amide lithium (4,81 ml; to 4.81 mmol) (1M solution in hexano). The reaction mixture was heated to room temperature. After stirring for 10 minutes the reaction mixture was suppressed by the addition of 1M HCl and distributed between tO and saturated NaCl. The layers were separated, and the organic layer was dried (Na2SO4) and concentrated under reduced pressure to get crude yellow solid, which was used without purification in the next stage.

Stage B: Obtaining 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

To a solution of crude 2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridines-3-carboxamide (0,585 g; 1.20 mmol) in ethanol (10 ml) was added aqueous 2M HCl (3 ml). The reaction mixture was stirred for 45 minutes at room temperature. the pH of the reaction mixture was brought to pH 7 using 1M NaOH. The reaction mixture was diluted tO and H2O. the Organic layer was separated and about ivali saturated NaCl. The combined aqueous layers was extracted again tO (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification column flash chromatography on silica gel (methylene chloride/Meon, 15:1) gave 2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridines-3-carboxamide (0,421 g; 76% over two stages) in the form of a pale yellow solid. MS ESI (+) m/z 462, sample (M+1);1H NMR (400 MHz, CDCl3) δ 9.77 (s, 1H), 8.50 (s, 1H), 7.47 (d, 1H), 7.36 (d, 1H), 6.43 (t, 1H), 4.04 (br s, 2H), 3.85 (br s, 1H), 3.74 (br s, 2H), 3.29 (s, 3H), 2.14 (s, 3H).

Example 16A

The Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

Stage 1: obtain the methyl ester of 2-(2-fluoro-4-iodine-phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid

To a stirred solution of 2-fluoro-4-joanina (182 g, 0.77 mol) in THF (5,25 l) at -45°C. in a nitrogen atmosphere was added a 1M solution of bis(trimethylsilyl)amide lithium in hexano (1260 g) for 28 minutes at a temperature of -43 to -41,6°C. After 1 hour, was added methyl ether 2-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylic acid (155 g; to 0.72 mol) in THF (1.05 liters) for 43 minutes. The mixture was stirred for 1 hour 55 minutes at -46°C., then left to warm to -13°C and extinguished with water (186 ml of 10.3 mol) over 5 minutes, to support the Wai temperature between -13°C and -11°C. The mixture was then left to warm to 0°C for 30 minutes. Then was added 2M HCl for 1 hour until, until reaching pH 7-8 (added 1855 ml). After standing overnight the mixture was left to warm to ambient temperature and the solution was added sodium chloride (1 l, 15% wt./vol.). The lower (aqueous) layer was discarded, and the THF layer was concentrated by distillation to about 1.4 liters To the mixture at approximately 52°C for 1 hour and 15 minutes was added isohexane (4,65 l), and then the mixture was cooled to 20°C for 3 hours. After exposure for 1 hour at 20°C. the mixture was cooled to 0°C and kept at this temperature during the night. The reaction mixture is then filtered, and the solid is washed with cold isohexane (5°C) (2×1.25 l). The solid was dried in a vacuum oven at 45°C To produce methyl ester 2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylic acid (248 g; of 0.60 mol; yield 83%).1H NMR (D6-DMSO): δ 7.75 (d, 1H, J 1 Hz, ArH), 7.68 (dd, 1H, J 11, 2 Hz, ArH), 7.42 (d, 1H, J 8.5 Hz, ArH), 6.62 (~t, 1H, J 8.5 Hz, ArH), 3.69 (s, 3H, och3), 3.22 (s, 3H, N3), 2.03 (s, 3H, Agsn3).

Stage 2: Obtain (2-vinyloxy-ethoxy)-amide 2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylic acid

To a stirred solution of methyl ester of 2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-carboxylic acid (221 g; of 0.53 mol) and O-(2-vinyloxyethyl)-hydroxylamine (63 g, 0.61 mol) in THF (2,85 l), under nitrogen atmosphere, was added a 1M solution of bis(trimethylsilyl)amide lithium in hexano (1431 g) for 55 minutes, maintaining the temperature from -14,7 up by 12,4°C. After aging for 2 hours at -15°C. to the mixture was added water (165 ml, 9.2 mol), then 2M HCl solution (1,98 l), which was added during 20 minutes. The mixture was then left to warm to 22°C. and the lower aqueous phase (2.25 liters) was separated and discarded. The organic phase is washed with sodium chloride solution (15% wt./mass., 1100 ml), and the volume was reduced to approximately 1.75 liter distillation 2.25 liters of solvent at ambient pressure. To the mixture for 2.5 hours was added isohexane (3,35 l), maintaining the temperature at approximately 58°C. After a further 1 hour at this temperature, the mixture was cooled to 20°C., maintained for 1 hour, then was cooled to 0°C and kept at this temperature during the night. Added more isohexane (500 ml), and the mixture was stirred for 1 hour, then added isohexane (500 ml). After holding for 45 minutes at 0°C. the suspension was filtered, and the solid was washed with chilled isohexanol (1.1 l), then dried in a vacuum drying Cabinet at 30°C To produce (2-vinyloxyethoxy)-amide 2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylic acid (190 g; 0.39 to say is; yield 74%).1H NMR (D6-DMSO): δ 7.63 (dd, 1H, J 11, 2 Hz, ArH), 7.52 (s, 1H, ArH), 7.38 (d, 1H, J 8.5 Hz, ArH), 6.55-6.46 (m, 2H, ArH/OCH=CH2), 4.18 (dd, 1H, J 14, 2 Hz, och=CH2), 3.99 (dd, 1H, J 7, 2 Hz, och=CH2), 3.90-3.88 (m, 2H, och2), 3.81-3.79 (m, 2H, och2), 3.25 (s, 3H, N3), 2.02 (s, 3H, Agsn3).

Stage 3: the Form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

To a stirred solution of (2-vinyloxyethoxy)-amide 2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylic acid (170 g; 0.35 mol) in nitrogen atmosphere in THF (850 ml) was added 2M HCl (318 ml) for 15 minutes at 17-22°C. After 1 hour the reaction was completed (which showed HPLC), was added 2M sodium hydroxide solution (318 ml) over 10 minutes, maintaining a temperature of approximately 22°C. the pH of the mixture was approximately 8. The mixture is then distributed with MIBK (methyl isobutyl ketone) (1,02 l), and the lower aqueous layer was separated and discarded. Then the organic solution was reduced by distillation at ambient pressure and at a temperature of shirts 85-95°C. After removal of 750 ml of solvent the rate of distillation was decreased significantly, and the mixture was cooled to approximately 22°C. To the mixture was added crystalline Form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide (1 g; seed obtained as described in the Example 16), then ethyl acetate (170 ml). After 5 minutes the mixture began to crystallize, and added isohexane (1.7 l) at 23-25°C for 50 minutes. The suspension was kept at 25°C for 80 minutes and then filtered. The solid is washed with isohexane (680 ml), then dried in a vacuum drying Cabinet at 30°C with obtaining specified in the header of the substance (147 g, 0.31 mol; yield 89%).1H NMR (D6-DMSO): δ 7.63 (dd, 1H, J 11, 2 Hz, AGN), 7.55 (s, 1H, ArH), 7.38 (d, 1H, J 8.5 Hz, ArH), 6.52 (~t, 1H, J 8.5 Hz, ArH), 4.91-4.35 (bs, 1H, OH), 3.74 (~t, 2H, J 5 Hz, och2), 3.51 (~t, 2H, J 5 Hz, och2), 3.25 (s, 3H, NCH3), 2.02 (s, 3H, Agsn3). MS (ESI) (+) m/z484 (27%, [M+Na]+), 462 (100%, [M+H]+), 385 (8%), 100 (26%).

Stage 4: the Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

To a stirred suspension of the product from step 3 (123 g) in ethyl acetate (2.0 l) at 50°C was added in the Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide (4.9 g) (obtained as described in Stage 5), and the residual substance was rinsed into the vessel with ethyl acetate (0.45 l). The mixture was stirred at this temperature for 64 hours. The analysis of the sample showed that this substance is mainly represented a Form 2. After another 1 hour, the temperature of the mixture was raised to 60°C and after 6 hours of storage at this temperature was additionally added 3.25 g of the Form 1 2-2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide (obtained, as described in Example 16G) and washed with ethyl acetate (100 ml). Stirring at 60°C. continued for the next 16 hours, after which the analysis has shown that a number of the Form 2 remained. Then the volume of the mixture was reduced by distillation of the solvent was removed 780 ml) at a temperature in a mixture of 52°C and 400 mbar (40 kPa). Stirring at 60°C and then continued throughout the night, and the mixture was analyzed again, however, the analysis showed that a number of the Form 2 still remained. After an additional 7 hours in a reactor were placed additional turbulization, and stirring is continued until the next day. Then add an additional amount of ethyl acetate (0.5 l) in order to increase the efficiency of mixing, and the mixture was stirred over the next 2 hours at 60°C. it Was found that the selected at this point the sample was a Form 1. In General, the time spent on the transformation from Form 2 to Form 1, amounted to 143 hours. The substance was kept over night at 50°C., then was cooled to 12°C and was filtered. The filter cake was washed with ethyl acetate (400 ml) at 12°C, then dried in a vacuum drying Cabinet during the weekend days (68 hours) at 35°C with the receipt of Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide (109 g).

Example 16B

The Form 1 2-(2-ft is R-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

To the rapidly stirred mixture of (2-vinyloxyethoxy)-amide 2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylic acid (4,2 g; charged 8.52 mmol) (obtained according to Example 16A, step 2) in ethyl acetate (126,00 ml) was added hydrogen chloride (17,05 ml; 17,0493 g; 17,05 mmol). After 2 hours, less than 1% of the original substances (according to HPLC analysis), and the phases were left to stand until separation. The lower aqueous phase was separated and discarded and the organic phase is washed with sodium chloride (42 ml, 15% wt./vol.; then 2×25 ml, 9% wt./vol.). Then the volume was reduced by distillation of the solvent (44 ml) at atmospheric pressure (temperature of the head ring 65°C). The solution is then cooled to 70°C. and was added in the Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide (40,3265 mg)obtained according to Example 16A, step 4. The mixture was stirred for 20 hours at 70°C. the Temperature was lowered to 24°C for 4 hours and 15 minutes and then reduced to 1°C for 1 hour. Then the suspension was filtered, the precipitate washed with cold ethyl acetate (17 ml), and the solid was dried in a vacuum oven at 45°C with the receipt of the Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide (3,15 g; 76%).

Example 16B

The Form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-Digue is dropyridine-3-carboxamide

A mixture of (2-vinyloxy-ethoxy)-amide 2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (500 mg, 915 mmol) and hydrogen chloride (1 ml) in tetrahydrofuran (5 ml) was stirred over night. Then added sodium hydroxide (1M; 2,00 ml) and another 10 minutes to the mixture was added methyl isobutyl ketone (3 ml) and ethyl acetate (3 ml). The layers were separated, and the organic solution was washed with 50% brine (4 ml), then evaporated (approximately half of the material was lost due to leakage). The residue was transferred into methyl isobutyl ketone (3 ml) and ethyl acetate (1 ml), and the mixture was heated to the temperature of reflux distilled. After cooling to 50°C. the mixture became turbid and was added isohexane (5 ml). This led to the crystallization of solids, and the mixture was cooled to 20°C. followed by the addition of an additional amount isohexane (5 ml). The solid was then filtered off, washed with isohexane (1 ml) and dried in a vacuum drying Cabinet at 40°C To produce specified in the connection header 140 mg.

Example 16G

The Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

The final product from Example 16 (25 mg) were placed in the reaction tube Syn 10 (Both) together with the magnetic core and the substance was dissolved in methanol by adding a single aliquot (1 ml) of methanol, n is evritania heated to 50°C. under stirring. In the reaction tube were added 5 mg of methanol to when cooled to obtain a supersaturated solution. When most of the solids had dissolved, the resulting solution was filtered through a Pall filter 0.45 µm PTFE Acrodisc CR13 second tube Syn 10 at 50°C. the Tube was then cooled to 0°C at a rate of 3°C/min and kept at 0°C as long as the substance is not crystallized. The samples were filtered, dried by suction, and then keeping in environmental conditions. A solid substance was carefully removed with filter paper and examined by XRPD method.

Example 16D

The x-ray diffraction on the powder (XRPD)

Picture of x-ray diffraction by the powder Form 1 and Form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide was determined by placing the sample of the crystalline substance in the holder, representing a plate of single crystal silicon (SSC) Siemens, and distribution of the sample in a thin layer using the object-glass of the microscope. The sample was rotated at 30 revolutions per minute (to improve the statistical account) and was irradiated with x-rays generated by long copper tube operated at 40 kV and 40 mA, with a wavelength of 1,5406 angstroms, using powder x-ray diffractometer Bruker D500 (Bruker AXS, Banner Lane Coventry CV4 9GH). A collimated x-ray beam was passed through the slit with automatic divergence set to 20, and the reflected radiation is directed through the anti-scattering slit of 2 mm and a receiving slit of 0.2 mm, the Sample was subjected to exposure for 1 second increments 2-theta 0.02 degrees (continuous scan mode) in the range from 2 degrees to 40 degrees 2-theta in theta-theta. The instrument was equipped with a scintillation counter as a detector. Receiving control data and the experimental data was performed using the display terminal Dell Optiplex 686 NT 4.0 operating software Diffract+. Data were collected in the range of 2-theta from 2 to 40 degrees with a step of 2-theta 0.02 degree, 4 with a step.

The specialist is aware that may be a picture of the x-ray diffraction on the powder, which has one or more measurement errors depending on the measurement conditions (such as equipment, sample preparation or the device used). In particular, it is well known that the intensity of the picture x-ray diffraction on the powder may vary depending on the measurement conditions and sample preparation. For example, expert it is clear that the relative intensity of the peaks can be affected, for example, particles larger than 30 microns and neonatesmelatonin sizes, that may affect the analysis of samples. The specialist also it is clear that the position of the reflections can influence the exact height at which the sample is located in the diffractometer, and the zero-calibration of the diffractometer. The flatness of the surface of the sample can also produce a small effect. Therefore, the person skilled in the art will understand that these diffraction patterns are presented in this description should not be construed as absolute (for further information see Jenkins, R & Snyder, R.L., "Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, 1996). Therefore, it should be borne in mind that the crystalline form of 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide is not limited to the crystals that give a picture of the x-ray diffraction on the powder, identical to the pictures of the x-ray diffraction on the powder presented on Figure 10-13, and any crystals, giving a picture of the x-ray diffraction on the powder is essentially the same as shown in Figure 10-13, are within the scope of the present invention. Specialist in the field of x-ray diffraction on the powder is able to assume the substantial identity of paintings by x-ray diffraction on the powder.

Example A

Differential scanning calorimetry

Analysis by the method of differential scanning ka is Gimatria (DSC) was performed on plates 1 and 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide, using Mettler DSC820e. Samples are typically less than 5 mg of the substance, placed in an aluminum sample cell 40 ál with pierced lid and heated in the temperature range from 25°C to 325°C at a constant heating rate of 10°C per minute. As the purge gas used nitrogen at a flow rate of 100 ml per minute.

The results show that the Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide demonstrates a large, sharp endotherm with an onset temperature 169,7°C due to melting (Fig), and the Form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide has a large, sharp endotherm with the onset temperature 154,3°C due to melting (Fig). After melting is observed large exothermic event due to decomposition. It should be borne in mind that the temperatures of the beginning and/or the temperature peak in the DSC may slightly vary from device to device, from method to method or from sample to sample, so the values should not be construed as absolute.

(S)-2-(4-Bromo-2-forgenerating)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

Stage A: Methyl 2-(4-bromo-2-forgenerating)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxylate was converted to (S)-2-(4-bromo-2-CFT is freilino)-N-(2-(tert-butyldimethylsilyloxy)propoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide according to the method described in Stage a of Example 14.

Stage B: To a solution of (S)-2-(4-bromo-2-forgenerating)-N-(2-(tert-butyldimethylsilyloxy)propoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide (0.037 g; 0,0682 mmol) in THF (1,00 ml) was added 1M HCl (0,682 ml; 0,682 mmol). The reaction mixture was stirred for one hour at room temperature. The reaction mixture was diluted tO and washed with saturated Panso3(3×), saturated NaCl (1×), dried (PA2SO4) and concentrated under reduced pressure. Purification column flash chromatography (methylene chloride/methanol 30:1) gave 0,020 g (69%) pure desired product as a yellow solid. MS ESI (+) m/z 428, 430 (M+, the sample with VG);1H NMR (400 MHz, CD3OD) δ 7.55 (s, 1H), 7.40 (d, 1H), 7.24 (d, 1H), 6.68 (t, 1H), 3.86 (m, 1H), 3.71 (m, 1H), 3.58 (m, 1H), 3.40 (s, 3H), 2.12 (s, 3H), 1.10 (d, 3H).

Methyl-2-(4-bromo-2-forgenerating)-5-ethyl-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate

Stage A. Obtaining methyl-2-chloro-5-ethyl-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate

Methyl-5-bromo-2-chloro-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate was converted to methyl 2-chloro-5-ethyl-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate, as described in Stage G of Example 13, using diethylzinc (1M in hexano), to obtain the target product as a yellow crystalline solid.

Stage B. Methyl-2-(4-bromo-2-forgenerating)-5-this is l-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate

Methyl 2-chloro-5-ethyl-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate was converted to methyl 2-(4-bromo-2-forgenerating)-5-ethyl-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate, as described in Stage D of Example 13. MS ESI (+) m/z 383, 385 (M+, the sample with VG);1H NMR (400 MHz, CDCl3) δ 9.59 (s, 1H), 7.76 (s, 1H), 7.32 (d, 1H), 7.18 (d, 1H), 6.59 (t, 1H), 3.86 (s, 3H), 3.28 (s, 3H), 2.56 (q, 2H), 1.22 (t, 3H).

2-(4-Bromo-2-forgenerating)-5-ethyl-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

Methyl-2-(4-bromo-2-forgenerating)-5-ethyl-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate was bound and deprived of protection as described in Example 14, to obtain the target product as a yellow solid. MS APCI (+) m/z 428, 430 (M+, the sample with VG);1H NMR (400 MHz, DMSO-d6) δ 11.51 (br s, 1H), 9.54 (br s, 1H), 7.57 (d, 1H), 7.47 (s, 1H), 7.25 (d, 1H), 6.69 (t, 1H), 4.67 (br s, 1H), 3.74 (m, 2H), 3.50 (m, 2H), 3.24 (s, 3H), 2.43 (q, 2H), 1.14 (t, 3H).

Methyl-2-(4-bromo-2-forgenerating)-5-chloro-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate

To a solution of methyl 2-(4-bromo-2-forgenerating)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate in DMF was added N-chlorosuccinimide. The reaction mixture was stirred at room temperature for 25 minutes and then extinguished with saturated sodium bisulfite. The reaction mixture was diluted with H2O and distributed between a mixture of tO/diethyl ether and saturated NaCl. The layers were separated, and in the hydrated layer was extracted again tO (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification column flash chromatography (methylene chloride/tO, 15:1) gave the desired product as a white solid. MS ESI (+) m/z 389, 391, 393 (M+, the sample with Cl, Br).1H NMR (400 MHz, CDCl3) δ 9.88 (s, 1H), 8.13 (s, 1H), 7.34 (d, 1H), 7.24 (d, 1H), 6.69 (t, 1H), 3.87 (s, 3H), 3.29 (s, 3H).

2-(4-Bromo-2-forgenerating)-5-chloro-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

Methyl-2-(4-bromo-2-forgenerating)-5-chloro-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate was bound and deprived of protection as described in Example 14, to obtain the target product as a pale yellow solid. MS APCI (+) m/z 434, 436, 438 (M+, the sample with Cl, Br);1H NMR (400 MHz, DMSO-d6) δ 11.56 (br s, 1H), 9.75 (br s, 1H), 7.91 (s, 1H), 7.57 (d, 1H), 7.26 (d, 1H), 6.89 (t, 1H), 4.68 (br s, 1H), 3.70 (m, 2H), 3.50 (m, 2H), 3.28 (s, 3H).

Methyl-5-cyano-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate

Stage A: Obtaining methyl-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate

To the solution prepared from methyl 2-chloro-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate and 2-fluoro-4-(methylthio)benzoylamino in THF (5 ml) at -78°C in an atmosphere of N2was added dropwise bis(trimethylsilyl)amide lithium (1M solution in hexano). Reactionuses was stirred for one hour at -78°C. Then was added dropwise methyl-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate in the form of a solution in THF and the reaction mixture was stirred for one hour at -78°C. the Reaction mixture was suppressed by the addition of N2O, and the pH was brought to pH 7 with saturated NH4Cl and then diluted tO. The organic layer was separated and washed with saturated NaCl, dried (Na2SO4) and concentrated under reduced pressure. Purification column flash chromatography (methylene chloride/tO, 15:1) gave the target product.

Stage B: Obtain methyl 5-bromo-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate

To a solution of methyl 2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate was added N-bromosuccinimide. The reaction mixture was stirred at room temperature for 25 minutes and then extinguished with saturated sodium bisulfite. The reaction mixture was diluted with H2Oh and distributed between a mixture of tO/diethyl ether and saturated NaCl. The layers were separated, and the aqueous layer was extracted again tO (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification column flash chromatography (methylene chloride/tO, 15:1) gave methyl 5-bromo-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate.

With the adiya In: Methyl-5-cyano-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate

A mixture of methyl 5-bromo-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate (0,020 g; 0,050 mmol), Tris(dibenzylideneacetone)-diplodia(0) (0,046 g; 0,050 mmol), 1,1'-bis(diphenylphosphino)-ferrocene (to 0.055 g; 0,100 mmol) and Zn(CN)2(0,006 g; by 0.055 mmol) was heated at 120°C for 2 hours. The reaction mixture was diluted tO and H2O and the layers were separated. tO layer was washed with saturated NH4CL and saturated NaCl, dried (Na2SO4) and concentrated under reduced pressure to a dark yellow resin. Purification column flash chromatography (methylene chloride/tO, 10:1) gave 0,005 grams (29%) of pure desired product as a yellow solid. MS APCI (-) m/z 346 (M-1);1H NMR (400 MHz, CDCl3) δ 10.84 (s, 1H), 8.39 (s, 1H), 6.95-7.06 (m, 3H), 3.90 (s, 3H), 3.17 (s, 3H), 2.50 (s, 3H).

The following compounds were obtained according to the methods described in the above Examples, unless otherwise indicated.

(S)-2-(4-Bromo-2-forgenerating)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

Stage A: Getting 2-chloro-6-oxo-1,6-dihydropyridines-3-carboxylic acid

2-Chloro-6-oxo-1,6-dihydropyridines-3-carboxylic acid was obtained from dichloro-nicotinic acid (3.00 g; 15.6 mmol, Aldrich) by the method described in U.S. patent No. 3682932 (1972), with 1.31 g (48%) of the target product.

Stage B: Obtain methyl 2-chloro-1-methyl-6-oxo-1,6-dihydropyri the Jn-3-carboxylate

To a solution of 2-chloro-6-oxo-1,6-dihydropyridines-3-carboxylic acid (0,644 g; 3,71 mmol) in DMF (20 ml) was added lithium hydride (95%, 0,078 g; 9.28 are mmol)and the reaction mixture was stirred for 40 minutes in an atmosphere of N2. Then add methyliodide (0,508 ml of 1.16 g, 8.16 mmol)and the reaction mixture was stirred for an additional 45 minutes. The reaction mixture was extinguished 2M HCl up until the pH became 6-7. The reaction mixture was diluted tO and saturated NaCl, and the layers were separated. The aqueous layer was extracted again tO (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to get crude yellow solid. HPLC analysis showed the presence of two products with a ratio of 4:1, which was separated by column flash chromatography (methylene chloride/tO, from 15:1 to 10:1) to obtain the 0,466 g (62%) of pure desired product as a white crystalline solid. Also identified a minor product in the form of a pale yellow crystalline solid and identified it as regioisomer methyl-2-chloro-6-methoxynicotinate.

Stage: Obtaining methyl-2-(4-bromo-2-forgenerating)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate

To a solution of 4-bromo-2-foronline (0,192 g; 1.01 mmol) in THF (5 ml) at -78°C in an atmosphere of N2was added dropwise bis(trimethylsilyl)amide lithium (1.50 ml; 1.50 IMO the ü; 1M solution in hexano). The reaction mixture was stirred for one hour at -78°C. Then was added dropwise methyl-2-chloro-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate (0,202 g; 1.00 mmol) in solution in THF (5 ml)and the reaction mixture was stirred for one hour at -78°C. the Reaction mixture was suppressed by the addition of H2O, and the pH was brought to pH 7 with saturated NH4CL and then diluted tO. The organic layer was separated and washed with saturated NaCl, dried (Na2SO4) and concentrated under reduced pressure. Purification column flash chromatography (methylene chloride/tO, 15:1) gave 0,232 g (65%) of pure desired product as a white crystalline solid.

Stage G: Obtaining (S)-2-(4-bromo-2-forgenerating)-N-(2-(tert-butyldimethylsilyloxy)propoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

To a solution of methyl 2-(4-bromo-2-forgenerating)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate (0,050 g; 0.14 mmol) and (S)-O-(2-(tert-butyldimethylsilyloxy)propyl)hydroxylamine (0,072 g; 0.35 mmol) in THF (1.50 ml) at 0°C was slowly added bis(trimethylsilyl)amide lithium (to 0.70 ml, 0.70 mmol). After the addition, the reaction mixture was stirred for 1 hour at room temperature and then extinguished saturated Panso3. The reaction mixture was distributed between tO and saturated NaCl. The layers were separated, and the aqueous layer was again extragere the Ali tO (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to get crude brown solid, which was used in the next stage without additional purification.

Stage D: Obtaining (S)-2-(4-bromo-2-forgenerating)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

To a solution of (S)-2-(4-bromo-2-forgenerating)-N-(2-(tert-butultimately-silyloxy)propoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide (0,074 g; 0.14 mmol) in THF (1.50 ml) was added 1M aqueous HCl (1.4 ml; 1.4 mmol). The reaction mixture was stirred for 16 hours at room temperature. The reaction mixture was diluted tO and washed with saturated aqueous Panso3(3×) and saturated aqueous NaCl. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure to get crude white solid. Purification of the crude product by rubbing with Et2O and the allocation of the obtained solid substance gave (S)-2-(4-bromo-2-forgenerating)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide (0,030 g; 52% over two stages) in the form of a white solid. MS ESI (+) m/z 414, 416 (M+) sample with Br;1H NMR (400 MHz, CD3OD) δ 7.65 (d, 1H), 7.42 (dd, 1H), 7.28 (m, 1H), 6.81 (t, 1H), 6.28 (d, 1H), 3.88 (m, 1H), 3.70 (dd, 1H), 3.58 (dd, 1H), 3.38 (s, 3H), 1.11 (d, 3H).

2-(2-Fluoro-4-itfinally)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS ESI (+) m/z 388, sample (M+1);1H NMR (400 MHz, CDCl3) δ 10.8 (s, 1H), 7.47 (d, 2H), 7.39 (d, 1H), 6.54 (t, 1H), 6.26 (d, 1H), 5.59 (br s, 2H), 3.24 (s, 3H).

N-Ethoxy-2-(2-fluoro-4-itfinally)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS ESI (+) m/z 432, sample (M+1);1H NMR (400 MHz, DMSO-d6) δ 11.4 (br s, 1H), 9.83 (br s, 1H), 7.66 (dd, 1H), 7.58 (d, 1H), 7.43 (d, 1H), 6.65 (t, 1H), 6.18 (d, 1H), 3.70 (q, 2H), 3.21 (s, 3H), 1.10 (t, 3H).

2-(2-Fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS ESI (+) m/z 448, sample (M+1);1H NMR (400 MHz, CD3OD) δ 7.66 (d, 1H), 7.56 (m, 1H), 7.46 (m, 1H), 6.65 (t, 1H), 6.28 (d, 1H), 3.85 (t, 2H), 3.67 (t, 2H), 3.36 (s, 3H).

(S)-2-(2-Fluoro-4-itfinally)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS ESI (+) m/z 462, sample (M+1);1H NMR (400 MHz, CD3OD) δ 7.66 (d, 1H), 7.56 (d, 1H), 7.46 (d, 1H), 6.65 (t, 1H), 6.28 (d, 1H), 3.85 (m, 1H), 3.67 (m, 1H), 3.57 (m, 1H), 3.38 (s, 3H), 1.11 (d, 3H).

N-Ethoxy-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide.

MS APCI (+) m/z 352, sample (M+1);1H NMR (400 MHz, CD3OD) δ 7.64 (d, 1H), 7.12 (dd, 1H), 7.05 (m, 1H), 6.86 (t, 1H), 6.21 (d, 1H), 3.85 (q, 2H), 3.32 (s, 3H), 2.47 (s, 3H), 1.22 (t, 3H).

2-(2-Fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-di is hydropyridine-3-carboxamide

MS ESI (+) m/z 368, sample (M+1);1H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H), 8.48 (s, 1H), 7.38 (d, 1H), 7.00 (m, 1H), 6.96 (m, 1H), 6.79 (t, 1H), 6.19 (d, 1H), 4.04 (m, 2H), 3.88 (m, 1H), 3.75 (m, 2H), 3.22 (s, 3H), 2.48 (s, 3H).

(S)-2-(2-Fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS ESI (+) m/z 382, sample (M+1);1H NMR (400 MHz, CD3OD) δ 7.64 (d, 1H), 7.12 (d, 1H), 7.04 (d, 1H), 6.85 (t, 1H), 6.21 (d, 1H), 4.01 (m, 1H), 3.90 (m, 1H), 3.71 (m, 1H), 3.60 (m, 1H), 3.32 (s, 3H), 2.47 (s, 3H), 1.10 (d, 3H).

2-(4-Bromo-2-chlorpheniramine)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

(S)-2-(4-Bromo-2-chlorpheniramine)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

2-(2-Chloro-4-itfinally)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS APCI (+) m/z 464, 466 (M+, the sample Cl);1H NMR (400 MHz, DMSO-d6) δ 11.59 (brs, 1H), 10.06 (brs, 1H), 7.86 (d, 1H), 7.64 (d, 1H), 7.54 (dd, 1H), 6.53 (d, 1H), 6.21 (d, 1H), 4.67 (t, 1H), 3.78 (t, 2H), 3.52 (m, 2H), 3.13 (s, 3H).

(S)-2-(2-Chloro-4-itfinally)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS APCI (+) m/z 478, 480 (M+, the sample Cl);1H NMR (400 MHz, DMSO-d6) δ 11.59 (s, 1H), 9.99 (s, 1H), 7.86 (d, 1H), 7.64 (d, 1H), 7.54 (dd, 1H), 6.53 (d, 1H),6.21 (d, 1H), 4.73 (m, 1H), 3.75 (m, 1H), 3.58 (m, 2H), 3.14 (s, 3H), 1.02 (d, 3H).

2-(2-Chloro-4-iodine is amino)-N-methoxy-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

(S)-2-(2-Fluoro-4-itfinally)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS ESI (+) m/z 476 sample (M+1);1H NMR (400 MHz, CDCl3) δ 9.79 (s, 1H), 8.53 (s, 1H), 7.46 (d, 1H), 7.35 (m, 1H), 6.44 (t, 1H), 4.15 (m, 1H), 3.92 (dd, 1H), 3.69 (dd, 1H), 3.28 (s, 3H), 2.14 (s, 3H), 1.14 (d, 3H).

(S)-4-(2-Fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 395 (M-1);1H NMR (400 MHz, CD3D) δ 7.10 (dd, 1H), 7.03 (d, 1H), 6.87 (t, 1H), 4.00 (m, 1H), 3.85 (dd, 1H), 3.79 (s, 3H), 3.72 (dd, 1H), 2.47 (s, 3H), 1.75 (s, 3H), 1.16 (d, 3H).

(S)-4-(2-Fluoro-4-itfinally)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 475 (M-1);1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (dd, 1H), 6.63 (t, 1H), 3.98 (m, 1H), 3.84 (dd, 1H), 3.79 (s, 3H), 3.72 (dd, 1H), 1.78 (s, 3H), 1.16 (d, 3H).

2-(2-Fluoro-4-itfinally)-N-methoxy-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

The following compounds were obtained according to the methods described in the Examples above.

2-(4-Bromo-2-forgenerating)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

2-(2-Fluoro-4-itfinally)-N-methoxy-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

N-Ethoxy-2-(2-fluoro-4-itfinal the Mino)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

N-Ethoxy-2-(2-fluoro-4-(methylthio)phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS APCI (+) m/z 366, sample (M+1);1H NMR (400 MHz, DMSO-d6) δ 11.38 (br s, 1H), 9.79 (br s, 1H), 7.54 (s, 1H), 7.23 (dd, 1H), 6.99 (dd, 1H), 6.73 (t, 1H), 3.76 (q, 2H), 3.19 (s, 3H), 2.46 (s, 3H), 2.01 (s, 3H), 1.12 (t, 3H).

2-(2-Fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS APCI (+) m/z 382, sample (M+1);1H NMR (400 MHz, DMSO-d6) δ 11.48 (brs, 1H), 9.78 (brs, 1H), 7.56 (s, 1H), 7.23 (dd, 1H), 6.99 (m, 1H), 6.73 (t, 1H), 4.68 (brs, 1H), 3.76 (t, 2H), 3.51 (t, 2H), 3.19 (s, 3H), 2.46 (s, 3H), 2.01 (s, 3H).

(S)-2-(2-Fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS APCI (+) m/z 396, sample (M+1);1H NMR (400 MHz, DMSO-d6) δ 11.48 (br s, 1H), 9.68 (br s, 1H), 7.55 (s, 1H), 7.23 (dd, 1H), 6.99 (dd, 1H), 6.73 (t, 1H), 4.73 (d, 1H), 3.74 (m, 1H), 3.56 (d, 2H), 3.20 (s, 3H), 2.46 (s, 3H), 2.01 (s, 3H), 1.02 (d, 3H).

2-(4-Bromo-2-chlorpheniramine)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

(S)-2-(4-Bromo-2-chlorpheniramine)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

2-(2-Chloro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

Detected: MS APCI (+) m/z 478, 480 (M+, the sample Cl);1 H NMR (400 MHz, CD3OD) δ 7.79 (d, 1H), 7.59 (s, 1H), 7.52 (dd, 1H), 6.39 (d, 1H), 3.89 (t, 2H), 3.67 (t, 2H), 3.34 (s, 3H), 2.13 (s, 3H).

(S)-2-{2-Chloro-4-itfinally)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

2-(2-Chloro-4-itfinally)-N-methoxy-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

5-Chloro-2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS ESI (+) m/z 482, 484 (M+, the sample Cl);1H NMR (400 MHz, DMSO-d6) δ 11.56 (br s, 1H), 9.69 (br s, 1H), 7.89 (s, 1H), 7.64 (dd, 1H), 7.40 (dd, 1H), 6.72 (t, 1H), 4.66 (t, 1H), 3.67 (t, 2H), 3.49 (m, 2H), 3.28 (s, 3H).

(S)-5-Chloro-2-(2-fluoro-4-itfinally)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

4-(2-Chloro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 477, 479 (M-1, the sample Cl);1H NMR (400 MHz, CD3OD) δ 7.77 (d, 1H), 7.54 (dd, 1H), 6.51 (d, 1H), 4.01 (t, 2H), 3.81 (s, 3H), 3.75 (t, 2H), 1.74 (s, 3H).

(S)-4-(2-Chloro-4-itfinally)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 491, 493 (M-1, the sample Cl);1H NMR (400 MHz, CD3OD) δ 7.77 (d, 1H), 7.54 (dd, 1H), 6.51 (d, 1H), 4.00 (m, 1H), 3.87 (dd, 1H), 3.80 (s, 3H), 3.75 (dd, 1H), 1.74 (s, 3H), 1.16 (d, 3H).

4-(4-Bromo-2-chlorpheniramine)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 429, 431, 433 (M-1, the sample with Br, Cl);1H NMR (400 MHz, CD3OD) δ 7.62 (d, 1H), 7.38 (dd, 1H), 6.67 (d, 1H), 4.02 (t, 2H), 3.81 (s, 3H), 3.75 (t, 2H), 1.73 (s, 3H).

(S)-4-(4-Bromo-2-chlorpheniramine)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

Additional compounds of the present invention include compounds of General formula Ia, IVa, IV, IVC, characterise reflexes IVG, IV, and IVe IV, which are presented in the following Tables 1-8.

Additional examples according to the invention include the following examples, which can be obtained by the methods described above unless otherwise indicated.

4-(2-Fluoro-4-(methylthio)phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyri Azin-3-carboxamide

MS APCI (-) m/z 321 (M-1);1H NMR (400 MHz, CD3OD) δ 7.09 (dd, 1H), 7.04 (d, 1H), 6.87 (t, 1H), 3.81 (s, 3H), 2.48 (s, 3H), 1.70 (s, 3H).

5-fluoro-4-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 385 (M-1);1H NMR (400 MHz, CD3OD) δ 7.14 (td, 1H), 7.07 (m, 2H), 4.05 (t, 2H), 3.79 (s, 3H), 3.78 (t, 2H), 2.49 (s, 3H).

(S)-5-fluoro-4-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 399 (M-1);1H NMR (400 MHz, CD3D) δ 7.14 (td, 1H), 7.07 (m, 2H), 4.04 (m, 1H), 3.93 (dd, 1H), 3.81 (m, 1H), 3.80 (s, 3H), 2.49 (s, 3H), 1.18 (d, 3H).

5-Chloro-4-(2-Fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 401, 403 (M-1, the sample Cl);1H NMR (400 MHz, CD3OD) δ 7.06 (m, 3H), 3.94 (t, 2H), 3.81 (s, 3H), 3.73 (t, 2H), 2.49 (s, 3H).

(S)-5-Chloro-4-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 415, 417 (M-1, the sample Cl);1H NMR (400 MHz, CD3OD) δ 7.06 (m, 3H), 3.98 (m, 1H), 3.81 (m, 1H), 3.80 (s, 3H), 3.69 (dd, 1H), 2.49 (s, 3H), 1.16 (d, 3H).

4-(2-Fluoro-4-(methylthio)phenylamino)-N-(3-hydroxypropyl)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 379 (M-1);1H NMR (400 MHz, CD3OD) δ 7.09 (dd, 1H), 7.03 (d, 1H), 6.86 (t, 1H), 3.81 (s, 3H) 3.64 (t, 2H), 3.43 (t, 2H), 2.47 (s, 3H), 1.80 (m, 2H), 1.71 (s, 3H).

(S)-N-(2,3-Dihydroxypropyl)-4-(2-fluoro-4-(methylthio)phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 395 (M-1);1H NMR (400 MHz, CD3OD) δ 7.10 (dd, 1H), 7.03 (dd, 1H), 6.86 (t, 1H), 3.81 (s, 3H), 3.80 (m, 1H), 3.51 (m, 3H), 3.37 (dd, 1H), 2.47 (s, 3H), 1.71 (s, 3H).

4-(4-Bromo-2-forgenerating)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 353, 355 (M-1, the sample with VG);1H NMR (400 MHz, CD3OD) δ 7.38 (dd, 1H), 7.27 (m, 1H), 6.80 (t, 1H), 3.82 (s, 3H), 1.72 (s, 3H).

(R)-4-(4-Bromo-2-forgenerating)-N-(2,3-dihydroxypropane)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 443, 445 (M-1, the sample with VG);1H NMR (400 MHz, CD3OD) δ 7.39 (dd, 1H), 7.27 (m, 1H), 6.79 (t, 1H), 4.03 (m, 1H), 3.89 (m, 2H), 3.80 (s, 3H), 3.59 (m,2H), 1.77 (s, 3H).

4-(4-Bromo-2-forgenerating)-N-(1-hydroxy-2-methylpropan-2-yloxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 441, 443 (M-1, the sample with VG);1H NMR (400 MHz, CD3OD) δ 7.38 (dd, 1H), 7.27 (d, 1H), 6.79 (t, 1H), 3.81 (s, 3H), 3.38 (s, 2H), 1.78 (s, 3H), 1.25 (s, 6H).

4-(2-Fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 401 (M-1);1H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1H), 8.25 (s, 1H), 7.90 (s, 1H), 7.65 (s, 1H), 7.43 (s, 1H), 6.63 (t, 1H), 3.71 (s, 3H), 1.63 (s, 3H).

4-(4-Br the m-2 forgenerating)-5-fluoro-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 417, 419 (M-1, the sample with Br);1H NMR (400 MHz, CDCl3) δ 9.66 (br. s, 1H), 9.30 (br. s, 1H), 7.28 (m, 2H), 6.97 (td, 1H), 4.11 (t, 2H), 3.84 (t, 2H), 3.82 (s, 3H), 3.51 (t, 1H).

4-(2-Fluoro-4-itfinally)-N,1,5-trimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 415 (M-1);1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (m, 1H), 6.61 (t, 1H), 3.81 (s, 3H), 2.87 (s, 3H), 1.74 (s, 3H).

N-(Cyclopropylmethyl)-4-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 455 (M-1);1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (dd, 1H), 6.62 (t, 1H), 3.83 (s, 3H), 3.18 (d, 2H), 1.75 (s, 3H), 1.06 (m, 1H), 0.51 (dd, 2H), 0.27 (dd, 2H).

4-(2-Fluoro-4-itfinally)-N-(3-hydroxypropyl)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 459 (M-1);1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (dd, 1H), 6.62 (t, 1H), 3.81 (s, 3H), 3.63 (t, 2H), 3.43 (t, 2H), 1.79 (m, 2H), 1.74 (s, 3H).

5-fluoro-4-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 465 (M-1);1H NMR (400 MHz, CD3OD) δ 7.55 (dd, 1H), 7.50 (d, 1H), 6.95 (td, 1H), 4.05 (t, 2H), 3.80 (s, 3H), 3.78 (t, 2H).

4-(2-Fluoro-4-itfinally)-N-(2-hydroxyethyl)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 445 (M-1);1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (dd, 1H), 6.62 (t, 1H), 3.82 (s, 3H), 3.68 (t, 2H), 3.46 (t, 2H), 1.74 (s, 3H).

N-(2,3-Dihydroxypropyl)-4-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 475 (M-1);1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (dd, 1H), 6.62 (t, 1H), 3.82 (s, 3H), 3.80 (m, 1H), 3.52 (m, 3H), 3.36 (dd, 1H), 1.74 (s, 3H).

5-Chloro-4-(2-Fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 481, 483 (M-1, the sample Cl);1H NMR (400 MHz, CD3OD) δ 7.53 (dd, 1H), 7.49 (d, 1H), 6.88 (t, 1H), 3.97 (t, 2H), 3.81 (s, 3H), 3.74 (t, 2H).

(S)-5-Chloro-4-(2-fluoro-4-itfinally)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 495, 496 (M-1, the sample Cl);1H NMR (400 MHz, CD3OD) δ 7.53 (dd, 1H), 7.49 (d, 1H), 6.88 (t, 1H), 3.99 (m, 1H), 3.83 (m, 1H), 3.81 (s, 3H), 3.71 (dd, 1H), 1.17 (d, 3H).

5-Chloro-4-(2-fluoro-4-itfinally)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 421, 423 (M-1, the sample Cl);1H NMR (400 MHz, CDCl3/CD3OD) δ 7.56 (td, 1H), 7.46 (m, 1H), 6.82 (t, 1H), 3.87 (s, 3H).

5-Chloro-N-(2,3-dihydroxypropyl)-4-(2-fluoro-4-itfinally)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (+) m/z 497, 499 (M+1, the sample Cl);1H NMR (400 MHz, CD3OD) δ 7.53 (dd, 1H), 7.49 (d, 1H), 6.86 (t, 1H), 3.84 (s, 3H), 3.80 (m, 1H), 3.55 (d, 2H), 3.50 (m, 1H), 3.37 (dd, 1H).

(S)-N-(2,3-Dihydroxypropyl)-4-(2-fluoro-4-itfinally)-1,5-dimethyl-6-eye-1,6-dihydropyridin-3-carboxamide

MS APCI (-) m/z 475 (M-1);1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.44 (d, 1H), 6.62 (t, 1H), 3.82 (s, 3H), 3.80 (m, 1H), 3.52 (m, 3H), 3.36 (dd, 1H), 1.74 (s, 3H).

(S)-5-Chloro-N-(2,3-dihydroxypropyl)-4-(2-fluoro-4-itfinally)-1-methyl-6-oxo-1,6-dihydropyridin-3-carboxamide

MS APCI (+) m/z 497, 499 (M+1, the sample Cl);1H NMR (400 MHz, CD3OD) δ 7.52 (dd, 1H), 7.48 (d, 1H), 6.86 (t, 1H), 3.84 (s, 3H), 3.80 (m, 1H), 3.55 (d, 2H), 3.51 (d, 1H), 3.37 (dd, 1H).

2-(2-Fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS APCI (+) m/z 308, a sample of (M+1);1H NMR (400 MHz, DMSO-d6) δ 11.38 (s, 1H), 7.92 (br s, 1H), 7.89 (d, 1H), 7.45 (br s, 1H), 7.25 (dd, 1H), 7.04 (dd, 1H), 6.88 (t, 1H), 6.09 (d, 1H), 3.07 (s, 3H), 2.48 (s, 3H).

5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

Stage A: Getting 2-chloro-5-fluoro-6-oxo-1,6-dihydropyridines-3-carboxylic acid

A mixture of 2,6-dichloro-5-fornicating acid (15,00 g; 71,43 mmol, Lancaster synthesis) and 2 N. NaOH (178,6 ml; 357,2 mmol) was stirred at the temperature of reflux distilled for 2 hours and then at room temperature for 16 hours. The reaction mixture was cooled to 0°C and acidified 12 N. HCl (32,74 ml; 392,9 mmol). The mixture was cooled for 30 minutes in an ice bath, the solid was filtered and washed with H2A. Preparing a suspension of the selected solids in the heat of the tO, was filtered and then washed with warm tO. The solids were collected and dried under vacuum overnight to obtain the target product (6.4 g; 47%) as a beige solid.

Stage B: Obtain methyl 2-chloro-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate

To a solution of 2-chloro-5-fluoro-6-oxo-1,6-dihydropyridines-3-carboxylic acid (6,37 g; of 33.26 mmol) in DMF (250 ml) at 0°C was added LiH (95%; 0,661 g; 83,14 mmol). The reaction mixture was stirred for 45 minutes and then added logmean (4,56 ml; 73,16 mmol). The reaction mixture was stirred at room temperature for 2 hours and then extinguished 2M HCl up until the pH of the reaction mixture did not reach 6-7. The reaction mixture was diluted tO and saturated NaCl, and the layers were separated. The aqueous layer was extracted again tO (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure to get crude yellow oil. HPLC analysis showed the presence of two products in a ratio of 5:1, which was separated by column flash chromatography (methylene chloride/tO, 15:1) to obtain the target product (of 5.40 g; 74%) as a pale yellow solid. Also identified a minor product in the form of a pale yellow crystalline solid and identified it as regioisomer methyl-2-chloro-5-fluoro-6-methoxynicotinate.

Stage: Getting ethyl-5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate

To a solution of 2-fluoro-4-(methylthio)aniline (0,236 g; 1.50 mmol) in THF (10 ml) at -78°C in an atmosphere of N2was added dropwise bis(trimethylsilyl)amide lithium (3.42 ml; of 3.42 mmol, 1 M solution in hexano). After complete addition, the reaction mixture was stirred for one hour at -78°C. Then was added dropwise methyl-2-chloro-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate (0,300 g; 1.37 mmol) in solution in THF (5 ml)and the reaction mixture was stirred for 30 minutes at -78°Creational mixture was suppressed by the addition of 1M HCl up until the pH of the reaction mixture did not reach the 5, and then was diluted tO and saturated NaCl. The organic layer was separated, dried (Na2SO4) and concentrated under reduced pressure. Purification column flash chromatography (methylene chloride/tO, 15:1) gave the pure target product (0,359 g; 75%) as a white solid.

Stage G: Obtain 5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridines-3-carboxamide

To a mixture of methyl 5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxylate (0,100 g; 0,294 mmol) and O-(2-(vinyloxy)ethyl)-hydroxylamine (0,045 ml; 0,441 mmol) in THF (2 ml) at 0°C was added dropwise bis(trimethylsilyl)amide lithium (of 1.18 ml, 1.18 mmol, 1 M solution in hexano). The reaction mixture was stirred for 20 minutes, reduce 1M HCl, and then distributed and between tO and saturated NaCl. The layers were separated, and the aqueous layer was extracted again tO (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated under reduced pressure to get crude yellow solid, which was used in the next stage without purification.

Stage D: Obtain 5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1.6-dihydropyridines-3-carboxamide

To a solution of 5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-1-methyl-6-oxo-N-(2-(vinyloxy)ethoxy)-1,6-dihydropyridines-3-carboxamide (0,121 g; 0,294 mmol) in tO (3 ml) was added 2M HCl (0.75 ml). The reaction mixture was stirred at room temperature for 16 hours. the pH of the reaction mixture was brought to pH 7 using 1 M NaOH. The reaction mixture was diluted tO and H2O. the Organic layer was separated and washed with saturated NaCl. The combined aqueous layers was extracted again tO (1×). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Purification column flash chromatography on silica gel (methylene chloride/Meon, 15:1) gave 5-fluoro-2-(2-fluoro-4-(methylthio)-phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide (0,079 g, 70% over two stages) in the form of a white solid. MS ESI (+) m/z 386, sample (M+1);1H NMR (400 MHz, DMSO-d6) δ 11.54 (br s, 1H), 9.65 (br s, 1H), 7.65 (d, 1H), 7.23 (dd, 1H), 6.99 (dd, 1H), 6.81 (t, 1H), 4.67 (t, 1H), 3.74 (t, 2H), 3.51 (q, 2H), 3.25 (s, 3H), 2.46 (s, 3H).

5-Chloro-2-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS ESI (+) m/z 402, 404 (M+, the sample Cl);1H NMR (400 MHz, DMSO-d6) δ 11.59 (brs, 1H), 10.00 (brs, 1H), 7.93 (s, 1H), 7.23 (dd, 1H), 7.01 (dd, 1H), 6.93 (t, 1H), 4.66 (t, 1H), 3.73 (t, 2H), 3.51 (m, 2H), 3.24 (s, 3H), 2.47 (s, 3H).

(S)-5-fluoro-2-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS APCI (+) m/z 400, a sample of (M+1);1H NMR (400 MHz, DMSO-d6) δ 11.54 (brs, 1H), 9.61 (brs, 1H), 7.64 (d, 1H), 7.22 (dd, 1H), 6.99 (dd, 1H), 6.81 (t, 1H), 4.73 (s, 1H), 3.73 (m, 1H), 3.54 (d, 2H), 3.25 (s, 3H), 2.46 (s, 3H), 1.01 (d, 3H).

(S)-5-Chloro-2-(2-fluoro-4-(methylthio)phenylamino)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS APCI (+) m/z 416, 418 (M+, the sample Cl);1H NMR (400 MHz, DMSO-d6) δ 11.59 (br s, 1H), 9.94 (br s, 1H), 7.92 (s, 1H), 7.23 (dd, 1H), 7.01 (dd, 1H), 6.94 (t, 1H), 4.71 (d, 1H), 3.75 (m, 1H), 3.54 (d, 2H), 3.24 (s, 3H), 2.47 (s, 3H), 1.02 (d, 3H).

2-(2-Fluoro-4-(methylthio)phenylamino)-N-methoxy-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS ESI (+) m/z 338, sample (M+1);1H NMR (400 MHz, CDCl3) δ 10.33 (s, 1H), 8.39 (s, 1H), 7.40 (d, 1H), 7.02 (dd, 1H), 6.96 (dd, 1H), 6.75 (t, 1H), 6.20 (d, 1H), 3.83 (s, 3H), 3.23 (s, 3H), 2.47 (s, 3H).

2-(2-Fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS ESI (+) m/z 402, brezec (M+1); 1H NMR (400 MHz, DMSO-d6) δ 10.75 (s, 1H), 7.85 (br s, 1H), 7.78 (s, 1H), 7.66 (d, 1H), 7.40 (m, 2H), 6.54 (t, 1H), 3.13 (s, 3H), 2.00 (s, 3H).

2-(2-Fluoro-4-itfinally)-N-(3-hydroxypropyl)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS ESI (+) m/z 460, sample (M+1);1H NMR (400 MHz, DMSO-d6) δ 10.34 (s, 1H), 8.27 (t, 1H), 7.72 (s, 1H), 7.64 (dd, 1H), 7.38 (dd, 1H), 6.50 (t, 1H), 4.41 (t, 1H), 3.17 (s, 5H), 2.01 (s, 3H), 1.55 (s, 2H).

(S)-5-Chloro-2-(2-fluoro-4-itfinally)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS APCI (+) m/z 460, sample (M+1);1H NMR (400 MHz, DMSO-d6) δ 11.54 (br s, 1H), 9.62 (br s, 1H), 7.86 (s, 1H), 7.62 (dd, 1H), 7.38 (dd, 1H), 6.69 (t, 1H), 4.69 (m, 1H), 3.46 (m, 2H), 3.27 (s, 3H), 0.99 (d, 3H).

(3)-2-(2-Chloro-4-itfinally)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS APCI (+) m/z 492, sample (M+1);1H NMR (400 MHz, CD3OD) δ 7.79 (d, 1H), 7.58 (m, 1H), 7.52 (dd, 1H), 6.39 (d, 1H), 3.87 (m, 1H), 3.73 (dd, 1H), 3.62 (dd, 1H), 3.35 (s, 3H), 2.13 (s, 3H), 1.10 (d, 3H).

5-fluoro-2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide

MS ESI (+) m/z 466, sample (M+1);1H NMR (400 MHz, DMSO-d6) δ 11.53 (br s, 1H), 9.37 (br s, 1H), 7.64 (dd, 1H), 7.62 (d, 1H), 7.37 (dd, 1H), 6.61 (t, 1H), 4.68 (t, 1H), 3.69 (t, 2H), 3.49 (q, 2H), 3.30 (s, 3H).

(S)-5-fluoro-2-(2-fluoro-4-itfinally)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carb is camid

MS APCI (+) m/z 480, sample (M+1);1H NMR (400 MHz, DMSO-d6) δ 11.49 (br s, 1H), 9.48 (br s, 1H), 7.61 (m, 2H), 7.36 (m, 1H), 6.59 (t, 1H), 4.77 (br s, 1H), 3.69 (m, 1H), 3.49 (s, 1H), 3.48 (d, 1H), 3.29 (s, 3H), 0.99 (d, 3H).

The above description is considered only as an illustration of the principles of the invention. Furthermore, since numerous modifications and changes will be obvious to experts in this field, it is undesirable to limit the invention to the precise demonstrated by the design and method as described above. Accordingly, all suitable modifications and equivalents may be considered as falling under the scope of the invention defined by the following claims.

The words "include", "includes", "include", "including" and "includes"when used in this description and the following claims are intended to accurately determine the presence of stated features, integers, components, or stages, but they do not deny the presence or addition of one or more other features, integers, components, stages or groups.

1. The connection, including the tautomers, the enantiomers and their pharmaceutically acceptable salts, having the formula IV:

where R1represents CL or F;
R3represents H, Me, Et, HE, MeO-, tO, NON2CH2Oh, NON2(The e) 2O-, (S)-MeCH(OH)CH2O-, (R)-HOCH2CH(OH)CH2O-, cyclopropyl-CH2O-, NON2CH2-,
,,,,or
R7represents methyl or ethyl, which may be substituted by one or more F;
R8represents Br, I or SMe; and
R9represents H, C1-C4alkyl, CL or CN, where the specified alkyl possibly substituted by one or more groups independently selected from F, or CN, provided that when
a) R represents F, R8represents Br, R9represents N, and R7is either Me, or Et, then R3can't imagine NON2CH2About;
b) R1represents F, R8is a I, R9represents N, and R3represents MeO, then R7can't represent Me;
in R1represents F, R8is a SMe, R9represents N, and R3represents NON2CH2Oh, then R7can't represent Me, and
g) R1represents F, R8represents Br, R9represents N, and R3represents cyclopropyl 2Oh, then R7can't represent Me.

2. The compound according to claim 1, where R9represents H, Me, Et, Cl or CN.

3. The compound having the formula VI:

or its pharmaceutically acceptable salt,
where R1represents Cl or F;
R3represents H, HOCH2CH2O or (S)-MeCH(OH)CH2O; and
R9represents H, Me, F or Cl.

4. The compound according to claim 3, where R1represents F, R3represents NON2CH2O-, and R9represents methyl, or its pharmaceutically acceptable salt.

5. The compound according to claim 3, which is:
2-(2-chloro-4-itfinally)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide;
(S)-2-(2-chloro-4-itfinally)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide;
2-(2-fluoro-4-itfinally)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide;
2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide;
(S)-2-(2-fluoro-4-itfinally)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide;
(S)-2-(2-fluoro-4-itfinally)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide;
2-(2-chloro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide;
5-chloro-2-(2-fluoro-4-itfinally)-N-2-is hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide;
(S)-2-(2-chloro-4-itfinally)-N-(2-hydroxypropoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide; or
(S)-5-chloro-2-(2-fluoro-4-itfinally)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide.

6. The compound according to claim 3 selected from:
5-fluoro-2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide; and
(S)-5-fluoro-2-(2-fluoro-4-itfinally)-N-(2-hydroxypropoxy)-1-methyl-6-oxo-1,6-dihydropyridines-3-carboxamide.

7. The compound according to claim 3, which is 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide.

8. The crystalline form of the compound of formula XI

essentially in the Form 2 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide, characterized by a pattern of x-ray diffraction with characteristic peaks at about a 9.5 and 12.6 on the 2θ scale.

9. The crystalline form of the compound of formula XI of claim 8, characterized by a pattern of x-ray diffraction with characteristic peaks at about 9,5; 12,6; and 14,7 19,6 on the 2θ scale.

10. The crystalline form of the compound of formula XI of claim 8, characterized by a pattern of x-ray diffraction is essentially the same as shown in Figure 10.

11. The crystalline form of the compound of formula XI

essentially in the Form 1 2-(2-fluoro-4-itfinally)-N-(2-hydroxyethoxy)-1,5-dimethyl-6-oxo-1,6-dihydropyridines-3-carboxamide, characterized by a pattern of x-ray diffraction with characteristic peaks at approximately 9.2 and 13.0 on the 2θ scale.

12. The crystalline form of the compound of formula XI according to claim 11, characterized by a pattern of x-ray diffraction with characteristic peaks at approximately 9.2; 13,0; 18,3; and 21.7 21,0 on the 2θ scale.

13. The crystalline form of the compound of formula XI according to claim 11, characterized by a pattern of x-ray diffraction, essentially as shown figure 11.

14. The compound according to any one of claims 1, 3, 8 and 11 for use as a drug, which inhibits MEK (kinase mitogen-activated ERK (kinases regulated by extracellular signals)).

15. The compound according to any one of claims 1, 3, 8 and 11 for use as a drug for the treatment of hyperproliferative disorders, or inflammatory conditions.

16. The use of compounds according to any one of claims 1, 3, 8 and 11 in the manufacture of medicinal products for the treatment of hyperproliferative disorders, or inflammatory conditions.

17. Pharmaceutical composition, which inhibits MEK containing compound according to any one of claims 1, 3, 8 and 11 together with a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: medicine.

SUBSTANCE: invention concerns compounds of general formula (I), where: A represents O, CH2, S, SO or SO2; X and Y are chosen from Br, Cl and -CN3; R1 is chosen from the group consisting of -(CH2)nCOOH, -NHC(=O)COOH, -NHCH2COOH, ;

Z represents H or -C=H; R2 is lower alkyl; R3 - H or lower alkyl; n means 1, 2 or 3; p means 1 or 2; or to their pharmaceutically acceptable salts or esters. Besides the invention covers a pharmaceutical composition based on said compounds expressing an agonist activity in relation to thyroid hormone receptor.

EFFECT: said compounds and pharmaceutical compositions containing thereof there can be effective for treatment of such diseases as obesity, hyperlipidemia, hypercholesterolemia and diabetes, and the other similar conditions and diseases, and can be used for treatment of the other diseases, such as NASH, atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer and the other similar conditions and diseases.

25 cl, 1 tbl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention concerns bonds, applicable for treatment of diseases mediated by the HIV virus, formula I where X1 is chosen from R5O, R5S(O)n, R5CH2, R5CH2O, R5CH2S(O)n, R5OCH2 and R5S(O)nCH2; R1 and R2 are chosen from H, NH2, alkyl, haloalkyl, cycloalkyl, alkoxy, alkylthio, halogen, alkylamino, dialkylamino, nitro and cyano; or in common form-CH=CH-CH=CH- or five-term heterocycle with the heteroatom chosen from O and S; R3 is chosen from H, halogen, nitro and cyano; R4 is chosen from H, NH2, alkyl, haloalkyl, cycloalkyl, alkoxy, alkylthio, halogen, alkylamino, dialkylamino, nitro and cyano; R5 the pyridine-N-oxide, indole, chinoline, chinoline-N-oxide is chosen from alkyl, cycloalkyl and unessentially replaced phenyl, naphthyl, pyridinil; R7 and R8 are chosen from H, NH2, an alkylamin, dialkylamine and unessentially substituted C1-C6alkyl; n is chosen from 0, 1, 2.

EFFECT: obtaining of new inhibitors by reverse transcriptase.

2 cl, 46 ex, 3 tbl

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to phenylpyridazine derivative of general formula I , wherein R1 represents C1-C12-alkyl optionally comprising cyclic C3-C6-alkyl structures and optionally substituted by phenyl, which may be substituted by 1-2 halogen atoms; or C1-C12-alkenyl substituted by optionally halogen-substituted phenyl; R2 and R3, independently form each other, represent hydrogen, C1-C12-alkyl, C1-C12-hydroxyalkyl, C1-C12-dihydroxyalkyl, or C1-C12-alkynyl; or R2 and R3, together with adjacent nitrogen atom form 5-6-membered saturated heterocyclic group containing 1-2 nitrogen atoms and optionally oxygen atom, indicated heterocyclic group being optionally substituted by C1-C12-alkyl group, C1-C12-alkoxydicarboxylic group or phenyl-C1-C7-alkyl group; X, Y, and Z, independently form each other, represent hydrogen, halogen, optionally halogen(s)-substituted C1-C12-alkyl, C1-C12-alkoxy, C1-C12-alkylthio, C1-C12-alkylsulfinyl, C1-C12-alkylsulfonyl, or phenyl; and n is a number from 0 to 5; provided that R2 and R3 cannot be simultaneously hydrogen atoms or identical C1-C3-alkyl groups when R1 is benzyl or C1-C3-alkyl group; and salts of compounds I. Foregoing compounds manifest inhibitory activity against production of interleukin IL-1β being well dissoluble in water and characterized by good oral absorption. Invention also relates to therapeutical agent inhibiting production of interleukin 1β, pharmaceutical composition, employment of above-defined compounds, a method for treating disease caused by interleukin 1β production stimulation as well as methods for treating immune system disturbances, inflammatory conditions, ischemia, osteoporosis, or septicemia using above compounds.

EFFECT: expanded therapeutical possibilities.

22 cl, 4 dwg, 2 tbl, 217 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

The invention relates to the derivatives of pyridazine General formula I, in which R1represents phenyl or pyridyloxy group which may be substituted by 1-3 substituents selected from halogen and lower alkoxygroup; R2represents a phenyl group which may be substituted at the 4th position of the lower alkoxygroup, lower alkylthiol, lower alkylsulfonyl or lower alkylsulfonyl group and in other positions 1 or 2 substituents selected from halogen atoms, lower CNS groups, lower alkylthio, lower alkylsulfonyl groups and lower alkylsulfonyl groups;3represents a hydrogen atom; a lower CNS group; halogenated lower alkyl group; a lower cycloalkyl group; phenyl, pyridyloxy or fenoxaprop, which may be substituted by 1-3 substituents selected from halogen atoms, lower alkyl groups, lower CNS groups, carboxyl groups, lower alkoxycarbonyl groups, nitro, amino, lower alkylamino and lower alkylthio; unsubstituted or substituted lower alkyl group piperidino, piperidinyl, piperazine derivatives or morpholinopropan; unsubstituted or zameshannuu lower alkylamino group piperazinylcarbonyl group; A represents a linear or branched lower alkylenes or lower alkynylamino group having 1-6 carbon atoms; or And can mean single bond when R3represents the lower cycloalkyl or halogenated lower alkyl group; X represents an oxygen atom or a sulfur atom; provided that the following combinations are excluded: R1and R2represent 4 metoksifenilny, X represents an oxygen atom, a represents a single bond, and R3represents a hydrogen atom or 2-chloraniline group; or their salts

The invention relates to heterocyclic-benzoylpyridine formula (I):

< / BR>
where R1and R2each independently of one another, denote hydrogen, fluorine, chlorine, bromine, iodine

FIELD: chemistry.

SUBSTANCE: present invention relates to derivatives of substituted pyridazinylamine of formula or to their pharmaceutically acceptable salts or hydrates, where X is C or N; Y is O or S; W is C or N; R1, R2, R3 each independently represents hydrogen or halogen; R4, R5, R6 each independently represents hydrogen, halogen, C1-C8-straight or branched alkyl, C1-C8-straight or branched alkoxy, nitro, cyano, -COOR7, -CH2COOR7, -COR7; R7 independently represents hydrogen or C1-C8-straight or branched alkyl. The invention also relates to a method of producing said compounds, to pharmaceutical compositions containing said compounds and to use of the said compounds as picornavirus inhibitors for preventing and/or treating diseases caused by pircornaviruses.

EFFECT: novel compounds have useful biological properties.

10 cl, 1 tbl, 33 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes phenylpyridazine compounds represented by the following formula (I): wherein R1 represents unsubstituted or substituted phenyl wherein substitutes are taken among the group comprising halogen atom, lower alkyl, lower alkoxy-group and phenylthio-group, or pyridyl; R2 represents lower alkoxy-group, lower alkylthio-group, lower alkylsulfinyl or lower alkylsolfonyl; R3 represents hydrogen atom or lower alkoxy-group; or R2 and R3 can be condensed in common forming lower alkylenedioxy-group; R4 represents cyano-group, carboxyl, unsubstituted or substituted lower alkyl wherein substitutes are taken among the group comprising hydroxyl, carboxyl and N-hydroxy-N-lower alkylaminocarbonyl; lower alkenyl; lower alkylthio-group; lower alkylsulfinyl; lower alkylsulfonyl; lower alkylsulfonyloxy; unsubstituted or substituted phenoxy-group wherein substitutes are taken among the group comprising halogen atom, lower alkoxy-, nitro-, cyano-group; unsubstituted phenylthio-group or phenylthio-group substituted with halogen atom; pyridyloxy-; morpholino-group; morpholinylcarbonyl; 1-piperazinylcarbonyl substituted with lower alkyl; unsubstituted or substituted amino-group wherein substitutes are taken among the group comprising lower alkyl, benzyl, phenyl that can be substituted with halogen atoms or lower alkoxy-groups, and n = 0, or their salts. Proposed compounds possess the excellent inhibitory activity against biosynthesis of interleukin-1β and can be used in preparing a medicinal agent inhibiting biosynthesis of interleukin-1β, in particular, in treatment and prophylaxis of such diseases as diseases of immune system, inflammatory diseases and ischemic diseases. Also, invention proposes intermediate compounds for preparing compounds of the formula (I). Except for, invention proposes a medicinal agent and pharmaceutical composition that inhibit biosynthesis of interleukin-1β and inhibitor of biosynthesis of interleukin-1β.

EFFECT: valuable medicinal properties of compounds and composition.

7 cl, 1 tbl, 66 ex

The invention relates to compounds of the formula

< / BR>
and their pharmaceutically acceptable salts, in which:

R represents phenyl, substituted with 1-2 substituents, each independently from each other selected from halogen;

R1represents C1-4alkyl;

R2denotes H or C1-4alkyl; and

"Het", which are attached to adjacent carbon atom by a ring carbon atom, chosen from pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, "Het" optionally substituted C1-4the alkyl, C1-4alkoxy, halogen, CN, NH2or-NHCO2(C1-C4) alkyl

The invention relates to a technology for obtaining substituted derivatives of pyrazole, in particular to a method for producing derivatives of 3(5)-methylpyrazole

The invention relates to an improved method of producing chlorinol containing o-hydroxyphenyl group, of General formula I-III I

< / BR>
where Ia 4-CL; 2-o-HOC6H6; R = 6-CH3< / BR>
IB 4-CL; 2-o-HOC6H4; R = 6-CF3< / BR>
IB 4-Cl; 2-o-HOC6H4; R = 6-C6H5< / BR>
Iك 4-Cl; 2-o-HOC6H4; R = 5-CN

Ia 4-Cl; 2-o-HOC6H4; R = 5-COOC2H5< / BR>
Ie 4-Cl; 2-o-HOC6H4; R = 5-C6H5< / BR>
If 4-Cl; 2-o-HOC6H4; R = H

Z 4-Cl; 6-o-HOC6H4; R = H

AI 2-Cl; 4-o-HOC6H4; R = H

IC 2-Cl; 4-o-HOC6H4; R = 6-C6H5< / BR>
IIa R = H

IIb R = 4' -OC3H7< / BR>
IIb R = 5' -Br

G R = 5' -NO2< / BR>
D R = 3' , 5' -Cl2< / BR>
IIIa R = H is used as intermediate products in the synthesis of universal stabilizers for polyethylene, i.e

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to compound of general formula (I) or its pharmaceutically acceptable salt, mediated by glutamate receptor, and to based on them pharmaceutical composition. (I), where R1 stands for C1-6alkyl; R2 and R3 stand for hydrogen; p stands for 0; n stands for 1; R5 and R6 stand for hydrogen, and Het stand for thienyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, pyrazolyl, imidozolyl, each of which can be substituted with one or two groups, independently selected from the list, which consists of C1-6alkyl, C1-6alkoxy, acetyl, halogen, halogenC1-6alkyl, cyano.

EFFECT: creation of compound which has property to enhance response reaction.

4 cl, 2 tbl, 6 dwg, 38 ex

FIELD: medicine.

SUBSTANCE: invention refers to substituted pyrazolopyridines representing compound of formula (I) , where: 1) Ar-L-A represents: where X2 is chosen from N and CH; 2) A represents phenyl optionally substituted with substitutes in number 1 to 3 chosen from (C1-C6)alkyl, halogenated (C1-C6)alkyl, halogen, OH, O-(C1-C6)alkyl, halogenated O-(C1-C6)alkyl, S-(C1-C6)alkyl, halogenated 8-(C1-C6)alkyl, COOH, N(R8)CO(R9) where R8 represents H or (C1-C6)alkyl, and R9 represents (C1-C6)alkyl; herewith if A is disubsituted, two substitutes A together with benzene ring form benzodioxol fragment; 3) L is chosen from the group composed of: NH-CO-NH, NH-SO2; 4) one of radicals X, Y and Z is chosen from N, and other two radicals Z, Y and X represent CH; or to their pharmaceutically acceptable salts. The offered compounds inhibit reactions catalysed by kinase chosen from FAK, KDR and Tie2. Besides the inventive subject matters are a medicinal agent and a pharmaceutical composition applied for inhibition of specified kinases, particularly application of offered compounds for making the medicinal agent intended for therapy of cancer. There are also offered intermediate compounds for making the compound of formula I.

EFFECT: higher efficiency of new agents.

17 cl, 1 tbl, 41 ex

FIELD: chemistry.

SUBSTANCE: invention refers to new compounds of general formula (I) where R1 stands for hydrogen or linear, branched, saturated or unsaturated hydrocarbon radical; D stands for nitrogen atom or C-R2; E stands for nitrogen atom or C-R3; F stands for nitrogen atom or C-R4; G stands for nitrogen atom or C-R5; R2, R3, R4 and R5 are identical or different and individually represent hydrogen, halogen, alkoxy, linear or branched, saturated or unsaturated hydrocarbon radical; W stands for oxygen atom; X stands for radical of formula radical -(CH2)k-C(O)-(CH2)m-, -(CH2)n- or -(CH2)r-O-(CH2)s-, where k, m, r and s are equal to integers 0 to 6, and n is equal to an integer 1 to 6. Said radicals are optionally substituted with one or more substitutes independently chosen from the group consisting of R7; Y stands for radical of formula radical -(CH2)i-NH-C(O)-(CH2)j-, -(CH2)n-, -(CH2)r-O-(CH2)s-, -(CH2)t-NH-(CH2)u-, where i, j, n, r, s, t and u are equal to integers 0 to 6. Said radicals are optionally substituted C1-3alkyl, or C1-3alkyl-C1-3alkylsulphonylamino; radicals R7, B, R8, A, R9 are as it is presented in the patent claim. The invention also describes the pharmaceutical composition possessing inhibitory activity of receptor tyrosine kinase to KDR receptor including described compounds.

EFFECT: compounds possess inhibitory activity of receptor tyrosine kinase to KDR receptor and can be effective in therapy of the diseases associated uncontrolled angiogenesis.

29 cl, 746 ex, 6 tbl

FIELD: chemistry.

SUBSTANCE: description is given of N1-(3-fluorophenyl)-2-(4,6-dimethyl-5-chloro-3-cyano-2-pyridylsulfanil)-acetamide with formula I which is an antidote of 2,4-D on sunflower.

EFFECT: wide range of biologically active substances, obtained through synthetic methods, for use in agriculture as antidotes of 2,4-D.

1 tbl, 3 ex

FIELD: chemical technology.

SUBSTANCE: method for preparing tetrachloropicolinic acid involves interaction of 2-cyanopyridine and chlorine in liquid phase in the melt at temperature 120-200°C under pressure up to 0.6 MPa in the presence of catalysts wherein phosphorus chlorides and oxychlorides are used in the mole ratio of 2-cyanopyridine to catalyst = 1:(0.1-1.0) followed by dissolving the reaction mixture in inert solvent, addition of water at temperature 70-80°C, decomposition of phosphorus chlorides at increased temperature to yield hydrogen chloride and phosphoric acid, separation of phosphoric acid from organic layer and the following addition of sulfuric acid to organic layer and hydrolysis of residue by heating the mixture to 120-140°C. Method provides increasing yield and purity of the end product, simplifying technology, reducing cost for its preparing.

EFFECT: improved preparing method.

2 cl, 5 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention proposes a method for preparing 3,4,5,6-tetrachloro-2-cyanopyridine by interaction of 2-cyanopyridine with chlorine in the presence of phosphorus chlorides as a catalyst taken in the amount 2-60 weight % of the initial loads of 2-cyanopyridine. The chlorination process is carried out in the melt at temperature 120-200°C and under pressure up to 0.6 MPa. Method provides simplifying the process by using the standard equipment, improving ecological indices and decreasing energy consumptions.

EFFECT: improved preparing method.

3 cl, 8 ex

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