Pyridin-2-yl derivatives as immunomodulatory agents

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pyridine derivatives of formula (I) wherein A, R1, R2, R3, R4, R5, R6 and R7 are presented in the description, preparing and using them as pharmaceutically active compounds possessing SP1/EDG1 receptor agonist activity.

EFFECT: using the declared compounds or pharmaceutically acceptable salts thereof for preparing a pharmaceutical composition for preventing or treating the diseases or disorders associated with the activated immune system.

13 cl, 76 ex, 2 tbl

 

The scope of the invention

The present invention relates to agonists of S1P1/EDG1 receptor (lipid-activated, coupled with G-protein, specific sphingosine-1-phosphate receptor) of the formula (I) and their use as active ingredients in obtaining pharmaceutical compositions. The invention also concerns related aspects including methods of making the compounds, pharmaceutical compositions containing the compound of formula (I)and their use as compounds, improves vascular function, and as immunomodulatory agents, either alone or in combination with other active compounds or treatments.

Background of invention

The human immune system is designed to protect the body from foreign organisms and substances that cause infection or disease. Complex regulatory mechanisms provide the orientation of the immune response against the introduced substance or organism, but not against the owner. In some cases, such control mechanisms violated the regulation, which can lead to autoimmune responses. The consequence of uncontrolled response to inflammation is a serious danger to the body, cells, tissues or joints. With modern methods of treatment of the immune system so the cases in General are usually suppressed, but at the same time and the body's ability to respond to infection is also exposed to a serious risk. Typical medications used in this case include azathioprine, chlorambucil, cyclophosphamide, cyclosporine or methotrexate. Corticosteroids that reduce inflammation and suppress the immune response can cause side effects in long-term care. Nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce pain and inflammation, but they also have unwanted side effects. Alternative treatments include the use of agents, activating or blocking cytokine signaling.

Orally active compounds with immunomodulatory properties, without dangerous immune responses and with reduced side effects significantly improved modern methods of treatment of inflammatory diseases.

In the field of organ transplantation, the immune response of the host must be supressive to prevent organ rejection. The transplant organ recipient may be exposed to partial exclusion even when using immunosuppressive drugs. Rejection often occurs in the first few weeks after transplantation, but the cases of exclusion can occur also after a few months or even years after transplantation. The combination of IDPs shall be up to three or four drugs, used together, the most protected from rejection and minimize side effects. Modern standard medications used to treat rejection of transplanted organs, enter into interaction with discrete metabolism in the activation of T-type or b-type lymphocytes. Examples of such drugs are cyclosporine, daclizumab, basiliximab, everolimus or FK506, which interact with the processes of cytokine secretion or signal transmission; azathioprine or Leflunomide, which inhibits the synthesis of nucleotides; or 15-doxicillin, which is the inhibitor of differentiation of cells.

The best results are obtained when immunosuppressive therapy blood, relate to the effects of these drugs; however, generalized immunosuppression, which is achieved with the help of these drugs, weakens the body's immune defenses against infections and malignancies. In addition, standard immunosuppressive drugs are often used in large doses and can cause or accelerate the damage to the body.

Description of the invention

The present invention provides new compounds of formula (I), which are agonists for G protein-conjugated receptor S1P1/EDG1 and have potent and long-lasting immunomodulary the brilliant effect, which is achieved by reducing the number of circulating and infiltracinei T - and b-lymphocytes, without the provision of this damaging impact on their maturation, memory or expansion. Reduction of circulating T - and b-lymphocytes in the S1P1/EDG1 agonism, possibly in combination with the observed improvement of function of the endothelial cell layer associated with the S1P1/EDG1 activation, makes possible the use of such compounds for the treatment of uncontrolled inflammatory disease and improve vascular function.

Compounds of the present invention can be used alone or in combination with standard lekarstvennymi means any abscopal T-cell activation, providing a new together with immunomodulating therapy with reduced susceptibility to infection compared to standard immunosuppressive therapy. In addition, the compounds of the present invention can be used in combination with lower doses of drugs used in immunosuppressive therapy to achieve immunomodulatory activity, which is very important given that the reduction in damage to the transplanted organ is associated with the use of higher doses of immunosuppressive drugs. The results of monitoring to improve the function of endothelial cell SL is I, associated with the S1P1/EDG1 activation, additional evidence in favor of the considered compounds due to the resulting improvement in vascular function.

Nucleotide and amino acid sequences for human S1P1/EDG1 receptor known from the technical field of publications, for example, Hla T., and Maciag T., J. Biol. Chem., 265 (1990), 9308-9313; WO 91/15583 (published October 17, 1991); WO 99/46277 (published 16 September 1999). The potential and effectiveness of the compounds of formula (I) was studied by using GTPγS analysis by definition EC50values and by measuring circulating lymphocytes in rats after oral administration, respectively (see examples).

i) the Invention relates to new pyridine compounds of the formula (I)

where

But a

,or

where the asterisks indicate the bond which attach to the pyridine group of formula (I);

R1represents methyl, ethyl or methoxy group; R2represents hydrogen; and R3represents a C2-5alkyl or C1-4alkoxygroup; or

R1represents a C2-5alkyl or C1-4alkoxygroup; R2represents hydrogen; and R3represents methyl or ethyl; or

R1represents methyl, ethyl or methoxy group; R2represents a C3-5alkyl; and R3represents hydrogen;

R4represents hydrogen or a methoxy group;

R5represents hydrogen, C1-3alkyl or a methoxy group;

R6represents-CH2-(CH2)n-CONR61R62, 1-(3-carboxyethylidene)-3-propionyl, 1-(2-carboxypropyl)-3-propionyl, 1-(3-carboxypropyl)-3-propionyl, the hydroxy-group, hydroxys2-4alkoxygroup, di-(hydraxis1-2alkyl)-C1-2alkoxygroup, 2,3-dihydroxypropyl, -OCH2-(CH2)n-NR61R62, 2-[(azetidine-3-carboxylic acid)-1-yl]ethoxypropan, 2-[(C1-5alkilany broadcast azetidin-3-carboxylic acid)-1-yl]ethoxypropan, 2-[(pyrrolidine-3-carboxylic acid)-1-yl]ethoxypropan, 2-[(C1-5alkilany ether pyrrolidin-3-carboxylic acid)-1-yl]ethoxypropan, -OCH2-CH(OH)-CH2-NR61R62, 3-[(azetidine-3-carboxylic acid)-1-yl]-2-hydroxypropoxy, 3-[(C1-5alkilany broadcast azetidin-3-carboxylic acid)-1-yl]-2-hydroxypropoxy, 2-hydroxy-3-[(pyrrolidine-3-carboxylic acid)-1-yl]propoxylate, 2-hydroxy-3-[(C1-5alkilany ether pyrrolidin-3-carboxylic acid)-1-yl]propoxylate, 2-hydroxy-3-[(pyrrolidine-2-carboxylic who Isleta)-1-yl]propoxylate, 2-hydroxy-3-[(C1-5alkilany ether pyrrolidin-2-carboxylic acid)-1-yl]propoxylate, -och2-(CH2)n-NHSO2R63, -OCH2-CH(OH)-CH2-NHSO2R63, -OCH2-(CH2)n-NHCOR64or-och2-CH(OH)- CH2-NHCOR64;

R61represents hydrogen, methyl, ethyl, 2-hydroxyethyl, carboxymethyl, 1-(C1-5alkylcarboxylic)methyl, 2-carboxyethyl, 2-(C1-5alkylcarboxylic)ethyl, 2-amino-ethyl or 2-methylaminomethyl;

R62represents hydrogen or methyl;

R63represents a C1-3alkyl, methylaminopropyl, ethylamino or dimethylaminopropyl;

R64represents hydroxymethyl, 2-hydroxyethyl, aminomethyl, methylaminomethyl, 2-amino-ethyl or 2-methylaminomethyl;

n represents the integer 1 or 2; and

R7represents hydrogen, methyl or chlorine.

Common terms used in the description above and below, in the context of this invention, preferably have the following meanings, unless otherwise indicated.

The term "Cx-yalkyl, where x and y each denotes an integer that refers to a saturated, linear or branched alkyl groups that contain from x to y carbon atoms. For example, With1-5alkyl group contains from one to five carbon atoms. Typical examples1-5Ala the selected groups include methyl, ethyl, n-propyl, n-butyl, isobutyl, n-pentyl, 3-pentyl and isopentyl. Preferred examples

C1-3alkyl groups are methyl and ethyl. Preferred examples2-5alkyl groups are ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, 3-pentyl and isopentyl. Preferred examples2-4alkyl groups are ethyl, n-propyl, isopropyl, n-butyl and isobutyl.

The term "Cx-yalkoxygroup" (x and y each represents an integer) refers to alkyl-O-group, where the alkyl group refers to a linear or branched hydrocarbon chain, containing from x to y carbon atoms.

For example,

With1-4alkoxygroup contains from one to four carbon atoms and includes methoxy group, ethoxypropan, n-propoxylate, isopropoxy, n-butoxypropyl, isobutoxy, sec-butoxypropyl and tert-butoxypropan. Preferred examples1-4alkoxygroup are ethoxypropan, propoxylate, isopropoxide and isobutoxy. Preferred examples2-4alkoxygroup are ethoxypropan, n-propoxylate and isopropoxide. Examples of C1-3alkoxygroup are a methoxy group, ethoxypropan, n-propoxylate and isopropoxide.

ii) Another variant embodiment of the invention relates to a derivative of pyridine according to the var is the ant i), where a represents a

or

where the asterisks indicate the bond which attach to the pyridine group of formula (I).

iii) Another variant embodiment of the invention relates to a derivative of pyridine, under option i), where a is a

where the asterisks indicate the bond which attach to the pyridine group of formula (I).

iv) Another variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(iii), where R1represents a methyl or methoxy group, R2represents hydrogen, and R3represents a C2-4alkyl or C1-3alkoxygroup.

v) Another variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(iii), where R1represents methyl, R2represents hydrogen, and R3represents a C2-4alkyl or C1-3alkoxygroup.

vi) Another variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(iii), where R1represents a C2-4alkyl or C1-3alkoxygroup, R2represents hydrogen and R3isone methyl.

vii) Another variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(iii), where R1represents a C2-4alkyl, R2represents hydrogen and R3represents methyl.

viii) Another variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(iii), where R1represents methyl, R2represents a C2-4alkyl, and R3represents hydrogen.

ix) Another variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(viii), where at least one of the groups R4, R5and R7different from hydrogen.

x) Another particular variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(viii), where R4represents a methoxy group, and R5and R7represent hydrogen.

xi) Another particular variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(viii), where R4represents hydrogen, R5represents a C1-3alkyl or methoxy group, and R7represents methyl or chlorine.

xii) Another particular variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(viii), the de R 4represents hydrogen, R5represents a C1-2alkyl or methoxy group, and R7represents methyl or chlorine.

xiii) Another particular variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(viii), where R4represents hydrogen, R5represents ethyl or methoxy group, and R7represents methyl or chlorine.

xiv) Another particular variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(viii), where R4represents hydrogen, R5represents ethyl, and R7represents methyl.

xv) Another variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(xiv), where R6represents-CH2-(CH2)n-CONR61R62, 1-(3-carboxyethylidene)-3-propionyl, 1-(2-carboxypropyl)-3-propionyl, 1-(3-carboxypropyl)-3-propionyl, di-(hydraxis1-2alkyl)-C1-2alkoxygroup, 2,3-dihydroxypropyl, -OCH2-(CH2)n-NR61R62, 2-[(azetidine-3-carboxylic acid)-1-yl]ethoxypropan, 2-[(C1-alkilany broadcast azetidin-3-carboxylic acid)-1-yl]ethoxypropan, 2-[(pyrrolidine-3-carboxylic acid)-1-yl]ethoxypropan 2-[(C1-5alkilany ether pyrrolidin-3-carboxylic acid is you)-1-yl]ethoxypropan, -OCH2-CH(OH)-CH2-NR61R62, 3-[(azetidine-3-carboxylic acid)-1-yl]-2-hydroxypropoxy, 3-[(C1-3alkilany broadcast azetidin-3-carboxylic acid)-1-yl]-2-hydroxypropoxy, 2-hydroxy-3-[(pyrrolidine-3-carboxylic acid)-1-yl]propoxylate, 2-hydroxy-3-[(C1-5alkilany ether pyrrolidin-3-carboxylic acid)-1-yl]propoxylate, 2-hydroxy-3-[(pyrrolidine-2-carboxylic acid)-1-yl]propoxylate, 2-hydroxy-3-[(C1-5alkilany ether pyrrolidin-2-carboxylic acid)-1-yl]propoxylate or-och2-CH(OH)-CH2-NHCOR64.

xvi) Another variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(xiv), where R6represents-CH2-(CH2)n-CONR61R62, 1-(3-carboxyethylidene)-3-propionyl, 1-(2-carboxypropyl)-3-propionyl, 1-(3-carboxypropyl)-3-propionyl, 2,3-dihydroxypropyl, -OCH2-CH(OH)-CH2-NR61R62, 3-[(azetidine-3-carboxylic acid)-1-yl]-2-hydroxypropoxy, 3-[(C1-5alkilany broadcast azetidin-3-carboxylic acid)-1-yl]-2-hydroxypropoxy, 2-hydroxy-3-[(pyrrolidine-3-carboxylic acid)-1-yl]propoxylate, 2-hydroxy-3-[(C1-5alkilany ether pyrrolidin-3-carboxylic acid)-1-yl]propoxylate, 2-hydroxy-3-[(pyrrolidine-2-carboxylic acid)-1-yl]propox the group, 2-hydroxy-3-[(C1-5alkilany ether pyrrolidin-2-carboxylic acid)-1-yl]propoxylate or-och2-CH(OH)-CH2-NHCOR64.

xvii) Another variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(xiv), where R6represents a 2,3-dihydroxypropyl, 3-[(azetidine-3-carboxylic acid)-1-yl]-2-hydroxypropoxy, 2-hydroxy-3-[(pyrrolidine-3-carboxylic acid)-1-yl]propoxylate, 2-hydroxy-3-[(pyrrolidine-2-carboxylic acid)-1-yl]propoxylate or-OCH2-CH(OH)-CH2-NHCOR64.

xviii) Another variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(xiv), where R6represents a 2,3-dihydroxypropane or-och2-CH(OH)-CH2-NHCOR64.

xix) Another variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(xiv), where R6represents-OCH2-CH(OH)-CH2-NHCOR64.

XX) Another variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(xvi), where R61represents methyl, 2-hydroxyethyl, carboxymethyl, 2-amino-ethyl or 2-methylaminomethyl.

xxi) Another variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(xvi) and (XX), where R62 represents hydrogen.

xxii) Another variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(xiv) and (xx)xxi), where R63represents methyl.

xxiii) Another variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(xxii), where R64represents hydroxymethyl.

xxiv) Another variant embodiment of the invention relates to a derivative of pyridine according to one of the options (i)-(xvi) and (xx)-(xxiii), where n is an integer 1.

xxv) Another variant embodiment of the invention relates to a derivative of pyridine, under option i), where

And is aor,

where the asterisks indicate the bond which attach to the pyridine group of formula (I);

R1represents a methyl or methoxy group; R2represents hydrogen; and R3represents a C4alkyl; or

R1represents a C4alkyl; R2represents hydrogen; and R3represents methyl; or

R1represents methyl; R2represents Salkil; and R represents hydrogen;

R4represents hydrogen;

R5represents methyl or ethyl;

R6 2-(CH2)n-CONR61R62the hydroxy-group, 2,3-dihydroxypropyl, -OCH2-CH(OH)-CH2-NR61R62or-och2-CH(OH)-CH2-NHCOR64;

R61represents hydrogen, methyl, 2-hydroxyethyl, carboxymethyl, 2-carboxyethyl or 2-amino-ethyl;

R62represents hydrogen;

R64represents hydroxymethyl;

n represents the integer 1; and R7represents methyl.

xxvi) Another variant embodiment of the invention relates to a derivative of pyridine, under option i), where a is a

,or

where the asterisks indicate the bond which attach to the pyridine group of formula (I);

R1represents a methyl or methoxy group; R2represents hydrogen; and R3represents a C2-5alkyl such as isobutyl or 1-ethylpropyl; or

R1represents a C2-5alkyl such as isobutyl; R2represents hydrogen; and R3represents methyl; or

R1represents methyl; R2represents a C3-5alkyl such as isobutyl; and R3represents hydrogen;

R represents hydrogen or a methoxy group;

R represents hydrogen, C1-3alkyl (such as methyl, ethyl or n-propyl), or a methoxy group;

R6represents-CH2-(CH2)n-CONR61R62the hydroxy-group, hydroxy-C2-4alkoxygroup (such as 2-hydroxyethoxy), di-(hydroxy-C1-2alkyl)-C1-2alkoxygroup (such as di-(hydroxymethyl)methoxy group or 3-hydroxy-2-hydroxymethylpropane), 2,3-dihydroxypropyl, -OCH2-(CH2)n-NR61R62, 2-[(azetidine-3-carboxylic acid)-1-yl]ethoxypropan, -OCH2-CH(OH)-CH2-NR61R62,-OCH2-(CH2)n-NHSO2R63,-OCH2-CH(OH)-CH2-NHSO2R63, -OCH2-(CH2)n-NHCOR64or-OCH2-CH(OH)-CH2-NHCOR64;

R61represents hydrogen, methyl, 2-hydroxyethyl, 2-carboxyethyl, 2-(C1-5alkylcarboxylic)ethyl, 2-(methylcarbonate)ethyl, or 2-amino-ethyl;

R62represents hydrogen or methyl;

R63represents a C1-3alkyl (such as ethyl), or dimethylaminopropyl;

R64represents hydroxymethyl or methylaminomethyl;

n represents the integer 1; and

R7represents hydrogen, methyl or chlorine.

The compounds of formula (I) can contain one or more stereogenic or asymmetric the ski centers such as one or more asymmetric carbon atoms. The compounds of formula (I) may thus be present as mixtures of stereoisomers or, preferably, in the form of pure stereoisomers. Mixture of stereoisomers can be separated using methods known to experts in the field of engineering.

When using multiple forms of the compounds, salts, pharmaceutical compositions, disease, and similar terms refers to one form of the compound, salt or similar terms.

Any link above and further compound of formula (I) also implies a reference to salts, especially pharmaceutically acceptable salts of the compounds of formula (I), and its use is appropriate and reasonable.

The term "pharmaceutically acceptable salts" refers to non-toxic additive salts of inorganic or organic acids and/or bases. Reference may be salanauskaite "Salt selection for basic drugs", Int. J. Pharm.(1986), 33,201-217.

Examples of pyridine compounds of the formula (I) is chosen from the group including:

N-((S)-3-{2-ethyl-4-[5-(6-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido; N-((S)-3-{2-ethyl-4-[5-(4-isobutyl-6-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6 methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

2-hydroxy-N-((R)-2-hydroxy-3-{4-[5-(6-isobutyl-4-methoxyp the one-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propyl)ndimethylacetamide;

2-hydroxy-N-((S)-2-hydroxy-3-{4-[5-(6-isobutyl-4-methoxypyridine-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propyl)ndimethylacetamide;

N-((S)-3-{2-ethyl-4-[5-(6-isobutyl-4-methoxypyridine-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

(S)-3-{4-[5-(6-isobutyl-4-methoxypyridine-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}propane-1,2-diol;

(R)-3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,2-diol;

(S)-3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,2-diol;

N-((S)-3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;

3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-were}-N-(2-hydroxyethyl)propionamide; and

3-(3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-were}propionamido)propionic acid.

The following examples of pyridine compounds of the formula (I) chosen from:

2-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}ethylamine;

3-(2-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}ethylamine)propionic acid;

N-(2-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}ethyl)-2-hydroxyacetamido;

2-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol the-3-yl]-6-methylphenoxy}propane-1,3-diol;

(S)-1-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-3-(2-hydroxyethylamino)propan-2-ol;

((S)-3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)amide econsultancy acids;

3-((S)-3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropylamino)propionic acid;

(S)-3-(2-ethyl-4-{5-[6-(1-ethylpropyl)-4-methylpyridin-2-yl]-[1,2,4]oxadiazol-3-yl}-6-methylphenoxy)propane-1,2-diol;

N-[(S)-3-(2-ethyl-4-{5-[6-(1-ethylpropyl)-4-methylpyridin-2-yl]-[1,2,4]oxadiazol-3-yl}-6-methylphenoxy)-2-hydroxypropyl]-2-hydroxyacetamido. (S)-3-(2-ethyl-4-{5-[6-(1-ethylpropyl)-4-methoxypyridine-2-yl]-[1,2,4]oxadiazol-3-yl}-6-methylphenoxy)propane-1,2-diol;

(S)-3-(2-chloro-4-{5-[6-(1-ethylpropyl)-4-methoxypyridine-2-yl]-[1,2,4]oxadiazol-3-yl}-6-methylphenoxy)propane-1,2-diol;

N-[(S)-3-(2-ethyl-4-{5-[6-(1-ethylpropyl)-4-methoxypyridine-2-yl]-[1,2,4]oxadiazol-3-yl}-6-methylphenoxy)-2-hydroxypropyl]-2-hydroxyacetate;

N-[(S)-3-(4-{5-[6-(1-ethylpropyl)-4-methoxypyridine-2-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethylphenoxy)-2-hydroxypropyl]-2-hydroxyacetate;

N-[(S)-3-(2-chloro-4-{5-[6-(1-ethylpropyl)-4-methoxypyridine-2-yl]-[1,2,4]oxadiazol-3-yl}-6-methylphenoxy)-2-hydroxypropyl]-2-hydroxyacetate;

N-[(S)-3-(4-{5-[6-(1-ethylpropyl)-4-methoxypyridine-2-yl]-[1,2,4]oxadiazol-3-yl}-2-methoxy-6-methylphenoxy)-2-hydroxypropyl]-2-hydroxyacetate; and

N-((2S)-3-{2-ethyl-4-[3-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-5-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicines, for example, in the form of pharmaceutical compositions for enteral or parenteral administration, and are suitable for reducing the number of circulating lymphocytes and for the prevention and/or treatment of diseases or disorders associated with an activated immune system.

Preparation of pharmaceutical compositions may be carried out using methods known to anyone skilled in the art (see, for example: Remington, The Science and Ppactice of Pharmacy, 21st Edition (2005), Part 5, "Pharmaceutical Manufacturing" [published by Lippincott Williams & Wilkins]) by introducing compounds of formula (I) or their pharmaceutically acceptable salts, optionally in combination with other therapeutically useful substances in dosage form together with the appropriate, non-toxic, inert, pharmaceutically acceptable solid or liquid substance used as a carrier, and if necessary, standard pharmaceutical excipients.

Pharmaceutical compositions comprising a compound of formula (I) are applicable for the prevention and/or treatment of diseases or disorders associated is activated by the immune system.

Such diseases or disorders associated with an activated immune system for the prevention and/or treatment which can be applied to the compounds of formula (I)include the rejection of transplanted organs, tissues or cells; disease graft-versus-host caused by transplantation; autoimmune syndromes including rheumatoid arthritis; systemic lupus erythematosus; antiphospholipid syndrome; thyroiditis Hashimoto; lymphocytic thyroiditis; multiple sclerosis; heavy pseudoparalysis myasthenia; diabetes type I; uveitis (inflammation of the choroid); episcleritis; scleritis; Kawasaki disease, uveoretinitis; posterior uveitis; uveitis associated with Behcet's disease; syndrome woolright; allergic encephalomyelitis; chronic allotransplantation the disorder of vessels; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; inflammatory and hyperproliferative skin diseases; psoriasis; psoriatic arthritis; atopic dermatitis; myopathy; myositis; osteomyelitis; contact dermatitis; eczema dermatitis; subarray dermatitis; lichen planus; disease; bullous a disease; congenital bullous bullosa; hives; angioedema; vasculitis; erythema; dermal eosinophilia; acne; scleroderma; alopecia alopecia; keratoconjunctivitis; hroni the definition of bilateral conjunctivitis; keratitis; gerpicheskoy keratitis; epithelial corneal dystrophy; lakomy cornea; eye disease; ulcer Moray; ulcerative cerotic; scleritis; the ophthalmopathy of Graves; syndrome Vogt-Konagi-Harada; sarcoidosis; hay fever; reversible obstructive disease of the Airways; bronchial asthma; allergic asthma; congenital asthma; received asthma, dust asthma, chronic or inveterate asthma, late asthma and hyperphosphorylate respiratory tract; bronchiolitis; bronchitis; endometriosis; orchitis; a stomach ulcer; ischemic bowel disease; inflammatory bowel disease; necrotizing enterocolitis; damage to the intestinal tract associated with thermal burns; disease of the peritoneum; proctitis; eosinophilic gastroenteritis; mastocytosis; Crohn's disease; ulcerative colitis; vascular damage caused by ischemic diseases and thrombosis; atherosclerosis; fat heart; myocarditis; myocardial infarction; syndrome inflamed aorta; breakdown caused by viral disease; thrombosis; migraine; rhinitis; eczema; interstitial nephritis; IgA-induced nephropathy; syndrome?; haemolytic uraemic syndrome; diabetic nephropathy; glomerulosclerosis; glomerulonephritis; tubulointerstitial jade; interstitial cystitis; dermatomyositis; Guillain-Barre syndrome; disease Miniera; Polini the it; multiplet neuritis; myelitis; manometric; radiculopathy; hyperthyroidism; graves ' disease; thyrotoxicosis; pure krasnocletocnaya aplasia, aplastic anemia; gipoplasticheskaya anemia; idiopathic thrombocytopenic purple; autoimmune hemolytic anemia; autoimmune thrombocytopenia; agranulocytosis; malignant anemia; megaloblastic anemia; americaplay; osteoporos; or fibrous lung; idiopathic interstitial pneumonia; dermatitis; Leucoderma vulgaris; diffuse keratome vulgaris; photoallergic sensitivity; cutaneous T-cell lymphoma; Nowotny polyarthritis; horey Huntington; horey Sydenham; micardis; myocarditis; scleroderma; granuloma Wegener; Sjogren syndrome; adipose; eosinophilic fasciitis; damage to the gums, periodontal, alveoles connective tissue, tooth substance during the treatment; men alopecia alopecia or senile alopecia; muscular dystrophy; pyoderma; syndrome Cesari; hipofisis; chronic adrenal insufficiency; Addison disease; ischemia-reperfusion injury of organs which occur during storage; endotoxic shock; pseudomembranous colitis; colitis caused by drug or radiation; acute ischemic renal failure; chronic renal insufficiency; lung cancer; malignancy of lymphoid what about the origin; acute or chronic lymphocytic leukemia; lymphoma; enfisema lungs; cataracts; sideras; inflammation of the retina; senile spotted degeneration; scarring of the vitreous body; alkaline burns of the cornea; dermatite erythema, bullous dermatitis; cement dermatitis; gingivitis; periodontitis; sepsis; pancreatitis; disease of peripheral arteries; carcinogens; solid cancer; metastasis carcinoma; Garbaravicius; autoimmune hepatitis; primary liver cirrhosis; sclerotic cholangitis, partial liver resection, acute liver necrosis; cirrhosis; alcoholic cirrhosis; liver failure; fulminant hepatic failure; hidden hepatic failure; and "aimed at chronic" liver failure.

Preferred diseases and disorders that are subject to treatment and/or prevention using the compounds of formula (I)are selected from the group including rejection of transplanted organs such as kidney, liver, heart, lung, pancreas, cornea, and skin; disease graft-versus-host arising from the transplantation of cells of the spinal cord; autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease such as Crohn's disease and ulcerative colitis, psoriasis, psoriatic arthritis, thyroiditis is the aka, as thyroiditis Hashimoto, uveoretinitis; atopic diseases such as rhinitis, conjunctivitis, dermatitis; asthma; diabetes type I; post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis; solid cancers and tumor metastasis.

Particularly preferred diseases or disorders that are subject to treatment and/or prevention using the compounds of formula (I)are selected from the group including rejection of transplanted organs such as kidney, liver, heart and lung; disease "graft versus host", voznikayushie by transplantation of cells of the spinal cord; autoimmune syndromes including rheumatoid arthritis, multiple sclerosis, psoriasis, psoriatic arthritis, Crohn's disease and thyroiditis Hashimoto; and atopic dermatitis. Preferred diseases or diseases that are subject to treatment and/or prevention using the compounds of formula (I)are multiple sclerosis and psoriasis.

The present invention relates also to a method of prophylaxis or treatment of illnesses or diseases mentioned in the description above, which consists in the introduction of the subject of the pharmaceutically active amount of a compound of formula (I).

In addition, the compounds of formula (I) also apply in combination with one or more immunomodulatory agents, use the mi for the prevention and/or treatment of diseases or diseases, mentioned in the description above. According to a preferred variant of the invention, called agents are selected from the group including immunosuppressants, corticosteroids, NSAIDs, cytotoxic drugs, inhibitors molecular adhesion, cytokines, inhibitors of cytokines, receptor antagonists and recombinant cytokine receptors cytokine.

The present invention relates also to the use of compounds of formula (I) to obtain a pharmaceutical composition, optionally for use in combination with one or more immunomodulatory agents used for prophylaxis and/or treatment of diseases or disorders mentioned in the description above.

The compounds of formula (I) can be obtained by the methods given below, by the methods given in the examples, or similar methods. Optimal reaction conditions vary depending on the reagents or solvents, which may be selected by the specialist in the field of engineering through a series of optimized methods.

The compounds of formula (I) according to the present invention can be obtained according to the General sequence of reactions shown below. The following describes only some of the possible synthetic routes leading to the compounds of formula (I).

Soy is inane formula (I), which presents the derived 5-pyridin-2-yl-[1,2,4]oxadiazole, are obtained from compounds of structure (1) in a solvent such as xylene, toluene, benzene, pyridine, DMF, THF, dioxane, DME, dichloromethane, acetic acid, triperoxonane acid, and the like, at room or elevated temperatures in the presence or absence of auxiliaries such as acids (e.g., TFA, acetic acid, HCl, and the like), base (such as NaH, NaOAc, Na2CO3, K2CO3NEt3, and the like), salts of tetraalkylammonium, or absorption agents (for example, oxalicacid, carboxylic acid anhydride, POCl3, PCl3P4O10, molecular sieves, Burgess reagent, and the like) (see, for example, .R. Gangloff, J. Litvak, E.J. Shelton, D. Sperandio, V.R. Wang, K.D. Rice, Tetrahedron Lett., 42 (2001), 1441-1443; T. Suzuki, K. Iwaoka, N. Imanishi, Y. Nagakura, K. Miyta, H. Nakahara, M. Ohta, T. Mase, Chem. Pharm. Bull., 47 (1999), 120-122; R.F. Poulain. A.L. Tartar, B.P. Deprez, Tetrahedron Lett., 42 (2001), 1495-1498; R. Srivastava, F.J.S. Oliveira, D.S. Machado, R. Souto-Maior, Synthetic Commun., 29 (1999), 1437-1450; E.O. John, J.M. Shreeve, Inorganic Chemistry, 27 (1988), 3100-3104; B. Kaboudin, K. Navaee, Heterocycles, 60 (2003), 2287-2292).

Compounds of structure (1) can be obtained by the reaction of compounds of structure (2) with a compound of structure (3) in a solvent such as DMF, THF, DHM and the like, in the presence or absence of one or more condensing is hentov such as TBTU, DCC, EDC, hbtu, the CBI and the like, in the presence or absence of a base such as NEt3DIPEA, NaH, K2CO3, and the like (see, for example, A. Hamze, J.-F. Hernandez, P. Fulcrand, J. Martinez, J. Org. Chem. 68 (2003) 7316-7321; and the literature cited above).

The compounds of formula (I), which presents the derived 3-pyridin-2-yl-[1,2,4]oxadiazol receive a similar way (see, for example, CT Brain, J.M. Paul, Y. Loong, P.J. Oakley, Tetrahedron Lett., 40 (1999) 3275-3278) by reacting compounds of structure (4) with a compound of structure (5) and subsequent cyclization of the corresponding intermediate hydroxyamides of ester.

Compounds of structure (3) and (4) can be obtained by reaction of the compound of structure (6) and (7), respectively, with hydroxylamine or one of its salts in a solvent such as Meon, EtOH, pyridine, and the like, in the presence or absence of bases such as Na2CO3, K2CO3, tert-butyl potassium, NEt3, and the like (see,for example: E. Meyer, A.S. Joussef, H. Gallardo, Synthesis 2003, 899-905; WO 2004/035538 (Merck & Co., Inc., USA)).

Depending on the nature of functional groups present in the residues R4-R7in particular, R6in structures (3), (5) and (7) of these functional groups can been unnecessary the change temporary protection. Appropriate protective groups known to experts in the field of engineering and include, for example, benzyl or trialkylsilyl group for protection of the alcohol, catalog group for the protection of the diol, and the like, These protective groups can be used according to standard methods (for example, .W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rdEdition, Wiley, New York, 1991; P.J. Kocienski, Protecting Groups, Thieme Stuttgart, 1994). Alternatively, the desired residues R4-R7in particular, R6may also be entered at a later stage, followed by condensation of pyridine compounds of structure (2) or (4) with phenyl derivatives of structure (3) or (5), respectively, using a suitable prior compounds of structure (3) or (5). Phenyl compounds of structure (3) and (5), or their predecessors are either commercially available or can be obtained according to methods known to experts in the field of engineering.

The compounds of formula (I), which presents the derived 2-pyridin-2-yl-[1,3,4]oxadiazole, get similarly by reaction of the compound of structure (2) with hydrazine (by using condensing agents such as TBTU, DCC, EDC, hbtu, Rumor, the OED, and the like) to obtain the compound of structure (8), which is then condensed with a compound of structure (5), floor the tea compound of structure (9). The compound of structure (9) can be obtained by following the reverse reaction sequence, i.e. first by condensation patterns (5) with hydrazine followed by reaction of the corresponding intermediate hydrazide with a compound of structure (2). The dehydration of compounds of structure (9) with the formation of the desired derivative of 2-pyridin-2-yl-[1,3,4]oxadiazole is carried out by treating the compound of structure (9) with a reagent such as POCl3; CCl4and CBr4in combination with PPh3P2O5, Burgess reagent, and the like, in a solvent such as toluene, MeCN, dioxane, THF, CHCl3and the like, at temperatures from 20 to 120°C in the presence or absence of microwave irradiation (see, for example, M.A. Garcia, S. Martin-Santamaria, M. Cacho, F. Moreno de la Llave, Julian M., A. Martinez, B. De Pascual-Teresa, A. Ramos, J. Med. Chem. 48 (2005) 4068-4075; CT Brain, J.M. Paul, Y. Loong, P.J. Oakley, Tetrahedron Lett., 40 (1999) 3275-3278).

Alternatively, communication between the pyridine or phenyl ring and the Central oxadiazoline ring can be formed when applying a palladium catalyst using cross-reactions of condensation.

Methods that are effective for the conversion of compounds of structure (2) or (5) in the connection structure (6) or (7), respectively, or Vice versa, well-known specialists in the field of technology.

Compounds of structure (2), where R1isone methyl, ethyl or methoxy group, R2represents hydrogen and R3represents a C2-5alkyl (structure 13), can be obtained by sequentially carried out reactions presented below:

Picolina acid of structure (13) can be obtained by treating the compound of structure (10) (either commercially available or obtained analogously to the methods described in the literature, for example, T. Kaminski, P. Gros, Y. Fort, Eur. J. Org. Chem., 19 (2003) 3855-3860; U. Ziener, E. Breuning, J.-M. Lehn, E. Wegelius, K. Rissanen, G. Baum, D. Fenske, G. Vaughan, Chemistry-A European Journal, 6 (2000) 4132-4139; R.-A. Fallahpour, Synthesis, 2000 1665-1667; .G. Szczepankiewicz, et al. J. Med. Chem., 49 (2006) 3563-3580) with 2,4,6-trivinyl-cyclotrisiloxane in the conditions of the Suzuki reaction with the formation of compounds of structure (11), which are oxidized and converted into ester pikolinos acid patterns (12) (R represents for example methyl, ethyl, isopropyl, tert-butyl). Oxidation, followed by receipt of ester commercially available compounds of structure (14), may also lead to the compound of structure (12). The connection patterns (12) then either injected into the reaction cross-condensation in the conditions of the Suzuki reaction using a suitable 2,4,6-trialkyl-cyclotrisiloxane (obtained according to F. Kerins, D.F. O'shea, J. Org. Chem., 67 (2002) 4968-4971), hydronaut and omelet or process is sootvetstvuyuschim alkyl-Zn-reagent under the reaction conditions Negishi (see, for example, N. Matsushita, E. Negishi, J. Org. Chem., 47 (1982) 4161-4165) prior to saponification, getting the desired compound of structure (13).

Compounds of structure (2), where R1represents methyl, ethyl or methoxy group, R2represents hydrogen and R3represents a C1-4alkoxygroup (structure 17), can be obtained by sequentially carried out reactions presented below:

The compound of structure (10) is treated with an appropriate alcohol in the presence of a base, preferably a sodium alcoholate or potassium hydroxide, at temperatures ranging from 0 to 80°C (see, for example, S. Burstein, .W. Lehmann, F. Glorius, Tetrahedron, 61 (2005), 6207-6217; T. Nguyen, M.A. Wicki, V. Snieckus, J. Org. Chem., 69 (2004), 7816-7821), obtaining the compound of structure (15). The Suzuki reaction of compounds of structure (15) with 2,4,6-trivinyl-cyclotrisiloxane gives access to the connection patterns (16), which can be oxidized, for example, using KMnO4in acetone, to the desired compounds of structure (17).

Compounds of structure (2), where R1represents a C2-5alkyl, R2represents hydrogen and R3represents a methyl or ethyl (structure 22), can be obtained by sequentially carried out reactions presented below:

Thus, the connection structure (18) (either commercially available, is obtained for similar methods, described in the literature, for example, J.. Simeone et al., Bioorg. Med. Chem. Letters, 12 (2002), 3329-3332; D.L. Comins, N.B. Mantio, J. Org. Chem., 50 (1985), 4410-4411) process (NH4)2S2O8in a mixture of methanol, water, and H2SO4at elevated temperatures (Minisci reaction, see, for example, R.. Katz, J. Mistry, M.B. Mitchell, Synth. Commun., 19 (1989) 317-325; M.A.A. Biyouki, R.A.J. Smith, J.J. Bedford, J.P. Leader, Synth. Commun., 28 (1998) 3817-3825), obtaining the compound of structure (19). This compound can be oxidized to the compound of structure (20) using, for example, KMnO4in acetone. By treating the compound of structure (20) alcohol such as methanol, ethanol, isopropanol in the presence of acid such as H2SO4or HCl, can be obtained the corresponding compound of structure (21) (R represents, for example, methyl, ethyl or isopropyl). The compound of structure (21) then either injected into the reaction cross-condensation in the conditions of the Suzuki reaction using a suitable 2,4,6-trialkyl-cyclotrisiloxane, hydronaut and omelet or treated with the appropriate alkyl-Zn-reagent reaction conditions Negishi prior to saponification, getting the desired compound of structure (22).

Compounds of structure (2), where R1represents a C1-4alkoxygroup, R2represents hydrogen and R3represents a methyl or ethyl (structure 26), can be recip the us by sequentially carried out reactions below:

Therefore, the compound of structure (23) (for example, obtained according to the procedures described in the publications: .G. Szczepankiewicz et al., J. Med. Chem., 49 (2006) 3563-3580; M. Inouye, M. Waki, H. Abe, J. Am. Chem. Soc., 126 (2004), 2022-2027) is injected into the reaction with 2,4,6-tribunicia-Liborakina, receiving the connection patterns (24). Oxidation using, for example, KMnO4in acetone, the compound of structure (24) with subsequent conversion into ester leads to the compound of structure (25) (R = methyl, ethyl, isopropyl, tert-butyl, and the like). Compounds of structure (25) then either injected into the reaction cross-condensation in the conditions of the Suzuki reaction using a suitable 2,4,6-trialkyl-cyclotrisiloxane, hydronaut and omelet or treated with the appropriate alkyl-Zn-reagent under the reaction conditions Negishi prior to saponification, getting the desired compound of structure (26).

Compounds of structure (2), where R1represents methyl or ethyl, R2represents a C3-5alkyl, and R3represents hydrogen (structure 31), can be obtained by sequentially carried out reactions, poistaminen below:

Thus, the compound of structure (27) (either commercially available or obtained analogously to the methods described in the literature, for example, R. ierrat, P. Gros, Y. Fort, Synlett, 2004, 2319-2322) is injected into the reaction with 2,4,6-tribunicia-Liborakina in the conditions of the Suzuki reaction with formation of the compound of structure (28), which are oxidized and converted into an ester, receiving the connection patterns (29) (where R represents a C1-4alkyl). The Suzuki reaction with an appropriate (2,4,6-trialkyl-cyclotrisiloxane, hydrogenation and saponification, or the Negishi reaction with the corresponding alkyl-Zn-reagent with subsequent saponification of the compound of structure (30) leads to compounds of structure (31).

Compounds of structure (2), where R1represents a methoxy group, R2represents a C3-5alkyl, and R3represents hydrogen (structure 32), can be obtained by sequentially carried out reactions presented below:

By applying the reaction sequences involving either the Suzuki reaction, hydrogenation, saponification and conversion into ester or Negishi reaction and saponification, commercially available compound of structure (32) can be converted into a compound of structure (33). Compounds of structure (32) can be obtained, for example, by the reaction of 4,5-dichlorophenol acid with water in the presence of acid (see, for example, J. Prakt. Chem., 27 (1883), 293), resulting 4-chloro-5-hydroxypyridones acid. This connection may be the ATEM is alkylated similar methods, described in the literature (T. Vermonden; D. Branowska; ATM Marcelis; .J.R. Sudholter; Tetrahedron, 59 (2003), 5039-5045), with methyl ether 4-chloro-5-methoxyphenol acid, which is then hydrolized in an acidic or alkaline conditions to obtain the desired compound of structure (32).

Since the compounds of formula (I) are obtained in the form of a mixture of enantiomers, the enantiomers can be separated using methods known to any expert in the field of technology, for example by formation and separation of diastereomeric salts by HPLC using a chiral stationary phase such as a Regis Whelk-O1(R,R) (10 μm) column, Daicel ChiralCel OD-H (5-10 μm) column or Daicel ChiralPak IA (10 μm) or AD-H (5 μm) column. Typical conditions of chiral HPLC include the use isocrates mixture of eluent A (EtOH, in the presence or absence of an amine such as triethylamine or diethylamine) and eluent B (hexane)at the expiration of from 0.8 to 150 ml/min

Experimental part

The following examples illustrate the invention, without limiting its scope.

All temperature measured in °C.

Compounds were characterized by using:

1H-NMR (400 MHz) or13C-NMR (100 MHz) (Bruker; chemical shifts are given in memorial plaques relative to the solvent used; the multiplets: s = single, d = doublet, t = triplet; p = pintle, hex = getset, hept = septet, m = multiplet, to scanty mates are given in Hz);

LC-MS (Finnigan Navigator with HP 1100 Binary Pump and DAD, column: a 4.6×50 mm, Bond SB-AQ, 5 μm, 120 Å, gradient: 5-95% acetonitrile in water, 1 min, with 0.04% of triperoxonane acid, flow rate: 4.5 ml/min), tR(retention time) is given in min (retention times or LC-MS marked with *relate to LC conducted using basic conditions, for example, gradient elution with a solution of acetonitrile in water containing 13 mm ammonium hydroxide, or other established conditions, the retention times or LC-MS marked with **refer to LC carried out under the following conditions: column: Bond Extended C18, of 1.8 μm, a 4.6×20 mm, gradient: 5-95% MeCN in water, 1 min, with 0.04% of TFA, after: 4,5 ml/min); TLC (TLC-plates from Merck, silica gel 60 F254); or by melting.

Compounds purified using preparative HPLC (column: X-terra RP18, 50×19 mm, 5 μm, gradient: 10-95% MeCN in water containing 0.5% formic acid) or by using SGH (Labomatic MD 80-100 pump, Linear UVIS-201 detector, column: 350×18 mm, Labogel-RP-18-5s-100, gradient: 10% Meon in water to 100% Meon).

Abbreviations (used in this description):

Side - tert-butoxycarbonyl, BSA - bovine serum albumin, Bu is butyl, Burgess reagent - hydroxide of methoxycarbonylmethylene, DNS - carbonyldiimidazole, DC - dicyclohexylcarbodiimide, DHM - dichloromethane, DEAD - diethylazodicarboxylate, DIRAA - diisopropylethylamine (base Hunya, ethyldiethanolamine), DME - 1,2-dimethoxyethane, DMF - dimethylformamide, DMSO is dimethylsulfoxide, dppf is 1,1'-bis(diphenylphosphino)ferrocene, DFFP - 1,3-bis(diphenylphosphino)propane, EA - ethyl acetate, EDC - N-(3-dimethylaminopropyl)-N' - ethylcarbodiimide, Et is ethyl, EtOH - ethanol, EQ. equivalent(s)h hour(s), hbtu - hexaphosphate O-(benzotriazol-1-yl)-N,N,N',N' - tetramethylurea, HOBT - 1-hydroxybenzotriazole, VEHI - high performance liquid chromatography, LC-MS - liquid chromatography-mass spectrometry, MeCN is acetonitrile, Me is methyl, Meon - methanol min minute(s), SGH - liquid chromatography medium pressure, NaOAc - sodium acetate, NEts - triethylamine, SLA - acetate, Ph is phenyl, Robot - hexaphosphate benzotriazol-1 yloxy-Tris-pyrrolidinone, Rev. - preparative, feast upon. - rich, SIP - sphingosine 1-phosphate, TBME - tert-butyl methyl ether, TBTU - tetrafluoroborate 2-(1H-benzotriazol-1-yl)-1,2,3,3-tetramethylurea, TPA - triperoxonane acid, THF is tetrahydrofuran, and TLC is thin layer chromatography, tRthe retention time.

5-Isobutyl-4-methylpyridin-2-carboxylic acid (hydrochloride)

a) To a solution of 2,5-dibromo-4-picoline (9.00 g, 35.9 mmol) in DME (96 ml) is added a complex of 2,4,6-trivinylcyclohexane-pyridine (8,63 g, 35.9 mmol) and 2-normal aqueous solution of K2CO3(36 ml). The mixture Tegaserod and kept in an atmosphere of argon added before the eat Pd(PPh 3)4(746 mg, 0,646 mmol). The mixture is stirred at a temperature of 80°C for 15 h, then cooled to room temperature, diluted with diethyl ether (50 ml), washed with saturated aqueous NaHCO3(twice 30 ml), dried over MgSO4filter and concentrate. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane: EA in the ratio of 9:1 and receiving 5-bromo-4-methyl-2-vinylpyridine (? 7.04 baby mortality g) as a yellow oil.

LC-MS: tR=0,75 min; [M+1]+=198,22;1H NMR (CDCl3): δ is 2.41 (s, 3H), of 5.50 (d, J=10,8 Hz, 1H), 6,21 (d, J=17.3 Hz, 1H), 6,74 (dd, J=17,3, and 10.8 Hz, 1H), 7,22 (s, 1H), 8,59 (s, 1H).

b) To a solution of 5-bromo-4-methyl-2-vinylpyridine) - derivatives (? 7.04 baby mortality g, 35.5 mmol) in acetone (280 ml) and water (280 ml) is added KMnO4(28,81 g, 71.1 mmol). Dark-colored mixture was stirred at room temperature for 3 days, after which it is filtered through a porous glass filter. The colorless filtrate is evaporated, give crude 5-bromo-4-methylpyridin-2-carboxylic acid (10,9 g potassium salt) as a white solid.

LC-MS: tR=of 0.64 min, [M+1]+=215,90.

C) To a suspension of crude 5-bromo-4-methylpyridin-2-carboxylic acid (10,9 g, approximately 35.5 mmol) in ethanol (120 ml) add H2SO4(0.5 ml). The mixture is stirred at 70°C for 18 hours the pH Value clear solution is adjusted to p 9 by addition of saturated aqueous NaHCO 3and the mixture is extracted with diethyl ether (three times 300 ml). The combined organic extracts are dried over MgSO4, filtered and concentrated, obtaining the ethyl ester of 5-bromo-4-methylpyridin-2-carboxylic acid (8,20 g) as a green oil.

LC-MS: tR=of 0.87 min, [M+1]+=243,91.

g) To a solution of ethyl ester of 5-bromo-4-methylpyridin-2-carboxylic acid (a 4.03 g, 16.5 mmol) in DME (43 ml) was added to the complex of 2,4,6-tri-(2-methylpropenyl)collaboration-pyridine (are 5.36 g, 16.5 mmol)and then 2-normal aqueous solution of K2CO3(16 ml). The mixture Tegaserod and kept in an atmosphere of argon, and then add Pd(PPh3)4(343 mg, 0,297 mmol). The mixture is stirred at a temperature of 80°C for 6 h, then cooled to room temperature, diluted with diethyl ether (50 ml), washed with saturated aqueous NaHCO3(three times 30 ml), dried over MgSO4filter and concentrate. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane: EA in the ratio of 7:3 and thus the ethyl ester of 4-methyl-5-(2-methylpropenyl)pyridine-2-carboxylic acid (1,33 g) as a yellow oil.

LC-MS: tR=of 0.87 min, [M+1]+=220,08.

d) To a solution of ethyl ester of 4-methyl-5-(2-methylpropenyl)pyridine-2-carboxylic acid (1,33 g, 6.06 mmol) in THF (10 ml) and ethanol (10 ml) was carefully added Pd/C (00 mg, 10%Pd). The suspension is stirred at room temperature for 15 h under hydrogen pressure (2 bar). The catalyst is filtered off and the filtrate is concentrated and dried, obtaining the ethyl ester of 5-isobutyl-4-methylpyridin-2-carboxylic acid (1.27 g) as a colourless oil.

LC-MS: tR=0,86 min, [M+1]+=222,10.

e) a Solution of ethyl ester of 5-isobutyl-4-methylpyridin-2-carboxylic acid (1.27 g, USD 5.76 mmol) in 6-normal aqueous solution of HCl (110 ml) is stirred at 65°C for 48 h, after which the solvent is evaporated in vacuum. The remaining residue is suspended in DHM and filtered. The solid product is additionally washed DHM and dried in a high vacuum, receiving hydrochloride 5-isobutyl-4-methylpyridin-2-carboxylic acid (1,05 g) as a white solid.

LC-MS: tR=0,59 min; [M+1]+=194.28;1H NMR (D6-DMSO): δ of 0.90 (d, J=6.3 Hz, 6N), 1,85 is 1.96 (m, 1H), 2,69 (d, J=7,0 Hz, 2H), 8,18 (s, 1H), 8,58 (s, 1H), 11,80 (s extended, 1H).

6-Isobutyl-4-methylpyridin-2-carboxylic acid (hydrochloride)

a) a Solution of n-BuLi (21.1 ml, 33.8 mmol, 1,6-molar) in THF cooled to a temperature of -78°C and then added dropwise a solution of 2,6-dichloropyridine (5.0 g, 33.8 mmol) in THF (36 ml) for 20 min, the Reaction mixture was stirred at -78°C for 30 min, then add logmean (4,79 g, 33.8 mmol). The mixture is then again paramashiva the t for 30 min and quenched with saturated aqueous NH 4Cl at -78°C. the Mixture is extracted with diethyl ether, the organic extract was dried over MgSO4filter and concentrate. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane: EA in the ratio of 9:1, and while receiving 2,6-dichloro-4-methylpyridine (2,34 g) as a colourless oil containing spatial isomer 2,6-dichloro-3-methylpyridine.

LC-MS: tR=to 0.89 min, [M+1]+=161,97.

b) To a solution of 2,6-dichloro-4-methylpyridine (2,34 g, 14.4 mmol) and complex of 2,4,6-trivinylcyclohexane-pyridine (1.75 g, 7.26 mmol) in DME (27 ml) was added 2-molar aqueous solution of K2CO3(10 ml). The mixture Tegaserod and kept in an atmosphere of argon before adding Pd(PPh3)4(300 mg, 0.26 per mmol). The mixture is then stirred at a temperature of 80°C for 3 h, after which it is cooled to room temperature, diluted with diethyl ether and washed with saturated aqueous NaHCO3. The organic extract was dried over MgSO4filter and concentrate. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane: EA ratio in the ratio of 9:1. Thus obtained product is dissolved in ethyl acetate, washed again with 5%aqueous citric acid solution, dried over MgSO4, filtered and evaporated, getting 6-the ENT-4-methyl-2-vinylpyridine (1.24 g) as a colourless oil.

LC-MS: tRor =0.90 min, [M+1]+=154,03.

C) To a solution of 6-chloro-4-methyl-2-vinylpyridine) - derivatives (1.24 g, 8.06 mmol) in water (50 ml) and acetone (50 ml) was added KMnO4(6,53 g, 41.3 mmol). Dark-colored mixture when it is heated (40°C) and stirred at room temperature for 3 h, then filtered through a porous glass filter. Then from the colorless filtrate is evaporated the solvent to give crude potassium salt of 6-chloro-4-methylpyridin-2-carboxylic acid (3.2 g) as a colourless solid; LC-MS: tR=67 min, [M+1]+=171,99. This substance is suspended in ethanol (150 ml) and add H2SO4(2 ml) before formation of a colorless solution. The mixture is heated to a temperature of 70°C for 18 h, and then carefully diluted with saturated aqueous NaHCO3to pH 9. The mixture is then extracted three times with ethyl acetate. The combined organic extracts are dried over MgSO4filter and concentrate. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane: EA in the ratio 3:2 and thus obtaining the ethyl-6-chloro-4-methylpyridin-2-carboxylate (500 mg) in the form blignault oil.

LC-MS: tR=of 0.87 min; [M+1]+=200,04;1H NMR (CDCl3): δ of 1.45 (t, J=7,3 Hz, 3H), of 2.45 (s, 3H), 4,48 (q, J=6,8 Hz, 2H), 7,35 (s, 1H), 7,89 (s, 1H).

g) To a solution of ethyl-6-chloro-4-methylpyridin-2-carboxylate (500 mg ,51 mmol) and the complex of 2,4,6-Tris-(2-methylpropenyl)cyclotrisiloxane-pyridine (814 mg, 2.51 mmol) in DME (32 ml) was added 2-molar aqueous solution of K2CO3(12 ml). The mixture Tegaserod and kept in an atmosphere of argon before adding Pd(PPh3)4(52 mg, 0.045 mmol). The mixture is then stirred at a temperature of 80°C for 6 h, after which it is cooled to room temperature, diluted with diethyl ether (50 ml) and washed with saturated aqueous NaHCO3(twice 30 ml). The organic extract was dried over MgSO4filter and concentrate. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane: EA in the ratio of 9:1 and thus the ethyl ester of 4-methyl-6-(2-methylpropenyl)pyridine-2-carboxylic acid (176 mg) as a yellow oil.1H NMR (CDCl3): δ of 1.45 (t, J=7.0 Hz, 3H), of 1.97 (s, 3H), 2,12 (s, 3H), 2,42 (s, 3H), of 4.46 (q, J=7,0 Hz, 2H), 6,41 (s, 1H), 7,17 (s, 1H), of 7.75 (s, 1H).

d) To a solution of ethyl ester of 4-methyl-6-(2-methylpropenyl)pyridine-2-carboxylic acid (175 mg, 0.80 mmol) in THF (5 ml) and ethanol (5 ml) is added 10%Pd/C (50 mg). The mixture is stirred at 50°C for 15 min under hydrogen pressure (1 bar). The catalyst is filtered off through celite and the filtrate is evaporated the solvent, obtaining the ethyl ester of 6-isobutyl-4-methylpyridin-2-carboxylic acid (174 mg) as a colourless oil.

LC-MS: tR=0,84 min, [M+1]+=222,48.

e) a Solution of ethyl ester of 6-isobutyl-4-ethylpyridine-2-carboxylic acid (174 mg, 0.78 mmol) in 6 normal aqueous HCl (20 ml) is stirred at 65°C for 18 hours the Solvent is evaporated and the remaining residue is dried in high vacuum, obtaining the hydrochloride of 6-isobutyl-4-methylpyridin-2-carboxylic acid in the form of a green oil.

LC-MS: tR=0,58 min, [M+1]+=194,09.

6-(1-Ethylpropyl)-4-methylpyridin-2-carboxylic acid

a) Methyl 6-chloro-4-methylpyridin-2-carboxylate get similarly obtaining ethyl-6-chloro-4-methylpyridin-2-carboxylate.

LC-MS**: tR=0,49 min, [M+1]+=186,25;1H NMR (CDCl3): δ of 2.46 (s, 3H), was 4.02 (s, 3H), 7,37 (s, 1H), 7,92 (s, 1H).

b) Methyl-6-chloro-4-methylpyridin-2-carboxylate (500 mg, 2.69 mmol) is treated with 1-ethylpropylamine and amyraut, as described in the synthesis of 6-(1-ethylpropyl)-4-methoxypyridine-2-carboxylic acid, getting named the title compound (220 mg) as a pale yellow oil.

LC-MS**: tR=0,37 min, [M+1]+=208,29;1H NMR (CDCl3): δ 0,80 (t, J=7,3 Hz, 6N), 1,69-of 1.81 (m, 4H), 2,48 (s, 3H), 2,58-to 2.67 (m, 1H), 7,21 (s, 1H), to $ 7.91 (s, 1H).

4-Isobutyl-6-methylpyridin-2-carboxylic acid (hydrochloride)

a) To a solution of 4-bromo-2-methylpyridine (5,70 g, 32,14 mmol) in methanol (100 ml) add H2SO4(0.3 ml). The mixture is heated under reflux, then carefully add the solution peroxydisulfate ammonium (7,33 g, 32,14 mmol) in water (53 ml). The mixture is stirred at at at the revani under reflux for 2 h, then add two servings of peroxydisulfate ammonium (by double-7,33 g) in the form of saturated aqueous solution. Stirring is continued at reflux for 3 hours and Then the methanol is removed under reduced pressure and the remaining solution was diluted with saturated aqueous NaHCO3and extracted with ethyl acetate. The organic extract was dried over MgSO4filter and concentrate. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane: EA in the ratio of 3:7 and thus (4-bromo-6-methylpyridin-2-yl)methanol (1.31 g) as a pale yellow solid.

LC-MS: tR=0,31 min; [M+1]+=201,96;1H NMR (CDCl3): δ by 2.55 (s, 3H)and 3.59 (s extended, 1H), 4.72 in (s extended, 2H), 7,28 (s, 2H).

b) To a solution of (4-bromo-6-methylpyridin-2-yl)methanol (1.31 g, 6,48 mmol) in acetone (150 ml) is added KMnO4(2,61 g, 16.5 mmol). The mixture is stirred at 40°C for 2 h, after which it is filtered through a glass funnel with a porous bottom. The filtrate is evaporated without dried and the remaining solid is washed with water and dried in a high vacuum, obtaining the potassium salt of 4-bromo-6-methylpyridin-2-carboxylic acid (1,91 g) as a white solid.

LC-MS: tR=0,45 min, [M+1]+=217,89.

C) To a suspension of the potassium salt of 4-bromo-6-methylpyridin the-2-carboxylic acid (253 mg, 0,996 mmol) in ethanol (100 ml) is added dropwise H2SO4(2 ml). The mixture is heated to a temperature of 70°C for 16 h, after which it was carefully diluted with saturated aqueous NaHCO3. The mixture was then extracted three times with diethyl ether. The combined organic extracts are dried over MgSO4filter and concentrate. The crude product is purified using preparative TLC using a mixture of heptane: EA in the ratio 3:2 and thus the ethyl ester of 4-bromo-6-methylpyridin-2-carboxylic acid (105 mg) as a pale yellow oil.

LC-MS: tR=0,85 min, [M+1]+=244,22.

g) of the Hydrochloride of 4-isobutyl-6-methylpyridin-2-carboxylic acid get on the basis of the ethyl ester of 4-bromo-6-methylpyridin-2-carboxylic acid, following the methods used in stage d)e) upon receipt of 6-isobutyl-4-methylpyridin-2-carboxylic acid. LC-MS: tR=0,58 min; [M+1]+=194,08;1H NMR (CDCl3): δ 1,01 (d, J=6.3 Hz, 6N), 2,04-of 2.16 (m, 1H), 2,80 (d, J=7,0 Hz, 2H), to 3.09 (s, 3H), 7,56 (s, 1H), 8,04 (s, 1H), 9,74 (s extended, ~1H).

6-Isobutyl-4-methoxypyridine-2-carboxylic acid (hydrochloride)

a) To a stirred solution of 6-chloro-4-methoxypyridine-2-carboxylic acid (of 5.00 g, 26.7 mmol) in ethanol (75 ml) add chlorotrimethylsilane (15 ml). The reaction mixture was stirred at room temperature for 16 h, after which the solvent is evaporated. the STATCOM is dried in vacuum, getting ethyl ester of 6-chloro-4-methoxy-2-carboxylic acid (5,95 g) as a pale yellow oil.

LC-MS: tR=0,85 min; [M+1]+=215,97;1H NMR (CDCl3): δ of 1.44 (t, J=7.0 Hz, 3H), of 3.94 (s, 3H), 4,48 (q, J=7,0 Hz, 2H), 7,01 (d, J=2.0 Hz, 1H), to 7.61 (d, J=2.0 Hz, 1H).

b) Named in the title compound is obtained from the ethyl ester of 6-chloro-4-methoxy-2-carboxylic acid, following the methods used in stage d)e) upon receipt of 6-isobutyl-4-methylpyridin-2-carboxylic acid. LC-MS: tRor =0.51 min; [M+1]+=210,31;1H NMR (CDCl3): δ was 1.04 (d, J=6,5 Hz, 6N), 2,21 of-2.32 (m, 1 H), of 3.27 (d, J=7,0 Hz, 2 H), 4,20 (s, 3H), 7,12 (s, 1H), 7,83 (s, 1H).

6-(1-Ethylpropyl)-4-methoxypyridine-2-carboxylic acid

a) Methyl ester of 6-chloro-4-methoxy-2-carboxylic acid (1.89 g) are obtained similarly to obtain ethyl ester of 6-chloro-4-methoxy-2-carboxylic acid from 6-chloro-4-methoxypyridine-2-carboxylic acid (2.00 g; 10.7 mmol).

LC-MS**: tr=0,48 min; [M+1]+=202,23;1H NMR (CDCl3): δ of 3.95 (s, 3H), 4,01 (s, 3H), 7,03 (d, J=2.3 Hz, 1H), 7,63 (d, J=2.3 Hz, 1H).

b) a Solution of methyl ester of 6-chloro-4-methoxy-2-carboxylic acid (2,63 g, 13.0 mmol) in dioxane (150 ml) Tegaserod and kept in an atmosphere of argon, and then add Pd(dppf) (109 mg, 133 mcmole). Then to this mixture are added dropwise 1-ethylpropylamine (50 ml of a 0.5 molar solution in THF, 25.0 mmol). The mixture is stirred at a temperature of 76°C for 15 h, cooled to the room temperature, diluted with water and extracted twice with ethyl acetate. The combined organic extracts are dried over MgSO4filter and concentrate. The crude product is purified using GHSD on silica gel, elwira gradient mixture of ethyl acetate in heptane and thus the methyl ester of 6-(1-ethylpropyl)-4-methoxypyridine-2-carboxylic acid (450 mg) as a pale yellow oil.

LC-MS**: tR=0,46 min; [M+1]+=238,34.

C) a Solution of methyl ester 6-(1-ethylpropyl)-4-methoxypyridine-2-carboxylic acid (450 mg, 1.90 mmol) in 25%aqueous HCl is stirred at 65°C for 18 hours the Mixture is concentrated and dried, obtaining mentioned in the title compound (592 mg) as hydrochloride.

LC-MS**: tR=0,38 min; [M+1]+=224,32.

N-Hydroxy-5-isobutyl-4-methylpyridin-2-carboxamide

a) a Solution of isopropyl ester 5-isobutyl-4-methylpyridin-2-carboxylic acid (655 mg, 2.78 mmol, obtained similarly to the corresponding ethyl ether) in 7-normal solution of NH3in methanol (40 ml) is stirred in a sealed ampoule at a temperature of 75°C for 72 h and Then the solvent is removed in vacuum and the residue is again dissolved in 7-normal solution of NH3in methanol. The resulting solution was again stirred at a temperature of 75°C for 24 h the Solvent is evaporated, give crude amide 5-isobutyl-4-methylpiperid the h-2-carboxylic acid (535 mg); LC-MS: tR=0,80 min; [M+1]+=193,01. This substance is dissolved in DHM (20 ml) and added dropwise pyridine (1.08 g, 11,13 mmol). The mixture is stirred at room temperature for 5 min, after which the pin anhydride triperoxonane acid (1.75 g, 1.18 mmol). The mixture is stirred at room temperature for 16 h, diluted with DHM (100 ml), washed with saturated aqueous NaHCO3(three times 50 ml) and brine (50 ml). The organic extract was dried over Na2SO4filter and concentrate. The crude product is purified using GHSD on silica gel, elwira gradient mixture of ethyl acetate in heptane, and while receiving 5-isobutyl-4-methylpyridin-2-carbonitrile (106 mg) as a pale yellow oil.

LC-MS: tR=to 0.96 min; [M+1]+=175,03.

b) To a solution of 5-isobutyl-4-methylpyridin-2-carbonitrile (106 mg, 608 mcmole) in methanol (3 ml), add triethylamine (123 mg, 1.22 mmol) and hydroxylamine hydrochloride (63 mg, 913 mcmole). The mixture is stirred at a temperature of 75°C for 18 h, then concentrated. The residue is dissolved in aqueous solution of NaHCO3(pH 7-8) and extracted with DHM (6 times 50 ml). The organic extracts are combined dried over MgSO4, filtered, concentrated and dried, obtaining mentioned in the title compound (155 mg) as a white solid.

LC-MS: tR=to 0.67 min, [M+1]+=208,01;1H NMR (D 3OD): δ 0,97 (d, J=6,8 Hz, 6N), 1,84 is 1.96 (m, 1H), is 2.37 (s, 3H), 2,58 (d, J=7,3 Hz, 2H), to 7.67 (s, 1H), compared to 8.26 (s, 1H).

3-Ethyl-4-hydroxy-5-methylbenzonitrile

Named the title compound is obtained from 3-ethyl-4-hydroxy-5-methylbenzaldehyde following literature methods (A.K. Chakraborti, G. Kaur, Tetrahedron, 55 (1999) 13265-13268).

LC-MS: tRor =0.90 min;1H NMR (CDCl3): δ 1,24 (t, J=7,6 Hz, 3H), and 2.26 (s, 3H), 2.63 in (q, J=7,6 Hz, 2H), 5,19 (s, 1H), 7,30 (s, 2H).

3-Chloro-4-hydroxy-5-methylbenzonitrile

Named the title compound is obtained from commercially available 2-chloro-6-METHYLPHENOL similar literary techniques (see: 3-ethyl-4-hydroxy-5-methylbenzonitrile).

LC-MS: tR=0.85 min1H NMR (CDCl3): δ□ of 2.33 (s, 3H), 6,10 (s, 1H), 7,38 (s, 1H), 7,53 (d, J=1.8 Hz, 1H).

4-Hydroxy-3-methoxy-5-methylbenzonitrile

Named the title compound is obtained from commercially available 2-hydroxy-3-methoxytoluene similar literary techniques (see: 3-ethyl-4-hydroxy-5-methylbenzonitrile).

LC-MS: tR=0,84 min1H NMR (CDCl3): δ, and 2.27 (s, 3H), 3,93 (s, 3H), 6,24 (s, 1H), 6,97 (d, J=1.3 Hz, 1H), 7,12 (s, 1H).

3-Chloro-4-hydroxy-5-methoxybenzonitrile

Named the title compound is obtained from commercially available 3-chloro-4-hydroxy-5-methoxybenzaldehyde similar literary techniques (see: 3-ethyl-4-hydroxy-5-methylbenzonitrile).

LC-MS: tR=0,82 min;1H NMR (CDCl3): δ 3,98 (s, 3H), 6,36 (s, 1 H),? 7.04 baby mortality (s, 1H), 7,34 (s, 1H).

p> 4-Hydroxy-2-methoxybenzonitrile

Named the title compound is obtained from commercially available 4-hydroxy-2-methoxybenzaldehyde similar literary techniques (see: 3-ethyl-4-hydroxy-5-methylbenzonitrile).

LC-MS: tR=0,74 min1H NMR (D6-DMSO): δ of 3.84 (s, 3H), 6,47 (d, J=8.5 Hz, 1H), is 6.54 (s, 1H), 7,49 (d, J=8.5 Hz, 1H), 10,6 (s, 1H).

4,N-Dihydroxy-3,5-dimethylbenzamide

Named the title compound is obtained from commercially available 4-hydroxy-3,5-dimethylbenzonitrile according to literature methods (for example, E. Meyer, A.S. Joussef, H. Gallardo, Synthesis 2003, 899-905);

1H NMR (CD3OD): δ 7,20 (s, 2H), measuring 2.20 (s, 6H).

3-Ethyl-4,N-dihydroxy-5-methylbenzamide

Named the title compound is obtained from commercially available 2-ethyl-6-METHYLPHENOL following literature methods (G. Trapani, A. Latrofa, M. Franco, C. Altomare, E. Sanna, M. Usala, G. Biggio, G. Liso, J. Med. Chem., 41 (1998) 1846-1854; A.K. Chakraborti, G. Kaur, Tetrahedron, 55 (1999) 13265-13268; E. Meyer, A.S. Joussef, H. Gallardo, Synthesis 2003, 899-905).

LC-MS: tR=0,55 min;1H NMR (D6-DMSO): δ 9,25 (s extended, 1H), 7,21 (s, 2H), to 5.56 (s, 2H), by 2.55 (q, J=7,6 Hz, 2H), of 2.15 (s, 3H), 1,10 (t, J=7,6 Hz, 3H).

4,N-Dihydroxy-3-methyl-5-propylbenzamide

Named the title compound is obtained from commercially available 2-methyl-6-propylene similar to literature methods (see, for example, C. Roth et al. J. Med. Chem, 31 (1988) 122-129; and the cited literature for the synthesis of 3-ethyl-4,N-dihydroxy-5-methylben is amidine).

LC-MS: tR=0,54 min; [M+1]+=209,43;1H NMR (D6-DMSO): δ of 0.90 (t, J=7,3 Hz, 3H), 1,48-to 1.59 (m, 3H), 2,19 (s, 3H), of 2.56 (t, J=7,3 Hz, 2H), 7,37 (s, 1H), 7,40 (s, 1H), 9,34 (s, 1H).

3-Chloro-4,N-dihydroxy-5-methylbenzamide

Named the title compound is obtained from commercially available 2-chloro-6-METHYLPHENOL similar literary techniques (e.g., C. Roth et al. J. Med. Chem., 31 (1988) 122-129; and the cited literature for the synthesis of 3-ethyl-4,N-dihydroxy-5-methylbenzylidene); 3-chloro-4-hydroxy-5-methylbenzaldehyde:

LC-MS: tR=0,49 min; [M+1]+=201,00;1H NMR δ 2,24 (s, 2H), 2,35 (s, 4H), 5,98 (s extended, 1H), to 7.59 (d, J=1.8 Hz, 1H), 7,73 (d, J=1.8 Hz, 1H), 9,80 (s, 1H); 3-chloro-4,N-dihydroxy-5-methylbenzamide:1H NMR (D6-DMSO): δ of 2.21 (s, 3H), 5,72 (s extended, 2H), 7,40 (s, 1H), of 7.48 (s, 1H), 9,29 (s extended, 1H), 9,48 (s extended, 1H).

rat-4-(2,2-Dimethyl-[1,3]dioxolane-4-ylethoxy)-N-hydroxy-3,5-dimethylbenzamide

a) To a solution of 3,5-dimethyl-4-hydroxybenzonitrile (5.0 g, 34,0 mmol) in THF (40 ml) add rat-(2,2-dimethyl-[1,3]dioxolane-4-yl)methanol (4,49 g 34,0 mmol), and then triphenylphosphine (13,4 g of 50.9 mmol). The mixture is cooled in an ice bath, and then added dropwise DEAD (8,87 g of 50.9 mmol, and 23.4 ml of 40%solution in toluene). The mixture is stirred at room temperature for 1 h, the solvent is removed in vacuo and the residue purified by column chromatography on silica gel, elwira a mixture of heptane: EA in with the attitude from 9:1 to 92:8 and get rat-4-(2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)for 3,5-dimethylbenzonitrile (7.20 g) as a pale yellow oil;

LC-MS: tR=as low as 0.99 min, [M+1]+= not determined.

b) To a solution of potassium tert-butylate (6,18 g, 55.1 mmol) in methanol (125 ml) is added hydroxylamine hydrochloride (5,74 g, 82.7 mmol), and then a solution of rat-4-(2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)for 3,5-dimethylbenzonitrile (7.20 g, 27.6 mmol) in methanol (40 ml). The mixture is heated under reflux for 72 h, after which the solvent is removed in vacuum. The residue is purified using preparative HPLC (XBridge Prep 18, 30×75 mm, 5 μm, 2-95% acetonitrile in water containing 0.5% of a saturated aqueous solution of NH3), getting named the title compound (4,85 g) as a pale yellow solid.

LC-MS: tR=to 0.67 min, [M+1]+=295,06;1H NMR (CDCl3): δ was 1.43 (s, 3H), of 1.48 (s, 3H), to 2.29 (s, 6H), 3,76-3,81 (m, 1H), 3,83-3,88 (m, 1H), 3,93-to 3.99 (m, 1 H), 4,17-to 4.23 (m, 1H), 4,47-of 4.54 (m, 1H), 5,02 (s extended, 1H), 7,28 (s, 2H).

(S)-4-(2,2-Dimethyl-[1,3]dioxolane-4-ylethoxy)-N-hydroxy-3,5-dimethylbenzamide

Named in the header of the connection will receive is similar to getting rat-4-(2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-N-hydroxy-3,5-dimethylbenzamide, using (S)-(2,2-dimethyl-[1,3]dioxolane-4-yl)methanol.

LC-MS: tR=to 0.67 min, [M+1]+=295,01.

(R)-4-(2,2-Dimethyl-[1,3]dioxolane-4-ylethoxy)-3-ethyl-N-hydroxy-5-methylbenzamide

Named in the header of the connection will receive is similar to getting rat-4-(2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-N-hydroxy-,5-dimethylbenzamide of 3-ethyl-4-hydroxy-5-methylbenzonitrile and (R)-(2,2-dimethyl-[1,3]dioxolane-4-yl)methanol.

LC-MS**: tR=0,46 min, [M+H]+=309,23;1H NMR (D6-DMSO): δ of 1.17 (t, J=7.5 Hz, 3H), of 1.33 (s, 3H), of 1.38 (s, 3H), of 2.25 (s, 3H), 2.57 m-2,69 (m, 2H), of 3.73-a-3.84 (m, 3H), of 4.12 (t, J=7,0 Hz, 1H), 4,39 is 4.45 (m, 1H), USD 5.76 (s extended, 2H), 7,34 (s, 1H), was 7.36 (s, 1H), for 9.47 (s, 1H).

(R)-3-Chloro-4-(2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-N-hydroxy-5-methylbenzamide

Named in the title compound obtained as a colorless oil (1.39 g) is similar to getting rat-4-(2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-N-hydroxy-3,5-dimethylbenzylidene based on 3-chloro-4-hydroxy-5-methylbenzonitrile and L-α,β-isopropylideneglycerol.

LC-MS: tR=0,66 min, [M+H]+=314,96.

(R)-4-(2,2-Dimethyl-[1,3]dioxolane-4-ylethoxy)-N-hydroxy-3-methoxy-5-methylbenzamide

Named in the title compound obtained as a beige oil (1,16 g) is similar to getting rat-4-(2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-N-hydroxy-3,5-dimethylbenzylidene based on 4-hydroxy-3-methoxy-5-methylbenzonitrile and L-α,β-isopropylideneglycerol.

LC-MS: tR=0,65 min, [M+H]+=311,0.

(R)-3-Chloro-4-(2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-N-hydroxy-5-methoxybenzamide

Named in the header of the connection will receive is similar to getting rat-4-(2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-N-hydroxy-3,5-dimethylbenzylidene based on 3-chloro-4-hydroxy-5-methoxybenzonitrile and L-α,β-isopropylideneglycerol.

LC-MS: tR=0,42 min, [M+H]+=331,17;1H NMR (D 6-DMSO): δ of 1.30 (s, 3H), of 1.34 (s, 3H), 3,86 (s, 3H), a 3.87-3,93 (m, 2H), 4,00-4,12 (m, 2H), 4,36 (quintet, J=5.8 Hz, 1H), 5,90 (s, 2H), 7,32 (d, J=2.0 Hz, 1H), 7,34 (d, J=2.0 Hz, 1H),9,71 (s, 1H).

(R)-4-(2,2-Dimethyl-[1,3]dioxolane-4-ylethoxy)-N-hydroxy-2-methoxybenzamide

Named in the title compound obtained as a beige oil (2,46 g) is similar to getting rat-4-(2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-N-hydroxy-3,5-dimethylbenzylidene based on 4-hydroxy-2-methoxybenzonitrile and L-α,β-isopropylideneglycerol.

LC-MS: tR=0,62 min, [M+H]+=296,97.

(S)-4-(3-Amino-2-hydroxypropoxy)-3-ethyl-5-methylbenzonitrile

a) To a solution of 3-ethyl-4-hydroxy-5-methylbenzonitrile (of 5.06 g, 31.4 mmol) in THF (80 ml) was added PPh3(9,06 g, 34.5 mmol) and (R)-glycidol (to 2.29 ml, 34.5 mmol). The mixture is cooled to a temperature of 0°C, then add DEAD in toluene (15,8 ml, 34.5 mmol). The mixture is stirred for 18 h, at which time it warmed to room temperature. The solvent is evaporated and the crude product purified by column chromatography on silica gel, elwira a mixture of heptane: EA in the ratio of 7:3 and get 3-ethyl-5-methyl-4-oxiranylmethyl (5,85 g) as a yellow oil.

LC-MS: tR=to 0.96 min; [M+42]+=259,08.

b) Obtained above epoxide is dissolved in 7-normal solution of NH3in methanol (250 ml), and the solution was stirred at 65°C for 18 hours will Dissolve the eh then evaporated, give crude (S)-4-(3-amino-2-hydroxypropoxy)-3-ethyl-5-methylbenzonitrile (6,23 g) as a yellow oil.

LC-MS: tR=0,66 min; [M+1]+=235,11.

N-((S)-3-[2-Ethyl-4-(N-hydroxycarbamoyl)-6-methylphenoxy-2-hydroxypropyl)-2-hydroxyacetamido

a) To a solution of (S)-4-(3-amino-2-hydroxypropoxy)-3-ethyl-5-methylbenzonitrile (6,23 g, 26,59 mmol) in THF (150 ml) is added glycolic acid (2,43 g, 31.9 mmol), HOBT (or 4.31 g, 31.9 mmol) and EDC hydrochloride (6,12 g, 31.9 mmol). The mixture is stirred at room temperature for 18 h, after which it was diluted with saturated aqueous NaHCO3and twice extracted with ethyl acetate. The combined organic extracts are dried over MgSO4filter and concentrate. The crude product is purified by column chromatography using DHM containing 8% methanol, thus obtaining (S)-N-[3-(4-cyano-2-ethyl-6-methylphenoxy)-2-hydroxypropyl]-2-hydroxyacetate (7,03 g) as a yellow oil.

LC-MS: tR=to 0.74 min; [M+1]+=293,10;1H NMR (CDCl3): δ 1,25 (t, J=7.5 Hz, 3 H), 2,32 (s, 3H), 2,69 (q, J=7.5 Hz, 2H), 3,48 of 3.56 (m, 3H), 3,70-3,90 (m, 3H), 4,19 (s, advanced, 3H), 7,06 (m, 1H), was 7.36 (s, 1H), 7,38 (s, 1H).

b) Obtained above nitrile transform in N-hydroxybenzamide according to literature methods (for example, E. Meyer, A.S. Joussef, H. Gallardo, Synthesis 2003, 899-905).

LC-MS: tRor =0.51 min; [M+l]+=326,13;1H NMR (D6-DMSO): δ of 1.17 (t, J 7.4 Hz, 3H), 2,24 (s, 3H), ,62 (q, J 7.4 Hz, 2H), 3,23 (m, 1H), 3.43 points (m, 1H), to 3.67 (m, 2H), 3,83 (s, 2H), 3,93 (m, 1H), 5,27 (s extended, 1H), 5,58 (s extended, 1H), 5,70 (s, 2H), 7,34 (s, 1H), was 7.36 (s, 1H), to 7.67 (m, 1H), 9,46 (s extended, 1H).

(S)-2-Hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamoyl)-2,6-dimethylphenoxy] propyl} ndimethylacetamide

Named in the header connection receive similarly, to obtain N-((S)-3-[2-ethyl-4-(N-hydroxycarbamoyl)-6-methylphenoxy]-2-hydroxypropyl)-2-hydroxyacetamido.

LC-MS: tR=0,23 min, [M+1]+=312,25.

N-((S)-3-[2-Ethyl-4-(N-hydroxycarbamoyl)-6-methylphenoxy]-2-hydroxypropyl)-2-hydroxyacetamido

a) To a solution of 3-ethyl-4-hydroxy-5-methylbenzonitrile (of 5.06 g, 31.4 mmol) in THF (80 ml) was added PPh3(9,06 g, 34.5 mmol) and (R)-glycidol (to 2.29 ml, 34.5 mmol). The mixture is cooled to a temperature of 0°C, then add DEAD in toluene (15,8 ml, 34.5 mmol). The mixture is stirred for 18 h, at which time it warmed to room temperature. The solvent is evaporated, and the crude product purified by column chromatography on silica gel, elwira a mixture of heptane:EA in the ratio of 7:3 and get 3-ethyl-5-methyl-4-oxiranylmethyl (5,85 g) as a yellow oil.

LC-MS: tR=to 0.96 min; [M+42]+=259,08.

b) Obtained above epoxide dissolved V7-normal solution of NH3in methanol (250 ml) and the solution stirred at 65°C for 18 hours Then the solvent is evaporated give crude (S)-4-(3-amino-2-hydroxypropoxy)-3-ethyl-5-methylbenzonitrile (6,23 g) as a yellow oil.

LC-MS: tR=0,66 min; [M+1]+=235,11.

C) To a solution of (S)-4-(3-amino-2-hydroxypropoxy)-3-ethyl-5-methylbenzonitrile (6,23 g, 26,59 mmol) in THF (150 ml) is added glycolic acid (2,43 g, 31.9 mmol), HOBT (or 4.31 g, 31.9 mmol) and EDC hydrochloride (6,12 g, 31.9 mmol). The mixture is stirred at room temperature for 18 h, after which it was diluted with saturated aqueous NaHCO3and twice extracted with ethyl acetate. The combined organic extracts are dried over MgSO4filter and concentrate. The crude product is purified by column chromatography using DHM containing 8% methanol, thus obtaining (S)-N-[3-(4-cyano-2-ethyl-6-methylphenoxy)-2-hydroxypropyl]-2-hydroxyacetate (7,03 g) as a yellow oil.

LC-MS: tR=to 0.74 min; [M+1]+=293,10;1H NMR (CDCl3): δ 1,25 (t, J=7.5 Hz, 3H), 2,32 (s, 3H), 2,69 (q, J=7.5 Hz, 2H), 3,48 of 3.56 (m, 3H), 3,70-3,90 (m, 3H), 4,19 (s, advanced, 3H), 7,06 (m, 1H), was 7.36 (s, 1H), 7,38 (s, 1H).

g) Obtained above nitrile in turn named in the title compound according to literature methods (for example, Emauel, A.S. Joussef, H. Gallardo, Synthesis 2003, 899-905).

LC-MS: tRor =0.51 min; [M+1]+=326,13;1H NMR (D6-DMSO): δ of 1.17 (t, J=7.4 Hz, 3H), 2,24 (s, 3H), 2,62 (q, J 7.4 Hz, 2H), 3,23 (m, 1H), 3.43 points (m, 1H), to 3.67 (m, 2H), 3,83 (s, 2H), 3,93 (m, 1H), 5,27 (s extended, 1H), 5,58 (s extended, 1H), 5,70 (s, 2H), 7,34 (s, 1H), of 7.36 (s, 1H), to 7.67 (m, 1H), 9,46 (s extended, 1H).

(S)-N-(3-[2-Chloro-4-(N-hydroxyurs imidoyl)-6-methylphenoxy-2-hydroxypropyl)-2-hydroxyacetamido

Named in the title compound obtained as a beige waxy substances (1.1 g) similarly, to obtain N-((S)-3-[2-ethyl-4-(N-hydroxycarbamoyl)-6-methylphenoxy]-2-hydroxypropyl)-2-hydroxyacetamido based on 3-chloro-4-hydroxy-5-methylbenzonitrile.

LC-MS: tR=0,48 minp, [M+H]+=331,94.

(S)-2-Hydroxy-N-(2-hydroxy-3-[4-(N-hydroxycarbamoyl)-2-methoxy-6-methylphenoxy]propyl)ndimethylacetamide

Named in the title compound obtained as a reddish oil (1.3 g) similarly, to obtain N-((S)-3-[2-ethyl-4-(N-hydroxycarbamoyl)-6-methylphenoxy]-2-hydroxypropyl)-2-hydroxyacetamido based on 4-hydroxy-3-methoxy-5-methylbenzonitrile.

LC-MS: tr=0,49 min, [M+H]+=327,98.

4-(2,2-Dimethyl-[1,3]dioxane-5-ylethoxy)-3-ethyl-N-hydroxy-5-methylbenzamide

To a solution of 3-ethyl-4-hydroxy-5-methylbenzonitrile (480 mg, 2.98 mmol) in THF (10 ml) was added triphenylphosphine (1,17 g, 4.47 mmol) and (2,2-dimethyl-[1,3]dioxane-5-yl)methanol (478 mg, 3.28 mmol). The mixture is cooled to a temperature of 4°C, then add DEAD (1,94 g, 4.47 mmol, 2,05 ml of 40%solution in toluene). Stirring is continued at 4°C for 15 min and then at room temperature for 1 h the Solvent is removed in vacuo, and the crude product purified by column chromatography on silica gel, elwira a mixture of heptane: EA in the ratio of 9:1 and getting 4-(2,2-dimethyl-[13]dioxane-5-ylethoxy)-3-ethyl-5-methylbenzonitrile (240 mg) as a yellow oil;

LC-MS: tR=1,04 min; [M+1+CH3CN]+=330,97.

To a solution of this substance (240 mg, 829 mcmole) in methanol (5 ml) is added hydroxylamine hydrochloride (86 mg, 1.24 mmol) and NaHCO3(104 mg, 1.24 mmol). The mixture is stirred at 60°C for 5 h, after which it was diluted with ethyl acetate and washed with water. The organic extract was dried over MgSO4, filtered, concentrated and dried, obtaining mentioned in the title compound (280 mg) in the form blignault oil.

LC-MS: tR=0,72 min; [M+1+CH3CN]+=323,01.

3-Ethyl-4-[(S)-2-hydroxy-3-(2-hydroxyacetylamino)propoxy-5-methylbenzoic acid

a) To a cooled with ice to a solution of H2SO4(150 ml) in water (250 ml) is added 2-ethyl-6-methylaniline (15.0 g, 111 mmol). Then the solution is treated with ice (150 g), then added dropwise a solution of NaNO2(10.7 g, 155 mmol) in water (150 ml) and ice (50 g). The mixture is stirred at 0°C for 1 h, was added 50%aqueous solution of H2SO4(200 ml) and stirring is continued at room temperature for 18 hours the Mixture was then extracted with DHM and the organic extracts dried over MgSO4and evaporated. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane:EA in the ratio of 9:1 and get 2-ethyl-6-METHYLPHENOL (8.6 g) as a dark red oil

LC-MS: tR=0,89 min;1H NMR (CDCl3): δ 7.03 is-to 6.95 (m, 2H), 6,80 (t, J=7,6 Hz, 1H), 4,60 (s, 1H), 2,64 (q, J=7,6 Hz, 2H, in), 2.25 (s, 3H), 1,24 (t, J=7,6 Hz, 3H).

b) a Solution of 2-ethyl-6-METHYLPHENOL (8,40 g, 61.7 mmol) and hexamethylenetetramine (12,97 g, 92.5 mmol) in acetic acid (60 ml) and water (14 ml) is heated to a temperature of 115°C. the Water is then removed by distillation at a temperature of 117°C. and are selected by the apparatus of the Dean-stark. Water separator replace the reflux condenser and the mixture is heated for 3 hours the mixture is Then cooled to room temperature, diluted with water (100 ml) and extracted with ethyl acetate. The organic extract was washed with saturated aqueous NaHCO3, dried over MgSO4and evaporated. The remaining solid is dissolved in ethyl acetate and treated with heptane to initiate crystallization. The solid product is separated and dried, obtaining 3-ethyl-4-hydroxy-5-methylbenzaldehyde (3.13 g) as colorless crystalline powder.

1H NMR (CDCl3): δ 9,83 (s, 1H), 7,58-7,53 (m, 2H), and 5.30 (s extended, 1H), 2,69 (q, J=7,6 Hz, 2H), 2,32 (s, 3H), of 1.28 (t, J=7,6 Hz, 3H).

C) To a solution of 3-ethyl-4-hydroxy-5-methylbenzaldehyde (25,0 g, 152 mmol) in acetonitrile (250 ml) add K2CO3(42,1 g, 305 mmol), and then benzylbromide (26,0 g, 152 mmol). The suspension is stirred at 60°C for 18 h, after which the mixture was diluted with water (150 ml) and utilized the volume (150 ml). The organic extract is separated and the aqueous phase is again extracted with ethyl acetate (100 ml). The combined organic extracts washed with water (150 ml) and concentrated. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane: EA in the ratio of 9:1 and thereby obtain 4-benzyloxy-3-ethyl-5-methylbenzaldehyde (27,2 g) as a yellow oil.

LC-MS: tR=1,09 min;1H NMR (D6-DMSO): δ 1,19 (t, J=7.5 Hz, 3H), of 2.35 (s, 3H), 2,70 (q, J=7.5 Hz, 2H), 4,90 (s, 2H), 7,37-7,41 (m, 1H), 7,42-7,46 (m, 2H), 7,49-7,52 (m, 2H), 7,65-of 7.69 (m, 2H), 9,92 (s, 1H).

g) To a solution of 4-benzyloxy-3-ethyl-5-methylbenzaldehyde (25,0 g, 98.3 mmol) in acetone (500 ml) was added KMnO4(20.2 g, 127,8 mmol). The mixture thus heated (45°C). It is stirred at room temperature for 16 h, then filtered through a glass filter. Clear colorless filtrate is concentrated, diluted with water and acidified with 2-normal aqueous solution of HCl, and then extracted twice with ethyl acetate. The combined organic extracts are dried over MgSO4, filtered, concentrated and dried, obtaining 4-benzyloxy-3-ethyl-5-methylbenzoic acid (19.2 g) as a pale yellow solid.

LC-MS: tR=1,00 min;1H NMR (D6-DMSO): δ 1,13-1,22 (m, 3H), 2,32 (s, 3H), 2,64-of 2.72 (m, 2H), to 4.87 (s, 2H), 7,34-7,56 (m, 5H), of 7.69 (m, 2H), 12,66 (s extended, 1H).

d) To a suspension of 4-benzyloxy-3-ethyl-methylbenzoic acid (10.0 g, 37,0 mmol) in toluene (150 ml) is added di-tert-butylacetyl N,N-dimethylformamide (22,6 g, 111 mmol). The mixture is heated under reflux for 24 h, after which add another portion of di-tert-butylacetate N,N-dimethylformamide (22,6 g, 111 mmol). The reflux continued for another 24 h, then add another portion of di-tert-butylacetate N,N-dimethylformamide (22,6 g, 111 mmol). Then the mixture is again heated under reflux for 24 h, cooled to room temperature, diluted with ethyl acetate and washed with saturated aqueous Na2CO3. The organic extract was dried over MgSO4filter and concentrate. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane: EA in the ratio of 9:1, and while receiving tert-butions ether 4-benzyloxy-3-ethyl-5-methylbenzoic acid (9,02 g) in the form blignault oil.

LC-MS: tR=1,17 minutes

e) To a solution of tert-butyl methyl ether 4-benzyloxy-3-ethyl-5-methylbenzoic acid (9,02 g, 27.6 mmol) in THF (50 ml) and ethanol (50 ml) is added 10%Pd/C (400 mg). The suspension is stirred at room temperature for 24 h under hydrogen pressure (1 bar). The catalyst was then removed by filtration, the filtrate concentrated, dissolved again in THF (50 ml) and ethanol (50 ml), and again add 10%Pd/C (400 mg)Suspensio again stirred at room temperature for 24 h under hydrogen pressure (1 bar), the catalyst was removed by filtration, and the filtrate is concentrated and dried, obtaining tert-butlove ester 3-ethyl-4-hydroxy-5-methylbenzoic acid (7,13 g) as a pale yellow oil.

LC-MS: tR=1,01 min;1H NMR (CDCl3): δ of 1.28 (t, J=7.8 Hz, 3H), of 1.61 (s, 9H), is 2.30 (s, 3H), to 2.67 (q, J=7.5 Hz, 2H), 5,13 (s extended, 1H), 7.67 (s, 1H), 7,69 (s, 1H).

g) tert-Butyl ester 3-ethyl-4-[(S)-2-hydroxy-3-(2-hydroxyacetylamino)propoxy]-5-methylbenzoic acid (5,94 g) are obtained on the basis of the result of the above tert-butyl ester 3-ethyl-4-hydroxy-5-methylbenzoic acid (6,53 g, 27.6 mmol)following the method described to obtain N-((S)-3-[2-ethyl-4-(N-hydroxycarbamoyl)-6-methylphenoxy]-2-hydroxypropyl)-2-hydroxyacetamido.

LC-MS: tR=of 0.87 min; [M+H]+=368,11;1H NMR (CDCl3): δ of 1.17 (t, J=7.5 Hz, 3H), of 1.53 (s, 9H), 2.28 (s, 3H), of 2.66 (q, J=7.5 Hz, 2H), 3,17-3,26 (m, 1H), 3,38-of 3.46 (m, 1H), 3,65 of 3.75 (m, 2H), 3,83 (d, J=5.5 Hz, 2H), 3,91-of 3.97 (m, 1H), 5,28 (d, J=5.3 Hz, 1H), 5,54 (t, J=5.5 Hz, 1H), to 7.59 (s, 1H), 7,60 (s, 1H), 7,68 (t,J=5.5 Hz, 1H).

C) To a cooled (0°C.) solution of tert-butyl ester 3-ethyl-4-[(S)-2-hydroxy-3-(2-hydroxyacetylamino)propoxy]-5-methylbenzoic acid (5,94 g, 16.2 mmol) in DHM (100 ml) was added TFA (5 ml). The mixture is heated to room temperature and stirred for 2 h, then concentrated, dissolved in acetonitrile with water (6 ml) and was isolated using preparative HPLC, getting named the title compound (2.20 g) in the form of logo powder.

LC-MS: tR=0,41 min; [M+H]+=312,18.

The hydrazide of 4-benzyloxy-3,5-dimethylbenzoic acid

Named in the header of the connection will receive is equivalent to issuing a hydrazide of 4-benzyloxy-3-ethyl-5-methylbenzoic acid, as described below.

LC-MS: tR=0,78 min; [M+1]+=271,19;1H NMR (CDCl3): δ 2,30 (s, 6N), 3,86 (s extended, 2H), 4,82 (s, 2H), 7,30-to 7.50 (m, 7H), 7,58 (s extended, 1H).

The hydrazide of 4-benzyloxy-3-ethyl-5-methylbenzoic acid

a) To a solution of 3-ethyl-4-hydroxy-5-methylbenzaldehyde (34,9 g, 0,213 moles, obtained from 2-ethyl-6-METHYLPHENOL according to literature references are given for the preparation of 3-ethyl-4,N-dihydroxy-5-methylbenzylidene) in MeCN (350 ml) add K2CO3(58,7 g 0,425 moles) and benzylbromide cases (36.4 g, 0,213 moles). The mixture is stirred at 60°C for 2 h, after which it is cooled to room temperature, diluted with water and extracted twice with ethyl acetate. The organic extracts washed with water and concentrated give crude 4-benzyloxy-3-ethyl-5-methylbenzaldehyde (45 g) as an orange oil.

1H NMR (CDCl3): δ of 1.29 (t, J=7.5 Hz, 3H), 2.40 a (s, 3H), 2,77 (q, J=7.8 Hz, 2H), 4,90 (s, 2H), 7,31-7,52 (m, 5H), a 7.62 (d, J=1.5 Hz, 1H), 7,66 (d, J=1.8 Hz, 1H), 9,94 (s, 1H).

b) To a mixture of 4-benzyloxy-3-ethyl-5-methylbenzaldehyde (132 g, 0,519 moles) and 2-methyl-2-butene (364 g, 5,19 mol) in tert-butanol (1500 ml) was added a solution dihydrate NaH2PO4(249 is, 2.08 moles) in water (1500 ml). To this mixture are added in several portions of NaClO2(187,8 g, 2.08 moles). The temperature of the reaction mixture is kept lower than 30°C, while experiencing the allocation of gas. When you are finished adding orange two-phase mixture is thoroughly stirred for 3 h, after which it is diluted with TBME (1500 ml). The organic layer is separated and washed with 20%aqueous solution of NaHS (1500 ml) and water (500 ml). The organic phase is then extracted three times with 0.5 normal aqueous solution of NaOH (1000 ml), the aqueous phase is acidified with 25%aqueous HCl solution (500 ml) and extracted twice TBME (1000 ml). These organic extracts are combined and evaporated without dried, receiving 4-benzyloxy-3-ethyl-5-methylbenzoic acid.

1H NMR (D6-DMSO): δ of 1.17 (t, J=7.5 Hz, 3H), 2,31 (s, 3H), to 2.67 (q, J=7.5 Hz, 2H), a 4.86 (s, 2H), 7,34-7,53 (m, 5H), 7,68 (s, 2H), 12,70 (s, 1H).

C) 4-Benzyloxy-3-ethyl-5-methylbenzoic acid is converted into the hydrazide of 4-benzyloxy-3-ethyl-5-methylbenzoic acid, following stage C) synthesis of hydrazide 4-allyloxy-3,5-dimethylbenzoic acid.

LC-MS: tR=0,82 min, [M+1]+=285,44.

tert-Butyl ester 3-[4-(N-hydroxycarbamoyl)-2,6-dimetilfenil]propionic acid

a) To a cooled with ice to a solution of methyl ester 4-hydroxy-3,5-dimethylbenzoic acid (7,52 g, 41.7 mmol) in DHM (250 ml) and pyridine (10 ml) was added anhydride triftormetilfullerenov acid the (13,0 g, 45.9 mmol) for 20 min After complete addition, the ice bath removed and the reaction mixture stirred for another 1 h at room temperature. The mixture was then diluted with DHM (150 ml), washed with 10%aqueous citric acid solution, and then brine, dried over MgSO4, filtered and evaporated. The residue is purified using rapid chromatography on silica gel, elwira a mixture of heptane: EA in the ratio of 9:1, thus the methyl ester of 3,5-dimethyl-4-triftoratsetilatsetonom acid (11.8 g) as colorless fine crystals.

LC-MS: tR=1,08 minutes

b) To mix the solution obtained above triflate (11.8 g, 37.8 mmol) in dry DMF (155 ml) was successively added in a nitrogen atmosphere, the triethylamine (7.6 g, 75,6 mmol), tert-butyl acrylate (48,4 g, 378 mmol), DFFP (779 mg, 1.89 mmol) and Pd(OAc)2(424 mg, 1.89 mmol). The mixture is stirred at a temperature of 115°C for 18 h, then add the second portion DFFP (160 mg, 0.39 mmol) and Pd(OAc)2(80 mg, 0.36 mmol). Stirring is continued for 4 hours at a temperature of 115°C, and then the mixture is cooled to room temperature, diluted with diethyl ether (350 ml) and washed with 1-normal aqueous solution of HCl and saturated aqueous NaHCO3. The organic extract was dried over MgSO4, filtered and evaporated. The residue is purified using accelerated the Oh chromatography on silica gel, elwira a mixture of heptane: EA in the ratio of 4:1 and thus the methyl ester of 4-(2-tert-butoxycarbonylamino)for 3,5-dimethylbenzoic acid (11,21 g) as a colourless solid.

LC-MS: tR=1,09 minutes

C) To a solution of methyl ester 4-(2-tert-butoxycarbonylamino)for 3,5-dimethylbenzoic acid (11.2 g, 38.6 mmol) in ethanol (50 ml) and THF (50 ml) was added 10%Pd/C (1.0 g). The mixture is stirred for 16 h at room temperature under hydrogen pressure (2.5 bar). Then the catalyst is filtered off, the filtrate concentrated and dried in high vacuum, obtaining the methyl ester of 4-(2-tert-butoxycarbonylmethyl)for 3,5-dimethylbenzoic acid (10.8 g) as a colourless oil.

LC-MS: tR=1,08 minutes

g) To a solution of methyl ester 4-(2-tert-butoxycarbonylmethyl)for 3,5-dimethylbenzoic acid (10.8 g, 37,0 mmol) in ethanol (100 ml) was added 2-molar aqueous solution of LiOH (50 ml) at 0°C. the Cloudy mixture was stirred at 0°C for 30 min and then at room temperature for 4 h, diluted with 10%aqueous citric acid solution and extracted three times with diethyl ether. The combined organic extracts are dried over MgSO4filter and concentrate. The solid residue suspended in a mixture of diethyl ether/heptane, stirred at room temperature and filtered. The specified procedure in the art diethyl ether/heptane again. The solid product is separated and dried in a high vacuum, obtaining 4-(2-tert-butoxycarbonylmethyl)for 3,5-dimethylbenzoic acid (5,09 g) in the form of white crystalline powder.

LC-MS: tR=of 0.95 min, [M+1]+=279,14;1H NMR (CDCl3): δ of 1.47 (s, 9H), 2,30-to 2.40 (m, 2H), 2,39 (s, 6H), 2,94-3,03 (m, 2H), of 7.75 (s, 2H).

d) To a suspension of 4-(2-tert-butoxycarbonylmethyl)for 3,5-dimethylbenzoic acid (8.00 g, 28.7 mmol) in isopropanol (100 ml) was added HOBT (4,27 g, 31.6 mmol)and then EDC hydrochloride (6,34 g, 33.1 mmol). After stirring at room temperature for 1 h, add 25%aqueous ammonia solution (16.1 ml). Stirring is continued for 30 min, after which the isopropanol is evaporated under reduced pressure. The remaining solution was diluted with isopropylacetate (200 ml), washed three times around 0.5 normal aqueous solution of NaHCO3(100 ml)and then water (50 ml), dried over MgSO4, filtered, concentrated and dried, obtaining tert-butyl ether 3-(4-carbarnoyl-2,6-dimetilfenil)propionic acid (7.5 g) as off-white solid.

(e) cooled with ice to a solution of tert-butyl methyl ether 3-(4-carbarnoyl-2,6-dimetilfenil)propionic acid (7,00 g, 25.2 mmol) and triethylamine (7,66 g, 75.7 mmol) in DHM (100 ml) is slowly added anhydride triperoxonane acid (6,06 g, 28.8 mmol), maintaining the reaction temperature below 15°C. Tran is any yellow solution was stirred at room temperature for 1 h, then washed twice with water (100 ml) and concentrated. The crude product is purified by recrystallization from methanol, getting tert-butyl ether 3-(4-cyano-2,6-dimetilfenil)propionic acid (4,2 g) as a white solid.

1H NMR (CDCl3): δ to 1.48 (s, 9H), 2,33-is 2.37 (m, 2H), of 2.38 (s, 6H), 2,94-a 3.01 (m, 2H), 7,31 (s, 2H).

W) Solution of tert-butyl methyl ether 3-(4-cyano-2,6-dimetilfenil)propionic acid (4.1 g, 15.8 mmol), hydroxylamine hydrochloride (1.65 g, 23.7 mmol) and triethylamine (3,20 g, 31.6 mmol) in methanol (40 ml) is heated under reflux for 2 h, after which the solvent is removed in vacuum. The residue is transferred to isopropylacetate (50 ml) and washed twice with water (50 ml). The organic extract was dried over MgSO4, filtered, evaporated and dried, obtaining treat-butyl ester 3-[4-(N-hydroxycarbamoyl)-2,6-dimetilfenil]propionic acid (4.4 g) as a white solid.

tert-Butyl ester 3-[2-ethyl-4-(N-hydroxycarbamoyl)-6-were]propionic acid

Named in the header connection receive similarly to obtain tert-butyl ester 3-[4-(N-hydroxycarbamoyl)-2,6-dimetilfenil]propionic acid.

1H NMR (CDCl3): δ 1.26 in (t, J=7.5 Hz, 3H), 2,34-to 2.41 (m, 5H), 2,70 (q, J=7.8 Hz, 2H), 2,94-a 3.01 (m, 2H), 4,85 (s extended, 1H), 7,28 (s, 1H), 7,32 (s, 1H).

3-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol--yl]-6-were}propionic acid

a) To a solution of 5-isobutyl-4-methylpyridin-2-carboxylic acid (246 mg, 1.07 mmol) and DIPEA (415 mg, is 3.21 mmol) in DMF (4 ml) was added Rumor (589 mg, 1.13 mmol) at 0°C. the Mixture is stirred for 15 min at this temperature, then add tert-butyl ester 3-[2-ethyl-4-(N-hydroxycarbamoyl)-6-were]propionic acid (328 mg, 1.07 mmol) and stirring is continued within 1 h at 0°C. the Reaction is stopped by adding water, the reaction mixture was diluted with saturated aqueous NaHCO3and twice extracted with ethyl acetate. The combined organic extracts are dried over MgSO4, filtered and concentrated give crude intermediate hydroxyamides ester; LC-MS; tR=1,10 min, [M+H]+=482,27. This product is dissolved in dioxane (10 ml) and the mixture is stirred at a temperature of 80°C for 15 hours, the Solvent is evaporated and the crude product purified by column chromatography on silica gel, elwira a mixture of heptane: EA in the ratio of 7:3 and while receiving tert-botilony ester 3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-were}propionic acid (420 mg) in the form a colorless oil.

LC-MS: tR=1,26 min, [M+H]+=464,34.

b) Obtained above tert-butyl ester (437 mg, 0,943 mmol) dissolved in 6 normal aqueous HCl and the mixture paramesh who live at 65°C for 18 hours The solvent is removed in vacuum and the residue is washed with ethyl acetate and dried in a high vacuum, getting named the title compound (371 mg) as a white solid.

LC-MS: tR=1,10 min [M+H]+=408,21;1H NMR (D6-DMSO): δ 0,93 (d, J=6,5 Hz, 6N), of 1.23 (t, J=7.5 Hz, 3H), 1.91 a (septet, J=6,8 Hz), 2,37 is 2.43 (m, 5H), is 2.44 (s, 3H), 2,62 (d, J=7,0 Hz, 2H), 2,74 (q, J=7.5 Hz, 2H), 2.91 in are 2.98 (m, 2H), of 7.75 (s, 1H), 7,76 (s, 1H), 8,16 (s, 1H), 8,53 (s, 1H), 10,26 (s extended, 1H).

Examples

Example 1: N-((S)-3-{2-Ethyl-4-[5-(6-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido

To a solution of 6-isobutyl-4-methylpyridin-2-carboxylic acid (100 mg, 0,435 mmol) and DIPEA (169 mg, 1.31 mmol) in DMF (5 ml) was added, TBTU (210 mg, 0,653 mmol) at 0°C. the Mixture is stirred for 15 min at 0°C, then add N-((S)-3-[2-ethyl-4-(N-hydroxycarbamoyl)-6-methylphenoxy]-2-hydroxypropyl)-2-hydroxyacetamido (170 mg, 0,522 mmol). Stirring is continued at 0°C for 1 h Then the reaction is stopped by adding water. The mixture is diluted with saturated aqueous NaHCO3and extracted with ethyl acetate and twice DHM. The combined organic extracts are dried over MgSO4, filtered and concentrated give crude intermediate hydroxyamides ester. This product is dissolved in dioxane (5 ml) and the mixture is PE is amerivault at a temperature of 80°C for 24 hours The solvent is evaporated, and the crude product purified using preparative TLC using DHM containing 10% 7-normal solution of NH3in methanol, and then using preparative HPLC, getting named the title compound (21 mg) as a pale yellow oil.

LC-MS: tR=to 1.00 min, [M+H]+=483,26;1H NMR (CDCl3): δ 0,99 (d, J=6,8 Hz, 6N), of 1.29 (t, J=7.5 Hz, 3H), 2,21 (septet, J=6,8 Hz, 1H), a 2.36 (s, 3H), 2,48 (s, 3H), of 2.72 (q, J=7.5 Hz, 2H), and 2.79 (d, J=7,3 Hz, 2H), 3,47-3,55 (m, 1H), 3,74-to 3.92 (m, 3H), 4,16-4,24 (m, 3H), 7,18 (s, 1H), 7.23 percent (t advanced, J=5.8 Hz, 1H), 7,88 (s, 1H), of 7.90 (s, 1H), to 7.99 (s, 1H).

Example 2: 2-Ethyl-4-[5-(4-isobutyl-6-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-METHYLPHENOL

To a solution of 4-isobutyl-6-methylpyridin-2-carboxylic acid (480 mg, 2.09 mmol) and DIPEA (810 mg, 6,27 mmol) in DMF (20 ml) was added Rumor (1150 mg, of 2.21 mmol) at 0°C. the Mixture is stirred for 15 min at this temperature, then add 3-ethyl-4,N-dihydroxy-5-methylbenzamide (429 mg, of 2.21 mmol) and stirring is continued for 1 h at the same temperature. The reaction is stopped by adding water, the reaction mixture was diluted with saturated aqueous NaHCO3and twice extracted with ethyl acetate. The combined organic extracts are dried over MgSO4, filtered and concentrated give crude intermediate hydroxyamides ester. LC-MS: tRor =0.90 min, [M+H]+=370,16. This is t the product is dissolved in dioxane (10 ml) and the mixture is stirred at a temperature of 80°C for 15 hours Then the solvent is evaporated, and the crude product purified by column chromatography on silica gel, elwira a mixture of heptane: EA in the ratio of 7:3 and thus named the title compound (112 mg) as a reddish oil.

LC-MS: tR=1,12 min, [M+H]+=352,17.

Example 3: (S)-3-{2-Ethyl-4-[5-(4-isobutyl-6-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy} propane-1,2-diol

To a solution of 2-ethyl-4-[5-(4-isobutyl-6-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-METHYLPHENOL (41 mg, 0,116 mmol) in isopropanol (3 ml) and 3-normal aqueous solution of NaOH (0.4 ml) was added (S)-3-chloro-1,2-propandiol (66 mg, 0,577 mmol). The mixture is stirred at 65°C for 16 h, after which add one more portion (S)-3-chloro-1,2-propane diol (66 mg, 0,577 mmol) and 3-normal aqueous solution of NaOH (0.4 ml). Stirring is continued at 65°C for 24 h the Mixture is cooled to room temperature, diluted with water, and again extracted with diethyl ether. The combined organic extracts are dried over MgSO4filter and concentrate. The crude product is purified using preparative TLC using a mixture of DHM: methanol in the ratio 9:1 and thus named the title compound (16 mg) as a colourless oil.

LC-MS: tR=1,02 min, [M+H]+=426,17.

Example 4: (S)-1-amino-3-{2-ethyl-4-[5-(4-isobutyl-6-methylpyridin-2-yl)-[1,2,arsad the azole-3-yl]-6-methylphenoxy}propan-2-ol

a) To a solution of 2-ethyl-4-[5-(4-isobutyl-6-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-METHYLPHENOL (79 mg, 0,224 mmol) in THF (6 ml) was added (R)-(+)-glycidol (25 mg, 0,335 mmol) and triphenylphosphine (88 mg, 0,335 mmol). The mixture is stirred and cooled to a temperature of 0°C, then add DEAD (58 mg, 0,335 mmol, 40%solution in toluene). The mixture is heated to room temperature, and stirring is continued for 4 hours Then add another portion of (R)-(+)-glycidol (8 mg, 0,112 mmol), triphenylphosphine (30 mg, 0,112 mmol) and DEAD (19 mg, 0,112 mmol). Stirring is continued for 4 h, after which the solvent is evaporated. The crude product is purified using preparative TLC using a mixture of heptane:EA in the ratio of 7:3 and thereby obtain 2-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethyl)-[1,2,4]oxadiazol-5-yl]-4-isobutyl-6-methylpyridin (46 mg) as a yellow oil.

LC-MS: tR=at 1.17 min, [M+H]+=408,19.

b) Obtained above epoxide (46 mg, 0,114 mmol) dissolved in 7-normal solution of NH3in methanol (10 ml) and the mixture is stirred at 45°C for 6 h in a sealed ampoule. The solvent is evaporated, and the crude product purified using preparative TLC using DHM containing 6% 7-normal solution of NH3in methanol and thus named the title compound (38 mg) as a white solid.

LC-MS: tR=0,8 min, [M+H]+=425,24.

Example 5: N-((S)-3-{2-Ethyl-4-[5-(4-isobutyl-6-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido

To a solution of (S)-1-amino-3-{2-ethyl-4-[5-(4-isobutyl-6-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propan-2-ol (36 mg, 86 mcmole), HOBT (14 mg, 103 mcmole) and glycolic acid (8 mg, 103 mcmole) in THF (3 ml) is added EDC-HCl (20 mg, 103 mcmole). The mixture is stirred at room temperature for 18 h, after which it was diluted with saturated aqueous NaHCO3and twice extracted with ethyl acetate. The combined organic extracts are dried over MgSO4filter and concentrate. The crude product is purified using preparative TLC using DHM containing 11% of methanol, thus obtaining mentioned in the title compound (36 mg) as a pale yellow oil.

LC-MS: tR=0,98 min, [M+H]+=483,21;1H NMR (CDCl3): δ 0,98 (d, J=6.3 Hz, 6N), is 1.31 (t, J=7.5 Hz, 3H), 1,97-of 2.08 (m, 1H), of 2.38 (s, 3H), 2,59 (d, J=6,8 Hz, 2H), 2,69-2,78 (m, 5H), 2,81 (s extended, 1H), 3,42 (s extended, 1H), 3,48 is 3.57 (m, 2H), 3,74-3,93 (m, 2H), 4,17-of 4.25 (m, 3H), 7,05 (s extended, 1H), 7,19 (s, 1H), to 7.93 (s, 1H), 7,94 (s, 2H).

Example 6: 4-[5-(6-Isobutyl-4-methoxypyridine-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenol

Named in the header of the get connection similar to the connection example 2 from 6-isobutyl-4-methoxypyridine-2-carboxylic acid and 4,N-dihydroxy,5-dimethylbenzamide.

LC-MS: tR=a 1.01 min, [M+H]+=354,28;1H NMR (CDCl3): δ 0,99 (d, J=6,8 Hz, 6N). 2,19-of 2.28 (m, 1H), 2,35 (s, 6N), 2,78 (d, J=7.5 Hz, 2H), 3,98 (s, 3H), 4,96 (s, 1H), 6,85 (d, J=2.3 Hz, 1H), of 7.70 (d, J=2.3 Hz, 1H), 7,88 (s, 2H).

Examples 7-10

Compounds of the following examples, get similarly obtaining the compounds of the previous examples on the basis of 4-[5-(6-isobutyl-4-methoxypyridine-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenol.

ExampleA similar exampleRLC-MS
tR[min][M+H]+
740,98*427,04
840,98*427,02
950,86*485,26
105 0,85*485,21

Example 10

1H NMR (CDCl3): δ 0,99 (d, J=6,5 Hz, 6N), 2,16-of 2.27 (m, 1H), 2,36 (s, 6N), 2,78 (d, J=7,3 Hz, 2H), 3,47-3,71 (m, 2H), 3.72 points-to 3.92 (m, 4H), 3,98 (s, 3H), 4,14-to 4.23 (m, 3H), 6,86 (d, J=2.3 Hz, 1H), 7,15 (t, J=5.3 Hz), 7,69 (d, J=2.0 Hz, 1H), 7,88 (s, 2H).

Example 11: 2-Ethyl-4-[5-(6-isobutyl-4-methoxypyridine-2-yl)-[1,2,4]oxadiazol-3-yl]-6-METHYLPHENOL

Named in the header connection receive similarly to obtain example 2 from 6-isobutyl-4-methoxypyridine-2-carboxylic acid and 3-ethyl-4,N-dihydroxy-5-methylbenzamide.

LC-MS: tR=1,11 min, [M+H]+=368,12;1H NMR (CDCl3): δ 0,99 (d, J=6,8 Hz, 6N), 1,32 (t, J=7.8 Hz, 3H), 2,24 (septet, J=6,8 Hz)to 2.35 (s, 3H), by 2.73 (q, J=7.8 Hz, 2H), 2,78 (d, J=7,3 Hz, 2H), 3,98 (s, 3H), 5,02 (s, 1H), 6,85 (d, J=1.3 Hz, 1H), of 7.70 (d, J=1.3 Hz, 1H), 7,89 (s, 2H).

Examples 12-17

Compounds of the following examples, get similarly obtaining the compounds of the previous examples based on 2-ethyl-4-[5-(6-isobutyl-4-methoxypyridine-2-yl)-[1,2,4]oxadiazol-3-yl]-6-METHYLPHENOL.

ExampleA similar exampleRLC-MS
tR[min][M+H]+
1231.01442,12
1331,01442,11
1441,02*441,26
1540,86441,27
1650,96499,11
1750,97499,19

Example 17

1H NMR (CDCl3): δ 0,99 (d, J=6,5 Hz, 6N), is 1.31 (t, J=7,3 Hz, 3H), 2,18-of 2.28 (m, 1H), is 2.37 (s, 3H), by 2.73 (q, J=7.5 Hz, 2H), 2,78 (d, J=7,3 Hz, 2H), 3,01 (s extended, 1H), 3.46 in of 3.56 (m, 2H), 3,74-3,93 (m, 3H), 3,98 (s, 3H), 4,16-4,24 (m, 3H), 6,86 (s, 1H), 7,08 (s extended, 1H), of 7.70 (s, 1H), of 7.90 (s, 1H), to $ 7.91 (s, 1H).

Example 18: 4-[5-(6-Isobutyl-4-methods Sipiagin-2-yl)-N,3.4]oxadiazol-2-yl]-2,6-dimethylphenol

a) To a solution of 6-isobutyl-4-methoxypyridine-2-carboxylic acid (270 mg, 1.10 mmol), hydrazide of 4-benzyloxy-3,5-dimethylbenzoic acid (327 mg, 1.21 mmol) and DIPEA (455 mg, to 3.52 mmol) in DHM (15 ml) add Rumor (858 mg, 1.65 mmol) at 0°C. the Mixture is stirred for 30 min at room temperature, diluted with diethyl ether and washed with 1-normal aqueous solution of NaOH, and then 1-molar aqueous solution of NaH2PO4. The organic extract was dried over Na2SO4, filtered and concentrated give crude intermediate hydrazide; LC-MS: tR=to 1.00 min, [M+H]+=462,23. This product (1.13 g) was dissolved in DHM (15 ml) and pyridine (1 ml) and cooled to a temperature of 0°C., then added dropwise to the anhydride triftormetilfullerenov acid (1,38 g, 4,89 mmol). The mixture is then warmed to room temperature, and stirring is continued for 16 hours the Reaction is stopped by adding 3-dimethylamino-1-Propylamine (50 mg, 0.49 mmol). The reaction mixture was twice washed with 1-normal aqueous solution of NaH2PO4and then with water, dried over Na2SO4filter and concentrate. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane: EA in the ratio of 4:1 and thereby obtain 2-[5-(4-benzyloxy-3, 5dimethylphenyl)-[1,3,4]oxadiazol-2-yl]-6-isobutyl-4-methoxypyridine (mg) as a yellow oil.

LC-MS: tR=1,15 min, [M+H]+=444,21.

b) Obtained above benzyl ester (414 mg, 0,934 mmol) dissolved in THF (5 ml) and methanol (5 ml), then add 10%Pd/C (200 mg). Suspension hydronaut at room temperature under hydrogen pressure (1 bar) within 72 hours, the Catalyst was removed by filtration, and the filtrate is concentrated and dried, obtaining mentioned in the title compound (308 mg) as a white solid.

LC-MS: tr=0,77* min, [M+H]+=354,30;1H NMR (CDCl3): δ 1,01 (d, J=6,5 Hz, 6N), 2,19-of 2.30 (m, 1H), 2,36 (s, 6N), was 2.76 (d, J=7,3 Hz, 2H), of 3.97 (s, 3H), 5,07 (s, 1H), 6,80 (d, J=2.3 Hz, 1H), 7,66 (d, J=2.3 Hz, 1H), 7,88 (s, 2H).

Examples 19-24

Compounds of the following examples, receive from example 18 is similar to obtaining the compounds of the previous examples.

ExampleA similar exampleRLC-MS
tR[min][M+H]+
1930,91*428,18
203 0,98428,16
2140,84*427,07
2240,84*427,04
2350,78*489,25
2450,78489,24

Example 20

1H NMR (CDCl3): δ 0,99 (d, J=6,8 Hz, 6N), 2,15 (s extended, 1H), 2,19-of 2.27 (m, 1H), 2,39 (s, 6N), 2,78 (d, J=7,3 Hz, 2H), 3,82-of 3.97 (m, 5H), 3,98 (s, 3H), 4,13-4,20 (m, 1H), 6,86 (d, J=2.3 Hz, 1H), of 7.70 (d, J=2.0 Hz, 1H), to $ 7.91 (s, 2H).

Example 25: 2-Ethyl-4-[5-(6-isobutyl-4-methoxypyridine-2-yl)-[1,3,4]oxadiazol-2-yl]-6-METHYLPHENOL

Named in the header of the get connection similar to the connection of example 18 from 6-isobutyl-4-methoxypyridine-2-carboxylic acid hydrazide 4-benzyloxy-3-ethyl-5-methylbenzoic acid.

LC-MS: tR=the 1.04 min, [M+is] +=368,33.

Examples 26-31

Compounds of the following examples, receive from example 25 is similar to obtaining the compounds of the previous examples.

td align="center"> 0,80*
ExampleA similar exampleRLC-MS
tR[min][M+H]+
2630,94*442,24
2731,00442,11
2840,88*441,26
2940,87*441,25
305499,26
3150,80*499,26

Example 31

1H NMR (CDCl3): δ 1,01 (d, J=6,5 Hz, 6N), is 1.31 (t, J=7.5 Hz, 3H), 2,19-of 2.28 (m, 1H), 2,39 (s, 3H), 2,70-and 2.79 (m, 4H), 3,49-to 3.58 (m, 1H), 3,76-3,93 (m, 4H), of 3.97 (s, 3H), 4,18-of 4.25 (m, 3H), PC 6.82 (d, J=2.0 Hz, 1H), 7,07 (s advanced, 1H), 7,66 (d, J=2.0 Hz, 1H), of 7.90 (s, 1H), to $ 7.91 (s, 1H).

Example 32: 2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-METHYLPHENOL

Named in the header of the get connection similar to the connection example 2 starting from 5-isobutyl-4-methylpyridin-2-carboxylic acid and 3-ethyl-4,N-dihydroxy-5-methylbenzamide.

LC-MS: tR=1,12 min, [M+H]+=352,12.

Examples 33-36

Compounds of the following examples get proceeding from a compound of example 32 is similar to obtaining the compounds of the previous examples.

ExampleA similar exampleRLC-MS
tR[min][M+H]+
333 1,02426,12
3431,01426,45
3540,86425,46
3650,98483,16

Example 33

1H NMR (CDCl3): δ 1.00 each (d, J=6.8 Hz, 6H), 1,32 (t, J=7.5 Hz, 3H), 1,89 is 2.01 (m, 1H), 2,10 (t advanced, J=5.8 Hz, 1H), 2.40 a (s, 3H), 2,47 (s, 3H), 2.63 in (d, J=7,3 Hz, 2H), 2,72 is 2.80 (m, 3H), 3,81-3,98 (m, 4H), 4,13-4,20 (m, 1H), to 7.95 (s, 1H), 7.96 (s, 1H), of 8.09 (s, 1H), 8,55 (s, 1H).

Example 36

1H NMR (CDCl3): δ 0,99 (d, J=6,8 Hz, 6N), of 1.29 (t, J=7.5 Hz, 3H), 1,94 (septet, J=6,8 Hz), a 2.36 (s, 3H), of 2.46 (s, 3H), 2,62 (d, J=7,0 Hz, 2H), 2,72 (q, J=7.5 Hz, 2H), 3,37 (s extended, 1H), 3,47-3,55 (m, 1H), 3,64 (s extended, 2H), 3,74-to 3.92 (m, 3H), 4,16-4,24 (m, 3H), 7,16 (t, J=5.3 Hz, 1H), to $ 7.91 (s, 1H), to 7.93 (s, 1H), of 8.09 (s, 1H), 8,53 (s, 1H).

Example 37: 3-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-were}-N-methylpropionamide

To a solution of 3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-were}propionic acid (40 mg 9 mcmole) in DMF (5 ml) was added, DIPEA (35 mg, 268 mcmole). The mixture is cooled to a temperature of 0°C, then add Rumor (51 mg, 98 mcmole). The mixture is stirred at 0°C for 15 min, then added methylamine (58 μl of 2-molar solution in THF). The mixture is stirred at room temperature for 16 h, diluted with saturated aqueous NaHCO3and twice extracted with ethyl acetate. The combined organic extracts are dried over MgSO4filter and concentrate. The crude product is purified using preparative TLC using a mixture of heptane: EA in the ratio of 1:4 and thus named the title compound (35 mg) as a white solid.

LC-MS: tR=1,10 min, [M+H]+=421,25;1H NMR (CDCl3): δ 1.00 each (d, J=6,5 Hz, 6N), is 1.31 (t, J=7,3 Hz, 3H), 1,89 is 2.00 (m, 1H), 2,34-to 2.41 (m, 2H), 2,44 (s, 3H), 2,47 (s, 3H), 2.63 in (d, J=7,0 Hz, 2H), was 2.76 (q, J=7.8 Hz, 2H), 2,85 (d, J=4.5 Hz, 3H), 3,06-3,13 (m, 2H), 5,38 (s extended, 1H), to $ 7.91 (s, 1H), to 7.93 (s, 1H), 8,10(s, 1H), 8,55 (s, 1H).

Example 38: 3-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-were}-N-(2-hydroxyethyl)propionamide

Named in the header of the get connection similar to the connection of example 37, using ethanolamine.

LC-MS: tR=1,02 min, [M+H]+=451,23;1H NMR (CDCl3): δ 1.00 each (d, J=6.3 Hz, 6N), is 1.31 (t, J=7,3 Hz, 3H), 1,89 is 2.01 (m, 1H), 2,37 at 2.45 (m, 6N), 2,47 (s, 3H), 2.63 in (d, J=7,0 Hz, 2H), 2,73-of 2.81 (m, 2H), 3,07-3,14 (m, 2H), 3,44-to 3.50 (m, 2H), of 3.73-with 3.79 (m, 2H), of 5.84 (s extended, N), to $ 7.91 (s, 1H), to 7.93 (s, 1H), 8,10 (s, 1 H), 8,55 (s, 1H).

Example 39: N-(2-amino-ethyl)-3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-were}propionamide

a) tert-Butyl ether [2-(3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-were}propionamido)ethyl]carbamino acid get similarly obtaining compounds of example 37 by condensation of tert-butyl methyl ether (2-amino-ethyl)carbamino acid 3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-were}propionic acid.

LC-MS: tR=to 1.14 min, [M+H]+=550,33.

b) the Solution obtained above tert-butyloxycarbonyl-protected amine (44 mg, 80 mcmole) 4-molar solution of HCl in dioxane (5 ml) was stirred at room temperature for 18 hours the Solvent is removed in vacuo, and the crude product purified using preparative TLC using DHM containing 4% 7-normal solution of NH3in methanol, and thus named the title compound as a white solid.

LC-MS: tR=to 0.89 min, [M+H]+=450,21.

Example 40: 3-(3-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-were}propionamido)propionic acid

a) tert-Butyl ether 3-(3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-were}propionamido)propionic acid get similarly obtain the soedineniya example 37 condensation hydrochloride tert-butovogo ester 3-aminopropionic acid 3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxidiazol-3-yl]-6-were}propionic acid.

LC-MS: tR=1,18 min, [M+H]+=535,33.

b) the Solution obtained above tert-butyl ester (40 mg, 75 mcmole) 4-molar solution of HCl in dioxane (5 ml) was stirred at room temperature for 18 h, after which the solvent is evaporated. The crude product is purified using preparative TLC using a mixture of DHM: methanol in the ratio 9:1 and thus named the title compound (23 mg) as a white solid.

LC-MS: tR=1,03 min, [M+H]+=479,30;1H NMR (CDCl3): δ 0,99 (d, J=6.3 Hz, 6N), of 1.26 (t, J=7.8 Hz, 3H), 1,87-to 1.98 (m, 1H), 2,34-to 2.41 (m, 5H), 2,43 is 2.51 (m, 5H), 2,61 (d, J=6,8 Hz, 2H), 2,68-2,77 (m, 2H), 3,01-to 3.09 (m, 2H), 3,39-3,61 (m, 2H), 6,34 (s extended, 1H), of 7.82 (s, 1H), 7.84 (s, 1H), of 8.06 (s, 1H), charged 8.52 (s, 1H).

Example 41: 2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,3,4]oxadiazol-2-yl]-6-METHYLPHENOL

Named in the header of the get connection similar to the connection of example 18 starting from 5-isobutyl-4-methylpyridin-2-carboxylic acid hydrazide 4-benzyloxy-3-ethyl-5-methylbenzoic acid.

LC-MS: tR=of 1.07 min, [M+H]+=357,18.

Examples 42-44

Compounds of the following examples get proceeding from a compound of example 41 is similar to obtaining the compounds of the previous examples.

R
ExampleA similar exampleLC-MS
tR[min][M+H]+
4230,96426,15
4340,83425,27
4450,92483,23

Example 42

1H NMR (CDCl3): δ 1.00 each (d, J=6,5 Hz, 6N), is 1.31 (t, J=7,3 Hz, 3H), 1,94 (septet, J=6,5 Hz, 1H), 2.40 a (s, 3H), of 2.45 (s, 3H), 2,61 (d, J=7,0 Hz, 2H), was 2.76 (q, J=7.5 Hz, 2H), 3,81-3,98 (m, 4H), 4,15-is 4.21 (m, 1H), to 7.93 (s, 1H), 7,94 (s, 1H), 8,12 (s, 1H), and 8.50 (s, 1H).

Example 45: 2-Ethyl-4-[5-(6-isobutyl-4-methylpyridin-2-yl)-G,4]oxadiazol-3-yl-6-METHYLPHENOL

Named the title compound (30 mg) obtained as pale yellow oil is similar to obtaining compounds of example 2 from 6-isobutyl-4-methylpyridin-2-carboxylic acid (100 mg, 435 mcmole) and 3-ethyl-4,N-dihydroxy-5-methylbenzamide (85 mg, 435 mcmole).

LC-MS: tR=of 1.13 min, [M+H]+=352,28.

Example 46: (S)-3-{2-Ethyl-4-[5-(6-isobutyl-4-methylpyridin-2-yl)-G1,2,4]ACS is diazol-3-yl]-6-methylphenoxy}propane-1,2-diol

Named the title compound (32 mg) was obtained as a colorless oil similar to obtaining compounds of example 3 from the compound of example 45 (30 mg, 85 mcmole).

LC-MS: tR=of 1.07 min, [M+H]+=426,49;1H NMR (CDCl3): δ 0,98 (d, J=6,8 Hz, 6N), 1,31 (t. J=7.5 Hz, 3H), 2,22 (septet, J=7,0 Hz, 1H), of 2.38 (s, 3H), 2,45 (s extended, 1H), 2,47 (s, 3H), of 2.75 (q, J=7.5 Hz, 2H), and 2.79 (d, J=7,3 Hz, 2H), 3.00 and (s extended, 1H), 3,80-of 3.96 (m, 4H), 4,13-4,20 (m, 1H), 7,17 (s, 1H), to $ 7.91 (s, 1H), to 7.93 (s, 1H), to 7.99 (s, 1H).

Example 47: 2-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl-6-methylphenoxy}ethanol

To a solution of compound of example 32 (a 1.00 g, 2.85 mmol) in isopropanol (10 ml) and 3-molar aqueous solution of NaOH (3 ml) was added 2-bromoethanol (1.42 g, 11.4 mmol). The mixture is stirred at 60°C for 24 h, after which add another portion of 2-bromoethanol (176 mg, 1.41 mmol). Stirring is continued at 60°C for 6 hours the Mixture is diluted with ethyl acetate and washed with water. The organic extract was dried over MgSO4filter and concentrate. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane:EA in a ratio of from 4:1 to 3:1 and thus named the title compound (900 mg) as a colourless oil.

LC-MS: tR=1,10 min, [M+H]+=396,09.

Example 48: 2-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphen the XI}ethylamine

a) a Solution of compound of example 47 (900 mg, 2,.28 mmol) and triethylamine (322 mg, 3.18 mmol) in DHM (20 ml) cooled to 0°C, then add methanesulfonanilide (313 mg, 2.73 mmol). The mixture is stirred at room temperature for 90 min, diluted with DHM and washed with water. The organic extract was dried over MgSO4filter and concentrate. The crude product is purified by column chromatography on silica gel, elwira a mixture of heptane: EA in the ratio of 1:1 and get 2-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}ethyl ester methanesulfonic acid (1.10 g) as a white solid.

LC-MS: tR=to 1.16 min, [M+H]+=474,02.

b) the Solution obtained above of ester methanesulfonic acid (318 mg, 671 mcmole) 7-normal solution of NH3in methanol (10 ml) is stirred in a sealed vial at 60°C for 27 hours the Solvent is evaporated and the crude product purified using preparative TLC using a mixture of DHM: methanol in the ratio 9:1 and thus named the title compound (220 mg) as a colourless oil.

LC-MS: tR=0,86 min, [M+H]+=395,08.

Example 49: 1-(2-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}ethyl)-azetidin-3-carboxylic acid

A solution of 2-{2-ethyl-4-[5-(5-isobutyl-4-methylp ridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}ethyl ether methanesulfonate acid (300 mg, 633 mcmole), methyl ester of azetidin-3-carboxylic acid (218 mg, 1.84 mcmole) and triethylamine (129 mg, 1.26 mmol) in ethanol (10 ml) is stirred in a sealed ampoule at a temperature of 80°C for 96 hours the Mixture is cooled to room temperature, diluted with 3-molar aqueous solution of NaOH and again stirred at room temperature for 1 h, the Mixture is acidified by adding an aqueous solution of HCl, and then extracted with ethyl acetate (twice 25 ml). The organic extracts are combined dried over MgSO4filter and concentrate. The crude product is purified using preparative HPLC, getting named the title compound (170 mg) as a colourless oil.

LC-MS: tRor =0.90 min, [M+H]+=479,10;1H NMR (CDCl3): δ 0,98 (d, J=6,5 Hz, 6N), 1,282 (t, J=7.0 Hz, 3H), 1.93 and (septet, J=7,0 Hz, 1H), of 2.38 (s, 3H), of 2.45 (s, 3H), 2,61 (d, J=7,3 Hz, 2H), by 2.73 (q, J=7,3 Hz, 2H), 3,71-3,82 (m, 2H), 3,97-4,08 (m, 1H), 4,19-4,27 (m, 2H), 4,37-to 4.62 (m, 2H), 4,73 is equal to 4.97 (m, 2H), 7,87 (s, 1H), 7,89 (s, 1H), 8,07 (s, 1H), 8,53 (s, 1H).

Example 50: 3-(2-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}ethylamine)propionic acid

A solution of ethyl ester hydrochloride of β-alanine (88 mg, 570 mcmole) in ethanol (2 ml) filtered through a PL-HCO3Mr SPE ion exchange resin. The intermediate ester methanesulfonic acid of example 48 (90 mg, 190 mcmole) and triethylamine (77 mg, 760 mcmole) are added to the filtrate and the mixture paramashiva the t in a sealed ampoule at a temperature of 80°C for 18 hours The mixture is then cooled to room temperature and the solvent is evaporated. The crude ethyl ester of 3-(2-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}ethylamine)propionic acid is dissolved in ethanol (2 ml) and 1-normal aqueous solution of NaOH (2 ml) and the mixture is stirred at room temperature for 3 hours the Mixture is neutralized by adding 1-normal aqueous solution of HCl, the solvent is removed in vacuo and the residue allocate using preparative HPLC, getting named the title compound (24 mg) as a white solid.

LC-MS: tror =0.90 min, [M+H]+=466,79;1H NMR (CDCl3): δ 1.00 each (d, J=6,5 Hz, 6N), of 1.30 (t, J=7,3 Hz, 3H), 1,90 of 1.99 (m, 1H), of 2.38 (s, 3H), of 2.46 (s, 3H), 2,60 of 2.68 (m, 4H), by 2.73 (q, J=7.5 Hz, 2H), 3,20-of 3.27 (m, 2H), 3.27 to to 3.33 (m, 2H), 4,07-to 4.15 (m, 2H), 7,92 (s, 1H), 7,94 (s, 1H), 8,08 (s, 1H), 8,54 (s, 1H).

Example 51: N-(2-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}ethyl)-2-hydroxyacetamido

To a solution of compound of example 48 (50 mg, 127 mcmole) in THF (2 ml) and DMF (2 ml) was added EDC hydrochloride (27 mg, 139 mcmole), HOBT (19 mg, 139 mcmole), DIPEA (25 mg, 190 mcmole) and glycolic acid (11 mg, 139 mcmole). The mixture is stirred at room temperature for 1 h, then concentrated and allocate using preparative HPLC named the title compound (32 mg) as a colourless oil.

LC-MS: tR=of 1.05 min, [M+H]+=53,08; 1H NMR (CDCl3): δ 1.00 each (d, J=6,5 Hz, 6N), is 1.31 (t, J=7,3 Hz, 3H), 1,89 is 2.00 (m, 1H), is 2.37 (s, 3H), 2,47 (s, 3H), 2.63 in (d, J=7,0 Hz, 2H), by 2.73 (q, J=7.5 Hz, 2H), 3.75 to a 3.83 (m, 2H), 3,93-to 3.99 (m, 2H), 4,23 (s, 2H), 7.03 is-to 7.15 (m, 1H), 7,94 (s, 2H), of 8.09 (s, 1H), 8,55 (s, 1H).

Example 52: N-(2-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}ethyl)-2-methylaminoethanol

To a solution of compound of example 48 (50 mg, 127 mcmole) in THF (2 ml) and DMF (2 ml) was added EDC hydrochloride (27 mg, 139 mcmole), HOBT (19 mg, 139 mcmole), DIPEA (25 mg, 190 mcmole) and Side-sarcosin (26 mg, 139 mcmole). The mixture is stirred at room temperature for 1 h, then concentrated. The residue is dissolved in 4-molar solution of HCl in dioxane (2 ml), the mixture is stirred at room temperature for 30 min, concentrated and allocate using preparative HPLC named the title compound (23 mg) as a reddish oil.

LC-MS: tR=to 0.89 min, [M+H]+=466,05.

Example 53: (2-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}ethyl)amide econsultancy acid

A solution of ester intermediate methanesulfonic acid of example 48 (25 mg, 53 mcmole) and potassium salt of acanaloniidae (16 mg, 106 mcmole) in DMF (2 ml) is stirred at 60°C for 18 hours the Mixture is concentrated and allocate using preparative HPLC named the title compound (5 mg) as a colourless mA is La.

LC-MS: tR=to 1.14 min, [M+H]+=487,14.

Example 54: Amide N-(2-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}ethyl)-N',N'-dimethylsulfonium acid

To a solution of compound of example 48 (100 mg, 253 mcmole), DIPEA (39 mg, 304 mcmole) in acetonitrile (2 ml) is added N,N-dimethylsulphamoyl (40 mg, 279 mcmole). The mixture is stirred at 60°C for 18 hours the Solvent is removed in vacuo, and the crude product purified using preparative HPLC, getting named the title compound (47 mg) as a white solid.

LC-MS: tR=to 1.16 min, [M+H]+=502,17;1H NMR (CDCl3): δ 1.00 each (d, J=6,5 Hz, 6N), 1,32 (t, J=7.5 Hz, 3H), 1,89 is 2.01 (m, 1H), 2,39 (s, 3H), 2,47 (s, 3H), 2.63 in (d, J=7,3 Hz, 2H), 2,75 (q, J=7.5 Hz, 2H), 2,89 (s, 6N), 3,51 (q, J=5.3 Hz, 2H), 3,98 (t, J=5,0 Hz, 2H), and 4.75 (t, J=6.0 Hz, 1H), 7,95 (s, 1H), of 7.96 (s, 1H), of 8.09 (s, 1H), 8,55 (s, 1H).

Example 55: 2-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,3-diol

To a solution of compound of example 32 (100 mg, 285 mcmole) in acetonitrile (2 ml) was added K2CO3(56 mg, 427 mcmole), and then dimethylchlorosilane (57 mg, 341 mcmole). The mixture is stirred at 65°C for 18 h, diluted with ethyl acetate and washed with water. The organic extract was concentrated and the crude product purified using preparative TLC using a mixture of heptane: EA in the ratio of 4:1, and while receiving DIMET levy ester 2-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}malonic acid (95 mg) as a colourless oil; LC-MS: tR=at 1.17 min, [M+H]+=482,01. This product (95 mg, 197 mcmole) dissolved in ethanol (10 ml) and treated with NaBH4(60 mg, was 1.58 mmol). The mixture is stirred at 60°C for 1 h, after which the reaction is stopped by adding water. The mixture is extracted twice with ethyl acetate and the combined extracts concentrated. The crude product is purified using preparative TLC using a mixture of heptane: EA in the ratio of 1:1 and thus named the title compound (44 mg) as a colourless oil.

LC-MS: tR=1,02 min, [M+H]+=426,01;1H NMR (CDCl3): δ 1.00 each (d, J=6,5 Hz, 6N), is 1.31 (t, J=7,3 Hz, 3H), 1,95 (septet, J=6.3 Hz, 1H), 2,08 (t advanced r, J=5.5 Hz, 2H), 2,42 (s, 3H), 2,47 (s, 3H), 2.63 in (d, J=7,0 Hz, 2H), 2,80 (q, J=7.5 Hz, 2H), 3,91-of 4.05 (m, 4H), 4,19 (quintet, J=4.5 Hz, 1H), 7,95 (s, 1H), 7,98 (s, 1H), 8,10 (s, 1H), 8,55 (s, 1H).

Example 56: 2-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl-6-methylpenicillin} propane-1,3-diol

2-{3-[4-(2,2-Dimethyl-[1,3]dioxane-5-ylethoxy)-3-ethyl-5-were]-[1,2,4]oxadiazol-5-yl}-5-isobutyl-4-methylpyridine (200 mg) obtained as a colorless oil similar to obtaining compounds of example 1 from 4-(2,2-dimethyl-[1,3]dioxane-5-ylethoxy)-3-ethyl-N-hydroxy-5-methylbenzamide (281 mg, 871 mcmole) and 5-isobutyl-4-methylpyridin-2-carboxylic acid (200 mg, 871 mcmole); LC-MS: tR=1,24 min, [M+H]+=480,20. This product (200 mg, 417 mcmole) is dissolved in 4-molar R is the target of HCl in dioxane (5 ml) and the mixture is stirred at room temperature for 18 hours The solvent is evaporated, and the crude product purified using preparative TLC using a mixture of heptane: EA in the ratio of 1:1 and thus named the title compound as a colourless oil.

LC-MS: tR=the 1.06 min, [M+H]+=440,05;1H NMR (CDCl3): δ 1.00 each (d, J=6,5 Hz, 6N), is 1.31 (t, J=7.5 Hz, 3H), 1,90-2,00 (m, 1H), and 2.27 to 2.35 (m, 1H), 2,39 (s, 3H), 2,47 (s, 3H), 2.63 in (d, J=7,3 Hz, 2H), 2,75 (q, J=7.8 Hz, 2H), 3,94-Android 4.04 (m, 4H), of 4.05 (d, J=5,5 Hz, 4H), 7,94 (s, 1H), 7,95 (s, 1H), of 8.09 (s, 1H), 8,55 (s, 1H).

Example 57: (S)-1-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-3-methylaminopropane-2-ol

a) To a solution of compound of example 32 (315 mg, 896 mcmole) in isopropanol (10 ml) and 3-normal aqueous solution of NaOH (2 ml) was added (R)-epichlorohydrin (249 mg, 2.69 mmol). The mixture is stirred at room temperature for 18 h, after which add another portion of (R)-epichlorohydrin (249 mg, 2.69 mmol) and stirring is continued at room temperature for 24 hours the mixture is Then diluted with ethyl acetate and washed with water. The organic extract was concentrated and the crude product purified using preparative TLC using a mixture of heptane: EA in the ratio of 7:3 and thereby obtain 2-[3-((S)-3-ethyl-5-methyl-4-oxiranylmethyl)-[1,2,4]oxadiazol-5-yl]-5-isobutyl-4-methylpyridin (233 mg) as a colourless oil.

LC-MS: tR=1,18 min, [M+H]+=408,09.

b) the Solution obtained above sub is full of resin (20 mg, 49 mcmole) in 41%solution of methylamine in water (2 ml) and DMF (0.5 ml) was stirred at 80°C for 18 hours the Solvent is removed in vacuo, and the crude product is produce by using preparative HPLC, getting named the title compound (6 mg) as a reddish oil.

LC-MS: tR=to 0.89 min, [M+H]+=439,07.

Example 58: 1-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-3-((2S)-2-hydroxyethylamino)propan-2-ol

A solution of intermediate epoxide of example 57 (stage a, 25 mg, 61 mcmole) and ethanolamine (19 mg, 18 mcmole) in ethanol (5 ml) is stirred at 60°C for 18 hours the Solvent is removed in vacuo, and the crude product purified using preparative HPLC, getting named the title compound (9 mg) as a white solid.

LC-MS: tR=of 0.87 min, [M+H]+=469,12.

Example 59: ((2S)-3-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)amide econsultancy acid

A solution of intermediate epoxide of example 57 (stage a, 25 mg, 61 mcmole) and potassium salt of acanaloniidae (27 mg, 184 mcmole) in DMF (2 ml) is stirred at 60°C for 18 hours the Solvent is removed in vacuo, and the crude product purified using preparative HPLC, getting named the title compound (8 mg) as a colourless oil.

LC-MS: tR=1,07 is in, [M+H]+=517,12.

Example 60: Methyl ester of 3-((2S)-3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropylamino)propionic acid

A solution of intermediate epoxide of example 57 (stage a, 150 mg, 368 mcmole), hydrochloride of the methyl ester of β-alanine (113 mg, 736 mcmole) and triethylamine (93 mg, 920 mcmole) in methanol (5 ml) is stirred at 60°C for 20 hours the Solvent is removed in vacuo, and the crude product purified using preparative TLC using a mixture of DHM: methanol in the ratio of 10:1 and thus named the title compound (53 mg) as a colourless oil.

LC-MS: tR=to 0.92 min, [M+H]+=511,18.

Example 61: 3-((2S)-3-{2-Ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropylamino)propionic acid

A solution of the compound of example 60 (53 mg, 101 mcmole) in ethanol (1 ml) and 1 molar aqueous solution of NaOH (1 ml) was stirred at room temperature for 18 hours and Then the ethanol is evaporated and the remaining solution was neutralized by adding 1-normal aqueous solution of HCl, after which the mixture is separated using preparative HPLC, getting named the title compound (23 mg) as a white solid.

LC-MS: tR=0,88 min, [M+H]+=497,08;1H NMR (CDCl3): δ 0,98 (d, J=6,5 Hz, 6N), of 1.27 (t, J=7,3 Hz, 3H), 1.93 and (septet, J=7,0 Hz, 1H), 2,34 (s, 3H), 2,4 (s, 3H), 2,60 (d, J=7,3 Hz, 2H), 2,65-and 2.83 (m, 4H), 3,18 is 3.40 (m, 4H), 3,82-of 3.96 (m, 2H), to 4.52-br4.61 (m, 1H), 7,88 (s, 1H), 7,92 (s, 1H), of 8.06 (s, 1H), 8,51 (s, 1H).

Example 62: (S)-3-(2-Ethyl-4-{5-[6-(1-ethylpropyl)-4-methylpyridin-2-yl]-[1,2,4]oxadiazol-3-yl}-6-methylphenoxy)propane-1,2-diol

2-{(R)-3-[4-(2,2-Dimethyl-[1,3]dioxolane-4-ylethoxy)-3-ethyl-5-were]-[1,2,4]oxadiazol-5-yl}-6-(1-ethylpropyl)-4-methylpyridin (42 mg) obtained by condensation and cyclization of 6-(1-ethylpropyl)-4-methylpyridin-2-carboxylic acid (67 mg, 323 mcmole) with (R)-4-(2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-3-ethyl-N-hydroxy-5-methylbenzamide (130 mg, 420 mcmole), as described in example 1. This product is dissolved in dioxane (5 ml) and 2-molar aqueous HCl (1 ml) and the mixture is stirred at room temperature for 16 hours the mixture is Then concentrated and the crude product purified using preparative TLC using DHM containing 10% 7-normal solution of NH3 in methanol, and thus named the title compound (25 mg) as a pale yellow glassy substance.

LC-MS**: tR=0,80 min, [M+H]+=440,27;1H NMR (CDCl3): δ of 0.85 (t, J=7,3 Hz, 6N), 1,32 (t, J=7,3 Hz, 3H), between 1.79 (quintet, J=7,3 Hz, 4H), 2.40 a (s, 3H), 2.49 USD (s, 3H), 2,72-and 2.83 (m, 4H), 3,82-4,00 (m, 5H), 4,13-is 4.21 (m, 1H), 7,16 (s, 1H), to $ 7.91 (s, 1H), 7,92 (s, 1H), of 8.00 (s, 1H).

Example 63 N-[(S)-3-(2-Ethyl-4-{5-[6-(1-ethylpropyl)-4-methylpyridin-2-yl]-[1,2,4]|oxadiazol-3-yl}-6-methylphenoxy)-2-hydroxypropyl-2-hydroxyacetamido

Named the title compound(35 mg) obtained by condensation and cyclization of 6-(1-ethylpropyl)-4-methylpyridin-2-carboxylic acid (67 mg, 323 mcmole) and N-((S)-3-[2-ethyl-4-(N-hydroxycarbamoyl)-6-methylphenoxy]-2-hydroxypropyl)-2-hydroxyacetamido (137 mg, 420 mcmole), as described in example 1.

LC-MS*: tR=a 1.01 min, [M+H]+=497,23;1H NMR (CDCl3): δ of 0.85 (t, J=7.5 Hz, 6N), is 1.31 (t, J=7,3 Hz, 3H), between 1.79 (quintet, J=7,0 Hz, 4H), of 2.38 (s, 3H), 2.49 USD (s, 3H), 2.70 height is 2.80 (m, 3H), 3,48 of 3.56 (m, 2H), 3.75 to 3,93 (m, 3H), 4,18-4,24 (m, 3H), 7,11 (t, J=5.5 Hz, 1H), 7,16 (s, 1H), of 7.90 (s, 1H), to $ 7.91 (s, 1H), 8,00 (s, 1H).

Examples 64-68

Compounds of the following examples, get similarly in a compound of example 62 on the basis of 6-(1-ethylpropyl)-4-methoxypyridine-2-carboxylic acid and the corresponding 4-(2,2-dimethyl-[1,3]dioxolane-4-ylethoxy)-N-hydroxybenzamide.

ExampleRaRbRcLC-MS
tR[min][M+H]+
64NCH3CH2CH30,78456,32
65NCH30,78462,17
66NCH3OCH30,75458,29
67NOCH3Cl0,77478,18
68OCH3NN0,68444,21

Example 64

1H NMR (CDCl3): δ of 0.87 (t, J=7,3 Hz, 6N), of 1.33 (t, J=7.5 Hz, 3H), between 1.79 (quintet, J=7,3 Hz, 4H), 2,09 (t advanced, J=5.3 Hz, 1H), 2,41 (s, 3H), 2,72-of 2.81 (m, 4H), 3,82-of 3.94 (m, 2H), 3,94-of 3.97 (m, 2H), 3,99 (s, 3H), 4,14-4,20 (m, 1H), 6,85 (d, J=2.3 Hz, 1H), 7,71 (d, J=2.3 Hz, 1H), 7,92 (s, 1H), 7,92 (s, 1H).

Examples 69-72

Compounds of the following examples, get similarly in a compound of example 62 on the basis of 6-(1-ethylpropyl)-4-methoxypyridine-2-carboxylic acid and the corresponding 2-hydroxy-N-{2-hydroxy-3-[4-(N-hydroxycarbamoyl)phenoxy]propyl}ndimethylacetamide.

ExampleRa RbRcLC-MS**
tR[min][M+H]+
69HCH3CH2CH30,75513,80
70HCH3CH30,73499,22
71HCH3Cl0,75519,25
72HCH3OCH30,72515,20

Example 69

1H NMR (CDCl3): δ 0,86 (t, J=7.5 Hz, 6H), is 1.31 (t, J=7.5 Hz, 3H), of 1.78 (quintet, J=7,3 Hz, 4H), of 2.38 (s, 3H), 2.71 to and 2.79 (m, 3H), 2,92 (s extended, 1H), 3.45 points of 3.56 (m, 2H), 3,76-3,81 (m, 1H), 3,84 (dd, J=9,5, 6.3 Hz, 1H), 3,90 (dd, J=9,5, 4.8 Hz, 1H), 3,99 (s, 3H), 4,19-4,24 (m, 3H), 6,85 (d, J=2.3 Hz, 1H), 7,07 (t, J=5.3 Hz), 7,71 (d, J=2.3 Hz, 1H), of 7.90 (s, 1H), to $ 7.91 (s, 1H).

Example 73: 4-{5-[6-(1-Ethylpropyl)-4-methoxypyridine-2-yl]-[1,2,4]oxadiazol-3-yl}-2-m is Teal-6-propylene

Named the title compound (3 mg) obtained by condensation and cyclization of the hydrochloride of 6-(1-ethylpropyl)-4-methoxypyridine-2-carboxylic acid (64 mg, 246 mcmole) and 4, N-dihydroxy-3-methyl-5-propylbenzamide (54 mg, 259 mcmole), as described in example 1.

LC-MS**: tR=0,88 min, [M+H]+=396,29.

Example 74 N-((2S)-3-{2-Ethyl-4-[3-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-5-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido

Named the title compound (32 mg) obtained by condensation and cyclization of N-hydroxy-5-isobutyl-4-methylpyridin-2-carboxamidine (40 mg, 193 mcmole) with 3-ethyl-4-[(S)-2-hydroxy-3-(2-hydroxyacetylamino)propoxy]-5-methylbenzoic acid (60 mg, 193 mcmole), as described in example 1.

LC-MS: tR=of 0.95 min, [M+H]+=482,86.

Example 75: GTPγS analysis definition EU50values

Analyses GTPγS binding is carried out in 96-cellular tablets titration (Nunc, 442587) for a final volume of 200 µl, using membrane preparations of Cho cells expressing recombinant human S1P1 receptor. Condition analysis: 20 mm Hepes (company Fluka, 54461), 100 mm NaCl (company Fluka, 71378), 5 mm MgCl2(the company Fluka, 63064), 0.1% of BSA (firm Calbiochem, 126609), 1 μm GDP (firm Sigma, G-7127), 2.5% DMSO, Fluka, 41644), 50 pM35S-GTPγS (firm Amersham Biosciences, SJ1320), a pH of 7.4. Test compounds are dissolved and diluted using 100% DMSO, and pre-and cuberoot at room temperature for 30 min in 150 μl of the above buffer for analysis, in the absence of35S-GTPγS. After adding 50 μl of35S-GTPγS, analyzed the mixture incubated for 1 h at room temperature. Analysis of interrupt by transferring the reaction mixture into Multiscreen tablet (Millipore, MAHFC1H60)using the collector cells from firms Packard Biosciences, after which the tablets are washed with ice with a solution of 10 mm Na2HPO4/NaH2PO4(in the ratio of 70%:30%), dried, sealed in the lower division and, after adding 25 μl MicroScint20 (Packard Biosciences, order# 6013621), sealed at the top. Membrane binding35S-GTPγS was measured using TopCount from the company Packard Biosciences.

EU50represents the concentration of agonist, comprising 50% of the maximum specific35S-GTPγS binding. Specific binding is determined by subtracting nonspecific binding from the maximum binding. The maximum binding represents the number of pulses per minute associated with Multiscreen tablet in the presence of 10 μm S1P. Nonspecific binding represents the number of bindings in the absence of the agonist in the analysis.

Were measured EC50the magnitude of the compounds of examples 2, 6, 7, 8, 11, 14, 15, 21, 22, 28, 29, 45 and 60. Agonistic activity (EC50values) all other shown in the examples of the compounds were also measured. Measured EC50the amount of the compound of example 43 with which accounted for more than 10 μm. EU50the magnitudes of all other shown in the examples of compounds lie in the range from 0.2 to 7600 nm with an average value component of 345 nm. Agonistic activity of some compounds of formula (I) are shown in table 1.

Table 1
Connection exampleEU50[nm]
11,2
102,7
172,3
337,2
349,1
403,3
505,1
518,8
55the 4.7
5811,2
5911,9
612,3
622,2
659,4
693,1
702,8
710,8
728,8
749,0

Example 76: Evaluation of in vivo

The effectiveness of compounds of the formula (I) was estimated by the measurement of circulating lymphocytes after oral administration of from 3 to 30 mg/kg of the compounds of formula (I) normotensive male individuals of Wistar rats. The animals were kept in a controlled climate with a 12 h light/dark cycle and had access to normal rat food and water. Blood was sampled before and after 3, 6 and 24 h after drug administration. The whole blood was subjected to haematological analysis using the Advia Hematology system (Bayer Diagnostics, Zurich, Switzerland).

All data are presented as mean±SEM. Statistical analyses were performed using variance analysis (ANOVA) using Statistica (StatSoft) and Student-Newman-Keuls method for multiplet comparisons. Reduced to zero, the hypothesis is discarded when p<0,05.

As an example, table 2 shows the effect on the number of lymphocytes after 6 h after injection of 10 mg/kg of some compounds of the present invention normotensive male individuals cover the Wistar compared to a group of animals treated only with solvent. The number of lymphocytes was measured at 6 h after oral administration of the compounds of the 7 examples (table 2) and was in the field from -35% to -74% with an average value component -64%.

Table 2
Connection exampleThe number of lymphocytes
1-74%
5-67%
17-66%
34-70%
36-74%
40-35%
55-65%*
* after 3 h after injection

1. The compound of formula (I),
,
where And is a
,or
where the asterisks indicate the bond which attach to the pyridine group of formula (I);
R1represents methyl, ethyl or methoxy group; R2represents the waters of the rod; and R3represents a C2-5alkyl or C1-4alkoxygroup; or
R1represents a C2-5alkyl or C1-4alkoxygroup; R2represents hydrogen; and R3represents methyl or ethyl; or
R1represents methyl, ethyl or methoxy group; R2represents a C3-5alkyl; and R3represents hydrogen;
R4represents hydrogen;
R5represents hydrogen, C1-3alkyl or a methoxy group;
R6represents-CH2-(CH2)n-CONR61R62the hydroxy-group, hydroxys2-4alkoxygroup, di-(hydraxis1-2alkyl)-C1-2alkoxygroup, 2,3-dihydroxypropyl, -OCH2-(CH2)n-NR61R62, 2-[(azetidine-3-carboxylic acid)-1-yl]ethoxypropan, -OCH2-CH(OH)-CH2-NR61R62, OCH2-(CH2)n-NHSO2R63, -OCH2-CH(OH)-CH2-NHSO2R63, -Och2-(CH2)n-NHCOR64or-OCH2-CH(OH)-CH2-NHCOR64;
R61represents hydrogen, methyl, 2-hydroxyethyl, 2-carboxyethyl, 2-(C1-5alkylcarboxylic)ethyl or 2-amino-ethyl;
R62represents hydrogen or methyl;
R63represents a C1-3alkyl or dimethylaminopropyl;
R64is a hydro shall simetal or methylaminomethyl;
n represents the integer 1; and
R7represents hydrogen, methyl or chlorine;
or its pharmaceutically acceptable salt.

2. The compound according to claim 1, where a is a
or
where the asterisks indicate the bond which attach to the pyridine group of formula (I);
or its pharmaceutically acceptable salt.

3. The compound according to claim 1, where a is a

where the asterisks indicate the bond which attach to the pyridine group of formula (I);
or its pharmaceutically acceptable salt.

4. The connection according to one of claims 1 to 3, where R1represents a methyl or methoxy group, R2represents hydrogen and R3represents a C2-4alkyl or C1-3alkoxygroup; or its pharmaceutically acceptable salt.

5. The connection according to one of claims 1 to 3, where R1represents a C2-4alkyl or C1-3alkoxygroup, R2represents hydrogen and R3represents methyl; or its pharmaceutically acceptable salt.

6. The connection according to one of claims 1 to 3, where R1represents methyl, R2represents a C4alkyl, and R3represents hydrogen; or pharmaceutically acceptable with the Lee.

7. The connection according to one of claims 1 to 3, where R5represents a C1-3alkyl or methoxy group, and R7represents methyl or chlorine; or its pharmaceutically acceptable salt.

8. The connection according to one of claims 1 to 3, where R6represents a 2,3-dihydroxypropane or-OCH2-CH(OH)-CH2-NHCOR64; or its pharmaceutically acceptable salt.

9. The compound according to claim 1, selected from the group including:
N-((S)-3-{2-ethyl-4-[5-(6-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
N-((S)-3-{2-ethyl-4-[5-(4-isobutyl-6-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
2-hydroxy-N-((R)-2-hydroxy-3-{4-[5-(6-isobutyl-4-methoxypyridine-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propyl)acetamide", she
2-hydroxy-N-((S)-2-hydroxy-3-{4-[5-(6-isobutyl-4-methoxypyridine-2-yl)-[1,2,4]oxadiazol-3-yl]-2,6-dimethylphenoxy}propyl)acetamide", she
N-((S)-3-{2-ethyl-4-[5-(6-isobutyl-4-methoxypyridine-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
(S)-3-{4-[5-(6-isobutyl-4-methoxypyridine-2-yl)-[1,3,4]oxadiazol-2-yl]-2,6-dimethylphenoxy}propane-1,2-diol,
(R)-3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,2-diol,
(S)-3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,2-diol,
N-((S)-3-{2-the Teal-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido,
3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-were}-N-(2-hydroxyethyl)propionamide, and
3-(3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-were}propionamido)propionic acid;
or pharmaceutically acceptable salts of these compounds.

10. The compound according to claim 1, selected from the group including:
2-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}ethylamine,
3-(2-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}ethylamine)propionic acid,
N-(2-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}ethyl)-2-hydroxyacetamido,
2-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}propane-1,3-diol,
(S)-1-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-3-(2-hydroxyethylamino)propan-2-ol,
((S)-3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropyl)amide econsultancy acid,
3-((S)-3-{2-ethyl-4-[5-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methylphenoxy}-2-hydroxypropylamino)propionic acid,
(S)-3-(2-ethyl-4-{5-[6-(1-ethylpropyl)-4-methylpyridin-2-yl]-[1,2,4]oxadiazol-3-yl}-6-methylphenoxy)propane-1,2-diol,
N-[(S)-3-(2-ethyl-4-{5-[6-(1-ethylpropyl)-4-methylpyridin-2-yl]-[1,2,4]oxadiazol-3-yl}-6-methylphenoxy)-2-hydroxypropyl]-2-hydroxyacetic the ID,
(S)-3-(2-ethyl-4-(5-[6-(1-ethylpropyl)-4-methoxypyridine-2-yl]-[1,2,4]oxadiazol-3-yl}-6-methylphenoxy)propane-1,2-diol,
(S)-3-(2-chloro-4-{5-[6-(1-ethylpropyl)-4-methoxypyridine-2-yl]-[1,2,4]oxadiazol-3-yl}-6-methylphenoxy)propane-1,2-diol,
N-[(S)-3-(2-ethyl-4-{5-[6-(1-ethylpropyl)-4-methoxypyridine-2-yl]-[1,2,4]oxadiazol-3-yl}-6-methylphenoxy)-2-hydroxypropyl]-2-hydroxyacetamido,
N-[(S)-3-(4-{5-[6-(1-ethylpropyl)-4-methoxypyridine-2-yl]-[1,2,4]oxadiazol-3-yl}-2,6-dimethylphenoxy)-2-hydroxypropyl]-2-hydroxyacetamido,
N-[(S)-3-(2-chloro-4-{5-[6-(1-ethylpropyl)-4-methoxypyridine-2-yl]-[1,2,4]oxadiazol-3-yl}-6-methylphenoxy)-2-hydroxypropyl]-2-hydroxyacetamido,
N-[(S)-3-(4-{5-[6-(1-ethylpropyl)-4-methoxypyridine-2-yl]-[1,2,4]oxadiazol-3-yl}-2-methoxy-6-methylphenoxy)-2-hydroxypropyl]-2-hydroxyacetamido,and
N-((2S)-3-{2-ethyl-4-[3-(5-isobutyl-4-methylpyridin-2-yl)-[1,2,4]oxadiazol-5-yl]-6-methylphenoxy}-2-hydroxypropyl)-2-hydroxyacetamido;
or pharmaceutically acceptable salts of these compounds.

11. Pharmaceutical composition having agonistic activity against SP1/EDG1 receptor, comprising a therapeutically effective amount of a compound according to one of claims 1 to 10 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

12. The connection according to one of claims 1 to 3, 9 and 10, or its pharmaceutically acceptable salt, or a pharmaceutical composition according to claim 11, having agonistic activity in respect SP1/EDG1 receptor, intended for use as a medicine.

13. The use of compounds according to one of claims 1 to 10 or its pharmaceutically acceptable salt to obtain a pharmaceutical composition for the prevention or treatment of diseases or disorders associated with an activated immune system.



 

Same patents:

Azole compounds // 2493154

FIELD: chemistry.

SUBSTANCE: invention relates to compounds which are pyridin-3-yl 4-(3-phenyl-1H-1,2,4-triazol-5-yl)piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-[3-(4-fluoromethyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-[5-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate, 2,6-dimethylpyridin-3-yl 4-[5-(3,4-difluorophenyl)-1,2,4-oxadiazol-3-yl]piperidine-1-carboxylate, 2-methylpyridin-3-yl 4-[3-(2-fluorophenyl)-1H-1,2,4-triazol-5-yl]piperidine-1-carboxylate, 6-methylpyridin-3-yl 4-(3-phenyl-1H-pyrazol-1-yl)piperidine-1-carboxylate, 2-methylpyridin-3-yl 4-[5-(3-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate and 6-methylpyridin-3-yl 4-[4-(4-fluorophenyl)-1,3-oxazol-2-yl]piperidine-1-carboxylate or to a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition based on said compounds, having inhibiting effect on fatty acid amide hydrolase (FAAH).

EFFECT: obtaining novel compounds and a pharmaceutical composition based on said compounds, which can be used in medicine for treating neuropathic pain.

13 cl, 38 tbl, 159 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel of 2,4-pyrimidine diamine compounds of formula I, which inhibit degranulation of immune cells and can be used in treating cell reactions mediated by FcεRI or FcγRl receptors. In formula (I) each R2 and R4 is independently phenyl substituted with one or more R8 groups or a heteroaryl selected from a group consisting of , where the heteroaryl is optionally substituted with one or more R8 groups and at least one of R2 and R4 is a heteroaryl; R5 is selected from a group consisting of (C1-C6)alkyl, optionally substituted with one or more identical or different R8 groups, -ORd, -SRd, fluorine, (C1-C3)halogenalkyloxy, (C1-C3)perhalogenalkyloxy, -NRcRc, (C1-C3)halogenalkyl, -CN, -NO2, -C(O)Rd, -C(O)ORd, -C(O)NRcRc, -C(NH)NRcRc, -OC(O)Rd, -OC(O)ORd, -OC(O)NRcRc; -OC(NH)NRcRc, - [NHC(O)]nORd, R35 is hydrogen or R8; each Y is independently selected from a group consisting of O, S and NH; each Y1 is independently selected from a group consisting of O, S and NH; each Y2 is independently selected from a group consisting of CH, CH2, S, N, NH and NR37. Other values of radicals are given in the claim.

EFFECT: improved efficiency.

19 cl, 6 tbl.

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to antibacterial compounds of formula (I) , where one or two of U, V, W and X represent N, the remaining ones represent CH or, in case X, can also represent CRa, where Ra represents fluorine; R1 represents alcoxygroup, halogen or cyanogroup; R2 represents H, CH2OH, CH2N3, CH2NH2, alkylcarbonylaminomethyl or triazol-1-ylmethyl; R3 represents H or, when n=1, R3 can also represent OH, NH2, NHCOR6 or triazol-1-yl; A represents CR4; K represents O, NH, OCH2, NHCO, NHCH2; CH2NH5 CH2CH2, CH=CH, CHOHCHOH or CHR5; R3 represents H or together with R5 forms bond, or R4 can also represent OH, when K is not O, NH, OCH2 or NHCO; R5 represents OH or together with R4 forms bond; R6 represents alkyl; m=0 or 1 and n=0 or 1; and G is specified in i.1 of the formula; and to salt of such compound.

EFFECT: obtaining antibacterial compounds.

19 cl, 1 tbl, 44 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel pyridine derivatives pyridine1-A-pyridine2 of formula (1), where pyridine1 represents

, , or , ,

where asterisks stand for bond, which contains pyridine1 ring with A; R1 represents C1-5alkyl, C1-4alkoxygroup, C3-6-cycloalkyl, hydroxymethyl or NR1aR1b, R1a represents C1-4alkyl; R1b represents hydrogen or C1-3alkyl; or R1a and R1b, together with nitrogen atom, which is bound to pyridine, form pyrrolidine ring; R2 represents hydrogen or C1-4alkyl, or in case, when R1 represents C1-5alkyl or C3-6-cycloalkyl, R2 can additionally represent methoxygroup; R3 represents C1-4alkyl, C1-4alkoxygroup, C3-6-cycloalkyl or NR3aR3b; R3a represents C1-4alkyl; R3b represents hydrogen or C1-3alkyl; R4 represents C1-4alkyl or hydrogen; R5 represents C1-5alkyl, methoxygroup or NR5aR5b; and R6 represents C1-2alkyl; R5a represents C1-4alkyl; R5 represents hydrogen or C1-3alkyl; or R5 represents C1-2alkyl or methoxygroup; and R6 represents C1-5alkyl or NR6aR6b; R6a represents C1-4alkyl; R6b represents hydrogen or C1-3alkyl; R7 represents C1-5alkyl; R8 represents C1-2alkyl or methoxygroup; R9 represents C1-5alkyl; R10 represents C1-2alkyl; A represents

, , or ,

where asterisks stand for bond, binding pyridine1 ring with A; pyridine2 represents

, , or , ,

where asterisks stand for bond, which binds pyridine ring with A; R11 represents C1-4alkyl; C1-3alkyloxy group, hydroxymethyl or NR11aR11b; R,1a represents C1-3alkyl; R11b represents hydrogen or C1-2alkyl; R12 represents hydrogen or C1-4alkyl; R13 represents C1-4alkyl or NR13aR13b; R13a represents C1-4alkyl; R13b represents hydrogen or C1-2alkyl; R14 represents C1-2alkyl; R15 represents C1-4alkyl or NR15aR15b; and R16 represents C1-2alkyl; R15a represents C1-3alkyl; R15b represents hydrogen or C1-3alkyl; or R15 represents C1-2alkyl; and R16 represents C1-4alkyl or NR16aR16b; R16a represents C1-3alkyl; R16b represents hydrogen or C1-2alkyl; R17 represents C1-4alkyl; R18 represents C1-2alkyl or methoxygroup; R19 represents C1-4alkyl; and R20 represents C1-2alkyl; with exception of 3-(2-ethyl-4-pyridyl)-5-(2-ethyl-4-pyridyl)-1,2,4-oxadiazole; or pharmaceutically acceptable salt of such compound.

EFFECT: obtaining pyridine derivatives, which possess agonistic activity with respect to S1P1/EDG1.

15 cl, 2 tbl, 131 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described are novel aminitriazole derivatives of formula (I), where A is phenyl, heterocyclyl or propan-1,3-diyl; E is *-C1-4alkyl-O-, -CH=CH- or , where asterisks stand for bond, through which binding with R1; Q- O or S occurs; R3 is hydrogen, C1-4alkyl, cyclopropyl, C1-4alkoxy-C1-4alkyl, benzyl or -CH2CH2C(O)O-tert-Bu; R1 is pyridyl or phenyl, possibly substituted with halogen, C1-4alkyl, C1-4alkoxy, C1-4fluoroalkyl, C1-4fluoroalkoxy, di-( C1-3alkyl)amino or C1-4alkoxy-C1-2alkyl; and R2 is -CO-C1-3alkyl,-CF2-C1-3alkyl or -SO2-C1-3alkyl; or their pharmaceutically acceptable salts, pharmaceutical composition, which contains them.

EFFECT: obtaining novel compounds for treatment of inflammatory disease or Alzheimer's disease.

20 cl, 105 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula 1:

or pharmaceutically acceptable salts thereof, where values of Cy1; Cy2; L1; L2, R; R1; Rx and Ry and R2 are given in claim 1.

EFFECT: compounds are suitable for use as Raf protein kinase inhibitors.

36 cl, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (I): or to its pharmaceutically acceptable ester, amide, carbamate, solvate or salt, including salt of such ester, amide or carbamate and solvate of such ester, amide, carbamate or salt, where values R1, R2, R3, R4, R5 and R6 are given in item of the formula, with the exception: 4-[3-(4,5-dihydro-1H-imidazol-2-yl)-2-(3,5-dimethylisoxazol-4-yl)indole-1-yl]phenol; 1-(4-hydroxyphenyl)-2-(4-methylimidazol-1-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-(1H-pyrazol-3-yl)-1H-indole-3-carbonitryl; 1-(3-chloro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-prop-1-inyl-1H-indole-3-carboxylic acid amide.

EFFECT: compounds I possess affinity of binding with estrogen receptor of p-subtype, which makes it possible to use them in pharmaceutical composition and in treatment or prevention of state, associated with disease or disorder, associated with activity of estrogen receptors of β-subtype.

27 cl, 271 ex

FIELD: biotechnologies.

SUBSTANCE: invention relates to derivatives of aminopyrazol with the formula of , where A, E, R1 and R2 have values specified in the invention claims, and to their pharmaceutically acceptable salts. Compounds of the formula (I) are agonists of the ALX receptor. Besides, the invention relates to a pharmaceutical composition on the basis of the compound of the formula (I) or its pharmaceutically acceptable salt and to application of these compounds for production of a medicinal agent for prevention or treatment of a disease selected from inflammatory diseases, wheezing diseases, allergic states, HIV-mediated retrovirus infections, cardiovascular diseases, neuroinflammations, neurological disorders, pain, prion-mediated diseases and amiloid-mediated diseases; and for modulation of immune responses.

EFFECT: higher efficiency of compound application.

23 cl, 1 tbl, 466 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an amide derivative of formula (I), where A is benzene or pyridine, where the benzene or pyridine optionally contain 1 or 2 or 3 identical or different substitutes selected from an alkyl containing 1-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, an alkoxy containing 1-6 carbon atoms, a halogen atom, nitro, cyano, alkylsulphonyl containing1-6 carbon atoms, amino, cyclic amine selected from 1,1-di-oxoisothiazolidinyl, 2-oxooxazolidinyl, oxopyrrolidinyl, 1,1-dioxothiazinyl and 2-oxoimidazolidinyl optionally having a substitute selected from an alkyl containing 1-6 carbon atoms and an alkylcarbonyl containing a total of 2-7 carbon atoms, acylamino containing a total of 2-7 carbon atoms, and an alkylsulphonyl amino containing 1-6 carbon atoms, wherein the right-side bond is linked to the carbonyl and the left-side bond is linked to the nitrogen atom, R1 and R2 are identical or different and each is a hydrogen, an alkyl containing 1-6 carbon atoms and optionally containing 3 halogen atoms as substitutes, a cycloalkyl containing 3-6 carbon atoms, a phenyl, a halogen atom or a cyano group and R1 and R2 are not a hydrogen atom at the same time, R3 is a hydrogen atom, an alkyl containing 1-6 carbon atoms, an alkenyl containing 2-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, or a halogen, R4a, R4b and R4c are each independently a hydrogen atom, an alkyl containing 1-6 carbon atoms, or an oxo, R5a, R5b and R5c are identical or different and each is a hydrogen atom, an alkyl containing 1-6 carbon atoms and optionally containing substitute(s) selected from phenyl, an alkoxy group containing 1-6 carbon atoms, optionally substituted with an alkoxy group containing 1-6 carbon atoms, a phyenylcarbonyloxy group and a hydroxy group, or a phenyl, X is a carbon atom (any of R4a, R4b and R4c can be bonded to a carbon atom, but the carbon atom is not substituted with oxo) or a nitrogen atom (if Y is a single bond, the nitrogen atom can be oxidised to form an N oxide), Y is a single bond, a carbonyl or an oxygen atom, Z1 and Z2 are each independently a carbon atom (substitute R3 is optionally bonded to a carbon atom) or a nitrogen atom, and m equals 1 or 2, a pharmacologically acceptable salt thereof. The amide derivative is used as a preventive/therapeutic drug for treating autoimmune diseases, inflammatory bowel diseases or osteoarthritis.

EFFECT: amide derivative which suppresses production of inductive type MMP-9.

14 cl, 4 tbl, 581 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to compound of formula (I): or to its pharmaceutically acceptable ester, amide, carbamate, solvate or salt, including salt of such ester, amide or carbamate and solvate of such ester, amide, carbamate or salt, where values R1, R2, R3, R4, R5 and R6 are given in item of the formula, with the exception: 4-[3-(4,5-dihydro-1H-imidazol-2-yl)-2-(3,5-dimethylisoxazol-4-yl)indole-1-yl]phenol; 1-(4-hydroxyphenyl)-2-(4-methylimidazol-1-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-(1H-pyrazol-3-yl)-1H-indole-3-carbonitryl; 1-(3-chloro-4-hydroxyphenyl)-2-(1-methyl-1H-pyrazol-4-yl)-1H-indole-3-carbonitryl; 1-(4-hydroxyphenyl)-2-prop-1-inyl-1H-indole-3-carboxylic acid amide.

EFFECT: compounds I possess affinity of binding with estrogen receptor of p-subtype, which makes it possible to use them in pharmaceutical composition and in treatment or prevention of state, associated with disease or disorder, associated with activity of estrogen receptors of β-subtype.

27 cl, 271 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to compounds of formula (I) or pharmaceutically acceptable salts thereof wherein A, R1, R2, R3 and m are specified in the patent claim. The present invention also refers to the number of specific compounds, and to a pharmaceutical composition containing the above compounds effective for inhibition of kinases, such as glycogen synthase kinase 3 (GSK-3), Rho kinase (ROCK), Janus kinase (JAK), AKT, PAK4, PLK, CK2, KDR, MK2, JNK1, aurora, pim 1 and nek 2.

EFFECT: preparing the specific compounds and pharmaceutical composition containing the above compounds effective for kinase inhibition.

18 cl, 393 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an amide derivative of formula (I), where A is benzene or pyridine, where the benzene or pyridine optionally contain 1 or 2 or 3 identical or different substitutes selected from an alkyl containing 1-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, an alkoxy containing 1-6 carbon atoms, a halogen atom, nitro, cyano, alkylsulphonyl containing1-6 carbon atoms, amino, cyclic amine selected from 1,1-di-oxoisothiazolidinyl, 2-oxooxazolidinyl, oxopyrrolidinyl, 1,1-dioxothiazinyl and 2-oxoimidazolidinyl optionally having a substitute selected from an alkyl containing 1-6 carbon atoms and an alkylcarbonyl containing a total of 2-7 carbon atoms, acylamino containing a total of 2-7 carbon atoms, and an alkylsulphonyl amino containing 1-6 carbon atoms, wherein the right-side bond is linked to the carbonyl and the left-side bond is linked to the nitrogen atom, R1 and R2 are identical or different and each is a hydrogen, an alkyl containing 1-6 carbon atoms and optionally containing 3 halogen atoms as substitutes, a cycloalkyl containing 3-6 carbon atoms, a phenyl, a halogen atom or a cyano group and R1 and R2 are not a hydrogen atom at the same time, R3 is a hydrogen atom, an alkyl containing 1-6 carbon atoms, an alkenyl containing 2-6 carbon atoms, a cycloalkyl containing 3-6 carbon atoms, or a halogen, R4a, R4b and R4c are each independently a hydrogen atom, an alkyl containing 1-6 carbon atoms, or an oxo, R5a, R5b and R5c are identical or different and each is a hydrogen atom, an alkyl containing 1-6 carbon atoms and optionally containing substitute(s) selected from phenyl, an alkoxy group containing 1-6 carbon atoms, optionally substituted with an alkoxy group containing 1-6 carbon atoms, a phyenylcarbonyloxy group and a hydroxy group, or a phenyl, X is a carbon atom (any of R4a, R4b and R4c can be bonded to a carbon atom, but the carbon atom is not substituted with oxo) or a nitrogen atom (if Y is a single bond, the nitrogen atom can be oxidised to form an N oxide), Y is a single bond, a carbonyl or an oxygen atom, Z1 and Z2 are each independently a carbon atom (substitute R3 is optionally bonded to a carbon atom) or a nitrogen atom, and m equals 1 or 2, a pharmacologically acceptable salt thereof. The amide derivative is used as a preventive/therapeutic drug for treating autoimmune diseases, inflammatory bowel diseases or osteoarthritis.

EFFECT: amide derivative which suppresses production of inductive type MMP-9.

14 cl, 4 tbl, 581 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing substituted pyrimidin-5-yl carboxylic acids of formula I and can be used in organic chemistry. The method is realised by reacting N-substituted guanidines and hetarylamidines with ethoxymethylene derivatives of 1,3-ketoesters according to a scheme given below (where the substitutes are as defined in the claim).

EFFECT: improved method of producing substituted pyrimidin-5-yl carboxylic acids of formula I.

2 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of general formula

, wherein X represents a halogen atom or C1-6-alkyl; and has the value of 0, 1, 2 or 3; R1 represents H; R2 represents or ; R3 represents C1-6-alkyl, C3-10-cycloalkyl, phenyl, 6-member heterocycloalkyl representing tetrahydropyranyl, or 5-10-member heteroaryl specified in pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzo[1,3]dioxolyl and 2,3-dihydrobenzo[1,4]dioxynyl; which be substituted and contains one to five substitutes specified in the patent claim. The invention also refers to pharmaceutical compositions possessing high affinity to dopamine D3 receptor and serotonin 5-HT2A receptor containing said compounds, and the use thereof in preparing drugs.

EFFECT: preparing the compounds of formula (I) possessing high affinity to dopamine D3 receptor and serotonine 5-HT2A receptor.

15 cl, 4 dwg, 5 tbl, 78 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing heterocycle-substituted pyridine derivatives of general formula (I) by reacting a compound of general formula (III) with a compound of formula (II) in a solvent and in the presence of a catalyst based on palladium or a base, where R1, R2, X, Y, Q, A, Z, R, R3 and R4 are described in the claim.

EFFECT: method enables to obtain pyridine derivatives on an industrial scale.

7 cl, 27 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to organic chemistry, specifically to 16-(1,2,4-oxadiazol-3-yl)-15,16-epoxilabdanoids of formula

wherein R=Me(Ia), Ph(1b), CH2Cl(lc) possessing an ability to inhibit human tumour cell growth. The compounds are produced of lambertianic acid contained in Siberian cedar gum and fir needles.

EFFECT: there are produced new compounds which possess considerable cytotoxic activity on human tumour cells.

1 cl, 1 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to the use of compounds of formula (wherein R1, R2, X, Y and n have the values specified in the patent claim) or their pharmaceutically acceptable salts for treating the diseases related to the biological function of the trace amine associated receptors, namely depression, anxiety disorders, bipolar disorders, attention deficit/hyperactivity disorder, stress-induced disorders, schizophrenia, neurological disorders, Parkinson's disease, neurodegenerative disorders, Alzheimer's disease, epilepsy, migraine, addictions, metabolic disorders, eating disorders, diabetes, diabetic complications, obesity, dyslipidemia, energy consumption and assimilation disorders, thermal homeostasis disorders and disturbances, sleeping and circadian rhythm disorders, and cardiovascular diseases. Besides, the invention refers to compounds of formulas I-A, I-B, I-C, I-D, l-E, l-F, I-G, I-H (structural formulas of which are presented in the patent claim) and to a pharmaceutical composition based on the compounds of formula (I) for treating the diseases related to the biological function of the trace amine associated receptors.

EFFECT: use of the compounds of formula 1 in preparing the drugs for treating the diseases related to the biological function of the trace amine associated receptors.

45 cl, 9 dwg, 1 tbl, 379 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel disubstituted phenylpyrrolidines of formula , any stereoisomers thereof or any mixtures of stereoisomers thereof, or N-oxides thereof, or pharmaceutically acceptable salts thereof, where Ar denotes phenyl; R1 denotes F, Cl; R2 denotes F and Cl; R3 denotes H, Me, Et, n-Pr, iso-Pr, n-Bu, iso-Bu, sec-Bu, tert-Bu, cyclopropylmethyl, CFH2CH2CH2-, CF2HCH2CH2-, CF3CH2CH2-, allyl and CH3OCH2CH2-; X denotes F, OH; under the condition that X denotes OH, R3 does not denote H.

EFFECT: compounds are capable of increasing levels of dopamine, norepinephrine and serotonin, which enables their use in treating central nervous system disorders.

16 cl, 21 dwg, 69 ex

FIELD: chemistry.

SUBSTANCE: invention relates to indole derivatives or pharmaceutically acceptable salts thereof of general formula (1): , where values of R1, R2, m are given in claim 1.

EFFECT: compounds have inhibiting activity on IKKβ, which enables their use as a preventive or therapeutic agent for treating IKKβ mediated diseases.

26 cl, 1 tbl, 29 ex

FIELD: medicine.

SUBSTANCE: invention refers to crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid (formula I), pharmaceutical compositions and dosage forms containing these crystalline forms, as well as to methods for preparing such crystalline forms and methods for using them for treating, preventing a disease or a disorder associated with premature terminating codon. There are prepared new crystalline forms of 3-[5-(2-fluorophenyl)-[1,2,4]oxadiazol-3-yl]benzoic acid which are non-absorbent and which can find application in medicine for treating or preventing such diseases or disorders as type III mucopolysaccharidosis, hemophilia A, hemophilia B, neurofibromatosis 1, neurofibromatosis 2, Parkinson's disease, cystic fibrosis, macular degeneration, cephalooculocutaneous telangiectasis, retinitis pigmentosa, tuberous sclerosis, Duchenne muscular dystrophy and Marfan's syndrome, cancer.

EFFECT: higher effectiveness of using the compounds and a method of treating.

46 cl, 11 dwg, 9 tbl

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