EA016300B1 - NOVEL HETEROCYCLIC NF-κB INHIBITORS - Google Patents

Abstract

The present invention relates to compounds of the general formula (Ih) or pharmaceutically acceptable salts thereof with an acid or a base, or pharmaceutically acceptable prodrugs or a stereoisomer thereof, where radical values such as defined in the invention description.

Description

The present invention relates to compounds of general formula (III), or a stereoisomer thereof, or their possible pharmaceutically acceptable salts with an acid or base, or pharmaceutically acceptable prodrugs of these compounds for use as a medicine. The compounds of the invention are particularly useful for the treatment of diseases associated with abnormal and hyperproliferation of mammalian cells, especially humans. In particular, they are useful for treating diseases characterized by hyperproliferation of T cells.

The present invention relates to compounds that are suitable for the treatment of diseases that can be treated by modulating cell signaling cascades in eukaryotes, for example cancer, immunological or inflammatory diseases and viral infections; and to additional methods for the preparation of these compounds and their use.

T-cell homeostasis is critical for maintaining immune tolerance. Defects in Cellular Homeostasis can lead to autoimmune pathology. Autoimmune diseases include a wide range of clinically different forms, which have a common etiology, an improper immune response directed against one's own body.

Such an immune response may also result from organ transplantation. Based on the data, it is assumed that in autoimmune diseases, T-cell reactivity plays a primary role. Measurement of proliferative responses in T-lymphocytes is a widely used assay for measuring immunocompetence (Ksche ^ esh, 1. e! A1. 1. No. 1, No. 133, 217-24, 2002).

The inventors used a non-radioactive method for measuring T-cell proliferation of ίη νίίτο (Ме55е1е. That is! А1. Сішса1 апб ΌίαβηοΠίο ЛаЬогаУгу 1тпіподод 687-692, 2000). Peripheral blood mononuclear cells (PBMCs) were isolated from human blood obtained from volunteer donors. PBMCs were isolated by centrifugation in the ACC & RGL system using SH8TORAO1; E.

PBMCs stimulated PHA (phytohemagglutinin) and cell proliferation was measured using a colorimetric method involving bromo-uridine using the Rosie solid-state enzyme-linked immunosorbent assay (EY8A) kit.

The regulation of the immune response is controlled by various signaling pathways, such as signal transduction from T-cell receptors or ΤΝΡ (tumor necrosis factor) (Syep, O. e! A1. 8c1epse 296, 1634-1635, 2002). To further characterize the targets of the compounds, which the inventors have found to be active in the analysis of T cell proliferation, the inventors tested the compounds for their ability to inhibit the human proteosome.

The highest neutral proteolytic activity in the cytosol and nucleus is possessed by the proteosome, which is a 208 particle (700 kDa) with multiple peptidase activity. The continuous circulation of cellular proteins along the ubiquitin-proteosome pathways is used by the immune system to screen for the presence of abnormal intracellular proteins (OapShta, H.P. e! A1. Ia1. B1ecbpo1. 2000, 18 (5), 538-43; O1bbegd, A.B. e! a1. Winge 357, 375, 1993).

The ubiquitin-proteosome pathway plays an important role in the regulation of ΝΕ-κΒ activity, being responsible for the degradation of the ΙκΒ-α inhibitor. In order to become a target for degradation in the proteosome, ΙΚΒ-α must first be subjected to selective phosphorylation at serine residues 32 and 36, and then ubiquitinylation (Syep, Ζ.Τ е! А1. Се11 84, 853-862, 1996; Βτο ^ η, K. e! a1. 8c1epse 267, 1485, 1995).

The transcription factor ΝΕ-κΒ regulates the transcription of an important set of genes involved in P.A.'s inflammatory responses. e! a1. Ce11 87, 1, 13-20, 1996). Proteosome inhibitors block the degradation of ΙκΒ-α and activation of ΝΕ-κΒ (Tgaeskpeg e! A1. ΕΜΒΟ 1. 13, 5433, 1994).

Patents describing proteosome inhibitors are indicated in the reviews (Abashk, 1. e! A1. App. Ret. Meb. Siet. 31, 279-288, 1996) and in patents I8 6117887, I8 5834487, XVΟ 00/004954, ΧΧΌ 00/04954, ΧΧΌ 00/170204, ΧΧΌ 00/33654, ΧΧΌ 00/64863, ΧΧΌ 00/114324, ΧΧΌ 99/15183, ΧΧΌ 99/37666.

In this invention, the authors describe new chemical compounds with proteosome inhibitory activity.

ΝΕ-κΒ (nuclear factor-κΒ) is a eukaryotic transcription factor of the heme family, which is localized in the cytoplasm in an inactive complex in the form of a homo- or heterodimer. Mostly, it exists as a heterodimer consisting of p50 and p65 subunits linked to inhibitor proteins of the ΙκΒ family, usually ΙκΒ-α (Β. Tyapok e! A1., Ce11 80, 529, 1995). ΝΕ-κΒ is activated in response to various stimuli, including inflammatory cytokines, ultraviolet (UV) radiation, phorbol esters, bacterial and viral infections. Stimulation triggers the release of ΝΕ-κΒ from ΙκΒ due to phosphorylation and subsequent degradation of the ΙκΒα protein (R.A. RaeneNe e! A1., Appy. Ret. Tshshipoy 12, 141, 1995) using a proteosome. After release, ΝΕ-κΒ is transferred to the nucleus, where it binds to DNA at specific κ сайта-sites and induces transcription of various genes encoding proteins involved in the control of immune and inflammatory responses, among others, interleukins, Т№-а, ΝΟ-synthase and cyclooxygenase ΙΙ type (8. Cptt! a1., 1.

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Vusyet. 290, 297, 1993). Accordingly, it is believed that ΝΡ-kB is an early mediator of immune and inflammatory responses and is involved in the control of cell proliferation and in the pathogenesis of various human diseases, such as rheumatoid arthritis (N. Vekeg e! A1., Syp. Exp. 1ttypo1. 99, 325 , 1995), ischemia (A. 8a1ttep e! A1., Vusyet. Vyuruz. Vez. Sot. 212, 939, 1995), arteriosclerosis (A.8. Ba14 ^ 1p, Appaz Veu. 1tipo1. 212, 649, 1996) as well as the pathogenesis of acquired immunodeficiency syndrome (AIDS).

Inhibition of ΝΡ-kV-mediated gene transcription can be achieved by inhibiting the phosphorylation of 1kV inhibitor protein, inhibiting 1kV degradation, inhibiting ΝΡ-kV nuclear translocation (p50 / p65), and inhibiting the binding of ΝΡ-kV to DNA or ΝΡ-kV-mediated DNA transcription (1.C Ruff! E! A1., Osodepe 18, 6896, 1999).

Summary of the invention

The present invention relates to compounds of the general formula (1p), or its pharmaceutically acceptable salts with an acid or base, or its pharmaceutically acceptable prodrugs or stereoisomers

where A represents ΝΒ ² , 8 or O;

! equal to 0-4;

g is 0 or 1;

B ^2a independently represents H, OH, 8H, ΝΗ ₂ , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl or heteroaryl;

In ^3a is independently H, OH, 8H, ΝΗ2, ^ (ΝΒ ⁷⁾ ΝΒ ⁷ 'Β ^8, - (CH 2) _p aryl, - (CH ₂₎ ^{7 8} yB, -C (^ O V ⁷ B ⁸ , ^ = CB ⁷ B ⁸ , ^ B ⁷ C (O) B ⁸ , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl or heteroaryl;

In ^a represents H, halogen, alkyl, -C ^ WUB ⁷ 'B ⁸ , - (CH ₂ ) _R aryl, - (CH ₂ ) yB ⁷ B ⁸ , -C (O ^ B ⁷ B ⁸ , ^ = CB ⁷ B ⁸ , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

B ¹ represents —C (O) B ^7a , —C (O) START ⁷ B ⁸ , —COWB B8 — C (O) OB ⁷ , —B ⁷ C (O) B ^8, or —C (8) B ⁷ ;

B ² represents H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or B ¹ and B ² together with the атом atom or the C atom to which they are attached form a 3-8 membered saturated or, at least partially unsaturated monocyclic or polycyclic ring system, where at least one or more than one carbon atom in the ring is a heteroatom selected from O, Ν and 8, and the ring may be substituted with one or more than one In ⁹ ;

B ³ represents H, -C (O ^ B ^a B ^b , halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, 8H, \ B ⁴ OB ' ⁵ , Ν ^ hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl or haloalkyloxy;

B ^a is H, halogen, alkyl, ^ (ΝΒ ⁷ ) ΝΒ ⁷ В ⁸ , - (СН ₂ ) _p aryl, - (СНДуВ ^ ⁸ , aryl, -Ο ^ ΝΒ ^ ⁸ , -Ν ΓΒΊβ ⁸ , -ΝΒ ^^ Β ⁸ , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino or heteroaryl;

In ^b independently represents H, —CH — OH, —8H, —CO2B ⁴ ′, —C (O) B ⁴ ′, LOLK ⁴ . -ΝΒ ⁴ 'Β ⁵ ', -С ^^ В ^ В ⁸ , -8О2-alkyl, -8О ₂ В ⁴ ', 8О3В ⁴ ', -Ν ^ Β ^ Β ⁵ ', -ΝΒ ^ ΟΒ ⁴ , ^ В ^ -CO-haloalkyl, -ΝΘ2, -ΝΒ ⁴ '8О2-haloalkyl, ^ В ^ ЗО ^ alkyl, -ΝΒ ⁴ -CO-alkyl, -ΝΒ ⁴ (СН2) _p heteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio , halogen, haloalkyl, haloalkyloxy, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _h OCH ₃ , - ((ΝΒ ⁴ ) ΝΒ ⁴ benzimidazolyl, - ((ΝΒ ⁴ ) ΝΒ ⁴ benzthiazolyl, - ((ΝΒ ⁴ ) ΝΒ ⁴ benzoxazolyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl;

B ⁴ ', B ^4', B ⁵ 'independently represent H, halogen, alkyl, ^ (ΝΒ ^ ΝΒ ^ Β ^8, - (CH _{2) p} aryl, haloalkyl, - (SNDuV ^ ⁸ ^ In -SSO "^ ⁸ , - ^ CB ^^ WUO ^ ⁸ , cycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

B ⁷ , B ⁷ ′, B ⁸ independently represent H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino, heteroaryl or aryl;

B ^7a represents cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl or aryl;

B ⁷ represents H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl or aryl;

X represents ΝΒ ² , O or 8;

Ζ represents Ν or CB ² ;

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K ² represents H, alkyl, -0 (Θ) ΝΚ ⁷ , -C (O) K ^b , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

p is 1-6;

q is 1-6;

K ⁹ independently represents H, —ΟΝ, —OH, —ZN, alkoxy, alkylthio, —CO ₂ K ⁴ ′, —C (O ^ K ⁷ K ⁸ ,

^ K ⁴ -8O2-haloalkyl, ^ K ⁴ -8O2-alkyl, -ΝΚ ⁴ -CO-alkyl, -ΝΚ ⁴ (CH ₂ ) _p heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, halogen, haloalkyl, alkylamino, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _h OCH ₃ ,

-C ^ K ⁴ ) ΝΚ ⁴ benzimidazolyl, -C ^ K ⁴ ) ΝΚ ⁴ benzthiazolyl, -C ^ K ⁴ ) ΝΚ ⁴ benzoxazolyl, hydroxycycloalkyl, hydroxyalkylamino, haloalkyloxy, heterocycloalkyl, - (CH ^^^ COK ⁸ , aryl or heteroaryl ;

where a C ₁ -C ₆ alkyl group, unless otherwise indicated, means a linear or branched C ₁ -C ₆ alkyl, which may be optionally substituted with one or more than one substituent K ';

K 'independently represents H, -CO ₂ K``, -CONNA, -SK''O, -3O ^ K'',-ΝΚ''- CO-haloalkyl, ^ O ₂ , ^ K' ^ 3O ^ haloalkyl , ^ K '^ ZO ^ alkyl, -ZO ₂ -alkyl, -ΝΕ''- CO-alkyl, -ΟΝ, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -ZN, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl haloalkyloxy, aryl or heteroaryl;

K ″ independently represents H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;

C2-C6 alkenyl group, unless otherwise indicated, means a linear or branched C2C ₆ alkenyl which may optionally be substituted with one or more substituents K ';

an alkyl group, unless otherwise indicated, means a linear or branched C ₁ -C ₆ -alkyl, linear or branched C ₂ -C ₆ -alkenyl or linear or branched C ₂ -C ₆ -alkynyl group, which may be substituted by one or more than one substituent K '; where K 'is as defined above;

cycloalkyl group means a non-aromatic ring system containing from 3 to 8 carbon atoms, where one or more than one carbon atom in the ring may be substituted by one or more substituents K ', where K' is as defined above;

heterocycloalkyl group means a non-aromatic ring system containing from 2 to 10 carbon atoms and at least one heteroatom selected from O, Ν and 8, where one or more carbon atoms in the ring may be substituted by K ', as defined above;

alkoxy group means an O-alkyl group, wherein the alkyl group is as defined above;

alkylthio group means a 3-alkyl group, wherein the alkyl group is as defined above;

haloalkyl group means an alkyl group substituted by 1-5 halogen atoms, where the alkyl group is as defined above;

hydroxyalkyl group means HO-alkyl group, where the alkyl group is as defined above;

haloalkyloxy group means an alkoxy group substituted with 1-5 halogen atoms, where the alkyl group is as defined above;

hydroxyalkylamino group means a group (HO-alkyl ^ -Ν- or a group HO-alkyl ^ H-, where the alkyl group is as defined above;

alkylamino group means a group H ^ alkyl or Ν-dialkyl, where the alkyl group is as defined above;

the halogen group is fluoro, chloro, bromo or iodo;

aryl group means an aromatic group containing from 5 to 15 carbon atoms, which may be substituted by one or more substituents K ', where K' is as defined above;

arylamino group means a group H ^ aryl or Ν-diaryl, where the aryl group is as defined above;

heteroaryl group means a 5-10 membered aromatic heterocyclic group containing at least one heteroatom selected from O, Ν and 8, where the heterocyclic group may be fused to another ring and said heterocyclic group or fused ring may be independently substituted with one or more than one substituent K ', where K' is as defined above;

provided that the following compounds are excluded:

about where K ¹ independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl;

K ² independently represents -ΝΚ ³ Κ ⁴ ,

K ³ independently represents alkyl, cycloalkyl, alkoxy, alkylamine, —OH, —8H, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

K ⁴ independently represents alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

K ⁵ independently represents H, SOK ⁶ , CO2K ⁶ , 8OK ⁶ , 8O2K ⁶ , 8O3K ⁶ , alkyl, cycloalkyl, alkoxy, -ΝΗ2, alkylamine, -NK ⁷ SOK ⁶ , halogen, -OH, -8H, alkylthio, hydroxyalkyl haloalkyl, haloalkyloxy, aryl or heteroaryl;

K ⁶ independently represents H, alkyl, cycloalkyl, -ΝΗ ₂ , alkylamine, aryl or heteroaryl;

K ⁷ independently represents H, alkyl, cycloalkyl, alkoxy, —OH, —8H, alkylthio, hydroxyalkyl, aryl or heteroaryl;

p is 0 or 1; ς is 0 or 1;

X represents CO or 8O ₂ .

The present invention also relates to the use of a compound of general formula (1) or a pharmaceutically acceptable salt thereof with an acid or base, or pharmaceutically acceptable prodrugs or stereoisomers thereof, as a medicament.

The present invention also relates to a composition comprising a compound of general formula (III), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof and a pharmaceutically acceptable carrier or diluent.

The present invention also relates to the use of a compound of general formula (1), or a pharmaceutically acceptable salt thereof with an acid or base, or pharmaceutically acceptable prodrugs or stereoisomers thereof, for the manufacture of a medicament for the treatment or prevention of a disease characterized by cell hyperproliferation.

The present invention also relates to the use of a composition comprising a compound of general formula (III), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof and a pharmaceutically acceptable carrier or diluent for the manufacture of a medicament for the treatment or prevention of a disease characterized hyperproliferation of cells.

In a preferred embodiment, the disease characterized by hyperproliferation of the cells is selected from the group consisting of psoriasis, atopic dermatitis, alopecia areata, total alopecia, alopecia subtosis, universal alopecia, diffuse alopecia, lupus erythematosus, lichen planus, dermatomyositis, colorectal dermatomyositis, and atopic dermatomyositis, scleroderma, ordinary psoriasis, psoriasis of the scalp, drop-shaped psoriasis, psoriasis of skin folds, marginal alopecia areata, androgenic alopecia, and allergic contact eczema, irritating contact eczema, contact eczema, pemphigus vulgaris, leaf pemphigus, vegetative pemphigus, scarring pemphigoid mucous membranes, bullous pemphigoid, pemphigoid mucous membranes, dermatitis, herpetiformis dermatitis lymphoma, lymphatitis dermatitis, lymphoma dermatitis, lymphoma dermatitis, lymphoma dermatitis, lymphoma dermatitis, lymphoma dermatitis, lymphoma dermatitis, lymphoma dermatitis, lymphoma dermatitis, lymphoma dermatitis, lymphoma dermatitis, lymphoma dermatitis, dermatitis lymphoma limited chronic prurigo, nodular prurigo, acute prurigo, linear 1dA-dependent dermatosis, mild polymorphic dermatosis, solar er topics, sclerotrophic lichen, skin exanthema, drug exanthema, chronic progressive purpura, dyshidra eczema, eczema, fixed drug exanthema, photoallergic skin reaction, lichen lichen, perioral dermatitis and transplant versus host, acne, rosacea, scarring, keloid, vitiligo keratosis, hyperkeratoses such as epidermolytic hyperkeratosis, persistent lenticular hyperkeratosis, hairy keratosis, and ichthyosis.

In yet another preferred embodiment, the disease characterized by cell hyperproliferation is selected from the group consisting of hematologic or solid tumors.

The present invention also relates to the use of a compound of general formula (III), or a pharmaceutically acceptable salt thereof with an acid or base, or pharmaceutically acceptable prodrugs or stereoisomers thereof, for the manufacture of a medicament for the treatment or prevention of a disease caused by ischemia and / or organ reperfusion injury and / or body parts selected from the group consisting of the heart, brain, peripheral limb, kidney, liver, spleen and lung, and / or where endothelial dysfunction is associated with abolevaniyami selected from the group comprising infarctions such as myocardial infarction and critical limb ischemia, and / or

- 4 016300 where endothelial dysfunction is associated with diseases selected from the group including ischemic diseases, myocardial infarction and ischemic diseases of organs.

The present invention also relates to the use of a composition comprising a compound of general formula (CN), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof, and a pharmaceutically acceptable carrier or diluent for the manufacture of a medicament for the treatment or prevention of a disease caused by ischemia and / or reperfusion injury to organs and / or body parts selected from the group including the heart, brain, peripheral limb, kidney, chenium, spleen and lung, and / or where endothelial dysfunction is associated with diseases selected from the group consisting of heart attacks, such as myocardial infarction and critical limb ischemia, and / or where endothelial dysfunction is associated with diseases selected from the group consisting of ischemic diseases, myocardial infarction and ischemic diseases of organs.

The present invention also relates to the use of a compound of general formula (CN), or a pharmaceutically acceptable salt thereof with an acid or base, or pharmaceutically acceptable prodrugs or stereoisomers thereof, for the manufacture of a medicament for the treatment or prevention of neurological diseases or disorders selected from the group consisting of Alzheimer's disease , Parkinson's disease, Creutzfeldt-Jakob disease, dementia with Levi bodies, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, severe pseudo-paralytic myasthenia gravis, Huntington's disease, Down syndrome, nervous deafness and Meniere's disease.

The present invention also relates to the use of a composition comprising a compound of general formula (CN), or a pharmaceutically acceptable salt thereof with an acid or base, or a pharmaceutically acceptable prodrug or stereoisomer thereof and a pharmaceutically acceptable carrier or diluent for the manufacture of a medicament for the treatment or prevention of neurological diseases or disorders selected from the group including Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, dementia with Levi bodies, b amyotrophic fetal sclerosis, stroke, epilepsy, multiple sclerosis, severe pseudoparalytic myasthenia gravis, Huntington's disease, Down's syndrome, deafness and Meniere's disease.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds of general formula (III), or their pharmaceutically acceptable salts with an acid or base, or their pharmaceutically acceptable prodrugs or stereoisomers

where K ¹ represents -C (O) K ^7a , -C (O) SNK ⁷ K ⁸ , -ε (Ο) ΝΚ ⁷ Κ ⁸ , -C (O) OK ⁷ , -K ⁷ C (O) K ⁸ or —C (8) K ^7b ;

K ² represents H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or K ¹ and K ² together with the N atom or the C atom to which they are attached form a 3-8 membered saturated or, at least partially unsaturated monocyclic or polycyclic ring system, where at least one or more than one carbon atom in the ring is a heteroatom selected from O, N and 8, and the ring may be substituted with one or more than one to ⁹ ;

By ^4a represents H, C1 -C6 alkyl, C2 -C6 alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, -C (Ν Κ ⁷⁾ ΝΚ ⁷ K ^8, - (CH 2) _p aryl, - (MF 1 ₂ ) _p \ Ch <Ch < ⁸ , -C (O): ^ ⁷ K ⁸ , -Ν CIFF ⁸ , -ΝΚΥ ^ Κ ⁸ , halogen, heteroaryl or aryl;

K ³ represents H, —C (Ο) NΚ ^a Κ ^b , halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, 8H, ΝΚ ^ Κ ⁵ , ΝΗ ₂ , hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl or haloalkyloxy;

K ⁴ represents H, OH, 8H, ΝΗ2, alkoxy, galogenoalkiloksi, halogen, alkyl, - € (ΝΚ ⁷⁾ ΝΚ ⁷ Κ ^8, - (CH 2) _p aryl, - (€ Η _{2) ρ} ΝΚ ⁷ Κ ⁸ -C (O) \ H <H < ⁸ , -Ν CIFF ⁸ , -ΝΚΥ ^ Κ ⁸ , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

To ⁵ represents halogen, alkyl, - € (ΝΚ ⁷⁾ ΝΚ ⁷ Κ ^8, - (CH _{2) p} aryl, - (€ Η _{2) ρ} ΝΚ ⁷ Κ ^8, -C (O) \ B <H ^<8 , -Ν = € Κ ⁷ Κ ⁸ , -ΝΕΥ ^) ^, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

^And K represents H, halogen, alkyl, - € (ΝΚ ⁷⁾ ΝΚ ⁷ Κ ^8, - (CH _{2) p} aryl, - (ΟΗ _{2) ρ} ΝΚ ⁷ Κ ^8, -C (O) \ B <H < ⁸ ,

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-Y = CK ⁷ K ⁸ , -ΝΚ ⁷ Ο (Θ) Κ ⁸ , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

K ^b independently represents H, —CH — OH, —ZN, —CO2K ⁴ ′, —C (O) K ⁴ ′, -8Ο2ΝΚ ⁴ ', -ΝΚ ⁴ ' Κ ⁵ ', -C (O) XB ⁷ K ⁸ , -ЗО2-alkyl,, -ЗО2К ⁴ ', ЗО3К ⁴ ', -Ы = СК ⁴ 'К ⁵ ', -ЫК ⁴ 'С (О) К ⁴ , -ЫК ^ -CO-haloalkyl, -ΝΟ2, - ΝΚ ⁴ 'ZO2-haloalkyl, -IKAZO ^ alkyl, -I ^ -CO-alkyl, -KHK ⁴ (CH ₂ ) _p heteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -O (CH _{2) R} [O (CH _{2) p] q} OCH _3, - ^ HC ^ ^^ NK enzimidazolil, -ί '(ΝΚ ⁴ ^ M ^' benzothiazolyl, -C (CR ⁴ HC ^4). 'benzoxazolyl, hydroxyalkyl hydroxycycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl;

K ^4, K ^4, K ⁵ 'independently represent H, halogen, alkyl, - ^ ΝΚ ⁷⁾ ΝΚ ^7' Κ ^8, - (CH _{2) p} aryl, haloalkyl, - (CH _{2) p} CF ⁷ TO ⁸ —C (O) MK ⁷ K ⁸ , —Y = SK ⁷ K ⁸ , —MK ⁷ C (O) K ⁸ , cycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

K ⁷ , K ^{7 ′} , K ⁸ independently represent H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino, heteroaryl or aryl;

K ^7a represents cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl or aryl;

K ^7b represents H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl or aryl;

A represents CO or ZO ₂ ;

X represents ΝΚ ² , O or Z;

Ζ represents Ν or SC ² ';

K ² represents H, alkyl, —C (O) LK ⁷ , —C (O) K ^b , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

p is 1-6;

with. | equal to 1-6;

K ⁹ independently represents H, -ΟΝ, -OH, -ZN, alkoxy, alkylthio, -CO2K ⁴ ', -C (O) K ^4a , -C (O) MK ⁷ K ⁸ , -ZO; \ K ⁴ . -YK ⁴ 'K ⁵ ', -ZO2-alkyl, -ZO2K ⁴ ', ZO3K ⁴ ', -Ν == SK ⁴ 'K ⁵ ', -KHK ⁴ 'C (Ο) K ⁴ , -MK ⁴ ' -Haloalkyl , -YO2, -YK ⁴ '-ZO2 haloalkyl -HK ^ LP ^ alkyl -HV ^4' -CO-alkyl, -HK ⁴ '(CH2) rgeteroaril, alkyl, hydroxyalkyl, cycloalkyl, halo, haloalkyl, alkylamino, -O (CH2) p [O (CH2) P] CHOSN3 - ^ ^ X ^ X ^ 'benzimidazolyl, -C (CR ⁴⁾ x R ^4' benzothiazolyl, -Ο (ΝΒ ^'4) XB ^4' benzoxazolyl, hydroxycycloalkyl , hydroxyalkylamino, haloalkyloxy, heterocycloalkyl, - (CH2) _P LK ⁷ SOK ⁸ , aryl or heteroaryl;

where C ₁ -C ₆ -alkyl group, unless otherwise indicated, means a linear or branched C ₁ -C ₆ alkyl, preferably having a linear or branched chain consisting of 1-5 carbon atoms, which may be substituted by one or more than one Deputy K ';

C2-C6 alkenyl group, unless otherwise indicated, means a linear or branched C2-C6 alkenyl, preferably linear or branched chain, consisting of 2-6 carbon atoms, which may be substituted by one or more substituents K ';

an alkyl group, unless otherwise indicated, means a linear or branched C ₁ -C ₆ -alkyl, preferably a linear or branched chain of 1-6 carbon atoms, a linear or branched C2-C6 alkenyl or linear or branched C2-C6- an alkynyl group which may be substituted with one or more substituents K ';

R 'independently represents H, -CO ₂ R'', -SOHNK, -SK''O, -ZO ₂ It.V. -YK''- CO-haloalkyl, -YO _{2, LP-2} -HK -galogenoalkil - YK '' - ZO ₂ -alkyl, -ZO ₂ -alkyl, -YK '' - СО-alkyl, -ΟΝ, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -ZN, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl haloalkyloxy, aryl or heteroaryl;

K ″ independently represents H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;

cycloalkyl group means a non-aromatic ring system containing from 3 to 8 carbon atoms, preferably from 4 to 8 carbon atoms, where one or more carbon atoms in the ring may be substituted by a K 'group, which is as defined above; The C ₃ -C ₈ cycloalkyl radical may be selected from the group consisting of -cyclo-C ₃ H ₅ , -cyclo-C ₄ H ₇ , -cycloC5H9, -cyclo-C6H11, -cyclo-C7H13, -cyclo-C8H15;

heterocycloalkyl group means a non-aromatic ring system containing from 2 to 10 carbon atoms and at least one heteroatom selected from O, Ν and Z, where one or more than one carbon atom in the ring may be substituted by K ', as defined above; preferred heterocycloalkyl groups are morpholin-4-yl, piperazinyl, 1-alkylpiperazin-4-yl, piperidinyl, pyrrolidinyl, azepan-1-yl;

alkoxy group means an O-alkyl group, wherein the alkyl group is as defined above;

the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, tert-butoxy or pentoxy group;

alkylthio group means a 3-alkyl group, wherein the alkyl group is as defined above;

- 6 016300 haloalkyl group means an alkyl group substituted by 1-5 halogen atoms, where the alkyl group is as defined above;

the haloalkyl group is preferably —C (K ¹⁰ ) 3, —SK ¹⁰ (K ¹⁰ ) 2, —SK ¹⁰ (K ¹⁰ ) K ¹⁰ , —C2 (K ¹⁰ ) 5, —CH2-C (K ¹⁰ ) s, -CH2-CK ¹⁰ (K ¹⁰ ') 2, -CH2-CK ¹⁰ (K ¹⁰ ') K ¹⁰ , -Cz (K ¹⁰ ) 7 or -C2H4-C (K ¹⁰ ) s, where K ¹⁰ , K ¹⁰ ' , K ¹⁰ are G, C1, Br or I, preferably G;

hydroxyalkyl group means HO-alkyl group, where the alkyl group is as defined above;

haloalkyloxy group means an alkoxy group substituted with 1-5 halogen atoms, where the alkyl group is as defined above; the haloalkyloxy group is preferably —OC (K ¹⁰ ) s, —OCC ¹⁰ (K ¹⁰ ') 2, —OCC ¹⁰ (K ¹⁰ ') K ¹⁰ , —OC2 (K ¹⁰ ) 3, —OCH2-C (K ¹⁰ ) s , -ОСН2-СК ¹⁰ (К ¹⁰ ') 2, -ОСН2СК ¹⁰ (К ¹⁰ ) К ¹⁰ , -ОС3 (К ¹⁰ ) 7 or -ОС2Н4-С (К ¹⁰ ) 3, where К ¹⁰ , К ¹⁰ , К ¹⁰ represent G, C1, Br or I, preferably G;

hydroxyalkylamino group means a group (11O-a.lki.l) ₂ -Ν- or a group HO-alkyl-ΝΉ-, where the alkyl group is as defined above;

alkylamino group means a H # alkyl or Ν-dialkyl group, wherein the alkyl group is as defined above;

the halogen group is fluoro, chloro, bromo or iodo;

aryl group means an aromatic group containing from 5 to 15 carbon atoms, which may be substituted by one or more substituents K ', where K' is as defined above; the aryl group is preferably a benzyl group, a phenyl group, -ortho-C ₆ H ₄ -K ', meta-C ₆ H ₄ -K', -para-C ₆ H ₄ -K ', 1-naphthyl, 2- naphthyl, 1-anthracenyl or 2-anthracenyl, where K 'is as defined above;

arylamino group means a group H ^ aryl or Ν-diaryl, where the aryl group is as defined above;

heteroaryl group means a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from O, N and 8. This heterocyclic group may be fused to another aromatic ring. For example, this group can be selected from the group of thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2 -yl, oxazol-4-yl, oxazol-5-yl, isoxazol-3-yl, isoxazol-4-yl, isoxazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl , benzoisoxazol-3-yl, benzoisoxazol-4-yl, benzoisoxazol-5-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazole -3-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl , isothiazol-5-yl, benzoisothiazol-3yl, benzoisothiazol-4-yl, benzoisothiazol-5- l, 1,2,5-thiadiazol-3-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5 thiadiazol-4-yl, 4-imidazolyl, benzimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-furanyl, 3furanyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyranyl, 3-pyranyl, 4-pyranyl, 2pyrimidinyl, 4-pyrimidinyl, 5- pyrimidinyl, 6-pyrimidinyl, 2,4-dimethoxy-6-pyrimidinyl, 3pyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, 3-pyrazolyl, 4-pyrazolyl, 1,2,3-triazol-4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,5-triazol-6-yl, 2, 4-dimethoxy-1,3,5triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-3-yl, tetrazolyl, acridyl, fur azan, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolysin, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7indolyl, 1-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindol 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [b] furanyl, benzofurazan, benzothiofurazan, benzotriazol-1-yl, benzotriazole il, benzotriazol-5-yl, benzotriazol-6yl, benzotriazol-7-yl, benzotriazine, benzo [b] thiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazole 6-yl, benzimidazo -7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydrothieno [3,4th] imidazol-2-one, pyrazolo [5,1-c] [1,2,4] triazine, 2, 3-dihydrobenzo [1,4] dioxin-2-yl, 2,3-dihydrobenzo [1,4] dioxin-3-yl, 2,3-dihydrobenzo [1,4] dioxin-5-yl, 2,3 -dihydrobenzo [1,4] -dioxin-6yl, 2,6-dimethoxypyrimidin-3-yl, 2,6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazindene, thiatriazinodiazinopyrazine pyrazolopyrimidine, imidazopyridazine, imidazopyrimidine, midazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4- [1,2,4] triazolo [4,3a] pyridin-3-yl, 1-furo [2,3-c] pyridin-4-yl, 1 furo [2,3-c] pyridin-5-yl, 1-furo [2,3-c] pyridin-3-yl and triazolopyridazine. This heterocyclic group may be substituted with one or more than one substituent K ', where K' is as defined above;

provided that the following compounds are excluded:

about

- 7 016300 where K ¹ independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl;

K ² independently represents -ΝΚ ³ Κ ⁴ ,

K ³ independently represents alkyl, cycloalkyl, alkoxy, alkylamine, —OH, —8H, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

K ⁴ independently represents alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

K ⁵ independently represents H, SOK ⁶ , CO2 ⁶ , 8OK ⁶ , 8O2K ⁶ , 8O3K ⁶ , alkyl, cycloalkyl, alkoxy, -ΝΗ2, alkylamine, -KHK ⁷ SOK ⁶ , halogen, -OH, -8H, alkylthio, hydroxyalkyl haloalkyl, haloalkyloxy, aryl or heteroaryl;

K ⁶ independently represents H, alkyl, cycloalkyl, -ΝΗ ₂ , alkylamine, aryl or heteroaryl;

K ⁷ independently represents H, alkyl, cycloalkyl, alkoxy, —OH, —8H, alkylthio, hydroxyalkyl, aryl or heteroaryl;

p is 0 or 1;

q is 0 or 1;

X represents CO or 8O ₂ .

The present invention also relates to compounds of general formula (III), or their pharmaceutical

g is 0 or 1;

K ^2a independently represents H, OH, 8H, ΝΗ ₂ , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl or heteroaryl;

By ^3a is independently H, OH, 8H, ΝΙΙ2, ^ (ΝΚ ⁷⁾ ΝΚ ⁷ Κ ^8, - (CH 2) _p aryl, - (CH ₂₎ pKK. ⁷ K ⁸ , -C (O) NK ⁷ K ⁸ , -Ν SKA ⁸ , -XK ⁷ C (O) K ⁸ , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl or heteroaryl ;

K ⁴ represents H, halogen, alkyl, ^ (ΝΚ ⁷ ) ΝΚ ⁷ Κ ⁸ , - (CH ₂ ) _p aryl, - (CH ₂ ) _p NK ⁷ K ⁸ , -C (O) KK ⁷ K ⁸ , - H = SK ⁷ K ⁸ , —CHK ⁷ C (O) K ⁸ , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

K ¹ represents —C (O) K ^7a , —C (O) SNK ⁷ K ⁸ , —iOLKS — C (O) OK ⁷ , —K ⁷ C (O) K ^8, or —C (8) K ^7b ;

K ² represents H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or K ¹ and K ² together with the Ν atom or the C atom to which they are attached form a 3-8 membered saturated or, at least partially unsaturated monocyclic or polycyclic ring system, where at least one or more than one carbon atom in the ring is a heteroatom selected from O, Ν and 8, and the ring may be substituted with one or more than one K ⁹ ;

By ^4a represents H, C1 -C6 alkyl, C2 -C6 alkenyl, cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, ^ (ΝΚ ⁷⁾ ΝΚ ⁷ Κ ^8, - (CH 2) _p aryl, - (SNDDKK ⁸ -SDAOK ⁸ , -Ν CAA ⁸ , -HC ⁷ C (O) K ⁸ , halogen, heteroaryl or aryl;

K ³ represents H, —C (O) Hk ^a K ^b , halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, 8H, ChK ⁴ OK ⁵ , ΝΙΙ ₂ , hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl or haloalkyloxy;

K ^a represents H, halogen, alkyl, Υ (ΝΚ ⁷ ) ΝΚ ⁷ Κ ⁸ , - (CH ₂ ) _r aryl, - (CH ^ rNAc ⁸ , -C ^ ICC ⁸ , -I = CK ⁷ K ⁸ , - BK ⁷ C (O) K ⁸ , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

K ^L is independently H, -SY, -OH, -8H, -SO2K ⁴ ', -C (O) K ^{4', 4} -8O2YK ', -ΝΚ ⁴ Κ ^5', -C (O) NK K ^{7 8} , -8О2-alkyl,, -8О2К ⁴ ', 8О3К ⁴ ', -КСАА ', -ΝΚ ^ ΟΚ ⁴ , -NΚ ⁴ ' -CO-haloalkyl, -ΝΘ2, -ΝΚ ⁴ '8О2-haloalkyl, -НК ⁴ -8O2-alkyl, -ΝΚ ⁴ -CO-alkyl, -ΝΚ ⁴ (CH ₂ ) _p heteroaryl, alkyl, cycloalkyl, alkyl

- 8 016300 mino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _h OCH ₃ , -C (NK ⁴ ) MV ⁴ 'benzimidazolyl, -C (NK ⁴ ) NK ⁴ 'benzthiazolyl, -C (XB ⁴ ) XB ⁴ ' benzoxazolyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl;

B ⁴ ', B ^4, B ^5' independently represent H, halogen, alkyl, - ^ ΝΒ ⁷⁾ ΝΒ ⁷ 'Β ^8, - (CH _{2) p} aryl, haloalkyl, - (ΟΗ _{2) Ρ} ΝΒ ⁷ Β ⁸ , —C (O) JB ⁷ B ⁸ , —Y = CB ⁷ B ⁸ —XB ⁷ C (O) B ⁸ , cycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

B ⁷ , B ⁷ , B ⁸ independently represent H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino, heteroaryl or aryl;

B ^7a represents cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl or aryl;

B ⁷ represents H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl or aryl;

X represents ΝΒ ² ', O or 8;

Ζ represents Ν or CB ² ';

B ² represents H, alkyl, —C (O ^ B ⁷ , —C (O) B ^b , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl;

p is 1-6;

with. | equal to 1-6;

B ⁹ independently represents H, -ΟΝ, -OH, -8H, alkoxy, alkylthio, -CO2B ⁴ ', -C (O) B ^4a , -C (O) JB ⁷ B ⁸ , -8Ο2ΝΒ ⁴ ', -ΝΒ ⁴ 'Β ⁵ ', -8О2-alkyl, -8О2В ⁴ ', 8О3В ⁴ ', -Ν СУИ / -ΝΒΑ (Ο) Β ⁴ , -Р1В ⁴ '-Halogenated, -ΝΟ2, -IV ⁴ ' -8О2-halogenated , -XB ⁴ '-8O2-alkyl, -BB ⁴ ' -CO-alkyl, -BB ⁴ '(CH2) _p heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, halogen, haloalkyl, alkylamino, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _h OCH ₃ , -C '(XB' ^| ) XB ' ^| 'benzimidazolyl. -C (XB ⁴ ) XB ⁴ 'benzthiazolyl, -C (XB ⁴ ) XB ⁴ ' benzoxazolyl, hydroxycycloalkyl, hydroxyalkylamino, haloalkyloxy, heterocycloalkyl, - (CDM ^ BAOW ⁸ , aryl or heteroaryl;

where C ₁ -C ₆ -alkyl group, unless otherwise indicated, means a linear or branched C ₁ -C ₆ alkyl, preferably having a linear or branched chain consisting of 1-5 carbon atoms, which may be substituted by one or more than one Deputy B ';

C2-C6 alkenyl group, unless otherwise indicated, means a linear or branched C2-C6 alkenyl, preferably a linear or branched chain, consisting of 2-6 carbon atoms, which may be substituted by one or more than one substituent B ';

an alkyl group, unless otherwise indicated, means a linear or branched C1-C6 alkyl, preferably linear or branched chain, consisting of 1-6 carbon atoms, linear or branched C2-C6 alkenyl or linear or branched C2-C6 alkynyl group which may be substituted by one or more than one substituent B ';

B 'independently represents H, -CO ₂ V, -SOHNI, -SBO, -8Ο ₂ ΝΒ, -ΝΒ''- CO-haloalkyl, -ΝΟ ₂ , -ВВ-8О ₂ -haloalkyl, -ВВ-8О ₂ - alkyl, -8O ₂ -alkyl, -ΝΒ "-CO-alkyl, -ΟΝ, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -8H, alkylthio, hydroxyalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl;

B independently represents H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl;

cycloalkyl group means a non-aromatic ring system containing from 3 to 8 carbon atoms, preferably from 4 to 8 carbon atoms, where one or more carbon atoms in the ring may be substituted by group B ', which is as defined above; The C ₃ C ₈ cycloalkyl residue may be selected from the group consisting of -cyclo-C ₃ H ₅ , -cyclo-C-H-, -cyclo-C ₅ H ₉ , -cyclo-C ₆ H ₁₁ , -cyclo-C ₇ H ₁₃ , -cyclo-C ₈ H ₁₅ ;

heterocycloalkyl group means a non-aromatic ring system containing from 2 to 10 carbon atoms and at least one heteroatom selected from O, Ν and 8, where one or more than one carbon atom in the ring may be substituted by B 'as defined above;

preferred heterocycloalkyl groups are morpholin-4-yl, piperazinyl, 1-alkylpiperazin-4-yl, piperidinyl, pyrrolidinyl, azepan-1-yl;

alkoxy group means an O-alkyl group, wherein the alkyl group is as defined above;

the alkoxy group is preferably a methoxy, ethoxy, isopropoxy, tert-butoxy or pentoxy group;

alkylthio group means an 8-alkyl group, wherein the alkyl group is as defined above;

haloalkyl group means an alkyl group substituted by 1-5 halogen atoms, where the alkyl group is as defined above;

the haloalkyl group is preferably —C (B ¹⁰ ) 3, —CB ¹⁰ (B ^{10 ′} ) 2, —CB ¹⁰ (B ^{10 ′} ) B ¹⁰ , —C2 (B ¹⁰ ) 5, —CH ₂ —C (B ¹⁰ ) 3, -CH2-CB ¹⁰ (B ¹⁰ ') 2, -CH ₂ -CB ¹⁰ (B ¹⁰ ') B ¹⁰ , -C3 (B ¹⁰ ) 7 or -C ₂ H ₄ -C (B ¹⁰ ) ₃ , where B ¹⁰ , B ¹⁰ ', B ¹⁰ are P, C1, Br or I, preferably P;

hydroxyalkyl group means HO-alkyl group, where the alkyl group is such

- 9 016300 as defined above;

haloalkyloxy group means an alkoxy group substituted with 1-5 halogen atoms, where the alkyl group is as defined above; the haloalkyloxy group is preferably —OC (K ¹⁰ ) s, —OCC ¹⁰ (K ¹⁰ ′) 2, —OCC ¹⁰ (K ¹⁰ ′) K ¹⁰ , —OC2 (K ¹⁰ ) 5, —OCH2C (K ¹⁰ ) s, - ОСН2СК ¹⁰ (К ¹⁰ ') 2, -ОСН2СК ¹⁰ (К ¹⁰ ') К ¹⁰ , -ОСз (К ¹⁰ ) 7 or-ОС2Н ₄ С (К ¹⁰ ) s; where K ¹⁰ , K ¹⁰ ', K ¹⁰ are E, C1, Br or I, preferably E;

hydroxyalkylamino group means a group (HO-alkyl) ₂ -Y- or a group HO-alkyl-XH-, where the alkyl group is as defined above;

alkylamino group means a group of HX-alkyl or Ν-dialkyl, where the alkyl group is as defined above;

the halogen group is fluoro, chloro, bromo or iodo;

aryl group means an aromatic group containing from 5 to 15 carbon atoms, which may be substituted by one or more substituents K ', where K' is as defined above; the aryl group is preferably a benzyl group, a phenyl group, -ortho-C ₆ H ₄ -K ', meta-C ₆ H ₄ -K', -para-C ₆ H ₄ -K ', 1-naphthyl, 2- naphthyl, 1-anthracenyl or 2-anthracenyl; where K 'is as defined above;

arylamino group means a group of HX-aryl or Ν-diaryl, where the aryl group is as defined above;

heteroaryl group means a 5- or 6-membered heterocyclic group containing at least one heteroatom selected from O, N and 8. This heterocyclic group may be fused to another aromatic ring. For example, this group can be selected from the group of thiadiazole, thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazol-3-yl, isothiazol-4-yl, isothiazol-5-yl, oxazol-2 -yl, oxazol-4-yl, oxazol-5-yl, isoxazol-z-yl, isoxazol-4-yl, isoxazol-5-yl, benzoxazol-2-yl, benzoxazol-4-yl, benzoxazol-5-yl , benzoisoxazol-z-yl, benzoisoxazol-4-yl, benzoisoxazol-5-yl, 1,2,4-oxadiazol-z-yl, 1,2,4-oxadiazol-5-yl, 1,2,5-oxadiazole -z-yl, 1,2,5-oxadiazol-4-yl, 1,2,4-thiadiazol-z-yl, 1,2,4-thiadiazol-5-yl, isothiazol-z-yl, isothiazol-4-yl , isothiazol-5-yl, benzoisothiazol-zyl, benzoisothiazol-4-yl, benzoisothiaz l-5-yl, 1,2,5-thiadiazol-z-yl, 1-imidazolyl, 2-imidazolyl, 1,2,5 thiadiazol-4-yl, 4-imidazolyl, benzimidazol-4-yl, 1-pyrrolyl, 2-pyrrolyl, z-pyrrolyl, 2-furanyl, zfuranyl, 2-thienyl, z-thienyl, 2-pyridyl, z-pyridyl, 4-pyridyl, 2-pyranyl, z-pyranyl, 4-pyranyl, 2pyrimidinyl, 4- pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2,4-dimethoxy-6-pyrimidinyl, zpyridazinyl, 4-pyridazinyl, 2-pyrazinyl, 1-pyrazolyl, z-pyrazolyl, 4-pyrazolyl, 1,2, z-triazole 4-yl, 1,2,3-triazol-5-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,3,5-triazol-6- il, 2,4-dimethoxy-1,3,5triazol-6-yl, 1H-tetrazol-2-yl, 1H-tetrazol-z-yl, tetrazolyl, acre idyl, furazan, indazolyl, phenazinyl, carbazolyl, phenoxazinyl, indolysin, 2-indolyl, z-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7indolyl, 1-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5- isoindolyl, 6-isoindolyl, 7-isoindolyl, 2-indolinyl, 3-indolinyl, 4-indolinyl, 5-indolinyl, 6-indolinyl, 7-indolinyl, benzo [b] furanyl, benzofurazan, benzothiofurazan, benzotriazole-1-yl, 4-yl, benzotriazol-5-yl, benzotriazol-6yl, benzotriazol-7-yl, benzotriazine, benzo [b] thiophenyl, benzimidazol-2-yl, 1H-benzimidazolyl, benzimidazol-4-yl, benzimidazol-5-yl, benzimidazol-6-yl, be zimidazol-7-yl, benzothiazolyl, quinazolinyl, quinoxazolinyl, cinnoline, quinolinyl, tetrahydroquinolinyl, isoquinolinyl, tetrahydrothieno [3, 4] imidazol-2-one, pyrazolo [5,1-c] [1,2,4] triazine 3-dihydrobenzo [1,4] dioxin-2-yl, 2,3-dihydrobenzo [1,4] dioxin-3-yl, 2,3-dihydrobenzo [1,4] dioxin-5-yl, 2, 3-dihydrobenzo [1,4] dioxin-6yl, 2,6-dimethoxypyrimidin-z-yl, 2,6-dimethoxypyrimidin-4-yl, tetrahydroisoquinolinyl, purine, phthalazine, pteridine, thiatetraazaindene, thiatriazinodiazinopyrazido , pyrazolopyrimidine, imidazopyridazine, imidazo irimidine, imidazopyridine, imidazolotriazine, triazolotriazine, triazolopyridine, triazolopyrazine, triazolopyrimidine, 4- [1,2,4] triazolo [4, per] pyridin-3-yl, 1-furo [2,3-c] pyridin-4-yl 1-furo [2,3-c] pyridin-5-yl, 1-furo [2,3-c] pyridin-3-yl and triazolopyridazine. This heterocyclic group may be substituted with one or more than one substituent K ', where K' is as defined above;

provided that the following compounds are excluded:

where K ¹ independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl;

K ² independently represents —KHK ³ K ⁴ ,

- 10 016300

K ³ independently represents alkyl, cycloalkyl, alkoxy, alkylamine, —OH, —8H, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl,

K ⁴ independently represents alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl;

K ⁵ independently represents H, SOK ⁶ , CO2K ⁶ , 8OK ⁶ , 8O2K ⁶ , 8O3K ⁶ , alkyl, cycloalkyl, alkoxy, -ΝΗ2, alkylamine, -IK ⁷ SOK ⁶ , halogen, -OH, -8H, alkylthio, hydroxyalkyl haloalkyl, haloalkyloxy, aryl or heteroaryl;

K ⁶ independently represents H, alkyl, cycloalkyl, -ΝΗ ₂ , alkylamine, aryl or heteroaryl;

K ⁷ independently represents H, alkyl, cycloalkyl, alkoxy, —OH, —8H, alkylthio, hydroxyalkyl, aryl or heteroaryl;

p is 0 or 1;

c] is 0 or 1;

X represents CO or 8O ₂ .

A preferred embodiment of the invention in compounds of formula (III) are compounds of formula (111a)

where K ³ represents H, methyl, methoxy, CP ₃ or OCP ₃ ;

K ⁴ , K ⁵ , K ^7a are as defined above;

X represents ΝΗ ² , O or 8;

Ζ is as defined above.

In another preferred embodiment of the invention, the compounds of formula (III) are compounds of formula (Sha), where ΙΥ - ΝΙ 1-aryl.

In another preferred embodiment of the invention, the compounds of formula (III) are compounds of formula (SH)

where K ³ represents H, methyl, methoxy, CP ₃ or OCP ₃ ;

K ⁵ is as defined above;

X represents ΝΠ ² , O or 8;

if Ζ represents Ν, then X represents Ν & ² , O or 8, or if Ζ represents SC ² , then X represents O;

Υ 'represents O or Ν & ² , where K ² is as defined above.

In another preferred embodiment of the invention, the compounds of formula (III) are compounds of formula (Cc)

- 11 016300

where K ¹¹ , K ¹² independently represent H, -ΟΝ, -OH, -8H, -CO2K ⁴ , -C (O) K ⁴ , -8Θ2ΝΚ ⁴ , -ΝΚ ⁴ Κ ⁵ , -8O2-alkyl, -8O2K ⁴ ', 8O3K ⁴ ', ^ = SK ⁴ 'K ⁵ ', -ΝΚ ⁴ Ο (Θ) Κ ⁴ , -J ⁴ '-CO-haloalkyl, -ΝΟ2, -ΝΚ ⁴ ' -8Θ2 haloalkyl, -Ν ^ -8О2- alkyl, -ΝΚ ⁴ -CO-alkyl, -ΝΚ ⁴ (CH ₂ ) heteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _h OCH ₃ , -C (\ 1 <') ΝΚ ⁴ benzimidazolyl, -C (\ 1 <') ΝΚ ⁴ benzthiazolyl, - ('(XK' ¹ ) ΝΚ ⁴ benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or ;

K ⁴ , K ⁴ , K ⁵ are as defined above;

K ³ represents H, methyl, methoxy, CT ₃ or OSG ₃ ;

X represents ΝΕ ² , O or 8, K ⁴ is as defined above, K ⁷ and K ⁷ are as defined above,

K ¹¹ , K ¹² independently represent H, -ΟΝ, -OH, -8H, -CO2K ⁴ , -C (O) K ⁴ , -ZO ^ K ⁴ , -J ⁴ K ⁵ , -8O2-alkyl, -8O ₂ TO ⁴ ', 8O3K ^4' - ^ SC ^ K ⁵ ', -NK ^4' C (Ο1) K ⁴ -ZHASO haloalkyl -SH2, -NK ⁴ '-8O2galogenoalkil, -Ν ^ ⁴ -8O ₂ -alkyl, -KhK ^ -CO-alkyl, -Ν ^ (CH ₂ ) _p heteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _h OCH ₃ , -C ^ K ⁴ ) ΝΗ ⁴ benzimidazolyl, -C ^ K ⁴ ) ΝΗ ⁴ benzthiazolyl, -C ^ K ⁴ ) Ν ^ benzoxazolyl hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or heterocycle; and K ^{4 ′} , K ⁴ , K ^{5 ′} are as defined above;

where K ³ represents H, methyl, methoxy, CT ₃ or OSG ₃ ;

X represents YK ² , O or 8;

K ⁴ is as defined above;

K ⁷ and K ^{7 '} are as defined above;

Υ and K ¹¹ , K ¹² are as defined above for formula (111c);

Υ represents O or Ν ^ ² ;

K ² are as defined above.

In yet another more preferred embodiment of the invention, the compounds of formula (III) are compounds of formula (111e)

where K ³ , K ⁴ and K ⁵ are as defined above;

X represents O or 8;

K ¹¹ and K ¹² are as defined above in formula (111c), and if Ζ is Ν, then X is IR ² , O or 8, if Ζ is CH, then X is O.

- 12 016300

In another more preferred embodiment of the invention, the compounds of formula (III) are compounds of formula (III!)

where Ζ represents N or CH;

K ³ represents H, methyl, methoxy, SG ₃ or OSG ₃ ;

X represents ΝΚ ² , O or 8;

K is as defined above;

K ⁷ and K ⁷ are as defined above;

K ² is as defined above;

Υ and K, K, K, K are as defined above in the formula (Sche).

A preferred embodiment of the invention are compounds of formula (Sha)

where K ¹ represents SOK ^7a ;

K ² and K ^3a are H;

A represents ΝΗ;

K ⁷ is as defined above;

Ζ represents Ν;

X represents Νβ ² , O or 8;

K ³ represents H, methyl, ethyl, methoxy, amine, alkylamine, morpholino, метил-methylpiperazine, SG ₃ or OSG ₃ ;

I is 0;

g is 1;

K ^2a represents a possibly substituted aryl, benzyl or heteroaryl.

In yet another preferred embodiment of the invention, compounds of formula (Ίη) are compounds of formula (Sha), wherein K ^7a is optionally substituted aryl, benzyl or heteroaryl.

In yet another preferred embodiment of the invention, the compounds of formula (III) are compounds of formula (III)

where K ^3a represents H; A represents ΝΗ;

X represents Νβ ² , O or 8;

Υ 'represents O or ΝΗ ² ;

K ^{2 ′} is as defined above;

K ³ represents H, methyl, ethyl, methoxy, amine, alkylamine, morpholino, метил-methylpiperazine, SG ₃ or OSG ₃ ;

I is 0;

- 13 016300 g is 1;

K ^2a represents a possibly substituted aryl, benzyl or heteroaryl.

In yet another more preferred embodiment of the invention, compounds of formula (Ιη) are compounds of formula (Sche)

where K ^3a represents H;

A represents ΝΗ;

X represents NK ² , O or 8;

K ¹¹ and K ¹² independently represent H, -CH, -OH, -8H, -CO2K ⁴ , -C (O) K ⁴ , -8O2NA ⁴ , -NK ⁴ K ⁵ , -8O2-alkyl, -8O2K ⁴ ' , 8O3K ⁴ ', -H = SK ⁴ ' K ⁵ ', -NK ⁴ ' C (O) K ⁴ , -NK ⁴ '-CO-haloalkyl, -NO2, -NK ⁴ ' -8O2 haloalkyl, -NC ⁴ -8O2 -alkyl, -NK ⁴ -CO-alkyl, -NK ⁴ (CH ₂ ) heteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, -O (CH ₂ ) _p [O (CH ₂ ) _p ] _h OCH ₃ , - C (NK ⁴ ) NK ⁴ benzimidazolyl, -C (NK ⁴ ) NK ⁴ benzthiazolyl, -C (NK ⁴ ) NK ⁴ benzoxazolyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, halogen, haloalkyl, haloalkyloxy, aryl, arylalkyl or heterocycle;

K ⁴ , K ⁴ , K ⁵ are as defined above;

K ² is as defined above;

K ³ represents H, methyl, ethyl, methoxy, amine, alkylamine, morpholino, N-methylpiperazine, CE ₃ or OSE ₃ ;

I is 0; g is 1;

K ^2a represents a possibly substituted aryl, benzyl or heteroaryl.

In addition, the present invention provides methods for producing a compound of the invention.

The compounds of the invention can be prepared in various ways.

Piperidin-4-yl-thiazole-4-carboxamide can be prepared by various methods described in the literature. One such example is the oxidation of the corresponding 2,5-dihydrothiazoles, as described in Hoybn-eu1, 2002, 730. Dihydrothiazoles can also be synthesized by the methods described in the same reference, or as described in Uoi, 8., Kagau1, N. , Ke11u, .1. \\ '. Up \ y. SEES. 2003, 115, 87 or in KaPizka, A.K., Ca1, S., 8i / ik1, K., 8shd11, 8.K. I. Ogd. SEES. 2004, 69, 811-814, and in the references mentioned in both articles. Alternative methods are described in UAZISŠka 8. e1. a1. Not! Hisosus1ez, νοί. 57, But. 5, 2002.

Compounds of formula (II), (1c) and (III), bearing an additional substituent on the heterocycle, can be prepared by various methods described in Ogdats 8UnChez, Co11. νο1. 9, p. 155; and νο1. 74, p. 229; I. Ogd. CEES., 1975, νο1. 40, But. 10, p. 1521, I. At. Sows. 8os. 96: 19 / 8er! ExBb 18, 1974; I. Ogd. SEet., 1990, 55, 4484-4487; Sentence Vepsl, 1968, 101 (1), 302-307; AdNsi11iga1 Syet181gu apd Vyu esEpo1odu, 2002, 45 (1), p. 37-42.

One of the possibilities for the synthesis of compounds of formula (III), substituted with benzimidazole, is described in 8Sez18, 2006, 4, 597-602.

One of the possibilities for the synthesis of compounds of formula (Sha, c and Na, b) (see Scheme 1) includes the step of reacting a compound of formula (V) with a compound of formula (VI) under classical amide coupling reaction conditions, such as, for example, HBT (O -benzotriazole-H, H, H ', H'-tetramethyluronium hexafluorophosphate), 1Pg ₂ HE1, ΏΜΕ (dimethylformamide), from 0 ° C to room temperature (rt) to give intermediate (VII). Another alternative for this step may be reaction (V) with the corresponding acid chloride (VI) to give (VII). In a second step, compound (VII) is saponified with a solution of 1 M NaOH to give the expected acid (VIII) in almost quantitative yield. This step can also be carried out under acidic conditions. Finally, another stage of the combination of amides (with primary or secondary amines), which is identical to stage 1 described above, completes the synthesis of compounds of the type (Sha, c and Na, and b).

- 14 016300

Scheme 1

Synthesis of derivatives of type (Sha, c) and (Na, b).

(V) (VI) OS)

Compounds having the structure (SH, b, e, ί) and (Hc, b) can be synthesized in accordance with the method shown in Scheme 2. Here, the heterocycle (IX) is reacted with a bromine-containing compound (X) via a nucleophilic substitution reaction to obtain a bicyclic ester (XI), which is then saponified under standard and well-known conditions to acid (XII), completing the synthesis with another stage of the combination described above in scheme 1.

Scheme 2

Synthesis of derivatives of the type (W, b, e, ί) and (Hc, b), where Ζ = Ν.

If Ζ = € .'Η, then the structures (Hb, b, e, ί) and (Hc, b) of typical compounds can be easily synthesized according to the protocol presented in Scheme 3, where the heterocycle (XIII) is converted to the compound ( XV) at the stage of cyclocondensation. After saponification, compound (XVI) is combined with an amine to give the desired product (SH, b, e, ί) or (Hc, b).

- 15 016300

Scheme 3

Synthesis of derivatives of type (III, 6, e, ί) and (He, 6), where Ζ = ΌΗ.

For compounds of the invention, the term stereoisomer above means cis / trans or Ε / Ζ isomerism. More specifically, the possible double bond (s) represented in the various substituents of the compounds of the present invention may have an E or Ζ configuration. These pure or unrefined geometric isomers, alone or as a mixture, form an integral part of the compounds of the invention. The term stereoisomer also includes all isomeric forms, alone or in the form of a mixture, resulting from the presence of one or more axes and / or centers of symmetry in the molecules and leading to the rotation of a beam of polarized light. More specifically, it includes enantiomers and diastereoisomers in pure form or as a mixture.

The compounds of the invention may form salts with inorganic or organic acids or bases. Examples of pharmaceutically acceptable salts include, without limitation, non-toxic inorganic or organic salts, such as acetate derived from acetic acid; aconitate derived from aconitic acid; ascorbate derived from ascorbic acid; benzoate derived from benzoic acid; cinnamate derived from cinnamic acid; citrate derived from citric acid; an embonate derived from embonic acid; enanthate derived from heptanoic acid; formate derived from formic acid; fumarate derived from fumaric acid; glutamate derived from glutamic acid; glycolate derived from glycolic acid; chloride obtained from hydrochloric acid; hydrobromide derived from hydrobromic acid; lactate derived from lactic acid; maleate derived from maleic acid; malonate derived from malonic acid; mandelate derived from mandelic acid; methanesulfonate derived from methanesulfonic acid; naphthalene-2-sulfonate obtained from naphthalene-2-sulfonic acid; nitrate derived from nitric acid; perchlorate derived from perchloric acid; phosphate derived from phosphoric acid; phthalate derived from phthalic acid; salicylate derived from salicylic acid; sorbate derived from sorbic acid; stearate derived from stearic acid; succinate derived from succinic acid; sulfate derived from sulfuric acid; tartrate derived from tartaric acid; toluene-para-sulfate obtained from para-toluenesulfonic acid and others. Such salts can be prepared by methods known to those skilled in the art and described in the prior art.

Other salts, such as oxalate derived from oxalic acid, which is not pharmaceutically acceptable, may be suitable as intermediates for the preparation of the compounds of the invention or their pharmaceutically acceptable salt or pharmaceutically acceptable prodrugs or stereoisomers thereof.

The invention encompasses the aforementioned pharmaceutically acceptable salts, as well as salts, which make it possible to appropriately separate or crystallize compounds of formula (1a), (1b), (1c), (II) or (III), such as salts prepared with chiral amines.

The compounds of the invention above also include prodrugs of these compounds.

As used herein, the term prodrug refers to compounds that, when administered to a patient, are not pharmaceutically active (prodrugs) themselves, but which are chemically

- 16 016300 and / or are biologically converted into their pharmaceutically active form (compounds of the invention) ίη νίνο, i.e. in a subject to whom the compound is administered.

The compounds of the invention and the drugs prepared from them are generally suitable for the treatment of cell proliferation disorders, for the treatment or prophylaxis of immunological diseases and conditions (such as, for example, inflammatory diseases, neuroimmunological diseases, autoimmune diseases or others). The compounds of the present invention are useful for the treatment of diseases caused by malignant cell proliferation, such as all forms of solid tumors, leukemia and lymphoma. Thus, the compounds of the invention and the drugs prepared from them are generally useful for regulating cell activation, cell proliferation, cell survival, cell differentiation, cell cycle, cell maturation and cell death, or for inducing systemic changes in metabolism, such as changes in sugar lipid or protein metabolism. They can also be used to maintain the formation of a cell population, including the growth and generation of blood cells (hematopoietic effect) after depletion or destruction of cells caused, for example, by toxic substances, radiation, immunotherapy, growth defects, malnutrition, malabsorption, immune regulation, anemia, etc., or to provide therapeutic control over the reproduction and destruction of tissues and therapeutic modification of the maintenance of cells and tissues, as well as homeostasis of blood cells.

These diseases and conditions include, but are not limited to, cancer, such as blood cancer (e.g., leukemia, lymphoma, myeloma) or solid tumors (e.g., cancer of the breast, prostate, liver, bladder, lung, esophagus, stomach, colorectal, genitourinary, gastrointestinal tract, skin, pancreas, brain, uterus, colon, head and neck, cervix and ovaries, melanoma, astrocytoma, small cell lung cancer, glioma, basal cell and squamous cell carcinoma, sarcomas, such sarcoma Sarcoma and osteosarcoma), or the compounds can be used for treating diseases which are treated or alleviated by the inhibition of one or more kinases and / or phosphatases.

It is believed that the treatment in accordance with the present invention means the complete or partial cure of the disease, or the alleviation or termination of the development of the disease.

Thus, in one embodiment, the invention relates to the use of compounds of the invention or their pharmaceutically acceptable salts or pharmaceutically acceptable prodrugs or stereoisomers, if desired, with appropriate adjuvants and additives for the preparation of a medicament for the treatment or prevention of a disease characterized by hyperproliferation of keratinocytes and / or T cells, in particular inflammatory and immune disorders, preferably selected from the group consisting of situ Addison's disease, alopecia areata, ankylosing spondylitis, haemolytic anemia (apesh1a yaeto1uBsa), pernicious anemia (apet1a regshsyuka), aphthae, aphthous stomatitis, arthritis, arteriosclerotic disorders, osteoarthritis, rheumatoid arthritis, disorders of spermatogenesis, bronchial asthma, autoimmune asthma, autoimmune hemolysis, Behcet’s disease, Beck’s disease, inflammatory bowel disease, Burkitt’s lymphoma, Crohn’s disease, choroiditis, ulcerative colitis, celiac disease, cryoglobulinemia, herpetiform dermatitis dermatomyositis, insulin-dependent type I diabetes, juvenile diabetes, idiopathic diabetes insipidus, insulin-dependent diabetes mellitus, autoimmune demyelinating diseases, Dupuytren's contractility, encephalomyelitis, allergic encephalomyelopathic enanthaloma leptomyopathy, endo-anaphylactic leukemia, lymphoma, chronic fatigue syndrome, rheumatic fever, glomerulonephritis, Goodpass syndrome hera, Graves' disease, Hammen-Rich's disease (Nagptap-KyuB), Hashimoto's disease, Hashimoto's disease, sudden hearing loss, sensory-neuronal hearing loss, chronic hepatitis, Hodgkin's disease, paroxysmal hemoglobinuria, hypogonadism, regional ileitis, iritis, leukopenia, disseminated lupus erythematosus, systemic lupus erythematosus, cutaneous lupus erythematosus, malignant lymphogranuloma, infectious mononucleosis, severe pseudoparalytic myasthenia gravis, transverse myelitis, primary idiopathic myxedema, n phrosis, sympathetic ophthalmia, granulomatous orchitis, pancreatitis, pemphigus, vulgar pemphigus, nodosa polyarteritis, primary chronic polyarthritis, polymyositis, acute polyradiculoneuritis, psoriasis, purpura, gangrenous pyoderma, subacute atherosclerosis, thyroid sclerosis, thyroid syndrome, thyroid syndrome, thyroid syndrome , scleroderma, multiple sclerosis, multiple sclerosis, acquired atrophy of the spleen, infertility due to the presence of antisperm antibodies, thrombocytopenia, idiopathic thrombocytopenic purpura, thymoma, acute anterior uveitis, vitiligo, AIDS, HIV (human immunodeficiency virus), 8CGO (severe combined immunodeficiency) and diseases associated with Epstein-Barr virus, such as Sjogren's syndrome, B-cell lymphoma with viruses (AIDS or EVU (Epstein-Barr virus)), parasitic diseases such as leishmaniasis; and disease conditions associated with a weakened immune system, such as viral infections after allotransplantation, AIDS, cancer,

- 17 016300 chronic active hepatitis, diabetes, toxic shock syndrome and food poisoning.

The invention further relates to a method for treating or preventing diseases, comprising administering an effective amount of the compounds of the invention, or their pharmaceutically acceptable salts, or pharmaceutically acceptable prodrugs, or their stereoisomers.

The invention also provides a pharmaceutical composition comprising a compound of the invention in free form or in the form of pharmaceutically acceptable salts and pharmaceutically acceptable prodrugs together with a pharmaceutically acceptable diluent or carrier.

In a preferred embodiment, the invention relates to the use of the compounds of the invention or their pharmaceutically acceptable salts or pharmaceutically acceptable prodrugs or their stereoisomers, if desired, with suitable adjuvants and additives for the preparation of a medicament for the treatment or prevention of skin diseases in which T cells play a role ; particularly preferred when skin diseases are selected from the group consisting of psoriasis, atopic dermatitis, alopecia areata, total alopecia, alopecia areata, universal alopecia, diffuse alopecia, lupus erythematosus, lichen planus, skin dermatomyositis, atopic eczema, annular scleroderma, common psoriasis, psoriasis of the scalp, teardrop-shaped psoriasis, psoriasis of skin folds, marginal alopecia areata, androgenetic alopecia, allergic contact eczema, contact eczema, contact eczema, pemphigus vulgaris, leaf pemphigus, vegetative pemphigus, scarring pemphigoid mucous membranes, bullous pemphigoid pemphigoid, mucous pemphigoid, dermatitis, herpetiformis dermatitis, urticaria neuritis, chronic pyorrhea, necrhoida, necrobiculitis, knotty prurigo, acute prurigo, linear ^ L-dependent dermatosis, mild polymorphic dermatosis, solar erythema, scleroatrophic lichen, exan emy skin, drug exanthema, purpura, chronic progressive, disgidraticheskoy eczema, eczema, fixed drug exanthema, photoallergic skin reaction, lichen simplex, perioral dermatitis, and graft versus host disease, acne, rosacea, scarring, keloids and vitiligo.

In addition, the compounds of the present invention can be used to treat diseases caused by ischemia and / or reperfusion damage to organs and / or body parts selected from the group consisting of heart, brain, peripheral limbs, kidney, liver, spleen and lungs and / or where endothelial dysfunction is associated with diseases selected from the group consisting of heart attacks, such as myocardial infarction and critical limb ischemia, and / or where endothelial dysfunction is associated with a disease s selected from the group consisting of ischemic diseases such as peripheral arterial occlusive disease, such as critical leg ischemia, myocardial infarction and ischemic diseases of organs such as kidney, spleen, brain and lung.

The compounds of this invention can be used for the prevention and treatment of neurological diseases or disorders (diseases or disorders associated with the brain and nervous system), including, but not limited to, Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, body dementia Levy, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, severe pseudoparalytic myasthenia gravis, Huntington's disease, Down's syndrome, deafness and Meniere's disease. Other neurological diseases and disorders will be apparent to those skilled in the art and are encompassed by this definition as used in this invention.

The compounds of the present invention, in addition, can be used for diseases that are caused by protozoan invasion in humans and animals. Such protogenic pathogens for animals and humans are preferably intracellular active parasites of the type Lruotrhexa or 8agsota 5doryoga, especially Tguraiozota, Iaztosha, Leitasha, Baiszla and TBeIe, Stur! 8astosu5Yba, Ltoyaa, SossSha and Tpsyotopa Sha. These active substances or the corresponding drugs are particularly suitable for the treatment of tropical malaria caused by Iaztobsthalis tratum, three-day malaria caused by Iaztobsthalpis or Iaztobsthas uiae, and for the treatment of four-day malaria caused by Iaztobsthalitas. They are also suitable for the treatment of toxoplasmosis caused by Toxophoria dopbi, coccidiosis caused by, for example, Eosroptum ulcera, intestinal sarcosporidiosis caused by Apococcus spermisum, dysentery caused by Ecococcus pylori, cryptosporidiosis of the disease, caused by Chromatosis disease Bruising, bruising, or bruising, cutaneous and visceral, as well as other forms of leishmaniasis. They are also suitable for treating animals infected with pathogenic protozoa, such as TNePepa ratua: a pathogen that causes theileriosis in cattle; Turapozota sopdo1epze sopdo1epze or Turapozota utuah utuah, Tturaiozota Ltis1 bisexual pathogens that cause Nagan's disease in cattle in Africa; Tturaiozot btice1 euapzg pathogen causing trypanosomiasis; Vaeya Ydetpa: a pathogen that causes Texas fever in cattle and buffalo; Vaeca bogey: a pathogen that causes babesiosis in European cattle, as well as babesiosis in dogs, cats and sheep; 8atsosu 5Y8 otuapy and oyeyez: pathogens that cause sarcocystosis in sheep,

- 18 016300 cattle and pigs; Sgur! Okrogt61a: a pathogen that causes cryptosporidiosis in cattle and birds; E1tegt and 1cocrog species: pathogens causing coccidiosis in rabbits, cattle, sheep, goats, pigs and birds, especially chickens and turkeys. The use of the compounds of the present invention is preferred, in particular, for the treatment of coccidiosis or malaria infections, or for the preparation of a medicament or feed product for the treatment of these diseases. This treatment may be prophylactic or therapeutic. In the treatment of malaria, the compounds of the present invention can be combined with other antimalarial agents.

The compounds of the present invention, in addition, can be used for the prevention and / or treatment of infectious diseases caused, inter alia, by bacteria and viruses, including opportunistic infections in mammals, including humans. The method comprises administering to the mammal at least one compound of the invention and / or its pharmaceutically acceptable salts in an amount effective to prevent and / or treat said infectious disease and / or opportunistic infection.

Infectious diseases can be selected from the group of AIDS, a disease caused by alveolar echinococcus (ANI, echinococcosis), and amoebiasis (infection caused by E. coli erythrocytes). angiostrongilidosis, anisakiasis, anthrax, babesiosis (infection caused by BaBeck1a), balantid infection (balantidiasis), baylisascaridosis (raccoon ascaris), bilgarciosis (schistosomiasis, bacillus fibrosis, bacillosis, bacillus arthritis, B8E (bovine spongiform encephalopathy), candidiasis, capillariosis (SarShapa infection), SB8 (chronic fatigue syndrome), Chagas disease (South American trypanosomiasis), chickenpox (chickenpox virus, infection caused by syphilis eu, chronic fatigue syndrome, CHF (Creutzfeldt-Jakob disease), clonorchisis (infection caused by S1pogsYk), Sb (Ci! apeoic Lagua M1dgapk, hookworm infection), coccidoidomycosis, conjunctivitis, coxocystic A16 virus, bladder disease, infection caused by Sgur! okroght 6pcs (cryptosporidiosis), Cxex toxic (carrier of West Nile virus), CgCapeoic lagua M1dgapc (CM), cyclosporiasis (infection caused by Cuciocorogia), cysticercosis (neurocysticercosis, cysticerciosis, cirrhosis) caused by I1ru116 t (helminth carried by fleas of dogs and cats), hemorrhagic fever caused by Ebola virus, echinococcosis (infection caused by alveolar echinococcus), encephalitis, infection caused by Ecotoxicum infection, infection caused by infection, infection, ANOTHER 1NK1O1UISA (amoebiasis), infection caused by EIOTOI po1esk1, enterobiasis (infection caused by pinworms), enterovirus infection (not poliovirus), infection caused by Epstein-Barr virus; Exxepsoy soy infection; foodborne infection; foot and mouth disease (£ oo! -ap6-shoy! y Shkeake), fungal dermatitis, gastroenteritis, a disease caused by group A streptococcus, a disease caused by group B streptococcus; diseases caused by staphylococcal infections (8! aryu1ossoss aigeyik and other types of 8! aryu1ossossik); diseases caused by infections of Rkeybotopac aegidshock and other types of Rkeibotopac; Vshkyo 16epa seraaa infection; Hansen's disease (leprosy), hantavirus pulmonary syndrome, infection with head lice (head lice), infection caused by Neusbac! hematologic disease, Hendra virus infection, hepatitis, herpes zoster (herpes zoster), HIV infection, human ehrlichiosis, human parainfluenza virus infection, flu, isosporosis (1cocroger infection), Lassa fever, leishmaniasis, (kala-azar, infection caused by Le1kitasha), leprosy, lice (wearable (head) lice, head lice, pubic lice), Lyme disease, Marburg hemorrhagic fever, measles, meningitis; mosquito-borne diseases; infection caused by the Muso bac! complex aust (MAS) complex; infection caused by no1; nosocomial infections, non-pathogenic intestinal amoebic infection, onchocerciasis (river blindness), opisthorchiasis (infection caused by Ork! - syncytial virus (CBU), rheumatic fever, RiftWalli fever, river blindness (onchocerciasis), rotavirus infection, roundworm infection, salmonellosis, infection caused by 8a1shope11a Ep! egyg61k, scabies, scabies, ah, sleeping sickness, smallpox, streptococcal infection, teniidosis (Laesh infection), tetanus, toxic shock syndrome, tuberculosis, peptic ulcer disease (peptic ulcer), Rift Valley fever; infection caused by Ulbryu rahayayetouysik; infection caused by Ulbr, l1, s1; s; viral hemorrhagic fever, warts, infectious diseases transmitted through water, infection caused by West Nile virus (West Nile encephalitis), spasmodic cough, yellow fever.

The compounds of the invention and their pharmaceutically acceptable salts can be administered to animals, preferably mammals, and in particular to humans, dogs and chickens as medicaments per se, in mixtures with another medicinal product or in the form of pharmaceutical preparations which are suitable for enteral or parenteral administration and which, being the active component, contain an effective dose of at least one compound of the invention or its

- 19 016300 salt in addition to conventional pharmaceutically harmless excipients and additives. The compounds of the invention can also be administered in the form of their salts, obtained by reacting the corresponding compounds with physiologically acceptable acids and bases.

The preparation of drugs containing compounds of the formula according to the invention, and their use can be carried out in accordance with well-known pharmaceutical methods.

Although the compounds of the invention for use in therapy can be administered in the form of a crude chemical compound, it is preferable to administer the active ingredient, possibly in the form of a physiologically acceptable salt, in the pharmaceutical composition together with one or more than one excipient, excipient, carrier, buffer, diluent and / or other conventional pharmaceutical excipients. Such salts of the compounds may be anhydrous or solvated.

In a preferred embodiment of the present invention, there are provided medicaments comprising the compounds of the invention or their pharmaceutically acceptable salts or pharmaceutically acceptable prodrugs or their stereoisomers together with one or more pharmaceutically acceptable carriers and possibly other therapeutic and / or prophylactic ingredients. The carrier (s) must (s) be acceptable (s) in terms of compatibility with other ingredients of the composition and harmless to their recipient.

The medicament of the invention may be a medicament suitable for oral, rectal, bronchial, nasal, local, buccal, sublingual, transdermal, vaginal or parenteral (including skin, subcutaneous, intramuscular, intraperitoneal, intravenous, intraarterial, intracerebral, intraocular or intraocular injections ) administration, or in a form suitable for administration by inhalation or insufflation, including the administration of powders and liquid aerosol, or by System with sustained release. Suitable examples of sustained release systems include semipermeable matrices of solid hydrophobic polymers containing a compound of the invention, said matrices being in the form of shaped articles, for example, films or microcapsules.

Thus, the compounds of the invention, together with the usual excipient, carrier or diluent, can be prepared in the form of a medicament and its unit dosage forms. Such forms include solid forms, in particular tablets, filled capsules, powder and granular forms, and liquids, in particular aqueous and anhydrous solutions, suspensions, emulsions, elixirs and capsules filled with the same contents for oral administration, suppositories for rectal administration and sterile injectable solutions for parenteral administration. Such drugs and its unit dosage forms may contain standard ingredients in conventional proportions with or without additional active compounds or active ingredients, and such unit dosage forms may contain any suitable effective amount of the active ingredient according to the intended daily dosage range used.

The compound used in accordance with the invention may be administered in various oral and parenteral unit dosage forms. It will be apparent to those skilled in the art that the following dosage forms may contain, as an active component, any compound of the invention or a pharmaceutically acceptable salt thereof or a stereoisomer thereof.

For the preparation of a medicament from the compounds of the invention, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dragees, capsules, sachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that can also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or encapsulating material.

In powders, the carrier is a finely divided solid in admixture with the finely divided active component. In tablets, the active component is mixed with a carrier having the necessary binding ability, in appropriate proportions and compressed in the desired shape and size. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, cocoa butter and the like. The term “preparation” is intended to include the preparation of an active compound with encapsulating material as a capsule-forming carrier in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it. Similarly, sachets and tortillas are included. Tablets, powders, capsules, granules, sachets and lozenges can be used in solid form suitable for oral administration.

To prepare suppositories, a low-melting wax, for example a mixture of fatty acid glyceride or cocoa butter, is first melted, and the active component is homogeneously distributed in it, for example, by mixing. The molten homogeneous mixture is then poured into molds of suitable sizes,

- 20 016300 left to cool and at the same time harden. Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the active ingredient, carriers which are known in the art to be suitable. Liquid formulations include solutions, suspensions, and emulsions, for example, aqueous or aqueous propylene glycol solutions. For example, parenteral injection liquid preparations may be prepared as solutions in an aqueous solution of polyethylene glycol.

The compounds of the present invention, therefore, can be formulated for parenteral administration (for example, by injection, for example, a bolus injection or continuous infusion) and can be presented in unit dosage form in ampoules, prefilled syringes, small volume infusions, or in multi-dose containers with added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain drug agents, such as suspending agents, stabilizers and / or dispersants. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of a sterile solid or by lyophilization from solution, for reconstitution with a suitable vehicle, for example sterile pyrogen-free water, before use.

Aqueous solutions suitable for oral administration can be prepared by dissolving the active ingredient in water and adding, if desired, suitable colorants, flavoring agents, stabilizers and thickeners. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with a viscous substance such as natural or synthetic resins, polymers, methyl cellulose, sodium carboxymethyl cellulose, or other well-known suspending agents.

Also included are solid form preparations intended to be converted to liquid form preparations for oral administration immediately prior to use. Such liquid forms include solutions, suspensions and emulsions. These preparations may contain, in addition to the active component, colorants, flavoring agents, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

In one embodiment of the present invention, the drug is administered topically or systemically, or through a combination of the two.

In a particularly preferred embodiment of the present invention, the drug is administered topically. This reduces possible side effects, and limits the necessary treatment only to the affected areas.

Preferably, the medicament is in the form of an ointment, gel, patch, emulsion, lotion, foam, cream based on a mixed phase or amphiphilic emulsion system (oil / water-water / mixed oil phase), liposomes, transfersomes, pastes or powders.

Ointments and creams, for example, can be prepared on a water or oil basis with the addition of suitable thickeners and / or gelling agents. Lotions can be prepared on a water or oil basis and usually contain one or more than one emulsifier, stabilizer, dispersant, suspending agent, thickener or coloring agent.

Compositions suitable for topical administration in the oral cavity include lozenges containing a flavoring active agent, usually sucrose, arabian gum or tragacanth; lozenges that contain the active ingredient in an inert basis, such as gelatin and glycerin or sucrose and gum arabic; and mouthwashes that contain the active ingredient in a suitable liquid carrier.

Solutions and suspensions are administered directly into the nasal cavity using conventional means, for example, using a dropper bottle, pipette or spray. Compositions can be offered in single dose or multi-dose form. In the latter case of the use of a dropper bottle or pipette, a suitable predetermined volume of solution or suspension is administered to the patient. In the case of a spray, the process is carried out, for example, using a metering spray.

The administration to the respiratory tract can also be carried out using an aerosol preparation in which the active ingredient is in a sealed package under pressure with a suitable propellant such as chlorofluorocarbon (CEC), for example dichlorodifluoromethane, trichlorofluoromethane or dichlorotetrafluoroethane, carbon dioxide or other suitable gas. For convenience, the aerosol may also contain a surfactant, such as lecithin. The dose of the drug can be controlled using a measuring valve.

Alternatively, the active ingredients may be provided in the form of a dry powder, for example, a powder mixture of the compound in a suitable powder base, such as lactose, starch, starch derivatives, such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PPP). The carrier powder usually forms a gel in the nasal cavity. The powder composition may be presented in unit dosage form, for example, in capsules or cartridges, for example, from gelatin, or in blister packs, from which the powder can be administered via an inhaler.

In compositions intended for administration to the respiratory tract, including compositions for

21 016300 of transnasal administration, the compound usually has a small particle size, for example of the order of 5 microns or less. Such a particle size can be obtained by methods known in the art, for example by micronization.

If desired, compositions adapted for sustained release of the active ingredient may be used.

The pharmaceutical preparations are preferably presented in unit dosage forms. In this form, the preparation is divided into single doses containing suitable amounts of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, for example tablets, capsules and powders in vials or ampoules. In addition, the unit dosage form may be a capsule, tablet, sachet or lozenge, or it may be a suitable amount of any of these forms in a package. Tablets and capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.

Additional information on the methods of preparation and administration of the compositions can be found in the most recent edition of KSTTDUp'h Ryagtaseijs1 8s1spes5 (Maask RyuYppd So. EaLop. Ra.).

The pharmaceutical compositions may also contain two or more compounds of the invention or their pharmacologically acceptable salts, as well as other therapeutically active substances.

Thus, the compounds of the present invention can be used as a separate compound or in combination with other active compounds, for example, with already known drugs for the treatment of the aforementioned diseases, and in the latter case, a favorable additional enhancing effect is noted. Suitable amounts for administration of the drug may vary from 5 to 500 mg.

Pharmaceutical inert inorganic or organic excipients may be used to prepare pharmaceutical preparations. For preparing dragees, tablets, coated tablets and hard gelatine capsules, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used. Excipients for soft gelatin capsules and suppositories are, for example, fats, waxes, semi-solid and liquid polyols, natural or hardened oils, and the like. Suitable excipients for the preparation of solutions and syrups are, for example, water, sucrose, invert sugar, glucose, polyols and the like. Suitable excipients for the preparation of injectable solutions are, for example, water, alcohols, glycerin, polyols or vegetable oils.

The dose can vary within wide limits and should be selected depending on individual conditions in each case. An adequate dosage for the above applications will vary depending on the route of administration, the particular condition being treated, and the desired effect. However, as a rule, satisfactory results are achieved when the dosage is in the range from about 1 to 100 mg / kg of animal body weight, preferably from 1 to 50 mg / kg. In general, a suitable dosage for larger mammals, such as humans, may be in the range of about 10 mg to 3 g / day, given once, in divided doses 2-4 times a day, or in a sustained release form.

Typically, a daily dose of from about 10 to 5000 mg, preferably from 50 to 500 mg per person, is suitable for oral administration. In the case of other forms of administration, the daily dose is in similar ranges. For local delivery, depending on the permeability of the skin, the type and severity of the disease, and depending on the type of preparation and frequency of administration, different concentrations of active compounds in the drug, it may be sufficient to achieve a therapeutic effect when applied topically. Preferably, the concentration of the active compound or its pharmaceutically acceptable salt or physiologically functional derivative or its stereoisomer in the drug of the invention is in the range of 1 μmol / L to 100 mmol / L.

The following examples and drawings are included to demonstrate preferred embodiments of the invention. Specialists in the art should take into account that the methodology disclosed in the following examples is a methodology discovered by the inventors to ensure the good functioning of the invention in practice, and thus are preferred methods for its application. However, in light of the description of the present invention, it will be understood by those skilled in the art that many changes are possible in the specific embodiments that are disclosed without departing from the spirit and scope of the invention, as presented in the attached claims. All references cited are hereby incorporated by reference.

- 22 016300

Examples

Abbreviations: min - minute (s); h - hour (s); c.t. - room temperature; ΐ- - tertiary.

Nuclear Magnetic Resonance Spectra (NMR): Vgikeg Luapse 300 MHz. The spectra were recorded at 300 MHz ( ^! H-NMR), respectively, using the peak of the residual solvent as the internal standard (DMSO (dimethyl sulfoxide) -ph, 5 _N = 2.49; SEZOE, δ _Η = 3.31; СОС1 ₃ , δ _Η = 7.26; SPzSN δ _Η = 1,93; (SPSCHSO, 5 N = 2.05).

Analytical LC / IER-MS (liquid chromatography / electrospray ionization - mass spectrometry): 2 x solvent supply system company \ Wa1eg5 600, loop for samples with a volume of 50 μl. Column: SbotoShB Zreeb VOE BP18e (Megsk, Pagt81ab1), 50x4.6 mm, with a 2 micron pre-filter (Megsk). Eluent A: H ₂ O + 0.1% HCO ₂ N; eluent B: MeSC Gradient: from 5% B to 100% B over 5 min; flow rate: 3 ml / min. \ Wa1eg5 BS'U is a single quadrupole mass spectrometer with an electrospray source. MS method: M88ttrm-8O-800-20V; scanning method of positive / negative ions: t / ζ 80 - 800 for 1 s; capillary: 3.5 kV; cone voltage: 20 V; voltage multiplier: 400 V; probe and desolvation gas temperatures: 120 and 350 ° C, respectively. Absorption detector of the firm

Preparative HPLC (High Performance Liquid Chromatography) -MS: a solvent supply system from \ Wa1eg5 600 with preparative pump heads. Loop for samples with a volume of 2000 or 5000 μl. Column: \ Wa1eg5 X-Tegg BP18, 7 microns, 19x150 mm with a safety cartridge X-Tegg BP18, 7 microns, 19x10 mm; used at a flow rate of 20 ml / min or UMS OEZ-L, 120 A, 40x150 mm with a safety cartridge X-Tegg BP18, 7 μm, 19x10 mm; used at a flow rate of 50 ml / min. Solvent system: MeC ^ - H ₂ O - HCO ₂ H 80: 20: 0.05 (vol: vol: vol). Eluent A: H ₂ O + 0.1% HCO ₂ N; Eluent B: MeC ^ Various linear gradients from 5 to 100% of eluent B, adapted for the sample. Injection volume: 500-2000 μl depending on the sample. Va1eg5 ΖΟ is a single quadrupole mass spectrometer with an electron sputtering source. Scanning method of positive / negative ions: t / ζ 80-800 in 1 s; capillary: 3.5 kV or 3.0 kV; cone voltage: 20 V; voltage multiplier: 400 V; sample and desolvation gas temperatures: 120 and 350 ° C, respectively. Collector of fraction II of the company \\\\\ 5 with mass-triggered selection of fractions. Detector \ Wa1eg5 996 based on a photodiode array.

Synthesis of 4- (methoxymethylcarbamoyl) piperidine-1-carboxylic acid tert-butyl ester.

Piperidin-1,4-dicarboxylic acid mono-tert-butyl ester (1.0 eq., 21.8 mmol) was dissolved under inert conditions in 35 ml of anhydrous Ν, Ν-dimethylformamide. Then, O, No. dimethylhydroxylamine hydrochloride (1.03 eq., 22.5 mmol), benzotriazole-1-ol monohydrate (1.03 eq., 22.5 mmol) and triethylamine (1.5 eq., 32.7 mmol) were added. ) The reaction mixture was cooled to 0 ° С, Ν- (3-dimethylaminopropyl) - \ - ethylcarbodiimide hydrochloride (1.0 eq., 21.8 mmol) was added over 10 min, and the mixture was vigorously stirred at 0 ° С for 1 h and at t within 18 hours

The solvent was removed in vacuo and the residue suspended in 400 ml of ethyl acetate. The organic layer was extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and twice with 100 ml of brine, dried over MgO ₄ and filtered. The solvent was removed and the residue was purified by distillation in 80% yield.

Synthesis of 4-formylpiperidin-1-carboxylic acid tert-butyl ester.

4- (methoxymethylcarbamoyl) piperidine-1-carboxylic acid tert-butyl ester (1.0 eq., 16.4 mmol) was dissolved in 100 ml of dry tetrahydrofuran in an inert atmosphere. This solution was added dropwise over 1 h to a suspension of lithium alanate (3.0 eq., 49.6 mmol) in 70 ml of anhydrous tetrahydrofuran at -50 ° C. During the addition of the mixture, the temperature was maintained at −50 ° C., and then the mixture was allowed to warm to 0 ° C. for 3 hours.

The mixture was cooled to −78 ° C. and carefully quenched with 100 ml of 1 M citric acid. The mixture was heated to r.t. and diluted with 400 ml of ethyl acetate. The phases were separated and the aqueous phase was extracted 3 times with 70 ml of ethyl acetate. The combined organic layers were extracted 3 times with 100 ml of 1 M citric acid, aqueous sodium carbonate and 2 times with 100 ml of brine, dried over MD8O4 and filtered. The solvent was removed and the residue was purified by distillation in 85% yield.

Synthesis of 4- (4-ethoxycarbonyl-4,5-dihydrothiazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester.

4-Formylpiperidin-1-carboxylic acid tert-butyl ester (1.0 eq., 13 mmol) was dissolved under inert conditions in 40 ml of toluene. L cysteine ethyl ester hydrochloride (1.6 eq., 21 mmol) and triethylamine (1.6 eq., 21 mmol) were added to this solution. The mixture was refluxed for 14 hours. The resulting water was removed using a Dean-Stark trap.

The solvent was removed and the residue was dissolved in 100 ml of ethyl acetate. The organic layer was extracted 3 times with 50 ml of 1 M citric acid, aqueous potassium hydrogen carbonate and 2 times with 50 ml of brine, dried over MD8O4 and filtered. The solvent was removed and the residue was purified by silica gel chromatography using a gradient of PE (petroleum ether) / EA (ethyl acetate), 4: 1. Yield: 75%.

- 23 016300

Synthesis of 4- (4-ethoxycarbonylthiazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester. 4- (4-Ethoxycarbonyl-4,5-dihydrothiazol-2-yl) piperidin-1-carboxylic acid tert-butyl ester (1.0 eq., 8.7 mmol) was dissolved in 160 ml of toluene under inert conditions. To this solution was added MnO ₂ (15.0 eq., 130 mmol). The reaction mixture was heated to 70 ° C. with stirring for 5 hours. The mixture was filtered through celite and the filter agent was washed 3 times with 30 ml of toluene and ethyl acetate. The combined organic layers were distilled in vacuo. The residue was purified by silica gel chromatography using an ESM (dichloromethane) / MeOH gradient, 95: 5. Yield: 30%.

C-terminal functionalization.

4- (4-Ethoxycarbonylthiazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (1.0 eq., 2.9 mmol) was dissolved in an inert gas atmosphere in 40 ml of dioxane. With stirring, 1.5 ml of aqueous 2N was added dropwise over 10 minutes. No. OH. After that, the mixture was stirred for 2 hours at rt.

The reaction mixture was neutralized with 2n. HCl and the solvent were evaporated in vacuo. The residue was dissolved in 50 ml of ethyl acetate. The organic layer was extracted 3 times with 10 ml of 1 M citric acid and water, dried over MgSO ₄ and filtered. The solvent was removed and the residue was dried in vacuo. Yield: 95%.

4- (4-Carboxythiazol-2-yl) piperidine-1-carboxylic acid tert-butyl ester (1 eq.) was dissolved under inert conditions in dry dimethylacetamide (0.03 mmol / ml). Arylyl alkylamine (1 equiv.), Diisopropylethylamine (2 equiv.) And O-benzotriazol-1-ylΝ, Ν, Ν ', Ν'-tetramethyluronium hexafluorophosphate (2 equiv.) Were added to this solution. The reaction mixture was stirred for 12 hours at rt.

The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was extracted 3 times with 1 M citric acid, aqueous potassium hydrogen carbonate and 2 times with brine, dried over MgSO ₄ and filtered. The solvent was removed and the residue was purified by silica gel chromatography using an ESM / MeOH gradient of 95: 5. Yield: 40-80%.

Ν-Terminal functionalization.

The Защ-protected substrate was treated under inert conditions with a mixture of 4 M HC1 / dioxane (conc. 0.03 mmol of the substrate in 1 ml HC1 / dioxane) and stirred for 2 hours at rt.

The solvent was removed in vacuo to give the HC1 salt of the free amine without further purification.

The free amino compound (1 equiv.) Was dissolved under inert conditions in dry dimethylacetamide (0.03 mmol / ml). To this solution were added aryl or alkyl carboxylic acid (1 eq.), Diisopropylethylamine (2 eq.) And O-benzotriazol-1-yl-N, N, N ', N'-tetramethyluronium hexafluorophosphate (2 eq.) In this sequence and the reaction mixture was stirred for 12 hours at rt.

The solvent was removed in vacuo and the residue was dissolved in ethyl acetate. The organic layer was extracted 3 times with 1 M citric acid, aqueous potassium hydrogen carbonate and 2 times with brine, dried over MgSO ₄ and filtered.

The solvent was removed in vacuo and the residue was purified by silica gel chromatography using an ESM / MeOH gradient of 95: 5. Yield: 40-80%.

General synthesis of compounds of type (III) and (II).

The synthesis method for compounds of the type (Sha), (Shs), (Pa) and (Pb) 7.3x10 ^-4 mol of the benzoic acid derivative (VI) was dissolved in 5 ml of EME (dimethylformamide) and 1 equiv. Hyunig base, stirring the reaction mixture for several minutes, followed by the addition of 1 equiv. HBT and additional mixing at rt within 2 minutes After this, 1 equiv. 2-aminothiazole-4-carboxylic acid ethyl ester, stirring the mixture overnight at the same temperature. Then, the solvent was removed by filtration, and the residue was redissolved in 5 ml of dioxane and treated with 0.5 ml of a 1 M solution of NO. After completion of the reaction, the pH was reduced to 1-2 with a 1 M HC1 solution and the precipitated product (VII) was filtered and dried in vacuo. In a next step, intermediate (VII) was dissolved in 3 ml of EME and 1 equiv. Hyunig base, stirring the reaction mixture for several minutes, followed by the addition of 1 equiv. NVTI and additional stirring at rt for 2 minutes After this, 1 equiv. amine component by stirring the mixture overnight at the same temperature. Then the solvent was removed by filtration and the crude product was redissolved in 10 ml of ethyl acetate, washed twice with 10 ml of citric acid (1 M solution), 10 ml of sat. solution No. HCO ₃ and 10 ml of water. The organic phase was then evaporated and the residue was dried over MgSO ₄ . The solvent was removed and final purification was performed using preparative HPLC as described above.

As a second variant of the first step, the corresponding acid chloride derivative of compound (VI) can be reacted with 2-amino-thiazole-4-carboxylic acid ethyl ester (1: 1) using 1.1 eq. founding Hyunig.

The method of synthesis of compounds of the type (SH, 6, e, 1) and (Ps, 6).

6.3x10 ^-4 mol of 2-bromo-thiazole-4-carboxylic acid ethyl ester (X) was dissolved in 10 ml of THF (tetrahydrofuran) together with 2.2 eq. the corresponding piperazine (IX), leaving to reflux overnight. After that, the solvent was removed in vacuo and the residue was purified with

- 24 016300 using preparative thin layer chromatography (TLC) (PE / EE, 2/1).

The second and third stage of the interaction was carried out as described above for the method of synthesis of compounds of type (Na) and (Hc).

A method for the synthesis of compounds of the type (B, b, e, £ and He, b), where Ζ = ^, see ΧΟ 2004/058750.

Representative compounds of the present invention include, but are not limited to, the following compounds.

Connection Title Weight LC / (+) - IERMS: Biological activity ¹¹ 74 (7-Fluoro-2,3- dihydrobenzo [1,4] dioxin-5yl) amide 4- {4- [4- (3-trifluoromethylphenyl) piperazine-1carbonyl] thiazol-2-yl} piperidine- 1-carboxylic acid 619 620 [M + H] ⁺ ++ 75 (2,3-dihydrobenzo [1,4] dioxin-6yl) amide 4- {4- [4- (3trifluoromethylphenyl) piperazin-1 carbonyl] thiazol-2-yl} piperidine- 1-carboxylic acid 601 602 [M + H] ⁺ ++ 76 (5-Methyl-2-trifluoromethylfuran-3yl) amide 4- {4- [4- (3trifluoromethylphenyl) piperazin-1 carbonyl] thiazol-2-yl} piperidine- 1-carboxylic acid 615 616 [m + nr ++ 77 (2-Thiophen-2-yl-ethyl) amide 4- {4- [4- (3-trifluoromethylphenyl) piperazin-1-carbonyl] thiazole-2- 577 578 [M + H] ⁺ +++

- 25 016300

78 silt} piperidin-1-carboxylic acid Isopropylamide 4- {4- [4- (3trifluoromethylphenyl) piperazine-1 carbonyl] thiazol-2-yl} piperidine- 1-carboxylic acid 509 510 [M + H] ⁺ + 79 (2-Trifluoromethoxy-phenyl) amide 4- (4- [4- (3-trifluoromethylphenyl) piperazine-1-carbonyl] thiazol-2yl} piperidine-1-carboxylic acid 627 628 [M + H] ⁺ +++ 80 (3-Methoxyphenyl) amide 4- {4- [4- (3trifluoromethylphenyl) piperazine-1 carbonyl] thiazol-2-yl} piperidine- 1-carboxylic acid 573 574 [M + H] ⁺ + 81 (3,4,5-Trimethoxyphenyl) amide 4 {4- [4- (3-trifluoromethylphenyl) piperazin-1-carbonyl] thiazol-2yl} piperidine-1-carboxylic acid 633 634 [M + H] ⁺ ++ 114 4- (4_ {4- [4- (3- T rifluoromethylphenyl) piperazin-1 carbonyl] thiazol-2-yl} piperidine- 1-carbonyl) benzonitrile 568 569 [M + H] ⁺ + 134 Phenylamide 4- {4- [4- (3- Trifluoromethylphenyl) piperazin-1carbonyl] thiazol-2-yl} piperidine- 1-carboxylic acid 543 544 [M + H] ⁺ + 142 (3-Fluorophenyl) amide 4- {4- [4- (3- trifluoromethylphenyl) piperazin-1carbonyl] thiazol-2-yl} piperidine- 1-carboxylic acid 561 562 [M + H] ⁺ ++ 143 (4-Fluorophenyl) amide 4- {4- [4- (3trifluoromethylphenyl) piperazin-1 carbonyl] thiazol-2-yl} piperidin- 1-carboxylic acid 561 562 [M + H] ⁺ +

¹⁾ Biological data refer to the results obtained in the analysis of inflammation using ΝΡ-κΒ.

+ means 50-80% inhibition, ++ means 80-90%, and +++ means 90-100% inhibition.

Examples of representative compounds of the present invention include, but are not limited to, the following compounds.

Connection Title Weight LC / (+) - IERMS: Biological activity ¹ ' 103 2- {5-Methyl-2- [1- (2- trifluoromethoxybenzoyl) piperidin-4-yl] thiazol-4-yl} -1- [4- (3-trifluoromethylphenyl) - piperazin-1-yl] ethanone 640 641 [M + H] ⁺ ++ 128 1- [4- (3-Chlorophenyl) piperazin-1yl] -2- {5-methyl-2- [1 - (2trifluoromethoxybenzoyl) piperidin-4-yl] thiazol-4yl} ethanone 606 607 [M + H] ⁺ +++

¹⁾ Biological data refer to the results obtained in the analysis of inflammation using ΝΡ-κΒ.

+ means 50-80% inhibition, ++ means 80-90%, and +++ means 90-100% inhibition.

- 26 016300

Examples of representative compounds of the present invention include, but are not limited to, the following compounds: ___________________________________________________

Connection Title Weight LC / (+) - IERMS: Biological activity ¹¹ 150 [1 - (5-Chloro-2-methylaminophenyl) - 654 655 ++ 3,4-dihydro-1H-isoquinolin-2-yl] {2- [1 - (2-trifluoromethoxybenzoyl) piperidin-4-yl] thiazol-4yl} methanone [M + H] ⁺ 160 1 - {4- [4- (6,7-Dihydroxy-3,4dihydro-1 H-isoquinoline-2carbonyl) thiazol-2-yl] piperidine- 1-yl} -2- (4-fluorophenyl) ethanone 495 496 [M + H] ⁺ + 161 1 - {4- [4- (6,7-Dimethoxy-3,4dihydro-1 H-isoquinoline-2carbonyl) thiazol-2-yl] piperidine- 1-yl} -2- (4-fluorophenyl) ethanone 523 524 [M + H] ⁺ + 163 1 - {4- [4- (3,4-Di hydro-1Nisoquinoline-2-carbonyl) thiazol-2yl] piperidin-1-yl} -2- (4fluorophenyl) ethanone 463 464 [M + H] ⁺ + 232 1- {4- [4- (6,7-Dimethoxy-3-methyl-3,4- dihydro-1 H-isoquinoline-2carbonyl) thiazol-2-yl] piperidine- 1-yl} -2- (4-fluorophenyl) ethanone 537 538 [M + Hp + 233 1 - {4- [4- (6,7-Dihydroxy-1-methyl- 3,4-dihydro-1 H-isoquinolin-2carbonyl) thiazol-2-yl] piperidine- 1-yl} -2- (4-fluorophenyl) ethanone 509 510 [M + H] ⁺ + 234 1 - {4- [4- (6,7-Dimethoxy-1-methyl-3,4-dihydro-1 H-isoquinoline-2carbonyl) thiazol-2-yl] piperidine- 1-yl} -2- (4-fluorophenyl) ethanone 537 538 [M + H] ⁺ + 235 1- (4- {4- [1- (5-Chloro-2- methylaminophenyl) -3,4-dihydro1H-isoquinoline-2-carbonyl] thiazole- 2-yl} piperidin-1-yl) -2- (4 fluorophenyl) ethanone 602 603 [M + H] ⁺ +

¹⁾ Biological data refer to the results obtained in the analysis of inflammation using ΝΡ-κΒ.

+ means 50-80% inhibition, ++ means 80-90%, and +++ means 90-100% inhibition.

- 27 016300

Examples of representative compounds of the present invention include, but are not limited to, the following compounds. ______________________________________________

Connection Title Weight LC / (+) - IERMS: Biological activity ¹⁾ 3 M- (4- [4- (4-Fluoro-phenyl) piperazine- 1 -carbonyl] thiazol-2-yl} -2 trifluoromethoxybenzamide 494 495 [M + H] ⁺ ++ 5 M- [5- (4-Pyrimidin-2-ylpiperazin-1-carbonyl) thiazol-2yl] -2-trifluoromethoxybenzamide 478 479 [M + H] ⁺ + fifteen 2-Μθτοκομ-Ν- {4- [4- (3- trifluoromethylphenyl) piperazin-1 carbonyl] thiazol-2-yl} benzamide 490 491 [M + H] ⁺ +++ sixteen 3-Fluoro-4-trifluoromethyl-M- (1- (4- (4- (3-trifluoromethylphenyl) piperazin-1-carbonyl] thiazol-2yl} piperidin-4ylmethyl) benzamide 643 644 [M + H] ⁺ ++ 17 3-Cyclopentyl-1CH- (1- (4- (4- (3trifluoromethylphenyl) piperazine-1 carbonyl] thiazol-2-yl} piperidin4ylmethyl) propionamide 577 578 [M + H] ⁺ ++ eighteen 2-T rifluoromethoxy-bC 1 - (4- (4- (3 trifluoromethylphenyl) piperazine-1 carbonyl] thiazol-2-yl} piperidin4-ylmethyl) benzamide 641 642 [M + H] ⁺ ++ nineteen 4-cyano-m- (1 - (4- (4- (3- trifluoromethylphenyl) piperazin-1 - 582 583 [M + H] ⁺ ++

- 28 016300

carbonyl] thiazol-2-yl} piperidin- 4-ylmethyl) benzamide twenty [4- (3-T rifluoromethylphenyl) piperazin-1-yl] - {2- [4- (4trifluoromethylphenyl) piperazin-1 yl] thiazol-4-yl} methanone 569 570 [M + H] ⁺ ++ 21 {2- [4- (4-T rifluoromethoxyphenyl) piperazin-1-yl] thiazol-4-yl} - [4- (3 trifluoromethylphenyl) piperazin-1 yl] methanone 585 586 [M + H] ⁺ + 22 {2- [4- (2-Trifluoromethoxybenzyl) piperazin-1-yl] thiazol-4-yl} - [4- (3 trifluoromethylphenyl) piperazin-1 yl] methanone 599 600 [M + H] ⁺ +++ 23 {2- [4- (4-Bromobenzyl) piperazin-1yl] thiazol-4-yl} - [4- (3trifluoromethylphenyl) piperazin-1 yl] methanone 593 594 [M + H] ⁺ +++ 24 {2- [4- (3-T rifluoromethoxybenzyl) piperazin-1-yl] thiazol-4-yl} - [4- (3 trifluoromethylphenyl) piperazin-1 yl] methanone 599 600 [M + H] ⁺ +++ 32 2-T rifluoromethoxy-1CH- {4- [4- (3trifluoromethylphenyl) piperazine-1 carbonyl] thiazol-2-yl} benzamide 544 545 [M + H] ⁺ +++ 33 3-Cyclopentyl-M- {4- [4- (3trifluoromethylphenyl) piperazine-1 carbonyl] thiazol-2yl} propionamide 480 481 [M + H] ⁺ +++ 34 3-Fluoro-4-trifluoromethyl-M- {4- [4- (3trifluoromethylphenyl) piperazin-1 carbonyl] thiazol-2-yl} benzamide 546 547 [M + H] ⁺ +++

- 29 016300

37 3-Cyclopentyl-1 - (4- {4- [4- (3trifluoromethylphenyl) piperazin-1 carbonyl] thiazol-2-yl} piperazin1-yl) -propan-1-one 549 550 [M + H] ⁺ +++ 38 (2- [4- (2-Methoxybenzoyl) piperazin-1-yl] thiazol-4-yl} - [4- (3 trifluoromethylphenyl) piperazin-1 yl] methanone 559 560 [M + H] ⁺ +++ 39 (2- [4- (2-T rifluoromethoxybenzoyl) piperazin-1-yl] thiazol-4yl} - [4- (3-trifluoromethylphenyl) piperazin-1-yl] methanone 613 614 [M + H] ⁺ +++ 41 Ν- {4- [4- (3,4- Dichlorophenyl) piperazin-1 carbonyl] thiazol-2-yl} -2 trifluoromethoxybenzamide 544 545 [M + H] ⁺ +++ 44 Ν- {4- [4- (2- Methoxyphenyl) piperazin-1 carbonyl] thiazol-2-yl} -2 trifluoromethoxybenzamide 506 507 [M + H] ⁺ ++ 55 1 - (2-T rifluoromethoxyphenyl) -3- {4 [4- (3-trifluoromethylphenyl) piperazin-1-carbonyl] thiazol-2yl} urea 559 560 [M + H] ⁺ +++ 58 M- [4- (4-Benzhydrylpiperazin-1 carbonyl) thiazol-2-yl] -2 trifluoromethoxybenzamide 566 567 [M + H] ⁺ ++ 59 {2- (4- (3,5-Bistrifluoromethylbenzoyl) piperazine- 1-yl] thiazol-4-yl} - [4- (3 trifluoromethylphenyl) piperazin-1 yl] methanone 665 666 [M + H] ⁺ +

- 30 016300

60 {2- [4- (3-Fluoro-4trifluoromethylbenzoyl) piperazine- 1-yl] thiazol-4-yl} - [4- (3 trifluoromethylphenyl) piperazin-1 yl] methanone 615 616 [M + H] ⁺ +++ 61 4- (4- {4- [4- (3-Trifluoromethylphenyl) piperazine-1-carbonyl] thiazole-2yl} piperazine-1-carbonyl) benzonitrile 554 555 [M + H] ⁺ +++ 62 4- (4- {4- [4- (3-Trifluoromethylphenyl) piperazin-1-carbonyl] thiazol-2yl} piperazin-1ylmethyl) benzonitrile 540 541 [M + H] ⁺ +++ 63 4- {4- [4- (3trifluoromethylphenyl) piperazine-1 carbonyl] thiazol-2-yl} piperazine tert-butyl ester 1-carboxylic acid 525 526 [M + H] ⁺ ++ 64 (2-piperazin-1-ylthiazol-4-yl) - [4- (3-trifluoromethylphenyl) piperazin-1-yl] methanone 425 426 [M + H] ⁺ + 65 {2- [4- (2-Methoxyphenyl) piperazine- 1-yl] thiazol-4-yl} - [4- (3- trifluoromethylphenyl) piperazin-1 yl] methanone 531 532 [M + H] ⁺ ++ 66 1- [4- (4- {4- [4- (3- T rifluoromethylphenyl) piperazin-1 carbonyl] thiazol-2-yl} piperazin1-yl) phenyl] ethanone 543 544 [M + H] ⁺ ++ 67 [4- (3-T rifluoromethylphenyl) piperazin-1-yl] - {2- [4- (3trifluoromethylphenyl) piperazin-1 yl] thiazol-4-yl} methanone 569 570 [M + H] ⁺ +

- 31 016300

one hundred

101

102 [2- (4-Phenylpiperazin-1 yl) thiazol-4-yl] - [4- (3trifluoromethylphenyl) piperazin-1 yl] methanone {2- [4- (4-Fluoro-phenyl) piperazin-1yl] thiazol- 4-yl} - [4- (3-trifluoromethyl-phenyl) piperazin-1yl] methanone (4-benzhydrylpiperazin-1-yl) - [2 (4-benzylpiperazin-1-yl) thiazol-4yl] methanone [2- (4- Benzyl piperazin-1 yl) thiazol-4-yl] - [4- (3 trifluoromethylphenyl) piperazin-1 yl] methanone 3-Fluoro-4-trifluoromethyl-1CH- (1- {4- [4 (3-trifluoromethylphenyl) piperazin- 1 -carbonyl] thiazol-2yl} piperidin-4ylmethyl) benzamide

3- Cycopopentyl-M- (1 - {4- [4- (3 trifluoromethylphenyl) piperazine-1 carbonyl] thiazol-2-yl} piperidine-

4-ylmethyl) propionamide 2-Trifluoromethoxy-1 \ 1- (1- {4- [4- (3trifluoromethylphenyl) piperazin-1 carbonyl] thiazol-2-yl} piperidin4-ylmethyl) benzamide

4-cyano-M- (1- {4- [4- (3trifluoromethylphenyl) piperazin-1 carbonyl] thiazol-2-yl} piperidin4-ylmethyl) benzamide

501

519

537

515

642

576

640

581

520 [M + H]

538 [M + H] ⁺

516 [M + H] ⁺

643 [M + H]

577

641 [M + H] ⁺

582 [M + H] ⁺ ++ +++ +++

- 32 016300

241 {2- [1- (2,6-Dimethoxypyrimidin-4- il) piperidin-4-yl] -5methoxyoxazol-4-yl} - [4- (3trifluoromethylphenyl) piperazin-1 yl] methanone 576 577 [M + H] ⁺ ++ 242 {2- [1 - (4,6-Dimethoxy- [1,3,5] triazin-2-yl) piperidin-4yl] -5-methoxyoxazol-4-yl} - [4- (3 trifluoromethylphenyl) piperazin-1yl] methanone 577 578 [M + H] ⁺ ++ 243 {2- [1- (2,6-Dimethoxy-pyrimidin-4yl) piperidin-4-yl] -5 methoxyoxazol-4-yl} - [4- (5 trifluoromethylbenzotriazol-1 yl) piperidin-1-yl] methanone 616 617 [M + H] ⁺ ++ 244 {2- [1- (4,6-Dimethoxy [1,3,5] triazine- 2-yl) piperidin-4-yl] -5 methoxyoxazol-4-yl} - [4- (5 trifluoromethylbenzotriazol-1 yl) piperidin-1-yl] methanone 617 618 [M + H] ⁺ ++ 245 4- (4- {4- [4- (5- Trifluoromethylbenzotriazol-1yl) piperidin-1-carbonyl] thiazol2-yl} piperazin-1ylmethyl) benzonitrile 580 581 [M + H] ⁺ ++ 246 (2-Morpholin-4-yloxazol-4-yl) - [4 (3-trifluoromethylphenyl) piperazin-1-yl] methanone 410 411 [M + H] ⁺ +

¹⁾ Biological data refer to the results obtained in the analysis of inflammation using HP-kV.

+ means 50-80% inhibition, ++ means 80-90%, and +++ means 90-100% inhibition.

- 33 016300

Examples of compounds of formula (III) and (1b) of the present invention include, but are not limited to, the following compounds. ________________________

Connection Title Weight LC / (+) - IERMS: Biological activity ¹ * one (5,6-Dimethyl-1 H-benzimidazole-2yl) amide 2-morpholin-4-ylthiazole 4-carboxylic acid 357 358 [M + H] ⁺ + 2 (1H-Benzimidazol-2-yl) amide 2- [3- (2-trifluoromethoxyphenyl) ureido] thiazole-4-carboxylic acid 462 463 [M + H] ⁺ + 4 (5,6-Dimethyl-1 H-benzimidazole-2yl) amide 2- (2 fluorobenzoylamino) thiazole-4 carboxylic acid 409 410 [M + H] ⁺ + 6 Ν- {4- [Ν ’- (1 H-Benzimidazole-2yl) guanidinocarbonyl] thiazole-2yl} -3,4-difluorobenzamide 441 442 [M + H] ⁺ ++ 7 Ν- {4- [Ν ’- (1 H-Benzimidazole-2yl) guanidinocarbonyl] thiazole-2yl} -4-fluorobenzamide 423 424 [M + H] ⁺ ++ 8 Ν- {4- [Ν ’- (1 H-Benzimidazole-2yl) guanidinocarbonyl] oxazole-2yl} -2-trifluoromethoxybenzamide 473 474 [M + H] ⁺ +++ nine (4-Dimethylamino [1,3,5] triazin-2- il) 2- (2 trifluoromethoxybenzoylamino) thiazole-4-carboxylic acid amide 453 454 [M + H] ⁺ + 10 Ν- {4- [Ν ’- (1 H-Benzimidazole-2yl) guanidinocarbonyl] thiazole-2yl} -4-bromobenzamide 483 484 [M + H] ⁺ ++ eleven Ν- {4- [Ν ’- (1 H-Benzimidazole-2yl) guanidinocarbonyl] thiazole-2- 435 436 [M + H] ⁺ ++

- 34 016300

silt} -2-methoxybenzamide 12 Ν- {4- [Ν ’- (1 H-Benzimidazole-2yl) guanidinocarbonyl] thiazole-2yl} -2-trifluoromethoxybenzamide 489 490 [M + H] ⁺ +++ thirteen N- (1 H-Benzimidazol-2-yl) -1 \ G- {2 [4- (2-trifluoromethoxybenzoyl) piperazin-1-yl] thiazole-4carbonyl} guanidine 558 559 [M + H] ⁺ + 14 N- (1-Benzimidazol-2-yl) -1M ’- [2 (2,3-dihydrobenzo [1,4] dioxin-2yl) thiazole-4-carbonyl] guanidine 420 421 [M + H] ⁺ + 25 (5,6-Dimethyl-1 H-benzimidazole-2yl) amide 2- (2 trifluoromethoxybenzoylamino) thiazole-4-carboxylic acid 475 476 [M + H] ⁺ +++ 26 2- (3-Fluoro-4 trifluoromethylbenzoylamino) oxazole-4-carboxylic acid ethyl ester 536 537 [M + H] ⁺ +++ 27 Ν- {4- [Ν ’- (1 H-Benzimidazole-2yl) guanidinocarbonyl] oxazole-2yl} -3-fluoro-4trifluoromethylbenzamide 475 476 [M + H] ⁺ +++ thirty N- (1 H-Benzimidazol-2-yl) -№- [2 (4-benzyl piperazin-1-yl) thiazole 4-carbonyl] guanidine 460 461 [M + H] ⁺ +++ 31 (1H-Benzimidazol-2-yl) amide 2- (2 trifluoromethoxybenzoylamino) thiazole-4-carboxylic acid 447 448 [M + H] ⁺ +++ 36 N- (1 H-Benzimidazol-2-yl) -M ’- {2 [1 - (2-trifluoromethoxybenzoyl) piperidin-4-yl] thiazole-4carbonyl} guanidine 557 558 [M + H] ⁺ +++

- 35 016300

40 (5,6-Dimethyl-1 H-benzimidazole-2yl) amide 2- (2 trifluoromethoxybenzoylamino) oxazole-4-carboxylic acid 459 460 [M + H] ⁺ +++ 42 [6- (4-Methylpiperazin-1-yl) benzthiazol-2-yl] -amide 2- (2 trifluoromethoxybenzoylamino) thiazole-4-carboxylic acid 562 563 [M + H] ⁺ +++ 43 (5-Nitro-1 H-benzimidazole-2yl) amide of 2- (2 trifluoromethoxybenzoylamino) thiazole-4-carboxylic acid 492 493 [M + H] ⁺ + -H- 45 Ν- {4- [Ν ’- (1 H-benzimidazole-2yl) guanidinocarbonyl] thiazole-2yl} -2-cyclohexylbenzamide 487 488 [M + H] ⁺ +++ 46 (1-Methyl-1 H-benzimidazole-2yl) amide 2- (2 trifluoromethoxybenzoylamino) thiazole-4-carboxylic acid 461 462 [M + H] ⁺ +++ 47 [5- (Propan-1-sulfonyl) -1 Nbenzimidazol-2-yl] amide 2- (2 trifluoromethoxybenzoylamino) thiazole-4-carboxylic acid 553 554 [M + H] ⁺ +++ 49 N- (1 H-Benzimidazol-2-yl) -M ’- (2morpholin-4-ylthiazole-4carbonyl) guanidine 371 372 [M + H] ⁺ +++ 51 Ν- {4- [Ν ’- (1 H-Benzimidazole-2yl) guanidinocarbonyl] thiazole-2yl} -4-trifluoromethylbenzamide 473 474 [M + H] ⁺ +++ 52 [5- (Propan-1-sulfonyl) -1 Nbenzimidazol-2-yl] -amide 2- (1- (2trifluoromethoxybenzoyl) - 621 622 [M + H] ⁺ +++

- 36 016300

53 piperidin-4-yl] thiazole-4carboxylic acid 491 492 [M + H] ⁺ +++ 54 1- {4- [Ν ’- (1 H-Benzimidazole-2yl) guanidinocarbonyl] thiazol-2yl} -3- (2-trifluoromethoxyphenyl) urea 504 505 [M + H] ⁺ +++ 56 Ν- {4- [Ν ’- (1 H-Benzimidazole-2yl) guanidinocarbonyl] thiazole-2yl} -3-fluoro-4trifluoromethylbenzamide 491 492 [M + H] ⁺ +++ 57 Ν- {4- [Ν ’- (1 H-Benzimidazole-2yl) guanidinocarbonyl] thiazole-2yl} -2,6-difluorobenzamide 441 442 [M + H] ⁺ +++ 91 N- (1 H-Benzimidazol-2-yl) -1 \ G- (2morpholin-4-ylthiazol-4carbonyl) guanidine 371 372 [M + H] ⁺ + 250 N- (1 H-Benzimidazol-2-yl) -M ’- {2 [1- (4-cyanobenzyl) piperidin-4yl] thiazole-4-carbonyl} guanidine 484 485 [M + H] ⁺ ++ 251 M-Benzothiazol-2-yl-M ’- {2- [1 - (4 cyanobenzyl) piperidin-4yl] thiazole-4-carbonyl} guanidine 501 502 [M + H] ⁺ ++ 252 N- (1 H-Benzimidazol-2-yl) -M ’- {2 [4- (4-cyanobenzyl) piperazin-1yl] thiazole-4-carbonyl} guanidine 485 485 [M + H] ⁺ +++ 253 Ν- {2- [4- (4- Cyanobenzyl) piperazin-1yl] thiazole-4-carbonyl} -M ’- (4- 466 467 [M + H] ⁺ ++

- 37 016300

methylthiazol-2-yl) guanidine 254 M- (4-Methylthiazol-2-yl) -M ’- (2morpholin-4-ylthiazol-4carbonyl) guanidine 352 353 [M + Hp + 255 N- (1 H-Benzimidazol-2-yl) -Y ’- (2morpholin-4-ylthiazole-4carbonyl) guanidine 371 372 [M + Hp +++ 256 M-Benzothiazol-2-yl-M ’- (2morpholin-4-ylthiazol-4carbonyl) guanidine 388 389 [M + Hp +++ 257 N- (1 H-Benzimidazol-2-yl) -M ’- (2morpholin-4-yloxazole-4carbonyl) guanidine 355 356 [M + Hp ++ 258 M-Benzoxazol-2-yl-M ’- (2morpholin-4-ylthiazol-4carbonyl) guanidine 372 373 [M + Hp ++ 259 1 \ 1- (2-Morpholin-4-ylthiazol-4carbonyl) -M ’- (5-nitrobenzoxazol2-yl) guanidine 417 418 [M + H] ⁺ ++ 260 M- (5-Methylbenzoxazol-2-yl) -1M’- (2-morpholin-4-ylthiazole-4carbonyl) guanidine 386 387 [M + Hp + 261 M- (5-Chlorobenzoxazol-2-yl) -M ’- (2morpholin-4-ylthiazole-4carbonyl) guanidine 406 407 [M + Hp ++ 262 Ν- {2- [1- (4- Cyanobenzyl) piperidin-4yl] thiazole-4-carbonyl} -M ’- (4methylthiazol-2-yl) guanidine 465 466 [M + Hp + 263 M- (6-Chloro-1H-benzimidazol-2-yl) - Ν ’- {2- [1- (2- trifluoromethoxybenzoyl) - 591 592 [M + Hp +++

- 38 016300

piperidin-4-yl] thiazol-4carbonyl} guanidine 264 M- (5,6-Dichloro-1H-benzimidazole-2yl) -Y ’- {2- [1- (2trifluoromethoxybenzoyl) piperidin-4-yl] thiazole-4carbonyl} guanidine 625 626 [M + H] ⁺ ++ 265 [4- (5-Trifluoromethylbenzothiazole-2yl) phenyl] 2-morpholin-4ylthiazole-4-carboxylic acid amide 490 491 [M + H] ⁺ 266 (5-Benzothiazol-2-ylpyridin-2yl) amide 2-morpholin-4-ylthiazole 4-carboxylic acid 423 424 [M + H] ⁺ 267 (4-Benzothiazol-2-yl-2-fluorophenyl) 2-morpholine-4ylthiazole-4-carboxylic acid amide 440 441 [M + H] ⁺ 268 (4-Benzothiazol-2-yl-2 trifluoromethoxyphenyl) amide 2morpholin-4-ylthiazole-4carboxylic acid 506 507 [M + H] ⁺ 269 (5-Benzoyl-1 H-benzimidazole-2yl) amide 2- (1-furo [2,3-c] pyridin4-ylpiperidin-4-yl) thiazole-4carboxylic acid 548 549 [M + H] ⁺ 270 (5-Benzoyl-1 H-benzimidazol-2yl) amide 2- [1- (4,6-dimethoxy [1,3,5] triazin-2-yl) piperidin-4yl] thiazole-4-carboxylic acid 570 571 [M + H] ⁺ 271 (5-Fluorobenzothiazol-2-yl) amide 2 [1 - (4,6-dimethoxy [1,3,5] triazin-2yl) piperidin-4-yl] thiazole-4carboxylic acid 501 502 [M + H] ⁺

- 39 016300

272 (5-Benzoyl-1 H-benzimidazole-2yl) amide 2- (1- (4 cyanobenzyl) piperidin-4yl] thiazole-4-carboxylic acid 546 547 [M + H] ⁺ ++ 273 (5-Benzoyl-1 H-benzimidazole-2yl) amide 2- (1-thieno [3,2с1] pyrimidin-4-ylpiperidin-4yl) thiazole-4-carboxylic acid 565 566 [M + H] ⁺ ++ 274 (5-Benzoyl-1 H-benzimidazole-2yl) amide 2- (1- (4.6- dimethoxy [1,3,5] triazin-2yl) piperidin-4-yl] thiazole-4 carboxylic acid 570 571 [M + H] ⁺ +++ 275 (5-Benzoyl-1 H-benzimidazole-2yl) amide 2- (1- (6 trifluoromethylpyrimidin-4yl) piperidin-4-yl] thiazole-4carboxylic acid 577 578 [M + H] ⁺ ++ 276 (5-Ethoxy-1 H-benzimidazole-2yl) amide 2- (1- (4 cyanobenzyl) piperidin-4yl] thiazole-4-carboxylic acid 486 487 [M + H] ⁺ + 277 (5-Chloro-1 H-benzimidazole-2yl) amide 2- (1- (4 cyanobenzyl) piperidin-4yl] thiazole-4-carboxylic acid 476 477 [M + H] ⁺ ++ 278 (5,6-Dichloro-1 H-benzimidazole-2yl) amide 2- (1- (4cyanobenzyl) piperidin-4yl] thiazole-4-carboxylic acid 510 511 [M + H] ⁺ ++

¹¹ Biological data refer to the results obtained in the analysis of inflammation using ΝΕ-κΒ.

+ means 50-80% inhibition, ++ means 80-90%, and +++ means 90-100% inhibition.

Proteosome analysis.

The chymotrypsin activity of the 208 proteosomes (1sh11C8, TiNdep) was determined using a Tesap INga plate reader and 8is-ELUT-LMS as a substrate (Vasyesh). In the wells of a black 96-well polypropylene plate, 2 μl of the corresponding inhibitor dissolved in DMSO were mixed with 50 μl of a substrate solution (25 mM HEPE8, pH 7.5, at 20 ° C, 0.5 mM EDTA (ethylenediaminetetraacetic acid) and 8is- EEUT-AMS (at a suitable concentration), the reaction was initiated by adding 150 μl of a proteosome solution (1.3 μg / ml 208 proteosomes in 25 mM HEPE8, pH 7.5, at 20 ° С, 0.5 mM EDTA, 0.033% ( w / v) 8-8 (sodium dodecyl sulfate)). After hydrolysis of the substrate, fluorescence spectroscopy followed (excitation wavelength: 360 nm; radiation wavelength eniya: 465 nm) for 20 min at 30 ° C and initial velocities were calculated and expressed as change in relative fluorescence units (KEI) per second.

At least four different inhibitor concentrations were used to determine the 1C ₅₀ values (average inhibitory concentration). Each point was recorded in triplicate. The curves were adjusted using a suitable program.

Compounds have an average activity between 1 and 30 μM.

Analysis of the proliferation of T-lymphocytes.

Inhibition of stimulated peripheral blood monocytes (MIC).

MICs were isolated from the blood of healthy donors using ACCi8RSh ™ 8у§1esh Н181оради®-1077 tubes, washed and resuspended at a concentration of 10 ⁶ cells / ml in Dulbecco's modified Eagle medium containing 10% fetal calf serum and 2 mM glutamine.

Cells were stimulated with 2 μg / ml phytohemagglutinin in the presence of the test compound or control vehicle for 72 hours. 4 hours before the end of the incubation period, 5-bromo 2′-deoxyuridine (IUI) was added to label proliferating cells. After incubation, the cells were separated

- 40 016300 by trifugation and the culture supernatant was removed. The amount of included HBVI was determined using enzyme-linked immunosorbent assay.

At least four different inhibitor concentrations were used to determine 1C ₅₀ values (inhibitor concentration necessary for 50% inhibition). Each point was recorded in triplicate. Curves were built using a suitable program.

The effect of the compounds of the invention on the proliferation of T cells.

The compounds of examples 1-24 resulted in more than 50% inhibition compared to control experiments.

The average EC ₅₀ (effective concentration) for the compounds ranged from 3 to 40 μM.

Thus, the compounds of formula (I) are suitable for the treatment of inflammatory diseases or diseases associated with T cells.

Inhibition of,-kV-induced inflammation.

To determine the anti-inflammatory activity of the compounds, a rapid analysis of PKCSE88® ΝΙΝΑ from Ce11 Si Inge 8egu1se OTN was used. This assay is based on recombinant A549-SE-KB-8EAP reporter cells plated in 96-well flat-bottomed plates. Since the transfected reporter gene for 8EAP (secreted embryonic alkaline phosphatase) is under the transcriptional control of the к-kB-sensitive element, the expression of this reporter is activated by stimulation of ΤΝΤ-α. The secretion of 8EAP into the culture supernatant can be detected using a C8RB® chemiluminescent substrate. Test compounds that inhibit к-kB activation show reduced 8EAP activity and reduced luminescent reading.

After 18 hours of reactivation at 37 ° C, 5% CO ₂ and 90% relative humidity, the cells were incubated with 0.01-100 μM test compound for 4.5 hours before stimulation with 2 ng / ml ΤΝΤ-α. After stimulation with ΤΝΤ-α for 22 h, endogenous phosphatases were inactivated and C8PO® substrate was introduced for 40 min. The activity of 8EAP was then quantified by measuring luminescence in the form of relative light units (CI) using a Tesap CITA instrument. Each point was recorded in four replicates, and EC ₅₀ values were calculated by adjusting the function and using Mugokoi Exce1 8o1ueg.

Claims (11)

CLAIM 1. The compound of general formula (III), or its pharmaceutically acceptable salts with an acid or base, or its pharmaceutically acceptable prodrugs or stereoisomer g is 0 or 1; K ^2a independently represents H, OH, 8H, ΝΗ ₂ , alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl or heteroaryl; By ^3a is independently H, OH, 8H, ΝΙΙ2, - ^ ΝΚφΝΚ ⁷ ~ ^8, - (CH 2) _p aryl, - (A ^ SNAYAK ^8, -C (O) NK K, -№ = IC K, -ΝΚ C (O) K, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, alkoxy, alkylamino, hydroxyalkylamino, halogen, aryl or heteroaryl; K ^a represents H, halogen, alkyl, -CJOJAC ⁸ , - (CH ₂ ) _p aryl, - (C1 ΟρΝΙΤΕ ⁸ , -C (O) KK ⁷ K ⁸ , -Ν = ΟΚ ⁷ Κ ⁸ , cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; K ¹ represents —C (O) K ^7a , —C (O) SNK ⁷ K ⁸ , —C. OUK K ′, —C (O) OK ⁷ , —K ⁷ C (O) K ^8, or —C ( 8) K ^7b ; K ² represents H, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl, or K ¹ and K ² together with the Ν atom or the C atom to which they are attached form a 3-8 membered saturated or, at least partially unsaturated monocyclic or polycyclic ring system, where at least one or more than one carbon atom in the ring is a heteroatom selected from O, Ν and 8, and the ring may be substituted with one or more than one K ⁹ ; K ³ represents H, —C ^ LCC ¹³ , halogen, alkyl, haloalkyl, aryl, heteroaryl, OH, 8H, LC ⁴ OK ⁵ , ΝΙΙ ₂ , hydroxyalkylamino, alkylamino, alkoxy, cycloalkyl, heterocycloalkyl, hydroxyalkyl or haloalkyloxy; - 41 016300 K ^a represents H, halogen, alkyl, -Ο (ΝΚ ⁷ ) ΝΚ ⁷ 'Κ ⁸ , - (CH ₂ ) _p aryl, - (ΟΗ ₂ ) _Ρ ΝΚ ⁷ Κ ⁸ , aryl, -C (OJSC ⁸ , - Ν = ΟΚ ⁷ Κ ⁸ , -№ ⁷ C (O) K ⁸ , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino or heteroaryl; K ^b independently represents H, -ΟΝ, -OH, -8H, -CO2K ⁴ ', -C (O) K ⁴ ', -8O2: No. ⁴ ', -ΝΚ ⁴ Κ ⁵ ', -C (O) ^ No. ⁷ К ⁸ , -8О2-alkyl, -8О2К ⁴ ', 8О3К ⁴ ', -ΌΟ, -№ ⁴ 'С (О) К ⁴ , -№ ⁴ ' -CO-haloalkyl, -ΝΌ ;. -ΝΚ ⁴ '8O2-haloalkyl, -№ ⁴ -8О2-alkyl, -№ ⁴ -CO-alkyl, -ΝΚ ⁴ (СН2) _p heteroaryl, alkyl, cycloalkyl, alkylamino, alkoxy, alkylthio, halogen, haloalkyl, haloalkyloxy, - O (CH ₂ ) _P [O (CH ₂ ) _P ] _H OCH ₃ , -C ^ K ⁴ ^ K. '' ^|, benzimidazolyl. - (. '(- ΝΕ ⁴ ) -№ ⁴ ' benzthiazolyl, -C (: No. ⁴ ) -№ ⁴ 'benzoxazolyl, hydroxyalkyl, hydroxycycloalkyl, hydroxyalkylamino, heterocycloalkyl, aryl or heteroaryl; K ⁴ ', R ^4, R ^5' independently represent H, halogen, alkyl, -Ο (ΝΚ ⁷⁾ ΝΚ ^7, Κ ^8, - (CH _{2) p} aryl, haloalkyl, - (ΟΗ _{2) Ρ} ΝΚ ⁷ Κ ⁸ , -C (O) 1 \ 1K ⁷ K ⁸ , -Ν = ΟΚ ⁷ Κ ⁸ , -№ ⁷ C (O) K ⁸ , cycloalkyl, heterocycloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; K ⁷ , K ^{7 ′} , K ⁸ independently represent H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, arylamino, heteroaryl or aryl; K ^7a represents cycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl or aryl; K ^7b represents H, halogen, alkyl, cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, heteroaryl or aryl; X represents ΝΚ ² ', O or 8; Ζ represents Ν or SC ^{2 '} ; K ² represents H, alkyl, —C (O) NK ⁷ , —C (O) K ^b , cycloalkyl, heterocycloalkyl, haloalkyl, hydroxyalkyl, hydroxyalkylamino, alkylamino, heteroaryl or aryl; p is 1-6; with. | equal to 1-6; K ⁹ independently represents H, -ΟΝ, -OH, -8H, alkoxy, alkylthio, -CO2K ⁴ ', -C (O) ^ No. ⁷ K ⁸ , -8O2MK ⁴ ', -ΝΚ ⁴ Κ ⁵ ', -8O2 -alkyl, -8O2K ⁴ ', 8O3K ⁴ ', ^ = CK ⁴ 'K ⁵ ', -MK ⁴ 'C (O) K ⁴ , -MK ⁴ ' -CO-haloalkyl, - \ O ;, -: No. ⁴ '-8O2-haloalkyl, -NΚ ^4, -8Ο2-alkyl, -NΚ ^4, -CO-alkyl, -NΚ ^4, (СН2) _p heteroaryl, alkyl, hydroxyalkyl, cycloalkyl, halogen, haloalkyl, alkylamino, -O (CH ₂ ) _P [O (CH ₂ ) _P ] _H OCH ₃ , -C (NΚ ⁴ ) NΚ ^4, benzimidazolyl, -C (NΚ ⁴ ) NΚ ^4, benzthiazolyl, -C (NΚ ⁴ ) NΚ ^4, benzoxazolyl, hydroxycycloalkyl, hydroxyalkylamino, haloalkyloxy, heterocycloalkyl, - (CH ₂ ) _R NK ⁷ SOK ⁸ , aryl or heteroaryl; wherein _C1-C6 alkyl group, if not stated otherwise, denotes a linear or branched _C1-C6 alkyl which may be optionally substituted with one or more substituents R '; K 'independently represents H, -CO ₂ K``, -ίΌΝΗΚ'',-SK''O, -8Ο ₂ NΚ'',-ΝΚ''- CO-haloalkyl, ^ O ₂ , -NΚ''- 8Ο ₂ -haloalkyl, ^ K '^ O ^ alkyl, -8O ₂ -alkyl, -ΝΚ''- CO-alkyl, -ΟΝ, alkyl, cycloalkyl, alkylamino, alkoxy, -OH, -8H, alkylthio, hydroxyalkyl, hydroxyalkylamino , halogen, haloalkyl, haloalkyloxy, aryl or heteroaryl; K independently represents H, haloalkyl, hydroxyalkyl, alkyl, cycloalkyl, aryl or heteroaryl; C2-C6 alkenyl group, unless otherwise indicated, means a linear or branched C2-C6 alkenyl group which may optionally be substituted with one or more substituents K '; alkyl group, unless indicated otherwise, means a straight or branched _C1-C6 alkyl, linear or branched C2-C6-alkenyl or a linear or branched C2-C6 alkynyl group which may be substituted with one or more substituents R '; where K 'is as defined above; cycloalkyl group means a non-aromatic ring system containing from 3 to 8 carbon atoms, where one or more carbon atoms in the ring may be substituted by one or more substituents K ', where K' is as defined above; heterocycloalkyl group means a non-aromatic ring system containing from 2 to 10 carbon atoms and at least one heteroatom selected from O, Ν and 8, where one or more carbon atoms in the ring may be substituted by K ', as defined above; alkoxy group means an O-alkyl group, wherein the alkyl group is as defined above; alkylthio group means an 8-alkyl group, wherein the alkyl group is as defined above; haloalkyl group means an alkyl group substituted by 1-5 halogen atoms, where the alkyl group is as defined above; hydroxyalkyl group means HO-alkyl group, where the alkyl group is as defined above; haloalkyloxy group means an alkoxy group substituted with 1-5 halogen atoms, where the alkyl group is as defined above; hydroxyalkylamino group means a group (HO-alkyl-Ν- or a group HO-alkyl-IN-, where the alkyl group is as defined above; - 42 016300 alkylamino group means an IN-alkyl or Ν-dialkyl group, wherein the alkyl group is as defined above; the halogen group is fluoro, chloro, bromo or iodo; aryl group means an aromatic group containing from 5 to 15 carbon atoms, which may be substituted by one or more substituents K ', where K' is as defined above; arylamino group means an IN-aryl or Ν-diaryl group, wherein the aryl group is as defined above; heteroaryl group means a 5-10 membered aromatic heterocyclic group containing at least one heteroatom selected from O, Ν and 8, where the heterocyclic group may be fused to another ring and said heterocyclic group or fused ring may be independently substituted with one or more than one substituent K ', where K' is as defined above; provided that the following compounds are excluded: about where K ¹ independently represents hydrogen, alkyl, cycloalkyl, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl, substituted aryl, heteroaryl, substituted heteroaryl, arylalkyl or substituted arylalkyl; K ² independently represents-MK ³ K ⁴ , K ³ independently represents alkyl, cycloalkyl, alkoxy, alkylamine, —OH, —8H, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; K ⁴ independently represents alkyl, cycloalkyl, alkoxy, alkylamine, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; K ⁵ independently represents H, SOK ⁶ , CO2K ⁶ , 8OK ⁶ , 8O2K ⁶ , 8O3K ⁶ , alkyl, cycloalkyl, alkoxy, -№2, alkylamine, -MK ⁷ SOK ⁶ , halogen, -OH, -8H, alkylthio, hydroxyalkyl, haloalkyl, haloalkyloxy, aryl or heteroaryl; K ⁶ independently represents H, alkyl, cycloalkyl, —No ₂ , alkylamine, aryl or heteroaryl; K ⁷ independently represents H, alkyl, cycloalkyl, alkoxy, —OH, —8H, alkylthio, hydroxyalkyl, aryl or heteroaryl; p is 0 or 1; ς is 0 or 1; X represents CO or 8O ₂ . 2. The use of the compounds according to claim 1 as a medicine. 3. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent. 4. The use of a compound according to claim 1 for the manufacture of a medicament for the treatment or prevention of a disease characterized by hyperproliferation of cells. 5. The use of a composition according to claim 3 for the manufacture of a medicament for the treatment or prevention of a disease characterized by hyperproliferation of cells. 6. The use of a compound according to claim 1 for the manufacture of a medicament for the treatment or prevention of a disease caused by ischemia and / or reperfusion injury to organs and / or body parts selected from the group consisting of heart, brain, peripheral limb, kidney, liver, spleen, and lung, and / or where endothelial dysfunction is associated with diseases selected from the group consisting of heart attacks, such as myocardial infarction and critical limb ischemia, and / or where endothelial dysfunction is associated with diseases, selected from the group comprising ischemic diseases, myocardial infarction and ischemic diseases of organs. 7. The use of a composition according to claim 3 for the manufacture of a medicament for the treatment or prevention of a disease caused by ischemia and / or reperfusion injury to organs and / or body parts selected from the group consisting of heart, brain, peripheral limb, kidney, liver, spleen and lung, and / or where endothelial dysfunction is associated with diseases selected from the group consisting of heart attacks, such as myocardial infarction and critical limb ischemia, and / or where endothelial dysfunction is associated with diseases, selected from the group comprising ischemic diseases, myocardial infarction and ischemic diseases of organs. 8. The use of the compounds according to claim 1 for the manufacture of a medicinal product for the treatment or pres - 43 016300 to prevent neurological diseases or disorders selected from the group consisting of Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, dementia with Levi bodies, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, severe pseudoparalytic syndrome of Daasthenia myasthenia syndrome , deafness and Meniere's disease. 9. The use of the composition according to claim 3 for the manufacture of a medicament for the treatment or prevention of neurological diseases or disorders selected from the group consisting of Alzheimer's disease, Parkinson's disease, Creutzfeldt-Jakob disease, dementia with Levi bodies, amyotrophic lateral sclerosis, stroke, epilepsy, multiple sclerosis, severe pseudoparalytic myasthenia gravis, Huntington's disease, Down syndrome, nervous deafness and Meniere's disease. 10. The use according to claim 4 or 5, where the disease is selected from the group consisting of psoriasis, atopic dermatitis, alopecia areata, total alopecia, subtotal alopecia, universal alopecia, diffuse alopecia, lupus erythematosus, lichen planus, dermatomyositis, atopic eczema , annular scleroderma, scleroderma, common psoriasis, psoriasis of the scalp, teardrop psoriasis, psoriasis of skin folds, marginal alopecia areata, androgenetic alopecia, allergic contact eczema, irritating act eczema, contact eczema, pemphigus vulgaris, leaf pemphigus, vegetative pemphigus, scarring pemphigoid mucous membranes, bullous pemphigoid pemphigoid, mucous membrane pemphigoid, dermatitis, herpetiform dermatitis Dühring, urticaria neurotic lymphoma, nodular lymphoma, lipoid prurigo, acute prurigo, linear 1dA-dependent dermatosis, mild polymorphic dermatosis, solar erythema, sclerotrophic lichen, skin exanthema, drug exanthema, chronic progressive purpura, dyshidratic eczema, eczema, fixed drug exanthema, photoallergic skin reaction, lichen lichen, perioral dermatitis and graft versus host disease, acne, rosacea, scarring, keloids, vitiligo, actinic keratosis, hyperkeratosis, hyperkeratosis, persistent lenticular hyperkeratosis, hair keratosis, and ichthyosis. 11. The use according to claim 4 or 5, where the disease is selected from the group consisting of hematological or solid tumors. 4 ^ 8) Eurasian Patent Organization, EAPO Russia, 109012, Moscow, Maly Cherkassky per., 2