RU2298008C2 - Compounds, pharmaceutical compositions containing thereof and method for treatment of cytokine-mediated disease - Google Patents

Abstract

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes novel aromatic compounds that can be used in treatment of diseases or pathological states accompanying by inflammation, for example, chronic inflammation diseases. Invention describes compound of the formula (II):

wherein G means phenyl, pyridinyl, pyrazolyl and wherein G is substituted with one or some groups R₁, R₂ or R₃; Ar means naphthyl; X means (C₅-C₈)-cycloalkyl or cycloalkenyl optionally substituted with 1-2 oxo-groups, phenyl, furanyl, pyridinyl or pyrazolyl; Y means a bond or saturated either unsaturated branched or unbranched (C₁-C₄)-carbon chain wherein one or some methylene groups are optionally and independently substituted with oxygen (O) or nitrogen (N) atoms; Y is optionally substituted with oxo-group; Z means phenyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, morpholinyl, thiomorpholinyl, piperidinyl, piperidinonyl, piperazinyl, pentamethylenesulfoxidyl wherein each of them is optionally substituted with 1-3 (C₁-C₆)-alkyls or group -CONH₂, (C₁-C₆)-alkyl, nitrile, hydroxy-group, (C₁-C₆)-alkoxy-group, secondary or tertiary amine wherein amine nitrogen is bound covalently with (C₁-C₃)-alkyl or (C₁-C₅)-alkoxyalkyl, tetrahydrofuranyl-(C₁-C₃)-alkyl, nitrile-(C₁-C₃)-alkyl, carboxamide-(C₁-C₃)-alkyl; R₁ means independently in each case (C₁-C₁₀)-alkyl which is optionally partially or completely halogenated and optionally substituted with 1-3 hydroxy-groups, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl wherein each of them is optionally substituted with 1-3 groups -CN, halogen atom, (C₃-C₆)-alkynyl branched or unbranched carbon chain and one or some methylene groups is optionally replaced for atom O and indicated alkynyl group is optionally substituted with one or some (C₁-C₄)-alkyl groups; R₂ means branched or unbranched (C₁-C₆)-alkyl that is optionally partially or completely halogenated, branched or unbranched (C₁-C₄)-alkoxy-group that in each case is optionally partially or completely halogenated, halogen atom, (C₁-C₆)-alkoxy-group, hydroxy-group, mono- or di-(C₁-C₄)-alkyl-amino-group, group -OR₆, nitro-group or group mono- or di-(C₁-C₄)-alkyl-amino-S(O)₂ that is optionally partially or completely halogenated, or group -H₂NSO₂; R₃ in each case means independently phenyl, pyridinyl, pyrimidyl, pyrrolidinyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, (C₁-C₄)-alkynyl group or branched or unbranched (C₁-C₆)-alkoxy-group wherein each of them is optionally partially halogenated, -OR₁₈ or (C₁-C₆)-alkyl optionally substituted with group -OR₁₈, amino-group or mono- either di-(C₁-C₅)-alkyl-amino-group, (C₂-C₆)-alkynyl branched or unbranched carbon chain wherein one or some methylene groups are optionally replaced for atom O, and indicated alkynyl group is optionally substituted with one or some (C₁-C₄)-alkyl groups; R₆ means (C₁-C₄)-alkyl that is optionally partially or completely halogenated; in each case R₁₈ means independently hydrogen atom, (C₁-C₄)-alkyl; W means atom O, and its pharmaceutically acceptable derivatives. Also, invention describes a pharmaceutical composition containing these compounds and a method for treatment of disease mediated by cytokines and based on indicated compounds. Invention provides synthesis of novel compounds possessing valuable biological properties.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition, improved method of treatment.

12 cl, 1 tbl, 38 ex

Description

Application Date Details

This application claims the priority of provisional patent applications US 60/124148 dated March 12, 1999 and 60/165867 dated November 16, 1999

The technical field of the invention

The present invention relates to new compounds that inhibit the production of cytokines involved in inflammatory processes, and therefore can be used to treat diseases and pathological conditions accompanied by inflammation, such as chronic inflammatory diseases. The present invention also relates to methods for producing such compounds and to pharmaceutical compositions containing these compounds.

BACKGROUND OF THE INVENTION

Tumor necrosis factor (TNF) and interleukin-1 (IL-1) are important biological factors, generally called pro-inflammatory cytokines. Along with some other related molecules, they mediate the inflammatory response associated with the immunological recognition of infectious agents. An inflammatory response plays an important role in limiting the development of pathogenic infections and combating them.

Elevated levels of pro-inflammatory cytokines are also associated with numerous autoimmune diseases such as toxic shock syndrome, rheumatoid arthritis, osteoarthritis, diabetes, and inflammatory bowel disease (C. A. Dinarello et al., Rev. Infect. Disease 6: 51, 1984). In such diseases, a chronic increase in the inflammatory response exacerbates or causes many observed pathological manifestations. So, for example, with rheumatism inflammatory cells penetrate into the synovial tissue, which leads to the destruction of cartilage and bone (A.E. Koch et al., J. Invest. Med. 43: 28-38, 1995). In such diseases, an important and recognized therapeutic approach based on the possible use of drugs is to reduce the levels of pro-inflammatory cytokines, such as TNF (in the form of a form isolated from cells also called TNFα) and IL-1β. A large number of therapeutic agents are currently undergoing clinical trials for the treatment of cytokine-mediated diseases. For numerous autoimmune diseases, the efficacy of a monoclonal anti-TNFα antibody has been confirmed (P. Heath, "CDP571: An Engineered Human IgG4 Anti-TNFα Antibody," IBC Meeting on Cytokine Antagonists, Philadelphia, PA, April 24-25, 1997 .). Such applications include the treatment of rheumatoid arthritis, Crohn's disease, and ulcerative colitis (E.C. C. Rankin et al., British J. Rheum. 35: 334-342, 1997; W.A. Stack et al., Lancet 349: 521-524, 1997). A monoclonal antibody is believed to perform its function by binding to both soluble TNFα and membrane bound TNFα.

A soluble TNFα receptor that interacts with TNFα has been constructed. This approach is similar to that described above for monoclonal antibodies to TNFα; both agents bind to soluble TNFα, thereby reducing its concentration. For one embodiment of this construct, named Enbrel (Immunex, Seattle, Wash.), Recently, phase III clinical trials have demonstrated efficacy in treating rheumatoid arthritis (Brower et al., Nature Biotechnology 15: 1240, 1997). For another TNFα receptor variant, Ro 45-2081 (Hoffman-LaRoche Inc., Nutley, NJ), its efficacy has been demonstrated in various animal models of allergic pneumonia and acute lung injury. Ro 45-2081 is a recombinant chimeric molecule constructed by fusing a soluble human TNF receptor having a molecular weight of 55 kDa with the IgG1 heavy chain hinge gene, which is expressed in eukaryotic cells (Renzetti et al., Inflamm. Res. 46: p. 46: p. .143, 1997).

IL-1 as an immunological effector molecule is involved in the development of numerous diseases. An IL-1 receptor antagonist (IL-1ra) has been studied in clinical trials in humans. Its effectiveness in treating rheumatoid arthritis (antryl, amgen) has been demonstrated. In a phase III clinical trial in humans, IL-1ra reduced mortality in patients with septic shock syndrome (Dinarello, Nutrution 11, 492, 1995). Osteoarthritis is a poorly progressive disease characterized by destruction of the cartilage of the joint. IL-1 is found in synovial fluid and in the cartilage matrix of joints affected by osteoarthritis. On various experimental models of arthritis, it was found that antagonists of IL-1 can reduce the decomposition of the components of the cartilage matrix (Chevalier, Biomed Pharmacother., 51, 58, 1997). Recently, it has been found that nitric oxide, which is a mediator of cardiovascular homeostasis, transmission of nerve impulses and immune function, plays an important role in modulating bone repair. Strong stimulators of NO production are cytokines such as IL-1 and TNF. NO is a molecule that has an important regulatory function in the bone that affects the cells of the lining of the osteoblast and osteoclast (Evans et al., J. Bone Miner Res. 11, 300, 1996). Increased destruction of beta cells leading to the development of insulin-dependent diabetes mellitus depends on IL-1. Some of these lesions may be mediated by other effectors, such as prostaglandins and thromboxanes. IL-1 can influence this process by controlling the expression level of both cyclooxygenase II and inducible nitric oxide synthetase (McDaniel et al., Proc. Soc. Exp. Biol. Med. 211, 24, 1996). Cytokine production inhibitors are thought to block the expression of inducible cyclooxygenase (COX-2). It was found that the expression of COX-2 increases under the action of cytokines, and it is assumed that it is an isoform of cyclooxygenase, which causes inflammation (MKO'Banion et al., Proc. Natl. Acad. Sci. USA, 89, 4888, 1992) . Therefore, cytokine inhibitors, such as IL-1, should be expected to be effective against disorders that are currently treated with COX inhibitors, such as conventional non-steroidal anti-inflammatory drugs (NSAIDs). Such disorders include acute and chronic pain, as well as inflammatory symptoms and cardiovascular disease.

It has been found that certain cytokines increase in inflammatory bowel disease (IBD). Patients with IBD have an imbalance of IL-1 and IL-1ra in the intestinal mucosa. Insufficient production of endogenous IL-1ra can affect the pathogenesis of IBD (Cominelli et al., Aliment. Pharmacol. Ther. 10, 49, 1996). Alzheimer's disease is characterized by the presence of deposits of beta-amyloid protein, the presence of neurofibrillary plexuses and cholinergic dysfunction in the hippocampus. The structural and metabolic disorder found in Alzheimer's disease is probably due to a persistent elevated level of IL-1 (Holden et al., Med. Hypotheses, 45, 559, 1995). It has been established that IL-1 plays a role in the pathogenesis of human immunodeficiency virus (HIV). A clear connection has been established between IL-1ra and acute inflammation, as well as with various stages of the disease in the pathophysiology of HIV infections (Kreuzer et al., Clin. Exp. Immunol., 109, 54, 1997). IL-1 and TNF are involved in periodontal disease. The destruction process associated with periodontal disease may be due to dysregulation of both IL-1 and TNF (Howells, Oral Dis. 1, 266, 1995).

Pro-inflammatory cytokines, such as TNFα and IL-1β, are also important mediators of septic shock and associated cardiopulmonary dysfunction, acute adult respiratory distress syndrome (RDSV), and multiple organ failure. TNFα is also involved in cachexia and muscle tissue degradation associated with HIV infection (Lahdiverta et al., Amer. J. Med. 85, 289, 1988). Obesity is accompanied by an increased likelihood of infection, diabetes and cardiovascular disease. It was found that for each of the above conditions there are abnormalities in the expression level of TNFα (Loffreda et al., FASEB J. 12, 57, 1998). Elevated levels of TNFα are thought to be present in other nutritional disorders, such as anorexia nervosa and bulimia. Pathophysiological parallels between anorexia nervosa and cancer cachexia have been found (Holden et al., Med. Hypotheses 47, 423, 1996). Using an experimental model, it was found that the TNFα production inhibitor HU-211 improves rehabilitation after a closed brain injury (Shohami et al., J. Neuroimmunol. 72, 169, 1997). It is known that an inflammatory component is present in the development of atherosclerosis, and it is believed that cytokines such as IL-1 and TNF stimulate the development of the disease. In an animal model, it was found that an IL-1 receptor antagonist inhibits fat formation (Elhage et al., Circulation, 97, 242, 1998).

Abnormal expression of inducible nitric oxide synthetase (iNOS) was accompanied by the development of hypertension in rats with spontaneous hypertension (Chou et al., Hypertension, 31, 643, 1998). IL-1 affects the expression of iNOS and therefore can also be involved in the pathogenesis of hypertension (Singh et al., Amer. J. Hypertension, 9, 867, 1996).

It has been found that IL-1 induces the development of uveitis in rats, which can be inhibited using IL-1 blockers (Xuan et al., J. Ocular Pharmacol. And Ther., 14, 31, 1998). It has been demonstrated that cytokines, including IL-1, TNF, and GM-CSF, stimulate the proliferation of blasts of acute myelogenous leukemia (Bruserud, Leukemia Res. 20, 65, 1996). It has been established that IL-1 is important for the development of both inflammatory and allergic contact dermatitis. Skin surface sensitization can be prevented by administering a monoclonal antibody to IL-1 before applying the allergen to the skin (Muller et al., Am. J. Contact. Dermat. 7, 177, 1996). The results obtained in experiments on mice that lacked IL-1 indicate that this cytokine is crucial in the development of fever (Kluger et al., Clin. Exp. Pharmacol. Physiol., 25, 141, 1998). Various cytokines, including TNF, IL-1, IL-6, and IL-8, initiate the acute phase of the reaction, which is usually characteristic of fever, malaise, myalgia, headaches, cellular hypermetabolism, and numerous endocrine and enzymatic responses (Beisel, Am. J. Clin. Nutr. 62, 813, 1995). After trauma or infection by pathogenic organisms, the production of these inflammatory cytokines quickly begins.

Other pro-inflammatory cytokines are associated with various painful conditions. The level of IL-8 correlates with the influx of neutrophils to the site of inflammation or damage. Using blocking antibodies to IL-8, it was found that IL-8 plays a role in neutrophil-mediated tissue damage in acute inflammation (Harada et al., Molecular Medicine Today 2, 482, 1996). Thus, an inhibitor of IL-8 production can be used to treat diseases that are mainly mediated by neutrophils, such as stroke and myocardial infarction resulting from or without thrombolytic therapy, heat damage, adult respiratory distress syndrome (RDSV), multiple damage to organs as a result of trauma, acute glomerulonephritis, dermatoses, including components of acute inflammation, acute purulent meningitis or other disorders of the central nervous system, hemodialysis, leukoferis, syn Roma, associated with granulocyte transfusion, and necrotizing enterocolitis.

Rhinovirus initiates the production of various pro-inflammatory cytokines, predominantly IL-8, which leads to symptomatic diseases such as acute rhinitis (Winther et al., Am. J. Rhinol. 12, 17, 1998).

Other diseases in which IL-8 is involved include cardiac muscle ischemia and reperfusion, inflammatory bowel disease, and many other diseases.

The pro-inflammatory cytokine IL-6 is involved in the acute phase of the reaction. IL-6 is a growth factor in many cancers, including multiple myeloma and related plasma cell dysrasia (Treon et al., Current Opinion in Hematology 5: 42, 1998). It has been established that it is an important mediator of inflammation in the central nervous system. Elevated IL-6 levels have been identified in several neurological disorders, including AIDS-related dementia, Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus, CNS trauma, and viral and bacterial meningitis (Gruol et al., Molecular Neurobiology 15: 307, 1997) . IL-6 also plays an important role in osteoporosis. When simulated in mice, it was found that it mediates bone resorption and induces osteoclast activity (Ershler et al., Development and Comparative Immunol. 21: 487, 1997). Marked differences in cytokine levels, such as IL-6 levels, were found in vivo between osteoclasts of healthy bone and bone of patients suffering from Paget's disease (Mills et al., Calcif Tissue Int. 61, 16, 1997). It has been established that many cytokines are involved in the development of cancer cachexia. The severity of the main symptoms of cachexia can be reduced by treatment with antibodies to IL-6 or IL-6 receptor antagonists (Strassmann et al., Cytokins Mol. Ther. 1, 107, 1995). In some infectious diseases, such as influenza, IL-6 and IFNα are the main factors for both symptom formation and host protection (Hayden et al., J. Clin. Invest. 101, 643, 1998). Overexpression of IL-6 mediates the pathology of many diseases, including multiple myeloma, rheumatoid arthritis, Castleman’s disease, psoriasis and postmenopausal osteoporosis (Simpson et al., Protein Sci. 6, 929, 1997). Compounds that influence the production of cytokines, including IL-6 and TNF, have been shown to be effective in blocking passive cutaneous anaphylaxis in mice (Scholz et al., J. Med. Chem., 41, 1050, 1998).

GM-CSF is another pro-inflammatory cytokine associated with numerous therapeutic diseases. It affects not only the proliferation and differentiation of stem cells, but also regulates some other cells involved in acute and chronic inflammation. Attempts have been made to treat many disease states using GM-CSF, including healing of burn wounds, resorption of the skin graft, and mucositis induced by cytostatic agents and radiotherapy (Masucci, Medical Oncology 13: 149, 1996). GM-CSF probably also plays a role in the replication of human immunodeficiency virus (HIV) in macrophage lining cells during AIDS therapy (Crowe et al., Journal of Leukocyte Biology 62, 41, 1997). Bronchial asthma is characterized by the presence of an inflammatory process in the lungs. Participating cytokines include, but are not limited to, GM-CSF (Lee, J. R. Coil. Physicians Lond., 32, 56, 1998).

It has been established that interferon γ (IFN-γ) is involved in the development of many diseases. It is associated with increased collagen deposition, which is the main histopathological symptom of the graft versus host disease (Parkman, Curr. Opin. Hematol., 5, 22, 1998). In one of the patients after kidney transplantation, acute myelogenous leukemia was diagnosed. A retrospective analysis of peripheral blood cytokines revealed elevated levels of GM-CSF and IFN-γ. These elevated levels correlate with an increase in the number of leukocytes in peripheral blood (Burke et al., Leuk. Lymphoma. 19, 173, 1995). The development of insulin-dependent diabetes mellitus (type 1) may correlate with the accumulation in the cells of the pancreatic islet of T cells that produce IFN-α (Ablumunits et al., J. Autoimmun., 11, 73, 1998). IFN-γ, along with TNF, IL-2, and IL-6, leads to the activation of most peripheral T cells before developing damage to the central nervous system in diseases such as multiple sclerosis (PC) and AIDS-related dementia complex (Martino et al ., 1998, Ann Neurol. 43, 340). Atherosclerotic lesions cause arterial disease, which can lead to heart and brain infarction. In the areas of such lesions, many activated immune cells are present, mainly T cells and macrophages. These cells produce large amounts of pro-inflammatory cytokines, such as TNF, IL-1 and IFN-γ. These cytokines are believed to be involved in stimulating apoptosis (i.e., programmed cell death) of the surrounding smooth muscle cells of the vessels, resulting in atherosclerotic lesions (Geng, Heart Vessels Suppl., 12, 76, 1997). In the body of people suffering from allergies, after infection with wasp venom (R. Vespula), mRNA specific for IFN-γ is produced (Bonay et al., Clin. Exp. Immunol., 109, 342, 1997). It has been established that after a delayed-type hypersensitive reaction, the expression of many cytokines, including IFN-γ, increases, indicating the role of IFN-γ in the development of atopic dermatitis (Szepietowski et al., Br. J. Dermatol. 137, 195, 1997). For cases of fatal cerebral malaria, histopathological and immunohistopathological studies have been performed. An elevated level of IFN-α was detected compared with other cytokines, indicating its role in the development of this disease (Udomsangpetch et al., Am. J. Trop. Med. Hyg. 57, 501, 1997). It has been established that various free radicals are involved in the pathogenesis of various infectious diseases. In response to infection with certain viruses, the nitric oxide synthesis pathway is activated as a result of the induction of pro-inflammatory cytokines such as IFN-α (Akaike et al., Proc. Soc. Exp. Biol. Med. 217, 64, 1998). Patients who are chronic carriers of hepatitis B virus (HBV) may develop cirrhosis and liver cell carcinoma. Gene virus expression and replication in transgenic mice infected with HBV can be suppressed using a post-transcription mechanism mediated by IFN-α, TNF and IL-2 (Chisari et al., Springer Semin. Immunopathol. 17, 261, 1995). IFN-γ can selectively inhibit cytokine-induced bone resorption. This process probably occurs with the participation of nitric oxide (NO), which is an important regulatory agent that influences bone restoration. NO can be involved as a mediator of bone disease for diseases such as rheumatoid arthritis, osteolysis-associated tumors, and postmenopausal osteoporosis (Evans et al., J. Bone Miner Res. 11, 300, 1996). Studies in gene-deficient mice have demonstrated that IL-12-dependent IFN production plays a crucial role in controlling the growth of parasites at an early stage. Although this process does not depend on nitric oxide, the effectiveness of the fight against chronic infection seems to depend on NO (Alexander et al., Philos. Trans. R. Soc. Lond. B. Biol. Sci. 352, 1355, 1997) . NO is an important vasodilator, and there is evidence that it plays a role in the development of cardiovascular shock (Kilbourn et al., Dis. Mon. 43, 277, 1997) INF-γ is involved in the development of chronic intestinal inflammation in diseases like Crohn’s disease and inflammatory bowel disease (IBD), mainly due to the presence of CD4 + lymphocytes, which are believed to belong to the TH1 phenotype (Sartor, Aliment Pharmacol. Ther. 10, appendix 2, 43, 1996). Elevated serum IgE levels are associated with various atopic diseases, such as bronchial asthma and atopic dermatitis. The level of IFN-γ negatively correlates with the level of IgE in serum, which indicates the role of IFN-γ in the development of atopic diseases in patients (Teramoto et al., Clin. Exp. Allergy 28, 74, 1998).

Compounds that have the ability to modulate one or more of the above inflammatory cytokines can be used to treat diseases mediated by the release of these cytokines. Thus, for example, WO 98/52558 describes heteroarylurea derivatives that can be used to treat cytokine-mediated diseases. WO 99/23091 describes another class of urea derivatives that can be used as anti-inflammatory agents.

US Pat. No. 5,162,360 describes (N-substituted aryl) -N'-heterocyclyl substituted urea derivatives that can be used to treat hypercholesteromy and atherosclerosis.

The publications cited above suggest that inhibition of cytokine production may be important in various disease states. Some protein-based therapeutic agents are under development or are approved for use in certain cases. Protein-based therapies are expensive and have certain problems associated with bioavailability and stability. Therefore, there is a need for the development of new low molecular weight cytokine inhibitors having optimal efficacy, pharmacokinetic characteristics and safety profiles.

SUMMARY OF THE INVENTION

Given the above publications in the art there is a need for compounds that would inhibit the production of cytokines in order to treat various disease states.

Thus, the present invention was based on the task of obtaining new compounds that inhibit the release of inflammatory cytokines, such as interleukin 1 and tumor necrosis factor.

Another objective of the invention is to develop a method for the treatment of inflammatory diseases and pathological conditions, such as chronic inflammatory diseases, using the new compounds of the invention.

The objective of the invention is to further develop a method for producing the above new compounds.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with a first aspect, the invention provides compounds of formula (I):

wherein

Ar _{1 is} selected from the group consisting of pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene, while Ar ₁ may be substituted by one or more groups R ₁ , R ₂ or R ₃ ,

Ar ₂ means phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl or indole, each of which is optionally substituted with 0-3 R ₂ groups,

X means

a) C ₅ -C ₈ cycloalkyl or cycloalkenyl optionally substituted with 0-2 oxo groups or 0-3 branched or unbranched C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkylamino chains, or

b) phenyl, furan, thiophene, pyrrole, imidazolyl, pyridine, pyrimidine, pyridinone, dihydropyridinone, maleimide, dihydromaleimide, piperidine, piperazine or pyrazine, each of which is independently substituted by 0-3 substituents selected from the group consisting of or unbranched C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy group, hydroxy group, nitrile, mono or di (C ₁ -C ₃ alkyl) amino group, C ₁ -C ₆ alkyl-S (O) _m group or halogen,

Y is a bond or a saturated or unsaturated branched or unbranched C ₁ -C ₄ carbon chain that is optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S (O), S (O) _2, or S, and Y is optionally independently substituted with 0-2 oxo groups and one or more branched or unbranched C ₁ -C ₄ alkyl groups which may be substituted by one or more halogen atoms,

Z means

a) phenyl, pyridine, pyrimidine, pyridazine, imidazole, furan, thiophene, pyran, which are optionally substituted by 1-3 substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, hydroxy group, mono either a di (C ₁ -C ₃ alkyl) amino group, a C ₁ -C ₆ alkyl-S (O) _m group, a COOH group and a phenylamino group, wherein the phenyl ring is optionally substituted with 1-2 substituents selected from halogen, C ₁ - C ₆ alkyl and C ₁ -C ₆ alkoxy groups,

b) tetrahydropyran, tetrahydrofuran, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholinesulfoxide, piperidine, piperidinone, piperazine, tetrahydropyrimidone, pentamethylene sulfate, pentamethylene sulfate, penta tetramethylene sulfoxide or tetramethylene sulfone, which are optionally substituted with 1-3 substituents selected from nitrile, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy groups, hydroxy groups, mono- or di (C ₁ -C ₃ alkyl) amino-C ₁ -C ₃ alkyl, phenylamino-C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, or

c) a C ₁ -C ₆ alkoxy group, a secondary or tertiary amine, where amine nitrogen is covalently linked to groups selected from the group consisting of C ₁ -C ₃ alkyl, C ₁ -C ₅ alkoxyalkyl, pyridinyl-C ₁ -C ₃ alkyl, imidazolyl-C ₁ -C ₃ alkyl, tetrahydrofuranyl-C ₁ -C ₃ alkyl, a phenylamino group, where the phenyl ring is optionally substituted with 1-2 halogen atoms, C ₁ -C ₆ alkoxy groups, hydroxy groups or mono or di (C ₁ -C ₃ alkyl) amino, a group C ₁ -C ₆ alkyl-S (O) _m group and phenyl-S (O) _m, wherein the phenyl ring is optionally substituted by 1-2 halogen atoms, C ₁ -C ₆ alkoxy mi, hydroxy or mono- or di- (C ₁ -C ₃ alkyl) amino,

R ₁ is

a) branched or unbranched C ₃ -C ₁₀ alkyl, which is optionally partially or fully halogenated and optionally substituted with 1-3 phenyl, naphthyl or heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, with each such phenyl, naphthyl or heterocycle selected from the series described above in this paragraph being substituted with 0-5 substituents selected from the group consisting of halogen, branched or unbranched inventive C ₁ -C ₆ alkyl which is optionally partially or fully halogenated, C ₃ -C ₈ cycloalkyl, C ₅ -C ₈ cycloalkenyl, hydroxy, nitrile, C ₁ -C ₃ alkyloxy which is optionally partially or fully halogenated, NH ₂ group C (O) and di (C ₁ -C ₃ ) alkylaminocarbonyl,

b) C ₃ -C ₇ cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentanil, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheltanyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 C ₁ -C ₃ alkyl groups, or an analog of a similar cycloalkyl group, in which 1-3 ring methylene groups are replaced by groups independently selected from the series including O, S, CHOH,> C = O,> C = S and NH,

c) branched C ₃ -C ₁₀ alkenyl, which is optionally partially or fully halogenated and optionally substituted with 1-3 substituents selected from branched or unbranched C ₁ -C ₅ alkyl, phenyl, naphthyl or heterocyclic groups, each such heterocyclic group independently selected from the series consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each of these phenyl, naphthyl or heterocyclic groups is substituted with 0-5 substitution stitelyami selected from the group consisting of halogen, branched or unbranched C ₁ -C ₆ alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentane, cyclohexane tsiklogeptanil, bitsiklopentanil, bitsiklogeksanil, bitsiklogeptanil, hydroxy, nitrile, C ₁ -C ₃ alkoxy, which is optionally partially or fully halogenated, an NH ₂ C (O) group and a mono or di (C ₁ -C ₃ ) alkylaminocarbonyl,

d) a C ₅ -C ₇ cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, with each such cycloalkenyl group optionally substituted with 1-3 C ₁ -C ₃ alkyl groups,

e) nitrile or

e) branched or unbranched C ₁ -C ₆ alkoxycarbonyl, branched or unbranched C ₁ -C ₆ alkylaminocarbonyl, branched or unbranched C ₁ -C ₆ alkylcarbonylamino-C ₁ -C ₃ alkyl,

R ₂ means a branched or unbranched C ₁ -C ₆ alkyl that is optionally partially or fully halogenated, acetyl, aroyl, a branched or unbranched C ₁ -C ₄ alkoxy group that is optionally partially or fully halogenated, halogen, methoxycarbonyl or phenylsulfonyl,

R ₃ means

a) a phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, benzothiolinazole, benzothiol, benzoyl benzyl, iso-azinolinazole, benzothiol-benzyl-azinol-azinolinazole, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinosolinyl, purinyl and indazolyl, with such a phenyl, naphthyl or heterocyclic group being optionally substituted by 1-5 substituents selected from the group consisting of phenyl, naphthyl, heterocycle, selected from the series described above in this paragraph, branched or unbranched C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , cycloheptyl, bicyclopentyl, bicyclohexyl, bicycloheptyl, phenyl-C ₁ -C ₅ alkyl, naphthyl-C ₁ -C ₅ alkyl, halogen, hydroxy group, nitrile, C ₁ -C ₃ alkyloxy group, which optionally can be partially or fully halogenated, phenyloxy group naphthyloxy a group, a heteroaryloxy group, wherein the heterocyclic moiety is selected from the series described above in this paragraph, a nitro group, an amino group, a mono or di (C ₁ -C ₃ ) alkylamino group, a phenylamino group, a naphthylamino group, a heterocyclylamino group, where the heterocyclyl fragment is selected from the group described above , a group of NH ₂ C (O), mono- or di (C ₁ -C ₃ ) alkylaminocarbonyl, C ₁ -C ₅ alkyl-C (O) -C ₁ -C ₄ alkyl, amino-C ₁ -C ₅ alkyl, mono- or di (C ₁ -C ₃ ) alkylamino-C ₁ -C ₅ alkyl, an amino-S (O) ₂ group, a di (C ₁ -C ₃ alkylamino-S (O) ₂ , R ₄ -C ₁ group -C ₅ alkyl, R ₅ -C ₁ -C ₅ alkoxy, R ₆ -C (O) -C ₁ -C ₅ alkyl, a group R ₇ -C ₁ -C ₅ alkyl (R ₈ ) N, a carboxy-mono or di-C ₁ -C ₅ alkylamino group,

b) a fused aryl selected from the group consisting benzotsiklobutanil, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzotsiklogeptanil and benzotsiklogeptenil, or a fused heterocyclyl selected from the group consisting tsiklopentenopiridin, tsiklogeksanopiridin, tsiklopentanopirimidin, tsiklogeksanopirimidin, tsiklopentanopirazin, tsiklogeksanopirazin, tsiklopentanopiridazin, tsiklogeksanopiridazin, tsiklopentanohinolin , cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoic isoquinoline, cyclopentanoindole, cyclohex anoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene, selected phenyl, hetero, cycloheptane, substituted hetero group , pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, pa branching or unbranched C ₁ -C ₆ alkyl which is optionally partially or fully halogenated, halogen, nitrile, C ₁ -C ₃ alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the above described this paragraph of the group, a nitro group, an amino group, a mono- or di (C ₁ -C ₃ ) alkylamino group, a phenylamino group, a naphthylamino group, a heterocyclylamino group in which the heterocyclyl moiety is selected from that paragraph of the group, NH ₂ C (O) group, mono- or di (C ₁ -C ₃ ) alkylaminocarbonyl, C ₁ -C ₄ alkyl-OC (O) group, branched or unbranched C ₁ -C ₅ alkyl-C ( O) -C ₁ -C ₄ alkyl, amino-C ₁ -C ₅ alkyl, mono-or di (C ₁ -C ₃ ) alkylamino-C ₁ -C ₅ alkyl, R ₉ -C ₁ -C ₅ alkyl, R ₁₀ -C ₁ -C ₅ alkoxy group, R ₁₁ -C (O) -C ₁ -C ₅ alkyl and a group R ₁₂ -C ₁ -C ₅ alkyl (R ₁₃ ) N,

c) cycloalkyl selected from the group consisting of cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, wherein such cycloalkyl is optionally partially or fully halogenated and optionally substituted with 1-3 C ₁ -C ₃ alkyl groups,

d) a C ₅ -C ₇ cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein such a cycloalkenyl group is optionally substituted with 1-3 C ₁ -C ₃ alkyl groups,

e) acetyl, aroyl, alkoxycarbonylalkyl or phenylsulfonyl, or

e) branched or unbranched C ₁ -C ₆ alkyl which is optionally partially or fully halogenated, or

R ₁ and R ₂ together may optionally form a fused phenyl or pyridinyl ring,

R ₈ and R _{13 are} each independently selected from the group consisting of hydrogen and branched or unbranched C ₁ -C ₄ alkyl, which is optionally partially or fully halogenated

R ₄ , R ₅ , R ₆ , R ₇ , R ₉ , R ₁₀ , R ₁₁ and R _{12 are} each independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole,

m means 0, 1 or 2,

W means O or S,

and their pharmaceutically acceptable derivatives.

In one embodiment, compounds of formula (I) are preferred in which Ar ₂ is naphthyl, tetrahydronaphthyl, indanyl or indenyl, and W is O.

In another embodiment of the invention, among those directly indicated above, those compounds of formula (I) are preferred in which Ar _{1 is} selected from thiophene and pyrazole

X is C ₅ -C ₇ cycloalkyl or C ₅ -C ₇ cycloalkenyl, optionally substituted with 0-2 oxo groups or 0-3 branched or unbranched C ₁ -C ₄ alkyl groups, C ₁ -C ₄ alkoxy groups or C ₁ -C ₄ alkylamino groups or X represents phenyl, pyridine, tetrahydropyridine, pyrimidine, furan or thiophene, each independently of which is optionally substituted with 0-3 substituents selected from the group consisting of branched or unbranched C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy group, hydroxy group, nitrile, mono or di (C ₁ -C ₃ alkyl) amino group the group C ₁ -C ₆ alkyl-S (O) _m and halogen,

R ₁ means a branched or unbranched C ₁ -C ₄ alkyl, cyclopropyl or cyclohexyl, which are optionally partially or fully halogenated and optionally substituted with 1-3 C ₁ -C ₃ alkyl groups,

R ₃ means branched or unbranched C ₁ -C ₄ alkyl, phenyl, pyrimidinyl, pyrazolyl or pyridinyl, each of which is optionally substituted, as indicated in the description of the first object of the invention, alkoxycarbonylalkyl or cyclopropyl or cyclopentyl, each of which is optionally partially or fully halogenated and optionally substituted, as indicated in the description of the first object of the invention.

According to another embodiment of the invention, among those directly indicated above, those compounds of formula (I) are preferred in which

Ar ₁ means pyrazole and

X is cyclopentenyl, cyclohexenyl or cycloheptenyl, optionally substituted with oxo or 0-3 substituents selected from the group consisting of branched or unbranched C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy and C ₁ -C ₄ alkylamino, or X is phenyl , pyridine, furan or thiophene, each independently of which is optionally substituted with 0-3 substituents selected from the group consisting of branched or unbranched C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy group, hydroxy group, nitrile, mono or di (C ₁ -C ₃ alkyl) amino group, g a group of C ₁ -C ₆ alkyl-S (O) _m and halogen.

According to a further embodiment of the invention, those compounds of formula (I) in which

Y _is-CH2 -, - CH ₂ CH ₂ -, - CH ₂ NH -, - CH ₂ CH ₂ NH- or a bond and

Z is phenyl, imidazole, furan, piperazine, tetrahydropyran, morpholine, thiomorpholine, thiomorpholinesulfoxide, piperidine, pyridine, a secondary or tertiary amine, where amine nitrogen is covalently linked to groups selected from the group consisting of C ₁ -C ₃ alkyl and C ₁ - C ₅ alkoxyalkyl, or further means a phenylamino group in which the phenyl ring is optionally substituted with 1-2 substituents selected from halogen, a C ₁ -C ₆ alkoxy group, a hydroxy group and a mono or di (C ₁ -C ₃ alkyl) amino group, a C ₁ group -C ₆ alkyl-S (O) _m group and phenyl-S (O) _m, wherein the phenyl count tso optionally substituted with 1-2 substituents selected from halo, C ₁ -C ₆ alkoxy, hydroxy and mono- or di (C ₁ -C ₃ alkyl) amino groups.

In accordance with another embodiment of the invention, among those directly indicated above, those compounds of formula (I) are preferred in which

Ar ₁ means 5-tert-butylpyrazol-3-yl, where the pyrazole ring may be substituted with an R ₃ group, wherein

R ₃ means branched or unbranched C ₁ -C ₄ alkyl, phenyl, pyrimidinyl, pyrazolyl or pyridinyl, each of which is optionally substituted, as described in the description of the first object of the invention, alkoxycarbonylalkyl or cyclopropyl or cyclopentyl, each of which is optionally substituted, as it indicated when describing the first object of the invention.

In another embodiment of the invention, among those directly indicated above, those compounds of formula (I) in which X is pyridinyl are preferred.

According to a further embodiment of the invention, those compounds of formula (I) in which pyridinyl is attached to Ar ₁ in the 3rd position of pyridinyl are preferred among the directly indicated above.

As examples of compounds of formula (I) according to the invention, the following can be mentioned:

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (morpholin-4-yl) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (morpholin-4-ylmethyl) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (2- (morpholin-4-yl) ethyl) phenyl) naphthalene-1- silt] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4-dimethylaminophenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (morpholin-4-yl) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (morpholin-4-ylmethyl) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5-morpholin-4-ylmethylpyridin-2-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5-morpholin-4-ylmethylfur-2-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (b-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene- 1-yl] urea,

1- [5-tert-butyl-2-methyl-2H-pyrazol-3-yl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-phenyl-2H-pyrazol-3-yl] -3- [4- (4-piperidin-1-ylmethylphenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-phenyl-2H-pyrazol-3-yl] -3- [4- (4- (4-methylpiperazin-1-yl) methylphenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3,4-di (morpholin-4-ylmethyl) phenyl) naphthalen-1-yl] urea

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6-pyridin-4-ylmethylpyridin-3-yl) naphthalene- 1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (b- (1-oxothiomorpholin-4-ylmethyl) pyridin-3 -yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (1-oxothiomorpholin-4-ylmethyl) pyridin-3-yl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6-tetrahydropyran-4-ylmethylpyridin-3-yl) naphthalene- 1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (1-oxo-tetrahydrothiophen-3-ylmethyl) pyridin-3 -yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (imidazol-1-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [2- (3-dimethylaminomethylphenyl) -5- (1-methylcyclohexyl) -2H-pyrazol-3-yl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1- silt] urea,

1- [2- (5- (1-methylcyclohexyl) -2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6-morpholin-4-ylmethylpyridin-3 -yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-morpholin-4-ylmethylpyrimidin-5-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3-methoxy-5- (2-morpholin-4-yl-ethoxy) ) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (2-morpholin-4-yl-ethoxy) phenyl) naphthalene -1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4-3- (dimethylamino) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4-3- (methylsulfonyl) phenyl) naphthalen-1-yl] urea,

5-tert-butyl-3- [3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} thiophene-2-carboxylic acid methyl ester,

5-tert-butyl-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido] thiophene-2-carboxylic acid methylamide,

5-tert-butyl-1-methyl-3- [3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} -1H-pyrrole-2-carboxylic acid methyl ester ,

5-tert-butyl-1-methyl-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} -1H-pyrrole-2-carboxylic acid methylamide,

2-acetylamino-N- (5-tert-butyl-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido] thiophen-2-ylmethyl) acetamide,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-morpholin-4-ylcyclohex-1-enyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-morpholin-4-ylcyclohept-1-enyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (2-morpholin-4-yl-ethylamino) cyclohex-1-enyl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-morpholin-4-ylcyclohept-1-enyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (pyridin-4-ylmethylamino) cyclohex-1-enyl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (dimethylaminoethylamino) cyclohex-1-enyl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (pyridin-3-ylmethylamino) cyclohex-1-enyl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (phenylmethylamino) cyclohex-1-enyl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (2-phenylethylamino) cyclohex-1-enyl) naphthalene -1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (furan-2-ylmethylamino) cyclohex-1-enyl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (2-pyridin-2-yl-ethylamino) cyclohex-1 phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (2-piperidin-1-yl-ethylamino) cyclohex-1 phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (2-imidazol-4-yl-ethylamino) cyclohex-1 phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (pyridin-2-ylmethylamino) cyclohex-1-enyl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (2- (4-methoxyphenyl) ethylamino) cyclohex- 1-enyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4-morpholin-4-ylmethyl-3-oxocyclohex-1-enyl) naphthalene-1- silt] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (1-oxo-tetrahydrothiophen-3-ylmethyl) -3-oxocyclohex-1-enyl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (1-oxothiomorpholin-4-ylmethyl) -3-oxocyclohex-1-enyl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4-methylpiperazin-1-ylmethyl) -3-oxocyclohex-1-enyl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- {6-oxo-1- (tetrahydropyran-4-ylmethyl) - 1,2,3,6-tetrahydropyridin-4-yl} naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (2-oxo-1-pyridin-4-ylmethylpiperidin-4- il) naphthalene-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6-oxo-1-pyridin-4-yl-1,2,3,6- tetrahydropyridin-4-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6-oxo-1-pyridin-4-yl-1, 2,3,6-tetrahydropyridin-4-yl) naphthalen-1-yl] urea,

5-tert-butyl-3- {3- [4- (6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydropyridin-4-yl) naphthalen-1-yl] ureido methyl ester } thiophene-2-carboxylic acid,

5-tert-butyl-1-methyl-3- [3- [4- (6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydropyridin-4-yl) naphthalene-methyl ester -yl] ureido} pyrrole-2-carboxylic acid,

5-tert-butyl-1-methyl-3- {3- [4- (6-oxo-1-pyridin-4-yl-1,2,3,6-tetrahydropyridin-4-yl) naphthalene-1- methylamide yl] ureido} pyrrole-2-carboxylic acid,

5-tert-butyl-3- {3- [4- (3-morpholin-4-ylcyclohex-1-enyl) naphthalen-1-yl] ureido} thiophene-2-carboxylic acid methyl ester,

5-tert-butyl-1-methyl-3- {3- [4- (3-morpholin-4-ylcyclohex-1-enyl) naphthalen-1-yl] ureido} pyrrole-2-carboxylic acid methyl ester and

5-tert-butyl-1-methyl-3- [3- [4- (3-morpholin-4-ylcyclohex-1-enyl) naphthalen-1-yl] ureido} pyrrole-2-carboxylic acid methylamide,

and their pharmaceutically acceptable derivatives.

According to yet another embodiment of the invention, the following compounds of formula (I) are also provided therein:

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (morpholin-4-ylmethyl) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (2- (morpholin-4-yl) ethyl) phenyl) naphthalene-1- silt] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (morpholin-4-ylmethyl) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5-morpholin-4-ylmethylpyridin-2-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5-morpholin-4-ylmethylfur-2-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene- 1-yl] urea,

1- [5-tert-butyl-2-methyl-2H-pyrazol-3-yl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

and their pharmaceutically acceptable derivatives.

The second object of the invention are compounds of formula (Ia):

wherein

Ar ₁ means pyrrole, pyrrolidine, pyrazole, imidazole, oxazole, thiazole, furan and thiophene, while Ar _{1 is} optionally substituted with one or more groups R ₁ , R ₂ or R ₃ ,

Ar ₂ means phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl and indole, each of which is optionally substituted with 0-3 groups R ₂ ,

X means

- C ₅ -C ₈ cycloalkyl or cycloalkenyl, optionally substituted with 1-2 oxo groups or 1-3 C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkylamino chains, each of which is branched or unbranched,

- phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, tetrahydropyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinil, maleimidyl, dihydromaleimidyl, piperidinyl, benzimidazole, 3H-imidazirinyl, pyridinyl, 4,5-b, of which are independently optionally substituted with 1-3 substituents selected from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy group, hydroxy group, nitrile, amino group, mono- or di (C ₁ -C ₃ alkyl) amino group, mono either di (C ₁ -C ₃ alkylamino) carbonyl, an NH ₂ C (O) group, a C ₁ -C ₆ alkyl-S (O) group _m and halogen

Y is a bond or a saturated or unsaturated branched or unbranched C ₁ -C ₄ carbon chain that is optionally partially or fully halogenated, with one or more C-atoms being optionally replaced with O, N or S (O) _m , a Y in each the case is independently optionally substituted with 1-2 oxo groups, nitrile, phenyl, hydroxy group or one or more C ₁ -C ₄ alkyl groups optionally substituted with one or more halogen atoms,

Z means

aryl, indanyl, heteroaryl selected from benzimidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl, heterocycle selected from piperazinyl, tetra-2-nanoxylanedio-2-cyclonyl-2-tetrahydro-2-alkanedio-2-alkanedio-2-alkanedio-2-alkanone thia-5-azabicyclo [2.2.1] heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidil, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidil or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxo Anon, 1,3-dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino, tiomorfolinosulfoksidil, tiomorfolinosulfonila, piperidinyl, piperidinone, pyrrolidinyl and dioxolanyl,

wherein each of the above as values of Z groups is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxycarbonyl, aroyl, heteroaryl, heterocycle C ₁ -C ₃ acyl, where heteroaryl and heterocycle have the meanings indicated above in this paragraph, C ₁ -C ₃ acyl, oxo group, hydroxy group, pyridinyl-C ₁ -C ₃ alkyl, imidazolyl-C ₁ -C ₃ alkyl, tetrahydrofuranyl-C ₁ -C ₃ alkyl, nitrile-C ₁ -C ₃ alkyl, nitrile, carboxy group, phenyl, and the phenyl ring is optional it is substituted with 1-2 substituents selected from the group consisting of halogen, C ₁ -C ₆ alkoxy group, hydroxy group and mono or di (C ₁ -C ₃ alkyl) amino group, amino-S (O) _m group, C ₁ - group C ₆ alkyl-S (O) _m and a phenyl-S (O) _m group, where the phenyl ring is optionally substituted with 1-2 halogen atoms, C ₁ -C ₆ alkoxy groups, hydroxy groups or mono or di (C ₁ -C ₃ alkyl ) amino groups, or Z is optionally substituted with 1-3 substituents selected from the group consisting of amino group, aminocarbonyl and amino-C ₁ -C ₃ alkyl, where the N-atom is independently optionally mono or disubstituted amino C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl, aryl C ₀ -C ₃ alkyl, C ₁ -C ₅ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₅ alkoxy group, aroyl, C ₁ -C ₃ acyl, group C ₁ -C ₃ alkyl-S (O) _m - or an arylC ₀ -C ₃ alkyl-S (O) _m - group, each of the above alkyls and aryls attached to the amino group, optionally substituted with 1-2 substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, hydroxy group and mono or di (C ₁ -C ₃ alkyl) amino group, or Z is optionally substituted with 1-3 substituents selected from the group including aryl, heterocycle or hetero aryl, as defined above in this paragraph, with each of these substituents, in turn, optionally substituted with halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxygroup,

or Z is a hydroxy group, hydroxyC ₁ -C ₃ alkyl, halogen, nitrile, amino group, where the N atom is independently optionally mono-or disubstituted with C ₁ -C ₆ alkyl, aminoC ₁ -C ₆ alkyl, arylC ₀ -C ₃ alkyl, C ₁ -C ₅ alkoxy-C ₁ -C ₃ alkyl, C ₁ -C ₅ alkoxy, aroyl, C ₁ -C ₃ acyl, C ₁ -C ₃ alkyl-S (O) _m -, arylC ₀ -C ₃ alkyl-S (O) _m -, nitrile C ₁ -C ₄ alkyl or C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, with each of the above alkyls and aryls attached to the amino group optionally substituted with 1-2 substituents selected from the group consisting of halogen, C ₁ -C ₆ and keel, C ₁ -C ₆ alkoxy, hydroxy and mono- or di (C ₁ -C ₃ alkyl) amino, C ₁ -C ₆ alkoksigeteroarilS ₀ -C ₃ alkyl, geteroarilS ₀ -C ₃ alkyl or geterotsiklS ₀ -C ₃ alkyl where heteroaryl and heterocycle have the meanings given in this paragraph, or Z is a branched or unbranched C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₃ acylamino group, nitrile C ₁ -C ₄ alkyl, C ₁ -C ₆ alkyl-S (O) _m and phenyl-S (O) _m, wherein the phenyl ring is optionally substituted by 1-2 halogen atoms, C ₁ -C ₆ alkoxy, hydroxy or mono- or di- (C ₁ -C ₃ alkyl) amino Rupp,

R ₁ is

a) branched or unbranched C ₁ -C ₁₀ alkyl, which is optionally partially or fully halogenated and optionally substituted with 1-3 substituents selected from the group consisting of phenyl, naphthyl and heterocyclic groups selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl , pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, with each of these phenyl, naphthyl or heterocyclic groups selected from the above series being substituted with 0-5 substituents selected from g groups comprising halogen, branched or unbranched C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated, C ₃ -C ₈ cycloalkyl, C ₅ -C ₈ cycloalkenyl, hydroxy, nitrile, C ₁ -C ₃ alkyloxy, which is optionally partially or completely halogenated, the group NH ₂ C (O) and di (C _1-3 ) alkylaminocarbonyl,

b) C ₃ -C ₇ cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 C ₁ -C ₃ alkyl groups, or an analog of a similar cycloalkyl group, in which 1-3 ring methylene groups are replaced by groups independently selected from the series including O, S, CHOH,> C = O,> C = S and NH,

c) branched C ₃ -C ₁₀ alkenyl, which is optionally partially or completely halogenated and optionally substituted with 1-3 substituents selected from the group consisting of branched or unbranched C ₁ -C ₅ alkyl, phenyl, naphthyl and heterocyclic groups, where each is heterocyclic the group is independently selected from the series consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, and each of such phenyl, naphthyl or heterocyclic groups is substituted with 0-5 mestitelyami, selected from the group consisting of halogen, branched or unbranched C ₁ -C ₆ alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentane, cyclohexane tsiklogeptanil, bitsiklopentanil, bitsiklogeksanil, bitsiklogeptanil, hydroxy, nitrile, C ₁ -C ₃ alkoxy, which is optionally partially or completely halogenated, an NH ₂ C (O) group and a mono or di (C ₁ -C ₃ ) alkylaminocarbonyl,

d) a C ₅ -C ₇ cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, wherein each such cycloalkenyl group is optionally substituted with 1-3 C ₁ -C ₃ alkyl groups,

e) nitrile or

e) branched or unbranched C ₁ -C ₆ alkoxycarbonyl, branched or unbranched C ₁ -C ₆ alkylaminocarbonyl, branched or unbranched C ₁ -C ₆ alkylcarbonylamino-C ₁ -C ₃ alkyl,

R ₂ means a branched or unbranched C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated and optionally substituted with nitrile,

or R ₂ is acetyl, aroyl, a branched or unbranched C ₁ -C ₄ alkoxy group which is optionally partially or fully halogenated, halogen, methoxycarbonyl or phenylsulfonyl,

R ₃ means

a) phenyl, naphthyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, isothiazolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl and indazolyl, while such a phenyl, naphthyl or heterocyclic group is optionally substituted with 1-5 Deputy stitelyami selected from the group consisting of phenyl, naphthyl, heterocycle selected from the above in this paragraph number, branched or unbranched C ₁ -C ₆ alkyl which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bitsiklopentil , bicyclohexyl, bicycloheptyl, phenyl-C ₁ -C ₅ alkyl, naphthyl-C ₁ -C ₅ alkyl, halogen, hydroxy group, oxo group, nitrile, C ₁ -C ₃ alkoxy group, which is optionally partially or fully halogenated, C ₁ -C ₃ alkoxyC ₁ -C ₅ alkyl, C ₁ -C ₃ thioalki l, C ₁ -C ₃ thioalkylC ₁ -C ₅ alkyl, phenyloxy group, naphthyloxy group, heteroaryloxy group in which the heterocyclic moiety is selected from the series described above in this paragraph, a nitro group, an amino group, a mono or di (C ₁ -C ₃ ) alkylamino group, phenylamino group, naphthylamino group, heterocyclylamino group in which the heterocyclyl fragment is selected from the series described above in this paragraph, NH ₂ C (O) group, mono or di (C ₁ -C ₃ ) alkylaminocarbonyl, C ₁ -C ₅ alkyl-C (O ) -C ₁ -C ₄ alkyl, amino-C ₁ -C ₅ alkyl, mono- or di (C ₁ -C ₃ ) alkylamino-C ₁ -C ₅ alkyl, an amino-S (O) ₂ group, di (C ₁ -C ₃ ) alkylamino-S (O) ₂ group, R ₄ -C ₁ -C ₅ alkyl, R ₅ -C ₁ -C ₅ alkoxy group, R ₆ -C (O) -C ₁ -C ₅ alkyl, a group R ₇ -C ₁ -C ₅ alkyl (R ₈ ) N and a carboxy-mono or di (C ₁ -C ₅ ) alkylamino group,

b) a fused aryl selected from the group consisting benzotsiklobutanil, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzotsiklogeptanil and benzotsiklogeptenil, or a fused heterocyclyl selected from the group consisting tsiklopentenopiridin, tsiklogeksanopiridin, piklopentanopirimidin, tsiklogeksanopirimidin, tsiklopentanopirazin, tsiklogeksanopirazin, tsiklopentanopiridazin, tsiklogeksanopiridazin, tsiklopentanohinolin , cyclohexanoquinoline, cyclopentanoisoquinoline, cyclohexanoisoquinoline, cyclopentanoindole, cyclohex anoindole, cyclopentanobenzimidazole, cyclohexanobenzimidazole, cyclopentanobenzoxazole, cyclohexanobenzoxazole, cyclopentanoimidazole, cyclohexanoimidazole, cyclopentanothiophene and cyclohexanothiophene, i a group including pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoc azolyl and isothiazolyl, branched or unbranched C ₁ -C ₆ alkyl which is optionally partially or fully halogenated, halogen, nitrile, C ₁ -C ₃ alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the series described above, a nitro group, an amino group, a mono- or di (C ₁ -C ₃ ) alkylamino group, a phenylamino group, a naphthylamino group, a heterocyclylamino group in which the heterocyclyl fragment is selected from the described the above row, an NH ₂ C (O) group, mono- or di (C ₁ -C ₃ ) alkylaminocarbonyl, a C ₁ -C ₄ alkyl-OS (O) group, branched or unbranched C ₁ -C ₅ alkyl-C ( O) -C ₁ -C ₄ alkyl, amino-C ₁ -C ₅ alkyl, mono-di (C ₁ -C ₃ ) alkylamino-C ₁ -C ₅ alkyl, R ₉ -C ₁ - ₅ alkyl, R ₁₀ -C ₁ -C ₅ alkoxy group, R ₁₁ -C (O) -C ₁ -C ₅ alkyl and the group R ₁₂ -C ₁ -C ₅ alkyl (R ₁₃ ) N,

c) cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl and bicycloheptyl, wherein such cycloalkyl is optionally partially or fully halogenated and optionally substituted with 1-3 C ₁ -C ₃ alkyl groups,

d) a C ₅ -C ₇ cycloalkenyl selected from the group consisting of cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl and bicycloheptenyl, while such a cycloalkenyl group is optionally substituted with 1-3 C ₁ -C ₃ alkyl groups,

d) acetyl, aroyl, C ₁ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl or phenylsulfonyl or

e) branched or unbranched C ₁ -C ₆ alkyl which is optionally partially or fully halogenated, or

R ₁ and R ₂ together optionally form a fused phenyl or pyridinyl ring,

R ₈ and R _{13 are} each independently selected from the group consisting of hydrogen and branched or unbranched C ₁ -C ₄ alkyl, which is optionally partially or fully halogenated

R ₄ , R ₅ , R ₆ , R ₇ , R ₉ , R ₁₀ , R ₁₁ and R _{12 are} each independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole,

m means 0, 1 or 2,

W means O or S,

wherein X is directly attached to one or two —Y — Z groups,

and their pharmaceutically acceptable derivatives.

In one embodiment, compounds of formula (Ia) are preferred in which Ar ₂ is naphthyl, tetrahydronaphthyl, indanyl or indenyl, and W is O.

In another embodiment of the invention, those compounds of formula (Ia) in which

Ar ₁ means thiophene or pyrazole, each of which is independently substituted by 1-3 groups of R ₁ , R ₂ or R ₃ ,

X means

- C ₅ -C ₇ cycloalkyl or cycloalkenyl, optionally substituted with 1-2 oxo groups or 1-3 C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkylamino chains, each of which is branched or unbranched,

- phenyl, indanyl, furanyl, thienyl, imidazolyl, pyridinyl, pyrazinyl, tetrahydrapyridinyl, pyrimidinyl, pyridinonyl, piperidinyl, benzimidazole or piperazinyl, each of which is independently substituted by 1-3 substituents selected from the group consisting of C ₁ -C ₄ alkyl, C ₁ - ₄ alkoxy, hydroxy, nitrile, amino, mono- or di (C ₁ -C ₃ alkyl) amino, mono- or di (C ₁ -C ₃ alkylamino) carbonyl group NH ₂ C (O) the group C ₁ -C ₆ alkyl-S (O) _m and halogen,

Y is a bond or a saturated or unsaturated branched or unbranched C ₁ -C ₄ carbon chain that is optionally partially or fully halogenated, with one or more C-atoms being optionally replaced with O or N, and Y is independently optionally substituted in each case 1 -2 by oxo groups, nitrile, phenyl, a hydroxy group or one or more C ₁ -C ₄ alkyl groups optionally substituted with one or more halogen atoms,

Z means

- phenyl, heteroaryl selected from pyridinyl, imidazolyl, furanyl and thienyl, a heterocycle selected from piperazinyl, 2-oxa-5-azabicyclo [2.2.1] heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxyl, pentamethylene sulfonyl group, tetrahydrofluorofluorofirogen sulfonyl, tetrahydroform each of the above as values of Z groups is optionally substituted by 1-3 substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl , C ₁ -C ₆ alkoxycarbonyl, aroyl, morpholine carbonyl, C ₁ -C ₆ acyl, oxo group, hydroxy group, pyridinyl-C ₁ -C ₃ alkyl, imidazolyl-C ₁ -C ₃ alkyl, tetrahydrofuranyl-C ₁ -C ₃ alkyl, nitrile-C ₁ -C ₃ alkyl, nitrile , carboxy group, phenyl, where the phenyl ring is optionally substituted with 1-2 halogen atoms, C ₁ -C ₆ alkoxy groups, hydroxy groups or mono or (C ₁ -C ₃ alkyl) amino groups, an amino-S (O) _m group, a C group ₁ -C ₆ alkyl-S (O) _m and a phenyl-S (O) _m group, where the phenyl ring is optionally substituted with 1-2 halogen atoms, C ₁ -C ₆ alkoxy groups, hydroxy groups or mono or di (C ₁ -C ₃ alkyl) amino groups,

or Z is optionally substituted with 1-3 substituents selected from the group consisting of amino, aminocarbonyl and amino-C ₁ -C ₃ alkyl, where the N-atom in each case is independently optionally mono-or disubstituted with amino C ₁ -C ₆ alkyl, C ₁ - With ₃ alkyl, arylC ₀ -C ₃ alkyl, C ₁ -C ₅ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₅ alkoxy, aroyl, C ₁ -C ₃ acyl, C ₁ -C ₃ alkyl-S (O ) _m- or arylC ₀ -C ₃ alkyl-S (O) _m - group, wherein each of the indicated alkyls and aryls attached to the amino group is optionally substituted with 1-2 substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group, or Z is optionally substituted with 1-3 aryl, heterocyclic or heteroaryl groups, as described above in this paragraph, each of which, in turn, is optionally substituted with halogen, C ₁ - C ₆ alkyl or C ₁ -C ₆ alkoxy group,

or Z is a hydroxy group, hydroxyC ₁ -C ₃ alkyl, halogen, nitrile, amino group, where the N atom in each case is independently optionally mono or disubstituted with aroyl, C ₁ -C ₃ acyl, C ₁ -C ₆ alkyl, C ₁ - C ₅ alkoxyC ₁ -C ₃ alkyl, pyridinyl C ₁ -C ₆ alkyl, tetrahydrafuranyl C ₁ -C ₃ alkyl, nitrile C ₁ -C ₄ alkyl or phenyl, with the phenyl ring optionally substituted with 1-2 substituents selected from the group consisting of halogen, A C ₁ -C ₆ alkoxy group, a hydroxy group and a mono or di (C ₁ -C ₆ alkyl) amino group, or Z is a branched or unbranched C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group or nitrile C ₁ -C ₆ alkyl,

R ₁ is

branched or unbranched, optionally partially or fully halogenated C ₁ -C ₄ alkyl,

- cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, which are optionally partially or completely halogenated and optionally substituted with 1-3 C ₁ -C ₃ alkyl groups, or an analog of such a cycloalkyl group in which 1-3 ring methylene groups are replaced by groups independently from each other selected from O, S and NH,

branched C ₃ -C ₁₀ alkenyl, which is optionally partially or fully halogenated and optionally substituted with 1-3 branched or unbranched C ₁ -C ₅ alkyl groups,

- cyclopentenyl and cyclohexenyl, optionally substituted with 1-3 C ₁ -C ₆ alkyl groups,

R ₂ means a branched or unbranched C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated and optionally substituted with nitrile,

R ₃ means

a phenyl or heterocyclic group selected from the range consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl and pyrazolyl, wherein such a phenyl or heterocyclic group is optionally substituted with 1-5 substituents selected from the group consisting of phenyl, a heterocycle selected from the above paragraph of the series, branched or unbranched C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentyl, bicyclohexyl, bicyclohe ptyl, phenyl-C ₁ -C ₆ alkyl, naphthyl-C ₁ -C ₅ alkyl, halogen, hydroxy group, oxo group, nitrile, C ₁ -C ₃ alkoxy group, which is optionally partially or fully halogenated, C ₁ -C ₆ alkoxyC ₁ - C ₅ alkyl, C ₁ -C ₃ thioalkyl, C ₁ -C ₃ thioalkyl C ₁ -C ₅ alkyl, phenyloxy group, naphthyloxy group, heteroaryloxy group in which the heterocyclic moiety is selected from the series described above in this paragraph, a nitro group, an amino group, a mono or di (C ₁ -C ₃₎ alkylamino, phenylamino, naphthylamino, geterotsiklilaminogruppu wherein heterocyclyl frag ent selected from the above-described series in this paragraph, a group NH ₂ C (O), mono- or di (C ₁ -C ₃₎ alkylaminocarbonyl, C ₁ -C ₅ alkyl-C (O) -C ₁ -C ₄ alkyl, amino-C ₁ -C ₅ alkyl, mono-or di (C ₁ -C ₃ ) alkylamino-C ₁ -C ₅ alkyl, amino-S (O) ₂ group, di (C ₁ -C ₃ ) alkylamino-S group (O) ₂ , R ₄ -C ₁ -C ₅ alkyl, R ₆ -C ₁ -C ₅ alkoxy group, R ₆ -C (O) -C ₁ -C ₅ alkyl, R ₇ -C ₁ -C ₅ alkyl group (R ₈ ) N and a carboxy-mono or di (C ₁ -C ₅ ) -alkylamino group,

- condensed aryl selected from the group consisting of benzocyclobutanil, indanyl, indenyl, wherein such condensed aryl is substituted with 0-3 substituents independently selected from the group consisting of phenyl, naphthyl and heterocyclyl selected from pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl , pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, branched or unbranched C ₁ -C ₆ alkyl which is optionally partially or fully halogenated, halogen, nitrile, C ₁ -C ₃ alkoxy group which I optionally partially or fully halogenated, phenyloxy, naphthyloxy, heterocyclyloxy wherein the heterocyclyl moiety is selected from the above group in this paragraph, nitro, amino, mono-or di (C ₁ -C ₃₎ alkylamino, phenylamino, naphthylamino, geterotsiklilaminogruppu in wherein the heterocyclyl fragment is selected from the group described above in this paragraph, the group NH ₂ C (O), and mono- or di (C ₁ -C ₃ ) alkylaminocarbonyl, the group C ₁ -C ₄ alkyl-OS (O), branched or unbranched C ₁ -C ₅ alkyl-C (O) -C ₁ -C ₄ alkyl, amino-C ₁ -C ₅ alkyl, mono- or di (C ₁ -C ₃ ) alkylamino-C ₁ -C ₅ alkyl, R ₉ -C ₁ -C ₅ alkyl, R ₁₀ -C ₁ - A C ₅ alkoxy group, R ₁₁ -C (O) -C ₁ -C ₅ alkyl and a group R ₁₂ -C ₁ -C ₅ alkyl (R ₁₃ ) N,

- cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, wherein such cycloalkyl is optionally partially or fully halogenated and optionally substituted with 1-3 C ₁ -C ₃ alkyl groups,

- C ₁ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl, or

R ₁ and R ₂ together optionally form a fused phenyl or pyridinyl ring,

R ₈ and R _{13 are} each independently selected from the group consisting of hydrogen and branched or unbranched C ₁ -C ₄ alkyl, which is optionally partially or fully halogenated, and

R ₄ , R ₅ , R ₆ , R ₇ , R ₉ , R ₁₀ , R ₁₁ and R _{12 are} each independently selected from the group consisting of morpholine, piperidine, piperazine, imidazole and tetrazole,

wherein X is directly attached to one —Y — Z group.

In a further embodiment of the invention, those compounds of formula (Ia) in which

Ar ₁ means pyrazole,

X means

- cyclopentenyl, cyclohexenyl, cycloheptenyl, optionally substituted by oxo or 1-3 C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkylamino chains, each of which is branched or unbranched,

- phenyl, furanyl, thienyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl, each of which is independently optionally substituted with 1-3 substituents selected from the group consisting of C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy group, hydroxy group and halogen,

Z means

phenyl, heteroaryl selected from pyridinyl, imidazolyl and furanyl, heterocycle selected from 2-oxa-5-azabicyclo [2.2.1] heptane, pentamethylene, pentametilensulfoksidila, pentamethylene sulfone, tetragidrofu wounded, tetrahydropyranyl, piperazinyl, morpholino, thiomorpholino, piperidinyl and tiomorfolinosulfoksida ,

wherein each of the above as values of Z groups is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxycarbonyl, aroyl, morpholinocarbonyl, C ₁ -C ₃ acyl, oxo group, hydroxy group, pyridinyl-C ₁ -C ₃ alkyl, imidazolyl-C ₁ -C ₃ alkyl, tetrahydrofuranyl-C ₁ -C ₃ alkyl , _{nitrile-C1 3} alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted by 1-2 halogen atoms, C ₁ -C ₆ alkoxy, hydroxy or mono- or d (C ₁ -C ₃ alkyl) amino groups, amino group-S (O) _m, group C ₁ -C ₆ alkyl-S (O) _m group and phenyl-S (O) _m, wherein the phenyl ring is optionally substituted with 1-2 halogen atoms, C ₁ -C ₆ alkoxy groups, hydroxy groups or mono or di (C ₁ -C ₆ alkyl) amino groups, or Z is optionally substituted with 1-3 amino groups, aminocarbonyl groups or amino-C ₁ -C ₆ alkyl groups, where N -atom is optionally, in each case, independently mono- or disubstituted by amino C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl, aryl C ₀ -C ₃ alkyl, C ₁ -C ₅ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₅ alkoxy group , aroyl, C ₁ -C ₃ tsilom, group C ₁ -C ₃ alkyl-S (O) _m -, piridinilS ₀ -C ₃ alkyl, tetragidrafuranilS ₀ -C ₃ alkyl or arylC ₀ -C ₃ alkyl-S (O) _m -, wherein each of the above alkyls and aryls attached to the amino group, optionally substituted with 1-2 halogen atoms, C ₁ -C ₆ alkyl groups or C ₁ -C ₆ alkoxy groups,

or Z denotes a hydroxy group, hydroxyC ₁ -C ₃ alkyl, halogen, nitrile, amino group, where the N-atom is optionally independently mono or disubstituted in each case with C ₁ -C ₆ alkyl, pyridinyl C ₀ -C ₃ alkyl, tetrahydrofuranyl C ₀ -C ₃ alkyl, C ₁ -C ₅ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₃ acyl, nitrile C ₁ -C ₄ alkyl or phenyl, with the phenyl ring optionally substituted with 1-2 halogen atoms, C ₁ -C ₆ alkoxy groups, hydroxy groups or mono or di (C ₁ -C ₃ alkyl) amino groups, or Z is a branched or unbranched C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group or n itril C ₁ -C ₄ alkyl,

R ₁ is

branched or unbranched C ₁ -C ₄ alkyl, which is optionally partially or fully halogenated,

- cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl and cycloheptanyl, which are optionally partially or completely halogenated and optionally substituted with 1-3 C ₁ -C ₃ alkyl groups, or an analog of such a cycloalkyl group in which 1-3 ring methylene groups are replaced by groups independently selected from O, S and NH,

- branched C ₃ -C ₁₀ alkenyl, which is optionally partially or fully halogenated and optionally substituted with 1-3 branched or unbranched C ₁ -C ₃ alkyl groups,

- cyclopentenyl and cyclohexenyl, optionally substituted with 1-3 C ₁ -C ₃ alkyl groups,

R ₂ means a branched or unbranched C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated and optionally substituted with nitrile,

R ₃ means

a phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl, pyridazinyl and pyrazolyl, wherein such a phenyl or heterocyclic group is optionally substituted with 1-5 substituents selected from the group consisting of phenyl, a heterocycle selected from the group described above in this paragraph branched or unbranched C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated, phenyl-C ₁ -C ₅ alkyl, halogen, hydroxy, oxo, nitrile, C ₁ -C ₃ alkoxy, which is optionally partially or fully halogenated, C ₁ -C ₃ thioalkyl, C ₁ -C ₃ thioalkyl C ₁ -C ₅ alkyl, amino group, mono or di (C ₁ -C ₃ ) alkylamino group, NH ₂ C (O) group or mono or di (C ₁ -C ₃ ) alkylamino carbonyl,

- C ₁ -C ₆ alkoxycarbonyl C ₁ -C ₆ alkyl,

or R ₃ means cyclopropyl or cyclopentyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 C ₁ -C ₃ alkyl groups, or

R ₁ and R ₂ together optionally form a fused phenyl or pyridinyl ring.

According to a further embodiment of the invention, those compounds of formula (Ia) in which

Y is —CH ₂ -, —O— (CH ₂ ) _0-3 -, —CH ₂ CH ₂ -, —CH ₂ NH—, —CH ₂ CH ₂ —NH—, NH — CH ₂ CH ₂ -, - CH ₂ -NH-CH ₂ -, -NH -, - NH-C (O) -, -C (O) -, -CH (OH) -, -CH ₂ (CH ₂ CH ₃ ) - or a bond,

X means

cyclohexenyl optionally substituted by oxo or 1-3 C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkylamino chains, each of which is branched or unbranched,

- phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl, each of which is optionally independently substituted by 1-3 substituents selected from the group consisting of C ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy group, hydroxy group and halogen,

Z means

- phenyl, heteroaryl selected from pyridinyl, imidazolyl and furanyl, heterocycle selected from 2-oxa-5-azabicyclo [2.2.1] heptane, pentamethylene, pentametilensulfoksidila, pentamethylene sulfone, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, morpholino, thiomorpholino, piperidinyl and tiomorfolinosulfoksida ,

wherein each of the above as values of Z groups is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxycarbonyl, aroyl, morpholinocarbonyl, C ₁ -C ₃ acyl, oxo group, hydroxy group, pyridinyl-C ₁ -C ₃ alkyl, imidazo-lyl-C ₁ -C ₃ alkyl, tetrahydrofuranyl-C ₁ - C ₃ alkyl, _{nitrile-C1 3} alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted by 1-2 halogen atoms, C ₁ -C ₆ alkoxy, hydroxy or mono- or and (C ₁ -C ₃ alkyl) amino groups, amino group-S (O) _m, group C ₁ -C ₆ alkyl-S (O) _m and phenyl-S (O) group m, wherein the phenyl ring is optionally substituted with 1- 2 by halogen atoms, C ₁ -C ₆ alkoxy groups, hydroxy groups, or mono- or di (C ₁ -C ₃ alkyl) amino groups, or Z is optionally substituted by 1-3 amino groups or aminocarbonyl groups, where the N atom is optionally independently mono-in each case or disubstituted by amino C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl, aryl C ₀ -C ₃ alkyl, C ₁ -C ₅ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₅ alkoxy, aroyl, C ₁ -C ₃ acyl a group C ₁ -C ₃ alkyl-S (O) _m - Whether group arylC ₀ -C ₃ alkyl-S (O) _m -, wherein each of the aforementioned alkyl and aryl attached to the amino group is optionally substituted by 1-2 halogen atoms, C ₁ -C ₆ alkyl groups or C ₁ -C ₆ alkoxy groups, or Z means a hydroxy group, hydroxyC ₁ -C ₃ alkyl, halogen, nitrile, amino group, where the N-atom is optionally independently mono or disubstituted in each case with C ₁ -C ₃ alkyl, pyridinyl C ₁ -C ₂ alkyl, tetrahydrafuranyl C ₁ - C ₂ alkyl, C ₁ -C ₃ alkoksiS ₁ -C ₃ alkyl, C ₁ -C ₃ acyl, nitrilS ₁ -C ₄ alkyl, phenyl, wherein the phenyl ring neobyazat flax substituted by 1-2 halogen atoms, C ₁ -C ₆ alkoxy, hydroxy or mono- or di- (C ₁ -C ₃ alkyl) amino, or Z is a branched or unbranched C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or nitrile C ₁ -C ₄ alkyl,

R ₁ means a branched or unbranched C ₁ -C ₄ alkyl, which is optionally partially or fully halogenated,

R ₂ means a branched or unbranched C ₁ -C ₃ alkyl, which is optionally partially or fully halogenated and optionally substituted with nitrile,

R ₃ means

a phenyl or heterocyclic group selected from the group consisting of pyridinyl, pyrimidinyl and pyrazolyl, wherein such a phenyl or heterocyclic group is optionally substituted with 1-5 substituents selected from the group consisting of branched or unbranched C ₁ -C ₃ alkyl, which is optionally partially or fully halogenated, a C ₁ -C ₃ alkoxy group which is optionally partially or fully halogenated, C ₁ -C ₃ thioalkyl, C ₁ -C ₃ thioalkyl C ₁ -C ₅ alkyl, an amino group or an NH ₂ C (O) group,

- C ₁ -C ₃ alkoxycarbonyl,

or R ₃ is cyclopropyl or cyclopentyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 C ₁ -C ₃ alkyl groups.

In accordance with another embodiment of the invention, among those directly indicated above, those compounds of formula (Ia) in which

Ar ₁ means 5-tert-butylpyrazol-3-yl, where the pyrazole ring in each case is independently substituted by 1-2 groups of R ₂ or R ₃ ,

X means

cyclohexenyl

- phenyl, pyridinyl, pyrazinyl, piperidinyl or pyrimidinyl, each of which is optionally independently substituted with a C ₁ -C ₂ alkoxy group or hydroxy group,

Z means

phenyl, heteroaryl selected from pyridinyl and furanyl, a heterocycle selected from 2-oxa-5-azabicyclo [2.2.1] heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, tetrahydrofuranyl, piperazinyl, morpholino group, each of the above and above thiomorpholino group Z groups are optionally substituted with 1-3 substituents selected from the group consisting of C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, oxo, hydroxy and NH ₂ C (O) -, or Z is hydroxy-C ₁ -C ₃ alkyl, amino, N-atoms wherein optionally in each m case independently mono- or disubstituted piridinilmetilom, tetragidrafuranilmetilom, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, C ₁ -C ₃ acyl or nitrilS ₁ -C ₄ alkyl, or Z is nitrilS ₁ -C ₄ alkyl ,

R ₃ means

a phenyl or heterocyclic group selected from the series consisting of pyridinyl, pyrimidinyl and pyrazolyl, wherein such a phenyl or heterocyclic group is optionally substituted with 1-2 substituents selected from the group consisting of C ₁ -C ₂ alkyl, which is optionally partially or fully halogenated, A C ₁ -C ₂ alkoxy group which is optionally partially or fully halogenated, C ₁ -C ₂ thioalkyl, C ₁ -C ₂ thioalkyl-C ₁ -C ₃ alkyl, an amino group and an NH ₂ C (O) group,

- C ₁ -C ₃ alkoxycarbonyl,

or R ₃ is cyclopropyl or cyclopentyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 C ₁ -C ₃ alkyl groups.

In another embodiment, among those directly indicated above, those compounds of formula (Ia) in which X is pyridinyl are preferred.

According to a further embodiment of the invention, those compounds of formula (Ia) in which pyridinyl is attached to Ar ₁ in the 3rd position of pyridinyl are preferred among the directly indicated above.

As examples of compounds of formula (Ia) according to the invention, the following can be mentioned:

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4-morpholin-4-ylmethylphenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [3- (4-morpholin-4-ylmethylphenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5-morpholin-4-ylmethylfuran-2-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (morpholin-4-ylmethyl) cyclohexenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (4-morpholin-4-yl) ethylphenyl) naphthalen-1-yl] urea ,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4-dimethylamino-methylphenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5- (morpholin-4-ylmethyl) pyridin-2-yl) naphthalen-1-yl urea

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1-yl urea

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2-methyl-2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1-yl] urea ,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (2- (morpholin-4-yl) ethylamino) cyclohexenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3,4- (morpholin-4-ylmethyl) phenyl) naphthalen-1-yl] urea ,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4-methylpiperazin-1-ylmethyl) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (piperidin-1-ylmethyl) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (2- (pyridin-2-yl) ethylamino) cyclohexenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (2- (pyridin-4-yl) ethylaminomethyl) phenyl) naphthalene-1- silt] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (pyridin-3-ylmethylaminomethyl) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (3,4-dimethoxyphenylmethyl) -3-hydroxyphenyl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6-oxo-1,6-dihydropyridin-3-yl) naphthalen-1-yl] urea

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (morpholin-4-ylmethyl) phenyl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (morpholin-4-ylmethyl) imidazol-1-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (morpholin-4-ylmethyl) imidazol-1-yl) naphthalen-1-yl urea

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (furan-3-ylmethyl) -3-hydroxyphenyl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (4-hydroxybutylamino) pyridin-3-yl) naphthalene -1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (pyridin-3-ylmethyl) -3-hydroxyphenyl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (4-methyl-3-carbamylphenyl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (imidazol-2-ylmethyl) -3-hydroxyphenyl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (3-hydroxymorpholin-4-ylmethyl) phenyl) naphthalene -1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N-2-methoxyethyl-N-methylaminomethyl) phenyl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (4-hydroxymorpholin-4-ylmethyl) phenyl) naphthalene -1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (morpholin-4-ylmethyl) cyclohexenyl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (tetrahydrofuran-3-ylmethyl) -3-hydroxyphenyl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N, N-di- (2-methoxyethyl) aminomethyl) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (3-cyanopropoxy) pyridin-3-yl) naphthalene -1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4-morpholin-4-ylmethylpiperidine1) naphthalen-1-yl] urea

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N, N-di (2-cyanoethyl) aminomethyl ) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (1-morpholin-4-ylindan-5-yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (furan-2-ylmethyl) -3-hydroxyphenyl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (thiomorpholin-4-ylmethyl) phenyl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (3-carboxamidomorpholin-4-ylmethyl) phenyl) naphthalene -1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (2-methyl-3-oxopiperazin-1-ylmethyl) ) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (4-hydroxybutyloxy) pyridin-3-yl) naphthalene -1-yl] urea,

1- [3-tert-butyl-1'H- [1,4 '] bipyrazol-5-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (furan-2-ylmethyl) -3-methoxyphenyl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (5- (morpholin-4-carbonyl) pyrazin-2-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (tetrahydrothiopyran-4-ylamino) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (2-cyanoethyl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (2,6-dimethylmorpholin-4-ylmethyl) pyridine -3-yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (2-methoxypyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (2-aminopyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-oxo-1,6-dihydropyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) ) pyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-yl-4-carbonyl) pyridine -3-yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (2-oxa-5-azabicyclo [2.2.1 ] hept-5-ylmethyl) pyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (3-carbamylphenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N- (2-cyanoethyl) -N- ( pyridin-3-ylmethyl) aminomethyl) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N- (2-cyanoethyl) -N- ( pyridin-2-ylmethyl) aminomethyl) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N- (2-cyanoethyl) -N- ( tetrahydrofuran-2-ylmethyl) aminomethyl) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) -4-methoxypyridine- 3-yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (1-morpholin-4-ylpropyl) pyridin-3 -yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (N- (3-methoxypropyl) amino) pyridine- 3-yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (N- (3-methoxypropyl) -N-methylamino ) pyridin-3-yl) naphthalen-1-yl] urea,

1- [3-tert-butyl-1'-methyl-1'H- [1,4 '] bipyrazol-5-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3- il) naphthalene-1-yl] urea,

1- [5-tert-butyl-2-benzyl-2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1-yl] urea ,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (NN-di (2-cyanoethyl) aminomethyl) phenyl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (4-carbamylphenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (1-oxo-tetrahydrothiopyran-4-ylamino) pyridine -3-yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (tetrahydropyran-4-ylamino) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [3-tert-butyl-1 '- (3-cyanopropyl) -1'H- [1,4'] bipyrazol-5-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-methanesulfinylphenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-methanesulfonylphenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-sulfonamidophenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (morpholin-4-yl) carbonylphenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (5- (tetrahydrothiopyran-4-ylamino) pyrazin-2-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (methylcarbonylamino) pyridin-3-yl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-yl-4-carbonyl) phenyl) naphthalen-1-yl urea

1- [3-tert-butyl-1 '- (3-methylsulfanylpropyl) -1'H- [1,4'] bipyrazol-5-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5- (morpholin-4-yl-carbonyl) pyridin-3-yl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (5- (morpholin-4-ylmethyl) pyrazin-2-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6-aminopyridin-3-yl) naphthalen-1-yl] urea

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (1-methylpiperidin-4-ylamino) pyridin-3 -yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (2-methyl-3-oxopiperazin-1-ylmethyl) ) pyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-yl-carbonyl) pyridin-3 -yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (N, N-di (2-methoxyethyl) aminomethyl ) pyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (1-oxothiomorpholin-4-ylmethyl) pyridin-3 -yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (tetrahydropyran-4-ylamino) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (5- (morpholin-4-ylmethyl) pyrazin-2-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (2-methylthiopyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (2-methyl-3-oxopiperazin-1-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (pyridin-3-yloxy) pyridin-3-yl) naphthalen-1-yl urea

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (pyridin-3-ylamino) pyridin-3-yl) naphthalen-1-yl urea

1- [5-tert-butyl-2- (2-methoxypyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5-carbamylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (2-aminopyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (4- (morpholin-4-ylmethyl) phenyl) naphthalene-1 -yl] urea,

1- [3-tert-butyl-1'-methyl-1'H- [1,4 '] bipyrazol-5-yl] -3- [4- (6- (morpholin-4-ylmethyl) phenyl) naphthalene- 1-yl] urea,

1- [5-tert-butyl-2- (2-cyclopropylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (pyridin-3-ylamino) pyrimidin-5-yl) naphthalen-1-yl urea

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (1-oxo-tetrahydrothiopyran-4-ylamino) pyridin-3-yl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (thiomorpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1-yl urea

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-benzyl-3H-imidazo [4,5-b] pyridin-6-yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (pyridin-3-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (morpholin-4-ylcarbonyl) pyrimidin-5-yl) naphthalen-1-yl urea

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (morpholin-4-ylmethyl) pyrimidin-5-yl) naphthalen-1-yl urea

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3-amino-4-carbamylphenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (1-oxothiomorpholin-4-ylmethyl) pyridin-3-yl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (pyridin-3-ylmethyl) pyridin-3-yl) naphthalen-1-yl urea

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (hydroxypyridin-3-ylmethyl) pyridin-3-yl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (2-methshirimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (2- (morpholin-4-ylmethyl) pyrimidin-5-yl ) naphthalene-1-yl] urea,

and their pharmaceutically acceptable derivatives.

According to yet another embodiment of the invention, it also provides the following compounds of formula (Ia):

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5- (morpholin-4-ylmethyl) pyridin-2-yl) naphthalen-1-yl ]urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1-yl ]urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (2- (pyridin-2-yl) ethylamino) cyclohexenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (pyridin-3-ylmethylaminomethyl) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (morpholin-4-ylmethyl) phenyl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (4-hydroxybutylamino) pyridin-3-yl) naphthalene -1-yl] urea,

1- [5-tert-butyl-2- (4-methyl-3-carbamylphenyl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (3-hydroxypiperidin-1-ylmethyl) phenyl) naphthalene -1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (4-hydroxymorpholin-4-ylmethyl) phenyl) naphthalene -1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (morpholin-4-ylmethyl) cyclohexenyl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (tetrahydrofuran-3-ylmethyl) -3-hydroxyphenyl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N, N-di (2-methoxyethyl) aminomethyl ) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (3-cyanopropoxy) pyridin-3-yl) naphthalene -1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4-morpholin-4-ylmethylpiperidine1) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N, N-di (2-cyanoethyl) aminomethyl ) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (furan-2-ylmethyl) -3-hydroxyphenyl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (thiomorpholin-4-ylmethyl) phenyl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (3-carboxamidopiperidin-1-ylmethyl) phenyl) naphthalene -1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (2-methyl-3-oxopiperazin-1-ylmethyl) ) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (4-hydroxybutyloxy) pyridin-3-yl) naphthalene -1-yl] urea,

1- [3-tert-butyl-1'H- [1,4 '] bipyrazol-5-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (tetrahydrothiopyran-4-ylamino) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (2-cyanoethyl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (2,6-dimethylmorpholin-4-ylmethyl) pyridine -3-yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (2-methoxypyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (2-aminoupyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-yl-4-carbonyl) pyridine -3-yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (2-oxa-5-azabicyclo [2.2.1 ] hept-5-ylmethyl) pyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N- (2-cyanoethyl) -N- ( pyridin-3-ylmethyl) aminomethyl) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N- (2-cyanoethyl) -N- ( tetrahydrofuran-2-ylmethyl) aminomethyl) phenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4 (6 (morpholin-4-ylmethyl) -4-methoxypyridin-3- il) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (1-morpholin-4-ylpropyl) pyridin-3 -yl) naphthalene-1-yl] urea,

1- [3-tert-butyl-1'-methyl-1'H- [1,4 '] bipyrazol-5-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3- il) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (1-oxo-tetrahydrothiopyran-4-ylamino) pyridine -3-yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (tetrahydropyran-4-ylamino) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (5- (tetrahydrothiopyran-4-ylamino) pyrazin-2-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (methylcarbonylamino) pyridin-3-yl) naphthalene-1 -yl] urea,

1- [3-tert-butyl-1 '- (3-methylsulfanylpropyl) -1'H- [1,4'] bipyrazol-5-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (1-oxothiomorpholin-4-ylmethyl) pyridin-3 -yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (tetrahydropyran-4-ylamino) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (2-methylthiopyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (2-aminopyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea,

1- [3-tert-butyl-1'-methyl-1'H- [1,4 '] bipyrazol-5-yl] -3-14- (6- (morpholin-4-ylmethyl) phenyl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3-14- (6- (1-oxo-tetrahydrothiopyran-4-ylamino) pyridin-3-yl) naphthalene- 1-yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (thiomorpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1-yl ]urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (morpholin-4-yl-carbonyl) pyrimidin-5-yl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (morpholin-4-ylmethyl) pyrimidin-5-yl) naphthalen-1-yl ]urea,

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (1-oxothiomorpholin-4-ylmethyl) pyridin-3-yl) naphthalene-1 -yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (2- (morpholin-4-ylmethyl) pyrimidin-5-yl ) naphthalene-1-yl] urea

and their pharmaceutically acceptable derivatives.

In accordance with a third aspect of the invention, it further provides compounds of formula (II):

wherein

G means

- aromatic C ₆ -C ₁₀ carbocycle or saturated or unsaturated non-aromatic C ₃ -C ₁₀ carbocycle,

- 6-10 membered heteroaryl containing one or more heteroatoms selected from O, N and S,

A 5-8 membered monocyclic heterocycle containing one or more heteroatoms selected from O, N and S, or

An 8-11 membered bicyclic heterocycle containing one or more heteroatoms selected from O, N and S, wherein G is substituted with one or more groups R ₁ , R ₂ or R ₃ ,

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl, each of which is optionally substituted by one or more groups R ₄ or R _5,

X means

- C ₅ -C ₈ cycloalkyl or cycloalkenyl, optionally substituted with 1-2 oxo groups or 1-3 C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkylamino chains,

- phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperidinyl, benzimidazole, 3H-imidazo [4,5-b] pyridinyl, pyridinyl, pyridinyl, pyridinyl,

Y is a bond or a saturated or unsaturated branched or unbranched C ₁ -C ₄ carbon chain that is optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced with O, N or S (O) _m , and Y is optionally independently substituted by 1-2 oxo groups, phenyl or one or more C ₁ -C ₄ alkyl groups optionally substituted by one or more halogen atoms,

Z means

- phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, pyranyl, each of which is optionally substituted by 1-3 substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, hydroxy group, amino group, mono or di (C ₁ -C ₃ alkyl) amino group, C ₁ -C ₆ alkyl-S (O) _m group, CN group, CONH ₂ group, COOH group and phenylamino group, where the phenyl ring is optionally substituted with 1-2 halogen atoms, C ₁ -C ₆ alkyl groups or C ₁ -C ₆ alkoxy groups,

- tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioksolanonil, 1,3-dioxanone, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, tiomorfolinosulfoksidil, tiomorfolinosulfonil, piperidinyl, piperidinenil, piperazinyl, tetragidropirimidonil, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentametilensulfoksidil, pentamethylene sulfone, tetrametilensulfid , tetramethylene sulfoxidyl or tetramethylene sulfonyl, each of which is optionally substituted with 1-3 substituents selected from the group consisting of nitrile, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxygroup pu, hydroxy group, amino group, mono- or di (C ₁ -C ₃ alkyl) amino-C ₁ -C ₃ alkyl, CONH ₂ group, phenylamino-C ₁ -C ₃ alkyl and C ₁ -C ₃ alkoxy-C ₁ - C ₃ alkyl

- halogen, C ₁ -C ₄ alkyl, nitrile, amino group, hydroxy group, C ₁ -C ₆ alkoxy group, NH ₂ C (O) group, mono or di (C ₁ -C ₃ alkyl) aminocarbonyl, mono or di ( A C ₁ -C ₃ alkyl) amino group, a secondary or tertiary amine, while the amine nitrogen is covalently linked to C ₁ -C ₃ alkyl or C ₁ -C ₅ alkoxyalkyl, pyridinyl-C ₁ -C ₃ alkyl, imidazolyl-C ₁ -C ₃ alkyl, tetrahydrofuranyl-C ₁ -C ₃ alkyl, nitrile-C ₁ -C ₃ alkyl, carboxamide-C ₁ -C ₃ alkyl, phenyl, where the phenyl ring is optionally substituted with 1-2 halogen atoms, C ₁ -C ₆ alkoxy groups, hydroxy groups or mono or di (C ₁ -C ₃ alkyl) a mino groups, a group C ₁ -C ₆ alkyl-S (O) _m or a phenyl-S (O) _m group, where the phenyl ring is optionally substituted with 1-2 halogen atoms, C ₁ -C ₆ alkoxy groups, hydroxy groups or mono or di ( C ₁ -C ₃ alkyl) amino groups,

- C ₁ -C ₆ alkyl-S (O) _m and phenyl-S (O) _m , where the phenyl ring is optionally substituted with 1-2 halogen atoms, C ₁ -C ₆ alkoxy groups, hydroxy groups or mono or di (C ₁ - C ₃ alkyl) amino groups,

R ₁ in each case independently means

- C ₁ -C ₁₀ alkyl, which is optionally partially or fully halogenated and optionally substituted with 1-3 substituents selected from the group consisting of C ₃ -C ₁₀ cycloalkanyl, hydroxy, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, with each of the above substituents optionally substituted with 1-5 substituents selected from halogen, C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated, C ₃ -C ₈ cycloalkanyl, C ₅ -C ₈ cycloalkyl yl, hydroxy, nitrile, C ₁ -C ₃ alkoxy which is optionally partially or fully halogenated, NH ₂ group C (O), mono- or di (C ₁ -C ₃ alkyl) amino groups and mono- or di (C ₁ - C ₃ alkyl) aminocarbonyl,

- cyclopropyloxy group, cyclobutyloxy group, cyclopentyloxy group, cyclohexyloxy group or cycloheptyloxy group, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 substituents selected from the group consisting of C ₁ -C ₃ alkyl, which is optionally partially or fully halogenated, CN group, hydroxy ₁ -C ₃ alkyl and aryl, or an analogue of such a picloalkyl group in which 1-3 ring methylene groups are independently replaced by O, S (O) _m , CHOH,> C = O,> C = S or NH,

a phenyloxy group or benzyloxy group, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 substituents selected from the group consisting of C ₁ -C ₃ alkyl, which is optionally partially or fully halogenated, a CN group, hydroxyC ₁ -C ₃ alkyl, and aryl, or an analogue of such a cycloaryl group, in which 1-2 ring methylene groups are independently replaced by N,

- cyclolropanil, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 substituents selected from the group consisting of C ₁ -C ₃ alkyl, which is optionally or partially halogenated, CN group, hydroxyC ₁ -C ₃ alkyl and aryl, or an analog of such a cycloalkyl group in which 1-3 ring methylene groups are independently replaced by O, S (O) _m , CHOH,> C = O,> C = S or NH,

- branched or unbranched C ₃ -C ₁₀ alkenyl, which in each case is optionally partially or fully halogenated and optionally substituted with 1-3 substituents selected from the group consisting of branched or unbranched C ₁ -C ₅ alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl , pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, with each of these substituents being substituted with 1-5 substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanil, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl and bicycloheptanyl, hydroxy group, nitrile, C ₁ -C ₃ alkyloxy group, which is optionally partially or fully halogenated with (O- and NH ₂ group C ₁ -alkylC ₃ aminocarbonyl, wherein such branched or unbranched C ₃ -C ₁₀ alkenyl is optionally interrupted by one or more heteroatoms selected from O, N and S (O) _m ,

- cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such a cycloalkenyl group is optionally substituted with 1-3 C ₁ -C ₃ alkyl groups,

- nitrile, halogen,

- methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl,

- silyl containing three C ₁ -C ₄ alkyl groups that are optionally partially or fully halogenated,

- a C ₃ -C ₆ alkynyl branched or unbranched carbon chain which is optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S (O) _m , and said alkynyl group is optionally independently substituted 1-2 oxo groups, pyrrolidinyl, pyrrolyl, one or more C ₁ -C ₄ alkyl groups optionally substituted with one or more halogen atoms, nitrile, morpholino group, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, trazolyl or a mono or di (C ₁ -C ₃ alkyl) amino group optionally substituted with one or more halogen atoms,

R ₂ , R ₄ and R ₅ each means

- branched or unbranched C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated, acetyl, aroyl, branched or unbranched C ₁ -C ₄ alkoxy, which in each case is optionally partially or fully halogenated, halogen, methoxycarbonyl, group C ₁ - C ₃ alkyl-S (O) _m , which is optionally partially or fully halogenated, or phenylsulfonyl,

A C ₁ -C ₆ alkoxy group, a hydroxy group, an amino group, a mono or di (C ₁ -C ₄ alkyl) amino group, a nitrile or a halogen,

- group OR ₆ ,

- nitro group or

- a group of mono or di (C ₁ -C ₄ alkyl) amino-S (O) ₂ , which is optionally partially or completely halogenated, or a group of H ₂ NSO ₂ ,

R ₃ in each case independently means

- phenyl, naphthyl, morpholinyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, thienyl, isinazolinyl, isinazolinyl, isinazolinyl , benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, purinyl or indazolyl, with each of the above radicals being optionally substituted with 1-3 substituents, select wounded from the group consisting of phenyl, naphthyl, heterocycle or heteroaryl, which are described above in this paragraph, branched or unbranched C ₁ -C ₆ alkyl, which is optionally partially or completely halogenated, cyclopropanyl, cyclobutanyl, cyclopentanil, cyclohexanyl, cycloheptanyl, bicyclic bicyclo , bitsiklogeptanil, phenyl-C ₁ -C ₅ alkyl, naphthyl-C ₁ -C ₅ alkyl, halogen, hydroxy, oxo, nitrile, C ₁ -C ₃ alkyloxy which is optionally partially or fully halogenated, phenyloxy, naftiloksigrup y, heteroaryloxy and geteropikloksigruppu wherein the heterocyclic or heteroaryl moiety is as described above in this paragraph, nitro, amino, mono- or di (C ₁ -C ₃ alkyl) amino, phenylamino, naphthylamino, heteroarylamino or geterotsiklaminogruppu wherein the heteroaryl or heterocyclic moiety as described above in this paragraph, an NH ₂ C (O) group, mono- or di (C ₁ -C ₃ alkyl) aminocarbonyl, C ₁ -C ₅ alkyl-C (O) -C ₁ -C ₄ alkyl, amino-C ₁ - C ₅ alkyl, mono- or di (C ₁ -C ₃ alkyl) amino-C ₁ -C ₅ alkyl amino group-S (O) ₂ group, a di (C ₁ -C ₃ alkyl) amine -S (O) _2, R ₇ -C ₁ -C ₅ alkyl, R ₈ -C ₁ -C ₅ alkoxy, R ₉ -C (O) -C ₁ -C ₅ alkyl group R ₁₀ -C ₁ -C ₅ alkyl (R ₁₁ ) N and a carboxy-mono or di (C ₁ -C ₅ alkyl) amino group,

- a fused aryl selected from benzotsiklobutanila, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzotsiklogeptanila and benzotsiklogeptenila or fused heteroaryl selected from tsiklopentenopiridinila, tsiklogeksanopiridinila, tsiklopentanopirimidinila, tsiklogeksanopirimidinila, tsiklopentanopirazinila, tsiklogeksanopirazinila, tsiklopentanopiridazinila, tsiklogeksanopiridazinila, tsiklopentanohinolinila, tsiklogeksanohinolinila, tsiklopentanoizohinolinila, tsiklogeksanoizohinolinila, cyclopentanoindolyl, iklogeksanoindolila, tsiklopentanobenzimidazolila, tsiklogeksanobenzimidazolila, tsiklopentanobenzoksazolila, tsiklogeksanobenzoksazolila, tsiklopentanoimidazolila, tsiklogeksanoimidazolila, and tsiklopentanotienila tsiklogeksanotienila, the fused aryl or fused heteroaryl ring is independently substituted with 0-3 substituents selected from the group consisting of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, C ₁ -C ₆ alkyl, which optionally partially or fully halogenated, halogen, nitrile, C ₁ -C ₃ alkyloxy group, which is optionally partially or fully halogenated, phenyloxy group, naphthyloxy group, heteroaryloxy group or heterocycloxy group, where the heteroaryl or heterocyclic group is described in the above section, either a di (C ₁ -C ₃ alkyl) amino group, a phenylamino group, a naphthylamino group, a heteroarylamino group or a heterocyclamino group, wherein a heteroaryl or heterocyclic moiety is described above in this paragraph, NH ₂ C (O) group, mono- or di (C ₁ -C ₃ alkyl) aminocarbonyl, C ₁ -C ₄ alkyl-OS (O), C ₁ -C ₅ alkyl-C (O) -C ₁ -C ₄ alkyl, amino-C ₁ -C ₅ alkyl, mono- or di (C ₁ -C ₃ ) alkylamino-C ₁ -C ₅ alkyl, R ₁₂ -C ₁ -C ₅ alkyl, R ₁₃ -C ₁ -C ₅ alkoxy group, R ₁₄ -C (O) -C ₁ -C ₅ alkyl and the group R ₁₅ -C ₁ -alkylC ₅ R ₁₆ ) N,

- cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 C ₁ -C ₃ alkyl groups, or an analog of such a cycloalkyl group in which 1-3 ring methylene groups are independently replaced by O, S, CHOH,> C = O,> C = S or NH,

- cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each of which is optionally substituted with 1-3 C ₁ -C ₃ alkyl groups,

- C ₁ -C ₄ alkylphenyl-C (O) -C ₁ -C ₄ alkyl-, C ₁ -C ₄ alkyl-C (O) -C ₁ -C ₄ alkyl- or C ₁ -C ₄ alkylphenyl-S ( O) _m -C ₁ -C ₄ alkyl-,

- a C ₁ -C ₆ alkyl group or a branched or unbranched C ₁ -C ₆ alkoxy group, each of which is optionally partially or fully halogenated or optionally substituted with an R ₁₇ group,

- OR ₁₈ or C ₁ -C ₆ alkyl optionally substituted with an OR ₁₈ group,

an amino group or a mono or di (C ₁ -C ₅ alkyl) amino group optionally substituted with an R ₁₉ group,

- R ₂₀ C (O) N (R ₂₁ ) -, R ₂₂ O-, R ₂₃ R ₂₄ NC (O) -, R ₂₆ (CH ₂ ) _m C (O) N (R ₂₁ ) - or R ₂₆ C (O) (CH ₂ ) _m N (R ₂₁ ) -,

- C ₂ -C ₆ alkenyl substituted with a group R ₂₃ R ₂₄ NC (O) -,

- a C ₂ -C ₆ alkynyl branched or unbranched carbon chain that is optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S (O) _m , and said alkynyl group is optionally independently substituted 1-2 oxo groups, pyrrolidinyl, pyrrolyl, morpholinyl, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, one or more C ₁ -C ₄ alkyl groups optionally substituted with one or more halogen atoms, nitrile, m an orpholino group, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl or a mono or di (C ₁ -C ₄ alkyl) amino group which may be substituted by one or more halogen atoms, or

- aroyl

R ₆ means C ₁ -C ₄ alkyl, which is optionally partially or fully halogenated and optionally substituted with a group R ₂₆ ,

R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₇ , R ₁₉ , R ₂₅ and R ₂₆ each independently of one another means nitrile, phenyl, morpholino group, piperidinyl, piperazinyl , imidazolyl, pyridinyl, tetrazolyl, an amino group or a mono or di (C ₁ -C ₄ alkyl) amino group, which is optionally partially or fully halogenated,

R ₁₁ and R ₁₆ each independently of one another means hydrogen or C ₁ -C ₄ alkyl, which is optionally partially or fully halogenated,

R ₁₈ in each case independently means hydrogen or C ₁ -C ₄ alkyl, which is optionally independently substituted by an oxo group or an R ₂₅ group,

R ₂₀ in each case independently means C ₁ -C ₁₀ alkyl, which is optionally partially or fully halogenated, phenyl or pyridinyl,

R ₂₁ in each case independently means hydrogen or C ₁ -C ₃ alkyl, which is optionally partially or fully halogenated,

R ₂₂ , R ₂₃ and R ₂₄ each independently of one another means hydrogen, C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated, said C ₁ -C ₆ alkyl being optionally interrupted by one or more O, N or S atoms, and also independently optionally substituted with a mono- or di (C ₁ -C ₃ alkyl) aminocarbonyl, phenyl, pyridinyl, amino group or a mono or di (C ₁ -C ₄ alkyl) amino group, with each of these substituents optionally partially or fully halogenated and optionally substituted with mono- or di (C ₁ -C ₃ alkyl) aminogru sing, or

R ₂₃ and R ₂₄ together optionally form a heterocyclic or heteroaryl ring,

m is 0, 1 or 2 and

W means O or S,

and their pharmaceutically acceptable derivatives.

According to one embodiment of the invention, among those directly indicated above, those compounds of formula (II) are preferred in which

G means

- phenyl, naphthyl, benzocyclobutanil, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl,

- pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzothiazhenyl-benzodi-benzo-2-azido-benzodi-benzo-2-azino-benzoylobenzido-benzoylobenzido-benzoylobenzido-benzoylobenzido-benzoylobenzido-benzoylobenzo benzodioxolyl, benzo [1,3] dioxol-2-onyl, benzofuran-3-onil, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl, chromoyl,

- oxetanyl, pyrrolidinyl, tetragidrofu wounded, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfone, tetramethylene, oxazolinyl, thiazolinyl, imidazolinyl, tetrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinoline, thiomorpholinyl, thiazolidinyl, digidrooksazinil, dihydropyranyl, oxocanil, heptacanil, thioxanil or dithianil,

wherein G is substituted with one or more groups R ₁ , R ₂ or R ₃ .

In another embodiment of the invention, among those directly indicated above, those compounds of formula (II) are preferred in which

G stands for phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indylene, indenyl indylene, indylene, indyl, indyl, indyl, indyl, indyl, indole or indole R ₁ , R ₂ or R ₃ ,

Ar means naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl or indolyl, each of which is optionally substituted with one or more R ₄ or R ₅ groups,

X is phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl,

Y is a bond or a saturated or unsaturated C ₁ -C ₄ carbon chain, wherein one of the carbon atoms is optionally replaced with O, N or S (O) _m , and Y is optionally independently substituted with 1-2 oxo groups, phenyl or one or more C ₁ -C ₄ alkyl groups optionally substituted with one or more halogen atoms,

Z means

- phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl, dihydrothiazolyl, digidrotiazolilsulfoksidil, pyranyl, pyrrolidinyl which are optionally substituted with 1-3 substituents selected from the group consisting of nitrile, C ₁ -C ₃ alkyl, C ₁ - A C ₃ alkoxy group, an amino group, a mono or di (C ₁ -C ₃ alkyl) amino group, a CONH ₂ group and an OH group,

- tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinosulfoxidyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrylmethylphenylmethylene sulfonethenylmethylene sulfonethenylmethylene sulfonethenylmethylene sulfonethenylmethylene sulfonethenylmethylene sulfonated optionally substituted by 1-3 substituents selected from the group consisting of nitrile, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy group, amino group, mono or di (C ₁ -C ₃ alkyl) amino group, CONH group ₂ and OH group,

- nitrile, C ₁ -C ₆ alkyl-S (O) _m , halogen, hydroxy group, C ₁ -C ₄ alkoxy group, amino group, mono or di (C ₁ -C ₆ alkyl) amino group, mono or di ( C ₁ -C ₃ alkyl) aminocarbonyl or an NH ₂ C (O) group,

R ₁ in each case independently means

- C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated and optionally substituted with 1-3 substituents selected from the group consisting of C ₃ -C ₆ cycloalkyl, phenyl, thienyl, furyl, isoxazolyl and isothiazolyl, where each of these substituents is optional substituted by 1-3 substituents selected from halogen, C ₁ -C ₄ alkyl, which is optionally partially or fully halogenated, hydroxy groups, nitrile and C ₁ -C ₃ alkoxy groups, which are optionally partially or fully halogenated,

- cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 substituents selected from the group consisting of C ₁ -C ₃ alkyl, which is optionally partially or fully halogenated, the CN group , hydroxyC ₁ -C ₃ alkyl and phenyl, or an analogue of such a cycloalkyl group in which 1-3 ring methylene groups are independently replaced by O, S, CHOH,> C = O,> C = S or NH, or

- silyl containing three C ₁ -C ₄ alkyl groups that are optionally partially or fully halogenated,

R ₂ in each case independently means halogen, a C ₁ -C ₃ alkoxy group, a C ₁ -C ₃ alkyl-S (O) _m group which is optionally partially or fully halogenated, phenylsulfonyl or nitrile,

R ₃ in each case independently means

- phenyl, morpholino group, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, each of which is optionally substituted by 1-3 substituents selected from the group consisting of phenyl, naphthyl, heterocycle or heteroaryl, which are described above in this paragraph, C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl-C ₁ -C ₅ alkyl, naphthyl-C ₁ -C ₅ -alkyl, alkyl hydro sigruppu, nitrile, C ₁ -C ₃ alkyloxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or geterotsikloksigruppu wherein the heteroaryl or heterocyclic moiety as described above in this paragraph, nitro, amino, mono- or di (C ₁ -C ₃ alkyl) amino, phenylamino, naphthylamino, heteroaryl or-nogruppu geterotsiklaminogruppu wherein the heteroaryl or heterocyclic moiety as described above in this paragraph, a group NH ₂ C (O), mono- or di (C ₁ -C ₃ alkyl) amine carbonyl, C ₁ -C ₅ alkyl-C (O) -C ₁ -C ₄ alkyl, mono- or di (C ₁ -C ₃ alkyl) amino, mono- or di (C ₁ -C ₃₎ alkylamino-C ₁ -C ₅ alkyl, a mono- or di (C ₁ -C ₃ alkyl) amino-S (O) ₂ group, R ₇ -C ₁ -C ₅ alkyl, R ₈ -C ₁ -C ₅ alkoxy group, R ₉ -C (O) -C ₁ -C ₅ alkl, a group R ₁₀ -C ₁ -C ₅ alkyl (R ₁₁ ) N and a carboxy-mono or di (C ₁ -C ₅ ) -alkyl amino group,

- a C ₁ -C ₃ alkyl group or a C ₁ -C ₄ alkoxy group, each of which is optionally partially or fully halogenated or optionally substituted with an R ₁₇ group,

- OR ₁₈ or C ₁ -C ₆ alkyl, optionally substituted with an OR ₁₈ group,

an amino group or a mono-di (C ₁ -C ₅ alkyl) amino group optionally substituted with an R ₁₉ group,

- R ₂₀ C (O) N (R ₂₁ ) -, R ₂₂ O-, R ₂₃ R ₂₄ NC (O) -, R _2b CH ₂ C (O) N (R ₂₁ ) - or R ₂₆ C (O) CH ₂ N (R ₂₁ ) -,

- C ₂ -C ₄ alkenyl substituted with a group R ₂₃ R ₂₄ NC (O) -, or

- a C ₂ -C ₄ alkynyl branched or unbranched carbon chain that is optionally partially or completely halogenated and optionally independently substituted with 1-2 oxo groups, pyrrolidinyl, pyrrolyl, morpholinyl, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl alone or ₁ -C ₄ alkyl groups which are optionally substituted with one or more halogen atoms, and

R ₂₃ and R ₂₄ together optionally form an imidazolyl, piperidinyl, morpholinyl, piperazinyl or pyridinyl ring.

According to another embodiment of the invention, among those directly indicated above, those compounds of formula (II) are preferred in which

G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzothiophenyl, dihydrobenzofuranyl, digidrobenzotiofenil, indanyl, indolyl, indolinyl, indolonyl or indolinones, wherein G is substituted by one or more groups R _1, R ₂ or R _3,

Ar means naphthyl,

X is phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl, each of which is optionally independently substituted by 1-3 substituents selected from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy group, hydroxy group, nitrile, amino group, mono or di (C ₁ -C ₃ alkyl) amino group, mono or di (C ₁ -C ₃ alkylamino) carbonyl, NH ₂ C (O) group, C ₁ -C ₆ alkyl-S ( O) _m and halogen,

Y is a bond or a saturated C ₁ -C ₄ carbon chain, wherein one of the carbon atoms is optionally replaced by O, N or S, and Y is optionally independently substituted by an oxo group,

Z means

phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl or pyrrolidinyl, which are optionally substituted with 1-2 C ₁ -C ₂ alkyl groups or C ₁ -C ₂ alkoxy groups,

- tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinosulfoxidyl, piperidinyl, piperidinonyl, piperazinyl or tetrahydropyrimidonyl, which are optionally substituted with 1-2 C ₁ -C ₂ alkyl groups or C ₁ -C ₂ alkoxy groups, or

- C ₁ -C ₃ alkoxygroup,

R ₁ in each case independently means

- C ₁ -C ₅ alkyl, which is optionally partially or fully halogenated and optionally substituted with phenyl, substituted with 0-3 substituents selected from the group consisting of halogen, C ₁ -C ₃ alkyl, which is optionally partially or fully halogenated, a hydroxy group, nitrile and A C ₁ -C ₃ alkoxy group which is optionally partially or fully halogenated,

- cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 substituents selected from the group consisting of C ₁ -C ₃ alkyl, which is optionally partially or fully halogenated, the CN group , hydroxyC ₁ -C ₃ alkyl and phenyl, or an analog of cyclopropyl, cyclobutyl, cyclopentanil, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, where one ring methylene group is replaced by O, or

- silyl independently containing three C ₁ -C ₂ alkyl groups which are optionally partially or fully halogenated,

R ₂ in each case independently means bromo, chloro, fluoro, methoxy, methylsulfonyl or nitrile,

R ₃ in each case independently means

- phenyl, morpholino group, pyridinyl, pyrimidinyl, pyrrolidinyl, 2,5-pyrrolidinedione, imidazolyl, pyrazolyl, each of these radicals optionally substituted by 1-3 substituents selected from the group consisting of C ₁ -C ₃ alkyl, which is optionally partially or fully halogenated, halogen, oxo group, hydroxy group, nitrile and C ₁ -C ₃ alkyloxy group, which is optionally partially or fully halogenated,

- a C ₁ -C ₃ alkyl group or a C ₁ -C ₃ alkoxy group that is optionally partially or fully halogenated or optionally substituted with an R ₁₇ group,

- OR ₁₈ or a C ₁ -C ₃ alkyl group optionally substituted with an OR ₁₈ group,

an amino group or a mono or di (C ₁ -C ₃ alkyl) amino group optionally substituted with an R ₁₉ group,

- R ₂₀ C (O) N (R ₂₁₎ -, R ₂₂ O-, R ₂₃ R ₂₄ NC (O) -, R ₂₆ CH ₂ C (O) N (R ₂₁₎ - or R ₂₆ C (O) CH ₂ N (R ₂₁ ) -,

- C ₂ -C ₄ alkenyl substituted with a group R ₂₃ R ₂₄ NC (O) -, or

- C ₂ -C ₄ alkynyl substituted with pyrrolidinyl or pyrrolyl, and

R ₂₃ and R ₂₄ together optionally form a morpholino group.

According to a further embodiment of the invention, those compounds of formula (II) in which

G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, dihydrobenzofuranyl, indanyl, indolinyl, indolonyl or indolinonyl, wherein G is substituted with one or more groups R ₁ , R ₂ or R ₃ ,

Ar is 1-naphthyl, X is phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl, Y is a bond or —CH ₂ -, —CH ₂ CH ₂ -, —C (O) -, —O— , -S-, -NH-CH ₂ CH ₂ CH ₂ -, -N (CH ₃ ) - or -NH-,

R ₁ in each case independently means

- C ₃ -C ₅ alkyl, which is optionally partially or fully halogenated and optionally substituted with phenyl,

- cyclopropyl, cyclopentanil, cyclohexanyl or bicyclopentanyl, optionally substituted with 1-3 substituents selected from the group consisting of methyl, which is optionally partially or fully halogenated, CN, hydroxymethyl and phenyl, or 2-tetrahydrofuranyl, substituted with methyl, or

- trimethylsilyl,

R ₃ in each case independently means

phenyl, morpholinyl, pyridinyl, pyrimidinyl, pyrrolidinyl, 2,5-pyrrolidinedione, imidazolyl or pyrazolyl, each of these radicals optionally substituted with C ₁ -C ₂ alkyl, which is optionally partially or fully halogenated,

- a C ₁ -C ₃ alkyl group or a C ₁ -C ₃ alkoxy group, each of which is optionally partially or fully halogenated or optionally substituted with a diethylamino group,

- OR ₁₈ or C ₁ -C ₃ alkyl optionally substituted with an OR ₁₈ group,

an amino group or a mono or di (C ₁ -C ₃ alkyl) amino group optionally substituted with an R ₁₉ group,

- CH ₃ C (O) NH-, R ₂₂ O-, R ₂₃ R ₂₄ NC (O) -, R ₂₆ CH ₂ C (O) N (R ₂₁ ) - or R ₂₆ C (O) CH ₂ N ( R ₂₁ ) -,

- C ₂ -C ₄ alkenyl substituted with a group R ₂₃ R ₂₄ NC (O) -, or

- C ₂ -C ₄ alkynyl substituted with pyrrolidinyl or pyrrolyl,

R ₂₃ and R ₂₄ mean H or R ₂₃ and R ₂₄ together optionally form a morpholino group and

R ₂₆ means a morpholino group.

In another embodiment of the invention, among those directly indicated above, those compounds of formula (II) are preferred in which

G is phenyl, pyridinyl or naphthyl, wherein G is substituted with one or more groups R ₁ , R ₂ or R ₃ ,

X is imidazolyl or pyridinyl,

Y is —CH ₂ -, —NH — CH ₂ CH ₂ -, or —NH—,

Z is a morpholino group,

R ₁ in each case independently means tert-butyl, sec-butyl, tertamyl or phenyl,

R ₂ means chlorine and

R ₃ in each case independently means methyl, methoxy group, methoxymethyl, hydroxypropyl, acetamide, morpholino group or morpholinocarbonyl.

In a further embodiment, among those directly indicated above, those compounds of formula (II) are preferred in which X is pyridinyl.

In accordance with another embodiment of the invention, among those directly indicated above, those compounds of formula (II) are preferred in which pyridinyl is attached to Ar at the 3-position of pyridinyl.

As examples of compounds of formula (II) according to the invention, the following can be mentioned:

1- (3-cyanophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (3-fluorophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-chloro-2-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-chloro-5-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (3,4-dimethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (3-iodophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3-m-tolylurea,

1- (4-methylsulfanylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (3-chloro-4-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-chloro-3-nitrophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2,5-dichlorophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3-naphthalene-2-ylurea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3-phenylurea,

1- (3-chlorophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-chloro-3-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (2,4,6-trichlorophenyl) urea,

1- (2-methyl-3-nitrophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-methyl-2-nitrophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2,3-dichlorophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-methoxy-5-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-chloro-6-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2,4-dichlorophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-methyl-3-nitrophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2,4-dimethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2,3-dimethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-cyanophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (3,4,5-trimethoxyphenyl) urea,

1-biphenyl-4-yl-3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2,5-difluorophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (3-chloro-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-fluoro-3-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-benzyloxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-methylsulfanylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-fluoro-6-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-fluoro-3-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (2,4,5-trimethylphenyl) urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (4-trifluoromethylphenyl) urea,

1- (3-methylsulfanylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-fluoro-5-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-methoxy-2-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-fluoro-5-nitrophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-ethoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2,5-dimethoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4,5-dimethyl-2-nitrophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-chloro-2-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-isopropyl-6-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-difluoromethoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-isopropylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- (3-ethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-ethoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-butoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

4- {3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1-yl] -ureido} benzoic acid ethyl ester,

1- (4-butyl-2-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2,6-dibromo-4-isopropylphenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1-yl] urea,

1- (3-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (4-trifluoromethylsulfanylphenyl) urea,

5- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} isophthalic acid dimethyl ester,

1- (3-cyclopentyloxy-4-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} benzoic acid ethyl ester,

1- (5-tert-butyl-2-hydroxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-hydroxymethyl-4-phenylcyclohexyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-methylsulfanyl-5-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (4-pentyloxybiphenyl-3-yl) urea,

4-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} benzoic acid methyl ester,

1- (2,5-diethoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1-benzothiazol-6-yl-3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

N- (2,5-diethoxy-4- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) benzamide,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (3-phenoxyphenyl) urea,

1- (5-ethanesulfonyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

4-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} -N-phenylbenzamide,

1- (2-methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1- silt] urea,

1- (2,3-dimethyl-1H-indol-5-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

N-butyl-4-methoxy-3- [3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} benzenesulfonamide,

1- [3- (2-methyl- [1,3] dioxolan-2-yl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (3-methoxy-5-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2,4-dimethoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-methyl-4-nitrophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-methoxy-4-nitrophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-chloro-2-nitrophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-chloro-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (3,5-dimethoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (4-trifluoromethoxyphenyl) urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (3-trifluoromethylsulfanylphenyl) urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (2-phenoxy-phenyl) urea,

1- (2-methoxy-5-nitrophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-chloro-2,4-dimethoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (3,5-bistrifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-tert-butyl-5-methylpyridin-4-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- (3-methylnaphthalen-2-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (3-tert-butylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-methylbiphenyl-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-tert-butylbiphenyl-2-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-chloro-2,4-dimethoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-isopropyl-2-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-sec-butyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxy-3-propylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxymethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methylphenyl) -3- (4- [6 - [(3-methoxypropyl) methylamino] pyridin-3-yl] naphthalen-1-yl) urea,

1- (5-tert-butyl-2-methylphenyl) -3- [4- (4-morpholin-4-ylmethylimidazol-1-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methylphenyl) -3- {4- [6- (3-methoxypropylamino) pyridin-3-yl] naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methylpyridin-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- (5-tert-butyl-2-morpholin-4-ylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (6-tert-butyl-2-chloro-3-methylpyridin-4-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (3-trifluoromethylphenyl) urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (4-trifluoromethoxyphenyl) urea,

1- [5- (1,1-dimethylpropyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (1H-pyrazol-4-yl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (3-hydroxypropyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (3-morpholin-4-yl-3-oxopropyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl urea

1- [5-tert-butyl-2- (morpholin-4-carbonyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) acetamide

and their pharmaceutically acceptable derivatives.

In addition to the compounds presented above as an example, by the general synthesis methods described below, the following possible compounds of formula (II) can also be prepared:

1- [4- (6 - {[bis (2-cyanoethyl) amino] methyl} pyridin-3-yl) naphthalen-1-yl] -3- (5-tert-butyl-2-methoxyphenyl) urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [4- (2-methyl-3-oxopiperazin-1-ylmethyl) phenyl] naphthalen-1-yl} urea,

1- [4- (6 - [[bis- (2-methoxyethyl) amino] methyl} pyridin-3-yl) naphthalen-1-yl] -3- (5-tert-butyl-2-methoxyphenyl) urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2-methyl-3-oxopiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (1-oxo - [(4-thiomorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea ,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6-thiomorpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methylphenyl) -3- [4- [6- (1-oxo-1l4-thiomorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methylphenyl) -3- {4- [6- (2-methyl-3-oxopiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [4- (1-oxo-1l-thiomorpholin-4-ylmethyl) phenyl] naphthalen-1-yl} urea,

1- [4- (4 - {[bis (2-cyanoethyl) amino] methyl} phenyl) naphthalen-1-yl] -3- (5-tert-butyl-2-methoxyphenyl) urea,

1- (2-methoxy-5-pentafluoroethylphenyl) -3- [4- (4-morpholin-4-ylmethylpiperidin-1-yl) naphthalen-1-yl] urea,

1- (2-methoxy-5-trifluoromethylpyridin-3-yl) -3- {4- [2- (4-oxopiperidin-1-ylmethyl) pyrimidin-5-yl] naphthalen-1-yl} urea,

1- (2-methoxy-5-trimethylsilanylphenyl) -3- {4- [4- (tetrahydropyran-4-ylamino) phenyl] naphthalen-1-yl} urea,

1- (3-methoxynaphthalen-2-yl) -3- [4- (4-morpholin-4-ylmethylpiperidin-1-yl) naphthalen-1-yl] urea,

1- (3-methylnaphthalen-2-yl) -3- [4- (4-morpholin-4-ylmethylphenyl) naphthalen-1-yl] urea,

1- (3-tert-butyl-5-methanesulfinyl phenyl) -3- {4- [6- (1-methylpiperidin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (3-tert-butylphenyl) -3- [4- (3-pyridin-3-ylpropoxy) naphthalen-1-yl] urea,

1- (3-tert-butylphenyl) -3- [4- (4-morpholin-4-ylmethylphenyl) naphthalen-1-yl] urea,

1- (4-methoxybiphenyl-3-yl) -3- {4- [4- (tetrahydropyran-4-ylmethyl) imidazol-1-yl] naphthalen-1-yl} urea,

1- (4-methylbiphenyl-3-yl) -3- {4- [4- (2-pyridin-4-yl-ethyl) piperazin-1-yl] naphthalen-1-yl} urea,

1- (4-tert-butylbiphenyl-2-yl) -3- [4- (pyridin-4-ylmethoxy) naphthalen-1-yl] urea,

1- (4-tert-butylbiphenyl-2-yl) -3- {4- [2- (1-oxo-114-thiomorpholin-4-ylmethyl) -3H-imidazol-4-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-hydroxyphenyl) -3- [4- (5-morpholin-4-ylmethylpyrazin-2-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxy-3-propylphenyl) -3- {4- [4- (pyrrolidin-1-carbonyl) phenyl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (2-morpholin-4-ylmethylpyrimidin-5-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (4-thiomorpholin-4-ylmethylphenyl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylphenyl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [4- (tetrahydropyran-4-ylamino) phenyl] naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (4-methylpiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxypyridin-3-yl) -3- [4- [6- (4-oxoliperidin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methylbenzoxazol-7-yl) -3- [4- (6-pyridin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- (5-tert-butyl-2-methylphenyl) -3- [4- (4-morpholin-4-ylmethylphenyl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-phenoxyphenyl) -3- {4- [6- (tetrahydropyran-4-yloxy) -pyridin-3-yl] naphthalen-1-yl] urea,

1- (5-tert-butyl-2-pyrrolidin-1-ylphenyl) -3- [4- (4-methoxy-6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-pyrrolidin-1-ylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-3-cyano-2-methoxyphenyl) -3- {4- [2- (2,6-dimethyl-morpholin-4-ylmethyl) pyrimidin-5-yl] naphthalen-1-yl }urea,

1- (5-tert-butyl-4'-dimethylaminobiphenyl-3-yl) -3- [4- (2-morpholin-4-ylmethylpyrimidin-5-yl) naphthalen-1-yl] urea,

1- (6-methoxy-3,3-dimethylindan-5-yl) -3- {4- [4- (morpholin-4-carbonyl) phenyl] naphthalen-1-yl} urea,

1- (6-tert-butyl-2-chloro-3-methylpyridin-4-yl) -3- [4- (6-thiomorpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (6-tert-butylbenzo [1,3] dioxo] -4-yl) -3- [4- [6- (morpholin-4-ylamino) pyridin-3-yl] naphthalen-1-yl} urea,

1- (7-methoxy-1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-6-yl) -3- [4- [6- (tetrahydropyran-4-yloxy) pyridin-3-yl ] naphthalene-1-yl} urea,

1- (7-tert-butyl-2,4-dimethyl-benzoxazol-5-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [2-methoxy-5- (1-methyl-1-phenylethyl) phenyl] -3- {4- [6- (2-pyridin-4-yl-ethyl) pyridazin-3-yl] naphthalen-1-yl} urea,

1- [2-methoxy-5- (1-methylcyclohexyl) phenyl] -3- {4- [4- (1-methylpiperidin-4-ylsulfanyl) phenyl] naphthalen-1-yl} urea,

1- [2-methoxy-5- (1-methylcyclopropyl) phenyl] -3- [4- (2-morpholin-4-ylmethylpyrimidin-5-yl) naphthalen-1-yl] urea,

1- [2-methoxy-5- (2-methyl-tetrahydrofuran-2-yl) phenyl] -3- [4- (5-morpholin-4-ylmethylpyridin-2-yl) naphthalen-1-yl] urea,

1- [2-methoxy-5- (3-trifluoromethylbicyclo [1.1.1] pent-1-yl) phenyl] -3- [4- (4-morpholin-4-ylmethylphenyl) naphthalen-1-yl] urea,

1- [3-tert-butyl-5- (1-methyl-1H-imidazol-4-yl) phenyl] -3- [4- (5-morpholin-4-ylmethylpyridin-2-yl) naphthalen-1-yl ]urea,

1- [3-tert-butyl-5- (2-pyrrolidin-1-yl-ethyl) phenyl] -3- {4- [6- (1-methylpiperidin-4-yloxy) -pyridin-3-yl] naphthalen-1- silt} urea,

1- [3-tert-butyl-5- (3-pyrrolidin-1-ylprop-1-ynyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl ]urea,

1- [4- (6-imidazol-1-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- [2-methoxy-5- (1-phenylcyclopropyl) phenyl] urea,

1- [5- (1,1-dimethylpropyl) -2-methoxyphenyl] -3- [4- (4-thiomorpholin-4-ylmethylphenyl) naphthalen-1-yl] urea,

1- [5- (1-cyanocyclopropyl) -2-methoxyphenyl] -3- [4- (2-morpholin-4-ylmethylpyrimidin-5-yl) naphthalene-1-yl] urea,

1- [5- (1-hydroxymethylcyclopropyl) -2-methoxyphenyl] -3- [4- (4-morpholin-4-ylmethylphenyl) naphthalen-1-yl] urea,

1- [5-tert-butyl-1- (2-diethylaminoethyl) -2-oxo-1,2-dihydropyridin-3-yl] -3- {4- [6- (1-methylpiperidin-4-yloxy) pyridine -3-yl] naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (1H-pyrazol-4-yl) phenyl] -3- [4- (2-morpholin-4-ylethoxy) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (1H-pyrazol-4-yl) phenyl] -3- {4- [4- (4-methylpiperazin-1-carbonyl) phenyl] naphthalen-1-yl} urea,

1- [5-tert-butyl-2- (2,5-dioxopyrrolidin-1-yl) phenyl] -3- [4- [6- (1H-imidazol-2-ylmethyl) pyridin-3-yl] naphthalene- 1-yl} urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) phenyl] -3- [4- (5-pyridin-4-ylmethylpyridin-2-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (2-morpholin-4-yl-2-oxoethoxy) phenyl] -3- [4- [6- (2-pyridin-4-yl-ethyl) pyridazin-3-yl] naphthalen-1-yl} urea,

1- [5-tert-butyl-2- (2-morpholin-4-yl-2-oxoethylamino) phenyl] -3- {4- [4- (1-methylpiperidin-4-ylamino) piperidin-1-yl] naphthalen-1-yl} urea,

1- [5-tert-butyl-2- (6-methylpyridin-3-yl) phenyl] -3- {4- [5- (2-pyrrolidin-1-yl-ethyl) pyridin-2-yl] naphthalen-1- silt} urea,

1- [5-tert-butyl-2-methoxy-3- (3-morpholin-4-yl-3-oxopropenyl) phenyl] -3- [4- (6-pyrrolidin-1-ylmethylpyridin-3-yl) naphthalene -1-yl] urea,

1- [5-tert-butyl-3- (2-diethylaminoethoxy) -2-methoxyphenyl] -3- [4- [4- (tetrahydropyran-4-yloxy) phenyl] naphthalen-1-yl} urea,

1- [5-tert-butyl-3- (2-pyrrolidin-1-yl-ethyl) benzofuran-7-yl] -3- [4- (4-morpholin-4-ylmethyl-phenyl) -naphthalen-1-yl] urea,

1- [6-tert-butyl-4- (2-dimethylaminoethyl) -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl] -3- {4- [6- (thiomorpholin-4-ylamino) pyridin-3-yl] naphthalen-1-yl} urea,

1- {5-tert-butyl-2-methoxy-3- [2- (1-methylpiperidin-4-yloxy) ethyl] phenyl} -3- [4- (4-morpholin-4-ylmethylphenyl) naphthalene-1- silt] urea,

2- (4-tert-butyl-2- [3- [4- (5-pyrrolidin-1-ylmethylpyridin-2-yl) naphthalen-1-yl] ureido} phenoxy) -N-methylacetamide,

2- [4-tert-butyl-2- (3- {4- [6- (2,6-dimethylmorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl} ureido) phenoxy] acetamide,

3- (5-tert-butyl-2-methoxy-3- [3- [4- (6-pyrrolidin-1-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) acrylamide,

3- {3-tert-butyl-5- [3- (4- {4- [2- (1-oxo-1l4-thiazolidin-3-yl) ethyl] phenyl} naphthalen-1-yl) ureido] phenyl} -N, N-dimethylpropionamide,

3- {4- [3- (5-tert-butyl-2-methoxyphenyl) ureido] naphthalen-1-yl} benzamide,

4-tert-butyl-2- [3- [4- (2-chloro-4-morpholin-4-ylmethylphenyl) naphthalen-1-yl] ureido} benzamide,

N- (4-tert-butyl-2- {3- [4- (6-oxo-1,6-dihydropyridin-3-yl) naphthalen-1-yl] ureido} phenyl) -2-morpholin-4-yl-acetamide ,

N- [3-tert-butyl-5- (3- {4- [5- (tetrahydropyran-4-ylamino) pyridin-2-yl] naphthalen-1-yl} ureido) phenyl] -2-morpholin-4- acetamide

N- [4-tert-butyl-2- (3- {4- [4- (1-methylpiperidin-4-yloxy) phenyl] naphthalen-1-yl} ureido) phenyl] acetamide

and their pharmaceutically acceptable derivatives.

According to yet another embodiment of the invention, the following compounds of formula (II) are also provided therein:

1- (2-tert-butyl-5-methylpyridin-4-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- (3-methylnaphthalen-2-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (3-tert-butylphenyl) -3- [4- (4-morpholin-4-ylmethylphenyl) naphthalen-1-yl] urea,

1- (3-tert-butylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-methylbiphenyl-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-tert-butylbiphenyl-2-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-chloro-2,4-dimethoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- (5-isopropyl-2-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-sec-butyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxy-3-propylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxymethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (2-morpholin-4-ylmethylpyrimidin-5-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (4-thiomorpholin-4-ylmethylphenyl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylphenyl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [4- (tetrahydropyran-4-ylamino) phenyl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (4-methylpiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methylphenyl) -3- (4- {6 - [(3-methoxypropyl) methylamino] pyridin-3-yl] naphthalen-1-yl) urea,

1- (5-tert-butyl-2-methylphenyl) -3- [4- (4-morpholin-4-ylmethylimidazol-1-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methylphenyl) -3- [4- (4-morpholin-4-ylmethylphenyl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methylphenyl) -3- {4- [6- (3-methoxypropylamino) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methylpyridin-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- (5-tert-butyl-2-morpholin-4-ylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (6-tert-butyl-2-chloro-3-methylpyridin-4-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (6-tert-butyl-2-chloro-3-methylpyridin-4-yl) -3- [4- (6-thiomorpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [2-methoxy-5- (1-methylcyclopropyl) phenyl] -3- [4- (2-morpholin-4-ylmethylpyrimidin-5-yl) naphthalen-1-yl] urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (3-trifluoromethylphenyl) urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (4-trifluoromethoxyphenyl) urea,

1- [5- (1,1-dimethylpropyl) -2-methoxyphenyl] -3- [4- (4-thiomorpholin-4-ylmethylphenyl) naphthalen-1-yl] urea,

1- [5- (1,1-dimethylpropyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5- (1-cyanocyclopropyl) -2-methoxyphenyl] -3- [4- (2-morpholin-4-ylmethylpyrimidin-5-yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (1H-pyrazol-4-yl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) phenyl] -3- [4- (5-pyridin-4-ylmethylpyridin-2-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (3-hydroxypropyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (3-morpholin-4-yl-3-oxopropyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl ]urea,

1- [5-tert-butyl-2- (morpholin-4-carbonyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

2- [4-tert-butyl-2- (3- {4- [6- (2,6-dimethylmorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl] ureido) phenoxy] acetamide,

3- {4- [3- (5-tert-butyl-2-methoxyphenyl) ureido] naphthalen-1-yl} benzamide,

4-tert-butyl-2- [3- [4- (2-chloro-4-morpholin-4-ylmethylphenyl) naphthalen-1-yl] ureido} benzamide

and their pharmaceutically acceptable derivatives.

In another embodiment, it further provides the following compounds of formula (II):

1- (2-tert-butyl-5-methylpyridin-4-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- (3-tert-butylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-methylbiphenyl-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-tert-butylbiphenyl-2-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-isopropyl-2-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-sec-butyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxymethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methylphenyl) -3- (4- {6 - [(3-methoxypropyl) methylamino] pyridin-3-yl] naphthalen-1-yl) urea,

1- (5-tert-butyl-2-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methylpyridin-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- [5- (1,1-dimethylpropyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (1H-pyrazol-4-yl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (3-hydroxypropyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (morpholin-4-carbonyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

N- (5-tert-butyl-2-methoxy-3- [3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) acetamide

and their pharmaceutically acceptable derivatives.

A fourth aspect of the invention are compounds of formula (III):

wherein

E is carbon or a heteroatom-containing group selected from —O—, —NH— and —S—,

G means

- aromatic C ₆ -C ₁₀ carbocycle or saturated or unsaturated non-aromatic C ₃ -C ₁₀ carbocycle,

A 6-14 membered monocyclic, bicyclic or tricyclic heteroaryl containing one or more heteroatoms selected from O, N and S,

A 6-8 membered monocyclic heterocycle containing one or more heteroatoms selected from O, N and S, or

An 8-11 membered bicyclic heterocycle containing one or more heteroatoms selected from O, N and S, wherein G is optionally substituted with one or more groups R ₁ , R ₂ or R ₃ ,

Ar is phenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzimidazolyl, benzofuranyl, dihydrobenzofuranyl, indolinyl, benzothienyl, dihydrobenzothienyl, indanyl, indenyl or indolyl, each of which is optionally substituted by one or more groups R ₄ or R _5,

X means

- C ₅ -C ₈ cycloalkyl or cycloalkenyl, optionally substituted with 1-2 oxo groups or 1-3 C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy or C ₁ -C ₄ alkylamino chains, each of which is branched or unbranched,

- aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperidinyl, benzimidazole, 3H-imidazo [4,5-b] pyridinyl, pyridinyl, pyridinyl, pyridinyl, optionally independently substituted by 1-3 substituents selected from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy, hydroxy, nitrile, amino, mono or di (C ₁ -C ₃ alkyl) amino, mono or di (C ₁ -C ₃ alkylamino) carbonyl, an NH ₂ C (O) group, a C ₁ -C ₆ alkyl-S (O) _m group and halogen,

Y is a bond or a saturated or unsaturated branched or unbranched C ₁ -C ₄ carbon chain that is optionally partially or fully halogenated, with one or more C atoms optionally replaced with O, N or S (O) _m , and Y is optionally independently substituted by 1-2 oxo groups, nitrile, phenyl or one or more C ₁ -C ₄ alkyl groups which are optionally substituted by one or more halogen atoms,

Z means

aryl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl and pyranyl, heterocycle selected from tetrahydropyrimidonyl, cyclohexanone-cyclo-2-thanol -azabicyclo [2.2.1] heptanyl, pentamethylene sulfidyl, pentamethylene sulfoxidil, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidil or tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolananonyl, 1,3-di 4-dioxapyl, morpholino group, thiomorpholino group, thiomorpholinosulfoxidil, thiomorpholinosulfonyl, piperidinyl, piperidinonyl, pyrrolidinyl and dioxolanyl,

wherein each of the above as values of Z groups is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy group, C ₁ -C ₃ alkoxy-C ₁ -C ₃ alkyl, C ₁ -C ₆ alkoxycarbonyl, aroyl, C ₁ -C ₃ acyl, oxo, hydroxy, pyridinyl-C ₁ -C ₃ alkyl, imidazolyl-C ₁ -C ₃ alkyl, tetrahydrofuranyl-C ₁ -C5 alkyl, nitrile-C _{C1 3} alkyl, nitrile, carboxy, phenyl wherein the phenyl ring is optionally substituted by 1-2 halogen atoms, C ₁ -C ₆ alkoxy, hydroxy or mono- or di- (C ₁ -C ₃ alkyl) Aminogen uppami, group C ₁ -C ₆ alkyl-S (O) _m group and phenyl-S (O) _m, wherein the phenyl ring is optionally substituted by 1-2 halogen atoms, C ₁ -C ₆ alkoxy, hydroxy or mono- or di- ( C ₁ -C ₃ alkyl) amino groups,

or Z is optionally substituted with 1-3 amino groups or amino-C ₁ -C ₃ alkyl groups, with the N-atom optionally independently mono-or disubstituted with amino C ₁ -C ₆ alkyl, C ₁ -C ₃ alkyl, arylC ₀ -C ₃ alkyl , C ₁ -C ₅ alkoxyC ₁ -C ₃ alkyl, C ₁ -C ₅ alkoxy group, aroyl, C ₁ -C ₃ acyl, C ₁ -alkyl-C ₃ (O) _m group or aryl C ₀ -C ₃ alkyl group -S (O) _m -, wherein each of these alkyls and aryls attached to the amino group is optionally substituted with 1-2 halogen atoms, C ₁ -C ₆ alkyl groups or C ₁ -C ₆ alkoxy groups, or Z is optionally substituted with 1- 3 aryl gr ppami, heterocyclic or heteroaryl groups as described above in this paragraph, wherein each of said groups in turn optionally substituted by halogen, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy, or Z is hydroxy, halogen, nitrile, an amino group, where the N atom is optionally independently mono-or disubstituted with C ₁ -C ₃ acyl, C ₁ -C ₆ alkyl or C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl, branched or unbranched C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, C ₁ -C ₃ acylamino, nitrilS ₁ -C ₄ alkyl group C ₁ -C ₆ alkyl-S (O) _m group or dryer L-S (O) _m, wherein the phenyl ring is optionally substituted by 1-2 halogen atoms, C ₁ -C ₆ alkoxy, hydroxy or mono- or di- (C ₁ -C ₃ alkyl) amino,

R ₁ in each case independently means

branched or unbranched C ₁ -C ₁₀ alkyl, which is optionally partially or fully halogenated, with one or more C-atoms optionally independently replaced by O, N or S (O) _m , and said C ₁ -C ₁₀ alkyl is optionally substituted 1 -3 substituents selected from the group consisting of C ₁ -C ₁₀ cycloalkyl, hydroxy, oxo, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolany, dioxazolany wherein each of said substituent optionally substituted with 1-5 substituents selected from halo, C ₁ -C ₆ alkyl which is optionally partially or fully halogenated, C ₃ -C ₈ cycloalkanyl, C ₅ -C ₈ cycloalkenyl, hydroxy, nitrile, C ₁ -C ₃ alkoxy, which is optionally partially or fully halogenated, NH ₂ C (O) groups, a mono or di (C ₁ -C ₃ alkyl) amino group and a mono or di (C ₁ -C ₃ alkyl) aminocarbonyl,

or R ₁ means

- cyclopropyloxy, tsiklobutiloksigruppu, cyclopentyloxy, cyclohexyloxy or cycloheptyloxy, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 substituents selected from the group consisting of C ₁ -C ₃ alkyl which is optionally partially or fully halogenated, nitrile, hydroxyC ₁ -C ₃ alkyl and aryl, or an analogue of such a cycloalkyl group, in which 1-3 ring methylene groups are independently replaced by O, S (O) _m , CHOH,> C = O,> C = S or NH,

- a phenyloxy group or benzyloxy group, each of which is optionally partially or completely halogenated and optionally substituted with 1-3 substituents selected from the group consisting of C ₁ -C ₃ alkyl, which is optionally partially or fully halogenated, nitrile, hydroxyC ₁ -C ₃ alkyl and aryl or an analog of such a cycloaryl group in which 1-2 ring methylene groups are independently replaced by N,

- cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 substituents selected from the group consisting of C ₁ -C ₃ alkyl, which is optionally partially or fully halogenated, nitrile, hydroxyC ₁ -C ₃ alkyl and aryl, or an analog of such a cycloalkyl group in which 1-3 ring methylene groups are independently replaced by O, S (O) _m , CHOH,> C = O,> C = S or NH

- branched or unbranched C ₃ -C ₁₀ alkenyl, which in each case is optionally partially or fully halogenated and optionally substituted with 1-3 substituents selected from the group consisting of branched or unbranched C ₁ -C ₅ alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl , pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl and isothiazolyl, with each of these substituents being substituted with 1-5 substituents selected from the group consisting of halogen, C ₁ -C ₆ alkyl, which is optionally partially il and fully halogenated, cyclopropanes, cyclobutanes, cyclopentanes, cyclohexane tsiklogeptanil, bitsiklopentanil, bitsiklogeksanil or bitsiklogeptanil, hydroxy, nitrile, C ₁ -C ₃ alkyloxy which is optionally partially or fully halogenated, NH ₂ group C (O) and mono- or di (C ₁ -C ₃ alkyl) aminocarbonyl, wherein said branched or unbranched C ₁ -C ₁₀ alkenyl is optionally interrupted by one or more heteroatoms selected from O, N and S (O) _m ,

- cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, wherein such a cycloalkenyl group is optionally substituted with 1-3 C ₁ -C ₃ alkyl groups,

- oxo group, nitrile, halogen,

- silyl containing three C ₁ -C ₄ alkyl groups that are optionally partially or fully halogenated, or

- a C ₃ -C ₆ alkynyl branched or unbranched carbon chain which is optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S (O) _m , and said alkynyl group is optionally independently substituted 1-2 oxo, hydroxy, pyrrolidinyl, pyrrolyl, tetrahydropyranyl, one or more C ₁ -C ₄ alkyl groups optionally substituted with one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazino , Imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di (alkyl) amino optionally substituted by one or more halogen atoms,

R ₂ , R ₄ and R ₅ each means

- branched or unbranched C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated, C ₁ -C ₆ acyl, aroyl, branched or unbranched C ₁ -C ₄ alkoxy, which in each case is optionally partially or fully halogenated, halogen, methoxycarbonyl a C ₁ -C ₃ alkyl-S (O) _m group that is optionally partially or fully halogenated, or a phenyl-S (O) _m group,

- OR ₆ , C ₁ -C ₆ alkoxy group, hydroxy group, nitrile, nitro group, halogen or

- an amino-S (O) _m - group, where the N-atom is optionally independently mono- or disubstituted by C ₁ -C ₆ alkyl or arylC ₁ -C ₆ alkyl, or an amino group, where the N-atom is optionally independently mono-or disubstituted by C ₁ -C ₃ alkyl, aryl C ₀ -C ₃ alkyl, C ₁ -C ₆ acyl, a group C ₁ -C ₆ alkyl-S (O) _{m -} or a group aryl C ₀ -C ₃ alkyl-S (O) _m -, when each of the alkyls and aryls referred to in this paragraph is optionally partially or fully halogenated and optionally substituted with 1-2 C ₁ -C ₆ alkyl groups or C ₁ -C ₆ alkoxy groups,

R ₃ in each case independently means

- phenyl, naphthyl, morpholino group, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, [1,3,4] oxadiazole, triazolyl, tetrazolyl, thienyl, isazuryl, tetrazolyl, furylazol, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl indobenylphenyl, optionally 1-3 substituents selected from the group consisting of phenyl, naphthyl, heterocycle or heteroaryl, which are described in this paragraph, branched or unbranched C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanil, cyclohexanyl, cycloheptanil , bicyclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl-C ₁ -C ₅ alkyl, naphthyl-C ₁ -C ₅ alkyl, halogen, hydroxy group, oxo group, nitrile, C ₁ -C ₃ alkoxy group, which is optionally partially or fully halogenated, phenyloxy group a naphthyloxy group, a heteroaryloxy group or a heterocycloxy group, where the heterocyclic or heteroaryl moiety is described above in this paragraph, a nitro group, an amino group, a mono or di (C ₁ -C ₃ alkyl) amino group, a phenylamino group, a heteroaryl aryl aryloarylamino group in this paragraph, the NH ₂ C (O) group, mono- or di (C ₁ -C ₃ alkyl) aminocarbonyl, C ₁ -C ₅ alkyl-C (O) -C ₁ -C ₄ alkyl, amino-C ₁ - C ₅ alkyl, mono or di (C ₁ -C ₅ alkyl) amino group, mono or di (C ₁ -C ₃ alkyl) am foreign C ₁ -C ₅ alkyl, an amino-S (O) ₂ group, a di (C ₁ -C ₃ alkyl) amino-S (O) ₂ group, R ₇ -C ₁ -C ₅ alkyl, R ₈ -C ₁ -C ₅ alkoxy group, R ₉ -C (O) -C ₁ -C ₅ alkyl, the group R ₁₀ -C ₁ -C ₅ alkyl (R ₁₁ ) N and carboxy-mono or di (C ₁ -C ₅ alkyl ) an amino group,

- a fused aryl selected from benzotsiklobutanila, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzotsiklogeptanila and benzotsiklogeptenila or fused heteroaryl selected from tsiklopentenopiridinila, tsiklogeksanopiridinila, tsiklopentanopirimidinila, tsiklogeksanopirimidinila, tsiklopentanopirazinila, tsiklogeksanopirazinila, tsiklopentanopiridazinila, tsiklogeksanopiridazinila, tsiklopentanohinolinila, tsiklogeksanohinolinila, tsiklopentanoizohinolinila, tsiklogeksanoizohinolinila, cyclopentanoindolyl, iklogeksanoindolila, tsiklopentanobenzimidazolila, tsiklogeksanobenzimidazolila, tsiklopentanobenzoksazolila, tsiklogeksanobenzoksazolila, tsiklopentanoimidazolila, tsiklogeksanoimidazolila, and tsiklopentanotienila tsiklogeksanotienila, said fused aryl or fused heteroaryl ring is independently substituted with 0-3 substituents selected from the group consisting of phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl , pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl, isothiazolyl, C ₁ -C ₆ al a keel that is optionally partially or fully halogenated, halogen, nitrile, a C ₁ -C ₃ alkyloxy group that is optionally partially or fully halogenated, a phenyloxy group, a naphthyloxy group, a heteroaryloxy group or a heterocycloxy group, wherein a heteroaryl or heterocyclic moiety is described above in this paragraph, a mono or di (C ₁ -C ₃ alkyl) amino group, phenylamino group, naphthylamino group, heteroarylamino group or heterocyclamino group, where a heteroaryl or heterocyclic fragment is described above in this paragraph, an NH ₂ C (O) group, mono- or di (C ₁ -C ₃ alkyl) aminocarbonyl, a C ₁ -C ₄ alkyl-OC (O) group, C ₁ -C ₅ alkyl-C ( O) -C ₁ -C ₄ alkyl, amino-C ₁ -C ₅ alkyl, mono-or di (C ₁ -C ₃ ) alkylamino-C ₁ -C ₅ alkyl, R ₁₂ -C ₁ -C ₅ alkyl, R ₁₃ -C ₁ -C ₅ alkoxy group, R ₁₄ -C (O) -C ₁ -C ₅ alkyl and the group R ₁₅ -C ₁ -alkylC ₅ R ₁₆ ) N,

- cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 C ₁ -C ₃ alkyl groups, or an analog of such a cycloalkyl group in which 1-3 ring methylene groups are independently replaced by O, S, CHOH,> C = O,> C = S or NH,

- cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadienyl, bicyclohexenyl or bicycloheptenyl, each of which is optionally substituted with 1-3 C ₁ -C ₃ alkyl groups,

- C ₁ -C ₄ alkylphenyl-C (O) -C ₁ -C ₄ alkyl-, C ₁ -C ₄ alkyl-C (O) -C ₁ -C ₄ alkyl- or C ₁ -C ₄ alkylphenyl-S ( O) _m -C ₁ -C ₄ alkyl-,

- a C ₁ -C ₆ alkyl group or a branched or unbranched C ₁ -C ₆ alkoxy group, each of which is optionally partially or fully halogenated or optionally substituted with an R ₁₇ group,

- OR ₁₈ or C ₁ -C ₆ alkyl, optionally substituted with an OR ₁₈ group,

an amino group or a mono or di (C ₁ -C ₅ alkyl) amino group optionally substituted with an R ₁₉ group,

- R ₂₀ C (O) N (R ₂₁ ) -, R ₂₂ O, R ₂₃ R ₂₄ NC (O) -, R ₂₆ (CH ₂ ) _m C (O) N (R ₂₁ ) -, R ₂₃ R ₂₄ NC (O) -C ₁ -C ₃ alkoxy group or R ₂₆ C (O) (CH ₂ ) _m N (R ₂₁ ) -,

- C ₁ -C ₆ alkenyl substituted with a group R ₂₃ R ₂₄ NC (O) -,

- a C ₂ -C ₆ alkynyl branched or unbranched carbon chain that is optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH, S (O) _m , and said alkynyl group is optionally independently substituted 1-2 oxo groups, pyrrolidinyl, pyrrolyl, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl one or more C ₁ -C ₄ alkyl groups which are optionally substituted by one or more halo atoms ene nitrile morfolinogrupoy, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or mono- or di (C ₁ -C ₄ alkyl) amino optionally substituted by one or more halogen atoms,

- C ₁ -C ₆ acyl or aroyl,

R ₆ means C ₁ -C ₄ alkyl, which is optionally partially or fully halogenated and optionally substituted with a group R ₂₆ ,

R ₇ , R ₈ , R ₉ , R ₁₀ , R ₁₂ , R ₁₃ , R ₁₄ , R ₁₅ , R ₁₇ , R ₁₉ , R ₂₅ and R ₂₆ each independently of one another means nitrile, phenyl, morpholino group, piperidinyl, piperazinyl , imidazolyl, pyridinyl, tetrazolyl, an amino group or a mono or di (C ₁ -C ₄ alkyl) amino group, which is optionally partially or fully halogenated,

R ₁₁ and R ₁₆ each independently of one another means hydrogen or C ₁ -C ₄ alkyl, which is optionally partially or fully halogenated,

R ₁₈ in each case independently means hydrogen or C ₁ -C ₄ alkyl, which is optionally independently substituted by an oxo group or an R ₂₅ group,

R ₂₀ in each case independently means C ₁ -C ₁₀ alkyl, which is optionally partially or fully halogenated, phenyl or pyridinyl,

R ₂₁ in each case independently means hydrogen or C ₁ -C ₃ alkyl, which is optionally partially or fully halogenated,

R ₂₂ , R ₂₃ and R ₂₄ each independently of one another means hydrogen, C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated, wherein said C ₁ -C ₆ alkyl is optionally interrupted by one or more O, N or S atoms and also independently optionally substituted with a mono- or di (C ₁ -C ₃ alkyl) aminocarbonyl, phenyl, pyridinyl, amino group or a mono or di (C ₁ -C ₄ alkyl) amino group, each of these radicals optionally partially or fully halogenated and optionally substituted with mono- or di (C ₁ -C ₃ alkyl) amino, whether

R ₂₃ and R ₂₄ together optionally form a heterocyclic or heteroaryl ring,

m is 0, 1 or 2 and

W means O or S,

and their pharmaceutically acceptable derivatives.

In another embodiment, among the above, preferred are those compounds of formula (III) in which

E means —CH ₂ -, —NH— or —O—,

W means O and

G means

- phenyl, naphthyl, benzocyclobutanil, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl,

- pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetragidrohinoil, isoquinolinyl, tetragidroizohinoil, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpirazolil, dihydrobenzofuranyl, dibenzofuranyl, digidrobenzotiofenil, benzooksazolonil, benzo [1,4] oxazin-3 -onyl, benzodioxolyl, benzo [1,3] dioxol-2-onyl, benzofuran-3-onyl, tetrahydrobenzopyranyl, indolyl, 2,3-dihydro-1H-indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl,

- oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholino, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, 3,4-dihydro-2H-azinodinyl-1,4-azinodinyl-1,4-azinodinyl] 1,4-azinodinyl] 1,4-di-azinodinyl] 1,4-dihydro-azinoyl-2-di-azinodinyl] pyrrolynyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholino group, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanil, heptacanil, thioxanil or dithianil, with G optionally substituted with one or more E groups R _1, R ₂ or R _3.

According to another embodiment of the invention, among those directly indicated above, those compounds of formula (III) are preferred in which

E means —NH—,

G means phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, benzimidazolyl, benzooxazolyl, benzooxazolonyl, benzofuranyl, benzothiophenyl, benzopyrazolyl, dihydrobenzofuranyl, dihydrobenzothiene-2-dienoyl-2-dienoyl-2-dienoyl-2-di-phenyl-2-di-phenyl-2-di-phenyl-2-di-phenyl-2-di-azheni-2-di-phenyl-2-di-phenyl-2-di-phenyl-2-di-phenyl-2-di-phenyl-2-di-phenyl-2-di-phenyl-2-di-phenyl-2-di-phenyl-benzothiophenyl indenyl, indolyl, indolinyl, indolonyl, 2,3-dihydro-1H-indolyl or indolinonyl, wherein G is optionally substituted with one or more groups R ₁ , R ₂ or R ₃ ,

Ar means naphthyl, quinolinyl, isoquinolinyl, tetrahydronaphthyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, indanyl, indenyl or indolyl, each of which is optionally substituted with one or more R ₄ or R ₅ groups,

X is phenyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl, independently of which 1 to 3 are optionally selected, C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy group, hydroxy group, nitrile, amino group, mono or di (C ₁ -C ₃ alkyl) amino group, mono or di (C ₁ -C ₃ alkylamino) carbonyl, NH group ₂ C (O), a group C ₁ -C ₆ alkyl-S (O) _m and halogen,

Y is a bond or a saturated or unsaturated C ₁ -C ₄ carbon chain, where one or more C atoms are optionally replaced with O, N or S (O) _m , and Y is optionally independently substituted with 1-2 oxo groups, nitrile, phenyl or one or more C ₁ -C ₄ alkyl groups optionally substituted with one or more halogen atoms,

Z means

phenyl, heteroaryl selected from pyridinyl, piperazinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl and pyranyl, heterocycle selected from 2-oxa-5-azabicyclo [2.2.1] heptane, tetragidropirimidonila, pentamethylene, pentametilensulfoksidila, pentamethylene sulfone, tetramethylene sulfidyl, tetramethylene sulfoxidil, tetramethylene sulfonyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholino group, thiomorpholino group, thiomorpholinosulfoxidyl, piperide nyl, piperidinonyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidil, pyrrolidinyl and dioxolanyl, each of which is optionally substituted with 1-3 substituents selected from the group consisting of nitrile, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy group, amino group, mono or di ( C ₁ -C ₃ alkyl) amino group, CONH ₂ group and OH group,

or Z is optionally substituted with phenyl, heterocycle or heteroaryl, as defined above in this paragraph, each of which, in turn, is optionally substituted with halogen, C ₁ -C ₃ alkyl or C ₁ -C ₃ alkoxy group,

or Z is nitrile, nitrile C ₁ -C ₃ alkyl, a group C ₁ -C ₆ alkyl-S (O) _m , halogen, hydroxy group, C ₁ -C ₃ alkyl, C ₁ -C ₃ acylamino group, C ₁ -C ₄ alkoxy group , an amino group, a mono or di (C ₁ -C ₃ alkyl) aminocarbonyl or an amino group, mono or disubstituted with an amino C ₁ -C ₆ alkyl or C ₁ -C ₃ alkoxyC ₁ -C ₃ alkyl,

R ₁ in each case independently means

- branched or unbranched C ₁ -C ₆ alkyl which is optionally partially or fully halogenated, wherein one or more C-atoms are optionally independently replaced with O, N or S (O) _m , and said C ₁ -C ₆ alkyl is optionally substituted 1-3 substituents selected from the group consisting of C ₃ -C ₆ cycloalkyl, oxo, phenyl, dioxolanyl, pyrrolidinyl, furyl, isoxazolyl or isothiazolyl, each of which is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C ₁ -C ₃ alkyl which is optionally partially or p lnostyu halogenated, hydroxy, nitrile and C ₁ -C ₃ alkoxy which is optionally partially or fully halogenated,

- cyclopropyl, cyclobutyl, cyclopentanil, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 C ₁ -C ₃ alkyl groups that are optionally partially or fully halogenated, nitrile, hydroxyC ₁ -C ₃ alkyl or phenyl, or an analog of such a cycloalkyl group, in which 1-3 ring methylene groups are independently replaced by O, S, CHOH,> C = O,> C = S or NH,

- oxo group,

- a C ₃ -C ₆ alkynyl branched or unbranched carbon chain which is optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, NH or S (O) _m , and said alkynyl group is optionally independently substituted 1-2 oxo, hydroxy, pyrrolidinyl, pyrrolyl, tetrahydropyranyl, C ₁ -C ₄ alkyl, which is optionally substituted by one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyrid Neal, tetrazolyl, or mono- or di (C ₁ -C ₃ alkyl) amino group which is optionally substituted by one or more halogen atoms, or

- silyl containing three C ₁ -C ₄ alkyl groups that are optionally partially or fully halogenated,

R ₂ in each case independently means

- branched or unbranched C ₁ -C ₅ alkyl, which is optionally partially or fully halogenated, acetyl, aroyl, branched or unbranched C ₁ -C ₄ alkoxy, which in each case is optionally partially or fully halogenated, halogen, methoxycarbonyl, group C ₁ - C ₂ alkyl-S (O) _m , which is optionally partially or fully halogenated, or a phenyl-S (O) _m group,

- a C ₁ -C ₃ alkoxy group, a hydroxy group, a nitrile, a nitro group, a halogen, or

an amino-S (O) _m - group, where the N atom is optionally independently mono- or disubstituted with C ₁ -C ₃ alkyl or arylC ₀ -C ₃ alkyl, or an amino group, where the N-atom is optionally independently mono- or disubstituted with C ₁ -C ₃ alkyl, aryl C ₀ -C ₃ alkyl, C ₁ -C ₃ acyl, a group C ₁ -C ₄ alkyl-S (O) _m - or an arylC ₀ -C ₃ alkyl-S (O) _m - group, with each of the alkyls and aryls indicated in this paragraph is optionally partially or completely halogenated and optionally substituted with 1-2 C ₁ -C ₃ alkyl groups or C ₁ -C ₃ alkoxy groups,

R ₃ in each case independently means

- phenyl, morpholino group, pyridinyl, pyrimidinyl, pyrazinyl, pyrrolyl, pyrrolidinyl, imidazolyl, [1,3,4] oxadiazole, pyrazolyl, each of which is optionally substituted by 1-3 substituents selected from the group consisting of phenyl, naphthyl, heterocycle or heteroaryl as described above in this paragraph, C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated, cyclopropanil, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bipiclopentanyl, bicyclohexanyl, bicycloheptanyl, phenyl-C _{1 -5-} alkyl, C ₁ -C ₅ alkyl, halogen, oxog Rupp, hydroxy, nitrile, C ₁ -C ₃ alkoxy which is optionally partially or fully halogenated, phenyloxy, naphthyloxy, heteroaryloxy or geterotsikloksigruppu wherein the heteroaryl or heterocyclic moiety as described above in this paragraph, nitro, amino, mono- or di (C ₁ -C ₃ alkyl) amino group, phenylamino group, naphthylamino group, heteroarylamino group or heterocyclamino group, where a heteroaryl or heterocyclic moiety is described above in this paragraph, an NH ₂ C (O) group, mono or di (C ₁ -C ₃ al keel) aminocarbonyl, C ₁ -C ₅ alkyl-C (O) -C ₁ -C ₄ alkyl, a mono- or di (C ₁ -C ₃ alkyl) amino group, a mono-or di (C ₁ -C ₃ ) alkylamino C ₁ -C ₅ alkyl, a mono- or di (C ₁ -C ₃ alkyl) amino-S (O) ₂ group, R ₇ -C ₁ -C ₅ alkyl, R ₈ -C ₁ -C ₅ alkoxy group, R ₉ -C (O) -C ₁ -C ₅ alkyl, a group R ₁₀ -C ₁ -C ₅ alkyl (R ₁₁ ) N and a carboxy-mono or di (C ₁ -C ₅ ) -alkylamino group,

- a C ₁ -C ₃ alkyl group or a C ₁ -C ₄ alkoxy group, each of which is optionally partially or fully halogenated or optionally substituted with an R ₁₇ group,

- OR ₁₈ or C ₁ -C ₆ alkyl, optionally substituted with an OR ₁₈ group,

an amino group or a mono or di (C ₁ -C ₅ alkyl) amino group optionally substituted with an R ₁₉ group,

- R ₂₀ C (O) N (R ₂₁ ) -, R ₂₂ O-, R ₂₃ R ₂₄ NC (O) -, R ₂₆ CH ₂ C (O) N (R ₂₁ ) -, R ₂₃ R ₂₄ NC ( O) -C ₁ -C ₂ alkoxy group or R ₂₆ C (O) CH ₂ N (R ₂₁ ) -,

- C ₂ -C ₄ alkenyl substituted with a group R ₂₃ R ₂₄ NC (O) -,

- a C ₂ -C ₄ alkynyl branched or unbranched carbon chain which is optionally partially or fully halogenated, wherein one of the methylene groups is optionally replaced by O and optionally independently substituted by 1-2 oxo groups, pyrrolidinyl, pyrrolyl, morpholino group, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl or one or more C ₁ -C ₄ alkyl groups optionally substituted with one or more halogen atoms, or

- C ₁ -C ₃ acyl and

R ₂₃ and R ₂₄ together optionally form an imidazolyl, piperidinyl, morpholine, piperazinyl or pyridinyl ring.

According to a further embodiment of the invention, among those directly indicated above, those compounds of formula (III) are preferred in which

G is phenyl, pyridinyl, pyridonyl, naphthyl, quinolinyl, isoquinolinyl, pyrazinyl, 3,4-dihydro-2H-benzo [1,4] oxazinyl, benzothiophenyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazolyl, indanylonyl indole or indolinyl indole wherein G is optionally substituted with one or more groups R ₁ , R ₂ or R ₃ ,

Ar means naphthyl,

X is phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl, each of which is optionally independently substituted by 1-3 substituents selected from the group consisting of C ₁ -C ₄ alkyl, C ₁ -C ₄ alkoxy group, hydroxy group, nitrile, amino group, mono or di (C ₁ -C ₃ alkyl) amino group, mono or di (C ₁ -C ₃ alkylamino) carbonyl, NH ₂ C (O) group, C ₁ -C ₆ alkyl-S ( O) _m and halogen,

Y is a bond or a saturated C ₁ -C ₄ carbon chain, where one or more C atoms is optionally replaced with O, N or S, and Y is optionally independently substituted with a nitrile or oxo group,

Z is phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, digidrotiazolilsulfoksid, pyranyl, pyrrolidinyl, phenylpiperazinyl, tetrahydropyranyl, tetrahydrofuranyl, dioxolanyl, 2-oxa-5-azabicyclo [2.2.1] heptanyl, morpholino, thiomorpholino, tiomorfolinosulfoksidil, piperidinyl, piperidinonyl, piperazinyl or tetrahydropyrimidonyl, each of which is optionally substituted with 1-2 C ₁ -C ₂ alkyl groups or C ₁ -C ₂ alkoxy groups, or

Z is hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ acylamino, C ₁ -C ₃ alkylsulfonyl, nitrile-C ₁ -C ₃ alkyl or amino, mono- or di-substituted by C ₁ - C ₃ alkoxyC ₁ -C ₃ alkyl,

R ₁ in each case independently means

- branched or unbranched C ₁ -C ₅ alkyl, which is optionally partially or fully halogenated, with one or more C-atoms optionally independently replaced by O, N or S (O) _m , and said C ₁ -C ₅ alkyl is optionally substituted oxo group, dioxolanyl, pyrrolidinyl, furyl or phenyl, each of which is optionally substituted with 1-3 substituents selected from the group consisting of halogen, C ₁ -C ₃ alkyl, which is optionally partially or fully halogenated, hydroxy group, nitrile and C ₁ -C ₃ alkoxy group which is optional partially or fully halogenated,

- cyclopropyl, cyclobutyl, cyclopentanil, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, each of which is optionally partially or fully halogenated and optionally substituted with 1-3 C ₁ -C ₃ alkyl groups that are optionally partially or fully halogenated, nitrile, hydroxyC ₁ -C ₃ alkyl or phenyl, or an analog of cyclopropyl, cyclobutyl, cyclopentanil, cyclohexanyl, bicyclopentanyl or bicyclohexanyl, in which one ring methylene group is replaced by O,

- oxo group,

- C ₂ -C ₄ alkynyl, which is optionally partially or fully halogenated, with one or more methylene groups optionally replaced by O, and optionally independently substituted by 1-2 oxo groups, hydroxy group, pyrrolidinyl, pyrrolyl, tetrahydropyranyl, C ₁ -C ₄ alkyl which is optionally substituted with one or more halogen atoms, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl or a mono or di (C ₁ -C ₃ alkyl) amino group which is optionally substituted with one him or several halogen atoms, or

- silyl containing three C ₁ -C ₂ alkyl groups that are optionally partially or fully halogenated,

R ₂ in each case independently means C ₁ -C ₄ alkyl, which is optionally partially or fully halogenated, C ₁ -C ₄ alkoxy, which is optionally partially or fully halogenated, bromine, chlorine, fluorine, methoxycarbonyl, methyl-S (O) group _m or ethyl-S (O) _m , each of which is optionally partially or fully halogenated, or a phenyl-S (O) _m group,

or R ₂ is a mono- or diC ₁ -C ₃ acylamino, amino group-S (O) _m or S (O) _m amino group, wherein N-atom mono- or disubstituted with C ₁ -C ₃ alkyl or phenyl, nitrile, a nitro group or an amino group,

R ₃ in each case independently means

- phenyl, morpholino group, pyridinyl, pyrimidinyl, pyrrolidinyl, 2,5-pyrrolidinedione, imidazolyl, [1,3,4] oxadiazole, pyrazolyl, each of which is optionally substituted by 1-3 substituents selected from the group consisting of C ₁ -C ₃ alkyl which is optionally partially or fully halogenated, halogen, oxo group, hydroxy group, nitrile and C ₁ -C ₃ alkoxy group, which is optionally partially or fully halogenated,

- a C ₁ -C ₃ alkyl group or a C ₁ -C ₃ alkoxy group that is optionally partially or fully halogenated or optionally substituted with an R ₁₇ group,

- OR ₁₈ or C ₁ -C ₃ alkyl optionally substituted with an OR ₁₈ group,

an amino group or a mono or di (C ₁ -C ₃ alkyl) amino group optionally substituted with an R ₁₉ group,

- R ₂₀ C (O) N (R ₂₁ ) -, R ₂₂ O-, R ₂₃ R ₂₄ NC (O) -, R ₂₆ CH ₂ C (O) N (R ₂₁ ) -, NH ₂ C (O) methoxy group or R ₂₆ C (O) CH ₂ N (R ₂₁ ) -,

- C ₂ -C ₄ alkenyl substituted with a group R ₂₃ R ₂₄ NC (O) -,

- C ₂ -C ₄ alkynyl substituted with pyrrolidinyl or pyrrolyl, or

- C ₁ -C ₃ acyl and

R ₂₃ and R ₂₄ together optionally form a morpholino group.

In accordance with another embodiment of the invention, among those directly indicated above, those compounds of formula (III) are preferred in which

G is phenyl, pyridinyl, pyridonyl, 2-naphthyl, quinolinyl, isoquinolinyl, dihydrobenzofuranyl, indanyl, 5-indolyl, 3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl, benzooxalolyl, 2,3-dihydrobenzooxazol-7-yl, 2-oxo-2,3-dihydro-1H-indol-5-yl, indolinyl, indolonyl or indolinonyl, wherein G is optionally substituted with one or more groups R ₁ , R ₂ or R ₃

Ar means 1-naphthyl,

X is phenyl, imidazolyl, pyridinyl, pyrimidinyl, piperidinyl, piperazinyl, pyridazinyl or pyrazinyl,

Y is a bond or —CH ₂ -, —CH ₂ CH ₂ -, —C (O) -, —O—, —S—, —NH — CH ₂ CH ₂ CH ₂ -, —N (CH ₃ ) -, CH ₂ (CN) CH ₂ —NH — CH ₂ or —NH—,

Z is a morpholino group, dioxolanyl, tetrahydrofuranyl, pyridinyl, 2-oxa-5-azabicyclo [2.2.1] heptanyl, C ₁ -C ₃ alkoxyphenylpiperazinyl, a hydroxy group, C ₁ -C ₃ alkyl, N, N-diC ₁ -C ₃ alkoxy -C ₁ -C ₃ alkylamino group, C ₁ -C ₃ acylamino group, C ₁ -C ₃ alkylsulfonyl or nitrile C ₁ -C ₃ alkyl,

R ₁ in each case independently means

- C ₁ -C ₅ alkyl, which is optionally partially or fully halogenated, wherein one or more C-atoms are optionally independently replaced with O or N, and said C ₁ -C ₅ alkyl is optionally substituted with oxo, dioxolanyl, pyrrolidinyl, furyl or phenyl optionally substituted with a C ₁ -C ₃ alkoxy group,

- cyclopropyl, cyclopentanil, cyclohexanyl and bicyclopentanyl, optionally substituted by 1-3 methyl groups that are optionally partially or completely halogenated, by nitrile, hydroxymethyl or phenyl, or 2-tetrahydrofuranyl, substituted by methyl,

trimethylsilyl or

- propynyl substituted with a hydroxy group or tetrahydropyran-2-yloxy group,

R ₂ is a mono- or diC ₁ -C ₃ acylamino, amino group-S (O) _m or S (O) _m amino group, wherein N-atom mono- or disubstituted with C ₁ -C ₃ alkyl or phenyl, bromo, chloro , fluorine, nitrile, nitro group, amino group, methylsulfonyl, which is optionally partially or fully halogenated, or phenylsulfonyl,

R ₃ in each case independently means

phenyl, morpholino group, pyridinyl, pyrimidinyl, pyrrolidinyl, 2,5-pyrrolidinyldionyl, imidazolyl, [1,3,4] oxadiazole or pyrazolyl, each of which is optionally substituted with C ₁ -C ₂ alkyl, which is optionally partially or fully halogenated,

- a C ₁ -C ₃ alkyl group or a C ₁ -C ₃ alkoxy group, each of which is optionally partially or fully halogenated or optionally substituted with a diethylamino group,

- OR ₁₈ or C ₁ -C ₃ alkyl optionally substituted with an OR ₁₈ group,

an amino group or a mono or di (C ₁ -C ₃ alkyl) amino group optionally substituted with an R ₁₉ group,

- CH ₃ C (O) NH-, R ₂₂ O-, R ₂₃ R ₂₄ NC (O) -, R ₂₆ CH ₂ C (O) N (R ₂₁ ) -, NH ₂ C (O) methoxy group or R ₂₆ C (O) CH ₂ N (R ₂₁ ) -,

- C ₂ -C ₄ alkenyl substituted with a group R ₂₃ R ₂₄ NC (O) -,

- C ₂ -C ₄ alkynyl substituted with pyrrolidinyl or pyrrolyl, or

- C ₁ -C ₂ acyl and

R ₂₃ and R ₂₄ mean H or R ₂₃ and R ₂₄ together optionally form a morpholino group and

R ₂₆ means a morpholino group.

In accordance with another embodiment of the invention, among those directly indicated above, those compounds of formula (III) are preferred in which

G is phenyl, pyridinyl, 5-indolyl, 3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl, benzooxalolyl, 2,3-dihydrobenzooxazol-7-yl, 2-oxo 2,3-dihydro-1H-indol-5-yl or 2-naphthyl, wherein G is optionally substituted with one or more groups R ₁ , R ₂ or R ₃ ,

X is imidazolyl, pyridinyl, pyrimidinyl or pyrazinyl,

Y is a bond, CH ₂ (CN) CH ₂ —NH — CH ₂ , —CH ₂ -, —NH — CH ₂ CH ₂ CH ₂ -, or —NH—,

Z is morpholin-4-yl, dioxolan-2-yl, tetrahydrofuranyl, pyridinyl, 2-oxa-5-azabicyclo [2.2.1] hept-5-yl, methoxyphenylpiperazinyl, hydroxy, methyl, N, N-dimethoxyethylamino, acetylamino methylsulfonyl or cyanoethyl,

R ₁ in each case independently means tert-butyl, sec-butyl, tert-amyl, phenyl, tetrahydropyran-2-yloxypropinyl, hydroxypropinyl, trihalomethyl, 2,2-diethylpropionyl or cyclohexanyl,

R ₂ means chlorine, nitro group, amino group, nitrile, methylsulfonylamino group, diacetylamino group, phenylsulfonylamino group, N, N-di (methylsulfonyl) amino group, methylsulfonyl or trihalomethylsulfonyl,

R ₃ in each case independently means methyl, C ₁ -C ₃ alkoxy group, methoxymethyl, hydroxypropyl, dimethylamino group, C ₁ -C ₄ alkylamino group, NH ₂ C (O) methoxy group, acetyl, pyrrolidinyl, imidazolyl, pyrazolyl, morpholinogroup or morpholinocarbon.

In another embodiment of the invention, among those directly indicated above, those compounds of formula (III) are preferred in which X is pyridinyl.

According to a further embodiment of the invention, among those directly indicated above, those compounds of formula (III) are preferred in which pyridinyl is attached to Ar at the 3-position of pyridinyl.

As examples of compounds of formula (III) according to the invention, the following can be mentioned:

1- (4-tert-butylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methylphenyl) -3- [4- (4-morpholin-4-ylmethylpiperidin-1-yl) naphthalen-1-yl] urea,

1- (6-chloro-4-trifluoromethylpyridin-2-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- (4-difluoromethoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (3-methylnaphthalen-2-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [2-methoxy-5- (1-methyl-1-phenylethyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

3- (5- [4- [3- (5-tert-butyl-2-methylphenyl) ureido] naphthalen-1-yl} pyridin-2-ylamino) propyl ether (5-tert-butyl-2-methylphenyl) carbamic acids

1- (6-tert-butylbenzo [1,3] dioxol-5-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

N- (5-tert-butyl-2-methoxy-3- [3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) acetamide,

1,3-bis [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-3- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -2-hydroxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3 -yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-2- (2-pyrrolidin-1-ylethoxy) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-3- (2,3-dihydroxypropyl) -2-hydroxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2,3-dimethyl-1H-indol-5-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (2-p-tolyloxy-5-trifluoromethylphenyl) urea,

1- [2- (2-methoxyphenoxy) -5-trifluoromethylphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3-naphthalene-1-ylurea,

1- [5-tert-butyl-2-methyl-3- [3- (tetrahydropyran-2-yloxy) prop-1-ynyl] phenyl} -3- [4- (6-morpholin-4-ylmethylpyridin-3- il) naphthalene-1-yl] urea,

1- {5-tert-butyl-2- [3- (tetrahydropyran-2-yloxy) prop-1-ynyl] phenyl} -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene- 1-yl] urea,

1- (5-hydroxymethyl-2-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2-methoxydibenzofuran-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2,5-di-tert-butylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [3- (4-bromo-1-methyl-1H-pyrazol-3-yl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea ,

1- (3-hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (1-acetyl-2,3-dihydro-1H-indol-5-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (3-oxazol-5-ylphenyl) urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (3- [1,3,4] oxadiazol-2-ylphenyl) urea,

1- (2-methoxy-5-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

(4-tert-butyl-2- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido] phenyl) furan-2-carboxylic acid amide,

1- (2-methoxy-4-phenylaminophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-methoxy-2-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (3-hydroxynaphthalen-2-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

N, N-diethyl-4-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} benzenesulfonamide,

1- (2,2-difluorobenzo [1,3] dioxo1-5-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5- (1,1-dimethylpropyl) -2-phenoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5- (2,2-dimethylpropionyl) -2-methylphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

2-chloro-5- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} benzoic acid isopropyl ester,

1- (4-amino-3,5-dibromophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-3- (3-hydroxyprop-1-ynyl) -2-methylphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea

1- [5-tert-butyl-2- (3-hydroxyprop-1-ynyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-3- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3 -yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-3- (2,3-dihydroxypropyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butoxy-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5- (1-cyanocyclopropyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-3- (2-diethylamino-ethyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6- [1,3] dioxolan-2-yl-pyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-pyrrolidin-1-ylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-dimethylaminophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-propoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6-hydroxymethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2,6-dimethylmorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl] urea,

2- (5-tert-butyl-2-methoxyphenyl) -N- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] acetamide,

1- (2-methoxy-5-phenoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-7-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1- silt] urea,

1- (5-tert-butyl-2-cyclopentyloxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [6- (3-pyridin-3-ylpyrrolidin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-cyclohexyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2,4-dimethoxy-5-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (6-tert-butyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-7-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3- il) naphthalene-1-yl] urea,

1- (5-tert-butyl-2-methoxy-3-nitrophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (3-amino-5-tert-butyl-2-methoxyphenyl) -3- [4- (6-methylpyridin-3-yl) naphthalen-1-yl] urea,

N-acetyl-N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) acetamide,

1- (6-tert-butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -3- [4- (6-morpholin-4- ilmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [6-tert-butyl-4- (2-morpholin-4-yl-ethyl) -3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl] -3- [4 - (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-ethoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-isopropoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-imidazol-1-ylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

N- (5-tert-butyl-2-methoxy-4- [3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) methanesulfonamide,

1- (5-tert-butyl-3-ethylamino-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) bis (methanesulfonyl) amide,

1- [5-tert-butyl-2- (1-methyl-1H-pyrazol-4-yl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl urea

1- (2-methanesulfinyl-5-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- (2-ethanesulfonyl-5-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [4- (6 - {[bis (2-methoxyethyl) amino] methyl} pyridin-3-yl) naphthalen-1-yl] -3- (5-tert-butyl-2-methoxyphenyl) urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [6- (3-dimethylaminopyrrolidin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

N- [1- (5- {4- [3- (5-tert-butyl-2-methoxyphenyl) ureido] naphthalen-1-yl} pyridin-2-ylmethyl) pyrrolidin-3-yl] acetamide,

1- (1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1- silt] urea,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) propionamide,

1- (5-tert-butyl-2-methylbenzoxazol-7-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (3-trifluoromethanesulfonylphenyl) urea,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) isobutyramide,

2- (4-tert-butyl-2- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenoxy) apetamide,

1- (5-tert-butyl-2-oxo-2,3-dihydrobenzoxazol-7-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (6-tert-butyl-3-piano-2-methoxymethoxypyridin-4-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (6-tert-butyl-3-cyano-2-hydroxypyridin-4-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-3-cyano-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (1,3,3-trimethyl-2,3-dihydro-1H-indol-5-yl) urea

1- (5-tert-butylbenzoxazol-7-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) benzenesulfonamide,

(5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) amidethanesulfonic acid,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (4-morpholin-4-ylmethylpiperidin-1-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (1-methyl-1H-pyrazol-4-yl) phenyl] -3- [4- (4-morpholin-4-ylmethylpiperidin-1-yl) naphthalen-1-yl urea

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (2-morpholin-4-ylmethylpyrimidin-5-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methylsulfanylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxypyridin-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

(5-tert-butyl-2-methoxy-3- [3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) amide 2,2,2-trifluoroethanesulfonic acids

N- (5- {4- [3- (5-tert-butyl-2-methylphenyl) ureido] naphthalen-1-yl} pyrazin-2-yl) methanesulfonamide,

1- [4- (6 - {[bis (2-cyanoethyl) amino] methyl} pyridin-3-yl) naphthalen-1-yl] -3- (5-tert-butyl-2-methoxyphenyl) urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (4-methylpiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6-thiomorpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [6- (2,6-dimethylpiperidin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (1-oxotetrahydrothiopyran-4-ylamino) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (tetrahydropyran-4-ylamino) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6 - {[(2-pianoethyl) - (tetrahydrofuran-2-ylmethyl) amino] methyl} pyridin-3-yl) naphthalene-1 -yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2-methoxymethylmorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- (4- {6 - [(2-morpholin-4-yl-ethylamino) methyl] pyridin-3-yl} naphthalen-1-yl) urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2-methyl-3-oxopiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5- {4- [3- (5-tert-butyl-2-methoxyphenyl) ureido] naphthalen-1-yl} pyridin-2-ylmethyl) piperidine-3-carboxylic acid amide,

1- (5- {4- [3- (5-tert-butyl-2-methoxyphenyl) ureido] naphthalen-1-yl} pyridin-2-ylmethyl) piperidine-4-carboxylic acid amide,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (1-oxo-1l4-thiomorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl] urea,

1- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1- silt] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [6- (3-oxopiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- {4- [6- (4-acetylpiperazin-1-ylmethyl) -pyridin-3-yl] naphthalen-1-yl} -3- (5-tert-butyl-2-methoxyphenyl) urea,

4- (5- {4- [3- (5-tert-butyl-2-methoxyphenyl) ureido] naphthalen-1-yl} pyridin-2-ylmethyl) piperazine-1-carboxylic acid ethyl ester,

1- (5-tert-butyl-2-methoxyphenyl) -3- (4- {6 - [(2-pyridin-3-yl-ethylamino) methyl] pyridin-3-yl] naphthalen-1-yl) urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- (4- {6 - [(tetrahydrofuran-3-ylamino) methyl] pyridin-3-yl] naphthalen-1-yl) urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6 - [[(2-pianoethyl) pyridin-3-ylmethylamino] methyl} pyridin-3-yl) naphthalen-1-yl] urea ,

1- (5-tert-butyl-2-methoxyphenyl) -3- (4- {6 - [(2-methylsulfanylethylamino) methyl] pyridin-3-yl} naphthalen-1-yl) urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl) pyridin-3-yl] naphthalene-1 -il} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2,6-dimethylmorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- (4- [6 - [(2-piperazin-1-yl-ethylamino) methyl] pyridin-3-yl} naphthalen-1-yl) urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (4-pyrimidin-2-ylpiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (4-pyridin-2-ylpiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- (4- {6- [4- (3-methoxyphenyl) piperazin-1-ylmethyl] pyridin-3-yl} naphthalen-1-yl) urea ,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [6- (morpholin-4-carbonyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2-thia-5-azabicyclo [2.2.1] hept-5-ylmethyl) pyridin-3-yl] naphthalene-1 -yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (5-morpholin-4-ylmethylpyrazin-2-yl) naphthalen-1-yl] urea,

1- (6-tert-butyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3- il) naphthalene-1-yl] urea,

1- (3-amino-5-tert-butyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

N- (5- [4- [3- (5-tert-butyl-2-methoxyphenyl) ureido] naphthalen-1-yl] pyridin-2-yl) acetamide,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido] phenyl) -N-methylacetamide,

N- (5-tert-butyl-2-methoxy-3- [3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido] phenyl) -2,2,2 trifluoroacetamide,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (pyridin-3-yloxy) pyridin-3-yl] naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [6- (pyridin-3-ylamino) pyridin-3-yl] naphthalen-1-yl] urea,

[4- (6-Morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] carbamic acid 3-tert-butylphenyl ester,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido] phenyl) methanesulfonamide

and their pharmaceutically acceptable derivatives.

According to yet another embodiment of the invention, it also provides the following compounds of formula (III):

1- (3-methylnaphthalen-2-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido] phenyl) acetamide,

1- [5-tert-butyl-3- (2,3-dihydroxypropyl) -2-hydroxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2,3-dimethyl-1H-indol-5-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- {5-tert-butyl-2-methyl-3- [3- (tetrahydropyran-2-yloxy) prop-1-ynyl] phenyl} -3- [4- (6-morpholin-4-ylmethylpyridin-3- il) naphthalene-1-yl] urea,

1- (2-methoxy-5-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- [5- (2,2-dimethylpropionyl) -2-methylphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-3- (3-hydroxyprop-1-ynyl) -2-methylphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (3-hydroxyprop-1-ynyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-3- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3 -yl) naphthalene-1-yl] urea,

1- [5-tert-butyl-3- (2,3-dihydroxypropyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butoxy-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5- (1-cyanocyclopropyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-3- (2-diethylaminoethyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6- [1,3] dioxolan-2-yl-pyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-pyrrolidin-1-ylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-dimethylaminophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-propoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6-hydroxymethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2,6-dimethylmorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl] urea,

1- (5-cyclohexyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (2,4-dimethoxy-5-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxy-3-nitrophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (3-amino-5-tert-butyl-2-methoxyphenyl) -3- [4- (6-methylpyridin-3-yl) naphthalen-1-yl] urea,

N-acetyl-N- (5-tert-butyl-2-methoxy-3- [3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) acetamide,

1- (6-tert-butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -3- [4- (6-morpholin-4- ilmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-ethoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-isopropoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-imidazol-1-ylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-3-ethylamino-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) bis (methanesulfonyl) amide,

1- [5-tert-butyl-2- (1-methyl-1H-pyrazol-4-yl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl ]urea,

1- (2-methanesulfinyl-5-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- [4- (6 - {[bis- (2-methoxyethyl) amino] methyl] pyridin-3-yl) naphthalen-1-yl] -3- (5-tert-butyl-2-methoxyphenyl) urea,

N- [1- (5- [4- [3- (5-tert-butyl-2-methoxyphenyl) ureido] naphthalen-1-yl} pyridin-2-ylmethyl) pyrrolidin-3-yl] acetamide,

1- (1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1- silt] urea,

N- (5-tert-butyl-2-methoxy-3- [3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) propionamide,

1- (5-tert-butyl-2-methylbenzoxazol-7-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (3-trifluoromethanesulfonylphenyl) urea,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) isobutyramide,

2- (4-tert-butyl-2- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenoxy) acetamide,

1- (5-tert-butyl-2-oxo-2,3-dihydrobenzoxazol-7-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-3-cyano-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- (5-tert-butylbenzoxazol-7-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) benzenesulfonamide,

(5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) amidethanesulfonic acid,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (2-morpholin-4-ylmethylpyrimidin-5-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methylsulfanylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxypyridin-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

(5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) amide 2,2,2-trifluoroethanesulfonic acids

N- (5- [4- [3- (5-tert-butyl-2-methylphenyl) ureido] naphthalen-1-yl} pyrazin-2-yl) methanesulfonamide,

1- [4- (6 - {[bis (2-cyanoethyl) amino] methyl} pyridin-3-yl) naphthalen-1-yl] -3- (5-tert-butyl-2-methoxyphenyl) urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [6- (4-methylpiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6-thiomorpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2,6-dimethylpiperidin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (1-oxotetrahydrothiopyran-4-ylamino) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [6- (tetrahydropyran-4-ylamino) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6 - {[(2-cyanoethyl) - (tetrahydrofuran-2-ylmethyl) amino] methyl} pyridin-3-yl) naphthalene-1 -yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [6- (2-methoxymethylmorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2-methyl-3-oxopiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5- [4- [3- (5-tert-butyl-2-methoxyphenyl) ureido] naphthalen-1-yl} pyridin-2-ylmethyl) piperidine-3-carboxylic acid amide,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (1-oxo-4-thiomorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1- silt] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (3-oxopiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- (4- {6 - [(tetrahydrofuran-3-ylamino) methyl] pyridin-3-yl} naphthalen-1-yl) urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6 - {[(2-cyanoethyl) pyridin-3-ylmethylamino] methyl} pyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl) pyridin-3-yl] naphthalene-1 -yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2,6-dimethylmorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- (4- {6- [4- (3-methoxyphenyl) piperazin-1-ylmethyl] pyridin-3-yl} -naphthalen-1-yl) urea ,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (morpholin-4-carbonyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (5-morpholin-4-ylmethylpyrazin-2-yl) naphthalen-1-yl] urea,

1- (6-tert-butyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3- il) naphthalene-1-yl] urea,

1- (3-amino-5-tert-butyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

N- (5- [4- [3- (5-tert-butyl-2-methoxyphenyl) ureido] naphthalen-1-yl} pyridin-2-yl) acetamide,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) -N-methylacetamide,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) -2,2,2 trifluoroacetamide,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (pyridin-3-yloxy) pyridin-3-yl] naphthalen-1-yl} urea,

[4- (6-Morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] carbamic acid 3-tert-butylphenyl ester,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) methanesulfonamide

and their pharmaceutically acceptable derivatives.

In addition to the compounds presented above as an example, according to the general synthesis methods described below, the following possible compounds of formula (III) can also be prepared:

1- (5-tert-butyl-2-methylsulfanylpyridin-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-chloropyridin-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- (5-tert-butyl-2-methylaminopyridin-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

N- (5-tert-butyl-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} -2-oxo-2H-pyridin-1-yl ) methanesulfonamide,

5-tert-butyl- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} benzoxazole-2-carboxylic acid amide,

2- (5-tert-butyl-7- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} benzoxazol-2-yl) acetamide,

5-tert-butyl-2-methoxy-3- [3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} benzamide

and their pharmaceutically acceptable derivatives.

Any compounds of the invention containing one or more asymmetric carbon atoms can exist as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. All such isomeric forms of these compounds are included within the scope of the present invention. Each stereogenic carbon atom may be in the R or S configuration, or in a combination of such configurations.

Some of the compounds of formulas (I), (Ia), (II) and (III) can exist in more than one tautomeric form. All such tautomers are included in the scope of the present invention.

All terms used in the present description, unless otherwise indicated, are generally accepted in the art. Thus, for example, a “C ₁ -C ₄ alkoxy group” is a C ₁ -C ₄ alkyl radical with an oxygen terminal atom, in particular a methoxy, ethoxy, propoxy, pentoxy and hexoxy group. All alkyl, alkenyl and alkynyl groups may have a branched or unbranched chain, if possible from the point of view of their structure and unless otherwise indicated. The following are definitions of other specific terms used in the present description.

The term "aroyl" in the context of the present description means "benzoyl" or "naphthoyl".

The term "carbocycle" means an aliphatic hydrocarbon radical containing from three to twelve carbon atoms. Carbocycles include hydrocarbon rings containing from three to ten carbon atoms. Such carbocycles can be either aromatic or non-aromatic ring systems. Non-aromatic ring systems may be mono- or polyunsaturated. Examples of preferred carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, benzene, benzyl, benzyl, tetrahydronaphthyl-octyl, decyl, benzene. Some terms that refer to cycloalkyl, such as cyclobutanyl and cyclobutyl, may be used interchangeably.

The term “heterocycle” refers to a stable non-aromatic 4-8 membered (but more preferably 5 or 6 membered) monocyclic or non-aromatic 8-11 membered bicyclic heterocyclic radical, which may be saturated or unsaturated. Each heterocycle consists of carbon atoms and one or more, preferably 1-4, heteroatoms selected from nitrogen, oxygen and sulfur. The heterocycle can be attached through any atom of the ring, which leads to the formation of a stable structure. Unless otherwise indicated, examples of heterocycles include, but are not limited to, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene azinyldinopyridinyl, tetramethylene azinyl di-sulfinyl, tetramethylene azinyl di sulfinyl, tetramethylene azinyl di-sulfinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanil, heptacanil, thioxanil, dithianil or 2-ok sa- or 2-thia-5-azabicyclo [2.2.1] heptanyl.

The term “heteroaryl” means an aromatic 5-8 membered monocyclic or 8-11 membered bicyclic ring containing 1-4 heteroatoms such as N, O and S. Unless otherwise specified, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzopyrazoles, benzhydrobenzofenoxy-benzoylobenazole-2-benzoylobenazole-2-azino-benzoylobenazole-2-azino-benzoylobenazole-2-benzoylobenazole-2-benzoylobenazole-2-benzoylobenazole-2-benzoylobenazole-benzoylobenazole-2-benzoylobenazole-2-benzoylobenazole-benzoylobenazole-benzoylobenazole-benzoylobenazole zo [1,3] dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl.

The term “heteroatom” as used herein refers to atoms other than a carbon atom, such as O, N, S, and P.

The term “aryl” as used herein means an aromatic carbocycle or heteroaryl as defined above.

Terms that are analogous to the above cyclic residues, such as aryloxy or heteroarylamine, mean aryl, heteroaryl, heterocycle, as defined above, attached to their corresponding group.

In the context of the present description, the terms "nitrogen" and "sulfur" include any oxidized form of nitrogen and sulfur and a quaternized form of any nitrogenous base.

The term "halogen" in the context of the present description means bromine, chlorine, fluorine or iodine.

The compounds of the invention include only those compounds that are considered to be “chemically stable” in the sense that is customary in the art. Thus, for example, a compound having a "floating valency" ("dangling valency"), or a "carbanion" are not included in the compounds of the invention.

Pharmaceutically acceptable derivatives of the compounds of formulas (I), (Ia), (II) and (III) are also included in the scope of the invention. The term “pharmaceutically acceptable derivative” refers to any pharmaceutically acceptable salt or pharmaceutically acceptable ester of a compound of the invention or any other compound which, when administered to a patient, is capable of being converted (directly or indirectly) to a compound of the invention, to its pharmacologically active metabolite or pharmacologically active residue . By "pharmacologically active metabolite" in this regard is meant any compound of the invention that is capable of metabolizing by enzymatic or chemical means. An example of such compounds are hydroxylated or oxidized derivatives of the compounds of formulas (I), (Ia), (II) or (III).

Pharmaceutically acceptable salts of the compounds of the invention include salts derived from pharmaceutically acceptable inorganic and organic acids and bases. Examples of the corresponding acids are hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicylic, succinic, toluene-p-sulfuric, tartaric, acetic, citric, methanesulfonic, formic, benzoic , naphthalene-2-sulfuric and benzenesulfonic acids. In addition, other acids can be used, for example, oxalic acid, which, although not pharmaceutically acceptable per se, can nevertheless be used to prepare salts suitable for use as intermediates in the preparation of compounds of the invention and their pharmaceutically acceptable acid addition salts. Salts derived from the corresponding bases include alkali metal salts (e.g. sodium), alkaline earth metal salts (e.g. magnesium), ammonium salts and N- (C ₁ -C ₄ alkyl) ₄ ⁺ salts.

In addition, prodrugs of the compounds of formulas (I), (Ia), (II) and (III) are referred to compounds of the invention. Prodrugs are those compounds which, as a result of a simple chemical transformation, are converted to compounds of the invention. Such simple chemical transformations are hydrolysis, oxidation, and reduction. Thus, in particular, when a prodrug of the invention is administered to a patient, such a prodrug can be converted to a compound of the invention, thereby exhibiting a targeted pharmacological effect.

Application methods

The invention provides methods for using the compounds of formulas (I), (Ia), (II) and (III). The compounds of the invention effectively block the production of inflammatory cytokines by cells. Inhibition of cytokine production is a promising method for the prevention and treatment of various diseases associated with excess production of cytokines, such as diseases and pathological conditions associated with inflammation. Thus, the compounds of the invention can be used to treat such conditions. These conditions include chronic inflammatory diseases, including (but not limited to) osteoarthritis, multiple sclerosis, Guillain-Barré syndrome, Crohn's disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus erythematosus, and insulin-dependent diabetes mellitus. The compounds of the invention can also be used to treat other disorders that are associated with the activity of proinflammatory cytokines present at elevated concentrations, such as reactions to various infectious agents and numerous autoimmune diseases such as rheumatoid arthritis, toxic shock syndrome, diabetes and inflammatory bowel disease, not related to the above diseases, and which are described in the "Background of the invention".

In addition, since the compounds of the invention are inhibitors of cytokine production, they should be expected to block the expression of inducible cyclooxygenase (COX-2). It has been established that the expression of COX-2 is enhanced by cytokines, and it is believed that this cyclooxygenase is an isoform of cyclooxygenase that is responsible for inflammation (M.K. O'Banion et al., Proc. Natl. Acad. Sci. USA, 89 , 4888, 1992). Therefore, the new compounds of the invention should be expected to be effective against diseases that are currently treatable with COX inhibitors, such as conventional non-steroidal anti-inflammatory drugs (NSAIDs). Such disorders include acute and chronic pain, as well as inflammatory symptoms and cardiovascular disease.

As indicated in the section "Background of the invention", IL-8 affects the influx of neutrophils at the site of inflammation or damage. Thus, in accordance with another aspect of the invention, the compounds of the invention can be used to treat diseases that are mainly mediated by neutrophils, such as stroke and myocardial infarction resulting from or without thrombolytic therapy, heat damage, adult respiratory distress syndrome (RDSV), multiple organ damage due to trauma, acute glomerulonephritis, dermatoses, including components of acute inflammation, acute purulent meningitis, or other central disorders th nervous system, hemodialysis, leukopherisis, syndromes associated with transfusion of granulocytes, and necrotic enterocolitis.

For therapeutic purposes, the compounds of the invention may be administered in any suitable dosage form by any conventional route. Such methods of administration include (but are not limited to) intravenous, intramuscular, subcutaneous, intrasinovial, infusion, sublingual, transdermal, oral, or administration by inhalation. Oral and intravenous routes of administration are preferred.

The compounds of the invention can be administered individually or in combination with adjuvants that increase the stability of inhibitors, facilitate the administration of certain types of pharmaceutical compositions containing them, provide higher solubility or dispersibility, increase inhibitory activity, provide the possibility of adjuvant therapy, etc., as well as other active substances. In such combination therapies, smaller doses of conventional therapeutic agents are preferably used, which avoids the possible toxic and harmful side effects that occur when such agents are used for monotherapy. The compounds of the invention can be combined physically with conventional therapeutic agents or other adjuvants in a single pharmaceutical composition. Preferably, the compounds should be administered together in a single unit dosage form. In particular embodiments, pharmaceutical compositions comprising such combinations of compounds comprise at least about 5%, more preferably at least about 20% (wt.%), Compounds of formula (I), (Ia), (II) or (III ) or a combination of these compounds. The optimal percentage (in wt.%) Of a compound of the invention may vary and should be determined by those skilled in the art. In another embodiment, the compounds can be administered individually (either sequentially or in parallel). Separate administration allows the use of a more flexible dosage regimen.

As indicated above, the dosage forms of the compounds of the present invention include pharmaceutically acceptable carriers and adjuvants known to those skilled in the art. Such carriers and adjuvants include, for example, ion exchange resins, alumina, aluminum stearate, lecithin, whey proteins, buffering agents, water, salts or electrolytes and cellulose-based compounds. Preferred dosage forms include tablets, capsules, droplets, liquids, solutions, suspensions, emulsions, troches, syrups, reconstitutable powders, granules, suppositories and transdermal plaques. Methods for preparing such dosage forms are known (see, for example, N. C. Ansel and N. G. Popovish, Pharmaceutical Dosage Forms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)). Dose levels and requirements are well known in the art and can be selected for a particular patient based on available methods and tools. In certain embodiments, dose levels are about 1-1000 mg / dose for a patient weighing 70 kg. Although it may be sufficient to use one dose per day, administration of up to 5 doses per day is nevertheless permissible. When administered orally, a dose of up to 2000 mg / day may be required. One of skill in the art can independently determine which lower or higher doses may be required depending on specific factors. So, for example, specific doses and modes of administration may depend on factors such as the general health of the patient, the severity and course of the disease in the patient, or the disposition to it, and they should be prescribed by the decision of the attending physician.

Below the invention is illustrated by examples. These examples illustrate preferred embodiments of the present invention and should not be construed as limiting in any way its scope.

Since, as indicated above, the following examples are illustrative, it will be apparent to those skilled in the art that, if necessary, specific reagents or reaction conditions for individual compounds can be changed accordingly. The starting products used in the reactions described below are either commercially available or can easily be obtained by those skilled in the art from commercially available products.

GENERAL SYNTHESIS METHODS

Compounds of the invention can be prepared according to method A, B or C, as illustrated in Scheme I, preferably according to method B. Additionally, similar methods are described, for example, in PCT / US 99/29165 and US patent applications 60/124148 and 60 / 165867. Each of these applications is fully incorporated into the present description by reference.

Scheme I

In the above scheme, D corresponds to the radical Ar ₁ (for compounds of formulas I and Ia) or G (for the compounds of formula II or III), D 'represents an Ar ₂ -XYZ group (or its precursor) for compounds of formulas I and Ia or a group Ar-XYZ (or its precursor) for the compounds of formula II or III.

According to Method A, a mixture of an amine of formula IV and an isocyanate of formula V is dissolved in a non-protic anhydrous solvent such as THF, ether, toluene, dioxane or ethyl acetate. The preferred solvent is THF. The mixture is stirred at a temperature of from 0 to 45 ° C, preferably at 25 ° C, for 2-24 hours and the volatile components are removed. By purifying the residue by recrystallization from a suitable solvent, such as ethyl acetate / hexanes, ethyl acetate / methanol, THF / petroleum ether, ethanol / water, or chromatography on silica gel using, for example, hexanes and ethyl acetate as eluents, a product of the formula I, Ia, II or III (E is NH).

According to method B, an amine of formula IV is dissolved in a halogenated solvent such as methylene chloride, chloroform or dichloroethane. The preferred solvent is methylene chloride. The mixture is diluted with aqueous alkali, such as sodium bicarbonate or potassium carbonate, cooled in an ice bath and phosgene is added. The mixture is stirred vigorously for 5-30 minutes, preferably for 10 minutes. The organic layer is dried with an agent such as MgSO ₄ or Na ₂ SO ₄ and the volatile components are removed to give the corresponding isocyanate DN = C = O. This isocyanate and amine of formula VI are then mixed in a non-protic anhydrous solvent such as THF, ether, toluene, dioxane, methylene chloride or ethyl acetate. The preferred solvent is THF. The mixture is stirred at a temperature of from 0 to 45 ° C, preferably at 25 ° C, for 2-24 hours and the volatile components are removed. Purification of the residue by recrystallization or chromatography on silica gel, as described above, yields a product of formula I, Ia, II or III (E is NH).

The desired isocyanate can also be obtained from carboxylic acid D-CO ₂ H by reaction with chloroformate, such as ethyl chloroformate, in the presence of an acceptable base, such as triethylamine, in a suitable solvent, such as THF, at a temperature of about 0 ° C. The resulting mixed anhydride is treated with an aqueous solution of sodium azide. When a solution of the resulting acyl azide is heated in a suitable solvent, such as toluene, at about the distillation temperature, rearrangement by the Curtius reaction occurs, resulting in the in situ production of isocyanate DN = C = O.

According to method B, an amine of formula IV is dissolved in an acceptable solvent, such as a halogenated solvent, for example methylene chloride, chloroform or dichloroethane. The preferred solvent is methylene chloride. An acceptable base such as triethylamine and then phenylchloroformate can be added. The mixture is stirred at a temperature of 0 to 85 ° C., preferably at a distillation temperature, for 2-24 hours and the volatile components are removed to give the carbamate of formula VII. This carbamate and amine of formula VI are mixed in a non-protic anhydrous solvent such as THF, ether, toluene, dioxane, methylene chloride or ethyl acetate. The preferred solvent is THF. The mixture is stirred at a temperature of from 0 to 110 ° C., preferably at a distillation temperature, for 2-24 hours and volatile components are removed. After purification of the residue, as described above, a product of the formula I, Ia, II or III (E is NH) is obtained. This method can be carried out in the reverse order, i.e. you can first get carbamate from D'NH ₂ and subject this carbamate to the interaction with the amine D-NH ₂ . Example 37 describes a synthesis process for a compound of formula III in which E is —O—, and example 38 describes the synthesis of a compound of formula III in which E is —CH ₂ -.

The process used to prepare the amines of formula IV depends on the nature of the target group D. In general, intermediates of formula IV can be prepared by methods known in the art. Some of these common methods are illustrated in the diagrams below. Compounds D'-NCO or D'-NH ₂ in scheme I are commercially available compounds or can be obtained by methods known in this field. If D 'is the precursor of the group Ar ₂ —XYZ or Ar-XYZ, then the target end product of the formula I, Ia, II or III can be obtained by methods known in the art. Illustrative examples of such methods are presented in the Synthesis Examples section below.

Aminopyrazoles of formula XV, which are necessary for the preparation of compounds of formula I or Ia, can be prepared according to Scheme II. A hydrazine of formula X carrying an R ₃ substituent can be prepared according to method G or D. According to method G, an aryl bromide of formula VIII is dissolved in a non-protic inert solvent such as THF, 1,4-dioxane or diethyl ether and cooled to a low temperature in an inert atmosphere . At the same time, the temperature of -77 ° C is preferred for the solution. Thereafter, a strong base dissolved in a non-protic inert solvent such as hexanes, THF or ether is added dropwise, maintaining the cancer temperature below 0 ° C, preferably below -60 ° C. Preferred bases are alkyl lithium reagents, most preferably sec-butyl lithium. After adding the base, the reaction mixture is stirred for 30-90 minutes until the starting aryl bromide is consumed. An excess of dialkyl azodicarboxylate is then added, keeping the reaction temperature below 0 ° C, preferably below -60 ° C. As the dialkyl azodicarboxylate, it is preferable to use di-tert-butyl azodicarboxylate. The reaction mixture was stirred at a reduced temperature and after 0.5-2 hours it was warmed to room temperature. The reaction was stopped by adding water and the product was extracted with a non-protic solvent, such as ethyl acetate, diethyl ether or chloroform. The organic layers are dried with agents such as MgSO ₄ or Na ₂ SO ₄ and volatiles are removed. The residue is dissolved in a protic solvent, such as methanol or isopropanol, cooled, preferably to 0-5 ° C., and treated with an acid. In this case, it is preferable to use hydrochloric, hydrobromic, sulfuric and trifluoroacetic acids. Most preferred is hydrochloric acid in gaseous form. After adding excess acid, the mixture was kept at the distillation temperature of the solvent until all of the starting material was consumed. After cooling, the resulting aryl hydrazine salt of formula X is filtered and dried.

Scheme II

According to Method D, an arylamine bearing an R ₃ substituent (Formula IX) is dissolved in concentrated aqueous acid, such as hydrochloric, hydrobromic or sulfuric acid, and cooled to the temperature of an ice bath. In this case, hydrochloric acid with a concentration of 3 N or more is most preferred. up to 8 n., more preferably 6 n. Then, a nitrosation agent in water is added dropwise, while maintaining the reduced temperature. Preferred is a temperature of 0-5 ° C. A preferred reagent is sodium nitrite. The reaction mixture is stirred for 10-90 minutes, and then a reducing agent is added while maintaining the reduced temperature. A temperature of 0-5 ° C. is preferred. As a reducing agent, zinc, iron, samarium iodide and tin (II) chloride can be used. The most preferred reducing agent is tin (II) chloride, dissolved in aqueous hydrochloric acid with a concentration of 3 N. up to 8 n., more preferably 6 n. The reaction mixture is stirred for 0.5-3 hours and then the reaction is stopped by adding alkali to bring the pH to 12-14. Alkaline reagents such as sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide can be used. The most preferred alkaline reagent is potassium hydroxide. The aqueous solution is extracted with a non-protic organic solvent such as diethyl ether, chloroform, ethyl acetate and methylene chloride. The organic layers are dried using agents such as MgSO ₄ and Na ₂ SO ₄ and the volatile components are removed to give an aryl hydrazine (Formula X), which can be used in the subsequent reaction without further purification.

β-Ketonitrile bearing the substituent R ₁ (formula XIV) can be prepared according to method E or G. According to method E, metal hydride, such as sodium hydride, potassium hydride or lithium hydride, is suspended in an anhydrous inert non-protic solvent, such as diethyl ether, THF and dioxane, at a temperature ranging from 35 to 85 ° C. The most preferred metal hydride is sodium hydride, and the most preferred solvent is THF at a temperature of 75 ° C. Then, an alkyl ether, preferably methyl ether (Formula XI) is dissolved in an anhydrous non-protic non-protic solvent such as diethyl ether, THF or dioxane, and acetonitrile and the resulting solution are added dropwise to the above metal hydride suspension. The preferred solvent is THF. The mixture was kept at elevated temperature for 3-24 hours, cooled to room temperature and diluted with a non-protic solvent and aqueous acid. The organic layer is then washed with water and brine, dried with agents such as MgSO ₄ and Na ₂ SO ₄ , and the volatile components are removed to give β-ketonitrile (Formula XIV), which can be used without further purification.

In another embodiment, according to method G, a solution of a strong base such as alkyl lithium and a metal amide, for example n-butyllithium, sec-butyl lithium, lithium methyl lithium and diisopropylamide, in an anhydrous inert non-protic solvent such as diethyl ether, THF and dioxane, is cooled to a temperature below 0 ° C. The preferred base is n-butyllithium, the preferred solvent is THF, and the preferred temperature is -77 ° C. Next, a solution of cyanoacetic acid (Formula XII) in an anhydrous inert non-protic solvent such as diethyl ether, THF and dioxane, more preferably THF, is maintained dropwise, keeping the reaction temperature below 0 ° C, preferably at -77 ° C. The reaction mixture is stirred for 10-45 minutes, heating it to 0 ° C. The cyanoacetic acid dianion solution is cooled to a temperature below -25 ° C, preferably to -77 ° C. Next, an alkyl acid chloride (Formula XIII) dissolved in an anhydrous inert non-protic solvent such as diethyl ether, THF and dioxane, more preferably THF, is added. The reaction mixture is heated for 10-30 minutes to 0 ° C and the reaction is stopped by the addition of aqueous acid. The product is extracted with an organic solvent such as chloroform, ethyl acetate, ether and methylene chloride. The combined organic extracts are dried using agents such as MgSO ₄ and Na ₂ SO ₄ and the volatile components are removed to give β-ketonitrile (Formula XIV), which can be used without further purification.

The desired aminopyrazole (formula XV) can then be prepared according to method 3 or I. According to method 3, an aryl hydrazine of formula X and β-ketonitrile of formula XIV are mixed in an organic solvent such as toluene, ethanol, isopropanol or tert-butanol. Ethanol is the preferred solvent. An acid such as hydrochloric acid, p-toluenesulfonic acid or sulfuric acid is then added. The preferred acid is concentrated hydrochloric acid. The mixture is then kept for 10-24 hours with heating at a temperature of 50-100 ° C, preferably at 80 ° C, and then cooled to room temperature. The mixture is diluted with a non-protic organic solvent such as ethyl acetate, ether, chloroform or methylene chloride, and washed with aqueous alkali such as sodium bicarbonate and potassium carbonate. The organic layer was dried using agents such as MgSO ₄ and Na ₂ SO ₄ and the volatiles were removed to give a residue, which was purified by recrystallization or silica gel chromatography using hexanes and ethyl acetate as eluents. Next, fractions with a high content of the product are collected and the volatile components are removed to obtain the desired aminopyrazole (formula XV).

In another embodiment, according to Method I, an arylhydrazine of formula X and β-ketonitrile of formula XIV are mixed in an organic solvent such as toluene, ethanol, isopropanol or tert-butanol. A preferred solvent is toluene. The mixture is maintained at a distillation temperature for 3-24 hours with azeotropic removal of water, and after processing as described above, aminopyrazole of formula XV is obtained.

Other necessary amino heterocycles that can be used in the synthesis of compounds of formula I or Ia can be obtained by methods known in the art and described in the literature. The examples given in the following schemes III-XV are illustrative, and therefore, which is obvious to specialists in this field, the specific reagents and reaction conditions may vary depending on the individual compounds. The intermediates used in the reactions in the schemes below are either commercially available or can be obtained by specialists in this field from commercially available materials in a simple way.

Scheme III, Method K, illustrates the general synthesis of the target aminothiophenes.

Scheme III

A mixture of 1-aryl-5-alkylbutane-1,4-dione (XVI) and a sulfating agent such as Lawesson's reagent or phosphorus (V) sulfide, preferably Lawesson's reagent, is dissolved in a non-protic anhydrous solvent such as toluene, THF or dioxane. A preferred solvent is toluene. The mixture is heated at an elevated temperature, preferably at a temperature of distillation of the solvent, for 1-10 hours. After removal of the volatile components, the residue is purified by silica gel chromatography using hexanes and ethyl acetate as an eluent. High product fractions were collected and volatiles removed to give substituted thiophene of formula XVII.

This substituted thiophene of formula XVII is dissolved in a solvent such as acetic anhydride or acetic acid. A preferred solvent is acetic anhydride. The mixture is cooled to 0-30 ° C, preferably to -10 ° C. Next, a solution of concentrated nitric acid in a solvent such as acetic anhydride or acetic acid, preferably acetic anhydride, is added, cooling the mixture to 0-30 ° C, preferably to -10 ° C. The mixture is then stirred for 10-120 minutes, poured onto ice and extracted with a non-protic solvent, such as diethyl ether, chloroform, ethyl acetate or methylene chloride. The organic extracts are washed with aqueous alkali, dried with agents such as MgSO ₄ and Na ₂ SO ₄ , and the volatile components are removed. The residue was purified by silica gel chromatography using hexanes and ethyl acetate as eluents. High product fractions were collected and volatiles removed to give 2-aryl-5-alkyl-3-nitrothiophene. This 2-aryl-5-alkyl-3-nitrothiophene is reduced with a metal such as iron, tin or zinc, or by catalytic hydrogenation. It is preferable to use iron in acetic acid for reduction and to carry out such reduction at a temperature in the range from 50 to 110 ° C, more preferably at 100 ° C, for 5-30 minutes. After cooling to room temperature, the reaction mixture is diluted with water, neutralized with an alkali, such as sodium hydroxide, potassium hydroxide, potassium carbonate or sodium bicarbonate, and extracted with a non-protic solvent, such as diethyl ether, ethyl acetate or methylene chloride. The organic extracts are dried using agents such as MgSO ₄ and Na ₂ SO ₄ and the volatiles are removed to obtain the desired aminothiophene of formula XVIII.

Scheme IV illustrates a general method for preparing the desired aminofurans, as described by Stevenson et al. (J. Am. Chem. Soc., 1937, 59, 2525). Ethyl aroyl acetate (formula XIX) is dissolved in a non-protic solvent, such as ether or THF, and treated with a strong base such as sodium, sodium ethoxide or sodium hydride, and the resulting anion is reacted with bromomethylalkyl ketone (formula XX) at a reduced temperature, for example at 0 ° C. After stirring the reaction mixture until all of the starting material has been consumed, it is poured into cold water and extracted with a non-protic solvent. Then, the combined extracts are dried using agents such as MgSO ₄ or Na ₂ SO ₄ . The resulting diketoester (formula XXI) can be used subsequently without further purification or purified by distillation or chromatography on silica gel. Next, the diketoester in a protic solvent, such as ethanol, is heated in the presence of a mineral acid, such as sulfuric or hydrochloric acid, for 5-10 hours and extracted with a non-protic solvent. Then, the combined extracts are dried using agents such as MgSO ₄ or Na ₂ SO ₄ . The resulting furan ether (formula XXII) can be used subsequently without further purification or purified by distillation or chromatography on silica gel. Further, this furan ether in a protic solvent, such as ethanol, is treated with hydrazine hydrate and the mixture is maintained with heating for 2-5 days. After that, hydrazine is isolated according to the method described above and treated with hot formic acid, after which the resulting furanamine (formula XXIII) is purified by distillation or chromatography on silica gel.

Scheme IV

Substituted 4-aminooxazoles can be synthesized similarly to the method described by Lakhan et al. (J. Het. Chem., 1988, 25, 1413) and illustrated in Scheme V. In this case, a mixture of aroyl cyanide (formula XXIV), aldehyde (formula XXV) and anhydrous ammonium acetate in acetic acid is maintained with heating at 100-110 ° C for 3-6 hours, cooled to room temperature and then the reaction is stopped by adding water. After extraction with a non-protic solvent, a product of formula XXVI is obtained, which can be used subsequently without further purification or purified by recrystallization or silica gel chromatography.

Scheme V

Substituted 3-aminopyrroles (Formula XXX) can be synthesized analogously to the method described by Aiello et al., J. Chem. Soc. Perkins Trans. I, 1981, 1. This method is illustrated in Scheme VI. The mixture of aryldioxoalkane (formula XXVII) and amine (formula XXVIII) in acetic acid is maintained with heating at 100-110 ° C for 3-6 hours and then processed in the usual way. Thereafter, the obtained product (formula XXIX) in acetic acid is treated with a nitration agent such as nitric acid or potassium nitrate in concentrated sulfuric acid. The mixture is poured further into cold water and extracted with a non-protic solvent. Then, the combined extracts are dried using agents such as MgSO ₄ and Na ₂ SO ₄ . Obtained after removal of the volatile components, nitropyrrole can be used subsequently without additional purification or purified by recrystallization or chromatography on silica gel. This nitropyrrole is reduced to an amine using iron in acetic acid or by catalytic hydrogenation using palladium on activated carbon. The obtained aminopyrrole (formula XXX) can be used subsequently without further purification or purified by recrystallization or chromatography on silica gel.

Scheme VI

Similarly, a mixture of an amine of formula XXXI and 3-aryl-2,5-dioxoalkane (formula XXXII) in acetic acid was heated at 80-110 ° C. for 2-24 hours. Then, the reaction mixture was diluted with water and extracted with an organic solvent. After that, the combined extracts are dried using agents such as MgSO ₄ or Na ₂ SO ₄ , and then the volatile components are removed. The resulting pyrrole is treated with a nitration agent, and then reduced to the compound of formula XXXIII by the procedure described above. The resulting product can be used subsequently without further purification or purified by recrystallization or chromatography on silica gel. This process is illustrated in diagram VII.

Scheme VII

Substituted 5-aminothiazoles (formula XXXVII) can be obtained analogously to the method described by Gerwald et al., J. Prakt. Chem. 1973, 315, 539. As shown in Scheme VIII, a base such as triethylamine is added dropwise to a mixture of an aminocyanide of formula XXXIV, an aldehyde of formula XXXV and sulfur in an anhydrous solvent such as ethanol or methanol. The mixture was kept heated at 50 ° C. for 1-3 hours. After that, the mixture was cooled and excess sulfur was removed. Next, acetic acid is added to the mixture to neutralize it and a solid is collected. The resulting imine of formula XXXVI is treated with an acid, such as hydrochloric or toluenesulfonic acid, in water and an organic solvent. After the starting material has been consumed, the reaction mixture is processed to obtain a product of formula XXXVII, which can be used without further purification or purified by recrystallization or chromatography on silica gel.

Scheme VIII

Substituted 2-aminothiophenes (formula XXXIX) can be synthesized analogously to the method described by Gewald et al. (J. Prakt. Chem., 1973, 315, 539) and illustrated in Scheme IX. In this case, a mixture of disubstituted thiophene-3-carboxylic acid (formula XXXVIII) in a protic solvent, such as acetic acid, is treated at a temperature of 0-50 ° C with a nitration agent, such as nitric acid or potassium nitrate, in concentrated sulfuric acid. After the starting material was consumed, the reaction mixture was poured onto ice and the product was extracted with a non-protic solvent. The combined extracts are dried with agents such as MgSO ₄ and Na ₂ SO ₄ and the volatiles removed. The obtained nitrothiophene is reduced to an amine using iron in acetic acid or catalytic hydrogenation using palladium on activated carbon. The resulting aminothiophene can be used subsequently without further purification or purified by recrystallization or chromatography on silica gel.

Scheme IX

1,5-disubstituted 3-aminopyrazoles (formula XLII) can be obtained in accordance with scheme X similarly to the method described by Ege and others (J. Het. Chem., 1982, 19, 1267). In this case, potassium is added to anhydrous tert-butanol and the mixture is cooled to 5 ° C. Then add hydrazine of formula XL, and then cyanodibromoalkane of formula XLI. The mixture is then heated under reflux for 3-10 hours at the distillation temperature. After this, the mixture is cooled to room temperature and poured into a mixture of water and ice. The resulting product was extracted with an organic solvent. The combined extracts are dried with agents such as MgSO ₄ or Na ₂ SO ₄ and the volatiles removed. The resulting product of formula XLII can be used subsequently without further purification or purified by recrystallization or chromatography on silica gel.

Pattern X

2-amino-3,5-disubstituted thiophenes can be synthesized according to Scheme XI in a manner similar to that described by Knoll et al., J. Prakt. Chem., 1985, 327, 463. The mixture of substituted N- (3-aminothioacryloyl) formamidine (Formula XLIII) and substituted bromide (Formula XLIV) in a protic solvent such as methanol or ethanol is heated, preferably it is maintained at the temperature of distillation at for 5-30 minutes and then cooled to a temperature below room temperature. The resulting thiophenimine is filtered and dried. Then, thiophenimine of formula XLV is converted into thiophenamine by treatment with aqueous acid (formula XLVI).

Scheme XI

1,4-disubstituted 2-aminopyrroles (Formula L) can be synthesized analogously to the method described by Brodrick et al. (J. Chem. Soc. Perkin Trans. I, 1975, 1910) and illustrated in Scheme XII. In this case, the potassium salt of formyl nitrile of formula XLVII in water is treated with an amine of formula XLVIII and acetic acid, and the mixture is heated with heating at 50-90 ° C for 5-30 minutes. After cooling, the resulting aminonitrile of formula XLIX was collected by filtration and then stirred at room temperature in the presence of a base, such as potassium ethanol ethoxide, for 2-5 hours and the volatiles removed. The residue was diluted with water and extracted with an organic solvent. The combined extracts are dried with agents such as MgSO ₄ and Na ₂ SO ₄ and the volatiles removed. The resulting product (formula L) can be used subsequently without further purification or purified by recrystallization or chromatography on silica gel.

Scheme XII

1,2-disubstituted 4-aminoimidazoles (formula LII) can be obtained by reduction of the corresponding nitro compound (formula LI), for example using iron in acetic acid or catalytic hydrogenation, according to the method described by Al-Shaar et al. (J. Chem. Soc Perkin Trans. I, 1992, 2779) and illustrated in Scheme XIII.

Scheme XIII

2,4-disubstituted 5-aminooxazoles (formula LVII) can be obtained analogously to the method described by Poupaert et al. (Synthesis, 1972, 622) and illustrated in Scheme XIV. The acid chloride of formula LIII is then added to a chilled mixture of 2-aminonitrile of formula LIV and a base such as triethylamine in a non-protic solvent such as THF, benzene, toluene or ether. A temperature of 0 ° C. is preferred. The mixture is stirred for 12-24 hours and washed with water. After removal of the volatile components, the resulting product of formula LV is treated with ethyl mercaptan and dry hydrogen chloride in dry methylene chloride for 5-30 minutes. Solid 5-imino-1,3-oxazole hydrochloride (formula LVI) was collected by filtration, dissolved in dry pyridine and the solution was saturated with hydrosulfide for 4 hours at 0 ° C. The mixture was diluted with an organic solvent, washed with water and dried. After removal of the volatile components, 5-amino-1,3-oxazole (formula LVII) is obtained, which can be used subsequently without further purification or purified by silica gel chromatography.

Scheme XIV

1,4-disubstituted 2-aminopyrazoles can be synthesized according to Scheme XV according to the method described by Lancini et al., J. Het. Chem., 1966, 3, 152. In this case, aqueous sodium hydroxide is added to a mixture of substituted aminoketone (formula LVIII) and cyanamide in water and acetic acid until the pH reaches 4.5. After that, the mixture is kept with heating at 50-90 ° C for 1-5 hours, cooled and made basic with ammonium hydroxide. The resulting product of formula LIX is collected by filtration and dried.

Scheme XV

The arylamine and heteroaryl amine intermediates of formula IV (G-NH ₂ ) for the synthesis of compounds of formulas II and III are either commercially available products or can be easily obtained by methods known in the art. For example, the necessary arylamines and heteroarylamines can be obtained by nitration and reduction of a substituted aryl or heteroaryl ring, as illustrated for the synthesis of certain 5-membered heterocyclic amines (Ar ₁ -NH ₂ ) in the above schemes. In another embodiment, the substituted aryl ester can be converted to arylamine, as illustrated for the substituted furan in Scheme IV above and described in Example 17 below. The Synthesis Examples section describes processes for the preparation of other compounds G-NH ₂ and Ar ₁ -NH ₂ .

Methods for preparing intermediates of formulas V and VI (Scheme I, D 'mean Ar-XYZ or Ar ₂ -XYZ group) are described below.

Scheme XVI

According to method A (Scheme XVI), a bromarylamine of formula LX, which can either be a commercially available product or can easily be obtained by a person skilled in the art, is reacted with a cycloalkenone of formula LXI in the presence of a transition metal catalyst, for example a palladium (II) catalyst ) such as bis (triphenylphosphine) palladium (II) chloride, and in the presence of a bis (triphenylphosphine) chelating agent such as 1,2-bis (diphenylphosphino) ethane (DPFE), 1,1'-bis (diphenylphosphino) ferrocene ( DFFP) or 1,3-bis (diphenylphos fino) propane (DFFP), preferably DFFP, and a base, preferably sodium bicarbonate, in an acceptable solvent, preferably in DMF, at a temperature of about 150 ° C. to give a compound of formula LXII. This compound of formula LXII can then be used (as a compound of formula VI) in method B (Scheme I) or converted to an isocyanate of formula LXIII by reaction with phosgene or phosgene equivalent in the presence of a base such as sodium bicarbonate in an acceptable solvent such as dichloromethane, at a temperature of about 0 ° C and use (as a compound of formula V) in method A. The resulting product of formula LXIV can be further modified by methods known to specialists in this field, to obtain the target compounds of formula I, as described ano in the synthesis examples below.

According to Method M, a bromide of the formula LXV is reacted in the presence of a strong base, such as tert-butyl lithium, in an acceptable solvent, such as THF, with tributyltin chloride at a temperature in the range of from about -50 to -100 ° C, preferably at about -78 ° C, to obtain a compound of formula LXVI. This compound of formula LXVI is further reacted with a compound of formula LX in an acceptable solvent, such as THF or 1,4-dioxane, in the presence of a transition metal catalyst, preferably tetrakis (triphenylphosphine) palladium (0), at a temperature of from about 50 to 150 ° C, preferably at about 100 ° C, in a hermetically sealed tube to give a compound of formula LXVII. This compound of formula LXVII can then be used (as a compound of formula VI) in method B or C (Scheme I) or converted into the corresponding isocyanate as described for method A and used (as a compound of formula V) in method A.

Scheme XVII illustrates methods for attaching Y and Z to X. According to the method of method H, if necessary, to obtain a product in which Y comprises amine nitrogen attached to X, a group X containing a ketone can be reacted with a group YZ containing a terminal primary or a secondary amine, under hydroamination conditions. Thus, for example, a ketone of formula LXIV is combined with a primary or secondary amine in an acceptable solvent, such as THF. An acid, such as acetic acid, and then an acceptable reducing agent, preferably sodium cyanoborohydride or (triacetoxy) sodium borohydride, are added to obtain the desired product of formula LXVIII.

Method O is illustrated by the process of producing a methylene group for Y and a primary or secondary amine for Z. In this case, group X carrying an aldehyde and halogen, preferably bromine (formula LXIX), can be reacted with a primary or secondary amine under hydroamination, as described for method H, to obtain a compound of formula LXX. This intermediate can then be used similarly to method M.

Scheme XVII

As in the cases discussed above, additional intermediate products corresponding to the formulas V, VI and VII can be synthesized by methods similar to those described in the literature or known to specialists in this field. A few examples of such synthesis are given in the Synthesis Examples section below.

SYNTHESIS EXAMPLES

Example 1

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2-cyclohexenon-3-yl) naphthalen-1-yl] urea

According to the method described above, 4-bromo-1-naphthylamine (LXXI) (1.97 g, 8.9 mmol, 1 equiv.), 2-cyclohexenone (1.65 g) is placed in a 350 ml hermetically sealed tube in an inert atmosphere , 17.2 mmol, 1.9 eq.), Sodium bicarbonate powder (2.17 g, 25.8 mmol, 2.9 eq.), 1,3-bis (diphenylphosphino) propane (177 mg, 0.43 mmol, 0.05 equiv.), bis (triphenylphosphine) palladium (II) chloride (302 mg, 0.43 mmol, 0.05 equiv.) and DMF (degassed, 100 ml). The mixture was heated at 150 ° C. for 8 hours. After cooling to ambient temperature again, the mixture was diluted with 100 ml EtOAc and filtered through diatomaceous earth. After this, the solution was transferred to a separatory funnel and washed with water (100 ml) and saturated brine (100 ml). After drying over MgSO _{4, the} volatile components are removed in vacuo. The product was then purified by column chromatography using EtOAc (10 to 50%) in hexanes as an eluent to give 1.3 g of material, which was recrystallized from a hot EtOAc / hexanes mixture to give 800 mg of a compound of formula LXXII (3.4 mmol, yield 38%) as a dark brown solid.

The compound of formula LXXII (100 mg, 0.42 mmol, 1 equiv.) Is dissolved in methylene chloride (20 ml) and a saturated aqueous solution of sodium bicarbonate (20 ml) is added. The mixture was vigorously stirred at 0 ° C for 15 minutes. Further, the stirring is interrupted and phosgene (approximately 2.0 molar solution in toluene, 0.63 ml, 1.26 mmol, 3.0 eq.) Is added to the organic layer in one portion with a syringe. Immediately after this, stirring is resumed and continued at 0 ° C. for 20 minutes. Then the layers are separated, after which the aqueous phase is extracted with methylene chloride (1 × 25 ml). The combined organic phases were dried (Na ₂ SO _4), filtered and _^3/4 of the solvent was removed in vacuo. Immediately thereafter, this isocyanate solution of formula LXXIII was diluted with anhydrous THF (8 ml) and treated with a compound of formula LXXIV at room temperature (method A). The mixture was then allowed to stir overnight under nitrogen, then MeOH (2 ml) was added and the volatiles removed in vacuo. In this way, the title compound 1 is obtained as an orange / red foamy substance (200 mg, 0.41 mmol, 74%). This product was recrystallized twice overnight from EtOAc to give 49 mg of yellow crystals ( _mp 168-170 ° C).

Example 2

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- [3- (morpholin-4-yl) cyclohexen-1-yl] naphthalen-1-yl }urea

According to the method described above, the product from example (1) (93 mg, 0.19 mmol, 1 equiv.) And morpholine (30 μl, 0.34 mmol, 1.8 equiv.) Are dissolved in 1.0 ml of anhydrous THF and treated with acetic acid (16 μl, 0.28 mmol, 1.5 eq.) and (triacetoxy) sodium borohydride (80 mg, 0.39 mmol, 2 eq.). The reaction mixture was stirred at room temperature for 2 days, and then a 5% aqueous NaOH solution (3 ml) was added, and then the reaction mixture was extracted with EtOAc (3 × 3 ml). The combined organic phases are washed once with water and then with brine, dried (Na ₂ SO ₄ ), filtered and the solvents removed in vacuo. Column chromatography using EtOAc / hexanes as eluent gives 64 mg of a tan foamy substance (0.11 mmol, 60%). This product was rechromatographed using 5% MeOH in methylene chloride to give the title compound 2 as a light purple foamy substance (50 mg).

Example 3

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- {4- [5- (morpholin-4-ylmethyl) fur-2-yl] naphthalen-1-yl }urea

According to the method described above, to a mixture of 5-bromo-2-furaldehyde (LXXV) (1.76 g) and morpholine (1.00 ml) in 40 ml of anhydrous THF, acetic acid (0.60 ml) was added at room temperature, and then sodium triacetoxyborohydride (3.28 g). The mixture was stirred at room temperature for 3 hours and then poured into saturated sodium bicarbonate solution (100 ml). After vigorous stirring for 5 minutes, the layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated to dryness. After purification of the residue by flash chromatography, 2.09 g (8.49 mmol, 84% yield) of compound LXXVI are obtained.

According to the method described above, compound LXXVI (0.678 g, 2.76 mmol) was dissolved in 10 ml of anhydrous THF in an inert gas atmosphere and the solution was cooled to -78 ° C. Next, tert-butyllithium (4.0 ml of a 1.7 molar solution in pentane) was added dropwise and the solution was stirred at -78 ° C for 30 minutes. Then tributyltin chloride (0.60 ml, 0.72 g, 2.2 mmol) was added and the solution was stirred for another 30 minutes at -78 ° C. Then, a pH 7 buffer (sat. NaH ₂ PO ₄ / Na ₂ HPO ₄ ) (10 ml) was added and the mixture was warmed to room temperature. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated to dryness. After purification of the residue by flash chromatography, 0.526 g (1.15 mmol, 42% yield) of compound LXXVII are obtained.

This compound LXXVII (0.399 g, 0.874 mmol) and compound LXXI (0.200 g, 0.901 mmol) according to the method described above are dissolved in 10 ml of anhydrous 1,4-dioxane in a hermetically sealed tube in an inert gas atmosphere. The solution is degassed and purged with nitrogen (twice). Then tetrakis (triphenylphosphine) palladium (0) (0.057 g, 0.049 mmol) is added, after which the solution is degassed and again purged with nitrogen (twice). The tube was hermetically sealed and heated to 100 ° C. for 24 hours. After cooling to room temperature, the mixture was diluted with EtOAc, a saturated aqueous solution of potassium carbonate (10 ml) was added, and the mixture was stirred for 1 hour at room temperature. The mixture is then filtered through diatomaceous earth and the layers are separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated to dryness. After purification of the residue by flash chromatography, 0.314 g of a yellow oil is obtained which contains the compound LXXVIII along with tributyltin bromide. This mixture is used in the next step without further purification.

Compound LXXVIII (0.283 g, 0.917 mmol) was reacted with phenylcarbamate LXXIV (0.395 g, 1.13 mmol) according to method B. The resulting product was purified by flash chromatography to give the title compound 3 as a yellow solid (0.338 g , 0.600 mmol, yield 65%), which is further purified by recrystallization to obtain 0.131 g of the title compound 3 ( _mp 144-146 ° C).

Example 4

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- {4- [6- (morpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl }urea

Similar to the method described by RJChambers and A.Marfat (Synthetic Communications, 1997, 27, 515), a mixture of 2,5-dibromopyridine (LXXIX) (9.90 g, 41.78 mmol), Pd (DFFP) Cl ₂ (1 51 g, 1.85 mmol), anhydrous MeOH (40 ml), anhydrous DMF (40 ml) and anhydrous triethylamine (12 ml) are blown in a Parr apparatus for 10 minutes with a stream of carbon monoxide and then stirred at a pressure of carbon monoxide of 80 pounds per square inch at 50 ° C. for 4 hours. The mixture was diluted with EtOAc (600 ml), washed with water (2 × 100 ml) and brine (1 × 100 ml), dried (sodium sulfate), filtered and evaporated to dryness. The residue was purified by flash chromatography on silica gel (40% EtOAc in hexanes) to give LXXX as a light orange solid (3.733 g, 17.28 mmol, 41%).

To a solution of compound LXXX (165.9 mg, 0.7679 mmol) in anhydrous THF (10 ml) at -78 ° C was added dropwise diisobutylaluminum hydride (1.0 molar solution in THF) (2.0 ml, 2.0 mmol). The mixture was stirred at -78 ° C for 2 hours, after which a saturated solution of potassium carbonate (0.6 ml) was added, the mixture was warmed to room temperature and stirred for another 30 minutes. Sodium sulfate is then added and the mixture is stirred for 10 minutes. The solid was removed by filtration and the filtrate was evaporated to dryness. The residue was purified by flash chromatography on silica gel (20% EtOAc in hexanes) to give the LXXXI aldehyde as a white solid (80 mg, 0.43 mmol, 56%).

To a solution of compound LXXXI (367.7 mg, 2.0 mmol) in anhydrous 1,2-dichloroethane (10 ml) was added morpholine (0.20 ml, 0.20 g, 2.3 mmol) and then glacial acetic acid (0.12 ml, 0.13 g, 2.1 mmol) and sodium triacetoxyborohydride (625 mg, 2.95 mmol). The mixture was stirred at room temperature for 30 minutes. A saturated sodium bicarbonate solution (10 ml) was added and the mixture was stirred vigorously for another 30 minutes. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 20 ml). The combined organic layers were washed with brine, dried (sodium sulfate), filtered and evaporated to dryness. After flash chromatography (1% triethylamine in EtOAc), the residue gives compound LXXXII as a pale yellow oil (460.8 mg, 1.79 mmol, 91%).

To a solution of tert-butyllithium (1.42 molar solution in pentane) (2.80 ml, 3.98 mmol) in anhydrous THF (20 ml) at -78 ° C, a solution of compound LXXXII (460.8 mg, 1.792 mmol) in anhydrous THF (10 ml) and the mixture was stirred at -78 ° C for 10 minutes. Tributyltin chloride (0.49 ml, 0.59 g, 1.8 mmol) was added and the mixture was stirred at -78 ° C for another 15 minutes. After this, a buffer of pH 7 (sat. Na ₂ HPO ₄ / NaH ₂ PO ₄ ) (10 ml) was added and the mixture was warmed to room temperature. The layers were separated and the aqueous layer was extracted with EtOAc (3 × 20 ml). The combined organic layers were washed with brine, dried (sodium sulfate), filtered and evaporated to dryness. Flash chromatography (EtOAc) of the residue gave LXXXIII as a colorless oil (548.8 mg, 1.17 mmol, 65%).

A degassed solution of compound LXXXIII (302 mg, 0.646 mmol), compound LXXI (177 mg, 0.797 mmol) and Pd (PPhg) 4 (55 mg, 0.48 mmol) in anhydrous 1,4-dioxane (10 ml) is heated to 100 ° C in a sealed tube for 16 hours. The black precipitate was removed by filtration and the tube was washed with EtOAc. The combined filtrates were mixed with potassium fluoride solution (40%) (10 ml) for 30 minutes. Next, water and brine were added, the layers were separated, and the aqueous layer was extracted with EtOAc (4 × 50 ml). The combined organic layers were washed with brine, dried (sodium sulfate), filtered and evaporated to dryness. After flash chromatography (5% MeOH and 1% triethylamine in EtOAc), the residue gives compound LXXXIV as a light brown solid (157.6 mg, 0.49 mmol, 76%).

Compound LXXXIV and phenylcarbamate LXIV were reacted according to Method B. After purification by flash chromatography using 5% MeOH and 1% triethylamine in EtOAc as eluent, followed by recrystallization from EtOAc / hexanes, the title compound 4 in as a white solid ( _mp 169-170 ° C).

Example 5

1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- {4- [3- (morpholin-4-yl) phenyl] naphthalen-1-yl} urea

3-bromaniline (3.0 ml, 4.7 g, 28 mmol), 2-bromoethyl ether (4.2 ml, 7.7 g, 33 mmol) and diisopropylethylamine (15 ml, 11 g, 86 mmol) are dissolved in anhydrous DMF (20 ml) in an inert gas atmosphere and heated to 100 ° C for 6 hours. After cooling to room temperature, the mixture was poured into water (300 ml) and extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated to dryness. After purification of the residue by flash chromatography, 2.9 g (12 mmol, 43% yield) of compound LXXXVI are obtained

Compound LXXXVI (1.73 g, 7.13 mmol) was dissolved in anhydrous THF (30 ml) and cooled to -78 ° C. Next, tert-butyllithium (10.0 ml of a 1.7 molar solution in pentane) was added dropwise and the solution was stirred at -78 ° C for 30 minutes. Then tributyltin chloride (1.90 ml, 2.28 g, 7.00 mmol) was added and the solution was stirred for another 45 minutes at -78 ° C. Then, a pH 7 buffer (sat. NaH ₂ PO ₄ / Na ₂ HPO ₄ ) (10 ml) was added and the mixture was warmed to room temperature. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated to dryness. After purification of the residue by flash chromatography, 2.28 g (5.36 mmol, 77% yield) of compound LXXXVII are obtained.

Compound LXXXVII (1.49 g, 3.51 mmol) and compound LXXI (0.69 g, 3.11 mmol) are dissolved in 20 ml of anhydrous 1,4-dioxane in a hermetically sealed tube in an inert gas atmosphere. Next, the solution is degassed and purged with nitrogen (twice). After this, tetrakis (triphenylphosphine) palladium (0) (0.21 g, 0.18 mmol) was added and the solution was again degassed and purged with nitrogen (twice). The tube was hermetically sealed and kept with heating at 100 ° C for 17 hours. After cooling to room temperature, the mixture was diluted with EtOAc, a saturated aqueous solution of potassium carbonate (10 ml) was added, and the mixture was stirred for 1 hour at room temperature. After that, the mixture is filtered through diatomaceous earth and the layers are separated. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried (Na ₂ SO ₄ ), filtered and evaporated to dryness. After purification of the residue by flash chromatography, 0.363 g (1.19 mmol, 38%) of compound LXXXVIII are obtained.

Compound LXXXVIII (0.360 g, 1.18 mmol) according to method B was reacted with phenylcarbamate LXIV (0.69 g, 1.97 mmol). The resulting product was purified by flash chromatography to give a colorless solid (0.433 g, 0.77 mmol, 66% yield), which was further purified by recrystallization from EtOAc / hexanes to give 0.344 g of the title compound 5 ( _mp 18-8-190 ° FROM).

Table 1 lists other compounds of the invention that are prepared by methods similar to those described above.

Table 1

Note No. R ₁ R ₃ X ^a Y ^b Z ⁱⁿ t _pl , ° C 6 tert-bu 4-meph phenyl 4-CH ₂ 4-morpholinyl 146-148 7 tert-bu 4-meph phenyl 3-CH ₂ 4-morpholinyl 120-122 8 tert-bu 4-meph phenyl communication 4 ^g - (4-morpholinyl) > 230 9 tert-bu 4-meph phenyl 4-CH ₂ 4-morpholinyl 183-186 10 tert-bu 4-meph phenyl 4-CH ₂ NMe ₂ 108-114 eleven tert-bu 4-meph 2-pyridyl 5-CH ₂ 4-morpholinyl foam 12 tert-bu 4-meph 1-cycloheptenyl communication 3 ^g - (4-morpholinyl) 133-135 13 tert-bu 6-Me-3-pyridyl 3-pyridyl 6- (CH ₂ ) 4-morpholinyl 162-165 fourteen tert-bu Me 3-pyridyl 6- (CH ₂ ) 4-morpholinyl foam fifteen tert-bu 6-Me-3-pyridyl 1-cyclohexenyl 3- [NH- (CH ₂ ) ₂ ] 4-morpholinyl Note:
^{and the} figure refers to position X, which is attached to the naphthalene ring (Ar ₂ ),
^{b the} figure refers to the position of X, which is attached to Y, ^the figure refers to the position of Z, which is attached to Y (or X, if Y denotes a connection),
^r digit refers to position X, which is attached to Z.

Example 16

1- [4- (6 - {[bis- (2-cyanoethyl) amino] methyl} pyridin-3-yl) naphthalen-1-yl] -3- (5-tert-butyl-2-methylphenyl) urea

To a solution of 4-tert-butyltoluene (33.7 mmol) in acetonitrile (150 ml) at 0 ° C was added nitrile tetrafluoroborate (40.5 mmol). After 30 minutes at room temperature, the reaction mixture was diluted with water (50 ml) and extracted with EtOAc (3 × 30 ml). The combined organic extracts were washed with brine and dried (MgSO ₄ ). The residue obtained after removal of the volatile components in vacuo was purified by flash chromatography using 10% methylene chloride / petroleum ether as eluent to give 4-tert-butyl-2-nitrotoluene.

4-tert-butyl-2-nitrotoluene (1.1 mmol) was dissolved in DMF (10 ml). Next, a catalyst (10% Pd / C, 5 mg) was added, and then di-tert-butyl dicarbonate (1.4 mmol) was added. This mixture was purged with argon and then held in a H ₂ atmosphere (1 atm) for 12 hours. The mixture was filtered through a pad of diatomaceous earth, the filtrate was diluted with water and extracted with EtOAc (3 × 10 ml). The combined organic extracts were washed with brine and dried (MgSO ₄ ). After evaporation of the volatile components, 265 mg of N-Boc-5-tert-butyl-2-methylaniline is obtained as a crystalline solid.

To a mixture of N-Boc-5-tert-butyl-2-methylaniline (0.8 mmol) and triethylamine (0.22 mol) in benzene (10 ml) at room temperature, boron trichloride (0.4 mmol) is added with a syringe . The resulting heterogeneous mixture was stirred at 80 ° C for 30 minutes. After that, the heat source is removed and LXXXIX aminonaphthalene (0.7 mmol) is added. The reaction mixture was stirred at room temperature for 16 hours. Then the reaction mixture was diluted with water (10 ml) and extracted with EtOAc (3 × 10 ml). The combined organic extracts were washed with brine and dried (MgSO ₄ ). The residue obtained after removal of volatile components in vacuo was purified by flash chromatography using 10% MeOH / EtOAc as eluent to obtain 300 mg of target urea cholesterol.

This urea is placed under acidic conditions to remove acetal, which exhibits the presence of aldehyde function. To this aldehyde in 1,2-dichloroethane is added 1.25 equivalents of bis (2-cyanoethyl) amine, and then sodium triacetoxyborohydride (1.5 equivalents) is added. Column chromatography (5% MeOH / EtOAc) gave the title compound 16.

Example 17

1- (6-tert-butyl-2-chloro-3-methylpyridin-4-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea

To a stirred solution of N-Boc-1-amino-4-bromonaphthalene (15.5 mmol) in anhydrous THF (40 ml) at -78 ° C was added n-BuLi (47 mmol). The resulting yellow-green solution was stirred at -78 ° C for 2 h, and then transferred to a solution of trimethyl borate (5.64 g, 54.2 mmol) in anhydrous THF (25 ml) at -42 ° C. The reaction mixture was allowed to warm to room temperature overnight as the bath was heated. After stirring for 16 hours, 5% aqueous HCl (25 ml) was added and the mixture was stirred for 15 minutes. The aqueous layer was saturated with NaCl and the layers were separated. The aqueous phase is extracted with diethyl ether (3 × 60 ml) and then the combined organic phases are extracted with a 0.5 molar NaOH solution (6 × 30 ml). The combined alkaline extracts were acidified with 3M HCl (about 30 ml) to about pH 2 and the suspension was extracted with diethyl ether (3 × 100 ml). The combined ether extracts were dried (MgSO ₄ ), filtered and the solvent removed to give XCI boronic acid as a beige solid (2.3 g), which was used without further purification.

5-bromo-2- (morpholin-4-ylmethyl) pyridine (0.70 mmol) and compound XCI (0.70 mmol) are dissolved in a two-phase mixture of dimethoxyethane (2 ml) and 2 molar aqueous Na ₂ CO ₃ (1 ml ) The reaction mixture was purged with stream N for 15 minutes, a Pd catalyst was added and the mixture was heated at 85 ° C for 16 hours. After that, the reaction mixture was cooled to room temperature and partitioned between water (10 ml) and EtOAc (75 ml) . The layers were separated and the organic phase was washed with brine (20 ml), dried (MgSO ₄ ), filtered and the solvent removed to give a brown solid. Column chromatography afforded the product XCII as a beige solid.

Compound XCII (0.50 mmol) was dissolved in 2 ml of anhydrous dioxane and HCl (2.5 mmol) was added. The solution was stirred at room temperature for 16 hours. Then, diethyl ether (5 ml) was added to the resulting suspension, and the mixture was cooled to 0 ° C. After neutralization with aqueous NaOH and filtration, 4-16- (morpholin-4-ylmethyl) pyridin-3-yl] -1-aminonaphthalene (XCIII) is obtained as a light brown solid (100 mg).

A mixture of 2-tert-butyl-6-chloro-5-methylpyridin-4-carboxylic acid methyl ester (2.27 g, 9.39 mmol) and LiOH monohydrate (2.36 g, 56.3 mmol) in MeOH (30 ml) and water (10 ml) were stirred at room temperature for 24 hours. Then the reaction mixture was concentrated and purified by silica gel chromatography (eluent: 5% TFA in dichloromethane) to give the corresponding carboxylic acid (1.41 g, 66, 3%).

Ethyl chloroformate (0) was added dropwise to a stirred solution of the carboxylic acid obtained in the previous step (0.54 g, 2.36 mmol) and triethylamine (0.66 ml, 4.75 mmol) in THF (6 ml) at -10 ° C. 34 ml, 3.51 mmol). The resulting mixture was stirred at 0 ° C for 1 h. After this, a solution of sodium azide (0.40 g, 6.0 mmol) in water (2 ml) was added and stirring was continued for another 1 h. The mixture was extracted with toluene. The organic phases are separated, dried with sodium sulfate and concentrated to a volume of 15 ml. The concentrate is heated under reflux for 2 hours, which is accompanied by the formation of an in situ isocyanate, and then a solution of compound XCIII (0.39 g, 1.23 mmol) in dichloromethane (5 ml) is added. The reaction mixture was stirred at room temperature overnight. After concentration and chromatography on silica gel (eluent: EtOAc), the title compound 17 (0.60 g, 89.9%) was obtained.

Example 18

1- (5-tert-butyl-2-methylphenyl) -3- (4- [6 - [(3-methoxypropyl) methylamino] pyridin-3-yl) naphthalen-1-yl) urea

2,5-dibromopyridine (100 mg) was heated in a hermetically sealed tube to 115 ° C in the presence of 3-methoxypropyl-1-methylamine (2 ml) for 48 hours to obtain compound XCIV. After a combination reaction of Suzuki of compound XCIV with compound XCI and removal of tert-butyl carbamate (similar to the process described in Example 17), the target naphthylamine XCV is obtained.

5-tert-butyl-2-methylaniline (0.56 mmol) was dissolved in dichloromethane (20 ml). After that, an equal volume of saturated aqueous sodium bicarbonate is added and the two-phase solution is cooled to 0 ° C. While phosgene was added (1.93 M in toluene, 0.80 ml), stirring was stopped. Immediately after this, stirring is resumed and continued for 15 minutes with the reaction mixture at 0 ° C. The layers are separated, the organic phases are dried over solid magnesium sulfate and the solution is concentrated to about 5 ml. Next, the necessary naphthylamine (XCVI, 0.47 mmol) in 5 ml of dichloromethane is added. The reaction mixture was stirred at room temperature for 16 hours. After flash chromatography using 7% MeOH / EtOAc as eluent and subsequent trituration with ether, the title compound 18 was obtained.

Example 19

1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (3-trifluoromethylphenyl) urea

A stirred solution of 3-trifluoromethylaniline (4.7 mmol) in dry THF (30 ml) was treated at 0 ° C with phenyl chloroformate (4.8 mmol). After 2 hours, the reaction was stopped by the addition of an aqueous saturated sodium bicarbonate solution and extracted with EtOAc. The combined organic layers were washed with aqueous saturated sodium bicarbonate and brine and dried over solid MgSO ₄ . After concentration, carbamate XCVI (97%) is obtained. After that, a mixture of compound XCIII (example 17) (0.06 mmol) and the specified carbamate (0.05 mmol) is heated for 2 days in a hermetically sealed tube. Then the reaction mixture was cooled to room temperature. Next, PS-trisamine (100 mg, Argonaut) and PS-isocyanate polymers (150 mg, Argonaut) are added and the reaction mixture is shaken for 3 days. Thereafter, the reaction mixture was filtered and concentrated to obtain the title compound 19.

Examples 20-25 illustrate the synthesis of aryl and heteroarylamines that can be used as intermediate IV in Methods AB (General Synthesis Methods section) to prepare compounds of formula II or III.

Example 20

1- [5-tert-butyl-2- (1H-pyrazol-4-yl) phenyl] amine

Methyl 4-tert-butylphenyl acetate (20 mmol) was dissolved in MeOH (160 ml) and treated with water (40 ml) and LiOH monohydrate (30 mmol). After this, the reaction mixture was allowed to stir at room temperature overnight. Then, the volatile components are removed under reduced pressure, the resulting residue is diluted with water and neutralized to pH 4 with 1 N. sulfuric acid. The resulting solid was filtered off, washed with water and dried to give 4-tert-butylphenylacetic acid as an off-white solid (3.8 g, 99%).

Anhydrous DMF (139 mmol) was cooled to 0 ° C and treated with POCl ₃ (79.6 mmol). After 5 min, 4-tert-butylphenylacetic acid (19.9 mmol) was added and the reaction vessel was placed in an oil bath at a temperature of 110 ° C. The reaction mixture was stirred for 2 hours, while all solids dissolved. After cooling to room temperature, the reaction mixture was poured into a stirred solution of NaPF ₆ (19.8 mmol) in water (200 ml). Upon completion of the precipitation, it is filtered off, washed with water and dried to obtain compound XCVII (7.8 g, 97%).

Compound XCVII (5 mmol) was dissolved in EtOH (50 ml) and the resulting suspension was treated with hydrazine hydrate (5 mmol). After that, the reaction vessel was placed in an oil bath at a temperature of 90 ° C and the reaction mixture was stirred under reflux for 2 hours. After cooling the reaction mixture to room temperature, the volatile components were removed under reduced pressure. The residue was dissolved in ice water, the solid was filtered off, washed with water and dried to give 4- (4-tert-butylphenyl) pyrazole (973 mg, 97%).

This 4- (4-tert-butylphenyl) pyrazole (0.5 mmol) was suspended in MeCN (2 ml), cooled to 0 ° C and treated with NO ₂ BF ₄ (0.6 mmol). The reaction mixture was allowed to slowly warm to room temperature and stirred at room temperature (CT) for 2 hours. After termination of the reaction by addition of aqueous NaHCO _{3, the} volatiles were removed under reduced pressure. The residue was dissolved in water and extracted with CH ₂ Cl ₂ . The organic phases are combined, dried over MgSO ₄ and concentrated to give a yellow oil, which is chromatographed on silica gel (eluent: CH ₂ Cl ₂ / EtOAc at a ratio of 6: 4), resulting in 4- (4-tert-butyl-2-nitrophenyl ) pyrazole as a yellow crystalline solid (71 mg, 58%).

4- (4-tert-butyl-2-nitrophenyl) pyrazole (0.27 mmol) was dissolved in EtOH (3 ml) and treated with 10% Pd / C (0.2 equiv. Based on the weight of the nitro compound), and then NH ₄ CO ₂ H (2.7 mmol). After 30 minutes, the catalyst was filtered through a pad of diatomaceous earth and the filtrate was concentrated under reduced pressure. The residue was dissolved in water, the resulting solid was filtered off, washed with water and dried (54 mg, 93%) to obtain the title compound 20.

Example 21

3-amino-2-methoxy-5-tert-butylpyridine

Ethyl nitroacetate (3.3 ml, 4.0 g, 29.7 mmol) was added to ammonium hydroxide (25 ml, 11%) and stirred overnight, as described by AVAmet et al., Russian Chemical Bulletin, 1996, 45 (2), 393-398. Next, the reaction mixture is alkalinized with 4n. hydrochloric acid, extracted with ether (3 × 25 ml) and then EtOAc (3 × 100 ml). The combined EtOAc extracts were dried (magnesium sulfate), filtered and evaporated to dryness to give nitroacetamide as a pale yellow solid (1.7 g, 16.3 mmol, 55%).

Trichloroaluminum (45.5 g, 341 mmol) is slowly added to 100 ml of ice-cooled nitromethane in a nitrogen atmosphere. After that, a solution of malononitrile (21.5 ml, 22.6 g, 341 mmol) in 50 ml of nitromethane is added dropwise over an hour, maintaining the temperature below 10 ° C. Then, a solution of tert-butyl chloride (88 ml, 74.9 g, 809 mmol) in 25 ml of nitromethane is slowly added over 2.5 hours, keeping the temperature below 10 ° C. The reaction mixture was closed and placed in a freezer for 60 hours. After that, saturated aqueous sodium bicarbonate (500 ml) was added dropwise to the reaction mixture in order to suppress the intense reaction of the reaction mixture for 4 hours, keeping the temperature below 10 ° C. Then the heterogeneous mixture is neutralized with solid sodium bicarbonate (50 g). The layers were separated and the aqueous layer was extracted with methylene chloride (3 × 250 ml). The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to give 42 g of a partially crystalline brown oil. The residue was distilled in vacuo at 100 ° C. The first fraction is collected, after which solid formation begins in the condenser. Then, the cooling water supply is turned off and the condenser is heated with a heating gun to melt the solid. This fraction is collected until solid formation ceases in the condenser when cooling water passes through it, resulting in the desired dinitrile as a cream-colored solid melting at low temperature (19 g, 155 mmol, 46%).

A solution of this dinitrile (961 mg, 7.9 mmol) in anhydrous hexanes (50 ml) was cooled in a nitrogen atmosphere to -70 ° C in a dry ice / acetone bath. After that, diisobutylaluminum hydride (DIBAG) (17.5 ml, 1.0 M in cyclohexane) was added dropwise over 20 minutes. The mixture was stirred at -70 ° C for 45 minutes and then at room temperature for 5 hours. The reaction mixture was cooled to 0 ° C, after which a 2 molar aqueous hydrochloric acid solution (45 ml) was slowly added, keeping the temperature below 10 ° C. The mixture was stirred at room temperature for 15 hours. The layers were separated and the aqueous layer was extracted with ether (3 × 25 ml). The combined organic extracts were dried (magnesium sulfate), filtered and evaporated to dryness to give the desired dialdehyde as a viscous yellow oil (600 mg, 4.68 mmol, 60%).

A solution of this aldehyde (271 mg, 2.11 mmol), nitroacetamide (223 mg, 2.14 mmol) and piperidine (20% in EtOH) (250 μl, 0.51 mmol) in absolute EtOH (3 ml) with heating at 65 ° C for 3 hours. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The residue was purified by flash silica gel chromatography (EtOAc) to afford the desired nitropyridone as a yellow solid (280 mg, 1.43 mmol, 67%).

A mixture of this nitropyridone (150 mg, 0.76 mmol), phosphorus pentachloride (199 mg, 0.96 mmol) and phosphorus oxychloride (1 drop) is heated to the distillation temperature in a hermetically sealed tube. After 2 hours, phosphorus oxychloride was removed in vacuo and the residue was stirred in ice water (10 ml) for 18 hours. After that, the desired product was collected as a brown solid (95 mg, 0.44 mmol, 58%).

To a solution of 2-chloro-3-nitro-5-tert-butylpyridine (30 mg, 0.14 mmol) in anhydrous MeOH (1.5 ml) in a nitrogen atmosphere is added a solution of sodium methoxide (1.57 g of sodium in 40 ml of anhydrous MeOH) (85 μl, 0.14 mmol). The reaction mixture is heated overnight in a hermetically sealed tube in an oil bath at a temperature of 80-90 ° C. After that, the volatiles were removed in vacuo, the residue was dissolved in EtOAc (15 ml), washed with water (10 ml) and brine (10 ml), dried (magnesium sulfate), filtered and evaporated to dryness. Flash chromatography of the residue on silica gel (10% EtOAc in hexanes) gives the desired 2-methoxy-3-nitro-5-tert-butylpyridine as a glassy yellow solid (12 mg, 0.057 mmol, 41%).

To a suspension of the intermediate obtained in the previous step (12 mg, 0.057 mmol) and Pd / C (10%, 14 mg) in absolute EtOH (1 ml), ammonium formate (22 mg, 0.35 mmol) was added and the mixture was heated to 50 ° C for 1 h. After cooling, the reaction mixture was filtered through diatomaceous earth and washed with MeOH. The filtrate was evaporated to dryness to afford the title compound 21 as a brown solid (10 mg, 0.055 mmol, 100%).

Example 22

N-acetyl-5-amino-3,3-dimethylindoline

A solution of oxindole (5.0 g, 37.5 mmol) in acetic anhydride (7.1 ml, 75.1 mmol) and acetic acid (25 ml) was heated under reflux for 20 hours. After cooling to room temperature, the reaction mixture diluted with water (200 ml). The resulting solid was filtered off, washed with water and dried to give N-acetyloxindole as a white solid (5.2 g, 79%).

A mixture of this N-acetyloxyindole (2.0 g, 11.4 mmol), iodomethane (1.56 ml, 25.1 mmol) and potassium carbonate (3.1 g, 22.8 mmol) in DMSO (20 ml) is stirred at room temperature for 20 hours. After this, the reaction mixture was diluted with water. The resulting solid was filtered off, washed with water and dried to give N-acetyldimethyloxindole as an orange solid (1.9 g, 84%).

A solution of this N-acetyldimethyloxindole (500 mg, 2.5 mmol) in 3 N. a solution of sulfuric acid (7 ml) and THF (7 ml) was heated under reflux for 4 hours. After cooling to room temperature, the reaction mixture was diluted with ether. The ether layer was washed with water and brine, dried (magnesium sulfate), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 30% EtOAc in hexanes) to give dimethyloxindole as a red solid (228 mg, 57%).

A solution of this dimethyloxindole (220 mg, 1.4 mmol) in toluene (5 ml) is treated with a 65% solution of Red-Al in toluene (0.64 ml, 2.05 mmol) at 80 ° C. After stirring at 100 ° C. for 4 hours, the reaction was stopped by the addition of 1N. sodium hydroxide solution. The organic layer was separated, washed with water and brine, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 25% EtOAc in hexanes) to give dimethylindoline as a light blue oil (121 mg, 60%).

A solution of this dimethylindoline (65 mg, 0.44 mmol) and triethylamine (0.12 ml, 0.88 mmol) in dry dichloromethane (3 ml) is treated with acetyl chloride (0.05 ml, 0.66 mmol) at 0 ° C. The mixture was allowed to warm to room temperature and stirred for 16 hours. Then the reaction was stopped by the addition of water and the product was extracted with ether. The organic layer was washed with water and brine, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 30% EtOAc in hexanes) to give N-acetyldimethylindoline as a pale yellow oil (68 mg, 82%).

A solution of this N-acetyldimethylindoline (65 mg, 0.34 mmol) in acetic acid (2 ml) was treated with fuming nitric acid (24 μl, 0.57 mmol) at room temperature and the resulting mixture was stirred for 1 h. After this, the reaction was stopped by adding a saturated solution of sodium bicarbonate and the product is extracted with EtOAc. The organic layer was washed with water and brine, dried (sodium sulfate), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 50% EtOAc in hexanes) to give the desired nitrated indoline as a pale orange solid (66 mg, 67%).

A mixture of N-acetyl-3,3-dimethyl-5-nitroindoline (64 mg, 0.27 mmol), ammonium formate (86 mg, 1.36 mmol) and 10% palladium on carbon (5 mg) in MeOH ( 5 ml) was stirred at room temperature for 2 hours. The reaction mixture was filtered through a short plug from diatomaceous earth. After that, the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluent: 50% EtOAc in hexanes) to give the title compound 22 as a white solid (48 mg, 87%).

Example 23

8-amino-6-tert-butyl-3-oxo-4-N-methylbenzoxazine

To a solution of 4-tert-butyl-2,6-dinitrophenol (3.15 g, 13.13 mmol) in 100 ml of acetonitrile, ammonium formate (5.0 g, 78.8 mmol) and 10% palladium on carbon are added (1.0 g). The mixture was heated under reflux for 20 minutes, after which it was allowed to cool and filtered through diatomaceous earth. The residue was washed with EtOAc and the combined organic phases were evaporated in vacuo. The residue was dissolved in dichloromethane and filtered through a short plug of silica gel. After removing the solvent in vacuo, 2-amino-4-tert-butyl-6-nitrophenol is obtained in the form of a red solid (4.86 mmol, 37% yield).

To a solution of this 2-amino-4-tert-butyl-6-nitrophenol (258 mg, 1.23 mmol) and benzyltriethylammonium chloride (BTEA) (280 mg, 1.23 mmol) in 5 ml of chloroform, finely divided NaHCO ₃ (413 mg, 4.92 mmol). The mixture was cooled to 0 ° C. and β-chloroacetyl chloride (0.12 ml, 1.47 mmol) in 1.5 ml of chloroform was added dropwise with a syringe over 15 minutes. Upon completion of the addition, the mixture was allowed to stir at 0 ° C for 1 h. The mixture was then allowed to warm to ambient temperature and finally gently heated under reflux for 6 h. The resulting crude orange mixture was allowed to cool, and then filtered through diatomaceous earth to separate white precipitate, which is thoroughly washed with a large amount of chloroform. After removing the solvent in vacuo, the oily residue was treated with water (40 ml) and stirred with a spatula, resulting in a yellow precipitate. This pure 6-tert-butyl-8-nitro-3-oxobenzoxazine is filtered and dried first in a stream of air and then in a vacuum (1.05 mmol, 85%).

To a solution of this 6-tert-butyl-8-nitro-3-oxobenzoxazine (51 mg, 0.20 mmol) in 3.5 ml of DMF at 0 ° C, sodium hydride (10 mg, 60% dispersion in mineral oil, 0.24 mmol). After 20 minutes, methyl iodide (20 μl, 0.24 mmol) was added via syringe. The mixture was allowed to slowly warm to ambient temperature overnight. A saturated aqueous solution of ammonium chloride was added to the crude mixture to terminate the reaction, and extracted with EtOAc (3 × 10 ml). The combined organic phases are washed with water and then with brine, and then dried over sodium sulfate. After filtration and removal of solvents in vacuo, 6-tert-butyl-8-nitro-3-oxo-4-N-methylbenzoxazine (100%) is obtained.

This 6-tert-butyl-8-nitro-3-oxo-4-N-methylbenzoxazine (53 mg, 0.2 mmol) was dissolved in 12.5 ml of acetonitrile. After this, cyclohexene (0.20 ml, 2.0 mmol) and 10% palladium on carbon (75 mg) are added. The mixture was refluxed for 1 h, then cooled to ambient temperature and filtered through diatomaceous earth. The residue was washed with EtOAc and the combined organic phases were evaporated in vacuo to give the title compound 23 (100%).

Example 24

7-amino-5-tert-butyl-3H-benzoxazol-2-one

To a solution of 2-amino-4-tert-butyl-6-nitrophenol (300 mg, 1.43 mmol) and pyridine (0.30 ml) in methylene chloride (30 ml) was added 4-nitrophenyl chloroformate (280 mg, 1.39 mmol) ) The mixture was stirred for 24 hours. The resulting solution was washed with aqueous sodium bicarbonate (2 × 20 ml), dried over solid magnesium sulfate and concentrated to an orange solid. Column chromatography (silica gel, eluent: 40% EtOAc / petroleum ether) gives 5-tert-butyl-7-nitro-3H-benzoxazol-2-one (70%).

This 5-tert-butyl-7-nitro-3H-benzoxazol-2-one (200 mg, 0.9 mmol) was dissolved in EtOH (10 ml). After this, cyclohexene (4 ml) and 10% palladium on carbon (50 mg) are added. The mixture was refluxed for 3 hours and then cooled to ambient temperature and filtered through diatomaceous earth. Column chromatography (silica gel, eluent: 25% EtOAc / petroleum ether) gave the title compound 24 (70%).

Example 25

7-amino-5-tert-butyl-2-methylbenzoxazole

2-amino-4-tert-butyl-6-nitrophenol was dissolved in triethyl orthoacetate (10 ml). The reaction mixture was stirred overnight at 100 ° C. After evaporation of the volatile components in vacuo, 5-tert-butyl-2-methyl-7-nitrobenzoxazole (110 mg) is obtained.

This 5-tert-butyl-2-methyl-7-nitrobenzoxazole (100 mg, 0.4 mmol) was dissolved in EtOH (20 ml). After this, a catalyst (10% Pd / C, 100 mg) was added, followed by ammonium formate (160 mg, 0.3 mmol). The resulting heterogeneous mixture was stirred at 100 ° C. for 1 h. After filtration and subsequent evaporation, the title compound 25 (85 mg) was obtained.

In examples 26-29, the synthesis of four heteroarylamines that can be used as intermediate IV in methods AB (section "General Synthesis Methods") for the preparation of compounds of formula I or Ia is considered.

Example 26

5- (5-amino-3-tert-butylpyrazol-1-yl) -2-methylbenzamide

3-iodo-4-methylphenylamine (10 g, 43 mmol) is dissolved in 6 N. HCl (40 ml) and cooled to 0 ° C, stirring vigorously throughout this process. Sodium nitrite (2.9 g, 1.03 equiv.) Was dissolved in water (5 ml) and this solution was added dropwise to the reaction mixture. After 30 minutes, tin (II) chloride dihydrate (22.8 g, 1 mol) in 6N was added via a dropping funnel. HCl (100 ml) and the reaction suspension were stirred at 0 ° C for 3 h. After that, the pH was adjusted to 14 with a 40% aqueous sodium hydroxide solution and the aqueous mixture was extracted with EtOAc (6 × 50 ml), dried (MgSO ₄ ) and concentrated to give 3-iodo-4-methylphenylhydrazine (7 g, 57%). This material is used directly in the subsequent reaction without further purification.

A solution of the above phenylhydrazine (5.08 g, 22 mmol) and 4,4-dimethyl-3-oxopentannitrile (3.06 g, 1.1 eq.) In EtOH (100 ml) containing conc. HCl (3 ml), heated under reflux for 17 h, and then cooled to room temperature. The pH was adjusted to 14 using a 40% aqueous sodium hydroxide solution. The aqueous mixture was extracted with EtOAc (3 × 50 ml), dried (MgSO ₄ ) and concentrated to give 5-tert-butyl-2- (3-iodo-4 -methylphenyl) -2H-pyrazol-3-ylamine (6.3 g, 86%). This material is used directly in the subsequent reaction without further purification.

5-tert-butyl-2- (3-iodo-4-methylphenyl) -2H-pyrazol-3-ylamine (2 g, 5.6 mmol) is combined with zinc cyanide (397 mg, 0.6 equiv.) And tetrakis (triphenylphosphine) palladium (0) (325 mg, 5 mol%) in deoxygenated dimethylformamide (10 ml). The resulting yellow suspension was maintained with heating at 100 ° C for 4 hours, cooled to room temperature, and then diluted with brine and 2 N. HCl. The aqueous mixture was extracted with EtOAc (6 × 10 ml), dried (MgSO ₄ ) and concentrated. The residue was purified by flash chromatography, eluting with 20% EtOAc / petroleum ether to give 1.3 g (91%) of the desired nitrile.

This nitrile (150 mg, 0.6 mmol) in EtOH (5 ml) is heated to 100 ° C for 2 hours in the presence of 10 N. NaOH. After this, the reaction mixture was cooled to room temperature, neutralized with 50% HCl, extracted with EtOAc (6 × 10 ml), dried (MgSO ₄ ) and concentrated to obtain the title compound 26 (130 mg, 80%).

Example 27

5-amino-2-methoxypyridine (5.0 g, 40 mmol) was dissolved in 6 N. HCl (10 ml) and cooled to 0 ° C, stirring vigorously throughout this process. Sodium nitrite (2.8 g, 41 mmol) was dissolved in water (10 ml) and this solution was added to the reaction solution. After 30 minutes, tin (II) chloride dihydrate (52 g, 230 mmol) in 6 N was added. HCl (20 ml) and the reaction suspension were stirred at 0 ° C for 2.5 hours. The pH was adjusted to 13 with a 40% aqueous sodium hydroxide solution. Ethyl ether was added and the mixture was extracted with EtOAc (4 × 70 ml) ), dried (MgSO ₄ ) and concentrated to give 5-hydrazino-2-methoxypyridine as an orange solid (5.1 g).

A solution of 5-hydrazino-2-methoxypyridine (2.5 g, 18 mmol) and 4,4-dimethyl-3-oxopentanenitrile (2.3 g, 18 mmol) in toluene (50 ml) was heated under reflux for 17 hours in a flask equipped with a Dean-Stark trap, and then cooled to room temperature. After this, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography, eluting with 30% EtOAc / petroleum ether, to give the title compound 27 as a tan solid (3.5 g, 80%).

Example 28

5-amino-3-tert-butyl-1- (2-pyridon-5-yl) pyrazole

To a solution of the product obtained in Example 27 (0.6 g, 2.4 mmol) in acetic acid (3 ml) was added 48% HBr in acetic acid (3 ml). The reaction mixture was heated to 120 ° C for 15 minutes, cooled to room temperature, and then the pH was adjusted to 7.5 using a 10% aqueous sodium hydroxide solution. The aqueous mixture was extracted with EtOAc (4 × 15 ml), dried (MgSO ₄ ) and concentrated to give a tan solid. The title compound 28 (0.46 g, 82%) was obtained after recrystallization from ether.

Example 29

5-amino-3-tert-butyl-1- (2-cyanoethyl) pyrazole

A solution of 2-cyanoethylhydrazine (3.0 g, 35 mmol) and 4,4-dimethyl-3-oxopentanenitrile (4.2 g, 34 mmol) in toluene (50 ml) was heated under reflux for 17 hours in a flask equipped Dean-Stark trap and then cooled to room temperature. The suspension is filtered and the filtrate is concentrated. Column chromatography of the residue on silica gel eluting with 50% EtOAc / petroleum ether gave the title compound 29 as a colorless solid (2.6 g, 40%).

Example 30

1- [5-tert-butyl-2- (2-methylthiopyrimidin-5-yl) -2H-pyrazol-3-yl] -3- {4- [6- (morpholin-4-ylmethyl) pyridin-3-yl ] naphthalene-1-yl} urea

Pinacolin (100 mmol) and diethyl oxalate (120 mmol) are dissolved in THF (200 ml), cooled to -78 ° C and treated with lithium hexamethyldisilazide (Li-HMDS, 120 mmol, 1 molar solution in THF). After that, the ice bath was removed and the reaction mixture was allowed to warm to room temperature. After 2 hours, the volatiles were removed and the crude residue was dissolved in ice-cold HOAc (200 ml). Then add hydrazine monohydrate (110 mmol), the reaction mixture is placed in an oil bath at a temperature of 90 ° C and stirred overnight. After this, the HOAc was removed under reduced pressure and the crude residue was dissolved in aqueous NaHCO ₃ to give a solution of pH 6. Next, the solid was filtered off, washed with water and dried to obtain the desired pyrazole ether (12.9 g, 66%).

KO-tert-Bu (67 mmol) was dissolved in DMSO (120 ml). Then, in one portion, the pyrazole ether obtained in the previous step (12 g, 61 mmol) is added and the reaction mixture is stirred for 15 minutes. After this, tert-butyl bromoacetate (92 mmol) was added and the reaction mixture was stirred at room temperature for 45 minutes. Then DMSO was removed under reduced pressure and the crude residue was diluted with ice water and extracted with CH ₂ Cl ₂ . The organic phases are combined, dried over MgSO ₄ and concentrated to give an isomeric mixture of pyrazoles as an orange oil (21 g). The desired isomer is isolated as an oil by silica gel chromatography, eluting with CH ₂ Cl ₂ (13.3 g, 70%).

The pyrazole diester (13.3 g, 43 mmol) was dissolved in pure TFA (150 ml) and stirred at room temperature for 3 hours. After that, volatiles were removed and the crude residue was diluted with ice water and extracted with CH ₂ Cl ₂ . The organic phases are combined, washed with water, dried over MgSO ₄ and concentrated to give the desired carboxylic acid as a thick oil that partially crystallizes (10.2 g, 94%).

Anhydrous DMF (282 mmol) was cooled to 0 ° C and treated with POCl ₃ (161 mmol). After 5 minutes, the pyrazole derivative of acetic acid (10.2 g, 40 mmol) obtained in the previous step is added and the suspension is placed in an oil bath with a temperature of 110 ° C. After this, the reaction mixture was stirred for 2 hours, while all solid was dissolved. After cooling to room temperature, the reaction mixture was poured into a stirred solution of NaPF ₆ (80 mmol) in water (400 ml). Upon completion of the precipitation, it is filtered off, washed with water and dried, to obtain the desired vinylamidinium salt XCVIII (14.6 g, 78%).

This XCVIII salt (233 mg, 0.5 mmol) was dissolved in DMSO (10 ml) and treated with S-methylisothiourea sulfate (0.25 mmol) and K ₂ CO ₃ (0.25 mmol). After that, the reaction mixture was placed in an oil bath with a temperature of 90 ° C and stirred for 2 hours. After cooling the reaction mixture to room temperature, volatiles were removed under reduced pressure. The residue was dissolved in ice water and extracted with diethyl ether. The organic phases are combined, dried over MgSO ₄ and concentrated to give a brown gum. The desired ethyl ester was purified by silica gel column chromatography, eluting with 1: 1 CH ₂ Cl ₂ / EtOAc to give a yellow oil, which crystallized upon standing (157 mg, 98%).

The ether (150 mg, 0.47 mmol) obtained in the previous step was dissolved in MeOH (4 ml) and water (1 ml), treated with LiOH monohydrate (0.7 mmol) and stirred at room temperature overnight. After that, volatiles are removed and the residue diluted with water and neutralized to pH 4 with 1 N. sulfuric acid. The solid is filtered off, washed with water and dried (113 mg, 82%).

The resulting carboxylic acid (105 mg, 0.36 mmol) was suspended in benzene (4 ml) and treated with triethylamine (0.61 mmol). The resulting solution was treated with diphenylphosphoryl azide (DFA) (0.54 mmol) and allowed to stir at room temperature for 6 hours. The organic phases were washed with aqueous NaHCO ₃ and water, dried over MgSO ₄ and filtered. The resulting solution was treated with compound LXXXIV (Example 4) (115 mg, 0.36 mmol) and the reaction mixture was placed for 1 h in an oil bath at a temperature of 90 ° C. After that, the volatiles were removed and the crude residue was purified by preparative thin layer chromatography on two plates, eluting with a 9: 1 CH ₂ Cl ₂ / MeOH mixture to give the title compound 30 as an off-white solid (61 mg, 28% )

By replacing the S-methylisothiourea sulfate used in the reaction with compound XCVIII, other substituted pyrimidines corresponding to formula XCVIV can be obtained. For example, using acetamide hydrochloride, a 2-methylpyrimidine analogue of compound XCVIV can be obtained. The use of O-methylisothiourea sulfate and guanidine carbonate makes it possible to obtain, respectively, 2-methoxypyrimidine and 2-aminopyrimidine analogues. By replacing S-methylisothiourea sulfate with hydrazine monohydrate or N-methylhydrazine, a pyrazol-4-yl or 1-methylpyrazol-4-yl ring, respectively, can be obtained instead of the substituted pyrimidine in compound XCVIV. Each of these analogues of compound XCVIV can be used in the methods described above to obtain the corresponding analogues of compound 30.

Examples 31-36 describe the synthesis of substituted naphthylamines that can be used as intermediate VI (D'-NH ₂ ), as described for methods B and C in the General Synthesis Methods section, to prepare various compounds of the invention.

Example 31

5- (4-aminonaphthalen-1-yl) -2-pyridin-3-ylmethylphenol

1.75 ml of 2-cyclohexen-1-one (18.0 mmol, 2.0) are added to a tube with a solution of 2.0 g of 1-amino-4-bromonaphthalene (9.0 mmol, 1 equiv.) In 70 ml of DMF equiv.), 2.3 g of sodium bicarbonate (27.0 mmol, 3.0 equiv.) and 186 mg of 1,3-bis (diphenylphosphino) propane (DFPP, 0.45 mmol, 0.05 equiv.). The mixture was bubbled through dry nitrogen gas for 15 minutes, after which 316 mg of bis (triphenylphosphino) palladium (II) chloride (0.45 mmol, 0.05 equiv.) Was added and the tube was hermetically sealed. The mixture was heated with heating at 150 ° C. for 8 hours and then cooled to ambient temperature, diluted with EtOAc (150 ml) and filtered through diatomaceous earth. The mixture is washed with water and then with brine. The organic layer was dried (MgSO ₄ ), filtered and concentrated. The crude oil is purified by SiO ₂ column chromatography using 10 to 50% EtOAc in hexanes mixtures as eluents to give 2.0 g of a thick liquid containing 3- (4-aminonaphthalen-1-yl) cyclohex-2-enone and DMF (respectively, in a molar ratio of 1: 2, 5.22 mmol of naphthylamine, yield 58% of theoretical).

To a solution of 4.0 g of 3- (4-aminonaphthalen-1-yl) cyclohex-2-enone in a mixture with DMF (1: 2, 10.4 mmol, 1 equiv.) In 50 ml of toluene, 2.72 g of di tert-butyl dicarbonate (12.5 mmol, 1.2 equiv.) and 1.5 ml of triethylamine (10.4 mmol, 1 equiv.). The mixture was maintained with heating at 100 ° C. overnight, after which it was cooled to ambient temperature. Next, the reaction mixture was washed with 0.1% aqueous HCl (2 × 50 ml), water and brine, dried (MgSO ₄ ), filtered and concentrated. The crude product is precipitated and washed with 10% EtOAc in hexane to obtain, after filtration, 2.5 g of the desired tert-butyl carbamate (7.4 mmol, 71% of theoretical yield).

To a solution of 186 mg of the tert-butylnaphthyl carbamate obtained in the previous step (0.55 mmol, 1 equiv.) In 1.6 ml of anhydrous tert-butanol was added 52 μl of pyridine-3-carboxaldehyde (0.55 mmol, 1 equiv.) and 1.65 ml of potassium tert-butoxide solution (1.0 M, 1.32 mmol, 3 eq.). This mixture was refluxed overnight and then cooled. Then, MeOH (5 ml) and a solution of HCl in dioxane (4.0 M) were added until the pH reached about 1, after which the reaction mixture was stirred for 1.5 h at ambient temperature. Then, a saturated aqueous solution of NaHCO _{3 was} added to the mixture to stop the reaction, and extracted with EtOAc (2 × 50 ml). The aqueous layer is treated with 4 N. aqueous NaOH until the pH reaches about 12, and then extracted twice more. The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated to give a crude product mixture containing naphthylamine in the form of still protected carbamate. After this, the residue was dissolved in dichloromethane (3 ml), treated with 2 ml of TFA and allowed to mix over the weekend at ambient temperature. Then the reaction in the mixture was stopped and the mixture was neutralized with saturated aqueous NaHCO ₃ , extracted with dichloromethane (3 × 50 ml), dried (MgSO ₄ ) and filtered. The volatiles were then removed in vacuo and the crude product was purified by SiO ₂ column chromatography using 50 to 100% EtOAc in hexanes mixtures as eluent to give 35 mg of the title compound 31 (0.11 mmol, 20% of theoretical )

Example 32

5- (4-aminonaphthalen-1-yl) -2- (tetrahydrofuran-3-ylmethyl) phenol

To a solution of 3.16 g of tetrahydro-3-furoic acid (27 mmol, 1 equiv.) In 25 ml of anhydrous dichloromethane, 7.85 g of dicyclohexylcarbodiimide (DCC, 38 mmol, 1.4 equiv.) And 4.54 ml of triethylamine ( 32.6 mmol, 1.2 equiv.). After this, N-methylmethanolamine hydrochloride is added, followed by 60 mg of DMAP ((4-dimethylamino) pyridine). In this case, an exothermic reaction occurs, and therefore another 25 ml of dichloromethane is added. The mixture was stirred at ambient temperature overnight, then filtered through diatomaceous earth and concentrated. The residue is taken up in ether, the white solid is filtered off and discarded. The solvent was removed from the mother liquor, and the residue was purified by SiO ₂ column chromatography using 15-25% EtOAc in hexanes as eluent mixtures to obtain the desired amide as a colorless oil (55% of theoretical yield), which still contained 10 % dicyclohexylurea. This product is used in the subsequent reaction without further purification.

To a solution of 1.0 g of the above amide (6.28 mmol, 1 equiv.) In 60 ml of anhydrous THF at -78 ° C, 12.6 ml of a 1.0 molar solution of DIBAG in toluene are added dropwise with a syringe (12, 6 mmol, 2.0 equiv.). After 30 minutes stirring at -78 ° C, 50 ml of MeOH and 50 ml of water are added to the reaction mixture to terminate the reaction. The reaction mixture was transferred to a separatory funnel and 250 ml of ether was added. After this, add 1 N. an aqueous HCl solution until all of the solid has dissolved. The layers were separated and the aqueous phase was further extracted twice with ether in 100 ml portions. The combined organic phases are washed with saturated aqueous NaHCO ₃ and then brine, dried over Na ₂ SO ₄ , filtered and concentrated. The crude product is purified by silica gel chromatography using 0-5% MeOH in dichloromethane as eluent mixtures. In this way, the desired 3-tetrahydrofuroic aldehyde is obtained in the form of an easily volatile, impurity containing a colorless oil (200 mg).

To a solution of 200 mg of tert-butylnaphthylcarbamate (0.59 mmol, 1 equiv.) In 1.6 ml of anhydrous tert-butanol, 200 mg of the 3-tetrahydrofuroic aldehyde obtained in the previous step (in excess) and 1.78 ml of a solution of tert-butoxide are added potassium in tert-butanol (1.0 M, 1.78 mmol, 3 eq.). The mixture was kept under heating at 40 ° C. overnight, then it was cooled and the reaction was stopped by the addition of a saturated aqueous solution of NH ₄ Cl. The resulting product was extracted with a mixture of dichloromethane with methanol (3 × 100 ml). The combined extracts were washed with brine, dried over MgSO ₄ and concentrated. Moreover, according to the data of ¹ H-NMR analysis, only 10% of enon is consumed. The residue (300 mg) was dissolved in 4.0 ml of dichloromethane and treated with 4 ml of a mixture of dichloromethane with TFA in a ratio of 1: 1. The reaction mixture was stirred for 1.5 hours, after which it was neutralized with saturated aqueous NaHCO ₃ , and alkalized with 4N. NaOH solution and extracted with dichloromethane / methanol (3 × 100 ml). The combined organic extracts were washed with brine, dried (MgSO ₄ ), filtered and concentrated. The crude product was purified by silica gel column chromatography using 10 to 50% EtOAc in hexanes as 3-point mixtures to give the title compound 32 (35 mg, 0.11 mmol, 19% theoretical yield).

Example 33

4- [5- (4-aminonaphthalen-1-yl) pyridin-2-yloxy] butyronitrile

To a solution of 2,5-dibromopyridine (500 mg, 2.1 mmol) and 3-cyano-1-propanol (270 mg, 3.1 mmol) in DMSO (2 ml) was added 1M sodium hexamethyldisilazide (Na-HMDS, 2, 1 ml, 2.1 mmol). After that, the reaction mixture was stirred at room temperature overnight. Next, EtOAc was added to the reaction mixture, and the mixture was washed with water (2 × 10 ml). The EtOAc fraction was dried over anhydrous sodium sulfate and evaporated on a rotary evaporator. The crude product was purified by flash column chromatography on silica gel using 40% EtOAc / Hexanes to give 200 mg of 5-bromo-2-cyanopropyloxypyridine as a pale yellow solid (39.3%).

To the intermediate obtained in the previous step (100 mg, 0.4 mmol) and CBZ-protected naphthylboronic acid XCVIX (obtained according to the method for producing the Boc analogue XCl in Example 17) (200 mg, 0.62 mmol) in DME (4 ml ) add a 2 molar solution of sodium carbonate (2 ml). The solution was purged with nitrogen for 10 minutes and then palladium tetrakistriphenylphosphine (20 mg) was added. The reaction mixture was heated at 90 ° C. for 48 hours, and then cooled to room temperature. Next, EtOAc was added to the reaction mixture, and the mixture was washed with water (2 × 10 ml). The EtOAc fraction was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 40% EtOAc / Hexanes to give 70 mg of product (39%).

To the product of the coupling reaction obtained in the previous step (70 mg, 0.16 mmol) in EtOH (5 ml), cyclohexene (263 mg, 3.2 mmol) and 10% Pd / C (20 mg) are added. The reaction mixture was maintained with heating under nitrogen overnight and cooled to room temperature. After that, the reaction mixture was filtered through diatomaceous earth, washed with MeOH and concentrated. The crude product was purified by flash column chromatography on silica gel eluting with 50% EtOAc / Hexanes to give 15 mg of the title compound 33 (31%).

Example 34

[5- (4-Aminonaphthalen-1-yl) pyridin-2-yl] - (tetrahydro-thiopyran-4-yl) amine dihydrochloride

To tetrahydro-1,4-thiopyrone (2.0 g, 17.2 mmol) and hydroxylamine hydrochloride (2.0 g, 28.7 mmol) in EtOH (10 ml), sodium acetate trihydrate (4.0 g, 29 , 4 mmol) in 20 ml of water. The reaction mixture was refluxed for 3 hours, cooled to room temperature and concentrated on a rotary evaporator to a volume of 15 ml. The residue was cooled in an ice bath and filtered to obtain 2.0 g of the oxime product as a white solid with a _mp 80-83 ° C (88.7%).

In a dry flask containing THF (20 ml) and 1M lithium aluminum hydride (AGL) in diethyl ether (19 ml) at room temperature, the oxime obtained in the previous step (500 mg, 3.82 mmol) is added. The reaction mixture was refluxed for 3 hours, cooled to room temperature, and the reaction of excess AHL was stopped by adding a mixture of ice and water. After extraction with EtOAc and concentration, 340 mg (76%) of the desired 4-aminotetrahydrothiopyran are obtained.

To the amine obtained in the previous step (170 mg, 1.4 mmol) in dry pyridine (1 ml), 2,5-dibromopyridine (250 mg, 1.1 mmol) was added, after which the reaction mixture was heated with heating at 110-120 ° C for 5 days. The reaction mixture was then extracted with EtOAc, washed with water, dried over anhydrous sodium sulfate and concentrated to give a crude product. This crude product was purified by flash column chromatography on silica gel using 30% EtOAc / hexanes as eluent to give 100 mg of pure product (33.3%).

To the intermediate obtained in the previous step (80 mg, 0.293 mmol) and BOC-protected naphthylboronic acid XCI (Example 17) (140 mg, 0.488 mmol) in DME (4 ml), 2M sodium carbonate (2 ml) and bis chloride ( triphenylphosphine) palladium (15 mg). The reaction mixture was heated at 90 ° C. under nitrogen for 18 hours and cooled to room temperature. After that, the reaction mixture was extracted with EtOAc, washed with water, dried over anhydrous sodium sulfate and concentrated to obtain a crude product. This crude product was purified by flash column chromatography on silica gel using a mixture of 30% EtOAc / Hexanes as eluent to give 110 mg of pure XX product (86.0%)

To compound XXX (35 mg, 0.08 mmol) in dioxane (1 ml) was added a mixture of 4M HCl / dioxane (0.6 ml). Then, the reaction mixture was stirred at room temperature for 48 hours. After adding diethyl ether, the product was obtained in the form of hydrochloride, which was filtered to obtain 18 mg (55%) of the title compound 34.

Example 35

Dihydrochloride of [5- (4-aminonaphthalen-1-yl) pyridin-2-yl] - (tetrahydro-pyran-4-yl) amine

To 2-amino-5-bromopyridine (250 mg, 1.44 mmol) and BOC-protected naphthylboronic acid XCl (example 17) (688 mg, 2.4 mmol) in 5 ml of DME add 2M sodium carbonate (2.5 ml ) and bis (triphenylphosphine) palladium chloride (30 mg). The reaction mixture was heated at 90 ° C. under nitrogen for 18 hours and cooled to room temperature. Then the reaction mixture was extracted with EtOAc, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with a mixture of 40% EtOAc / hexanes to give 370 mg of the product of the reaction of XLC coupling (76.4%).

To this intermediate (200 mg, 0.597 mmol) and tetrahydropyranone (120 mg, 1.19 mmol) in dichloroethane (5 ml) are added glacial acetic acid (0.2 ml, 3.58 mmol) and sodium triacetoxyborohydride (380 mg, 1.79 mmol). The reaction mixture was stirred at room temperature for 48 hours, and then extracted with EtOAc, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 50% EtOAc / hexanes as eluent to give 120 mg of compound XCXI (48.0%).

The compound XCXI obtained in the previous step is dissolved in dichloromethane (3 ml) and treated with trifluoroacetic acid (1 ml).

The reaction mixture was stirred for 3 hours and concentrated. The residue was dissolved in EtOAc (20 ml), washed with sodium bicarbonate solution, dried over anhydrous sodium sulfate and concentrated to give 90 mg of the title compound 35 (98.5%).

Example 36

[5- (4-aminonaphthalen-1-yl) pyridin-2-yl] - (1-methylpiperidin-4-yl) amine

To a mixture of compound XX (example 35) (110 mg, 0.33 mmol) and 1-methyl-4-piperidone (80 mg, 0.7 mmol) in dichloroethane (6 ml) was added glacial acetic acid (120 mg, 2, 0 mmol) and sodium triacetoxyborohydride (220 mg, 1.03 mmol). The reaction mixture was stirred at room temperature for 96 hours, and then extracted with EtOAc, washed with water, dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel using 10% MeOH / CH ₂ Cl ₂ / 0.1 TEA (triethanolamine) as eluent to give 60 mg of pure product (42.0%).

The product obtained in the previous step is dissolved in dichloromethane (3 ml) and treated with trifluoroacetic acid (1 ml). The reaction mixture was stirred for 2.5 hours and concentrated to give 94 mg of the title compound 36 (100%).

Example 37

Example 37 illustrates the synthesis of a compound of formula III in which E is O.

[4- (6-Morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] carbamic acid 3-tert-butylphenyl ester

Compound LXXXIV (Example 4) (100 mg, 0.31 mmol) was dissolved in dichloromethane (20 ml). After that, an equal volume of saturated aqueous sodium bicarbonate is added and the two-phase solution is cooled to 0 ° C. Further, while adding phosgene (1.93 M in toluene, 0.40 ml), stirring was stopped. Immediately after this, stirring of the reaction mixture was resumed and continued for 15 minutes at 0 ° C. After that, the layers are separated, the organic phases are dried over solid magnesium sulfate and the solution is concentrated to a volume of about 5 ml. Then 3-tert-butylphenol (100 mg, 0.67 mmol) in dichloromethane (5 ml) was added. The reaction mixture was stirred at room temperature for 19 hours. After flash chromatography using EtOAc as eluent, 71 mg of the title compound 37 was obtained.

Example 38

Example 38 illustrates the synthesis of a compound of formula III in which E is CH ₂ .

2- (5-tert-butyl-2-methoxyphenyl) -N- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] acetamide

Compound LXXXIV (Example 4) (100 mg, 0.4 mmol) and 5-tert-butyl-2-methoxyphenylacetic acid sodium salt (154 mg, 0.4 mmol) were dissolved in dichloromethane (15 ml). Next, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (172 mg, 0.9 mmol) was added and the reaction mixture was stirred at ambient temperature for 16 hours. After purification by high-resolution liquid chromatography (HPLC), 30 mg of the title was obtained compound 38.

The following compounds are also prepared analogously to the methods described above:

1- (2-tert-butyl-5-methylpyridin-4-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- (5-tert-butyl-2-methylphenyl] -3- {4- [6- (morpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1- silt] urea,

1- (3-amino-5-tert-butyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- (3-tert-butylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-methylbiphenyl-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (4-tert-butylbiphenyl-2-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

amide 1- (5- {4- [3- (5-tert-butyl-2-methoxyphenyl) ureido] naphthalen-1-yl} pyridin-2-ylmethyl) piperidine-3-carboxylic acid,

1- (5-isopropyl-2-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-sec-butyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxymethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- (4- {6 - [(tetrahydrofuran-3-ylamino) methyl] pyridin-3-yl} naphthalen-1-yl) urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- (4- {6- [4- (3-methoxyphenyl) piperazin-1-ylmethyl] pyridin-3-yl} naphthalen-1-yl) urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (5-morpholin-4-ylmethylpyrazin-2-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6 - {[(2-cyanoethyl) - (tetrahydro-furan-2-ylmethyl) amino] methyl] pyridin-3-yl) naphthalene -1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6 - [[(2-cyanoethyl) pyridin-3-ylmethylamino] methyl] pyridin-3-yl) naphthalen-1-yl] urea ,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6-thiomorpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (1-oxo- [4-thiomorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [6- (1-oxotetrahydrothiopyran-4-ylamino) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2,6-dimethylmorpholin-4-ylmethyl) -pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2,6-dimethylpiperidin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2-methoxymethylmorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2-methyl-3-oxopiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl) pyridin-3-yl] naphthalene-1 -il} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [6- (2-thia-5-azabicyclo [2.2.1] hept-5-ylmethyl) pyridin-3-yl] naphthalene-1 -il} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [6- (3-oxopiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (4-methylpiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (4-pyridin-2-ylpiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [6- (morpholin-4-carbonyl) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [6- (pyridin-3-yloxy) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (tetrahydropyran-4-ylamino) pyridin-3-yl] naphthalen-1-yl} urea,

1- (5-tert-butyl-2-methylphenyl) -3- (4- [6 - [(3-methoxypropyl) methylamino] pyridin-3-yl} naphthalen-1-yl) urea,

1- (5-tert-butyl-2-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- (5-tert-butyl-2-methylpyridin-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea,

1- (6-tert-butyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3- il) naphthalene-1-yl] urea,

1- [4- (6 - [[bis (2-cyanoethyl) amino] methyl} pyridin-3-yl) naphthalen-1-yl] -3- (5-tert-butyl-2-methoxyphenyl) urea,

1- [5- (1,1-dimethylpropyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (1H-pyrazol-4-yl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (3-hydroxypropyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

1- [5-tert-butyl-2- (morpholin-4-carbonyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea,

N- (5- {4- [3- (5-tert-butyl-2-methoxyphenyl) ureido] naphthalen-1-yl} pyridin-2-yl) acetamide,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) acetamide,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) -N-methylacetamide,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) -2,2,2 trifluoroacetamide,

N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) methanesulfonamide.

Assessment of biological properties

Inhibition of TNF Production in THP Cells

Inhibition of cytokine production can be assessed by measuring the inhibition of TNFα in lipopolysaccharide-stimulated THP cells (see, for example, W.Prichett et al., J. Inflammation, 45, 97, 1995). All cells and reagents were diluted with RPMI 1640 medium containing phenol red and L-glutamine with the addition of another portion of L-glutamine (total: 4 mM), penicillin and streptomycin (50 units / ml each) and fetal bovine serum (FBS, 3%) (GIBCO, all concentrations are final concentrations). The analysis was carried out under sterile conditions; only the preparation of the test compound was carried out under non-sterile conditions. Stock mother liquors were prepared in DMSO and then diluted with RPMI 1640 medium to reach a concentration that was 2 times the final concentration required for analysis. Confluent THP.1 cells (final concentration 2 × 10 ⁶ cells / ml, American Type Culture Company, Rockville, Md.) Were added to 96-well polypropylene round-bottom culture plates (Costar 3790 type; sterile) containing 125 μl of test compounds (2-fold concentration) or a carrier representing DMSO (controls, pure). The final concentration of DMSO did not exceed 0.2%. The mixture containing the cells was preincubated for 30 min at 37 ° C, 5% CO ₂ , before stimulation with lipopolysaccharide (LPS; final concentration 1 μg / ml; Siga L-2630, from serotype 0111. E. coli B4. B4 ; stored at -80 ° C in the form of a mother liquor with a concentration of 1 mg / ml in distilled H ₂ O with constant monitoring of the presence of endotoxin). In the control samples (unstimulated) was added a carrier representing H ₂ O; the final incubation volume was 250 μl. Incubation overnight (18-24 hours) was performed according to the method described above. The process was stopped by centrifuging the plates at 1600 rpm (400xg) for 5 min at room temperature; supernatants were transferred to clean 96-well plates and stored at -80 ° C until analysis for human TNFβ using a commercially available ELISA kit (type Biosource # KHC3015, Camarillo, Calif.). The data were analyzed by nonlinear regression (using the Hill equation), obtaining a dose-response response using the SAS Software System software (SAS Institute, Inc., Carrie, North Carolina). The calculated IC ₅₀ value represents the concentration of the test compound, which leads to a 50% decrease in TNFα production compared to the maximum value.

Using this analysis method, the preferred compounds were evaluated, including the compounds shown in the synthesis examples, and it was found that for them the IC ₅₀ is less than 10 μm.

Inhibition of other cytokines

Inhibition of IL-1β, GM-CSF, IL can be demonstrated by similar methods using peripheral blood monocyte cells, appropriate stimuli, and commercially available ELISA kits (or using another detection method, such as radioimmunoassay) suitable for a particular cytokine. -6 and IL-8 (see, for example, JC Lee et al., Int. J. Immunopharmacol., 10, 835, 1988).

Claims (12)

1. The compound of formula (II)

in which G means phenyl, pyridinyl, pyrazolyl, wherein G is substituted by one or more groups R ₁ , R ₂ or R ₃ , Ar is naphthyl; X is C ₅ -C ₈ cycloalkyl or cycloalkenyl, optionally substituted with 1-2 oxo groups, phenyl, furanyl, pyridinyl or pyrazinyl, Y is a bond or a saturated or unsaturated branched or unbranched C ₁ -C ₄ carbon chain, wherein one or more methylene groups are optionally independently substituted with O or N, Y is optionally substituted with an oxo group, Z is phenyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, morpholinyl, thiomorpholinyl, piperidinyl, piperidinonyl, piperazinyl, pentamethylene sulfoxidyl, each of which is optionally substituted with 1-3 C ₁ -C ₆ alkyl or CONH ₂ , C ₁ -C ₆ group alkyl, nitrile, hydroxy, C ₁ -C ₆ alkoxy, secondary or tertiary amine, while the amine nitrogen is covalently linked to C ₁ -C ₃ alkyl or C ₁ -C ₅ alkoxyalkyl, tetrahydrofuranyl-C ₁ -C ₃ alkyl, nitrile- C ₁ -C ₃ alkyl, carboxamide-C ₁ -C ₃ alkyl, R ₁ in each case independently means C ₁ -C ₁₀ alkyl, which is optionally partially or fully halogenated and optionally substituted with 1-3 hydroxy groups, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, each of which is optionally substituted with 1-3 groups CN, halogen , A C ₃ -C ₆ alkynyl branched or unbranched carbon chain, wherein one or more methylene groups are optionally replaced with O, and said alkynyl group is optionally substituted with one or more C ₁ -C ₄ alkyl groups, R ₂ means a branched or unbranched C ₁ -C ₆ alkyl, which is optionally partially or fully halogenated, a branched or unbranched C ₁ -C ₄ alkoxy group, which in each case is optionally partially or fully halogenated, a halogen, a C ₁ -C ₆ alkoxy group, a hydroxy group mono- or di (C ₁ -C ₄ alkyl) amino group, OR ₆ group, nitro group or a mono- or di (C ₁ -C ₄ alkyl) amino-S (O) ₂ group which is optionally partially or fully halogenated, or an H ₂ NSO ₂ group, R ₃ in each case independently means phenyl, pyridinyl, pyrimidyl, pyrrolidinyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, a C ₁ -C ₆ alkynyl group or a branched or unbranched C ₁ -C ₆ alkoxy group, each of which is optionally partially halogen OR ₁₈ or C ₁ -C ₆ alkyl optionally substituted with an OR ₁₈ group, an amino group or a mono or di (C ₁ -C ₅ alkyl) amino group, a C ₂ -C ₆ alkynyl branched or unbranched carbon chain, with one or more methylene groups optional replacement are not O, and said alkynyl group is optionally substituted with one or more C ₁ -C ₄ alkyl groups, R ₆ means C ₁ -C ₄ alkyl, which is optionally partially or fully halogenated, R ₁₈ in each case independently means hydrogen, C ₁ -C ₄ alkyl, W means Oh and pharmaceutically acceptable derivatives thereof. 2. The compound according to claim 1, in which G means phenyl, pyridinyl, wherein G is substituted by one or more groups R ₁ , R ₂ or R ₃ . 3. The compound according to claim 2, in which G means phenyl, pyridinyl, wherein G is substituted by one or more groups R ₁ , R ₂ or R ₃ , Ar means naphthyl, X is phenyl, furanyl, pyridinyl or pyrazinyl, Y is a bond or a saturated or unsaturated branched or unbranched C ₁ -C ₄ carbon chain, with one methylene group being optionally substituted with O or N, and Y is optionally independently substituted with an oxo group, Z is phenyl, tetrahydropyranyl, tetrahydrofuranyl, 1,3- dioxolanonyl, morpholinyl, thiomorpholinyl, piperidinyl, piperidinonyl, piperazinyl, pentamethylene sulfoxidil, nitrile, hydroxy group, C ₁ -C ₄ alkoxy group, R ₁ in each case independently means C ₃ -C ₆ alkyl, which is optionally partially or fully halogenated and optionally substituted with 1-3 hydroxy groups, cyclopropanil, cyclobutanyl, cyclopentanil, each of which is substituted with 1-3 CN groups, R ₂ is halogen, a C ₁ -C ₆ alkoxy group, a C ₁ -C ₃ alkyl-S (O) ₂ group that is optionally partially or fully halogenated, or H ₂ NSO ₂ , R ₃ in each case independently means phenyl, pyridinyl, pyrimidinyl, pyrrolidinyl, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, C ₁ -C ₆ alkyl group or C ₁ -C ₆ alkoxy group, each of which is optionally partially halogenated, OR ₁₈ or C ₁ -C ₆ alkyl optionally substituted with OR ₁₈ , an amino group or a mono or di (C ₁ -C ₅ alkyl) amino group, a C ₂ -C ₄ alkynyl branched or unbranched carbon chain, with one or more methylene groups being optionally replaced on O, and the indicated alkynyl g Uppal optionally substituted by one or more C ₁ -C ₄ alkyl groups. 4. The compound according to claim 3, in which G means phenyl, pyridinyl, wherein G is substituted by one or more groups R ₁ , R ₂ or R ₃ , Ar is naphthyl, X is phenyl, pyridinyl or pyrazinyl, Y is a bond or a saturated C ₁ -C ₄ carbon chain, wherein one of the carbon atoms is optionally replaced by O or N, and Y is optionally independently substituted by an oxo group, Z is phenyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperidinyl, piperidinonyl, piperazinyl, which are optionally substituted with 1-2 C ₁ -C ₂ alkyl groups, R ₁ in each case independently means C ₃ -C ₅ alkyl, which is optionally partially or completely halogenated and optionally substituted with 1-3 hydroxy groups, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, R ₂ in each case independently means bromo, chloro, fluoro or methoxy, R ₃ in each case independently means phenyl, pyridinyl, pyrimidyl, pyrrolidinyl, an OR ₁₈ group or C ₁ -C ₃ alkyl optionally substituted with an OR ₁₈ group, an amino group or a mono or di (C ₁ -C ₃ alkyl) amino group. 5. The compound according to claim 4, in which G is phenyl, pyridinyl, wherein G is substituted with one or more groups R ₁ , R ₂ or R ₃ , Ar means 1-naphthyl, X is phenyl, pyridinyl or pyrazinyl, Y is a bond or -CH ₂ -, -CH ₂ CH ₂ -, -C (O) -, -NH-CH ₂ CH ₂ CH ₂ -, -N (CH ₃ ) - or -NH-, R ₁ in each case independently means C ₃ -C ₅ alkyl, which is optionally partially or fully halogenated, cyclopropanyl, cyclobutanyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, each of which is substituted by 1-3 substituents selected from the group consisting of methyl, which is optionally substituted 1-3 groups of CN, R ₃ in each case independently means phenyl, pyridinyl, pyrimidinyl, pyrrolidinyl, a C ₁ -C ₆ alkyl group, each of which is optionally partially or completely halogenated, OR ₁₈ or a C ₁ -C ₆ alkyl optionally substituted with an OR ₁₈ group, an amino group or a mono or di (C ₁ -C ₃ alkyl) amino group. 6. The compound according to claim 5, in which G means phenyl or pyridinyl, wherein G is substituted by one or more groups R ₁ , R ₂ or R ₃ , X is pyridinyl Y is —CH ₂ -, —NH — CH ₂ CH ₂ CH ₂ -, or —NH—, Z is a morpholino group, R ₁ in each case independently means tert-butyl, sec-butyl, tert-amyl or phenyl, R ₂ means chlorine and R ₃ in each case independently means methyl or methoxy. 7. The compound according to claim 6, in which X is pyridinyl. 8. The compound according to claim 7, in which pyridinyl is attached to Ar in the third position of pyridinyl. 9. The compound of formula II according to claim 1, selected from the group including: 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (morpholin-4-yl-methyl) phenyl) naphthalene-1-yl] urea , 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (2- (morpholin-4-yl) ethyl) phenyl) naphthalene-1- silt] urea, 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (3- (morpholin-4-yl-methyl) phenyl) naphthalen-1-yl] urea , 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5-morpholin-4-ylmethylpyridin-2-yl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5-morpholin-4-ylmethylfur-2-yl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene- 1-yl] urea, 1- [5-tert-butyl-2-methyl-2H-pyrazol-3-yl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (5- (morpholin-4-ylmethyl) pyridin-2-yl) naphthalen-1-yl urea 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1-yl urea 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (2- (pyridin-2-yl) ethylamino) cyclohexenyl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (4- (pyridin-3-ylmethylaminomethyl) phenyl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (morpholin-4-yl-methyl) phenyl ) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (4-hydroxybutylamino) pyridin-3-yl) naphthalene -1-yl] urea, 1- [5-tert-butyl-2- (4-methyl-3-carbamylphenyl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (3-hydroxypiperidin-1-ylmethyl) phenyl) naphthalene -1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (4-hydroxymorpholin-4-ylmethyl) phenyl) naphthalene -1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (3- (morpholin-4-ylmethyl) cyclohexenyl) naphthalene-1 -yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (tetrahydrofuran-3-ylmethyl) -3-hydroxyphenyl) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N, N-di (2-methoxyethyl) aminomethyl ) phenyl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (3-cyanopropoxy) pyridin-3-yl) naphthalene -1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4-morpholin-4-ylmethylpiperidinyl) naphthalen-1-yl] urea 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N, N-di (2-cyanoethyl) aminomethyl ) phenyl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (furan-2-ylmethyl) -3-hydroxyphenyl) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (thiomorpholin-4-ylmethyl) phenyl) naphthalene-1 -yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (3-carboxamidopiperidin-1-ylmethyl) phenyl) naphthalene -1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (2-methyl-3-oxopiperazin-1-ylmethyl) ) phenyl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (4-hydroxybutyloxy) pyridin-3-yl) naphthalene -1-yl] urea, 1- [3-tert-butyl-1'H- [1,4 '] bipyrazol-5-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalene-1 -yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (tetrahydrothiopyran-4-ylamino) pyridin-3-yl ) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (2-cyanoethyl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalene-1 -yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (2,6-dimethylmorpholin-4-ylmethyl) pyridine -3-yl) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (2-methoxypyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (2-aminopyridin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-yl-4-carbonyl) pyridine -3-yl) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (2-oxa-5-azabicyclo [2.2.1 ] hept-5-ylmethyl) pyridin-3-yl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N- (2-cyanoethyl) -N- ( pyridin-3-ylmethyl) aminomethyl) phenyl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (4- (N- (2-cyanoethyl) -N- ( tetrahydrofuran-2-ylmethyl) aminomethyl) phenyl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) -4-methoxypyridine- 3-yl) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (1-morpholin-4-ylpropyl) pyridin-3 -yl) naphthalene-1-yl] urea, 1- [3-tert-butyl-1'-methyl-1'H- [1,4 '] bipyrazol-5-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3- il) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (1-oxo-tetrahydrothiopyran-4-ylamino) pyridine -3-yl) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (tetrahydropyran-4-ylamino) pyridin-3-yl ) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (5- (tetrahydrothiopyran-4-ylamino) pyrazin-2-yl ) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (6-methylpyridin-3-yl) -2H-pyrazol-3-yl] -3- [4- (6- (methylcarbonylamino) pyridin-3-yl) naphthalene-1 -yl] urea, 1- [3-tert-butyl-1 '- (3-methylsulfanylpropyl) -1'H- [1,4'] bipyrazol-5-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (1-oxothiomorpholin-4-ylmethyl) pyridin-3 -yl) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (tetrahydropyran-4-ylamino) pyridin-3-yl ) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (2-methylthiopyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea, 1- [5-tert-butyl-2- (2-aminopyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (6- (morpholin-4-ylmethyl) pyridin-3-yl ) naphthalene-1-yl] urea, 1- [3-tert-butyl-1'-methyl-1'H- [1,4 '] bipyrazol-5-yl] -3- [4- (6- (morpholin-4-ylmethyl) phenyl) naphthalene- 1-yl] urea, 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (1-oxo-tetrahydrothiopyran-4-ylamino) pyridin-3-yl) naphthalene -1-yl] urea, 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (thiomorpholin-4-ylmethyl) pyridin-3-yl) naphthalen-1-yl urea 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (morpholin-4-ylcarbonyl) pyrimidin-5-yl) naphthalen-1-yl urea 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (2- (morpholin-4-ylmethyl) pyrimidin-5-yl) naphthalen-1-yl urea 1- [5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl] -3- [4- (6- (1-oxothiomorpholin-4-ylmethyl) pyridin-3-yl) naphthalene-1 -yl] urea, 1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) -2H-pyrazol-3-yl] -3- [4- (2- (morpholin-4-ylmethyl) pyrimidin-5-yl ) naphthalene-1-yl] urea, 1- (2-tert-butyl-5-methylpyridin-4-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea, 1- (3-tert-butylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (4-methylbiphenyl-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (4-tert-butylbiphenyl-2-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-isopropyl-2-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-sec-butyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-methoxymethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-methylphenyl) -3- (4- {6 - [(3-methoxypropyl) methylamino] pyridin-3-yl} naphthalen-1-yl) urea, 1- (5-tert-butyl-2-methylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-methylpyridin-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea, 1- [5- (1,1-dimethylpropyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2- (1H-pyrazol-4-yl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2- (2-methylpyrimidin-5-yl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2- (3-hydroxypropyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- [5-tert-butyl-2- (morpholin-4-carbonyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) acetamide, 1- (3-methylnaphthalen-2-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido] phenyl) acetamide, 1- [5-tert-butyl-3- (2,3-dihydroxypropyl) -2-hydroxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (2,3-dimethyl-1H-indol-5-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- {5-tert-butyl-2-methyl-3- [3- (tetrahydropyran-2-yloxy) prop-1-ynyl] phenyl} -3- [4- (6-morpholin-4-ylmethylpyridin-3- il) naphthalene-1-yl] urea, 1- (2-methoxy-5-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- [5- (2,2-dimethylpropionyl) -2-methylphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- [5-tert-butyl-3- (3-hydroxyprop-1-ynyl) -2-methylphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea 1- [5-tert-butyl-2- (3-hydroxyprop-1-ynyl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- [5-tert-butyl-3- (2,2-dimethyl- [1,3] dioxolan-4-ylmethyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3 -yl) naphthalene-1-yl] urea, 1- [5-tert-butyl-3- (2,3-dihydroxypropyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butoxy-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- [5- (1-cyanocyclopropyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- [5-tert-butyl-3- (2-diethylaminoethyl) -2-methoxyphenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6-11,3] dioxolan-2-yl-pyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-pyrrolidin-1-yl-phenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-dimethylaminophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-propoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6-hydroxymethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [6- (2,6-dimethylmorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea, 1- (5-cyclohexyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (2,4-dimethoxy-5-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-methoxy-3-nitrophenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (3-amino-5-tert-butyl-2-methoxyphenyl) -3- [4- (6-methylpyridin-3-yl) naphthalen-1-yl] urea, N-acetyl-H- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) acetamide, 1- (6-tert-butyl-4-methyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -3- [4- (6-morpholin-4- ilmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-ethoxy-phenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-isopropoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-imidazol-1-ylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-3-ethylamino-2-methoxyphenyl) -3-14- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) bis (methanesulfonyl) amide, 1- [5-tert-butyl-2- (1-methyl-1H-pyrazol-4-yl) phenyl] -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl urea 1- (2-methanesulfinyl-5-trifluoromethylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea, 1- [4- (6 - {[bis (2-methoxyethyl) amino] methyl} pyridin-3-yl) naphthalen-1-yl] -3- (5-tert-butyl-2-methoxyphenyl) urea, N- [1- (5- [4- [3- (5-tert-butyl-2-methoxyphenyl) ureido] naphthalen-1-yl} pyridin-2-ylmethyl) pyrrolidin-3-yl] acetamide, 1- (1-acetyl-3,3-dimethyl-2,3-dihydro-1H-indol-5-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1- silt] urea, N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) propionamide, 1- (5-tert-butyl-2-methyl-benzooxazol-7-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea, 1- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] -3- (3-trifluoromethanesulfonylphenyl) urea, N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) isobutyramide, 2- (4-tert-butyl-2- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenoxy) acetamide, 1- (5-tert-butyl-2-oxo-2,3-dihydrobenzooxazol-7-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-3-cyano-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butylbenzooxazol-7-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido] phenyl) benzenesulfonamide, (5-tert-butyl-2-methoxy-3- [3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) ethanesulfonic acid amide, 1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (2-morpholin-4-ylmethylpyrimidin-5-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-methylsulfanylphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-methoxypyridin-3-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea, (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) amide 2,2,2-trifluoroethanesulfonic acid , N- (5- [4- [3- (5-tert-butyl-2-methylphenyl) ureido] naphthalen-1-yl} pyrazin-2-yl) methanesulfonamide, 1- [4- (6 - {[bis (2-cyanoethyl) amino] methyl} pyridin-3-yl) naphthalen-1-yl] -3- (5-tert-butyl-2-methoxyphenyl) urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (4-methylpiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6-thiomorpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2,6-dimethylpiperidin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (1-oxotetrahydrothiopyran-4-ylamino) pyridin-3-yl] naphthalen-1-yl} urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (tetrahydropyran-4-ylamino) pyridin-3-yl] naphthalen-1-yl} urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6 - {[(2-cyanoethyl) - (tetrahydrofuran-2-ylmethyl) amino] methyl} pyridin-3-yl) naphthalene-1 -yl] urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2-methoxymethylmorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl] urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2-methyl-3-oxopiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea, amide 1- (5- {4- [3- (5-tert-butyl-2-methoxyphenyl) ureido] naphthalen-1-yl} pyridin-2-ylmethyl) piperidine-3-carboxylic acid, 1- (5-tert-butyl-2-methoxyphenyl) -3- [4- [6- (1-oxothiomorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea, 1- (3,3-dimethyl-2-oxo-2,3-dihydro-1H-indol-5-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1- silt] urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (3-oxopiperazin-1-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- (4- {6 - [(tetrahydrofuran-3-ylamino) methyl] pyridin-3-yl} naphthalen-1-yl) urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (6 - [[(2-cyanoethyl) pyridin-3-ylmethylamino] methyl} pyridin-3-yl) naphthalen-1-yl] urea , 1- (5-tert-butyl-2-methoxyphenyl) -3- (4- [6- (2-oxa-5-azabicyclo [2.2.1] hept-5-ylmethyl) pyridin-3-yl] naphthalene-1 -il} urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (2,6-dimethylmorpholin-4-ylmethyl) pyridin-3-yl] naphthalen-1-yl} urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- (4- {6- [4- (3-methoxyphenyl) piperazin-1-ylmethyl] pyridin-3-yl} naphthalen-1-yl) urea , 1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (morpholin-4-carbonyl) pyridin-3-yl] naphthalen-1-yl} urea, 1- (5-tert-butyl-2-methoxyphenyl) -3- [4- (5-morpholin-4-ylmethylpyrazin-2-yl) naphthalen-1-yl] urea, 1- (6-tert-butyl-3-oxo-3,4-dihydro-2H-benzo [1,4] oxazin-8-yl) -3- [4- (6-morpholin-4-ylmethylpyridin-3- il) naphthalene-1-yl] urea, 1- (3-amino-5-tert-butyl-2-methoxyphenyl) -3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalene-1-yl] urea, N- (5- {4- [3- (5-tert-butyl-2-methoxyphenyl) ureido] naphthalen-1-yl} pyridin-2-yl) acetamide, N- (5-tert-butyl-2-methyl-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) -N-methylacetamide, N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) -2,2,2 trifluoroacetamide, 1- (5-tert-butyl-2-methoxyphenyl) -3- {4- [6- (pyridin-3-yloxy) pyridin-3-yl] naphthalen-1-yl] urea, [4- (6-Morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] carbamic acid 3-tert-butylphenyl ester, N- (5-tert-butyl-2-methoxy-3- {3- [4- (6-morpholin-4-ylmethylpyridin-3-yl) naphthalen-1-yl] ureido} phenyl) methanesulfonamide, and their pharmaceutically acceptable derivatives. 10. A pharmaceutical composition that inhibits the production of cytokines, containing a pharmaceutically effective amount of a compound according to claim 1. 11. A method of treating a disease mediated by cytokines, comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound according to claim 1. 12. The method according to claim 11, wherein said cytokine-mediated disease is a disease from the group comprising rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, multiple sclerosis, Guillain-Barré syndrome, psoriasis, graft versus host disease, systemic lupus erythematosus, diabetes, toxic shock, osteoporosis, Alzheimer's disease, acute and chronic pain, contact dermatitis and atherosclerosis.