KR101170175B1 - Cytokine inhibitors - Google Patents

Abstract

The present invention provides low molecular weight compounds and compositions thereof useful as cytokine inhibitors. In particular, the compounds of the present invention are useful as anti-inflammatory agents. Also provided are methods of making such agents and their use in preventing or treating symptoms mediated by cytokines such as arthritis.

Cytokine inhibitors, anti-inflammatory agents, arthritis,

Description

Cytokine Inhibitor {CYTOKINE INHIBITORS}

Cross-reference to related application

This application is directed to US Provisional Application No. 60 / 502,569 (filed Sep. 11, 2003), US Provisional Application No. 60 / 531,234 (filed Dec. 18, 2003), US Provisional Application No. 60 / 575,704 (May 28, 2004) Priority) and US Provisional Application No. 60 / 585,012, filed Jul. 2, 2004, the contents of which are incorporated herein by reference in their entirety.

The present invention relates to low molecular weight compounds and compositions thereof useful as cytokine inhibitors, and to their preparation. The invention also relates to methods of preventing and treating cytokine mediated diseases.

Tumor necrosis factor-α (TNF-α) and interleukin-1 (IL-1) are proinflammatory cytokines that mediate inflammatory responses associated with infectious agents and other cellular stresses. Overproduction of cytokines such as IL-1 and TNF-α can cause many inflammatory conditions, including rheumatoid arthritis (RA), Crohn's disease, inflammatory bowel disease, multiple sclerosis, endotoxin shock, osteoporosis, Alzheimer's disease, congestive heart failure and psoriasis It is believed to be fundamental in disease progression (Dinarello, CA et al., Rev. Infect. Diseases 1984, 6:51), Salituro et al., Curr. Med. Chem. 1999, 6: 807-823, Henry et al., Drugs Fut. 1999, 24: 1345-1354). Therapeutic approaches that have been accepted for potential drug intervention in this condition are the reduction of proinflammatory cytokines such as TNF-α (also referred to as TNFα) and interleukin-1β (IL-1b) and the like.

Recent data from clinical trials have shown that rheumatoid arthritis, Crohn's disease, pediatric chronic arthritis and psoriatic arthritis (Rankin et al., Br. J. Rheumatol. 1995, 34: 334-342, Galadari et al. Int J Dermatol. 2003, 42: 231-7], [Reimold, Am J Med Sci. 2003 325 (2): 75-92]), protein antagonists of cytokines, for example soluble TNFα receptor fusion proteins (eta Necept) [Moreland et al., Ann. Intern. Med. 1999, 130: 478-486] or monoclonal TNFα antibodies (Enbrel) are supported. Thus, small molecules that inhibit or antagonize the effects of cytokines such as TNFα and / or IL-1b are expected to be beneficial in the treatment of rheumatoid arthritis, Crohn's disease, chronic arthritis in children and psoriatic arthritis.

IL-1 is detected in synovial fluid and cartilage stromal joints in patients with osteoarthritis. IL-1 antagonists have been shown to reduce the degeneration of cartilage matrix components in various arthritis experimental models [Chevalier, Biomed Pharmacother. 1997, 51:58.

IL-1 receptor antagonists have been evaluated in humans [Bresnihan et al., Arthritis Rheum. 1998, 41: 2196-2204. Efficacy in the treatment of rheumatoid arthritis has been demonstrated (Antril, Amgen). IL-1 receptor antagonists have also been demonstrated to reduce mortality in patients with septic shock syndrome [Dinarello, Nutrition 1995, 11: 492].

Cytokines such as IL-1 and TNFα are potent stimulators in nitric oxide (NO) production. NO is a mediator of cardiovascular homeostasis, neurotransmission and immune function, and is a mediator of bone remodeling, affecting osteoblasts and osteoclasts ([van't Hof, Immunology 2001, 103 (3): 255-61], [ Evans, et al., J. Bone Miner. Res. 1996, 11: 300].

IL-1 is also associated with beta-cell destruction, one of the hallmarks of insulin-dependent diabetes mellitus. Other factors may also mediate beta-cell damage, but IL-1 is involved in this process through its effects on cyclooxygenase II (COX-2) and inducible NO synthase [McDaniel et al. , Proc Soc Exp Biol Med. 1996, 211: 24.

IL-1 has also been shown to induce uveitis in rats, which uveitis could be inhibited by IL-1 blockers [Xuan et al., J. Ocular Pharmacol. and Ther. 1998, 14:31. Cytokines, including IL-1, TNFα and GM-CSF, have been shown to stimulate proliferation of acute myeloid leukemia blasts [Bruserud, Leukemia Res. 1996, 20:65. IL-1 has been shown to be essential for the development of both irritant and allergic contact dermatitis. Epidermal sensitization can be prevented by administering anti-IL-1 monoclonal antibodies prior to epidermal application of allergens [Muller, et al., Am J Contact Dernat. 1996, 7: 177]. Data from IL-1 knockout mice indicate that this cytokine is heavily involved in fever [Kluger et al., Clin Exp Pharmacol Physiol. 1998, 25: 141. Various cytokines, including TNFα, IL-1, IL-6, and IL-8, initiate common acute phase responses in fever, boredom, myalgia, headache, hypertrophy and multiple endocrine and enzyme reactions [Beisel, Am J Clin Nutr. 1995, 62: 813. The production of these inflammatory cytokines occurs rapidly after trauma or invasion of pathogenic organisms.

Renovirus triggers the production of various proinflammatory cytokines, predominantly IL-8, leading to symptomatic diseases such as acute rhinitis [Winther et al., Am J Rhinol. 1998, 12:17.

Cytokine inhibitors are also expected to block inducible COX-2, an enzyme involved in inflammation [M. K. O'Banion et al., Proc. Natl. Acad. Sci. USA 1992, 89: 4888. Cytokine inhibitors such as, for example, IL-1 receptor antagonists (IL-1ra) and the like are expected to exert efficacy against the disorder in which COX-2 inhibitors (eg NSAIDs) will be used. Such disorders include, but are not limited to, inflammatory diseases, chronic pain and cardiovascular diseases.

Various cytokines are known to be elevated in inflammatory bowel disease (IBD) conditions. Imbalances of IL-1 and IL-1ra have been reported in IBD patients. Insufficient production of IL-1ra may contribute, at least in part, to the development of IBD. Cominelli, et al. Aliment Pharmacol. Ther. 1996, 10:49.

In Alzheimer's disease, beta-amyloid protein deposition, nerve fiber enrichment, and cholinergic insufficiency have been observed throughout the hippocampus. Maintaining sustained levels of cytokines such as, for example, IL-1 and / or TNFα can cause brain damage in Alzheimer's disease patients, at least in part (Grammas, Neurobiol. Aging 2001, 22 (6): 837-42 ], Rempel, J. Neurochem. 2001, 78 (3): 640-645).

Cytokines such as TNFα and IL-1 are also involved in the development of human immunodeficiency virus (HIV) infection and acute inflammatory events (Kreuzer, Clin. Exp. Immunol. 1997, 109 (1): 54-58), [ Baqui, Immunopharmacol Immunotoxicol 2000, 22 (3): 401-421]). The levels of cytokines and receptors are elevated in the bone marrow supernatant of HIV-infected patients with hematologic abnormalities, which have been shown to correlate with clinical parameters in these patients [Dallalio, J. Investig. Med. 1999, 47 (9): 477-483.

Pro-inflammatory cytokines such as TNFα and IL-1b and interleukin-6 (IL-6) are important mediators of septic shock, cardiopulmonary dysfunction, acute respiratory distress syndrome (ARDS) and multi-organ dysfunction. Patients admitted to putative sepsis have elevated cytokine levels compared to patients with discharged sepsis and putative non-infective systemic inflammatory response syndrome (SIRS), suggesting an association between cytokines and subsequent sepsis complications in these patients. Terregino, Ann. Emerg. Med. 2000, 35 (1): 26-34).

Cytokine imbalance is also associated with cachexia and muscle degeneration associated with HIV infection. Serum concentrations of inflammatory cytokines (IL-1b, TNFα, IL-6) and regulatory cytokines (interleukin-12) in 10 AIDS cachexia patients were studied and compared with controls. A significant increase in cytokine imbalance and pro-inflammatory cytokines (IL-1, IL-6, TNFα) was observed in this patient group [Baronzio, In Vivo 1999, 13 (6): 499-502].

Obesity is associated with an increased incidence of infections, diabetes and cardiovascular disease. Abnormal expression of TNFα has been noted in each of these conditions (Loffreda, et al., FASEB J. 1998, 12:57). Elevation of TNFα levels has been suggested to be associated with other eating-related disorders such as loss of appetite and anorexia nervosa. Pathophysiological parallelism is derived between anorexia nervosa and cancer cachexia (Holden, et al., Med Hypotheses 1996, 47: 423). HU-211, an inhibitor of TNFα production, has been shown to improve the incidence of closed brain injury in experimental models [Shohami, et al., J Neuroimmunol. 1997, 72: 169].

Evidence is emerging that inflammation plays a role in the development of coronary heart disease (CHD) and coronary artery disease (CAD). Elevated concentrations of acute phase reactants, such as C-reactive protein (CRP), have been identified in patients with acute coronary syndrome and are predicted to pose a later risk in apparently healthy subjects. Cytokines such as TNFα, IL-1 and IL-6 have been suggested to promote atherosclerosis and heart disease. Coronary disease patients are characterized by increased serum concentrations of TNFα. Immune activation (TNFα, soluble TNF receptors 1 and 2 (sTNFR 1, sTNFR 2) and interleukin-10 (IL-10)) in patients with coronary disease is believed to be related to serum lipid levels [Mizia-Stec, Acta Cardiol. 2003, 58 (1): 9-15].

A large proportion of acute coronary syndromes are the result of unstable plaque rupture and subsequent thrombus formation. This unstable plaque is characterized by an increase in inflammatory cells (macrophages and T lymphocytes). Serum concentrations of CRP (C-reactive protein) reflect the amount of inflammation in atheroplasmic plaques, which may provide a measure of instability of the plaques. Therefore, CRP is believed to have predictable value for plaque rupture occurrence. In addition, there are indications that CRP itself acts on the inflammatory process. Studies have shown that so-called high-sensitivity CRP (hsCRP) measurements can be used as a tool for determining the risk of acute coronary syndrome. Anti-inflammatory agents that can lower the level of hsCRP may contribute to reducing the risk of plaque rupture (Abjil, Ned Tijdschr Geneeskd 2003, 147 (1): 15-20), Ranger, J. Immunol. 2002, 168 ( 8): 4070-7]).

Elevated levels of TNFα have been shown to be associated with congestive heart failure, and levels of cytokines correlate with the severity of the disease. In patients with heart failure, serum levels of TNFα are elevated and both cardiac and invasive cells of the myocardial layer can produce these pro-inflammatory cytokines. Both studies of animal models and clinical investigations suggest that anti-TNFα therapy may limit the pathophysiological consequences of congestive heart failure [McTiernan, Curr. Cardiol. Rep. 2000, 2 (3): 189-97]. In addition, etanecept (soluble TNF receptor) treatment leads to significant dose-dependent improvement in left ventricular ejection fraction and remodeling, and tends to improve the patient's functional condition as measured by clinical composite score ( Bozkurt, Circulation 2001 Feb 27; 103 (8): 1044-7).

Levels of TNFα are elevated in the airways of patients with chronic obstructive pulmonary disease and may contribute to the development of the disease [M. A. Higham et al., Eur. Respiratory J. 2000, 15: 281. Cyclic TNFα may also contribute to weight loss associated with the disease [N. Takabatake et al., Amer. J. Resp. & Crit. Care Med. 2000, 161 (4 Pt 1): 1179]. Elevated levels of TNFα are also associated with congestive heart failure, which levels correlate with severity of disease [A. M. Feldman et al., J. Amer. College of Cardiology 2000, 35: 537. In addition, TNFα is impaired in lung [Borjesson et al., Amer. J. Physiol. 2000, 278: L3-12], kidney [Lemay et al., Transplantation 2000, 69: 959] and nervous system [Mitsui et al., Brain Res. 1999, 844: 192] is also associated with reperfusion injury. Proinflammatory cytokines are also known to play a role in ischemia-reperfusion injury of the heart, kidneys, small intestine, skin and liver. For example, TNFα and IL-1beta have been shown to assist in controlling the development of ischemia-reperfusion injury in the lungs. They are believed to alter the expression of pro- and anti-inflammatory cytokines to promote damage. Neutrophil recruitment and neutrophil accumulation in the lung were markedly reduced in animals that received anti-TNFα and anti-IL-1beta, and their combined blocking provided much greater protection [Krishnadasan, J. Thorac . Cardiovasc. Surg. 2003, 125 (2): 261-72. Upon brain injury, pretreatment with intravenous anti-TNFα antibodies reduced cortical and subcortical damage, improved cerebral blood flow during reperfusion, and improved neurological outcomes. This supports the argument that although TNFα is a harmful cytokine during stroke, circulating antibodies against TNF-alpha can protect the brain from reperfusion injury (Lavine, J. Cereb. Blood Flow Metab. 1998, 18 (1). ): 52-8], Mitsui, Brain Res. 1999, 844 (1-2): 192-5]. TNFα is also believed to be released in the kidney in response to renal ischemia-reperfusion injury and is associated with the development of renal ischemia-reperfusion injury [Doimahoo, J. Urol. 1999, 162 (1): 196-203.

Skeletal weight is maintained by the balance between bone resorption cells (osteoblasts) and bone forming cells (osteoblasts). Recent observations have identified members of the TNF family of ligands and receptors as important regulators of osteoclastogenesis [Horowitz, Cytokine Growth Factor Rev 2001, 12 (1): 9-18], TNFα and IL-1 alpha. It has been suggested that the same cytokines may play an important role in pathological bone resorption. These data support that TNFα is importantly involved in osteoclastogenesis and bone resorption during periprostate osteolysis, suggesting that TNFα inhibitors may be useful as therapeutic agents for diseases associated with bone resorption ([Childs , J. Bone Miner. Res. 2001, 16 (2): 338-47, Abu-Amer, J. Biol. Chem. 2000, 275 (35): 27307-10].

Periodontal disease is an important cause of adult tooth loss and is characterized by alteration and premature destruction of deep periodontal tissue. The results showed that IL-1 and TNF antagonists significantly reduced the decrease in connective tissue adhesion and the alveolar bone height. This suggests that decreased connective tissue adhesion and periodontal disease progression may be delayed by antagonists against cytokines such as IL-1 [Delima, J. Clin. Periodontol. 2001, 28 (3): 233-40.

TNFα plays a role in many aspects of glomerulonephritis progression. Studies have shown that neutralization of endogenous TNFα is effective in preventing acute glomerular inflammation and meniscus formation [Karkar, Nephrol. Dial. Transplant 2001, 16 (3): 518-24].

Ulcerative colitis (UC) and Crohn's disease (CD) are a series of inflammatory bowel diseases (IBDs) caused by chronic upregulation of the mucosal immune system and elevated levels of cytokines such as, for example, TNFα, IL-1b and IL-6. Include. Strategies aimed at reducing levels of cytokines such as TNFα in patients with inflammatory bowel disease include mouse / human chimeric monoclonal antibody infliximab, humanized monoclonal antibody CDP571, human soluble TNF p55 receptor lordcept onercept, human monoclonal antibody D2E7 (adalimumab), anti-TNF human antibody Fab 'fragment-polyethylene glycol (PEG) conjugate CDP870, and small molecule thalidomide and CNI-1493 MAP-kinase inhibitors (Escher et al., Inflamm. Bowel. Dis. 2003 Jan; 9 (1): 34-58), Sandbor et al., Best Pract. Res. Clin. Gastroenterol. 2003, 17 (1): 105-17]).

Immune response abnormalities are believed to play a role in the development of hypertension. Studies have shown that IL-1 and IL-6 production is increased when whole blood is stimulated ex vivo with lipopolysaccharide in patients with hypertension [Peeters, Eur. J. Clin. Invest. 2001, (1): 31-6. Inducible nitric oxide synthase (iNOS) present in vascular smooth muscle cells (VSMC) plays a role in nitric oxide (NO) production in the blood vessel wall, suggesting that it regulates vascular tension at normal and hypertension . IL-1beta has been shown to control iNOS gene expression at the level of transcription [Singh, Am. J. Hypertens. 1996, (9): 867-77], suggesting that cytokine inhibitors, such as IL-1 inhibitors, may be useful in the treatment of hypertension.

Diseases affected by IL-8 include myocardial ischemia and reperfusion, inflammatory bowel disease, and the like.

Pro-inflammatory cytokine IL-6 is associated with an acute phase response. IL-6 is a growth factor in many oncological diseases including multiple myeloma and related plasma cell diseases (Treon, et al., Current Opinion in Hematology 1998, 5:42). It has also been shown to be an important mediator of inflammation in the central nervous system. Elevated levels of IL-6 are found in several neurological disorders, including AIDS dementia complications, Alzheimer's disease, multiple sclerosis, systemic lupus erythematosus, CNS trauma, viral meningitis and bacterial meningitis [Gouol, et al., Molecular Neurobiology 1997 , 15: 307. IL-6 also plays an important role in osteoporosis. This has been shown to influence bone resorption and induce osteoclast activity in murine models [Ershler et al., Development and Comparative Immunol. 1997, 21: 487. Between osteoclasts of normal bone and osteoclasts of patients with Paget's disease, cytokine levels, such as IL-6 levels, present in vivo are significantly different [Mills, et al., Calcif Tissue Int. 1997, 61:16. Numerous cytokines have been shown to be associated with cancer cachexia. The severity of key parameters of cachexia can be reduced by treatment with anti-IL-6 antibodies or IL-6 receptor antagonists [Strassmann, et al., Cytokins Mol Ther. 1995, 1: 107. Several infectious diseases, such as influenza, indicate that IL-6 and IFN-alpha are key factors in both symptom expression and host defense [Hayden, et al., J Clin Invest. 1998, 101: 643. Overexpression of IL-6 is associated with the development of numerous diseases, including multiple myeloma, rheumatoid arthritis, Castleman's disease, psoriasis and menopausal osteoporosis [Simpson, et al., Protein Sci. 1997, 6: 929. Compounds that interfere with the production of cytokines, including IL-6 and TNFα, have been effective in blocking passive dermal anaphylaxis in mice [Scholz et al., J. Med. Chem. 1998, 41: 1050.

GM-CSF is another pro-inflammatory cytokine associated with numerous therapeutic diseases. It not only affects the proliferation and differentiation of stem cells but also regulates many other cells involved in acute and chronic inflammation. Treatment with GM-CSF has been attempted in a number of disease states, including burn- wound healing, skin graft efficiency resolution as well as cell proliferation and radiotherapy-induced mucositis [Masucci, Medical Oncology 1996, 13 : 149]. GM-CSF is also believed to play a role in the replication of human immunodeficiency virus (HIV) in cells of the macrophage lineage associated with AIDS therapy [Crowe et al., Journal of Leukocyte Biology 1997, 62:41 ]. Bronchial asthma is characterized by an inflammatory process in the lungs. Relevant cytokines include, among others, GM-CSF [Lee, J R Coll Physicians Lond 1998, 32:56].

Interferon-gamma (IFN-gamma) is associated with numerous diseases. This is associated with increased collagen deposition, a major histopathological feature in graft host disease [Parkman, Curr Opin Hematol. 1998, 5:22]. The patient after kidney transplantation was diagnosed with acute myeloid leukemia. Retrospective analysis of peripheral blood cytokines revealed elevated levels of GM-CSF and IFN-gamma. This elevation occurs concurrently with an increase in peripheral blood leukocyte counts [Burke, et al., Leuk Lymphoma. 1995, 19: 173. The incidence of insulin-dependent diabetes (type 1) may be correlated with the accumulation of T-cells that produce IFN-gamma in pancreatic islet cells [Ablumunits, et al., J Autoimmun. 1998, 11:73. IFN-gamma and TNFα, IL-2 and IL-6 induce activation of peripheral peripheral T-cells most often before lesion development in the central nervous system for diseases such as multiple sclerosis (MS) and AIDS dementia complications [Martino et al. al., Ann Neurol. 1998, 43: 340. Atherosclerosis results in arterial disease that can lead to heart infarction and cerebral infarction. There are many activated immune cells in these lesions, mainly T-cells and macrophages. These cells produce large amounts of pro-inflammatory cytokines such as TNFα, IL-1 and IFN-gamma. These cytokines are thought to be involved in promoting apoptosis or planned cell death of surrounding vascular smooth muscle cells, leading to atherosclerotic lesions (Geng, Heart Vessels 1997, Suppl 12:76). Allergic subjects produce mRNA specific for IFN-gamma after challenge with Vespula toxin [Bonay, et al., Clin Exp Immunol. 1997, 109: 342. Expression of numerous cytokines, including IFN-gamma, has been shown to increase after delayed-type hypersensitivity, indicating the role of IFN-gamma in atopic dermatitis [Szepietowski, et al., Br J Dermatol. 1997, 137: 195. Histopathological and immunohistochemical studies were performed on fetal cerebral malaria. Evidence has been observed that IFN-gamma is elevated above other cytokines, indicating that IFN-gamma plays a role in the disease [Udomsangpetch et al., Am J Trop Med Hyg. 1997, 57: 501]. The importance of free radical species in the development of various infectious diseases has been established. Nitric oxide synthesis pathways are activated through the induction of pro-inflammatory cytokines such as IFN-gamma and the like in response to certain viral infections [Akaike, et al., Proc Soc Exp Biol Med. 1998, 217: 64. Patients chronically infected with hepatitis B virus (HBV) may develop cirrhosis and hepatocellular carcinoma. Viral gene expression and replication in HBV transgenic mice can be inhibited by post-transcriptional mechanisms mediated by IFN-gamma, TNFα and IL-2 [Chisari, et al., Springer Semin Immunopathol. 1995, 17: 261. IFN-gamma can selectively inhibit cytokine induced bone resorption. This is believed to occur through the mediation of nitric oxide (NO), which is an important regulatory molecule in bone remodeling. NO may be involved as a mediator of bone diseases such as rheumatoid arthritis, tumor associated osteolysis and menopausal osteoporosis [Evans, et al., J Bone Miner Res. 1996, 11: 300. Studies with gene deficient mice have demonstrated that IL-12 dependent production of IFN-gamma is critical for early parasite growth control. Although this process is independent of nitric oxide, the control of chronic infection appears to be NO-dependent (Alexander et al., Philos Trans R Soc Lond B Biol Sci 1997, 352: 1355). There is solid evidence that NO is an important vasodilator and plays a role in cardiovascular shock [Kilboum, et al., Dis Mon. 1997, 43: 277. IFN-gamma is required for the progression of chronic intestinal inflammation, such as Crohn's disease and inflammatory bowel disease (IBD), presumably acting through mediation of CD4 ⁺ lymphocytes of the THI phenotype [Sartor, Aliment Pharmacol Ther. 1996, 10 Suppl 2:43]. Elevated levels of serum IgE are associated with various atopic diseases such as bronchial asthma and atopic dermatitis. The level of IFN-gamma is negatively correlated with serum IgE, suggesting the role of IFN-gamma in atopic patients (Teramoto et al., Clin Exp Allergy 1998, 28:74).

Recently, cytokine pathways have been shown to play a role in the induction and maintenance of embryonic stem cells (ES cells) [Proc Natl Acad Sci US A. 2004, 101: 6027], which together with stem cell therapies are cytokine inhibitors Implies a potential application of

WO 01/01986 discloses certain compounds claimed to have the ability to inhibit TNFα. Certain inhibitors disclosed are structurally distinct from the novel compounds disclosed herein, as disclosed herein below. Certain compounds disclosed in WO 01/01986 have been shown to be effective in the treatment of the following diseases: dementia associated with HIV infection, glaucoma, optic neuropathy, optic neuritis, retinal ischemia, laser damage, proliferative vitreoretinopathy due to surgery or trauma , Cerebral ischemia, hypoxia-ischemia, hypoglycemia, dome acid poisoning, anoxia, carbon monoxide or manganese or cyanide poisoning, Huntington's disease, Alzheimer's disease, Parkinson's disease, meningitis, multiple sclerosis and other demyelinating diseases, muscular dystrophy, head and Spinal cord trauma, seizures, convulsions, olive cerebellar atrophy, neuralgia syndrome, diabetic neuropathy, HIV-related neuropathy, MERRF and MELAS syndrome, Leber's disease, Wernicke encephalopathy, Rett's syndrome, homocysteineuria, hyperprolinemia, hypertension Homocysteineemia, non-ketone hyperglycineemia, hydroxybutyr aminouria, sulfite oxidase deficiency, multiple strains Ring and open encephalopathy, Tourette's syndrome, hepatic encephalopathy, drug addiction, drug tolerance, drug dependency, depression, anxiety and schizophrenia. WO 02/32862 discloses that inhibitors of pro-inflammatory cytokines, including TNFα, are useful for the treatment of acute and chronic inflammation of the lungs induced by inhalation of smoke, such as so-called tobacco smoke. TNFα antagonists are also apparently useful in the treatment of endometriosis (see EP 1022027 A1). In clinical trials for RA, infliximab has also been indicated to be useful for the treatment of various inflammatory diseases, including Behcet's disease, uveitis and ankylosing myelitis. Pancreatitis can also be regulated by inflammatory mediator production (J Surg Res 2000, 90 (2): 95-101, Shock 1998, 10 (3): 160-75).

It is known in the art that anti-inflammatory compounds, such as cytokine inhibitors, can be used in combination with other active ingredients in the treatment of diseases and pathological conditions. For example, cytokine inhibitors can be combined with anti-cholinergic agents for the purpose of treating airway disease (W0 03/084539 and the corresponding US application 2003/0225089, and W0 2004/004725 and the corresponding US application). 2004/0044020). Combinations of cytokine inhibitors with various other active ingredients are disclosed in US Patent Application 2004/0110755.

The need for new therapies is particularly important in the case of arthritis diseases. The primary incapacitating effects of osteoarthritis, rheumatoid arthritis and septic arthritis are progressive loss of articular cartilage and thus loss of normal joint function.

TNFα plays an important role in many cell types in mediating responses to external stimuli such as, for example, infections, trauma or mitogen.

Thus, there is a need for therapeutic agents useful for the treatment of cytokine mediated diseases. Although some protein therapeutics have been developed, they have bioavailability and stability issues. In particular, there is a need for low molecular weight compounds that inhibit TNFα and / or IL-1b production.

Summary of the Invention

The present invention provides low molecular weight compounds and pharmaceutical compositions thereof. In particular, the compounds of the present invention are useful as cytokine release inhibitory agents. Also provided are methods of making such compounds and their use in the prevention and treatment of various diseases mediated by cytokines.

Thus, according to the first aspect of the invention,

Targeting moieties other than urea groups, comprising at least one amide group having an amide NH, capable of forming at least one hydrogen bond with the target protein,

Pocket-extension residues, which are attached directly to the targeting residues and comprise planar residues attached to bulk non-planar hydrophobic residues that hydrophobicly interact with the target protein,

Coordination residues that include planar hydrophobic residues and are attached to different atoms of the targeting residue rather than pocket-extension residues, and can form π-π or edge-to-face aromatic interactions with the target protein.

Cytokine inhibitors are provided comprising a.

In this aspect of the invention, the cytokine inhibitor has the structure of PEM-TM-OM. At concentrations of 10 μM, these compounds typically inhibit at least about 50% of TNFα-release derived from cells.

The targeting moiety may hydrogen bond to the residue at the binding site of the target protein and may also include additional hydrogen bond donor or acceptor groups that also form a hydrogen bond to the target protein. Targeting moieties include amide and thioamide groups, methyl amide and thioamide groups, carbamates, hydroxymethyl amides, alpha-ketoamides, diamides, and the like. Also contemplated are cyclic targeting moieties such as imidazolinone, imidazoline dione and trione.

Pocket-expanding residues are residues of sufficient size to make a conformational change to the target protein, creating an expanded binding pocket therein. Such residues include, for example, pyrazolyl, oxazolyl, phenyl, and the like, each of which is substituted with a bulky residue. The bulky moiety fills a larger volume of space than, for example, methyl groups, and includes groups such as t-butyl, norbornyl and the like.

Orienting residues bind to hydrophobic pockets on the target protein to provide complete coordination of targeting and pocket-extending residues for the cytokine residue to bind its target protein. The planar hydrophobic residues that make up the coordination residue have little or no polar groups. Such residues include, for example, phenyl, naphthyl, indazolyl and the like.

In other embodiments, the cytokine inhibitor further comprises a hydrophilic moiety having at least one functional group selected from the group consisting of a hydrogen bond donor, a hydrogen bond acceptor, a basic heteroatom or an acidic heteroatom, wherein the hydrophilic moiety is attached to a hydrophobic coordination moiety. It can be indirectly attached to form a hydrogen bond with the backbone of the protein. Typically, hydrophilic moieties are attached to the coordinating moiety by an atomic linker chain of about 2 to about 10 GPa in length. Hydrophilic residues bind in or near the ATP-binding pocket on the target protein to form one or more hydrogen bonds with the residue of the ATP-binding pocket. Hydrophilic residues include, among others, morpholinyl, piperazinyl and pyrimidinyl groups. Such residues may be attached to the coordination residues, for example by oxy, ethylene, methyleneoxy and ethyleneoxy chains.

In certain embodiments of cytokine inhibitors of the invention, the cytokine inhibitor is PEM-CHR "C (O) NH-OM, wherein R" is H, or optionally partially or fully halogenated C _1-6 alkyl , Pocket-extension residues are not substituted 5-membered heterocyclic rings. In other embodiments, the targeting moiety is not a substituted tricyclic heterocyclyl ring having a nitrogen atom ring member bonded to the amide carbonyl of the targeting moiety.

According to another aspect of the present invention, there is provided a group 1 compound of formula (IA), a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, and a pharmaceutically acceptable salt thereof.

Where

X is C (O), C (S) or CH ₂ ,

G is C _{3 -10} and carbocyclyl, 5-8-membered monocyclic heterocyclyl, or 8-11 won bicyclic (containing one or more heteroatoms selected from O, N or S) heterocyclyl, one Substituted by the above R ¹ , R ² or R ³ ,

Ar is indazolyl, indolyl, isoindoleyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl , phthalazine possess, dihydro the run, rapid-fire benjoyi thiazolyl, dihydro benjoyi rapid fire group, the de-rotated stamp hideuroyi, benzo isothiazolyl, benzo isothiazolyl dioxide, C _{6 -10} aryl, - (C _{1 -3} alkyl ) - (C _6-10 aryl), - (Y) - (C _{0 -3} alkyl) - (C _{6 -10} aryl), or - (Y) - (C _{0 -3} alkyl) - (5-10 membered Heteroaryl), each optionally substituted with one or more R ⁴ or R ⁵ ,

Each Y is independently —CHZ—, —CZ ₂ —, —CHR—, —O—, —C (═CHR) —, —C (═C—CO ₂ R) —,

Z are each independently F, Cl, -OR, -NR ₂ , -SR, -NHCONHR or -NHCOR,

L is a covalent bond or a saturated or unsaturated branched or unbranched C _1-10 carbon chain, wherein one or more methylene groups are optionally replaced independently by heteroatoms selected from O, NR and S (O) _m , L is optionally substituted with 0-2 oxo groups and one or more C _1-4 branched or unbranched alkyl optionally substituted with one or more F, Cl, Br or I,

m is each independently 0, 1 or 2,

Q is hydrogen, -NR'R ', cycloalkyl, aryl, heterocyclyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, and -S (O) _m, or phenyl, -S (O) _m, wherein the cycloalkyl, , aryl, heterocyclyl, C _{1 -6} alkoxy, C _1-6 alkyl, -S (O) _m, or phenyl, -S (O) _m optionally substituted with one or more R ^27, respectively,

R are each independently hydrogen, or substituted or unsubstituted C _{1 -6} alkyl ring,

R 'is independently hydrogen, substituted or unsubstituted C _{1 -8} alkyl, substituted or unsubstituted (C _{0 -4} alkyl) - (C _{6 -10} aryl) or substituted or unsubstituted (C _0-4 alkyl) - (5-10 member heterocyclyl), and

R ¹ are each independently F, Cl, Br, I, cyano, -C (O) R, -C (O) NR ₂ , -C (O) OR, -OR, -NR'R ',- _{SiR 3, -S (O) m} R, substituted or unsubstituted linear or branched C _{1 -10} alkyl, C _2-10 alkenyl ring, or a C _{2 -10} alkenyl, substituted or unsubstituted C _{3 - 10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl or heterocyclyl Alkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ),

R ^2, R ⁴ and R ⁵ are each independently selected from F, Cl, Br, I, cyano, substituted or unsubstituted linear or branched unsubstituted C _{1 -6} alkyl, a substituted or unsubstituted C _{6 -10} aryl, Substituted or unsubstituted 5-10 membered heteroaryl, -OR ', -OR ⁶ , -C (O) R', -C (O) OR ', -C (O) NR' ₂ , -NR ' ₂ , -NO ₂ , -S (O) _m R ", NR'SO ₂ R", -NR'C (O) NR'R ', -NR'C (S) NR'R', -NR'C ( O) OR 'or -SO ₂ NR' ₂ ,

R "are each independently a substituted or unsubstituted C _{1 -8} alkyl, substituted or unsubstituted ring with C ₀ -C _{6 -10 -4} alkyl aryl or substituted or unsubstituted (C _{0 -4} alkyl) - (5-10 membered heterocyclyl),

R ³ are independently selected from each independently represent a substituted or unsubstituted C _{6 -10} aryl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl, or heterocyclylalkyl (N, O, S (O) _m a selected one, two, three, or containing from 4 heteroatoms), a a substituted or unsubstituted C _{3 -12} cycloalkyl, substituted or unsubstituted C _{5 -12} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted linear or branched C _{1 -8} ^{alkyl, 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 26 C (O) (CH 2) m N (R 21) -, a substituted or unsubstituted C _{2 -8} alkenyl, or a substituted or unsubstituted C _2-8 alkynyl, the above C _{1 -8} alkyl, C _{2 -8} alkenyl, or C _{2 -8} least one methylene group is O, NH or S (O) alkynyl of _m Arbitrarily replaced

R ⁶ are each optionally partially or fully halogenated, and optionally substituted C _{1 -6} branched or unbranched alkyl as R ^26,

Each R ²⁶ is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or optionally partially or fully halogenated mono- or di- (C _{0- ) 4} alkyl) amino,

R ²⁰ is a substituted or unsubstituted C _{1 -10} alkyl, substituted or unsubstituted C _{0 -6} alkyl-phenyl, a substituted or unsubstituted C _{0 -6} alkyl-heterocyclyl, OR 'or NR' ₂ ,

R ²¹ is hydrogen, or an optionally partially or completely halogenated C _{1 -4} branched or unbranched alkyl,

R ^22, R ²³ and R ²⁴ are each independently hydrogen, (which here, C _{1 -10} alkyl, optionally via one or more O, N or S) substituted or unsubstituted C _{1 -10} alkyl, substituted or unsubstituted C _{0 -6} alkyl-phenyl, substituted or unsubstituted C _{0 -6} alkyl-, or heterocyclyl, or R ²³ and R ²⁴ and are optionally form a heterocyclic or heteroaryl ring together,

R ²⁷ are each independently F, Cl, Br, I, cyano, -C (O) R ', -C (O) NR' ₂ , -C (O) OR ', -OR', -NR ' _{R ', -SiR' 3, -S} (O) m R ', substituted or unsubstituted linear or branched unsubstituted C _1-10 alkyl, C _{2 -10} alkenyl, or C _{2 -10} alkynyl, substituted or unsubstituted C _{3 -10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _7-20 aralkyl, substituted or unsubstituted 3-11 membered heterocyclyl Or heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ),

However, Ar is _{- (Y) - (C 6} -10 aryl), G is N- (substituted or unsubstituted phenyl) pyrazolyl one time, pyrazolyl adds one or more R ^1, R ² or a Substituted with R ³ ,

The compound of formula (IA) is not N- (5-tert-butyl-2-phenyl-2H-pyrazol-3-yl) -2- (4-chloro-phenyl) -acetamide.

In certain embodiments of Group 1 compounds of Formula (IA), the compound inhibits at least about 50% of TNFα-release derived from cells at a 10 μM concentration.

In some embodiments of the group 1 compound of Formula IA, G is

Phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran-3-one;

Pyrazolyl, pyrrolyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydro Quinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, Dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazoloyl, 4H-benzo [1,4] oxazine-3-onyl, benzodioxolyl, benzo [1,3] dioxol-2-onyl, tetra Hydrobenzopyranyl, indolyl, indolinyl, indolinyl, indolinonyl, phthalimidyl;

Pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxydyl, oxazolinyl, Thiazolinyl, imidazolinyl, tetrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl , Dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or ditianyl.

In another embodiment of the group 1 compound of Formula IA, G is phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl Or benzofuran-3-one. In another embodiment, G is pyrazolyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidy Neil, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazoloyl, benzo [1 , 4] oxazine-3-onyl, benzodioxolyl, benzo [1,3] dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolinyl, indolinonyl or phthalimidyl to be. Alternatively, G is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxydyl , Oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tetrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinoli Nil, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or ditianyl. In other embodiments, G is phenyl, naphthyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl or pyridinyl .

In certain embodiments of the group 1 compounds of Formula IA, Ar is indazolyl, indolyl, isoindoleyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl , Pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, or a C _{6 -10} aryl group. In some of the above embodiments, Ar is substituted with one or more R ⁴ or R ⁵ . Alternatively, Ar is indazolyl, isoindoleyl, pyrazolyl, pyrrolinyl, phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl or imidazolyl. In another such embodiment, Ar is indazolyl, phenyl, tetrahydronaphthyl or naphthyl.

In certain embodiments of compounds of formula IA, Ar is - (C _{1 -3} alkyl) - (C _{6 -10} aryl), - (Y) - ( C 0-3 alkyl) - (C _{6 -10} aryl group), or - (Y) - is a (5-10 membered heteroaryl) - (C _{0 -3} alkyl). In some of the above embodiments, Ar is substituted with one or more R ⁴ or R ⁵ . In some of the above embodiments, Y is —CZ ₂ — and each Z is independently F, —OR, or —CHR. For example, Y is -CF _2- . In other embodiments, Y is -CHR or -CHZ- and Z is -OR. Thus, for example, Y is -CHOH-. Alternatively, Y is -O- or -CH _2- . The yet another embodiment, C _{6 -10} aryl is phenyl or naphthyl (or), 5-10 membered heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl possess. The In another embodiment, Ar is - (C _{6 -10} aryl) - (C _{1 -3} alkyl).

In some embodiments of the group 1 compounds of Formula IA, one or more methylene groups of L are independently replaced by a heteroatom selected from O, N or S (O) _m . In other embodiments, L is a covalent bond, C ₁ -C ₉ alkoxy, -C (O) O-, -NH-, or -O-.

As mentioned above, Q other than -H or -NR'R 'is optionally substituted with R ²⁷ . In certain embodiments of Group 1 compounds of Formula (IA), Q is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, furanyl, Thienyl, pyranyl, naphthylpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolo [3,4-b] pyrimidinyl, purinyl, pyrrolo [2,3-b ] Pyridinyl, pyrazolo [3,4-b] pyridinyl, tuberdininyl, oxazo [4,5-b] pyridinyl, or imidazo [4,5-b] pyridinyl, tetrahydropyranyl , Tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinyl , Piperidinyl, piperidinyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfide Oxide or tetramethylene sulfone, C _{1 -6} alkoxy, sec or tert-amine (wherein the amino nitrogen is a C _{1 -3} being covalently bonded to an alkyl or alkoxy C _{1 -5} alkyl), phenylamino, C _{1 -6} Alkyl-S (O) _m or phenyl-S (O) _m . In the some embodiments, R ²⁷ is C _{1 -6} alkyl, C _{1 -6} alkoxy, hydroxy, amino, substituted or unsubstituted 5-10 member heterocyclyl, mono-or di - (C _{1 -3} alkyl ) amino, mono- or di- (phenyl -C _{1 -3} alkyl) amino, C _{1 -6} alkyl, -S (O) _m, -C _{1 -3-phenyl-alkoxy} or phenylamino (wherein the phenyl ring is 1 to 2 is halogen, C _{1 -6} alkyl, or C _{1 -6} optionally substituted by alkoxy).

In some other embodiments of the Group 1 compounds of Formula (IA), Q is hydrogen, phenyl, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinoyl, oxazinyl, diazepinonyl, imidazolyl , Pyridinyl or morpholino. In other embodiments, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. The In some embodiments, R ²⁷ is -C (O) OR ', -NR'R ', substituted or unsubstituted linear or branched C _{1 -10} alkyl, ring substituted or unsubstituted C _{7 -20} aralkyl Or substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl or heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ) to be. Alternatively, Q is pyrimidinyl and R ²⁷ is -NR'R ', or 1 independently selected from substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl (N, O, S (O) _m . , 2, 3 or 4 heteroatoms). In another such embodiment, Q is pyridinyl and R ²⁷ is -NR'R ', substituted or unsubstituted C _1-6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl Or heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ).

In some embodiments of the group 1 compounds of Formula IA, -LQ is not -H in the absence of R ⁴ and R ⁵ .

In some embodiments of the group 1 compound of Formula IA, each R ¹ is independently

Optionally partially or fully halogenated, 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, Thienyl, furyl, isoxazolyl or isothiazolyl (these are 1 to 5 halogens, optionally partially or fully halogenated C _1-6 branched or unbranched alkyl, C _3-8 cycloalkyl, C _5-8 Optionally substituted with cycloalkenyl, hydroxy, cyano, optionally partially or fully halogenated C _1-3 alkoxy and NH ₂ C (O) or mono- or di- (C _1-3 alkyl) aminocarbonyl) C _3-10 branched or unbranched alkyl optionally substituted with;

Optionally partially or fully halogenated, one to three optionally partially or completely halogenated C _{1 -3} alkyl, cyano, hydroxy C _{1 -3} alkyl or aryl optionally substituted by cyclopropyl, cyclobutyl to, fentanyl cycloalkyl, Cyclohexanyl, cycloheptanyl, bicyclohexanyl or bicycloheptanyl, or 1 to 3 ring methylene groups are independently replaced by O, S (O) _m , CHOH, C═O, C = S or NH Analogs of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl;

Optionally partially or fully halogenated, one to three C _{1 -5} branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl thiazolyl, thienyl, furyl, isoxazolyl, isothiazolyl (the abovementioned groups are each optionally partially or fully halogenated), optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopropyl fentanyl, cyclohexanone carbonyl, bicyclo heptanyl, bicyclo fentanyl, non-cyclohexanone carbonyl or bicyclo heptanyl, hydroxy, cyano, an optionally partially or completely halogenated C _{1 -3} alkoxy, NH ₂ C (O) or a mono- or di - (C _{1 -3} alkyl) amino-carboxylic alkenyl optionally substituted C _{3 -10} branched or unbranched (herein, C _{3 -10} branched or unbranched alkenyl group is one More than O, N or S (O) _m is optionally interrupted);

Each optionally substituted with one to three C _{1 -3} alkyl substituted cyclopentenyl, cyclohexenyl, cyclohexanone dienyl, bicyclo heptenyl, bicyclo hepta-dienyl, non-cyclohexenyl or bicyclo heptenyl;

Cyano, F, Cl, Br or I;

Methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;

Silyl optionally partially or fully halogenated branched to three C _{1 -4} independent or containing a non-branched alkyl group;

C _{2 -6} branched or unbranched alkyl, -C (O), C _{2 -6} branched or unbranched -S, C _{2 -6} branched or unbranched -S (O), C _{2 -6} branched or Unbranched-S (O) ₂ ;

Optionally partially or completely halogenated C _{2 -6} branched or unbranched alkynyl group (where one or more of the methylene groups is optionally replaced by O, NH and S (O) _m, wherein the alkynyl group optionally 0-2 oxo groups, pyrrolidinyl, pyrrolyl, one or more by one or more halogen atoms, optionally substituted C _{1 -4} branched or unbranched alkyl, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl is pyridinyl, tetrazolyl, or being independently substituted with one or more of a halogen atom, optionally substituted C _{1 -4} branched or unbranched alkylamino).

In other embodiments of Group 1 compounds of Formula (IA), each R ¹ is independently, optionally partially or fully halogenated, and 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyri Midinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of which is 1 to 5 halogens, optionally partially or fully halogenated C _{1 -6} branched or unbranched alkyl, C _3-8 cycloalkyl, C _5-8 cycloalkenyl, hydroxy, cyano, optionally partially or fully halogenated C _1-3 alkoxy and NH ₂ C (O) or C _3-10 branched or unbranched alkyl optionally substituted with mono- or di- (C _1-3 alkyl) aminocarbonyl). For example, each R ¹ is independently C _3-10 branched or unbranched alkyl.

In some embodiments of Group 1 compounds of Formula IA, R ² is each independently —OR ′, —OR ⁶ , —C (O) R ′, —C (O) OR ′, —C (O) NR ′ ₂ , -NR ' ₂ , -NO ₂ , -S (O) _m R ", -NR'SO ₂ R", -NR'C (O) NR'R', -NR'C (S) NR'R ', -NR'C (O) OR' or -SO ₂ NR ' ₂ . Alternatively, R ² is each independently —NR ′ ₂ , —NO ₂ , —C (O) NR ′ ₂ , —NR′SO ₂ R ″, —NR′C (O) NR′R ′, —NR ′ C (S) NR'R ', -NR'C (O) OR' or -SO ₂ NR ' ₂ .

In some embodiments of the group 1 compound of Formula IA, each R ³ is independently

Hydrogen or each optionally optionally partially or completely halogenated, 1 to 3 phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione , Imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimida Zolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterridinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, fury carbonyl, indazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, fentanyl, cyclohexanone carbonyl, bicyclo heptanyl, bicyclo fentanyl, non-cyclohexanone carbonyl, non- Cycloheptanyl, phenyl C1-5 alkyl, i Naphthyl C1-5 alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heterocyclyl, aryloxy, nitro, amino, mono- or di - (C _1-3 alkyl) amino, phenylamino, naphthylamino, heterocyclyl, amino, NH ₂ C (O), mono- or di - (C _1-3 alkyl) amino carbonyl, C _{1 -5} alkyl, -C ( O), -C _1-4 alkyl, amino -C _{1 -5} alkyl, mono- or di - (C _{1 -3} alkyl) amino -C _{1 -5-alkyl,} amino, -S (O) _2, di - (C _{1 -3} alkyl) amino ^{_{-S (O) 2, R 7}} -C 1 -5 alkyl, R ⁸ -C _{1 -5} ^{alkoxy, R 9 -C (O) -C} 1 -5 alkyl, R ¹⁰ -C _{1 - 5} alkyl (R ¹¹⁾ N, carboxy-mono-or di - (C _{1 -5-alkyl)} amino optionally substituted phenyl, naphthyl, or heterocyclyl with;

Fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or cyclopentenopyridine, cyclohexanopyridine, cyclopentano Pyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclopentanoindol, cyclohexanoindole, cyclobenzimidazole, cyclopentanoimidazole, cyclohexanoimida Fused heterocycles selected from sol, cyclopentanothiophene and cyclohexanothiophene (the fused aryl or fused heterocyclic ring may optionally be phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl , Pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazole ,-Triazolyl, isothiazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heteroaromatic heterocyclyl-oxy, heteroaryl, aryloxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino, NH ₂ C (O), mono- di or - (C _{1 -3} alkyl) amino carbonyl, C _{1 -4} alkyl, -C (O), C _{1 -5} alkyl amino -S (O) _2, mono- or di - (C _{1 -3} alkyl) amino -C _1-5 alkyl, R ¹² -C _{1 -5} alkyl, R ¹³ -C _{1 -5} ^{alkoxy, R 14 -C (O) -C} 1 -5 alkyl, R ¹⁵ -C _{1 -5} alkyl (R ¹⁶ ) independently substituted with 1 to 3 groups selected from N);

Optionally partially or fully halogenated, one to three optionally partially or completely halogenated C _{1 -3} alkyl, cyano, hydroxy C _{1 -3} alkyl or aryl optionally substituted by cyclopropyl, cyclobutyl to, fentanyl cycloalkyl, Cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, or one to three ring methylene groups are represented by O, S (O) _m , CHOH, C = O, C = S or NH Analogs of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, independently substituted by;

Each optionally substituted with 1 to 3 C _{1 -3} alkyl cyclopentenyl, cyclohexenyl, cyclohexanone dienyl, bicyclo heptenyl, bicyclo hepta-dienyl, non-cyclohexenyl, bicyclo heptenyl;

C _{1 -4} alkyl, or alkylene-phenyl -C (O) -C _{0 -4} alkyl or alkylene, C _{1 -4} alkyl or alkylene -C (O) -C _0-4 alkyl, or alkylene, C _{1 -4} alkyl, or alkylene-phenyl -S (O) _m -C _{0 -4} alkyl or alkylene;

Each optionally partially or fully halogenated, or R ^17, amino, OR ^18, or R ¹⁹ with an optionally substituted C _{1 -5} mono- or di-optionally substituted C _{1 -6} alkyl, C _{1 -6} alkoxy, alkylamino ;

Optionally partially or fully halogenated, one to three optionally partially or fully halogenated C _{1 -3} alkyl group optionally substituted by cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyloxy, cyclohexyloxy, cyclo-heptyloxy (where , 1 to 3 ring methylene groups are independently replaced by O, S (O) _m , CHOH, C═O, C═S or NH);

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 ) —;

^{R 23 R 24 NC (O)} - in a C _{2 -6} alkenyl optionally substituted;

Optionally partially or completely halogenated C _{2 -6-alkynyl} branched or unbranched carbon chain (wherein one or more of the methylene groups is optionally replaced by O, is optionally replaced by an NH or S (O) _m, wherein the alkynyl group optionally 0-2 two oxo groups, pyrrolidinyl, pyrrolyl, one or more by one or more halogen atoms, optionally substituted C _{1 -4} branched or unbranched alkyl, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl , being independently substituted with phenyl, pyridinyl, tetrazolyl or one or more of a halogen atom, optionally substituted C _{1 -4} branched or unbranched alkyl-amino); or

Benzoyl or naphthoyl,

Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁹ and R ²⁵ are each independently cyano, morpholino, piperidinyl, pipe piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or an optionally partially or completely halogenated mono- or di - (C _{0 -4} alkyl) amino;

R ¹¹ and R ¹⁶ are each independently hydrogen, or an optionally partially or completely halogenated to be a C _{1 -4} minutes, branched or unbranched alkyl;

R ¹⁸ is independently hydrogen, or an optionally oxo-substituted C _{1 -4,} or independently, branched or unbranched alkyl as R ^25.

In some of the above embodiments, R ³ is each independently, each optionally partially or fully halogenated, and 1-3 phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrroly Diyl, 2,5-pyrrolidine-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl , Isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, putrindinyl, phthalazinyl, naphthylpyri pyridinyl, quinoxalinyl carbonyl, quinazolinyl, Fourier carbonyl, indazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, fentanyl, cyclohexanone carbonyl, cycloalkyl heptanyl , Bicyclopentanyl, bicyclohexanyl, non Bicyclo heptanyl, phenyl C _{1 -5} alkyl, naphthyl C _{1 -5} alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heterocyclyl alkyloxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heterocyclyl, amino, NH ₂ C (O), mono- or di - (C _{1 -3} alkyl ) aminocarbonyl, C _{1 -5} alkyl, -C (O) -C _{1 -4} alkylene, amino -C _{1 -5} alkyl, mono- or di - (C _{1 -3} alkyl) amino -C _1-5 alkyl, amino -S (O) _2, di - (C _{1 -3} alkyl) amino ^{_{-S (O) 2, R 6}} -C 1 -5 alkyl, R ⁸ -C _1-5 alkoxy, R ⁹ -C (O) -C _{1 -5} alkyl, R ¹⁰ -C _{1 -5} alkyl (R ¹¹⁾ N, or carboxy-mono- or di - (C _1-5 alkyl) amino optionally is substituted phenyl, naphthyl or heterocyclyl, . In another embodiment, R ³ is, each independently, each optionally partially or fully halogenated, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino optionally substituted phenyl, pyridazinyl or pyridyl; Each optionally partially or fully halogenated, or R ^17, amino, OR ^18, R ¹⁹ optionally substituted with C _{1 -5-mono-} or di-alkyl amino, optionally substituted C _{1 -6} alkyl, C _{1 -6} alkoxy; 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 ) —. For example, R ³ can be phenyl or tolyl.

In some embodiments of the group 1 compound of Formula IA, X is C═O.

In another aspect of the present invention, there is provided a group 1 compound of formula IB, stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof.

Where

X is C (O), C (S) or CH ₂ ,

G is C _{3 -10} and carbocyclyl, 5-8-membered monocyclic heterocyclyl, or 8-11 won bicyclic (containing one or more heteroatoms selected from O, N or S) heterocyclyl, one Substituted by the above R ¹ , R ² or R ³ ,

Ar is indazolyl, indolyl, isoindoleyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl , phthalazine possess, dihydro the run, rapid-fire benjoyi thiazolyl, dihydro benjoyi rapid fire group, the de-rotated stamp hideuroyi, benzo isothiazolyl, benzo isothiazolyl dioxide, C _{6 -10} aryl, - (C _{1 -3} alkyl ) - (C _6-10 aryl), - (Y) - (C _{0 -3} alkyl) - (C _{6 -10} aryl), or - (Y) - (C _{0 -3} alkyl) - (5-10 membered Heteroaryl), each of which is optionally substituted with one or more R ⁴ or R ⁵ ,

Each Y is independently —CHZ—, —CZ ₂ —, —CHR—, —C (═CHR) —, —C (═C—CO ₂ R) —,

Z are each independently F, Cl, -OR, -NR ₂ , -SR, -NHCONHR or -NHCOR,

L is a covalent bond or a saturated or unsaturated branched or unbranched C _1-10 carbon chain, wherein one or more methylene groups are optionally replaced independently by heteroatoms selected from O, NR and S (O) _m , L is optionally substituted with 0-2 oxo groups and one or more C _1-4 branched or unbranched alkyl optionally substituted with one or more F, Cl, Br or I,

m is each independently 0, 1 or 2,

Q is hydrogen, -NR'R ', cycloalkyl, aryl, heterocyclyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, and -S (O) _m, or phenyl, -S (O) _m, wherein the cycloalkyl, , aryl, heterocyclyl, C _{1 -6} alkoxy, C _1-6 alkyl, -S (O) _m, or phenyl, -S (O) _m optionally substituted with one or more R ^27, respectively, with the proviso that R ⁴ and R ⁵ In the absence of -LQ is not -H,

R are each independently hydrogen, or substituted or unsubstituted C _{1 -6} alkyl ring,

R 'is independently hydrogen, substituted or unsubstituted C _{1 -8} alkyl, substituted or unsubstituted (C _{0 -4} alkyl) - (C _{6 -10} aryl) or substituted or unsubstituted (C _0-4 alkyl) - (5-10 member heterocyclyl), and

R ¹ are each independently F, Cl, Br, I, cyano, -C (O) R, -C (O) NR ₂ , -C (O) OR, -OR, -NR'R ',- _{SiR 3, -S (O) m} R, substituted or unsubstituted linear or branched C _{1 -10} alkyl, C _2-10 alkenyl ring, or a C _{2 -10} alkynyl, substituted or unsubstituted C _{3 - 10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl or heterocyclyl Alkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ),

R ^2, R ⁴ and R ⁵ are each independently selected from F, Cl, Br, I, cyano, substituted or unsubstituted linear or branched unsubstituted C _{1 -6} alkyl, a substituted or unsubstituted C _{6 -10} aryl, Substituted or unsubstituted 5-10 membered heteroaryl, -OR ', -OR ⁶ , -C (O) R', -C (O) OR ', -C (O) NR' ₂ , -NR ' ₂ , -NO ₂ , -S (O) _m R ", NR'SO ₂ R", -NR'C (O) NR'R ', -NR'C (S) NR'R', -NR'C ( O) OR 'or -SO ₂ NR' ₂ ,

R "are each independently a substituted or unsubstituted C _{1 -8} alkyl, substituted or unsubstituted ring with C ₀ -C _{6 -10 -4} alkyl aryl or substituted or unsubstituted (C _{0 -4} alkyl) - (5-10 membered heterocyclyl),

R ³ are independently selected from each independently represent a substituted or unsubstituted C _{6 -10} aryl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl, or heterocyclylalkyl (N, O, S (O) _m a selected one, two, three, or containing from 4 heteroatoms), a a substituted or unsubstituted C _{3 -12} cycloalkyl, substituted or unsubstituted C _{5 -12} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted linear or branched C _{1 -8} ^{alkyl, 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 26 C (O) (CH 2) m N (R 21) -, a substituted or unsubstituted C _{2 -8} alkenyl, or a substituted or unsubstituted C _2-8 alkynyl, the above C _{1 -8} alkyl, C _{2 -8} alkenyl, or C _{2 -8} least one methylene group is O, NH or S (O) alkynyl of _m Arbitrarily replaced

R ⁶ are each optionally partially or fully halogenated, and optionally substituted C _{1 -6} branched or unbranched alkyl as R ^26,

Each R ²⁶ is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or optionally partially or fully halogenated mono- or di- (C _{0- ) 4} alkyl) amino,

R ²⁰ is a substituted or unsubstituted C _{1 -10} alkyl, substituted or unsubstituted C _{0 -6} alkyl-phenyl, a substituted or unsubstituted C _{0 -6} alkyl-heterocyclyl, OR 'or NR' ₂ ,

R ²¹ is hydrogen, or an optionally partially or completely halogenated C _{1 -4} branched or unbranched alkyl,

R ^22, R ²³ and R ²⁴ are each independently hydrogen, (which here, C _{1 -10} alkyl, optionally via one or more O, N or S) substituted or unsubstituted C _{1 -10} alkyl, substituted or unsubstituted C _{-6 0-alkyl-phenyl,} substituted or unsubstituted C _{0 -6} alkyl-, or heterocyclyl, or R ²³ and R ²⁴ and are optionally form a heterocyclic or heteroaryl ring together,

R ²⁷ are each independently F, Cl, Br, I, cyano, -C (O) R ', -C (O) NR' ₂ , -C (O) OR ', -OR', -NR ' _{R ', -SiR' 3, -S} (O) m R ', substituted or unsubstituted linear or branched unsubstituted C _1-10 alkyl, C _{2 -10} alkenyl, or C _{2 -10} alkynyl, substituted or unsubstituted C _{3 -10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _7-20 aralkyl, substituted or unsubstituted 3-11 membered heterocyclyl Or heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ).

In some embodiments of the group 1 compound of Formula IB, the compound inhibits at least about 50% of TNFα-release derived from cells at 10 μM concentration.

In certain embodiments of group 1 compounds of Formula (IB), G is

Phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran-3-one;

Pyrazolyl, pyrrolyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydro Quinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, Dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazoloyl, 4H-benzo [1,4] oxazine-3-onyl, benzodioxolyl, benzo [1,3] dioxol-2-onyl, tetra Hydrobenzopyranyl, indolyl, indolinyl, indolinyl, indolinonyl, phthalimidyl;

Pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxydyl, oxazolinyl, Thiazolinyl, imidazolinyl, tetrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl , Dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or ditianyl.

In another embodiment of the group 1 compound of formula (IB), G is phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl Or benzofuran-3-one. In another embodiment, G is pyrazolyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidy Neil, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazoloyl, benzo [1 , 4] oxazine-3-onyl, benzodioxolyl, benzo [1,3] dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolinyl, indolinonyl or phthalimidyl to be. In another embodiment, G is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfonate Foxidyl, oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tetrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroiso Quinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or ditianyl. In another embodiment, G is phenyl, naphthyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl or pyridinyl to be.

In certain embodiments of the Group 1 compounds of Formula IB, Ar is indazolyl, indolyl, isoindoleyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl , Piperidinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindoleyl, benzoisothiazolyl, benzoisothia pyridazinyl a dioxide, or C _{6 -10} aryl group. In some of the above embodiments, Ar is substituted with one or more R ⁴ or R ⁵ . In other embodiments, Ar is indazolyl, isoindoleyl, pyrazolyl, pyrrolinyl, phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl or imidazolyl. For example, Ar is indazolyl, phenyl, naphthyl or tetrahydronaphthyl. In another embodiment, Ar is - (C _{1 -3} alkyl) - (C _6-10 aryl), - (Y) - ( C 0 -3 alkyl) - (C _{6 -10} aryl) or - (Y) - a (5-10 membered heteroaryl) - (C _{0 -3} alkyl). In some of the above embodiments, Ar is substituted with one or more R ⁴ or R ⁵ . In other embodiments, Y is -CHR or -CHZ- and Z is -OR. For example Y is -CH _2- . The yet another embodiment, C _{6 -10} aryl is phenyl or naphthyl or a 5-10 membered heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl possess. Alternatively, Ar is - (C _{6 -10} aryl) - (C _{1 -3} alkyl).

In some embodiments of the group 1 compounds of Formula (IB), one or more methylene groups of L are independently replaced by a heteroatom selected from O, N or S (O) _m . In other embodiments, L is a covalent bond, C ₁ -C ₉ alkoxy, -C (O) O-, -NH-, or -O-.

As mentioned above, Q other than -H or -NR'R 'is optionally substituted with R ²⁷ . In certain embodiments of Group 1 compounds of Formula (IB), Q is phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, furanyl, Thienyl, pyranyl, naphthylpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolo [3,4-b] pyrimidinyl, purinyl, pyrrolo [2,3-b ] Pyridinyl, pyrazolo [3,4-b] pyridinyl, tuberdininyl, oxazo [4,5-b] pyridinyl, or imidazo [4,5-b] pyridinyl, tetrahydropyranyl , Tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinyl , Piperidinyl, piperidinyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfide Oxide or tetramethylene sulfone, C _{1 -6} alkoxy, sec or tert-amine (wherein the amino nitrogen is a C _{1 -3} being covalently bonded to an alkyl or alkoxy C _{1 -5} alkyl), phenylamino, C _{1 -6} Alkyl-S (O) _m or phenyl-S (O) _m . In the some embodiments, R ²⁷ is C _{1 -6} alkyl, C _{1 -6} alkoxy, hydroxy, amino, substituted or unsubstituted 5-10 member heterocyclyl, mono-or di - (C _{1 -3} alkyl ) amino, mono- or di- (phenyl -C _{1 -3} alkyl) amino, C _{1 -6} alkyl, -S (O) _m, -C _{1 -3-phenyl-alkoxy} or phenylamino (wherein the phenyl ring is 1 to 2 is halogen, C _{1 -6} alkyl, or C _{1 -6} optionally substituted by alkoxy). Alternatively, Q is hydrogen, phenyl, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinoyl, oxazinyl, diazepinyl, imidazolyl, pyridinyl or morpholino. In another embodiment, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. Wherein in some embodiments, R ²⁷ is -C (O) OR, -NR'R ' , substituted or unsubstituted linear or branched C _{1 -10} alkyl, substituted or unsubstituted C _{7 -20} aralkyl, Or substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl or heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ) . Alternatively, Q is pyrimidinyl and R ²⁷ is -NR'R ', or 1 independently selected from substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl (N, O, S (O) _m . , 2, 3 or 4 heteroatoms). In another embodiment, Q is pyridinyl and R ²⁷ is -NR'R ', substituted or unsubstituted C _1-6 alkyl, or substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl or Heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ).

In some embodiments of the group 1 compound of Formula IB, each R ¹ is independently

Optionally partially or fully halogenated, 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, Thienyl, furyl, isoxazolyl or isothiazolyl (these are 1 to 5 halogens, optionally partially or fully halogenated C _1-6 branched or unbranched alkyl, C _3-8 cycloalkyl, C _5-8 Optionally substituted with cycloalkenyl, hydroxy, cyano, optionally partially or fully halogenated C _1-3 alkoxy and NH ₂ C (O) or mono- or di- (C _1-3 alkyl) aminocarbonyl) C _3-10 branched or unbranched alkyl optionally substituted with;

Optionally partially or fully halogenated, one to three optionally partially or completely halogenated C _{1 -3} alkyl, cyano, hydroxy C _{1 -3} alkyl or aryl optionally substituted by cyclopropyl, cyclobutyl to, fentanyl cycloalkyl, Cyclohexanyl, cycloheptanyl, bicyclohexanyl or bicycloheptanyl, or 1 to 3 ring methylene groups are independently replaced by O, S (O) _m , CHOH, C═O, C = S or NH Analogs of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl;

Optionally partially or fully halogenated, one to three C _{1 -5} branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl thiazolyl, thienyl, furyl, isoxazolyl, isothiazolyl (the abovementioned groups are each optionally partially or fully halogenated), optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopropyl fentanyl, cyclohexanone carbonyl, bicyclo heptanyl, bicyclo fentanyl, non-cyclohexanone carbonyl or bicyclo heptanyl, hydroxy, cyano, an optionally partially or completely halogenated C _{1 -3} alkoxy, NH ₂ C (O) or a mono- or di - (C _{1 -3} alkyl) amino-carboxylic alkenyl optionally substituted C _{3 -10} branched or unbranched (herein, C _{3 -10} branched or unbranched alkenyl group is one More than O, N or S (O) _m is optionally interrupted);

Each optionally substituted with one to three C _{1 -3} alkyl substituted cyclopentenyl, cyclohexenyl, cyclohexanone dienyl, bicyclo heptenyl, bicyclo hepta-dienyl, non-cyclohexenyl or bicyclo heptenyl;

Cyano, F, Cl, Br or I;

Methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;

Optionally partially or fully silyl containing three halogenated C _{1 -4} independently represent a branched or unbranched alkyl group or shed some light;

C _{2 -6} branched or unbranched alkyl, -C (O), C _{2 -6} branched or unbranched -S, C _{2 -6} branched or unbranched -S (O), C _{2 -6} branched or Unbranched-S (O) ₂ ;

Optionally partially or completely halogenated C _{2 -6} branched or unbranched alkynyl group (where one or more of the methylene groups is optionally replaced by O, NH and S (O) _m, wherein the alkynyl group optionally 0-2 oxo groups, pyrrolidinyl, pyrrolyl, one or more by one or more halogen atoms, optionally substituted C _{1 -4} branched or unbranched alkyl, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl is pyridinyl, tetrazolyl, or being independently substituted with one or more of a halogen atom, optionally substituted C _{1 -4} branched or unbranched alkylamino).

In other embodiments of the Group 1 compounds of Formula (IB), each R ¹ is independently, optionally partially or fully halogenated, and 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyri Midinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of which is 1 to 5 halogens, optionally partially or fully halogenated C _{1 -6} branched or unbranched alkyl, C _3-8 cycloalkyl, C _5-8 cycloalkenyl, hydroxy, cyano, optionally partially or fully halogenated C _1-3 alkoxy and NH ₂ C (O) or C _3-10 branched or unbranched alkyl optionally substituted with mono- or di- (C _1-3 alkyl) aminocarbonyl). For example, each R ¹ is independently C _3-10 branched or unbranched alkyl.

In certain embodiments of the group 1 compound of formula IB, R ² is each independently —OR ′, —OR ⁶ , —C (O) R ′, —C (O) OR ′, —C (O) NR ′ ₂ , -NR ' ₂ , -NO ₂ , -S (O) _m R ", -NR'SO ₂ R", -NR'C (O) NR'R', -NR'C (S) NR'R ', -NR'C (O) OR' or -SO ₂ NR ' ₂ . In other embodiments, R ² is independently —NR ′ ₂ , —NO ₂ , —C (O) NR ′ ₂ , —NR′SO ₂ R ″, —NR′C (O) NR′R ′, —NR 'C (S) NR'R', -NR'C (O) OR 'or -SO ₂ NR' ₂ .

In some embodiments of the group 1 compound of Formula IB, each R ³ is independently

Hydrogen or each optionally optionally partially or completely halogenated, 1-3 phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione , Imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimida Zolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterridinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, fury carbonyl, indazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl titanyl, cyclohexanone carbonyl, bicyclo heptanyl, bicyclo fentanyl, non-cyclohexanone carbonyl, bicyclo heptanyl, phenyl C _{1 -5} alkyl, naphthyl C _{1 -5} alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heterocyclyl, aryloxy, nitro, amino, mono- or di - (C _1-3 alkyl) amino, phenylamino, naphthylamino, heterocyclyl, amino, NH ₂ C (O), mono- or di - (C _1-3 alkyl) amino carbonyl, C _{1 -5} alkyl, -C ( O) -C _{1 -4} alkyl, -C _1-5 alkyl, amino, mono- or di - (C _{1 -3} alkyl) amino -C _{1 -5} alkyl, amino, -S (O) _2, di - (C _{1 -3} alkyl) amino ^{_{-S (O) 2, R 7}} -C 1 -5 alkyl, R ⁸ -C _{1 -5} ^{alkoxy, R 9 -C (O) -C} 1 -5 alkyl, R ¹⁰ -C _{1 - 5} alkyl (R ¹¹⁾ N, carboxy-mono-or di - (C _{1 -5-alkyl)} amino optionally substituted phenyl, naphthyl, or heterocyclyl with;

Fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or cyclopentenopyridine, cyclohexanopyridine, cyclopentano Pyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclopentanoindole, cyclohexanoindole, cyclobenzimidazole, cyclopentanoimidazole, cyclohexanoimida Fused heterocycles selected from sol, cyclopentanothiophene and cyclohexanothiophene (the fused aryl or fused heterocyclic ring may optionally be phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl , Pyrrolyl, pyrrolidinyl, 2,5-pyrrolidin-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazole , Triazolyl, isothiazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heteroaromatic heterocyclyl-oxy, heteroaryl, aryloxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino, NH ₂ C (O), mono- or di - (C _{1 -3} alkyl) amino carbonyl, C _{1 -4} alkyl, -C (O), C _{1 -5} alkyl amino -S (O) _2, mono- or di - (C _{1 -3} alkyl) amino -C _1-5 alkyl, R ¹² -C _{1 -5} alkyl, R ¹³ -C _{1 -5} ^{alkoxy, R 14 -C (O) -C} 1 -5 alkyl, R ¹⁵ -C _{1 -5} alkyl (R ¹⁶ ) independently substituted with 1 to 3 groups selected from N);

Optionally partially or fully halogenated, one to three optionally partially or completely halogenated C _{1 -3} alkyl, cyano, hydroxy C _{1 -3} alkyl or aryl optionally substituted by cyclopropyl, cyclobutyl to, fentanyl cycloalkyl, Cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, or one to three ring methylene groups are represented by O, S (O) _m , CHOH, C = O, C = S or NH Analogs of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, independently substituted by;

Each one to three C _{1 -3} alkyl group optionally substituted by cyclopentenyl, cyclohexyl hekse carbonyl, cyclohexanone dienyl, bicyclo heptenyl, bicyclo hepta-dienyl, non-cyclohexenyl, bicyclo heptenyl;

C _{1 -4} alkyl, or alkylene-phenyl -C (O) -C _{0 -4} alkyl or alkylene, C _{1 -4} alkyl or alkylene -C (O) -C _0-4 alkyl, or alkylene, C _{1 -4} alkyl, or alkylene-phenyl -S (O) _m -C _{0 -4} alkyl or alkylene;

Each optionally partially or fully halogenated, or R ^17, amino, OR ^18, or R ¹⁹ with an optionally substituted C _{1 -5} mono- or di-optionally substituted C _{1 -6} alkyl, C _{1 -6} alkoxy, alkylamino ;

Optionally partially or fully halogenated, one to three optionally partially or fully halogenated C _{1 -3} alkyl group optionally substituted by cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyloxy, cyclohexyloxy, cyclo-heptyloxy (where , 1 to 3 ring methylene groups are independently replaced by O, S (O) _m , CHOH, C═O, C═S or NH);

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 ) —;

^{R 23 R 24 NC (O)} - in a C _{2 -6} alkenyl optionally substituted;

Optionally partially or completely halogenated C _{2 -6-alkynyl} branched or unbranched carbon chain (wherein one or more of the methylene groups is optionally replaced by O, is optionally replaced by an NH or S (O) _m, wherein the alkynyl group optionally 0-2 two oxo groups, pyrrolidinyl, pyrrolyl, one or more by one or more halogen atoms, optionally substituted C _{1 -4} branched or unbranched alkyl, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl , being independently substituted with phenyl, pyridinyl, tetrazolyl or one or more of a halogen atom, optionally substituted C _{1 -4} branched or unbranched alkyl-amino); or

Benzoyl or naphthoyl,

Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁹ and R ²⁵ are each independently cyano, morpholino, piperidinyl, pipe piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or an optionally partially or completely halogenated mono- or di - (C _{0 -4} alkyl) amino;

R ¹¹ and R ¹⁶ are each independently hydrogen, or an optionally partially or completely halogenated C _{1 -4} minutes, branched or unbranched alkyl;

R ¹⁸ is independently hydrogen, or an optionally oxo-substituted C _{1 -4,} or independently, branched or unbranched alkyl as R ^25.

In some of the above embodiments, R ³ is each independently, each optionally partially or fully halogenated, and 1-3 phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrroly Diyl, 2,5-pyrrolidine-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl , Isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, putrindinyl, phthalazinyl, naphthylpyri pyridinyl, quinoxalinyl carbonyl, quinazolinyl, Fourier carbonyl, indazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, fentanyl, cyclohexanone carbonyl, cycloalkyl heptanyl , Bicyclopentanyl, bicyclohexanyl, non Bicyclo heptanyl, phenyl C _{1 -5} alkyl, naphthyl C _{1 -5} alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heterocyclyl alkyloxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heterocyclyl, amino, NH ₂ C (O), mono- or di - (C _{1 -3} alkyl ) aminocarbonyl, C _{1 -5} alkyl, -C (O) -C _{1 -4} alkyl, amino -C _{1 -5} alkyl, mono- or di - (C _{1 -3} alkyl) amino -C _1-5 alkyl, amino -S (O) _2, di - (C _{1 -3} alkyl) amino ^{_{-S (O) 2, R 7}} -C 1 -5 alkyl, R ⁸ - C _1-5 alkoxy, R ⁹ -C (O) -C _{1 -5} alkyl, R ¹⁰ -C _{1 -5} alkyl (R ¹¹⁾ N, or carboxy-mono- or di - (C _1-5 alkyl) amino optionally is substituted phenyl, naphthyl or heterocyclyl, . In another embodiment, R ³ is, each independently, each optionally partially or fully halogenated, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino optionally substituted phenyl, pyridazinyl or pyridyl; Each optionally partially or fully halogenated, or R ^17, amino, OR ^18, R ¹⁹ optionally substituted with C _{1 -5-mono-} or di-alkyl amino, optionally substituted C _{1 -6} alkyl, C _{1 -6} alkoxy; 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 ) —. For example, R ³ can be phenyl or tolyl.

In certain embodiments of group 1 compounds of Formula (IB), X is C═O.

According to another aspect of the present invention, there is provided a second group of compounds of formula (IA), stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof.

<Formula IA>

Where

X is C (O) or C (S),

G is C _{3 -10} and carbocyclyl, 5-8-membered monocyclic heterocyclyl, or 8-11 won bicyclic (containing one or more heteroatoms selected from O, N or S) heterocyclyl, one Substituted by the above R ¹ , R ² or R ³ ,

Ar is - (Y) - (C _{0 -3} alkyl) - (bicyclic aryl), or - (Y) - (C _{0 -3} alkyl) - (bicyclic heteroaryl), and one or more R ⁴ or R ⁵ Optionally substituted with, the bicyclic heteroaryl is indazolyl, isoindoleyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydro Benzoisoxazolyl, dihydroisoindolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl, or benzoisothiazolyl dioxide, provided that bicyclic aryl is 1,1,4,4-tetra Not methyl-1,2,3,4-tetrahydro-naphthyl,

Y is -C (O)-, -C (NNRC (O) OR)-, -C (NNRR)-, -C (NNC (O) NRR) or -C (NOR)-,

L is a covalent bond or a saturated or unsaturated branched or unbranched C _1-10 carbon chain, wherein one or more methylene groups are optionally replaced independently by heteroatoms selected from O, NR and S (O) _m , L is optionally substituted with 0 or 2 oxo groups and one or more C _1-4 branched or unbranched alkyl optionally substituted by one or more F, Cl, Br or I,

m is each independently 0, 1 or 2,

Q is hydrogen, -NR'R ', cycloalkyl, aryl, heterocyclyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, and -S (O) _m, or phenyl, -S (O) _m, wherein the cycloalkyl, , aryl, heterocyclyl, C _{1 -6} alkoxy, C _1-6 alkyl, -S (O) _m, or phenyl, -S (O) _m optionally substituted with one or more R ^27, respectively, with the proviso that R ⁴ and R ⁵ In the absence of -LQ is not -H,

R are each independently hydrogen, or substituted or unsubstituted C _{1 -6} alkyl ring,

R 'is independently hydrogen, substituted or unsubstituted C _{1 -8} alkyl, substituted or unsubstituted (C _{0 -4} alkyl) - (C _{6 -10} aryl) or substituted or unsubstituted (C _0-4 alkyl) - (5-10 member heterocyclyl), and

R ¹ are each independently F, Cl, Br, I, cyano, -C (O) R, -C (O) NR ₂ , -C (O) OR, -OR, -NR'R ',- _{SiR 3, -S (O) m} R, substituted or unsubstituted linear or branched C _{1 -10} alkyl, C _2-10 alkenyl ring, or a C _{2 -10} alkynyl, substituted or unsubstituted C _{3 - 10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl or heterocyclyl Alkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ),

R ^2, R ⁴ and R ⁵ are each independently selected from F, Cl, Br, I, cyano, substituted or unsubstituted linear or branched unsubstituted C _{1 -6} alkyl, a substituted or unsubstituted C _{6 -10} aryl, Substituted or unsubstituted 5-10 membered heteroaryl, -OR ', -OR ⁶ , -C (O) R', -C (O) OR ', -C (O) NR' ₂ , -NR ' ₂ , -NO ₂ , -S (O) _m R ", NR'SO ₂ R", -NR'C (O) NR'R ', -NR'C (S) NR'R', -NR'C ( O) OR 'or -SO ₂ NR' ₂ ,

R "are each independently a substituted or unsubstituted C _{1 -8} alkyl, substituted or unsubstituted ring with C ₀ -C _{6 -10 -4} alkyl aryl or substituted or unsubstituted (C _{0 -4} alkyl) - (5-10 membered heterocyclyl),

R ^3, independently, is H, a substituted or unsubstituted C _{6 -10} aryl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl, or heterocyclylalkyl (N, O, S (O) _m independently selected from one, two, three or four also contain a hetero atom), a substituted or unsubstituted C _{3 -12} cycloalkyl, substituted or unsubstituted C _{5 -12} from the cycloalkenyl, substituted or unsubstituted hwandoen C _{7 -20} aralkyl group, a substituted or unsubstituted linear or branched C _{1 -8} ^{alkyl, 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 26 C (O) (CH 2) m N (R 21) -, a substituted or unsubstituted C _{2 -8} alkenyl , or is a substituted or unsubstituted C _2-8 alkynyl, a C _{1 -8} alkyl, C _{2 -8} alkenyl, or C _{2 -8} least one methylene group is O, NH or S (O) of the alkynyl optionally substituted with _m ,

R ⁶ are each optionally partially or fully halogenated, and optionally substituted C _{1 -6} branched or unbranched alkyl as R ^26,

Each R ²⁶ is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or optionally partially or fully halogenated mono- or di- (C _{0- ) 4} alkyl) amino,

R ²⁰ is a substituted or unsubstituted C _{1 -10} alkyl, substituted or unsubstituted C _{0 -6} alkyl-phenyl, a substituted or unsubstituted C _{0 -6} alkyl-heterocyclyl, OR 'or NR' ₂ ,

R ²¹ is hydrogen, or an optionally partially or completely halogenated C _{1 -4} branched or unbranched alkyl,

R ^22, R ²³ and R ²⁴ are each independently hydrogen, (which here, C _{1 -10} alkyl, optionally via one or more O, N or S) substituted or unsubstituted C _{1 -10} alkyl, substituted or unsubstituted C _-6 alkyl, _0-phenyl, a substituted or unsubstituted C _{0 -6} alkyl-, or heterocyclyl, or R ²³ and R ²⁴ and are optionally form a heterocyclic or heteroaryl ring together,

R ²⁷ are each independently F, Cl, Br, I, cyano, -C (O) R ', -C (O) NR' ₂ , -C (O) OR ', -OR', -NR ' _{R ', -SiR' 3, -S} (O) m R ', substituted or unsubstituted linear or branched unsubstituted C _1-10 alkyl, C _{2 -10} alkenyl, or C _{2 -10} alkynyl, substituted or unsubstituted C _{3 -10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _7-20 aralkyl, substituted or unsubstituted 3-11 membered heterocyclyl Or heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ),

Provided that when Ar is-(Y)-(bicyclic aryl) and G is N- (substituted or unsubstituted phenyl) -pyrazolyl, then pyrazolyl is additionally one or more R ¹ , R ² or R ³ Substituted with

Compound of formula (IA) is N- (4-chloro-3-methyl-isothiazol-5-yl) -2- [2- (2,2-dimethyl-propyl) -benzooxazol-5-yl] -2 It is not oxo-acetamide.

In certain embodiments of a compound of Formula (IA), the compound inhibits at least about 50% of TNFα-release derived from cells at a 10 μM concentration.

In certain embodiments of Group 2 compounds of Formula (IA), G is

Phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, cyclopropyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran-3-one;

Pyrazolyl, pyrrolyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydro Quinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, Dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazoloyl, 4H-benzo [1,4] oxazine-3-onyl, benzodioxolyl, benzo [1,3] dioxol-2-onyl, tetra Hydrobenzopyranyl, indolyl, indolinyl, indolinyl, indolinonyl, phthalimidyl;

Pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxydyl, oxazolinyl, Thiazolinyl, imidazolinyl, tetrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl , Dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or ditianyl.

In another embodiment, G is phenyl, naphthyl, cyclopropyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl or benzofuran-3 -On. Alternatively, G is pyrazolyl, pyridinyl, pyridinyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl , Benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazoloyl, benzo [1,4] jade Photo-3-onyl, benzodioxolyl, benzo [1,3] dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolinyl, indolinyl or phthalimidyl. In another embodiment, G is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfonate Foxidyl, oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tetrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroiso Quinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or ditianyl. In another embodiment, G is phenyl, naphthyl, cyclopropyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl Or pyridinyl.

In certain embodiments of Group 2 compounds of Formula (IA), Ar is-(Y)-(C _{0 -3} alkyl)-(bicyclic aryl) and the bicyclic aryl is naphthyl, tetrahydronaphthyl, dihydro Naphthyl, indenyl, indanyl or azulenyl. In some of the above embodiments, Ar is substituted with one or more R ⁴ or R ⁵ . In other embodiments, Y is -C (O)-, -C (NNRC (O) OR)-or -C (NOR)-. Alternatively, Ar is -C (O)-(bicyclic aryl) or -C (NOR)-(bicyclic aryl), wherein the bicyclic aryl is naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl , Indenyl or azulenyl. In another embodiment, Ar is - (bicyclic heteroaryl) - (Y) - (C _{0 -3} alkyl). In some of the above embodiments, Ar is substituted with one or more R ⁴ or R ⁵ . In other embodiments, Y is -C (O)-, -C (NNRC (O) OR)-or -C (NOR)-. In another embodiment, Ar is -C (O)-(bicyclic heteroaryl) or -C (NOR)-(bicyclic heteroaryl). For example, the bicyclic heteroaryl is quinolinyl, isoquinolinyl, phthalazinyl or quinazolinyl.

In certain embodiments of Group 2 compounds of Formula (IA), one or more methylene groups of L are independently replaced by a heteroatom selected from O, N or S (O) _m . Alternatively, L is a covalent bond, C ₁ -C ₉ alkoxy, —C (O) O—, —NH— or —O—.

In certain embodiments of Group 2 compounds of Formula (IA), Q is hydrogen, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, fura Neil, thienyl, pyranyl, naphthylpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolo [3,4-b] pyrimidinyl, purinyl, pyrrolo [2,3 -b] pyridinyl, pyrazolo [3,4-b] pyridinyl, tubassidinyl, oxazo [4,5-b] pyridinyl, or imidazo [4,5-b] pyridinyl, tetrahydro Pyranyl, tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, p Ferrazinyl, piperazinyl, oxazinyl, diazepanonyl, piperidinyl, piperidinyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, Pentame Alkylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone, C _{1 -6} alkoxy, (where secondary or tertiary amine, an amino nitrogen is covalently bonded to the C _{1 -3} alkyl, C _{1 -5} alkyl, alkoxy search), phenyl amino, C _{1 -6} alkyl, -S (O) _m -phenyl or -S (O) _m. In the some embodiments, R ²⁷ is C _{1 -6} alkyl, C _{1 -6} alkoxy, hydroxy, amino, substituted or unsubstituted 5-10 member heterocyclyl, mono-or di - (C _{1 -3} alkyl ) amino, mono- or di- (phenyl -C _{1 -3} alkyl) amino, C _{1 -6} alkyl, -S (O) _m, -C _{1 -3-phenyl-alkoxy} or phenylamino (wherein the phenyl ring is 1 to 2 is halogen, C _{1 -6} optionally substituted by alkyl or C _1-6 alkoxy).

In another embodiment of Group 2 compounds of Formula (IA), Q is hydrogen, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinoyl, oxazinyl, diazepinonyl, imidazolyl, pyridinyl Or morpholino. In another embodiment, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. Wherein in some embodiments, R ²⁷ is -C (O) OR ', -NR'R ', substituted or unsubstituted linear or branched C _{1 -10} alkyl, ring substituted or unsubstituted C _{7 -20} aralkyl Or substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl or heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ) to be. For example, Q is pyrimidinyl and R ²⁷ is independently selected from -NR'R ', or substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl (N, O, S (O) _m Containing 1, 2, 3 or 4 heteroatoms). Alternatively, Q is a pyridinyl, R ²⁷ is -NR'R ', substituted or unsubstituted C _{1 -6} alkyl, or a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl or heterocyclyl Alkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ).

In certain embodiments of Group 2 compounds of Formula (IA), each R ¹ is independently

Optionally partially or fully halogenated, 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, Thienyl, furyl, isoxazolyl or isothiazolyl (these are 1 to 5 halogens, optionally partially or fully halogenated C _1-6 branched or unbranched alkyl, C _3-8 cycloalkyl, C _5-8 Optionally substituted with cycloalkenyl, hydroxy, cyano, optionally partially or fully halogenated C _1-3 alkoxy and NH ₂ C (O) or mono- or di- (C _1-3 alkyl) aminocarbonyl) C _3-10 branched or unbranched alkyl optionally substituted with;

Optionally partially or fully halogenated, one to three optionally partially or completely halogenated C _{1 -3} alkyl, cyano, hydroxy C _{1 -3} alkyl or aryl optionally substituted by cyclopropyl, cyclobutyl to, fentanyl cycloalkyl, Cyclohexanyl, cycloheptanyl, bicyclohexanyl or bicycloheptanyl, or 1 to 3 ring methylene groups are independently replaced by O, S (O) _m , CHOH, C═O, C = S or NH Analogs of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl;

Optionally partially or fully halogenated, one to three C _{1 -5} branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl thiazolyl, thienyl, furyl, isoxazolyl, isothiazolyl (the abovementioned groups are each optionally partially or fully halogenated), optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopropyl fentanyl, cyclohexanone carbonyl, bicyclo heptanyl, bicyclo fentanyl, non-cyclohexanone carbonyl or bicyclo heptanyl, hydroxy, cyano, an optionally partially or completely halogenated C _{1 -3} alkoxy, NH ₂ C (O) or a mono- or di - (C _{1 -3} alkyl) amino-carboxylic alkenyl optionally substituted C _{3 -10} branched or unbranched (herein, C _{3 -10} branched or unbranched alkenyl group is one More than O, N or S (O) _m is optionally interrupted);

Each optionally substituted with one to three C _{1 -3} alkyl substituted cyclopentenyl, cyclohexenyl, cyclohexanone dienyl, bicyclo heptenyl, bicyclo hepta-dienyl, non-cyclohexenyl or bicyclo heptenyl;

Cyano, F, Cl, Br or I;

Methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;

Silyl optionally partially or fully halogenated branched to three C _{1 -4} independent or containing a non-branched alkyl group;

C _{2 -6} branched or unbranched alkyl, -C (O), C _{2 -6} branched or unbranched -S, C _{2 -6} branched or unbranched -S (O), C _{2 -6} branched or Unbranched-S (O) ₂ ;

Optionally partially or fully halogenated C _2-6 branched or unbranched alkynyl, wherein one or more methylene groups are optionally replaced by O, NH and S (O) _m , said alkynyl groups optionally being 0 to 2 oxo Group, pyrrolidinyl, pyrrolyl, one or more C _1-4 branched or unbranched alkyl, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl optionally substituted by one or more halogen atoms , Pyridinyl, tetrazolyl, or C _1-4 branched or unbranched alkylamino optionally substituted by one or more halogen atoms. Alternatively, R ¹ is each independently, optionally partially or fully halogenated, and 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, Pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl (these are 1 to 5 halogens, optionally partially or fully halogenated C _1-6 branched or unbranched alkyl, C _3-8 cycloalkyl, C _5-8 cycloalkenyl, hydroxy, cyano, optionally partially or fully halogenated C _1-3 alkoxy and NH ₂ C (O) or mono- or di- (C _1-3 Alkyl) optionally substituted with aminocarbonyl) C _3-10 branched or unbranched alkyl. For example, each R ¹ is independently C _3-10 branched or unbranched alkyl.

In certain embodiments of Group 2 compounds of Formula (IA), each R ² is independently —OR ′, —OR ⁶ , —C (O) R ′, —C (O) OR ′, —C (O) NR ′ ₂ , -NR ' ₂ , -NO ₂ , -S (O) _m R ", -NR'SO ₂ R", -NR'C (O) NR'R', -NR'C (S) NR'R ', -NR'C (O) OR' or -SO ₂ NR ' ₂ . Alternatively, R ² is independently —NR ′ ₂ , —NO ₂ , —C (O) NR ′ ₂ , —NR′SO ₂ R ″, —NR′C (O) NR′R ′, —NR′C (S) NR'R ', -NR'C (O) OR' or -SO ₂ NR ' ₂ .

In certain embodiments of Group 2 compounds of Formula (IA), each R ³ is independently

Hydrogen or each optionally optionally partially or completely halogenated, 1 to 3 phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione , Imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimida Zolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterdininyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, Purifying carbonyl, indazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, fentanyl, cyclohexanone carbonyl, bicyclo heptanyl, bicyclo fentanyl, non-cyclohexanone carbonyl, bicyclo heptanyl, phenyl C _{1 -5} alkyl, Peutil C _{1 -5} alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heterocyclyl, aryloxy, nitro, amino, mono- or di- ( C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heterocyclyl, amino, NH ₂ C (O), mono- or di - (C _{1 -3} alkyl) amino carbonyl, C _{1 -5} alkyl, -C (O) -C _{1 -4} alkyl, amino -C _{1 -5} alkyl, mono- or di - (C _{1 -3} alkyl) amino -C _{1 -5} alkyl, amino, -S (O) _2, di - (C _1-3 alkyl) amino ^{_{-S (O) 2, R 7}} -C 1 -5 alkyl, R ⁸ -C _{1 -5} ^{alkoxy, R 9 -C (O) -C} 1 -5 alkyl, R ¹⁰ -C _{1 -5} alkyl (R ¹¹⁾ N, carboxy-mono-or di - (C _{1 -5-alkyl)} amino optionally substituted phenyl, naphthyl, or heterocyclyl with;

Fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or cyclopentenopyridine, cyclohexanopyridine, cyclopentano Pyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclopentanoindole, cyclohexanoindole, cyclobenzimidazole, cyclopentanoimidazole, cyclohexanoimida Fused heterocycles selected from sol, cyclopentanothiophene and cyclohexanothiophene (the fused aryl or fused heterocyclic ring may optionally be phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrida) Genyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazole ,-Triazolyl, isothiazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heteroaromatic heterocyclyl-oxy, heteroaryl, aryloxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino, NH ₂ C (O), mono- di or - (C _{1 -3} alkyl) amino carbonyl, C _{1 -4} alkyl, -C (O), C _{1 -5} alkyl amino -S (O) _2, mono- or di - (C _{1 -3} alkyl) amino -C _1-5 alkyl, R ¹² -C _{1 -5} alkyl, R ¹³ -C _{1 -5} ^{alkoxy, R 14 -C (O) -C} 1 -5 alkyl, R ¹⁵ -C _{1 -5} alkyl (R ¹⁶ ) independently substituted with 1 to 3 groups selected from N);

Optionally partially or fully halogenated, one to three optionally partially or completely halogenated C _{1 -3} alkyl, cyano, hydroxy C _{1 -3} alkyl or aryl optionally substituted by cyclopropyl, cyclobutyl to, fentanyl cycloalkyl, Cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, or one to three ring methylene groups are represented by O, S (O) _m , CHOH, C = O, C = S or NH Analogs of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, independently substituted by;

Each optionally substituted with 1 to 3 C _{1 -3} alkyl cyclopentenyl, cyclohexenyl, cyclohexanone dienyl, bicyclo heptenyl, bicyclo hepta-dienyl, non-cyclohexenyl, bicyclo heptenyl;

C _{1 -4} alkyl, or alkylene-phenyl -C (O) -C _{0 -4} alkyl or alkylene, C _{1 -4} alkyl or alkylene -C (O) -C _0-4 alkyl, or alkylene, C _{1 -4} alkyl, or alkylene-phenyl -S (O) _m -C _{0 -4} alkyl or alkylene;

Each optionally partially or fully halogenated, or R ^17, amino, OR ^18, or R ¹⁹ with an optionally substituted C _{1 -5} mono- or di-optionally substituted C _{1 -6} alkyl, C _{1 -6} alkoxy, alkylamino ;

Optionally partially or fully halogenated, one to three optionally partially or fully halogenated C _{1 -3} alkyl group optionally substituted by cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyloxy, cyclohexyloxy, cyclo-heptyloxy (where , 1 to 3 ring methylene groups are independently replaced by O, S (O) _m , CHOH, C═O, C═S or NH);

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 ) —;

^{R 23 R 24 NC (O)} - in a C _{2 -6} alkenyl optionally substituted;

Optionally partially or completely halogenated C _{2 -6-alkynyl} branched or unbranched carbon chain (wherein one or more of the methylene groups is optionally replaced by O, is optionally replaced by an NH or S (O) _m, wherein the alkynyl group optionally 0-2 two oxo groups, pyrrolidinyl, pyrrolyl, one or more by one or more halogen atoms, optionally substituted C _{1 -4} branched or unbranched alkyl, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl , being independently substituted with phenyl, pyridinyl, tetrazolyl or one or more of a halogen atom, optionally substituted C _{1 -4} branched or unbranched alkyl-amino); or

Benzoyl or naphthoyl,

Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁹ and R ²⁵ are each independently cyano, morpholino, piperidinyl, pipe piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or an optionally partially or completely halogenated mono- or di - (C _{0 -4} alkyl) amino;

R ¹¹ and R ¹⁶ are each independently hydrogen, or an optionally partially or completely halogenated C _{1 -4} minutes, branched or unbranched alkyl;

R ¹⁸ is independently hydrogen, or an optionally oxo-substituted C _{1 -4,} or independently, branched or unbranched alkyl as R ^25.

In some of the foregoing embodiments of Group 2 compounds of Formula IA, R ³ is each independently, each optionally optionally partially or fully halogenated, and 1-3 phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyri Dazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetra Zolyl, Isothiazolyl, Quinolyl, Isoquinolyl, Indolyl, Benzimidazolyl, Benzofuranyl, Benzoxazolyl, Benzoisoxazolyl, Benzpyrazolyl, Benzothiofuranyl, Cinnolinyl, Putrindinyl , phthalazine possess, naphthyl, pyridinyl, quinoxalinyl carbonyl, quinazolinyl, Fourier carbonyl, indazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, fentanyl , Cyclohexanyl, cycloheptanyl, bicyclo Fentanyl, non-cyclohexanone carbonyl, bicyclo heptanyl, phenyl C _{1 -5} alkyl, naphthyl C _{1 -5} alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy , naphthyloxy, heterocyclyl, aryloxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heterocyclyl, amino, NH ₂ C (O), mono- or di - (C _{1 -3} alkyl) amino carbonyl, C _{1 -5} alkyl, -C (O) -C _{1 -4} alkyl, -C _1-5 alkyl, amino, mono- or di - (C _{1 -3} alkyl) amino -C _{1 -5} alkyl, amino, -S (O) _2, di - (C _{1 -3} al Kiel) amino ^{_{-S (O) 2, R 7}} -C 1 -5 alkyl, R ⁸ -C _{1 -5} ^{alkoxy, R 9 -C (O) -C} 1 -5 alkyl, R ¹⁰ -C _{1 -5} alkyl (R ¹¹⁾ N, or carboxy-mono- or di-(C _{1 -5-alkyl)} amino optionally substituted Phenyl, naphthyl or heterocyclyl. In the other embodiments, R ³ are each optionally partially or fully halogenated, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, hydroxy, oxo, cyano, optionally partially or fully halogenated a C _{1 -3} alkoxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino optionally substituted phenyl, pyridazinyl or pyridyl; Each optionally partially or fully halogenated, or R ^17, amino, OR ^18, R ¹⁹ optionally substituted with C _{1 -5-mono-} or di-alkyl amino, optionally substituted C _{1 -6} alkyl, C _{1 -6} alkoxy; 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 ) —.

In some embodiments of Group 2 compounds of Formula (IA), X is C═O.

In certain embodiments of Group 2 compounds of Formula (IA), Ar is-(Y) -naphthyl-, Y is -C (O)-or -C (= NOH)-, G is phenyl, pyridinyl, Pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl. In other embodiments, Ar is-(Y) -naphthyl-, Y is -C (O)-or -C (= NOH)-and G is phenyl or pyridyl. Wherein in some embodiments, R ¹ is each independently a substituted or unsubstituted linear or branched C _{1 -10} alkyl ring, R ³ are each independently ^{R 23 R 24 NC (O)} -, R 20 -C (O ) -NR ²¹ -or OR ²² . In some of the above embodiments, R ² is each independently —NR′SO ₂ R ″, —Cl, —Br, —F, —C (O) —NR ′ ₂ , substituted or unsubstituted linear or branched C _{1 -6} alkyl, -NR ' ₂ , or -OR'.

In another embodiment of Group 2 compounds of Formula (IA), Ar is-(Y) -naphthyl-, Y is -C (O)-or -C (= NOH)-and G is pyrazolyl, thienyl Or isoxazolyl. In some of the above embodiments, R ¹ is each independently substituted or unsubstituted linear or branched C _1-10 alkyl, and R ³ is each independently 1, 2 or 3 -F, -Cl, substituted or unsubstituted hwandoen C _{1 -6} branched or a C _{1 -4} alkoxy optionally substituted unbranched alkyl, substituted or unsubstituted, can be a phenyl or a pyridinyl imidazol.

According to another aspect of the present invention, a second group of compounds of Formula (IB), stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof are provided.

<Formula IB>

Where

X is C (O) or C (S),

G is G '- (Y) -, wherein G' is C _{3 -10} carbocyclyl, 5-8-membered monocyclic heterocyclyl, or 8-11, except for indolyl won bicyclic heterocyclyl (O , Containing one or more heteroatoms selected from N or S), substituted by one or more R ¹ , R ² or R ³ ,

Ar is bicyclic aryl or 8-11 membered bicyclic heteroaryl (containing one or more heteroatoms selected from O, N or S), optionally substituted with one or more R ⁴ or R ⁵ ,

Y is independently -C (O)-, -C (NNRC (O) OR)-, -C (NNRR)-, -C (NNC (O) NRR) or -C (NOR)-,

L is a covalent bond or a saturated or unsaturated branched or unbranched C _1-10 carbon chain, wherein one or more methylene groups are optionally replaced independently by heteroatoms selected from O, NR and S (O) _m , L is optionally substituted with 0 or 2 oxo groups and one or more C _1-4 branched or unbranched alkyl optionally substituted by one or more F, Cl, Br or I,

m is each independently 0, 1 or 2,

Q is hydrogen, -NR'R ', cycloalkyl, aryl, heterocyclyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, and -S (O) _m, or phenyl, -S (O) _m, wherein the cycloalkyl, , aryl, heterocyclyl, C _{1 -6} alkoxy, C _1-6 alkyl, -S (O) _m, or phenyl, -S (O) _m optionally substituted with one or more R ^27, respectively, with the proviso that R ⁴ and R ⁵ In the absence of -LQ is not -H,

R are each independently hydrogen, or substituted or unsubstituted C _{1 -6} alkyl ring,

R 'is independently hydrogen, substituted or unsubstituted C _{1 -8} alkyl, substituted or unsubstituted (C _{0 -4} alkyl) - (C _{6 -10} aryl) or substituted or unsubstituted (C _0-4 alkyl) - (5-10 member heterocyclyl), and

R ¹ are each independently F, Cl, Br, I, cyano, -C (O) R, -C (O) NR ₂ , -C (O) OR, -OR, -NR'R ',- _{SiR 3, -S (O) m} R, substituted or unsubstituted linear or branched C _{1 -10} alkyl, C _2-10 alkenyl ring, or a C _{2 -10} alkynyl, substituted or unsubstituted C _{3 - 10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl or heterocyclyl Alkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ),

R ^2, R ⁴ and R ⁵ are each independently selected from F, Cl, Br, I, cyano, substituted or unsubstituted linear or branched unsubstituted C _{1 -6} alkyl, a substituted or unsubstituted C _{6 -10} aryl, Substituted or unsubstituted 5-10 membered heteroaryl, -OR ', -OR ⁶ , -C (O) R', -C (O) OR ', -C (O) NR' ₂ , -NR ' ₂ , -NO ₂ , -S (O) _m R ", NR'SO ₂ R", -NR'C (O) NR'R ', -NR'C (S) NR'R', -NR'C ( O) OR 'or -SO ₂ NR' ₂ ,

R "are each independently a substituted or unsubstituted C _{1 -8} alkyl, substituted or unsubstituted ring with C ₀ -C _{6 -10 -4} alkyl aryl or substituted or unsubstituted (C _{0 -4} alkyl) - (5-10 membered heterocyclyl),

R ³ are independently selected from each independently represent a substituted or unsubstituted C _{6 -10} aryl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl, or heterocyclylalkyl (N, O, S (O) _m a selected one, two, three, or containing from 4 heteroatoms), a a substituted or unsubstituted C _{3 -12} cycloalkyl, substituted or unsubstituted C _{5 -12} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted linear or branched C _{1 -8} ^{alkyl, 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 26 C (O) (CH 2) m N (R 21) -, a substituted or unsubstituted C _{2 -8} alkenyl, or a substituted or unsubstituted C _2-8 alkynyl, the above C _{1 -8} alkyl, C _{2 -8} alkenyl, or C _{2 -8} least one methylene group is O, NH or S (O) alkynyl of _m Arbitrarily replaced

R ⁶ are each optionally partially or fully halogenated, and optionally substituted C _{1 -6} branched or unbranched alkyl as R ^26,

Each R ²⁶ is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or optionally partially or fully halogenated mono- or di- (C _{0- ) 4} alkyl) amino,

R ²⁰ is a substituted or unsubstituted C _{1 -10} alkyl, substituted or unsubstituted C _{0 -6} alkyl-phenyl, a substituted or unsubstituted C _{0 -6} alkyl-heterocyclyl, OR 'or NR' ₂ ,

R ²¹ is hydrogen, or an optionally partially or completely halogenated C _{1 -4} branched or unbranched alkyl,

R ^22, R ²³ and R ²⁴ are each independently hydrogen, (which here, C _{1 -10} alkyl, optionally via one or more O, N or S) substituted or unsubstituted C _{1 -10} alkyl, substituted or unsubstituted C _{0 -6} alkyl-phenyl, substituted or unsubstituted C _{0 -6} alkyl-, or heterocyclyl, or R ²³ and R ²⁴ and are optionally form a heterocyclic or heteroaryl ring together,

R ²⁷ are each independently F, Cl, Br, I, cyano, -C (O) R ', -C (O) NR' ₂ , -C (O) OR ', -OR', -NR ' _{R ', -SiR' 3, -S} (O) m R ', substituted or unsubstituted linear or branched unsubstituted C _1-10 alkyl, C _{2 -10} alkenyl, or C _{2 -10} alkynyl, substituted or unsubstituted C _{3 -10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _7-20 aralkyl, substituted or unsubstituted 3-11 membered heterocyclyl Or heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ),

Provided that the compound of formula (IB) is not 2- [6- (2-biphenyl-4-yl-2-oxo-acetylamino) -indol-1-ylmethyl] -benzoic acid.

In certain embodiments of Group 2 compounds of Formula (IB), the compound inhibits at least about 50% of TNFα-release derived from cells at 10 μM concentration.

In some embodiments of Group 2 compounds of Formula (IB), G ′ is

Phenyl, naphthyl, cyclopropyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran-3-one;

Pyrazolyl, pyrrolyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydro Quinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, Dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazoloyl, 4H-benzo [1,4] oxazine-3-onyl, benzodioxolyl, benzo [1,3] dioxol-2-onyl, tetra Hydrobenzopyranyl, indolyl, indolinyl, indolinyl, indolinonyl, phthalimidyl;

Pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxydyl, oxazolinyl, Thiazolinyl, imidazolinyl, tetrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl , Dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or ditianyl.

In another embodiment of Group 2 compounds of Formula (IB), G ′ is phenyl, naphthyl, cyclopropyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, Nil, indenyl or benzofuran-3-one. In another embodiment, G 'is pyrazolyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyri Midinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazoloyl, benzo [ 1,4] oxazine-3-onyl, benzodioxolyl, benzo [1,3] dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolinyl, indolinonyl or phthalimide It's a deal. Alternatively, G 'is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxy Dill, oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tetrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoqui Nolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or ditianyl. In another embodiment, G 'is phenyl, naphthyl, cyclopropyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thier Nil or pyridinyl.

In certain embodiments of Group 2 compounds of Formula (IB), Y is -C (O)-, -C (NNRC (O) OR)-or -C (NOR)-.

In certain embodiments of Group 2 compounds of Formula (IB), Ar is naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl or azulenyl. Alternatively, Ar is indazolyl, isoindoleyl, quinolinyl, isoquinolinyl, phthalazinyl, indolyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl , Dihydroisoindolyl, benzimidazolyl, benzothienyl, benzothiazolyl, benzoisothiazolyl or benzoisothiazolyl dioxide.

In certain embodiments of Group 2 compounds of Formula (IB), one or more methylene groups of L are independently replaced by a heteroatom selected from O, N or S (O) _m . Alternatively, L is a covalent bond, C ₁ -C ₉ alkoxy, —C (O) O—, —NH— or —O—.

In certain embodiments of Group 2 compounds of Formula (IB), Q is hydrogen, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, fura Neil, thienyl, pyranyl, naphthylpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolo [3,4-b] pyrimidinyl, purinyl, pyrrolo [2,3 -b] pyridinyl, pyrazolo [3,4-b] pyridinyl, tubassidinyl, oxazo [4,5-b] pyridinyl, or imidazo [4,5-b] pyridinyl, tetrahydro Pyranyl, tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, p Ferrazinyl, piperazinoyl, oxazinyl, diazepanonyl, piperidinyl, piperidinyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, Pentamethyl Alkylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone, C _{1 -6} alkoxy, (where secondary or tertiary amine, an amino nitrogen is covalently bonded to the C _{1 -3} alkyl, C _{1 -5} alkyl, alkoxy search), phenyl amino, C _{1 -6} alkyl, -S (O) _m -phenyl or -S (O) _m. In the some embodiments, R ²⁷ is C _{1 -6} alkyl, C _{1 -6} alkoxy, hydroxy, amino, substituted or unsubstituted 5-10 member heterocyclyl, mono-or di - (C _{1 -3} alkyl ) amino, mono- or di- (phenyl -C _{1 -3} alkyl) amino, C _{1 -6} alkyl, -S (O) _m, -C _{1 -3-phenyl-alkoxy} or phenylamino (wherein the phenyl ring is 1 to 2 is halogen, C _{1 -6} optionally substituted by alkyl or C _1-6 alkoxy).

In another embodiment of Group 2 compounds of Formula (IB), Q is hydrogen, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinoyl, oxazinyl, diazepinonyl, imidazolyl, pyridinyl Or morpholino. In another embodiment, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. The In some embodiments, R ²⁷ is -C (O) OR ', -NR'R ', substituted or unsubstituted linear or branched C _{1 -10} alkyl, ring substituted or unsubstituted C _{7 -20} aralkyl Or substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl or heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ) to be. For example, Q is pyrimidinyl and R ²⁷ is independently selected from -NR'R ', or substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl (N, O, S (O) _m Containing 1, 2, 3 or 4 heteroatoms). Alternatively, Q is a pyridinyl, R ²⁷ is -NR'R ', substituted or unsubstituted C _{1 -6} alkyl, or a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl or heterocyclyl Alkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ).

In certain embodiments of group 2 compounds of Formula (IB), each R ¹ is independently

Optionally partially or fully halogenated, 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, Thienyl, furyl, isoxazolyl or isothiazolyl (these are 1 to 5 halogens, optionally partially or fully halogenated C _1-6 branched or unbranched alkyl, C _3-8 cycloalkyl, C _5-8 Optionally substituted with cycloalkenyl, hydroxy, cyano, optionally partially or fully halogenated C _1-3 alkoxy and NH ₂ C (O) or mono- or di- (C _1-3 alkyl) aminocarbonyl) C _3-10 branched or unbranched alkyl optionally substituted with;

Optionally partially or fully halogenated, one to three optionally partially or completely halogenated C _{1 -3} alkyl, cyano, hydroxy C _{1 -3} alkyl or aryl optionally substituted by cyclopropyl, cyclobutyl to, fentanyl cycloalkyl, Cyclohexanyl, cycloheptanyl, bicyclohexanyl or bicycloheptanyl, or 1 to 3 ring methylene groups are independently replaced by O, S (O) _m , CHOH, C═O, C = S or NH Analogs of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl;

Optionally partially or fully halogenated, one to three C _{1 -5} branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl thiazolyl, thienyl, furyl, isoxazolyl, isothiazolyl (the abovementioned groups are each optionally partially or fully halogenated), optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopropyl fentanyl, cyclohexanone carbonyl, bicyclo heptanyl, bicyclo fentanyl, non-cyclohexanone carbonyl or bicyclo heptanyl, hydroxy, cyano, an optionally partially or completely halogenated C _{1 -3} alkoxy, NH ₂ C (O) or a mono- or di - (C _{1 -3} alkyl) amino-carboxylic alkenyl optionally substituted C _{3 -10} branched or unbranched (herein, C _{3 -10} branched or unbranched alkenyl group is one More than O, N or S (O) _m is optionally interrupted);

Each optionally substituted with one to three C _{1 -3} alkyl substituted cyclopentenyl, cyclohexenyl, cyclohexanone dienyl, bicyclo heptenyl, bicyclo hepta-dienyl, non-cyclohexenyl or bicyclo heptenyl;

Cyano, F, Cl, Br or I;

Methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;

Silyl optionally partially or fully halogenated branched to three C _{1 -4} independent or containing a non-branched alkyl group;

C _{2 -6} branched or unbranched alkyl, -C (O), C _{2 -6} branched or unbranched -S, C _{2 -6} branched or unbranched -S (O), C _{2 -6} branched or Unbranched-S (O) ₂ ;

Optionally partially or completely halogenated C _{2 -6} branched or unbranched alkynyl group (where one or more of the methylene groups is optionally replaced by O, NH and S (O) _m, wherein the alkynyl group optionally 0-2 oxo groups, pyrrolidinyl, pyrrolyl, one or more by one or more halogen atoms, optionally substituted C _{1 -4} branched or unbranched alkyl, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl is pyridinyl, tetrazolyl, or being independently substituted with one or more of a halogen atom, optionally substituted C _{1 -4} branched or unbranched alkylamino).

In other embodiments, each R ¹ is independently, optionally partially or fully halogenated, and 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyrida Genyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of which is 1 to 5 halogens, optionally partially or fully halogenated C _1-6 branched or unbranched alkyl , C _3-8 cycloalkyl, C _5-8 cycloalkenyl, hydroxy, cyano, optionally substituted or partially halogenated C _1-3 alkoxy and NH ₂ C (O) or mono- or di- (C ₁ C _3-10 branched or unbranched alkyl optionally substituted with _-3 alkyl) optionally substituted with aminocarbonyl). For example, each R ¹ is independently C _3-10 branched or unbranched alkyl.

In certain embodiments of Group 2 compounds of Formula (IB), each R ² is independently —OR ′, —OR ⁶ , —C (O) R ′, —C (O) OR ′, —C (O) NR ′ ₂ , -NR ' ₂ , -NO ₂ , -S (O) _m R ", -NR'SO ₂ R", -NR'C (O) NR'R', -NR'C (S) NR'R ', -NR'C (O) OR' or -SO ₂ NR ' ₂ . In other embodiments, R ² is each independently —NR ′ ₂ , —NO ₂ , —C (O) NR ′ ₂ , —NR′SO ₂ R ″, —NR′C (O) NR′R ′, — NR'C (S) NR'R ', -NR'C (O) OR' or -SO ₂ NR ' ₂ .

In certain embodiments of Group 2 compounds of Formula (IB), each R ³ is independently

Hydrogen or each optionally optionally partially or completely halogenated, 1-3 phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione , Imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimida Zolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterridinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, fury carbonyl, indazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, fentanyl, cyclohexanone carbonyl, bicyclo heptanyl, bicyclo fentanyl, non-cyclohexanone carbonyl, non- bicyclo heptanyl, phenyl C _{1 -5} alkyl, naphthyl C _{1 -5} alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heterocyclyl, aryloxy, nitro, amino, mono- or di - (C _1-3 alkyl) amino, phenylamino, naphthylamino, heterocyclyl, amino, NH ₂ C (O), mono- or di - (C _1-3 alkyl) amino carbonyl, C _{1 -5-alkyl-C} ( O) -C _{1 -4} alkyl, -C _1-5 alkyl, amino, mono- or di - (C _{1 -3} alkyl) amino -C _{1 -5} alkyl, amino, -S (O) _2, di - (C _{1 -3} alkyl) amino ^{_{-S (O) 2, R 7}} -C 1 -5 alkyl, R ⁸ -C _{1 -5} ^{alkoxy, R 9 -C (O) -C} 1 -5 alkyl, R ¹⁰ -C _{1 - 5} alkyl (R ¹¹⁾ N, carboxy-mono-or di - (C _{1 -5-alkyl)} amino optionally substituted phenyl, naphthyl, or heterocyclyl with;

Fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or cyclopentenopyridine, cyclohexanopyridine, cyclopentano Pyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclopentanoindole, cyclohexanoindole, cyclobenzimidazole, cyclopentanoimidazole, cyclohexanoimida Fused heterocycles selected from sol, cyclopentanothiophene and cyclohexanothiophene (the fused aryl or fused heterocyclic ring may optionally be phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl , Pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazole , Triazolyl, isothiazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heteroaromatic heterocyclyl-oxy, heteroaryl, aryloxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino, phenylamino, naphthyl amino furnace, a heterocyclic or heteroaryl amino, NH ₂ C (O), mono or di - (C _{1 -3} alkyl) amino carbonyl, C _{1 -4} alkyl, -C (O), C _{1 -5} alkyl amino -S (O) _2, mono- or di - (C _{1 -3} alkyl ) amino -C _1-5 alkyl, R ¹² -C _{1 -5} alkyl, R ¹³ -C _{1 -5} ^{alkoxy, R 14 -C (O) -C} 1 -5 alkyl, R ¹⁵ -C _{1 -5} alkyl ( R ¹⁶ ) independently substituted with one to three groups selected from N);

Optionally partially or fully halogenated, one to three optionally partially or completely halogenated C _{1 -3} alkyl, cyano, hydroxy C _{1 -3} alkyl or aryl optionally substituted by cyclopropyl, cyclobutyl to, fentanyl cycloalkyl, Cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, or one to three ring methylene groups are represented by O, S (O) _m , CHOH, C = O, C = S or NH Analogs of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, independently substituted by;

Each optionally substituted with 1 to 3 C _{1 -3} alkyl cyclopentenyl, cyclohexenyl, cyclohexanone dienyl, bicyclo heptenyl, bicyclo hepta-dienyl, non-cyclohexenyl, bicyclo heptenyl;

C _{1 -4} alkyl, or alkylene-phenyl -C (O) -C _{0 -4} alkyl or alkylene, C _{1 -4} alkyl or alkylene -C (O) -C _0-4 alkyl, or alkylene, C _{1 -4} alkyl, or alkylene-phenyl -S (O) _m -C _{0 -4} alkyl or alkylene;

Each optionally partially or fully halogenated, or R ^17, amino, OR ^18, or R ¹⁹ with an optionally substituted C _{1 -5} mono- or di-optionally substituted C _{1 -6} alkyl, C _{1 -6} alkoxy, alkylamino ;

Optionally partially or fully halogenated, one to three optionally partially or fully halogenated C _{1 -3} alkyl group optionally substituted by cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyloxy, cyclohexyloxy, cyclo-heptyloxy (where , 1 to 3 ring methylene groups are independently replaced by O, S (O) _m , CHOH, C═O, C═S or NH);

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 ) —;

^{R 23 R 24 NC (O)} - in a C _{2 -6} alkenyl optionally substituted;

Optionally partially or completely halogenated C _{2 -6-alkynyl} branched or unbranched carbon chain (wherein one or more of the methylene groups is optionally replaced by O, is optionally replaced by an NH or S (O) _m, wherein the alkynyl group optionally 0-2 two oxo groups, pyrrolidinyl, pyrrolyl, one or more C _{1 -4} the bun by one or more halogen atoms, optionally substituted branched or unbranched al Kiel, nitrile, morpholino, piperidinyl, piperazinyl, already being independently substituted with thiazolyl, phenyl, pyridinyl, tetrazolyl or one or more of a halogen atom, optionally substituted C _{1 -4} branched or unbranched alkyl-amino); or

Benzoyl or naphthoyl,

Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁹ and R ²⁵ are each independently cyano, morpholino, piperidinyl, pipe piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or an optionally partially or completely halogenated mono- or di - (C _{0 -4} alkyl) amino;

R ¹¹ and R ¹⁶ are each independently hydrogen, or an optionally partially or completely halogenated C _{1 -4} minutes, branched or unbranched alkyl;

R ¹⁸ is independently hydrogen, or an optionally oxo-substituted C _{1 -4,} or independently, branched or unbranched alkyl as R ^25.

In some of the above embodiments, R ³ is each independently, each optionally partially or fully halogenated, and 1-3 phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrroly Diyl, 2,5-pyrrolidine-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl , Isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, putrindinyl, phthalazinyl, naphthylpyri pyridinyl, quinoxalinyl carbonyl, quinazolinyl, Fourier carbonyl, indazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, fentanyl, cyclohexanone carbonyl, cycloalkyl heptanyl , Bicyclopentanyl, bicyclohexanyl, non Bicyclo heptanyl, phenyl C _{1 -5} alkyl, naphthyl C _{1 -5} alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heterocyclyl alkyloxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heterocyclyl, amino, NH ₂ C (O), mono- or di - (C _{1 -3} alkyl ) aminocarbonyl, C _{1 -5} alkyl, -C (O) -C _{1 -4} alkyl, amino -C _{1 -5} alkyl, mono- or di - (C _{1 -3} alkyl) amino -C _1-5 alkyl, amino -S (O) _2, di - (C _{1 -3} alkyl) amino ^{_{-S (O) 2, R 7}} -C 1 -5 alkyl, R ⁸ -C _1-5 alkoxy, R ⁹ -C (O) -C _{1 -5} alkyl, R ¹⁰ -C _{1 -5} alkyl (R ¹¹⁾ N, or carboxy-mono- or di - (C _1-5 alkyl) amino optionally is substituted phenyl, naphthyl or heterocyclyl, . In the other embodiments, R ³ are each optionally partially or fully halogenated, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, hydroxy, oxo, cyano, optionally partially or fully halogenated a C _{1 -3} alkoxy, nitro, amido no, mono- or di - (C _{1 -3} alkyl) amino optionally substituted phenyl, pyridazinyl or pyridyl; Each optionally partially or fully halogenated, or R ^17, amino, OR ^18, R ¹⁹ optionally substituted with C _{1 -5} mono- or di-alkylamino optionally substituted by C _{1 -6} alkyl, or C _1-6 alkoxy; 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 ) —.

In some embodiments of Group 2 compounds of Formula (IB), X is C═O.

In certain embodiments of Group 2 compounds of Formula (IB), Ar is naphthyl, G is G '-(Y)-, Y is -C (O)-or -C (= NOH)-, and G' Is selected from phenyl, pyridinyl, pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl. In other embodiments, Ar is naphthyl, G is G '-(Y)-, Y is -C (O)-or -C (= NOH)-and G' is one or more R ¹ , R ² Or phenyl or pyridinyl substituted by R ³ . In the some embodiments, R ¹ is each independently a substituted or unsubstituted linear or branched C _{1 -10} alkyl ring. Here, R ³ may be each independently R ²³ R ²⁴ NC (O) —, R ²⁰ —C (O) —NR ²¹ — or OR ²² . In said other embodiments, each R ² is independently —NR′SO ₂ R ″, —Cl, —Br, —F, —C (O) —NR ′ ₂ , substituted or unsubstituted linear or branched C _{1 -6} alkyl, -NR ' ₂ , or -OR'.

In another embodiment of Group 2 compounds of Formula (IB), Ar is naphthyl, G is G '-(Y)-, wherein Y is selected from -C (O)-or -C (= NOH)- , G 'is pyrazolyl, isoxazolyl or furanyl substituted by one or more R ¹ , R ² or R ³ . In the some embodiments, R ¹ is each independently a substituted or unsubstituted linear or branched C _{1 -10} alkyl ring. Here, R ³ are each independently optionally substituted with one to three -F, -Cl, with a substituted or unsubstituted C _{1 -6} branched or unbranched alkyl, or substituted or unsubstituted C _{1 -4} alkoxy , may be a substituted or unsubstituted C _{1 -6} alkyl, phenyl or pyridinyl.

According to another aspect of the present invention, there is provided a third group of compounds of formula (IA), stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof.

<Formula IA>

Where

X is C (O) or C (S),

G is C _{3 -5} cycloalkyl, pyrazolyl, thiazolyl, oxazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyrrolinyl, pyridazinyl, pyrrolyl, imidazolyl, imidazole carbonyl movement speed Sazolyl, furanyl, thienyl, pyridonyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indanyl, indenyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolin Neyl, tetrahydroisoquinoyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothio Phenyl, benzoxazoloyl, 4H-benzo [1,4] oxazin-3-onyl, benzodioxolyl, benzo [1,3] dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl , Indolinyl, indolinonyl, phthalimidyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazin Nil, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxydyl, oxazolinyl, thiazolinyl, imidazolinyl, tetrahydropyridinyl, homopiperidinyl, pipe Rollinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxa Nil or ditianyl, substituted by one or more R ¹ , R ² or R ³ ,

Ar is - (Y) - (C _{0 -3} alkyl) - (phenyl), or - (Y) - (C _{0 -3} alkyl) -, and (monocyclic heteroaryl), with one or more R ⁴ or R ⁵ Optionally substituted,

Y is -C (O)-, -C (NNRC (O) OR)-, -C (NNRR)-, -C (NNC (O) NRR) or -C (NOR)-,

L is a covalent bond or a saturated or unsaturated branched or unbranched C _1-10 carbon chain, wherein one or more methylene groups are optionally replaced independently by heteroatoms selected from O, NR and S (O) _m , L is optionally substituted with 0 or 2 oxo groups and one or more C _1-4 branched or unbranched alkyl optionally substituted by one or more F, Cl, Br or I,

m is each independently 0, 1 or 2,

Q is hydrogen, -NR'R ', cycloalkyl, aryl, heterocyclyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, and -S (O) _m, or phenyl, -S (O) _m, wherein the cycloalkyl, , aryl, heterocyclyl, C _{1 -6} alkoxy, C _1-6 alkyl, -S (O) _m, or phenyl, -S (O) _m optionally substituted with one or more R ^27, respectively, with the proviso that R ⁴ and R ⁵ In the absence of -LQ is not -H,

R are each independently hydrogen, or substituted or unsubstituted C _{1 -6} alkyl ring,

R 'is independently hydrogen, substituted or unsubstituted C _{1 -8} alkyl, substituted or unsubstituted (C _{0 -4} alkyl) - (C _{6 -10} aryl) or substituted or unsubstituted (C _0-4 alkyl) - (5-10 member heterocyclyl), and

R ¹ are each independently F, Cl, Br, I, cyano, -C (O) R, -C (O) NR ₂ , -C (O) OR, -OR, -NR'R ', -SiR _{3, -S (O) m R} , substituted or unsubstituted linear or branched C _{1 -10} alkyl, C _2-10 alkenyl, or C _{2 -10} alkenyl, a substituted or unsubstituted C _{3 -10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl or heterocyclylalkyl (Containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ),

R ^2, R ⁴ and R ⁵ are each independently selected from F, Cl, Br, I, cyano, substituted or unsubstituted linear or branched unsubstituted C _{1 -6} alkyl, a substituted or unsubstituted C _{6 -10} aryl, Substituted or unsubstituted 5-10 membered heteroaryl, -OR ', -OR ⁶ , -C (O) R', -C (O) OR ', -C (O) NR' ₂ , -NR ' ₂ , -NO ₂ , -S (O) _m R ", -NR'SO ₂ R", -NR'C (O) NR'R ', -NR'C (S) NR'R', -NR'C (O) OR 'or -SO ₂ NR' ₂ ,

R "are each independently a substituted or unsubstituted C _{1 -8} alkyl, substituted or unsubstituted ring with C ₀ -C _{6 -10 -4} alkyl aryl or substituted or unsubstituted (C _{0 -4} alkyl) - (5-10 membered heterocyclyl),

R ³ are independently selected from each independently represent a substituted or unsubstituted C _{6 -10} aryl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl, or heterocyclylalkyl (N, O, S (O) _m a selected one, two, three, or containing from 4 heteroatoms), a a substituted or unsubstituted C _{3 -12} cycloalkyl, substituted or unsubstituted C _{5 -12} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted linear or branched C _{1 -8} ^{alkyl, 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 26 C (O) (CH 2) m N (R 21) -, a substituted or unsubstituted C _{2 -8} alkenyl, or a substituted or unsubstituted C _2-8 alkynyl, a C _{1 -8} alkyl, C _{2 -8} alkenyl or C ₂ at least one of the methylene _-8 alkynyl group by O, NH or S (O) _m Arbitrarily replaced,

R ⁶ are each optionally partially or fully halogenated, and optionally substituted C _{1 -6} branched or unbranched alkyl as R ^26,

Each R ²⁶ is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or optionally partially or fully halogenated mono- or di- (C _{0- ) 4} alkyl) amino,

R ²⁰ is a substituted or unsubstituted C _{1 -10} alkyl, substituted or unsubstituted C _{0 -6} alkyl-phenyl, a substituted or unsubstituted C _{0 -6} alkyl-heterocyclyl, OR 'or NR' ₂ ,

R ²¹ is hydrogen, or an optionally partially or completely halogenated C _{1 -4} branched or unbranched alkyl,

R ^22, R ²³ and R ²⁴ are each independently hydrogen, (which here, C _{1 -10} alkyl, optionally via one or more O, N or S) substituted or unsubstituted C _{1 -10} alkyl, substituted or Beach hwandoen ₀ C _{-6-alkyl-phenyl,} substituted or unsubstituted C _{0 -6} alkyl- and or heterocyclyl, or R ²³ and R ²⁴ optionally form a heterocyclic or heteroaryl ring together,

R ²⁷ are each independently F, Cl, Br, I, cyano, -C (O) R ', -C (O) NR' ₂ , -C (O) OR ', -OR', -NR'R _{', -SiR' 3, -S (} O) m R ', substituted or unsubstituted linear or branched unsubstituted C _1-10 alkyl, C _{2 -10} alkenyl, or C _{2 -10} alkenyl, substituted or unsubstituted hwandoen C _{3 -10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _7-20 aralkyl group, a substituted or unsubstituted 3-11 membered heterocyclyl, or Heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ),

Provided that when Ar is phenyl and G is N- (substituted or unsubstituted phenyl) -pyrazolyl, pyrazolyl is further substituted with one or more R ¹ , R ² or R ³ ,

The compound of formula (IA) is not 2- [6- (2-biphenyl-4-yl-2-oxo-acetylamino) -indol-1-ylmethyl] -benzoic acid.

In certain embodiments of Group III compounds of Formula (IA), the compound inhibits at least about 50% of TNFα-release derived from cells at a 10 μM concentration.

In certain embodiments of group III compounds of Formula (IA), G is cyclopropyl, cyclobutyl, or cyclopentyl. In other embodiments, G is cyclopropyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl thiazolyl, oxazolyl, isoxazolyl, furanyl, or thienyl.

In some embodiments of the third group of compounds of formula IA, Ar is - (Y) - (C _{0 -3} alkyl) - (phenyl), and, Y is -C (O) -, -C ( NNRC (O) OR )-Or -C (NOR)-. In some of the above embodiments, Ar is substituted by one or more R ⁴ or R ⁵ . In other embodiments, Ar is-C (O)-(phenyl). In another embodiment, Ar is-(Y)-(C _{0 -3} alkyl)-(monocyclic heteroaryl), and said monocyclic heteroaryl is pyrazolyl, imidazolyl, pyrazolinyl, pyrrolyl , Pyrrolinyl, pyridinyl, pyrimidinyl or pyridazinyl. In some of the above embodiments, Ar is substituted by one or more R ⁴ or R ⁵ . Alternatively, Y is -C (O)-, -C (NNRC (O) OR)-or -C (NOR)-. In another embodiment, Ar is -C (O)-(monocyclic heteroaryl) or -C (NOR)-(monocyclic heteroaryl). For example, the monocyclic heteroaryl may be pyrazolyl, imidazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyrimidyl or pyridazinyl.

In certain embodiments of group III compounds of Formula (IA), one or more methylene groups of L are independently replaced by a heteroatom selected from O, N or S (O) _m . In other embodiments, L is a covalent bond, C ₁ -C ₉ alkoxy, -C (O) O-, -NH-, or -O-.

In certain embodiments of Group III compounds of Formula (IA), Q is hydrogen, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, fura Neil, thienyl, pyranyl, naphthylpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolo [3,4-b] pyrimidinyl, purinyl, pyrrolo [2,3 -b] pyridinyl, pyrazolo [3,4-b] pyridinyl, tubassidinyl, oxazo [4,5-b] pyridinyl, or imidazo [4,5-b] pyridinyl, tetrahydro Pyranyl, tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, p Ferrazinyl, piperazinoyl, oxazinyl, diazepanonyl, piperidinyl, piperidinyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, Pentamethyl Alkylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone, C _{1 -6} alkoxy, (where secondary or tertiary amine, an amino nitrogen is covalently bonded to the C _{1 -3} alkyl, C _{1 -5} alkyl, alkoxy search), phenyl amino, C _{1 -6} alkyl, -S (O) _m -phenyl or -S (O) _m. In the some embodiments, R ²⁷ is C _{1 -6} alkyl, C _{1 -6} alkoxy, hydroxy, amino, substituted or unsubstituted 5-10 member heterocyclyl, mono-or di - (C _{1 -3} alkyl ) amino, mono- or di- (phenyl -C _{1 -3} alkyl) amino, C _{1 -6} alkyl, -S (O) _m, -C _{1 -3-phenyl-alkoxy} or phenylamino (wherein the phenyl ring is 1 to 2 is halogen, C _{1 -6} optionally substituted by alkyl or C _1-6 alkoxy).

In other embodiments, Q is hydrogen, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinoyl, oxazinyl, diazepinyl, imidazolyl, pyridinyl or morpholino. In another embodiment, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. Wherein in some embodiments, R ²⁷ is -C (O) OR ', -NR'R ', substituted or unsubstituted linear or branched C _{1 -10} alkyl, ring substituted or unsubstituted C _{7 -20} aralkyl , Substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl or heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ) . For example, Q is pyrimidinyl and R ²⁷ is independently selected from -NR'R ', or substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl (N, O, S (O) _m Containing 1, 2, 3 or 4 heteroatoms). Alternatively, Q is a pyridinyl, R ²⁷ is -NR'R ', substituted or unsubstituted C _{1 -6} alkyl, or a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl or heterocyclyl Alkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ).

In certain embodiments of group 3 compounds of Formula (IA), each R ¹ is independently

Optionally partially or fully halogenated, 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, Thienyl, furyl, isoxazolyl or isothiazolyl (these are 1 to 5 halogens, optionally partially or fully halogenated C _1-6 branched or unbranched alkyl, C _3-8 cycloalkyl, C _5-8 Optionally substituted with cycloalkenyl, hydroxy, cyano, optionally partially or fully halogenated C _1-3 alkoxy and NH ₂ C (O) or mono- or di- (C _1-3 alkyl) aminocarbonyl) C _3-10 branched or unbranched alkyl optionally substituted with;

Optionally partially or fully halogenated, one to three optionally partially or completely halogenated C _{1 -3} alkyl, cyano, hydroxy C _{1 -3} alkyl or aryl optionally substituted by cyclopropyl, cyclobutyl to, fentanyl cycloalkyl, Cyclohexanyl, cycloheptanyl, bicyclohexanyl or bicycloheptanyl, or 1 to 3 ring methylene groups are independently replaced by O, S (O) _m , CHOH, C═O, C = S or NH Analogs of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl;

Optionally partially or fully halogenated, one to three C _{1 -5} branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl thiazolyl, thienyl, furyl, isoxazolyl, isothiazolyl (the abovementioned groups are each optionally partially or fully halogenated), optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopropyl fentanyl, cyclohexanone carbonyl, bicyclo heptanyl, bicyclo fentanyl, non-cyclohexanone carbonyl or bicyclo heptanyl, hydroxy, cyano, an optionally partially or completely halogenated C _{1 -3} alkoxy, NH ₂ C (O) or a mono- or di - (C _{1 -3} alkyl) amino optionally value carboxylic hwandoen C _{3 -10} bun alkynyl branched or unbranched Al (wherein, C _{3 -10} bun alkenyl is a branched or unbranched More than o , N or S (O) _m is optionally interrupted);

Each optionally substituted with one to three C _{1 -3} alkyl substituted cyclopentenyl, cyclohexenyl, cyclohexanone dienyl, bicyclo heptenyl, bicyclo hepta-dienyl, non-cyclohexenyl or bicyclo heptenyl;

Cyano, F, Cl, Br or I;

Methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;

Silyl optionally partially or fully halogenated branched to three C _{1 -4} independent or containing a non-branched alkyl group;

C _{2 -6} branched or unbranched alkyl, -C (O), C _{2 -6} branched or unbranched -S, C _{2 -6} branched or unbranched -S (O), C _{2 -6} branched or Unbranched-S (O) ₂ ;

Optionally partially or completely halogenated C _{2 -6} branched or unbranched alkynyl group (where one or more of the methylene groups is optionally replaced by O, NH and S (O) _m, wherein the alkynyl group optionally 0-2 oxo groups, pyrrolidinyl, pyrrolyl, one or more by one or more halogen atoms, optionally substituted C _{1 -4} branched or unbranched alkyl, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl is pyridinyl, tetrazolyl, or being independently substituted) with one or more of a halogen atom, optionally substituted C _{1 -4} branched or unbranched amino al keel.

In some other embodiments of Group III compounds of Formula (IA), each R ¹ is independently, optionally partially or fully halogenated, and 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, Pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl (these are each 1 to 5 halogens, optionally partially or fully halogenated C) _1-6 branched or unbranched alkyl, C _3-8 cycloalkyl, C _5-8 cycloalkenyl, hydroxy, cyano, optionally partially or fully halogenated C _1-3 alkoxy and NH ₂ C (O) Or C _3-10 branched or unbranched alkyl optionally substituted with mono- or di- (C _1-3 alkyl) aminocarbonyl). For example, each R ¹ is independently C _3-10 branched or unbranched alkyl.

In certain embodiments of group 3 compounds of Formula (IA), each R ² is independently —OR ′, —OR ⁶ , —C (O) R ′, —C (O) OR ′, —C (O) NR ′ ₂ , -NR ' ₂ , -NO ₂ , -S (O) _m R ", -NR'SO ₂ R", -NR'C (O) NR'R', -NR'C (S) NR'R ', -NR'C (O) OR' or -SO ₂ NR ' ₂ . Alternatively, R ² is each independently —NR ′ ₂ , —NO ₂ , —C (O) NR ′ ₂ , —NR′SO ₂ R ″, —NR′C (O) NR′R ′, —NR ′ C (S) NR'R ', -NR'C (O) OR' or -SO ₂ NR ' ₂ .

In some embodiments of Group 3 compounds of Formula (IA), each R ³ is independently

Hydrogen or each optionally optionally partially or completely halogenated, 1-3 phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione , Imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimida Zolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterridinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, fury carbonyl, indazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, fentanyl, cyclohexanone carbonyl, bicyclo heptanyl, bicyclo fentanyl, non-cyclohexanone carbonyl, non- bicyclo heptanyl, phenyl C _{1 -5} alkyl, naphthyl C _{1 -5} alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heterocyclyl, aryloxy, nitro, amino, mono- or di - (C _1-3 alkyl) amino, phenylamino, naphthylamino, heterocyclyl, amino, NH ₂ C (O), mono- or di - (C _1-3 alkyl) amino carbonyl, C _{1 -5} alkyl, -C ( O) -C _{1 -4} alkyl, -C _1-5 alkyl, amino, mono- or di - (C _{1 -3} alkyl) amino -C _{1 -5} alkyl, amino, -S (O) _2, di - (C _{1 -3} alkyl) amino ^{_{-S (O) 2, R 7}} -C 1 -5 alkyl, R ⁸ -C _{1 -5} ^{alkoxy, R 9 -C (O) -C} 1 -5 al Kiel, R ¹⁰ -C _{1 -5} alkyl (R ¹¹⁾ N, carboxy-mono-or di - (C _{1 -5-alkyl)} amino optionally substituted phenyl, naphthyl, or heterocyclyl with;

Fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or cyclopentenopyridine, cyclohexanopyridine, cyclopentano Pyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclopentanoindole, cyclohexanoindole, cyclobenzimidazole, cyclopentanoimidazole, cyclohexanoimida Fused heterocycles selected from sol, cyclopentanothiophene and cyclohexanothiophene (the fused aryl or fused heterocyclic ring may optionally be phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl , Pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazole , Triazolyl, isothiazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heteroaromatic heterocyclyl-oxy, heteroaryl, aryloxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino, NH ₂ C (O), mono- or di - (C _{1 -3} alkyl) amino carbonyl, C _{1 -4} alkyl, -C (O), C _{1 -5} alkyl amino -S (O) _2, mono- or di - (C _{1 -3} alkyl) Ami no--C _1-5 alkyl, R ¹² -C _{1 -5} alkyl, R ¹³ -C _{1 -5} ^{alkoxy, R 14 -C (O) -C} 1 -5 alkyl, R ¹⁵ -C _{1 -5} alkyl ( R ¹⁶ ) independently substituted with one to three groups selected from N);

Optionally partially or fully halogenated, one to three optionally partially or completely halogenated C _{1 -3} alkyl, cyano, hydroxy C _{1 -3} alkyl or aryl optionally substituted by cyclopropyl, cyclobutyl to, fentanyl cycloalkyl, Cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, or one to three ring methylene groups are represented by O, S (O) _m , CHOH, C = O, C = S or NH Analogs of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, independently substituted by;

Each optionally substituted with 1 to 3 C _{1 -3} alkyl cyclopentenyl, cyclohexenyl, cyclohexanone dienyl, bicyclo heptenyl, bicyclo hepta-dienyl, non-cyclohexenyl, bicyclo heptenyl;

C _{1 -4} alkyl, or alkylene-phenyl -C (O) -C _{0 -4} alkyl or alkylene, C _{1 -4} alkyl or alkylene -C (O) -C _0-4 alkyl, or alkylene, C _{1 -4} alkyl, or alkylene-phenyl -S (O) _m -C _{0 -4} alkyl or alkylene;

Each optionally partially or fully halogenated, or R ^17, amino, OR ^18, or R ¹⁹ with an optionally substituted C _{1 -5} mono- or di-optionally substituted C _{1 -6} alkyl, C _{1 -6} alkoxy, alkylamino ;

Optionally partially or fully halogenated, one to three optionally partially or fully halogenated C _{1 -3} alkyl group optionally substituted by cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyloxy, cyclohexyloxy, cyclo-heptyloxy (where , 1 to 3 ring methylene groups are independently replaced by O, S (O) _m , CHOH, C═O, C═S or NH);

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 ) —;

^{R 23 R 24 NC (O)} - in a C _{2 -6} alkenyl optionally substituted;

Optionally partially or completely halogenated C _{2 -6-alkynyl} branched or unbranched carbon chain (wherein one or more of the methylene groups is optionally replaced by O, is optionally replaced by an NH or S (O) _m, wherein the alkynyl group optionally 0-2 two oxo groups, pyrrolidinyl, pyrrolyl, one or more by one or more halogen atoms, optionally substituted C _{1 -4} branched or unbranched alkyl, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl , being independently substituted with phenyl, pyridinyl, tetrazolyl or one or more of a halogen atom, optionally substituted C _{1 -4} branched or unbranched alkyl-amino); or

Benzoyl or naphthoyl,

Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁹ and R ²⁵ are each independently cyano, morpholino, piperidinyl, pipe piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or an optionally partially or completely halogenated mono- or di - (C _{0 -4} alkyl) amino;

R ¹¹ and R ¹⁶ are each independently hydrogen, or an optionally partially or completely halogenated C _{1 -4} minutes, branched or unbranched alkyl;

R ¹⁸ is independently hydrogen, or an optionally oxo-substituted C _{1 -4,} or independently, branched or unbranched alkyl as R ^25.

In some of the foregoing embodiments of the Group III compound of Formula IA, R ³ is each independently, each optionally optionally partially or fully halogenated, and 1-3 phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyri Dazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetra Zolyl, Isothiazolyl, Quinolyl, Isoquinolyl, Indolyl, Benzimidazolyl, Benzofuranyl, Benzoxazolyl, Benzoisoxazolyl, Benzpyrazolyl, Benzothiofuranyl, Cinnolinyl, Putrindinyl , phthalazine possess, naphthyl, pyridinyl, quinoxalinyl carbonyl, quinazolinyl, Fourier carbonyl, indazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, fentanyl , Cyclohexanyl, cycloheptanyl, bicycle Fentanyl, non-cyclohexanone carbonyl, bicyclo heptanyl, phenyl C _{1 -5} alkyl, naphthyl C _{1 -5} alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy , naphthyloxy, heterocyclyl, aryloxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heterocyclyl, amino, NH ₂ C (O), mono- or di - (C _{1 -3} alkyl) amino carbonyl, C _{1 -5} alkyl, -C (O) -C _{1 -4} alkyl, -C _1-5 alkyl, amino, mono- or di - (C _{1 -3} alkyl) amino -C _{1 -5} alkyl, amino, -S (O) _2, di - (C _{1 -3} alkyl) amino ^{_{-S (O) 2, R 7}} -C 1 -5 alkyl, R ⁸ -C _{1 -5} alkoxycarbonyl ^{, R 9 -C (O) -C} 1 -5 alkyl, R ¹⁰ -C _{1 -5} alkyl (R ¹¹⁾ N, or carboxy-mono- or di-substituted phenyl, optionally with amino (C _{1 -5} alkyl) , Naphthyl or heterocyclyl. In another embodiment, R ³ is, each independently, each optionally partially or fully halogenated, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino optionally substituted phenyl, pyridazinyl or pyridyl; Each optionally partially or fully halogenated, or R ^17, amino, OR ^18, R ¹⁹ optionally substituted with C _{1 -5-mono-} or di-alkyl amino, optionally substituted C _{1 -6} alkyl, C _{1 -6} alkoxy; 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 ) —.

In some embodiments of Group 3 compounds of Formula (IA), X is C═O.

In certain embodiments of Group III compounds of Formula (IA), Ar is-(Y) -phenyl-, Y is -C (O)-or -C (= NOH)-, G is pyrazolyl, pyrrolyl, Imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl. In other embodiments, Ar is-(Y) -phenyl-, Y is -C (O)-or -C (= NOH)-and G is pyrazole, thienyl or isoxazolyl. In the some embodiments, R ¹ is each independently a substituted or unsubstituted linear or branched C _{1 -10} alkyl ring. In these embodiments, R ³ are each independently one, two or three -F, -Cl, with a substituted or unsubstituted C _{1 -6} branched or unbranched alkyl, or substituted or unsubstituted C _{1 -4} Phenyl or pyridinyl, optionally substituted with alkoxy.

According to another aspect of the present invention, there is provided a third group of compounds of formula (IB), stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof.

<Formula IB>

Where

X is C (O) or C (S),

G is G '- (Y) -, wherein G' is C _{3 -10} cycloalkyl, phenyl, naphthyl, 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthyl Except for tetrahydronaphthyl, pyrazolyl, thiazolyl, pyridinyl, oxazolyl, isoxazolyl, isothiazolyl, thiadiazolyl, oxdiazolyl, pyridazinyl, imidazolyl, and furan-2-yl Thienyl, dihydronaphthyl, indanyl, indenyl, quinolinyl, isoquinolinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, ben except furanyl, thien-2-yl Isoxazolyl, benzpyrazolyl or homopiperidinyl, substituted by one or more R ¹ , R ² or R ³ ,

Ar is phenyl, pyrimidinyl, pyrazolyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, isothiazolyl, pyrrolinyl, pyridazinyl, pyrrolyl, imidazolyl, furanyl , Thienyl, pyrimidinyl, pyrazinyl, optionally substituted with one or more R ⁴ or R ⁵ ,

Y is independently -C (O)-, -C (NNRC (O) OR)-, -C (NNRR)-, -C (NNC (O) NRR)-or -C (NOR)-,

L is a covalent bond or a saturated or unsaturated branched or unbranched C _1-10 carbon chain, wherein one or more methylene groups are optionally replaced independently by heteroatoms selected from O, NR and S (O) _m , L is optionally substituted with 0 or 2 oxo groups and one or more C _1-4 branched or unbranched alkyl optionally substituted by one or more F, Cl, Br or I,

m is each independently 0, 1 or 2,

Q is hydrogen, -NR'R ', cycloalkyl, aryl, heterocyclyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, and -S (O) _m, or phenyl, -S (O) _m, wherein the cycloalkyl, , aryl, heterocyclyl, C _{1 -6} alkoxy, C _1-6 alkyl, -S (O) _m, or phenyl, -S (O) _m optionally substituted with one or more R ^27, respectively, with the proviso that R ⁴ and R ⁵ In the absence of -LQ is not -H,

R are each independently hydrogen, or substituted or unsubstituted C _{1 -6} alkyl ring,

R 'is independently hydrogen, substituted or unsubstituted C _{1 -8} alkyl, substituted or unsubstituted (C _{0 -4} alkyl) - (C _{6 -10} aryl) or substituted or unsubstituted (C _0-4 alkyl) - (5-10 member heterocyclyl), and

R ¹ are each independently F, Cl, Br, I, cyano, -C (O) R, -C (O) NR ₂ , -C (O) OR, -OR, -NR'R ',- _{SiR 3, -S (O) m} R, substituted or unsubstituted linear or branched C _{1 -10} alkyl, C _2-10 alkenyl ring, or a C _{2 -10} alkynyl, substituted or unsubstituted C _{3 - 10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl or heterocyclyl Alkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ),

R ^2, R ⁴ and R ⁵ are each independently selected from F, Cl, Br, I, cyano, substituted or unsubstituted linear or branched unsubstituted C _{1 -6} alkyl, a substituted or unsubstituted C _{6 -10} aryl, Substituted or unsubstituted 5-10 membered heteroaryl, -OR ', -OR ⁶ , -C (O) R', -C (O) OR ', -C (O) NR' ₂ , -NR ' ₂ , -NO ₂ , -S (O) _m R ", NR'SO ₂ R", -NR'C (O) NR'R ', -NR'C (S) NR'R', -NR'C ( O) OR 'or -SO ₂ NR' ₂ ,

R "are each independently a substituted or unsubstituted C _{1 -8} alkyl, substituted or unsubstituted ring with C ₀ -C _{6 -10 -4} alkyl aryl or substituted or unsubstituted (C _{0 -4} alkyl) - (5-10 membered heterocyclyl),

R ³ are independently selected from each independently represent a substituted or unsubstituted C _{6 -10} aryl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl, or heterocyclylalkyl (N, O, S (O) _m a selected one, two, three, or containing from 4 heteroatoms), a a substituted or unsubstituted C _{3 -12} cycloalkyl, substituted or unsubstituted C _{5 -12} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted linear or branched C _{1 -8} ^{alkyl, 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 26 C (O) (CH 2) m N (R 21) -, a substituted or unsubstituted C _{2 -8} alkenyl, or a substituted or unsubstituted ring, and the C _2-8 alkynyl, said C _{1 -8} alkyl, C _{2 -8} alkenyl, or C _{2 -8} methylene groups is optionally replaced by O, one or more of alkynyl, NH or S (O) _m Optionally substituted by

R ⁶ are each optionally partially or fully halogenated, and optionally substituted C _{1 -6} branched or unbranched alkyl as R ^26,

Each R ²⁶ is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or optionally partially or fully halogenated mono- or di- (C _{0- ) 4} alkyl) amino,

R ²⁰ is a substituted or unsubstituted C _{1 -10} alkyl, substituted or unsubstituted C _{0 -6} alkyl-phenyl, a substituted or unsubstituted C _{0 -6} alkyl-heterocyclyl, OR 'or NR' ₂ ,

R ²¹ is hydrogen, or an optionally partially or completely halogenated C _{1 -4} branched or unbranched alkyl,

R ^22, R ²³ and R ²⁴ are each independently hydrogen, (which here, C _{1 -10} alkyl, optionally via one or more O, N or S) substituted or unsubstituted C _{1 -10} alkyl, substituted or unsubstituted C _{-6 0-alkyl-phenyl,} substituted or unsubstituted C _{0 -6} alkyl-, or heterocyclyl, or R ²³ and R ²⁴ and are optionally form a heterocyclic or heteroaryl ring together,

R ²⁷ are each independently F, Cl, Br, I, cyano, -C (O) R ', -C (O) NR' ₂ , -C (O) OR ', -OR', -NR ' _{R ', -SiR' 3, -S} (O) m R ', substituted or unsubstituted linear or branched unsubstituted C _1-10 alkyl, C _{2 -10} alkenyl, or C _{2 -10} alkynyl, substituted or unsubstituted C _{3 -10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _7-20 aralkyl, substituted or unsubstituted 3-11 membered heterocyclyl Or heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ),

Provided that when Ar-LQ is -N- (substituted or unsubstituted phenyl) -pyrazolyl and G is phenyl, naphthyl, indan or tetrahydronaphthyl, pyrazolyl is additionally added to at least one R ⁴ or R ⁵ Substituted,

Compound of formula (IB) is N- {2-chloro-4- [2- (3,5-dimethyl-1-phenyl-1H-pyrazol-4-yl) -2-oxo-acetylamino] -5-hydroxy -Phenyl} -2- (3-pentadecyl-benzenesulfonyl) -butyramide or 5- (4-ethoxy-phenyl) -1-p-tolyl-4-p-tolylaminooxalyl-1H-pyra It is not a sol-3-carboxylic acid methyl ester.

In certain embodiments of Group III compounds of Formula (IB), the compound inhibits at least about 50% of TNFα-release derived from cells at 10 μM concentration.

In some embodiments of Group III compounds of Formula (IB), G ′ is phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydronaphthyl, pyrazolyl, thiazolyl, pyridinyl, oxazolyl, Isoxazolyl, isothiazolyl, thiadiazolyl, oxdiazolyl, pyridazinyl, imidazoyl, furanyl, thienyl, dihydronaphthyl, indanyl, indenyl, quinolinyl, isoquinolinyl, Pyrimidinyl or pyrazinyl. In other embodiments, G 'is phenyl, naphthyl, pyrazolyl, cyclopropyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl or pyridinyl.

In certain embodiments of group III compounds of Formula (IB), Y is -C (O)-, -C (NNRC (O) OR)-or -C (NOR)-.

In some embodiments of Group III compounds of Formula (IB), Ar is phenyl, pyrazolyl, imidazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, or pyrimidinyl.

In other embodiments of Group III compounds of Formula (IB), one or more methylene groups of L are independently replaced by a heteroatom selected from O, N or S (O) _m . Alternatively, L is a covalent bond, C ₁ -C ₉ alkoxy, —C (O) O—, —NH— or —O—.

In certain embodiments of Group III compounds of Formula (IB), Q is hydrogen, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, fura Neil, thienyl, pyranyl, naphthylpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolo [3,4-b] pyrimidinyl, purinyl, pyrrolo [2,3 -b] pyridinyl, pyrazolo [3,4-b] pyridinyl, tubassidinyl, oxazo [4,5-b] pyridinyl, or imidazo [4,5-b] pyridinyl, tetrahydro Pyranyl, tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, p Ferrazinyl, piperazinoyl, oxazinyl, diazepanonyl, piperidinyl, piperidinyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, Pentamethyl Alkylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone, C _{1 -6} alkoxy, (where secondary or tertiary amine, an amino nitrogen is covalently bonded to the C _{1 -3} alkyl, C _{1 -5} alkyl, alkoxy search), phenyl amino, C _{1 -6} alkyl, -S (O) _m -phenyl or -S (O) _m. In the some embodiments, R ²⁷ is C _{1 -6} alkyl, C _{1 -6} alkoxy, hydroxy, amino, substituted or unsubstituted 5-10 member heterocyclyl, mono-or di - (C _{1 -3} alkyl ) amino, mono- or di- (phenyl -C _{1 -3} alkyl) amino, C _{1 -6} alkyl, -S (O) _m, -C _{1 -3-phenyl-alkoxy} or phenylamino (wherein the phenyl ring is 1 to 2 is halogen, C _{1 -6} optionally substituted by alkyl or C _1-6 alkoxy).

In another embodiment of Group III compounds of Formula (IB), Q is hydrogen, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinoyl, oxazinyl, diazepinonyl, imidazolyl, pyridinyl Or morpholino. In another embodiment, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. The In some embodiments, R ²⁷ is -C (O) OR ', -NR'R ', substituted or unsubstituted linear or branched C _{1 -10} alkyl, ring substituted or unsubstituted C _{7 -20} aralkyl Or substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl or heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ) to be. For example, Q is pyrimidinyl and R ²⁷ is independently selected from -NR'R ', or substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl (N, O, S (O) _m Containing 1, 2, 3 or 4 heteroatoms). Alternatively, Q is a pyridinyl, R ²⁷ is -NR'R ', substituted or unsubstituted C _{1 -6} alkyl, or a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl or heterocyclyl Alkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ).

In certain embodiments of group III compounds of Formula (IB), each R ¹ is independently

Optionally partially or fully halogenated, 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, Thienyl, furyl, isoxazolyl or isothiazolyl (these are 1 to 5 halogens, optionally partially or fully halogenated C _1-6 branched or unbranched alkyl, C _3-8 cycloalkyl, C _5-8 Optionally substituted with cycloalkenyl, hydroxy, cyano, optionally partially or fully halogenated C _1-3 alkoxy and NH ₂ C (O) or mono- or di- (C _1-3 alkyl) aminocarbonyl) C _3-10 branched or unbranched alkyl optionally substituted with;

Optionally partially or fully halogenated, one to three optionally partially or completely halogenated C _{1 -3} alkyl, cyano, hydroxy C _{1 -3} alkyl or aryl optionally substituted by cyclopropyl, cyclobutyl to, fentanyl cycloalkyl, Cyclohexanyl, cycloheptanyl, bicyclohexanyl or bicycloheptanyl, or 1 to 3 ring methylene groups are independently replaced by O, S (O) _m , CHOH, C═O, C = S or NH Analogs of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl;

Optionally partially or fully halogenated, one to three C _{1 -5} branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl thiazolyl, thienyl, furyl, isoxazolyl, isothiazolyl (the abovementioned groups are each optionally partially or fully halogenated), optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopropyl fentanyl, cyclohexanone carbonyl, bicyclo heptanyl, bicyclo fentanyl, non-cyclohexanone carbonyl or bicyclo heptanyl, hydroxy, cyano, an optionally partially or completely halogenated C _{1 -3} alkoxy, NH ₂ C (O) or a mono- or di - (C _{1 -3} alkyl) amino-carboxylic alkenyl optionally substituted C _{3 -10} branched or unbranched (herein, C _{3 -10} branched or unbranched alkenyl group is one More than o , N or S (O) _m is optionally interrupted);

Each optionally substituted with one to three C _{1 -3} alkyl substituted cyclopentenyl, cyclohexenyl, cyclohexanone dienyl, bicyclo heptenyl, bicyclo hepta-dienyl, non-cyclohexenyl or bicyclo heptenyl;

Cyano, F, Cl, Br or I;

Methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;

Silyl optionally partially or fully halogenated branched to three C _{1 -4} independent or containing a non-branched alkyl group;

C _{2 -6} branched or unbranched alkyl, -C (O), C _{2 -6} branched or unbranched -S, C _{2 -6} branched or unbranched -S (O), C _{2 -6} branched or Unbranched-S (O) ₂ ;

Optionally partially or completely halogenated C _{2 -6} branched or unbranched alkynyl group (where one or more of the methylene groups is optionally replaced by O, NH and S (O) _m, wherein the alkynyl group optionally 0-2 oxo groups, pyrrolidinyl, pyrrolyl, one or more by one or more halogen atoms, optionally substituted C _{1 -4} branched or unbranched alkyl, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl is pyridinyl, tetrazolyl, or being independently substituted with one or more of a halogen atom, optionally substituted C _{1 -4} branched or unbranched alkylamino).

In other embodiments of Group III compounds of Formula (IB), each R ¹ is independently, optionally partially or fully halogenated, and 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyri Midinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of which is 1 to 5 halogens, optionally partially or fully halogenated C _{1 -6} branched or unbranched alkyl, C _3-8 cycloalkyl, C _5-8 cycloalkenyl, hydroxy, cyano, optionally partially or fully halogenated C _1-3 alkoxy and NH ₂ C (O) or C _3-10 branched or unbranched alkyl optionally substituted with mono- or di- (C _1-3 alkyl) aminocarbonyl). For example, each R ¹ is independently C _3-10 branched or unbranched alkyl.

In certain embodiments of group 3 compounds of Formula (IB), R ² is each independently —OR ′, —OR ⁶ , —C (O) R ′, —C (O) OR ′, —C (O) NR ′ ₂ , -NR ' ₂ , -NO ₂ , -S (O) _m R ", -NR'SO ₂ R", -NR'C (O) NR'R', -NR'C (S) NR'R ', -NR'C (O) OR' or -SO ₂ NR ' ₂ . Alternatively, R ² is each independently —NR ′ ₂ , —NO ₂ , —C (O) NR ′ ₂ , —NR′SO ₂ R ″, —NR′C (O) NR′R ′, —NR ′ C (S) NR'R ', -NR'C (O) OR' or -SO ₂ NR ' ₂ .

In certain embodiments of group III compounds of Formula (IB), each R ³ is independently

Hydrogen or each optionally optionally partially or completely halogenated, 1 to 3 phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione , Imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimida Zolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterridinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, fury carbonyl, indazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, fentanyl, cyclohexanone carbonyl, bicyclo heptanyl, bicyclo fentanyl, non-cyclohexanone carbonyl, non- bicyclo heptanyl, phenyl C _{1 -5} alkyl, or Peutil C _{1 -5} alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heterocyclyl, aryloxy, nitro, amino, mono- or di- ( C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heterocyclyl, amino, NH ₂ C (O), mono- or di - (C _{1 -3} alkyl) amino carbonyl, C _{1 -5} alkyl, -C (O) -C _{1 -4} alkyl, amino -C _{1 -5} alkyl, mono- or di - (C _{1 -3} alkyl) amino -C _{1 -5} alkyl, amino, -S (O) _2, di - (C _1-3 alkyl) amino ^{_{-S (O) 2, R 7}} -C 1 -5 alkyl, R ⁸ -C _{1 -5} ^{alkoxy, R 9 -C (O) -C} 1 -5 al Kiel, R ¹⁰ -C _1-5 alkyl (R ¹¹⁾ N, carboxy-mono-or di - (C _1-5 alkyl) amino optionally substituted phenyl, naphthyl, or heterocyclyl with;

Fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or cyclopentenopyridine, cyclohexanopyridine, cyclopentano Pyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclopentanoindole, cyclohexanoindole, cyclobenzimidazole, cyclopentanoimidazole, cyclohexanoimida Fused heterocycles selected from sol, cyclopentanothiophene and cyclohexanothiophene (the fused aryl or fused heterocyclic ring may optionally be phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl , Pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazole , Triazolyl, isothiazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heteroaromatic heterocyclyl-oxy, heteroaryl, aryloxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino, NH ₂ C (O), mono- or di - (C _{1 -3} alkyl) amino carbonyl, C _{1 -4} alkyl, -C (O), C _{1 -5} alkyl amino -S (O) _2, mono- or di - (C _{1 -3} alkyl) Ami no--C _1-5 alkyl, R ¹² -C _{1 -5} alkyl, R ¹³ -C _{1 -5} ^{alkoxy, R 14 -C (O) -C} 1 -5 alkyl, R ¹⁵ -C _{1 -5} alkyl ( R ¹⁶ ) independently substituted with one to three groups selected from N);

Optionally partially or fully halogenated, one to three optionally partially or completely halogenated C _{1 -3} alkyl, cyano, hydroxy C _{1 -3} alkyl or aryl optionally substituted by cyclopropyl, cyclobutyl to, fentanyl cycloalkyl, Cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, or one to three ring methylene groups are represented by O, S (O) _m , CHOH, C = O, C = S or NH Analogs of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, independently substituted by;

Each optionally substituted with 1 to 3 C _{1 -3} alkyl cyclopentenyl, cyclohexenyl, cyclohexanone dienyl, bicyclo heptenyl, bicyclo hepta-dienyl, non-cyclohexenyl, bicyclo heptenyl;

C _{1 -4} alkyl, or alkylene-phenyl -C (O) -C _{0 -4} alkyl or alkylene, C _{1 -4} alkyl or alkylene -C (O) -C _0-4 alkyl, or alkylene, C _{1 -4} alkyl, or alkylene-phenyl -S (O) _m -C _{0 -4} alkyl or alkylene;

Each optionally partially or fully halogenated, or R ^17, amino, OR ^18, or R ¹⁹ with an optionally substituted C _{1 -5} mono- or di-optionally substituted C _{1 -6} alkyl, C _{1 -6} alkoxy, alkylamino ;

Optionally partially or fully halogenated, one to three optionally partially or fully halogenated C _{1 -3} alkyl group optionally substituted by cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyloxy, cyclohexyloxy, cyclo-heptyloxy (where , 1 to 3 ring methylene groups are independently replaced by O, S (O) _m , CHOH, C═O, C═S or NH);

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 ) —;

^{R 23 R 24 NC (O)} - in a C _{2 -6} alkenyl optionally substituted;

Optionally partially or completely halogenated C _{2 -6-alkynyl} branched or unbranched carbon chain (wherein one or more of the methylene groups is optionally replaced by O, is optionally replaced by an NH or S (O) _m, wherein the alkynyl group optionally 0-2 two oxo groups, pyrrolidinyl, pyrrolyl, one or more by one or more halogen atoms, optionally substituted C _{1 -4} branched or unbranched alkyl, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl , being independently substituted with phenyl, pyridinyl, tetrazolyl or one or more of a halogen atom, optionally substituted C _{1 -4} branched or unbranched alkyl-amino); or

Benzoyl or naphthoyl,

Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁹ and R ²⁵ are each independently cyano, morpholino, piperidinyl, pipe piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or an optionally partially or completely halogenated mono- or di - (C _{0 -4} alkyl) amino;

R ¹¹ and R ¹⁶ are each independently hydrogen, or an optionally partially or completely halogenated C _{1 -4} minutes, branched or unbranched alkyl;

R ¹⁸ is independently hydrogen, or an optionally oxo-substituted C _{1 -4,} or independently, branched or unbranched alkyl as R ^25.

In some of the foregoing embodiments of the Group III compound of Formula IB, each R ³ is independently, each optionally optionally partially or fully halogenated, and 1-3 phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyri Dazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetra Zolyl, Isothiazolyl, Quinolyl, Isoquinolyl, Indolyl, Benzimidazolyl, Benzofuranyl, Benzoxazolyl, Benzoisoxazolyl, Benzpyrazolyl, Benzothiofuranyl, Cinnolinyl, Putrindinyl , phthalazine possess, naphthyl, pyridinyl, quinoxalinyl carbonyl, quinazolinyl, Fourier carbonyl, indazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, fentanyl , Cyclohexanyl, cycloheptanyl, bicycle Fentanyl, non-cyclohexanone carbonyl, bicyclo heptanyl, phenyl C _{1 -5} alkyl, naphthyl C _{1 -5} alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy , naphthyloxy, heterocyclyl, aryloxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heterocyclyl, amino, NH ₂ C (O), mono- or di - (C _{1 -3} alkyl) amino carbonyl, C _{1 -5} alkyl, -C (O) -C _{1 -4} alkyl, -C _1-5 alkyl, amino, mono- or di - (C _{1 -3} alkyl) amino -C _{1 -5} alkyl, amino, -S (O) _2, di - (C _{1 -3} alkyl) amino ^{_{-S (O) 2, R 7}} -C 1 -5 alkyl, R ⁸ -C _{1 -5} alkoxycarbonyl ^{, R 9 -C (O) -C} 1 -5 alkyl, R ¹⁰ -C _{1 -5} alkyl (R ¹¹⁾ N, or carboxy-mono- or di-substituted phenyl, optionally with amino (C _{1 -5} alkyl) , Naphthyl or heterocyclyl. In the other embodiments, R ³ are each optionally partially or fully halogenated, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, hydroxy, oxo, cyano, optionally partially or fully halogenated a C _{1 -3} alkoxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino optionally substituted phenyl, pyridazinyl or pyridyl; Each optionally partially or fully halogenated, or R ^17, amino, OR ^18, R ¹⁹ with an optionally substituted C _{1 -5} mono- or di-optionally substituted with C _{1 -6} alkyl or amino al Kill C _{1 -6} alkoxy ; 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 ) —.

In some embodiments of Group III compounds of Formula (IB), X is C═O.

In some embodiments of Group III compounds of Formula (IB), Ar is phenyl, G is G '-(Y)-, Y is -C (O)-or -C (= NOH)-, and G' is Phenyl, pyridinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl. In other embodiments, Ar is phenyl, G is G '-(Y)-, Y is -C (O)-or -C (= NOH)-and G' is one or more R ¹ , R ² or Phenyl or pyridinyl substituted by R ³ . In the some embodiments, R ¹ is each independently a substituted or unsubstituted linear or branched C _{1 -10} alkyl ring. Here, R ³ may be each independently R ²³ R ²⁴ NC (O) —, R ²⁰ —C (O) —NR ²¹ — or OR ²² . Alternatively, R ² are each independently selected from _{-NR'SO 2 R ", -Cl, -Br} , -F, -C (O) -NR '2, substituted or unsubstituted linear or branched unsubstituted C _{1 -6} alkyl , -NR ' ₂ , or -OR'.

In another embodiment of Group III compounds of Formula (IB), Ar is phenyl, G is G '-(Y)-, wherein Y is selected from -C (O)-or -C (= NOH)-, G 'is pyrazolyl, isoxazolyl or furanyl substituted by one or more R ¹ , R ² or R ³ . In the some embodiments, R ¹ is each independently a substituted or unsubstituted linear or branched C _{1 -10} alkyl ring. Here, R ³ are each independently optionally substituted with one to three -F, -Cl, with a substituted or unsubstituted C _{1 -6} branched or unbranched alkyl, or substituted or unsubstituted C _{1 -3} alkoxy , may be a substituted or unsubstituted C _{1 -6} alkyl, phenyl or pyridinyl.

According to another aspect of the invention, there is provided a compound of formula IC, a stereoisomer thereof, a tautomer thereof, a solvate thereof, a prodrug thereof, and a pharmaceutically acceptable salt thereof.

Where

The ring is maleimide, succinimide, imidazolidinone, imidazolidine-dione, imidazolidine-trione, triazolidine-dione or triazine-dione,

G is C _{3 -10} carbocyclyl, C _{4 -12} alkyl, carbocyclyl, 5-8-membered monocyclic heterocyclyl, or heterocyclylalkyl, or 8-11 won bicyclic heterocyclyl or heterocyclylalkyl Wherein said heterocyclyl ring contains one or more heteroatoms selected from O, N or S, and is substituted by one or more R ¹ , R ² or R ³ ,

Ar is indazolyl, indolyl, isoindoleyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolin Nil, phthalazinyl, dihydroindolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzothiazolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, C _{6 -10} aryl, or - (C _{1 -3} alkyl) - (C _{6 -10} aryl group), and optionally substituted with one or more R ⁴ or R ^5,

L is a covalent bond or a saturated or unsaturated branched or unbranched C _1-10 carbon chain, wherein one or more methylene groups are optionally replaced independently by heteroatoms selected from O, NR and S (O) _m , L is optionally substituted with 0-2 oxo groups and one or more C _1-4 branched or unbranched alkyl optionally substituted with one or more F, Cl, Br or I,

m is each independently 0, 1 or 2,

Q is hydrogen, -NR'R ', cycloalkyl, aryl, heterocyclyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, and -S (O) _m, or phenyl, -S (O) _m, wherein the cycloalkyl, , aryl, heterocyclyl, C _{1 -6} alkoxy, C _1-6 alkyl, -S (O) _m, or phenyl, -S (O) _m optionally substituted with one or more R ^27, respectively, with the proviso that R ⁴ and R ⁵ In the absence of -LQ is not -H,

R are each independently hydrogen, or substituted or unsubstituted C _{1 -6} alkyl ring,

R 'is independently hydrogen, substituted or unsubstituted C _{1 -8} alkyl, substituted or unsubstituted (C _{0 -4} alkyl) - (C _{6 -10} aryl) or substituted or unsubstituted (C _0-4 alkyl) - (5-10 member heterocyclyl), and

R ¹ are each independently F, Cl, Br, I, cyano, -C (O) R, -C (O) NR ₂ , -C (O) OR, -OR, -NR'R ',- _{SiR 3, -S (O) m} R, substituted or unsubstituted linear or branched C _{1 -10} alkyl, C _2-10 alkenyl ring, or a C _{2 -10} alkynyl, substituted or unsubstituted C _{3 - 10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl or heterocyclyl Alkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ),

R ^2, R ⁴ and R ⁵ are each independently selected from F, Cl, Br, I, cyano, substituted or unsubstituted linear or branched unsubstituted C _{1 -6} alkyl, a substituted or unsubstituted C _{6 -10} aryl, Substituted or unsubstituted 5-10 membered heteroaryl, -OR ', -OR ⁶ , -C (O) R', -C (O) OR ', -C (O) NR' ₂ , -NR ' ₂ , -NO ₂ , -S (O) _m R ", NR'SO ₂ R", -NR'C (O) NR'R ', -NR'C (S) NR'R', -NR'C ( O) OR 'or -SO ₂ NR' ₂ ,

R "are each independently a substituted or unsubstituted C _{1 -8} alkyl, substituted or unsubstituted ring with C ₀ -C _{6 -10 -4} alkyl aryl or substituted or unsubstituted (C _{0 -4} alkyl) - (5-10 membered heterocyclyl),

R ³ are independently selected from each independently represent a substituted or unsubstituted C _{6 -10} aryl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl, or heterocyclylalkyl (N, O, S (O) _m a selected one, two, three, or containing from 4 heteroatoms), a a substituted or unsubstituted C _{3 -12} cycloalkyl, substituted or unsubstituted C _{5 -12} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted linear or branched C _{1 -8} ^{alkyl, 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 26 C (O) (CH 2) m N (R 21) -, a substituted or unsubstituted C _{2 -8} alkenyl, or a substituted or unsubstituted C _2-8 alkynyl, the above C _{1 -8} alkyl, C _{2 -8} alkenyl, or C _{2 -8} least one methylene group is O, NH or S (O) alkynyl of _m Arbitrarily replaced

R ⁶ are each optionally partially or fully halogenated, and optionally substituted C _{1 -6} branched or unbranched alkyl as R ^26,

Each R ²⁶ is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or optionally partially or fully halogenated mono- or di- (C _{0- ) 4} alkyl) amino,

R ²⁰ is a substituted or unsubstituted C _{1 -10} alkyl, substituted or unsubstituted C _{0 -6} alkyl-phenyl, a substituted or unsubstituted C _{0 -6} alkyl-heterocyclyl, OR 'or NR' ₂ ,

R ²¹ is hydrogen, or an optionally partially or completely halogenated C _{1 -4} branched or unbranched alkyl,

R ^22, R ²³ and R ²⁴ are each independently hydrogen, (which here, C _{1 -10} alkyl, optionally via one or more O, N or S) substituted or unsubstituted C _{1 -10} alkyl, substituted or unsubstituted C _{0 -6} alkyl-phenyl, substituted or unsubstituted C _{0 -6} alkyl-, or heterocyclyl, or R ²³ and R ²⁴ and are optionally form a heterocyclic or heteroaryl ring together,

R ²⁷ are each independently F, Cl, Br, I, cyano, -C (O) R ', -C (O) NR' ₂ , -C (O) OR ', -OR', -NR ' _{R ', -SiR' 3, -S} (O) m R ', substituted or unsubstituted linear or branched unsubstituted C _1-10 alkyl, C _{2 -10} alkenyl, or C _{2 -10} alkynyl, substituted or unsubstituted C _{3 -10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _7-20 aralkyl, substituted or unsubstituted 3-11 membered heterocyclyl Or heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ).

In certain embodiments of a compound of Formula (IC), the compound inhibits at least about 50% of TNFα-release derived from cells at a 10 μM concentration.

In certain embodiments of a compound of Formula (IC), G is

Phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, cyclopropyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran-3-one;

Pyrazolyl, pyrrolyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydro Quinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, Dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazoloyl, 4H-benzo [1,4] oxazine-3-onyl, benzodioxolyl, benzo [1,3] dioxol-2-onyl, tetra Hydrobenzopyranyl, indolyl, indolinyl, indolinyl, indolinonyl, phthalimidyl;

Pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxydyl, oxazolinyl, Thiazolinyl, imidazolinyl, tetrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl , Dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or ditianyl.

In another embodiment of the compounds of Formula (IC), G is phenyl, naphthyl, cyclopropyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl Or benzofuran-3-one. In another embodiment, G is pyrazolyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidy Neil, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazoloyl, benzo [1 , 4] oxazine-3-onyl, benzodioxolyl, benzo [1,3] dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolinyl, indolinonyl or phthalimidyl to be. In another embodiment, G is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene Sulfoxydyl, oxazolinyl, isoxazolinyl, thiazolinyl, imidazolinyl, tetrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydro Isoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or ditianyl. For example, G is phenyl, naphthyl, cyclopropyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl or pyri Dinyne.

In certain embodiments of compounds of Formula (IC), Ar is indazolyl, indolyl, isoindoleyl, imidazolyl, benzimidazolyl, pyrazolyl, pyrazolinyl, pyrrolyl, pyrrolinyl, pyridinyl, pyrida Genyl, quinolinyl, isoquinolinyl, phthalazinyl, dihydroindolyl, benzoy soxazolyl, dihydrobenzoisoxazolyl, dihydroisoindolyl, benzoisothiazolyl, benzoisothiazolyl dioxide, or C _{6 -10} aryl. In some of the above embodiments, Ar is substituted with one or more R ⁴ or R ⁵ . Alternatively, Ar is indazolyl, isoindoleyl, pyrazolyl, pyrrolinyl, phenyl, naphthyl, tetrahydronaphthyl, dihydronaphthyl, indanyl, indenyl or imidazolyl. For example, Ar is indazolyl, phenyl, naphthyl or tetrahydronaphthyl.

In some embodiments of compounds of Formula IC, one or more methylene groups of L are independently replaced by a heteroatom selected from O, N or S (O) _m . Alternatively, L is a covalent bond, C ₁ -C ₉ alkoxy, —C (O) O—, —NH— or —O—.

In certain embodiments of compounds of Formula (IC), Q is hydrogen, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, furanyl, tier Neil, pyranyl, naphthylpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolo [3,4-b] pyrimidinyl, purinyl, pyrrolo [2,3-b] Pyridinyl, pyrazolo [3,4-b] pyridinyl, tubassidinyl, oxazo [4,5-b] pyridinyl, or imidazo [4,5-b] pyridinyl, tetrahydropyranyl, Tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinyl, Piperazinoyl, oxazinyl, diazepanonyl, piperidinyl, piperidinyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone , Tetramethylene sulfide, (as where the amino nitrogen is covalently bonded to the C _{1 -3} alkyl, C _{1 -5} alkoxycarbonyl alkyl) tetramethylene sulfoxide or tetramethylene sulfone, C _{1 -6} alkoxy, secondary or tertiary amine , phenyl, amino, C _{1 -6} alkyl, -S (O) _m -phenyl or -S (O) _m. In the some embodiments, R ²⁷ is C _{1 -6} alkyl, C _{1 -6} alkoxy, hydroxy, amino, substituted or unsubstituted 5-10 member heterocyclyl, mono-or di - (C _{1 -3} alkyl ) amino, mono- or di- (phenyl -C _{1 -3} alkyl) amino, C _{1 -6} alkyl, -S (O) _m, -C _{1 -3-phenyl-alkoxy} or phenylamino (wherein the phenyl ring is 1 to 2 is halogen, C _{1 -6} optionally substituted by alkyl or C _1-6 alkoxy).

In another embodiment of the compounds of Formula (IC), Q is hydrogen, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinyl, oxazinyl, diazepinonyl, imidazolyl, pyridinyl or morpholin No. In another embodiment, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. In the some embodiments, R ²⁷ is -C (O) OR ', -NR'R ', substituted or unsubstituted linear or branched C _{1 -10} alkyl, substituted or unsubstituted C _7-20 aralkyl, Or substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl or heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ) to be. For example, Q is pyrimidinyl and R ²⁷ is independently from —NR′R ′, or substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl (N, O, S (O) _m Containing 1, 2, 3 or 4 heteroatoms selected). Alternatively, Q is a pyridinyl, R ²⁷ is -NR'R ', substituted or unsubstituted C _{1 -6} alkyl, or a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl or heterocyclyl Alkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ).

In certain embodiments of a compound of Formula (IC), each R ¹ is independently

Optionally partially or fully halogenated, 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, Thienyl, furyl, isoxazolyl or isothiazolyl (these are 1 to 5 halogens, optionally partially or fully halogenated C _1-6 branched or unbranched alkyl, C _3-8 cycloalkyl, C _5-8 Optionally substituted with cycloalkenyl, hydroxy, cyano, optionally partially or fully halogenated C _1-3 alkoxy and NH ₂ C (O) or mono- or di- (C _1-3 alkyl) aminocarbonyl) C _3-10 branched or unbranched alkyl optionally substituted with;

Optionally partially or fully halogenated, one to three optionally partially or completely halogenated C _{1 -3} alkyl, cyano, hydroxy C _{1 -3} alkyl or aryl optionally substituted by cyclopropyl, cyclobutyl to, fentanyl cycloalkyl, Cyclohexanyl, cycloheptanyl, bicyclohexanyl or bicycloheptanyl, or 1 to 3 ring methylene groups are independently replaced by O, S (O) _m , CHOH, C═O, C = S or NH Analogs of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl;

Optionally partially or fully halogenated, one to three C _{1 -5} branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl thiazolyl, thienyl, furyl, isoxazolyl, isothiazolyl (the abovementioned groups are each optionally partially or fully halogenated), optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopropyl fentanyl, cyclohexanone carbonyl, bicyclo heptanyl, bicyclo fentanyl, non-cyclohexanone carbonyl or bicyclo heptanyl, hydroxy, cyano, an optionally partially or completely halogenated C _{1 -3} alkoxy, NH ₂ C (O) or a mono- or di - (C _{1 -3} alkyl) amino-carboxylic alkenyl optionally substituted C _{3 -10} branched or unbranched (herein, C _{3 -10} branched or unbranched alkenyl group is one More than O, N or S (O) _m is optionally interrupted);

Each optionally substituted with one to three C _{1 -3} alkyl substituted cyclopentenyl, cyclohexenyl, cyclohexanone dienyl, bicyclo heptenyl, bicyclo hepta-dienyl, non-cyclohexenyl or bicyclo heptenyl;

Cyano, F, Cl, Br or I;

Methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;

Silyl optionally partially or fully halogenated branched to three C _{1 -4} independent or containing a non-branched alkyl group;

C _{2 -6} branched or unbranched alkyl, -C (O), C _{2 -6} branched or unbranched -S, C _{2 -6} branched or unbranched -S (O), C _{2 -6} branched or Unbranched-S (O) ₂ ;

Optionally partially or completely halogenated C _{2 -6} branched or unbranched alkynyl group (where one or more of the methylene groups is optionally replaced by O, NH and S (O) _m, wherein the alkynyl group optionally 0-2 oxo groups, pyrrolidinyl, pyrrolyl, one or more by one or more halogen atoms, optionally substituted C _{1 -4} branched or unbranched alkyl, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl is pyridinyl, tetrazolyl, or being independently substituted with one or more of a halogen atom, optionally substituted C _{1 -4} branched or unbranched alkylamino).

In other embodiments of the compounds of Formula (IC), each R ¹ is independently, optionally partially or fully halogenated, 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, Pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl (these are 1 to 5 halogens, optionally partially or fully halogenated C _1-6 minutes, respectively) Topographic or unbranched alkyl, C _3-8 cycloalkyl, C _5-8 cycloalkenyl, hydroxy, cyano, optionally partially or fully halogenated C _1-3 alkoxy and NH ₂ C (O) or mono- or C _3-10 branched or unbranched alkyl optionally substituted with di- (C _1-3 alkyl) aminocarbonyl). For example, each R ¹ is independently C _3-10 branched or unbranched alkyl.

In certain embodiments of a compound of Formula (IC), each R ² is independently —OR ′, —OR ⁶ , —C (O) R ′, —C (O) OR ′, —C (O) NR ′ ₂ , — NR ' ₂ , -NO ₂ , -S (O) _m R ", -NR'SO ₂ R", -NR'C (O) NR'R', -NR'C (S) NR'R ',- NR'C (O) OR 'or -SO ₂ NR' ₂ . Alternatively, R ² is each independently —NR ′ ₂ , —NO ₂ , —C (O) NR ′ ₂ , —NR′SO ₂ R ″, —NR′C (O) NR′R ′, —NR ′ C (S) NR'R ', -NR'C (O) OR' or -SO ₂ NR ' ₂ .

In certain embodiments of a compound of Formula (IC), each R ³ is independently

Hydrogen or each optionally optionally partially or completely halogenated, 1 to 3 phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione , Imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimida Zolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterridinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, fury carbonyl, indazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, fentanyl, cyclohexanone carbonyl, bicyclo heptanyl, bicyclo fentanyl, non-cyclohexanone carbonyl, non- bicyclo heptanyl, phenyl C _{1 -5} alkyl, or Peutil C _{1 -5} alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heterocyclyl, aryloxy, nitro, amino, mono- or di- ( C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heterocyclyl, amino, NH ₂ C (O), mono- or di - (C _{1 -3} alkyl) amino carbonyl, C _{1 -5} alkyl, -C (O) -C _{1 -4} alkyl, amino -C _{1 -5} alkyl, mono- or di - (C _{1 -3} alkyl) amino -C _{1 -5} alkyl, amino, -S (O) _2, di - (C _1-3 alkyl) amino ^{_{-S (O) 2, R 7}} -C 1 -5 alkyl, R ⁸ -C _{1 -5} ^{alkoxy, R 9 -C (O) -C} 1 -5 alkyl, R ¹⁰ -C _{1 -5} alkyl (R ¹¹⁾ N, carboxy-mono-or di - (C _{1 -5-alkyl)} amino optionally substituted phenyl, naphthyl, or heterocyclyl with;

Fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or cyclopentenopyridine, cyclohexanopyridine, cyclopentano Pyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclopentanoindole, cyclohexanoindole, cyclobenzimidazole, cyclopentanoimidazole, cyclohexanoimida Fused heterocycles selected from sol, cyclopentanothiophene and cyclohexanothiophene (the fused aryl or fused heterocyclic ring may optionally be phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl , Pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazole ,-Triazolyl, isothiazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heteroaromatic heterocyclyl-oxy, heteroaryl, aryloxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino, NH ₂ C (O), mono- di or - (C _{1 -3} alkyl) amino carbonyl, C _{1 -4} alkyl, -C (O), C _{1 -5} alkyl amino -S (O) _2, mono- or di - (C _{1 -3} alkyl) amino -C _1-5 alkyl, R ¹² -C _{1 -5} alkyl, R ¹³ -C _{1 -5} ^{alkoxy, R 14 -C (O) -C} 1 -5 alkyl, R ¹⁵ -C _{1 -5} alkyl (R ¹⁶ ) independently substituted with 1 to 3 groups selected from N);

Optionally partially or fully halogenated, one to three optionally partially or completely halogenated C _{1 -3} alkyl, cyano, hydroxy C _{1 -3} alkyl or aryl optionally substituted by cyclopropyl, cyclobutyl to, fentanyl cycloalkyl, Cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, or one to three ring methylene groups are represented by O, S (O) _m , CHOH, C = O, C = S or NH Analogs of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, independently substituted by;

Each optionally substituted with 1 to 3 C _{1 -3} alkyl cyclopentenyl, cyclohexenyl, cyclohexanone dienyl, bicyclo heptenyl, bicyclo hepta-dienyl, non-cyclohexenyl, bicyclo heptenyl;

C _{1 -4} alkyl, or alkylene-phenyl -C (O) -C _{0 -4} alkyl or alkylene, C _{1 -4} alkyl or alkylene -C (O) -C _0-4 alkyl, or alkylene, C _{1 -4} alkyl, or alkylene-phenyl -S (O) _m -C _{0 -4} alkyl or alkylene;

Each optionally partially or fully halogenated, or R ^17, amino, OR ^18, or R ¹⁹ with an optionally substituted C _{1 -5} mono- or di-optionally substituted C _{1 -6} alkyl, C _{1 -6} alkoxy, alkylamino ;

Optionally partially or fully halogenated, one to three optionally partially or fully halogenated C _{1 -3} alkyl group optionally substituted by cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyloxy, cyclohexyloxy, cyclo-heptyloxy (where , 1 to 3 ring methylene groups are independently replaced by O, S (O) _m , CHOH, C═O, C═S or NH);

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 ) —;

^{R 23 R 24 NC (O)} - in a C _{2 -6} alkenyl optionally substituted;

Optionally partially or completely halogenated C _{2 -6-alkynyl} branched or unbranched carbon chain (wherein one or more of the methylene groups is optionally replaced by O, is optionally replaced by an NH or S (O) _m, wherein the alkynyl group optionally 0-2 two oxo groups, pyrrolidinyl, pyrrolyl, one or more by one or more halogen atoms, optionally substituted C _{1 -4} branched or unbranched alkyl, nitrile, morpholino, piperidinyl, piperazinyl, imidazolyl , being independently substituted with phenyl, pyridinyl, tetrazolyl or one or more of a halogen atom, optionally substituted C _{1 -4} branched or unbranched alkyl-amino); or

Benzoyl or naphthoyl,

Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁹ and R ²⁵ are each independently cyano, morpholino, piperidinyl, pipe piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or an optionally partially or completely halogenated mono- or di - (C _{0 -4} alkyl) amino;

R ¹¹ and R ¹⁶ are each independently hydrogen, or an optionally partially or completely halogenated C _{1 -4} minutes, branched or unbranched alkyl;

R ¹⁸ is independently hydrogen, or an optionally oxo-substituted C _{1 -4,} or independently, branched or unbranched alkyl as R ^25.

In some of the foregoing embodiments of the compound of formula IC, R ³ is each independently, each optionally optionally partially or fully halogenated, 1-3 phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, Pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, iso Thiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthala possess, naphthyl, pyridinyl, quinoxalinyl carbonyl, quinazolinyl, Fourier carbonyl, indazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, fentanyl, cyclohexanone Nyl, Cycloheptanyl, Bicyclopenta , Non-cyclohexanone carbonyl, bicyclo heptanyl, phenyl C _{1 -5} alkyl, naphthyl C _{1 -5} alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heterocyclyl, aryloxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heterocyclyl, amino, NH ₂ C (O), a mono- or di - (C _{1 -3} alkyl) amino carbonyl, C _{1 -5} alkyl, -C (O) -C _{1 -4} alkyl, -C _1-5 alkyl, amino, mono- or di - (C _{1 -3} alkyl) amino -C _{1 -5} alkyl, amino, -S (O) _2, di - (C _{1 -3} alkyl) amino ^{_{-S (O) 2, R 7}} -C 1 -5 alkyl, R ⁸ -C _{1 -5} alkoxycarbonyl, _{^{R 9 -C (O) -C 1}} -5 alkyl, R ¹⁰ -C _{1 -5} alkyl (R ¹¹⁾ N, or carboxy-mono- or di-optionally substituted phenyl amino (C _{1 -5} alkyl), Naphthyl or heterocyclyl. In the other embodiments, R ³ are each optionally partially or fully halogenated, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, hydroxy, oxo, cyano, optionally partially or fully halogenated a C _{1 -3} alkoxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino optionally substituted phenyl, pyridazinyl or pyridyl; Each optionally partially or fully halogenated, or R ^17, amino, OR ^18, R ¹⁹ optionally substituted with C _{1 -5-mono-} or di-alkyl amino, optionally substituted C _{1 -6} alkyl, C _{1 -6} alkoxy; 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 ) —.

In certain embodiments of compounds of Formula (IC), the ring is maleimide, succinimide or triazine-dione. In another embodiment, the ring is succinimide-1,4-diyl, maleimide-1,4-diyl, imidazolidin-2-one-1,3-diyl, imidazolidine-2,4, 5-trione-1,3-diyl, [1,2,4] triazolidine-3,5-dione-1,4-diyl or 2H- [1,2,4] triazine-3,5- Dion-4,6-diyl.

In another aspect of the invention, there is provided a compound of Formula II, a stereoisomer thereof, a tautomer thereof, a solvate thereof, and a pharmaceutically acceptable salt thereof.

Where

G is C _{3 -10} and carbocyclyl, 5-8-membered monocyclic heterocyclyl, or 8-11 won bicyclic (containing one or more heteroatoms selected from O, N or S) heterocyclyl, one Substituted by the above R ¹ , R ² or R ³ ,

X is CR '= CR', CR '= N, NR', CR ' ₂ , O or S,

Ar is phenyl, naphthyl, quinoline, isoquinoline, tetrahydronaphthyl, pyridinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, tetrahydroquinoline, tetrahydroisoquinoline, benzimidazole, benzofuran, indanyl, indenyl, indole, or the following structural formula - (Y ') - (C 0-3 alkyl) - (C _{6 -10} aryl), and which is optionally substituted respectively with one or more R ^4,

Y 'is absent or is -O- or -NH-,

L is a covalent bond or a saturated or unsaturated branched or unbranched C _1-10 carbon chain, wherein one or more methylene groups are optionally replaced independently by heteroatoms selected from O, NR and S (O) _m , L is optionally substituted with 0 or 2 oxo groups and one or more C _1-4 branched or unbranched alkyl optionally substituted by one or more F, Cl, Br or I,

m is each independently 0, 1 or 2,

Q is hydrogen, -NR'R ', cycloalkyl, aryl, heterocyclyl, C _{1 -6} alkoxy, C _{1 -6} alkyl, and -S (O) _m, or phenyl, -S (O) _m, wherein the cycloalkyl, , aryl, heterocyclyl, C _{1 -6} alkoxy, C _1-6 alkyl, -S (O) _m, or phenyl, -S (O) _m optionally substituted with one or more R ^27, respectively,

R are each independently hydrogen, or substituted or unsubstituted C _{1 -6} alkyl ring,

R 'is independently hydrogen, substituted or unsubstituted C _{1 -8} alkyl, substituted or unsubstituted (C _{0 -4} alkyl) - (C _{6 -10} aryl) or substituted or unsubstituted (C _0-4 alkyl) - (5-10 member heterocyclyl), and

R ¹ are each independently F, Cl, Br, I, cyano, -C (O) R, -C (O) NR ₂ , -C (O) OR, -NR'R ', -OR,- _{SiR 3, -S (O) m} R, substituted or unsubstituted linear or branched C _{1 -10} alkyl, C _2-10 alkenyl ring, or a C _{2 -10} alkynyl, substituted or unsubstituted C _{3 - 10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl or heterocyclyl Alkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ),

R ² and R ⁴ are each independently selected from F, Cl, Br, I, cyano, substituted or unsubstituted linear or branched C _{1 -6} alkyl, a substituted or unsubstituted C _{6 -10} aryl, substituted or Unsubstituted 5-10 membered heteroaryl, -OR ', -OR ⁶ , -C (O) R', -C (O) OR ', -C (O) NR' ₂ , -NR ' ₂ , -NO ₂ , -S (O) _m R ", NR'SO ₂ R", -NR'C (O) NR'R ', -NR'C (S) NR'R', -NR'C (O) OR 'Or -SO ₂ NR' ₂ ,

R "are each independently a substituted or unsubstituted C _{1 -8} alkyl, substituted or unsubstituted ring with C ₀ -C _{6 -10 -4} alkyl aryl or substituted or unsubstituted (C _{0 -4} alkyl) - (5-10 membered heterocyclyl),

R ^3, independently, is H, a substituted or unsubstituted C _{6 -10} aryl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl, or heterocyclylalkyl (N, O, S (O) _m independently selected from one, two, three or four also contain a hetero atom), a substituted or unsubstituted C _{3 -12} cycloalkyl, substituted or unsubstituted C _{5 -12} from the cycloalkenyl, substituted or unsubstituted hwandoen C _{7 -20} aralkyl group, a substituted or unsubstituted linear or branched C _{1 -8} ^{alkyl, 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 26 C (O) (CH 2) m N (R 21) -, a substituted or unsubstituted C _{2 -8} alkenyl , or is a substituted or unsubstituted C _2-8 alkynyl, a C _{1 -8} alkyl, C _{2 -8} alkenyl, or C _{2 -8} least one methylene group is O, NH or S (O) of the alkynyl optionally substituted with _m ,

R ⁶ are each optionally partially or fully halogenated, and optionally substituted C _{1 -6} branched or unbranched alkyl as R ^26,

Each R ²⁶ is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or optionally partially or fully halogenated mono- or di- (C _{0- ) 4} alkyl) amino,

R ²⁰ is an optionally partially or completely halogenated C _{1 -10} branched or unbranched alkyl, phenyl, pyridinyl, OR 'or NR' _2,

R ²¹ is hydrogen, or an optionally partially or completely halogenated C _{1 -4} branched or unbranched alkyl,

R ^22, R ²³ and R ²⁴ are independently hydrogen, aminocarbonyl, mono-or di -C _{1 -3} alkyl or amino-mono or di -C _{1 -3} alkyl optionally substituted by a C _{1 -6} branched or unbranched alkyl (wherein, C _{1 -6} alkyl is optionally partially or fully halogenated, one or more O, N or S optionally being interposed), phenyl, pyridine, optionally partially or fully halogenated mono-or di -C _{0 -4} bun or a branched or unbranched alkyl amino and alkyl, or R ²³ and and R ²⁴ and are optionally form a heterocyclic or heteroaryl ring together,

R ²⁷ are each independently F, Cl, Br, I, cyano, -C (O) R ', -C (O) NR' ₂ , -C (O) OR ', -OR', -NR ' _{R ', -SiR' 3, -S} (O) m R ', substituted or unsubstituted linear or branched unsubstituted C _1-10 alkyl, C _{2 -10} alkenyl, or C _{2 -10} alkynyl, substituted or unsubstituted C _{3 -10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _7-20 aralkyl, substituted or unsubstituted 3-11 membered heterocyclyl Or heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ).

In certain embodiments of a compound of Formula (II), the compound inhibits at least about 50% of TNFα-release derived from cells at a 10 μM concentration.

In certain embodiments of a compound of Formula (II), G is

Phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran-3-one;

Pyrazolyl, pyrrolyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydro Quinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, Dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazoloyl, 4H-benzo [1,4] oxazine-3-onyl, benzodioxolyl, benzo [1,3] dioxol-2-onyl, tetra Hydrobenzopyranyl, indolyl, indolinyl, indolinyl, indolinonyl, phthalimidyl;

Pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxydyl, oxazolinyl, Thiazolinyl, imidazolinyl, tetrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl , Dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or ditianyl.

In another embodiment of the compound of Formula (II), G is phenyl, naphthyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl, benzocycloheptenyl, indanyl, indenyl, benzofuran 3-one or 4H-benzo [1,4] oxazin-3-one. In another embodiment, G is pyrazolyl, pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidy Neil, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzoxazoloyl, benzo [1 , 4] oxazine-3-onyl, benzodioxolyl, benzo [1,3] dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolinyl, indolinonyl or phthalimidyl to be. In another embodiment, G is pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene Sulfoxydyl, oxazolinyl, thiazolinyl, imidazolinyl, tetrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, Thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl or ditianyl. In certain embodiments, G is phenyl, pyrazolyl, pyrrolyl, pyrrolidinyl, imidazolyl, imidazolonyl, thiazolyl, oxazolyl, isoxazolyl, furanyl, thienyl or pyridinyl.

In certain embodiments of a compound of Formula (II), Ar is indazolyl, isoindolyl, pyrazolyl, imidazolyl or imidazolonyl. In some of the above embodiments, Ar is substituted with one or more R ⁴ . Alternatively, Ar is indazolyl optionally substituted with one or more R ⁴ . In another embodiment, Ar is phenyl or naphthyl. In some of the above embodiments, Ar is substituted with one or more R ⁴ .

In another embodiment of the compounds of formula II, Ar is - (Y ') - is a (C _{6 -10} aryl) - (C _{0 -3} alkyl). In some of the above embodiments, Ar is substituted with one or more R ⁴ . In another embodiment, the C _{6 -10} aryl is phenyl or naphthyl. Alternatively, Y 'is -NH-.

In certain embodiments of a compound of Formula (II), one or more methylene groups of L are independently replaced by a heteroatom selected from O, N or S (O) _m . In other embodiments, L is a bond, C ₁ -C ₉ alkoxy, -C (O) O-, -NH- or -O-.

In some embodiments of compounds of Formula (II), Q is hydrogen, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrrolyl, pyrrolidinyl, benzimidazolyl, furanyl, tier Neil, pyranyl, naphthylpyridinyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolo [3,4-b] pyrimidinyl, purinyl, pyrrolo [2,3-b] Pyridinyl, pyrazolo [3,4-b] pyridinyl, tubassidinyl, oxazo [4,5-b] pyridinyl, or imidazo [4,5-b] pyridinyl, tetrahydropyranyl, Tetrahydrofuranyl, 1,3-dioxolanone, 1,3-dioxanone, 1,4-dioxanyl, morpholino, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinyl, Piperidinyl, piperidinyl, tetrahydropyrimidonyl, cyclohexanone, cyclohexanol, pentamethylene sulfide, pentamethylene sulfoxide, pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfide Oxide or tetramethylene sulfone, C _{1 -6} alkoxy, secondary or tertiary amines (wherein the amino nitrogen is a C _{1 -5} alkyl, or being covalently bonded to the C _{1 -3} alkoxy-alkyl), phenyl, amino, C _{1 -6} alkyl -S (O) _m or phenyl-S (O) _m . In the some embodiments, R ²⁷ is C _{1 -6} alkyl, C _{1 -6} alkoxy, hydroxy, amino, substituted or unsubstituted 5-10 member heterocyclyl, mono-or di - (C _{1 -3} alkyl ) amino, mono- or di- (phenyl -C _{1 -3} alkyl) amino, C _{1 -6} alkyl, -S (O) _m, -C _{1 -3-phenyl-alkoxy} or phenylamino (wherein the phenyl ring is 1 to 2 is halogen, C _{1 -6} alkyl, or C _{1 -6} optionally substituted by alkoxy).

In another embodiment of the compound of Formula (II), Q is hydrogen, thiomorpholino sulfoxide, thiomorpholino sulfone, piperazinoyl, oxazinyl, diazepinonyl, imidazolyl, pyridinyl or mor Polyno. In another embodiment, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl. In the some embodiments, R ²⁷ is -C (O) OR ', -NR'R ', substituted or unsubstituted linear or branched C _{1 -10} alkyl, substituted or unsubstituted C _7-20 aralkyl, Or substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl or heterocyclylalkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ) to be. For example, Q is pyrimidinyl and R ²⁷ is independently selected from -NR'R ', or substituted or unsubstituted saturated or unsaturated 3-11 membered heterocyclyl (N, O, S (O) _m Containing 1, 2, 3 or 4 heteroatoms). Alternatively, Q is a pyridinyl, R ²⁷ is -NR'R ', substituted or unsubstituted C _{1 -6} alkyl, or a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl or heterocyclyl Alkyl (containing 1, 2, 3 or 4 heteroatoms independently selected from N, O, S (O) _m ).

In certain embodiments of a compound of Formula (II), each R ¹ is independently

Optionally partially or fully halogenated, 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, Thienyl, furyl, isoxazolyl or isothiazolyl (these are 1 to 5 halogens, optionally partially or fully halogenated C _1-6 branched or unbranched alkyl, C _3-8 cycloalkyl, C _5-8 Optionally substituted with cycloalkenyl, hydroxy, cyano, optionally partially or fully halogenated C _1-3 alkoxy and NH ₂ C (O) or mono- or di- (C _1-3 alkyl) aminocarbonyl) C _3-10 branched or unbranched alkyl optionally substituted with;

Optionally partially or fully halogenated, one to three optionally partially or completely halogenated C _{1 -3} alkyl, cyano, hydroxy C _{1 -3} alkyl or aryl optionally substituted by cyclopropyl, cyclobutyl to, fentanyl cycloalkyl, Cyclohexanyl, cycloheptanyl, bicyclohexanyl or bicycloheptanyl, or 1 to 3 ring methylene groups are independently replaced by O, S (O) _m , CHOH, C═O, C = S or NH Analogs of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl;

Optionally partially or fully halogenated, one to three C _{1 -5} branched or unbranched alkyl, phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl thiazolyl, thienyl, furyl, isoxazolyl, isothiazolyl (the abovementioned groups are each optionally partially or fully halogenated), optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopropyl fentanyl, cyclohexanone carbonyl, bicyclo heptanyl, bicyclo fentanyl, non-cyclohexanone carbonyl or bicyclo heptanyl, hydroxy, cyano, an optionally partially or completely halogenated C _{1 -3} alkoxy, NH ₂ C (O) or a mono- or di - (C _{1 -3} alkyl) amino-carboxylic alkenyl optionally substituted C _{3 -10} branched or unbranched (herein, C _{3 -10} branched or unbranched alkenyl group is one More than O, N or S (O) _m is optionally interrupted);

Each optionally substituted with one to three C _{1 -3} alkyl substituted cyclopentenyl, cyclohexenyl, cyclohexanone dienyl, bicyclo heptenyl, bicyclo hepta-dienyl, non-cyclohexenyl or bicyclo heptenyl;

Cyano, F, Cl, Br or I;

Methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl;

Optionally partially or fully silyl containing a halogenated C _{1 -4} independently a branched or unbranched alkyl group;

C _{2 -6} branched or unbranched alkyl, -C (O), C _{2 -6} branched or unbranched -S, C _{2 -6} branched or unbranched -S (O), C _{2 -6} branched or Unbranched-S (O) ₂ ;

Optionally partially or completely halogenated C _{2 -6} branched or unbranched alkynyl group (where one or more of the methylene groups is optionally partially or fully halogenated, O, optionally being replaced by NH, and S (O) _m, wherein the alkynyl carbonyl group optionally 0-2 oxo groups, pyrrolidinyl, pyrrolyl, one or more by one or more halogen atoms, optionally substituted C _{1 -4} branched or unbranched alkyl, nitrile, morpholino, piperidinyl, piperazinyl, and imidazolyl, phenyl, pyridinyl, tetrazolyl, or being independently substituted with one or more of a halogen atom, optionally substituted C _{1 -4} branched or unbranched alkylamino).

In other embodiments of compounds of Formula (II), each R ¹ is independently, optionally partially or fully halogenated, and 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, Pyrazinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl (these are 1 to 5 halogens, optionally partially or fully halogenated C _1-6 minutes, respectively) Topographic or unbranched alkyl, C _3-8 cycloalkyl, C _5-8 cycloalkenyl, hydroxy, cyano, optionally partially or fully halogenated C _1-3 alkoxy and NH ₂ C (O) or mono- or C _3-10 branched or unbranched alkyl optionally substituted with di- (C _1-3 alkyl) aminocarbonyl). For example, each R ¹ is independently C _3-10 branched or unbranched alkyl.

In certain embodiments of a compound of Formula (II), each R ³ is independently

Hydrogen or each optionally optionally partially or completely halogenated, 1-3 phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione , Imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, isothiazolyl, quinolyl, isoquinolyl, indolyl, benzimida Zolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterridinyl, phthalazinyl, naphthylpyridinyl, quinoxalinyl, quinazolinyl, fury carbonyl, indazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, fentanyl, cyclohexanone carbonyl, bicyclo heptanyl, bicyclo fentanyl, non-cyclohexanone carbonyl, non- bicyclo heptanyl, phenyl C _{1 -5} alkyl, naphthyl C _{1 -5} alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heterocyclyl, aryloxy, nitro, amino, mono- or di - (C _1-3 alkyl) amino, phenylamino, naphthylamino, heterocyclyl, amino, NH ₂ C (O), mono- or di - (C _1-3 alkyl) amino carbonyl, C _{1 -5} alkyl, -C ( O) -C _{1 -4} alkyl, -C _1-5 alkyl, amino, mono- or di - (C _{1 -3} alkyl) amino -C _{1 -5} alkyl, amino, -S (O) _2, di - (C _{1 -3} alkyl) amino ^{_{-S (O) 2, R 7}} -C 1 -5 alkyl, R ⁸ -C _{1 -5} ^{alkoxy, R 9 -C (O) -C} 1 -5 alkyl, R ¹⁰ -C _{1 - 5} alkyl (R ¹¹⁾ N, carboxy-mono-or di - (C _{1 -5-alkyl)} amino optionally substituted phenyl, naphthyl, or heterocyclyl with;

Fused aryl selected from benzocyclobutanyl, indanyl, indenyl, dihydronaphthyl, tetrahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl, or cyclopentenopyridine, cyclohexanopyridine, cyclopentano Pyrimidine, cyclohexanopyrimidine, cyclopentanopyrazine, cyclohexanopyrazine, cyclopentanopyridazine, cyclopentanoindole, cyclohexanoindole, cyclobenzimidazole, cyclopentanoimidazole, cyclohexanoimida Fused heterocycles selected from sol, cyclopentanothiophene and cyclohexanothiophene (the fused aryl or fused heterocyclic ring may optionally be phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl , Pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazole ,-Triazolyl, isothiazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heteroaromatic heterocyclyl-oxy, heteroaryl, aryloxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heteroaryl or heterocyclic amino, NH ₂ C (O), mono- di or - (C _{1 -3} alkyl) amino carbonyl, C _{1 -4} alkyl, -C (O), C _{1 -5} alkyl amino -S (O) _2, mono- or di - (C _{1 -3} alkyl) amino -C _1-5 alkyl, R ¹² -C _{1 -5} alkyl, R ¹³ -C _{1 -5} ^{alkoxy, R 14 -C (O) -C} 1 -5 alkyl, R ¹⁵ -C _{1 -5} alkyl (R ¹⁶ ) independently substituted with 1 to 3 groups selected from N);

Optionally partially or fully halogenated, one to three optionally partially or completely halogenated C _{1 -3} alkyl, cyano, hydroxy C _{1 -3} alkyl or aryl optionally substituted by cyclopropyl, cyclobutyl to, fentanyl cycloalkyl, Cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl, or bicycloheptanyl, or one to three ring methylene groups are represented by O, S (O) _m , CHOH, C = O, C = S or NH Analogs of cyclopropyl, cyclobutyl, cyclopentanyl, cyclohexanyl, cycloheptanyl, bicyclopentanyl, bicyclohexanyl or bicycloheptanyl, independently substituted by;

Each optionally substituted with 1 to 3 C _{1 -3} alkyl cyclopentenyl, cyclohexenyl, cyclohexanone dienyl, bicyclo heptenyl, bicyclo hepta-dienyl, non-cyclohexenyl, bicyclo heptenyl;

Branched or unbranched C _{1 -4} alkyl-phenyl -C (O) -C _{0 -4} branched or unbranched alkyl, C _1-4 branched or unbranched alkyl, -C (O) -C _{0 -4} bun branched or unbranched alkyl, C _{1 -4} branched or unbranched alkyl-phenyl -S (O) _m -C _{0 -4} branched or unbranched alkyl;

Each optionally partially or fully halogenated minutes or R ¹⁷ optionally substituted with branched or unbranched C _{1 -6} alkyl, or C _{1 -6} branched or unbranched alkoxy group;

OR ^18, amino, or R ¹⁹ an optionally substituted C _{1 -5} branched or unbranched mono or di-alkylamino optionally substituted by a C _{1 -6} branched or unbranched alkyl or branched or C _{1 -6} Unbranched alkoxy;

Optionally partially or fully halogenated, one to three optionally partially or fully halogenated C _{1 -3} alkyl group optionally substituted by cyclopropyl-oxy, cyclobutyl-oxy, cyclopentyloxy, cyclohexyloxy, cyclo-heptyloxy (where , 1 to 3 ring methylene groups are independently replaced by O, S (O) _m , CHOH, C═O, C═S or NH);

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 ) —;

^{R 23 R 24 NC (O)} - in a C _{2 -6} alkenyl optionally substituted;

Optionally partially or completely halogenated C _{2 -6-alkynyl} branched or unbranched carbon chain (wherein one or more of the methylene groups is optionally partially or fully halogenated, O, is optionally replaced by an NH or S (O) _m, the alkynyl group optionally 0-2 oxo groups, pyrrolidinyl, pyrrolyl, one or more by one or more halogen atoms, optionally substituted C _{1 -4} branched or unbranched alkyl, nitrile, morpholino, piperidinyl , piperacillin search possess, already independently substituted with thiazolyl, phenyl, pyridinyl, tetrazolyl or one or more _1-4 minutes with a halogen atom, optionally substituted C branched or unbranched alkyl-amino); or

Benzoyl or naphthoyl,

Wherein R ⁷ , R ⁸ , R ⁹ , R ¹⁰ , R ¹² , R ¹³ , R ¹⁴ , R ¹⁵ , R ¹⁷ , R ¹⁹ and R ²⁵ are each independently cyano, morpholino, piperidinyl, pipe piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or an optionally partially or completely halogenated mono- or di - (C _{0 -4} alkyl) amino;

R ¹¹ and R ¹⁶ are each independently hydrogen, or an optionally partially or completely halogenated C _{1 -4} minutes, branched or unbranched alkyl;

R ¹⁸ is independently hydrogen, or an optionally oxo-substituted C _{1 -4,} or independently, branched or unbranched alkyl as R ^25.

In some of the foregoing embodiments of the compound of formula II, R ³ is each independently, each optionally optionally partially or fully halogenated, 1-3 phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, Pyrrolyl, pyrrolidinyl, 2,5-pyrrolidine-dione, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuryl, isoxazolyl, thiazolyl, oxazolyl, triazolyl, tetrazolyl, iso Thiazolyl, quinolyl, isoquinolyl, indolyl, benzimidazolyl, benzofuranyl, benzoxazolyl, benzoisoxazolyl, benzpyrazolyl, benzothiofuranyl, cinnolinyl, pterindinyl, phthala possess, naphthyl, pyridinyl, quinoxalinyl carbonyl, quinazolinyl, Fourier carbonyl, indazolyl, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, cyclopropyl, cyclobutyl, fentanyl, cyclohexanone Nyl, Cycloheptanyl, Bicyclopenta , Non-cyclohexanone carbonyl, bicyclo heptanyl, phenyl C _{1 -5} alkyl, naphthyl C _{1 -5} alkyl, hydroxy, oxo, cyano, optionally partially or completely halogenated C _{1 -3} alkoxy, phenyloxy, naphthyloxy, heterocyclyl, aryloxy, nitro, amino, mono- or di - (C _{1 -3} alkyl) amino, phenylamino, naphthylamino, heterocyclyl, amino, NH ₂ C (O), a mono- or di - (C _{1 -3} alkyl) amino carbonyl, C _{1 -5} alkyl, -C (O) -C _{1 -4} alkyl, -C _1-5 alkyl, amino, mono- or di - (C _{1 -3} alkyl) amino -C _{1 -5} alkyl, amino, -S (O) _2, di - (C _{1 -3} alkyl) amino ^{_{-S (O) 2, R 7}} -C 1 -5 alkyl, R ⁸ -C _{1 -5} alkoxycarbonyl, _{^{R 9 -C (O) -C 1}} -5 alkyl, R ¹⁰ -C _{1 -5} alkyl (R ¹¹⁾ N, or carboxy-mono- or di-optionally substituted phenyl amino (C _{1 -5} alkyl), Naphthyl or heterocyclyl. In another embodiment, R ³ are each optionally partially or fully halogenated, optionally partially or completely halogenated C _{1 -6} branched or unbranched alkyl, hydroxy, oxo, cyano, optionally partially or fully halogenated C _{1 -3} alkoxy, nitro, amino, or mono- or di - (C _{1 -3} alkyl) amino optionally substituted phenyl, pyridazinyl or pyridyl; Each optionally partially or fully halogenated, or R ^17, amino, OR ^18, R ¹⁹ optionally substituted with C _{1 -5-mono-} or di-alkyl amino, optionally substituted C _{1 -6} alkyl, C _{1 -6} alkoxy; 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 ) —. For example, R ³ is phenyl or tolyl.

In certain embodiments of compounds of Formula (II), X 'is NR', CR '= N or CR' = CR '.

According to another aspect of the invention, there is provided the following compounds, including representative examples of the compounds of formulas IA, IB, IC and II:

1H-indazol-3-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -amide;

3-tert-butyl-5-phenyl-1-p-tolyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalene- 1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-hydroxy-3-morpholin-4-ylmethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene-1- Il] -2-oxo-acetamide;

N- (5-tert-butyl-2-hydroxy-3-methyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo Acetamide;

N- (5-tert-butyl-2-methoxy-3-methyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2- Oxo-acetamide;

N- (5-tert-butyl-3-chloro-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo Acetamide;

N- (5-tert-butyl-2-methoxy-3-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [7-chloro-4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

5-tert-butyl-N-cyclopropyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetyl Amino} -benzamide;

N- [5-tert-butyl-2-methoxy-3- (piperidine-1-carbonyl) -phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide;

5-tert-Butyl-2-hydroxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -benzoic acid;

N- (2-benzenesulfonyl-5-tert-butyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

2- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

1-bicyclo [2.2.1] hept-2-yl-5-phenylamino-3-p-tolyl-1,3-dihydro-imidazo [4,5-b] pyridin-2-one;

3-p-tolyl-5-p-tolylamino-1,3-dihydro-imidazo [4,5-b] pyridin-2-one;

1-bicyclo [2.2.1] hept-2-yl-3-p-tolyl-5-p-tolylamino-1,3-dihydro-imidazo [4,5-b] pyridin-2-one;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2,2-difluoro-2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -N'-naphthalen-1-yl-oxalamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4- Mono-ethoxy) -naphthalen-1-yl] -acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-[(Z) -methoxyimino] -2- [4- (2-morpholine-4- Mono-ethoxy) -naphthalen-1-yl] -acetamide;

2- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamino) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl ]-ethanol;

1- (3-tert-butyl-phenyl) -4- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]-[1,2,4] triazolidine-3 , 5-dione;

4- (3-tert-butyl-phenyl) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]-[1,2,4] triazolidine-3 , 5-dione;

(E) -3- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl) -3- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -acrylic acid methyl ester;

N- (5-tert-butyl-2-methoxy-3- {3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2,5-dioxo- 2,5-dihydro-pyrrole-1-yl} -phenyl) -methanesulfonamide;

N- (5-tert-butyl-2-methoxy-3- {3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2,5-dioxo- Pyrrolidin-1-yl} -phenyl) -methanesulfonamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- Acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-oxo-2- [4- (2-piperidin-1-yl-pyrimidin-4-yljade C) -naphthalen-1-yl] -acetamide;

3-tert-butyl-1-p-tolyl-5- (3-trifluoromethyl-phenyl) -1,6-dihydro-imidazo [4,5-c] pyrazole;

1- (2-Morpholin-4-yl-ethyl) -1H-indazol-3-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -amide;

N- [4- (2-Morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-2- (2,4,6-trimethyl-phenyl) -acetamide;

1-phenyl-cyclopropanecarboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -amide;

N- [5-tert-butyl-2- (2,5-difluoro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetamide;

N- [5-tert-butyl-2- (3-chloro-benzoyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4- yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-2- (3-methanesulfonyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide;

4-[(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylcarbamoyl) -methyl] -piperidine-1-carboxylic acid tert-butyl ester;

N- [3- (benzenesulfonyl-carbamoylmethyl-amino) -5-tert-butyl-2-methoxy-phenyl] -2-naphthalen-1-yl-2-oxo-acetamide;

N- (3-tert-butyl-isoxazol-5-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-3-ethanesulfonylamino-2-methoxy-phenyl) -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- Succinic acid methyl ester;

2- (2-benzyl-5-tert-butyl-2H-pyrazol-3-yl) -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalene -1-yl] -2-oxo-acetamide;

5-tert-Butyl-2- (3-chloro-phenyl) -2H-pyrazole-3-carboxylic acid [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- amides;

2- (3-Bromo-4-methoxy-phenyl) -N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [3-fluoro-4- (2-morpholin-4- yl-ethoxy) -phenyl ] -Acetamide;

(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-(2,2-dimethyl-propyl) -amine;

2- (4-benzyloxy-phenyl) -N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-hydroxy-2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -acetamide;

N- [5-tert-butyl-2- (4-sulfamoyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl-2-oxo-acetamide;

5-tert-butyl-2-methoxy-3- (1-naphthalen-1-yl-3,5-dioxo- [1,2,4] triazolidin-4-yl) -benzamide;

2- (4-bromo-naphthalen-1-yl) -N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2-oxo-acetamide;

5-tert-butyl-2-hydroxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -benzamide ;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-hydroxy-2- (4-methoxy-naphthalen-1-yl) -acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1 -Yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-methylamino-pyrimidin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetamide ;

N- (5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-dimethylamino-pyrimidin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetamide ;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2- {4- [2- (1-oxo-1λ ⁴ -thiomorpholine- ⁴ -Yl) -ethoxy] -naphthalen-1-yl} -acetamide;

5-tert-butyl-3- {2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -Thiophene-2-carboxylic acid methyl ester;

N- [5-tert-butyl-2- (3-methanesulfonyl-phenyl) -2H-pyrazol-3-yl] -2-hydroxy-2- [4- (2-morpholin-4-yl -Ethoxy) -naphthalen-1-yl] -acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- {4- [2-((2R, 6R) -2,6-dimethyl-morpholine-4 -Yl) -ethoxy] -naphthalen-1-yl} -2-oxo-acetamide;

N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1- Il] -2-oxo-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [7-chloro-4- (2-morpholin-4-yl-ethoxy) -naphthalene-1 -Yl] -2-oxo-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl -Ethoxy) -naphthalen-1-yl] -acetamide;

N- (5-tert-butyl-2-methoxy-phenyl) -2- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -2-oxo Acetamide;

5-tert-butyl-N-cyclopropyl-2-methoxy-3- [2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetylamino] -benzamide;

4-tert-butyl-N- [4- (2-piperidin-1-yl-ethoxy) -naphthalen-1-yl] -benzamide;

N- (2-acetyl-5-tert-butyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide;

5-tert-butyl-N-cyclopropyl-3- {2-hydrazono-2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -2 Methoxy-benzamide;

N- (5-tert-butyl-2-methoxy-phenyl) -2-hydroxy-2- (4-methoxy-naphthalen-1-yl) -propionamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2-phenyl-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-hydrazono-2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -acetamide;

2,3-dihydro-indol-1-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -amide;

N- (3,4-Dimethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-cyclohexyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- (3,5-difluoro-phenyl) -acetamide;

N- (5-tert-butyl-2-methoxy-phenyl) -2-oxo-2- (4-pyridin-3-yl-naphthalen-1-yl) -acetamide;

N- (5-tert-butyl-isoxazol-3-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-diethylamino-ethoxy) -naphthalen-1-yl] -2-oxo Acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2- {4- [2- (3-oxo- [1,4] diazepan- 1-yl) -ethyl] -naphthalen-1-yl} -acetamide;

5-tert-butyl-N-ethyl-2-methoxy-3- [2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetylamino] -benzamide;

N- (5-tert-butyl-2-methoxy-phenyl) -2-oxo-2- {4- [6- (tetrahydro-pyran-4-ylamino) -pyridin-3-yl] -naphthalene- 1-yl} -acetamide;

5-tert-butyl-3-ethanesulfonylamino-2-methoxy-N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -benzamide;

2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2-oxo-N-m-tolyl-acetamide;

N- (2,5-dimethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

Pyrrolidine-1-carboxylic acid (5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetylamino} -phenyl) -amide;

2- (4-bromo-phenyl) -N- (5-tert-butyl-2-methoxy-phenyl) -acetamide;

N- (3-amino-5-tert-butyl-2-methoxy-phenyl) -2-oxo-2- {4- [2-((S) -1-phenyl-ethyl amino) -pyrimidine-4 -Ylamino] -naphthalen-1-yl} -acetamide;

5-tert-butyl-3- [1- (2,3-dimethyl-phenyl) -3,5-dioxo- [1,2,4] triazolidin-4-yl] -2-methoxy-benz amides;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-naphthalen-2-yl-acetamide;

5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -benzamide ;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-methoxy-2- (4-methoxy-naphthalen-1-yl) -propionamide;

5-tert-butyl-2-methoxy-N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-ylmethyl] -3-nitro-benzamide;

N- (5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -Phenyl) -benzamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- (2,5-difluoro-phenyl) -acetamide;

N- (3,5-di-tert-butyl-2-methoxy-phenyl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -acetamide;

N '-[1- (5-tert-butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -meth- (E) -ylidene] -hydrazinecarboxamide;

N- [2- (4-amino-phenyl) -5-tert-butyl-2H-pyrazol-3-yl] -2-hydroxy-2- [4- (2-morpholin-4-yl- Methoxy) -naphthalen-1-yl] -acetamide;

5-tert-butyl-3- {2-[(Z) -methoxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -Thiophene-2-carboxylic acid amide;

Ethanesulfonic acid (5-tert-butyl-2-methoxy-3- {3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2,5-dioxo- 2,5-dihydro-pyrrole-1-yl} -phenyl) -amide;

5-tert-butyl-N-cyclopropylmethyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo- Acetylamino} -benzamide;

5-Fluoro-1H-indazol-3-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -amide;

N- [5-tert-butyl-2-methoxy-3- (2-methoxy-acetylamino) -phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

7-bicyclo [2.2.1] hept-2-yl-9-p-tolyl-2-p-tolylamino-7,9-dihydro-purin-8-one;

N- (5-tert-butyl-2-isopropoxy-3-methanesulfonylamino-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-2- (3,4-dimethyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide;

3-tert-butyl-1- (3,4-dichloro-phenyl) -5-phenyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2- [4- (2-thiomorpholin-4-yl-ethoxy) -naphthalene -1-yl] -acetamide;

5-nitro-1H-pyrazole-3-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -amide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-dimethylamino-pyrimidin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetamide;

1- (2-Amino-4-tert-butyl-6- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino}- Phenyl) -pyridinium;

N- (5-tert-butyl-2-isopropoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide ;

N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2,5-bis-trifluoromethyl-benzamide;

2- (tert-butyl-dimethyl-silanyloxy) -N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- (4-methoxy-phenyl)- Acetamide;

N- (5-tert-butyl-2-m-tolyl-2H-pyrazol-3-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholine-4- Mono-ethoxy) -naphthalen-1-yl] -acetamide;

5-tert-butyl-2-methoxy-3- [2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetylamino] -benzamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2-phenyl-acetamide;

5-tert-butyl-2-methoxy-N- (2-methoxy-ethyl) -3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -benzamide;

(E) -3- (5-tert-butyl-3-ethanesulfonylamino-2-methoxy-phenylcarbamoyl) -3- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -acrylic acid methyl ester;

1-isopropyl-3-phenyl-5-phenylamino-1,3-dihydro-imidazo [4,5-b] pyridin-2-one;

N- (5-tert-butyl-isoxazol-3-yl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalen-1-yl] -2- Oxo-acetamide;

2- (2-benzyl-5-tert-butyl-2H-pyrazol-3-yl) -2-[(Z) -hydroxyimino] -N- [4- (2-morpholin-4-yl- Ethoxy) -naphthalen-1-yl] -acetamide;

2- (5-tert-butyl-2-methoxy-phenyl) -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- (2,4-dimethoxy-phenyl) -acetamide;

(5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -phenyl ) -Carbamic acid methyl ester;

3-tert-butyl-5- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -pyrazole-1-carboxyl Acid adamantan-1-ylamide;

3-tert-butyl-5-phenyl-1- (4-trifluoromethyl-phenyl) -1,6-dihydro-imidazo [4,5-c] pyrazole;

N- (5-tert-butyl-2-methoxy-3- {3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2,4,5-tri Oxo-imidazolidin-1-yl} -phenyl) -methanesulfonamide;

3-tert-butyl-1- (3-chloro-phenyl) -5-phenyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

5-tert-butyl-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -thiophene-2-carboxyl Acid amides;

2- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-hydroxy-N- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- {4- [2- (2,6-dimethyl-morpholin-4-yl) -ethyl] -Naphthalen-1-yl} -2-oxo-acetamide;

N- (5-tert-butyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acet amides;

N- [5-tert-butyl-2-methoxy-3- (propane-1-sulfonylamino) -phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -acetamide;

3-tert-butyl-5- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -pyrazole-1-carboxyl Acid tert-butylamide;

1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- (2,3-dichlorophenyl) -3 '-(carbamic acid ethyl ester) -urea;

2- (3,5-Difluoro-phenyl) -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

3-tert-butyl-5- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -pyrazole-1-carboxyl Acid amides;

N-allyl-5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino } -Benzamide;

N- (5-tert-butyl-isoxazol-3-yl) -2-[(Z) -methoxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -acetamide;

3- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -pyrrole -2,5-dione;

2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2-[(Z) -hydroxyimino] -N- [4- (2-morpholin-4-yl- Ethoxy) -naphthalen-1-yl] -acetamide;

3-tert-butyl-5-o-tolyl-1-p-tolyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-[(E) -hydroxyimino] -2-phenyl-acetamide;

N- (5-tert-butyl-2-methoxy-phenyl) -2-hydroxy-2-phenyl-acetamide;

N- (3-acetylamino-5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2- Oxo-acetamide;

1H-indazol-3-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -amide;

5-tert-butyl-2-methoxy-N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -3-nitro-benzamide;

5-tert-butyl-3- {2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalen-1-yl ] -Acetylamino} -thiophene-2-carboxylic acid amide;

N- [3- (4-acetyl-piperazin-1-carbonyl) -5-tert-butyl-2-methoxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -2-oxo-acetamide;

2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -N- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalene-1 -Yl] -2-oxo-acetamide;

N- (5-tert-butyl-4-methyl-2-p-tolyl-2H-pyrazol-3-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-mor Folin-4-yl-ethoxy) -naphthalen-1-yl] -acetamide;

2- [4- (2-Morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-N- (2-phenyl-cyclopropyl) -acetamide;

N- (5-tert-butyl-isoxazol-3-yl) -2- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -2-oxo Acetamide;

N- (5-tert-butyl-2,3-dimethoxy-phenyl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- (2-chloro-phenyl) -acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- {4- [2- (4-methyl-piperazin-1-yl) -ethyl] -naphthalene -1-yl} -2-oxo-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- (1H-indol-3-yl) -2-oxo-acetamide;

N- (5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-pyridin-4-ylamino) -naphthalen-1-yl] -2-oxo Acetamide;

N- (4-tert-butyl-6-trifluoromethyl-pyrimidin-2-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-o-tolyl-acetamide;

5-tert-butyl-3- {2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -Thiophene-2-carboxylic acid methylamide;

N- [5-tert-butyl-2- (3,5-dichloro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- {4- [2-((2R, 6S) -2,6-dimethyl-morpholine-4 -Yl) -ethoxy] -naphthalen-1-yl} -2-oxo-acetamide;

3-tert-butyl-1,5-diphenyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2-imidazol-1-yl-ethyl) -naphthalen-1-yl]- 2-oxo-acetamide;

3-tert-butyl-5- (3-chloro-phenyl) -1-p-tolyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

N- (5-tert-butyl-2-methoxy-3-phenylmethanesulfonylamino-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2- [4- (2-pyridin-4-yl-ethoxy) -naphthalene-1 -Yl] -acetamide;

1- (5-tert-butyl-2-methoxy-phenyl) -3- (4- {2-[(pyridin-2-ylmethyl) -amino] -pyrimidin-4-yloxy} -naphthalene-1 -Yl) -imidazolidine-2,4,5-trione;

N- [5-tert-butyl-2- (3-chloro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

5-methoxy-1H-indazol-3-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -amide;

N- [5-tert-butyl-2- (6-chloro-pyridazin-3-yl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-e Methoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-m-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- (2-methoxy-phenyl) -acetamide;

5-tert-Butyl-N-cyclopropyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalen-1-yl]- 2-oxo-acetylamino} -benzamide;

[(5-tert-Butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino}- Phenyl) -methanesulfonyl-amino] -acetic acid ethyl ester;

N- (5-tert-butyl-4-methyl-2-m-tolyl-2H-pyrazol-3-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-mor Folin-4-yl-ethoxy) -naphthalen-1-yl] -acetamide;

N- [5-tert-butyl-2- (2,5-dichloro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2- [1,4] oxazepan-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide;

1- (5-tert-butyl-2-methoxy-3-benzamide) -3- (4-methoxy-phenyl) -3 '-(carbamic acid ethyl ester) -urea;

N- [5-tert-butyl-2- (4-methoxy-phenyl) -2H-pyrazol-3-yl] -2- (4-methoxy-naphthalen-1-yl) -acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -4-chloro-benzamide;

N- (2-Bromo-5-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide ;

3-isopropyl-5-phenyl-1-p-tolyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

3,5-di-tert-butyl-1-p-tolyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

5-tert-butyl-N-cyclopentyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetyl Amino} -benzamide;

2- [5-tert-butyl-2- (3-fluoro-4-methyl-phenyl) -2H-pyrazol-3-yl] -N- [4- (2-morpholin-4-yl-e Methoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- (4-methoxy-phenyl) -2-oxo-acetamide;

1,3-di-tert-butyl-5-phenyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

4- (4-bromo-naphthalen-1-yl) -1- (3-tert-butyl-phenyl)-[1,2,4] triazolidine-3,5-dione;

N- [5-tert-butyl-2- (morpholin-4-carbonyl) -thiophen-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

3-tert-butyl-5- (3-methoxy-phenyl) -1-p-tolyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

N- (5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalen-1-yl] -2- Oxo-acetamide;

1-tert-butyl-5- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-ylamino] -3-p-tolyl-1,3-dihydro-imidazo [4 , 5-b] pyridin-2-one;

2- [5-tert-butyl-2- (3-fluoro-phenyl) -2H-pyrazol-3-yl] -2-[(Z) -hydroxyimino] -N- [4- (2- Morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetamide;

5-tert-butyl-2-p-tolyl-2H-pyrazole-3-carboxylic acid [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-ylmethyl] -amide;

2- [5-tert-butyl-2- (3-fluoro-phenyl) -2H-pyrazol-3-yl] -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl} -2-oxo-acetamide;

5-tert-butyl-N-cyclopropylmethyl-2-methoxy-3- [2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetylamino] -benzamide;

N- [5-tert-butyl-3- (3,3-diethyl-ureido) -2-methoxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-2- (4-fluoro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide;

N- (2-benzyl-5-tert-butyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-oxo-2- [4- (2-piperazin-1-yl-ethoxy) -naphthalene-1 -Yl] -acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-pyridin-4-ylamino) -naphthalene-1 -Yl] -2-oxo-acetamide;

(5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -phenyl ) -Carbamic acid isopropyl ester;

1- (5-tert-butyl-2-methoxy-phenyl) -3- [4- (2-dimethylamino-pyrimidin-4-yloxy) -naphthalen-1-yl] -imidazolidine-2 , 4,5-trione;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalene- 1-yl] -2-oxo-acetamide;

4- (3-tert-butyl-1-p-tolyl-1,6-dihydro-imidazo [4,5-c] pyrazol-5-yl) -2-methoxy-phenol;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- (3,4-dichloro-phenyl) -acetamide;

N- [3- (3-allyl-ureido) -5-tert-butyl-2-methoxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene-1 -Yl] -2-oxo-acetamide;

5-tert-butyl-N, N-diethyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo -Acetylamino} -benzamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2- [1,4] oxazepan-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

N- (3-tert-butyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

5-tert-butyl-N-ethyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -benzamide ;

N- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-2- (4-ureido-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-m-tolyl-2H-pyrazol-3-yl) -2- [4- (2-dimethylamino-ethoxy) -naphthalen-1-yl] -2-oxo Acetamide;

N- (5-tert-butyl-2-methoxy-phenyl) -2-oxo-2- [4- (2-piperidin-1-yl-pyrimidin-4-yloxy) -naphthalene-1- General] -acetamide;

N- [5-tert-butyl-2- (3-fluoro-4-methyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-e Methoxy) -naphthalen-1-yl] -2-oxo-acetamide;

Indazole-1-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -amide;

N- [3,5-bis- (1,1-dimethyl-propyl) -2-methoxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene-1- Il] -2-oxo-acetamide;

1-benzyl-3-tert-butyl-5-phenyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

2- (5-tert-butyl-2-methoxy-3-nitro-phenyl) -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo Acetamide;

4- {2- [4- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylaminooxalyl) -naphthalen-1-yloxy] -ethyl} -piperazine-1-car Acid ethyl esters;

2-hydroxy-N- (5-isopropyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4- yl-ethoxy) -naphthalene- 1-yl] -acetamide;

1-bicyclo [2.2.1] hept-2-yl-3-phenyl-5-phenylamino-1,3-dihydro-imidazo [4,5-b] pyridin-2-one;

N- (3-amino-5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalen-1-yl ] -2-oxo-acetamide;

N- [5-tert-butyl-3- (2-dimethylamino-acetylamino) -2-methoxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-methoxy-3- {6- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -3,5-dioxo- 2,5-dihydro-3H- [1,2,4] triazin-4-yl} -phenyl) -methanesulfonamide;

N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide;

(R) -N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-hydroxy-2-phenyl-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-dimethylamino-ethoxy) -naphthalen-1-yl] -2-oxo- Acetamide;

2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide;

N- [2- (3-amino-phenyl) -5-tert-butyl-2H-pyrazol-3-yl] -2-hydroxy-2- [4- (2-morpholin-4-yl-e Methoxy) -naphthalen-1-yl] -acetamide;

2- [5-tert-butyl-2- (3-chloro-phenyl) -2H-pyrazol-3-yl] -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

1,5-diphenyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

N- (5-tert-butyl- [1,3,4] thiadiazol-2-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholine-4- Mono-ethoxy) -naphthalen-1-yl] -acetamide;

N- (5-tert-butyl-3- {2-hydroxy-2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalen-1-yl] -ethylamino } -2-methoxy-phenyl) -methanesulfonamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -4-chloro-benzamide;

N- (5-tert-butyl-2-ethoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

(5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -phenyl ) -Carbamic acid 2-methoxy-ethyl ester;

(R) -N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-methoxy-2-phenyl-acetamide;

2- (5-tert-butyl-2-m-tolyl-2H-pyrazol-3-yl) -2-hydroxy-N- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -acetamide;

2-amino-N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-naphthalen-1-yl-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- Acrylamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2-imidazol-1-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (4-Bromo-3-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide ;

4- (4-benzyloxy-phenyl) -1- (3-tert-butyl-phenyl)-[1,2,4] triazolidine-3,5-dione;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [8-chloro-4- (2-morpholin-4-yl-ethoxy) -naphthalene-1 -Yl] -2-oxo-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-chloro-ethoxy) -naphthalen-1-yl] -2-oxo-acet amides;

5-tert-butyl-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -thiophene-2-carboxyl Acid dimethylamide;

1- (5-tert-butyl-isoxazol-3-yl) -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -imidazolidine-2, 4,5-trione;

N- (4-Chloro-3-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

1-benzoyl-3- (5-tert-butyl-2-methoxy-phenyl) -urea;

N '-[1- (5-tert-butyl-3-ethylcarbamoyl-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -meth- (Z) -ylidene] -hydrazinecarboxylic acid ethyl ester;

3-tert-butyl-5- (3-fluoro-phenyl) -1-p-tolyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

2- [3-bromo-4- (2-morpholin-4-yl-ethoxy) -phenyl] -N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl ) -Acetamide;

2- (2-Chloro-5-trifluoromethyl-phenyl) -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-2- (3-chloro-benzenesulfonyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide;

(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -carbamic acid p-tolyl ester;

N- (5-tert-butyl-2-diethylamino-3-methanesulfonylamino-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] Acetamide;

N- [5-tert-butyl-2-methoxy-3- (propane-1-sulfonylamino) -phenyl] -2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetamide ;

Propane-1-sulfonic acid (5-tert-butyl-2-methoxy-3- {4- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl-3,5-di Oxo- [1,2,4] triazolidin-1-yl} -phenyl) -amide;

3-amino-5-tert-butyl-2-methoxy-N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-ylmethyl] -benzamide;

2- [4- (2-Morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-N- (3-trifluoromethyl-phenyl) -acetamide;

4- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -6- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2H- [1,2,4] triazine-3,5-dione;

N- [5-tert-butyl-2- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -Naphthalen-1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-2-methoxy-3- (propane-1-sulfonylamino) -phenyl] -2- [4- (2-dimethylamino-pyrimidin-4-ylamino) -naphthalene -1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-phenyl-acetamide;

N- [5-tert-butyl-2-methoxy-3- (propane-1-sulfonylamino) -phenyl] -2- [4- (2-morpholin-4-yl-pyrimidin-4-yljade C) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- {4- [2- (2,6-dimethyl-morpholin-4-yl) -ethoxy] -Naphthalen-1-yl} -2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- (4-methoxy-naphthalen-1-yl) -acetamide;

3-tert-butyl-1-cyclohexyl-5-phenyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

3-tert-butyl-5- (4-fluoro-phenyl) -1-p-tolyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

N- (5-tert-butyl-2-methoxy-3- {4- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -3,5-dioxo- [1,2,4] triazolidin-1-yl} -phenyl) -methanesulfonamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2- {4- [2- (3-oxo-piperazin-1-yl)- Ethyl] -naphthalen-1-yl} -acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2- [4- (3-pyridin-4-yl-propoxy) -naphthalene-1 -Yl] -acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl -Ethoxy) -5,6,7,8-tetrahydro-naphthalen-1-yl] -acetamide;

N- [5-tert-butyl-2- (4-methanesulfonyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide;

2- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylcarbamoyl) -2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-imidazol-1-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide;

N- [5-tert-butyl-2- (3,5-dimethyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-pyridin-4-ylamino) -naphthalene- 1-yl] -2-oxo-acetamide;

N- {5-tert-butyl-3- [carbamoylmethyl- (propane-1-sulfonyl) -amino] -2-methoxy-phenyl} -2-naphthalen-1-yl-2-oxo-acet amides;

N '-[1- (5-tert-butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -meth- (Z) -ylidene] -hydrazinecarboxylic acid ethyl ester;

5-tert-butyl-N-cyclopropyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -benz amides;

N- [5-tert-butyl-2- (3-nitro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [3-chloro-4- (2-morpholin-4-yl-ethoxy) -phenyl] -2-oxo-acetamide;

N- (3-benzenesulfonylamino-5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide;

3-tert-butyl-5- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -pyrazole-1-carboxyl Acid cyclohexylamide;

N- [5-tert-butyl-2-methoxy-3- (2,2,2-trifluoro-ethanesulfonylamino) -phenyl] -2- [4- (2-morpholin-4-yl -Ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N '-[1- (5-tert-butyl-3-carbamoyl-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -meth- (E) -ylidene] -hydrazinecarboxylic acid ethyl ester;

5-tert-butyl-2-methoxy-N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -3- (propane-1- sulfonylamino) -benz amides;

N- (5-tert-butyl-2-methoxy-phenyl) -2-hydroxy-2- (4-methoxy-naphthalen-1-yl) -acetamide;

(5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -phenyl ) -Carbamic acid 2-dimethylamino-ethyl ester;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [7-fluoro-4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-isoxazol-3-yl) -2- [4- (2-morpholin-4-yl-pyridin-4-ylamino) -naphthalen-1-yl] -2-oxo Acetamide;

3-tert-butyl-1- (4-chloro-phenyl) -5-phenyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetamide;

2- [5-tert-butyl-2- (3,4-dimethyl-phenyl) -2H-pyrazol-3-yl] -2-[(Z) -hydroxyimino] -N- [4- (2 -Morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetamide;

N- (5-tert-butyl-isoxazol-3-yl) -2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetamide;

N- [5- (1,1-dimethyl-propyl) -2-p-tolyl-2H-pyrazol-3-yl] -2-hydroxy-2- [4- (2-morpholin-4-yl -Ethoxy) -naphthalen-1-yl] -acetamide;

N- [5-tert-butyl-2- (3-methoxy-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-dimethylamino-pyrimidin-4-ylamino)- Naphthalen-1-yl] -2-oxo-acetamide;

N- (2-Chloro-5-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [2,3-dichloro-4- (2-morpholin-4-yl-ethoxy) -phenyl ] -2-oxo-acetamide;

N- (3-methanesulfonylamino-2-methoxy-5-methyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2- Oxo-acetamide;

4- {2- [4- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylaminooxalyl) -naphthalen-1-yl] -ethyl} -piperazine-1-car Acid ethyl esters;

(1-benzyl-1H-benzoimidazol-2-yl)-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -amine;

N- (3,5-di-tert-butyl-2-hydroxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo Acetamide;

N- (5-tert-butyl-2-naphthalen-1-yl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene-1- Il] -2-oxo-acetamide;

N- (5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalen-1-yl] -2- Oxo-acetamide;

4- {2- [4- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylaminooxalyl) -naphthalen-1-yloxy] -ethyl} -piperazine-1- Carboxylic acid ethyl esters;

5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetyl Amino} -benzamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- (1-methyl-1H-indol-3-yl) -2-oxo-acetamide;

4-phenyl-piperidine-4-carboxylic acid (5-tert-butyl-2-methoxy-phenyl) -amide;

5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -benzamide;

N- [2- (4-acetyl-phenyl) -5-tert-butyl-2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] Imidazolidine-2,4,5-trione;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- (2,3-difluoro-phenyl) -acetamide;

N- [5-tert-butyl-3- (carbamoylmethyl-methanesulfonyl-amino) -2-methoxy-phenyl] -2-naphthalen-1-yl-2-oxo-acetamide;

N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2- [2-methyl-4- (2-morpholin-4-yl-ethoxy) -phenyl] -2 Oxo-acetamide;

N- [2- (4-Amino-phenyl) -5-tert-butyl-2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

(5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -phenyl ) -Carbamic acid phenyl ester;

N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acet amides;

N- (5-tert-butyl-2-isobutoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (4-tert-butyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-2- (3-methyl-benzoyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

5-tert-butyl-3- {2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -Thiophene-2-carboxylic acid amide;

1- (5-tert-butyl-2-methoxy-phenyl) -3- [4- (2-chloro-pyrimidin-4-yloxy) -naphthalen-1-yl] -imidazolidine-2, 4,5-trione;

(S) -N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-hydroxy-2-phenyl-acetamide;

N- [5-tert-butyl-2- (2,3-dimethyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-2- (4-nitro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

2- (5-tert-butyl-2-m-tolyl-2H-pyrazol-3-yl) -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

2-[(Z) -hydroxyimino] -N- (3-methanesulfonylamino-2-methoxy-5-methyl-phenyl) -2- [4- (2-morpholin-4-yl- Methoxy) -naphthalen-1-yl] -acetamide;

N- [5-tert-butyl-2- (morpholin-4-carbonyl) -thiophen-3-yl] -2-[(Z) -hydroxyimino] -2- [4- (2-mor Folin-4-yl-ethoxy) -naphthalen-1-yl] -acetamide;

N- (5-tert-butyl-2-phenyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide;

N '-[1- (5-tert-butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -meth- (E) -ylidene] -hydrazinecarboxylic acid ethyl ester;

N '-[1- (5-tert-butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -meth- (Z) -ylidene] -hydrazinecarboxamide;

N- [5-tert-butyl-2- (3-methoxy-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide;

5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -N- Pyridin-2-yl-benzamide;

N- [5-tert-butyl-3- (3,3-dimethyl-ureido) -2-methoxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide;

5-tert-butyl-3- {2- [7-chloro-4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -2-meth Oxy-benzamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-m-tolyl-acetamide;

1- (5-tert-butyl-2-methoxy-phenyl) -3- [4- (2-pyrrolidin-1-yl-pyrimidin-4-yloxy) -naphthalen-1-yl] -already Dazolidine-2,4,5-trione;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-hydroxy-2-phenyl-propionamide;

2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-N-quinolin-3-yl-acetamide;

1- (5-tert-butyl-2-m-tolyl-2H-pyrazol-3-yl) -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] Imidazolidine-2,4,5-trione;

(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-(3-trifluoromethyl-benzyl) -amine;

N- [5-tert-butyl-2-methoxy-3- (morpholine-4-carbonyl) -phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-3- (3-isopropyl-ureido) -2-methoxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-methoxy-2- (4-methoxy-naphthalen-1-yl) -acetamide;

N- (3-Amino-5-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalene-1 -Yl] -2-oxo-acetamide;

3-methyl-1,5-diphenyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

N- (5-tert-butyl-isoxazol-3-yl) -2-hydroxy-2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetamide ;

N- [4- (2-Morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-2- (2-phenyl-cyclopropyl) -acetamide;

2- {4- [2- (4-acetyl-piperazin-1-yl) -ethoxy] -naphthalen-1-yl} -N- (5-tert-butyl-3-methanesulfonylamino-2- Methoxy-phenyl) -2-oxo-acetamide;

2- (1H-Indol-3-yl) -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-2- (3-fluoro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide;

2- (3-amino-5-tert-butyl-2-methoxy-phenyl) -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo Acetamide;

N- [5-tert-butyl-2- (3,4-dichloro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-isoxazol-3-yl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalen-1-yl] -2- Oxo-acetamide;

N- [5-tert-butyl-2- (2,5-dimethyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -5,6,7,8 -Tetrahydro-naphthalen-1-yl] -2-oxo-acetamide;

1H-indazol-3-carboxylic acid (5-tert-butyl-2-pyridin-2-yl-2H-pyrazol-3-yl) -amide;

N- (4-Chloro-3-trifluoromethyl-phenyl) -2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetamide;

N- [5- (1,1-Dimethyl-butyl) -2-p-tolyl-2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide;

1H-indazol-3-carboxylic acid [5-tert-butyl-2- (4-methoxy-phenyl) -2H-pyrazol-3-yl] -amide;

1H-indazol-3-carboxylic acid [5-tert-butyl-2- (4-hydroxy-phenyl) -2H-pyrazol-3-yl] -amide;

N '-[1- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -meth- (E) -ylidene] -hydrazinecarboxamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -N '-[4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl ] -Oxalamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-methylamino-pyrimidin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-m-tolyl-2H-pyrazol-3-yl) -2-[(Z) -methoxyimino] -2- [4- (2-morpholine-4- Mono-ethoxy) -naphthalen-1-yl] -acetamide;

5-tert-Butyl-N-cyclopropyl-3- [2-[(E) -hydroxyimino] -2- (4-methoxy-naphthalen-1-yl) -acetylamino] -2-methoxy- Benzamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- {4- [2- (2,6-dimethyl-morpholin-4-yl) -ethoxy ] -Naphthalen-1-yl} -2-oxo-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [8-fluoro-4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- (3-fluoro-phenyl) -acetamide;

5-tert-butyl-N-furan-2-ylmethyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 -Oxo-acetylamino} -benzamide;

N- [5-tert-butyl-2- (3-trifluoromethyl-benzoyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -Naphthalen-1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-2-methoxy-3- (propane-1-sulfonylamino) -phenyl] -2- [4- (2-morpholin-4-yl-pyrimidin-4-yl Amino) -naphthalen-1-yl] -2-oxo-acetamide;

1- (5-tert-butyl-isoxazol-3-yl) -3- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalen-1-yl] -imida Zolidine-2,4,5-trione;

1- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -3 '-(Carbamic acid ethyl ester) -urea;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-oxo-2-4- [2- (3-oxo-piperazin-1-yl) -ethoxy ] -Naphthalen-1-yl} -acetamide;

2- {4- [2- (4-acetyl-piperazin-1-yl) -ethyl] -naphthalen-1-yl} -N- (5-tert-butyl-2-p-tolyl-2H-pyrazole -3-yl) -2-oxo-acetamide;

N- (5-tert-butyl-2-phenylacetyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2- {4- [2- (3-oxo-piperazin-1-yl)- Ethoxy] -naphthalen-1-yl} -acetamide;

2- (5-tert-butyl-2-m-tolyl-2H-pyrazol-3-yl) -2-[(Z) -hydroxyimino] -N- [4- (2-morpholin-4- Mono-ethoxy) -naphthalen-1-yl] -acetamide;

N- [5-tert-butyl-2- (3-ureido-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4- yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-[(Z) -methoxyimino] -2- [4- (2-morpholin-4-yl -Pyrimidin-4-yloxy) -naphthalen-1-yl] -acetamide;

N- [5-tert-butyl-2-methoxy-3- (3-oxo-piperazine-1-carbonyl) -phenyl] -2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -2-oxo-acetamide;

3-tert-butyl-5- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -pyrazole-1-carboxyl Acid propylamides;

5-tert-butyl-N-cyclopropyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalen-1-yl]- 2-oxo-acetylamino} -benzamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- {4- [2- (4-methyl-piperazin-1-yl) -ethoxy]- Naphthalen-1-yl} -2-oxo-acetamide;

N- (3-Amino-5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalen-1-yl ] -2-oxo-acetamide;

5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -N- Propyl-benzamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-hydroxy-2- (4-methoxy-phenyl) -acetamide;

N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl- Ethoxy) -naphthalen-1-yl] -acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- (3-phenoxy-phenyl) -acetamide;

N- (5-Isopropyl-2-methyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

7-isopropyl-9-phenyl-2-phenylamino-7,9-dihydro-purin-8-one;

(5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -phenyl ) -Carbamic acid pyridin-3-ylmethyl ester;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-ethylamino-ethoxy) -naphthalen-1-yl] -2-oxo- Acetamide;

N- (3,5-di-tert-butyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

2-amino-N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-naphthalen-2-yl-acetamide;

N- [5-tert-butyl-2- (3-fluoro-4-methyl-phenyl) -2H-pyrazol-3-yl] -2-hydroxy-2- [4- (2-morpholine- 4-yl-ethoxy) -naphthalen-1-yl] -acetamide;

2- [5-tert-butyl-2- (3,4-difluoro-phenyl) -2H-pyrazol-3-yl] -N- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -2-oxo-acetamide;

N- (3-Amino-5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-methylamino-pyrimidin-4-ylamino) -naphthalen-1-yl] -2- Oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalene -1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-2- (2,3-dichloro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide;

N- [3,5-bis- (1,1-dimethyl-propyl) -2-hydroxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene-1- Yl-2-oxo-acetamide;

4- {2- [4- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylaminooxalyl) -naphthalen-1-yloxy] -ethyl} -piperazine-1-car Acid tert-butyl esters;

3-tert-butyl-1-naphthalen-2-yl-5-phenyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

2-biphenyl-4-yl-N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -acetamide;

5-tert-butyl-N-isopropyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetyl Amino} -benzamide;

N- (5-tert-butyl-3-diethylaminomethyl-2-hydroxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide;

6-hydroxy-nicotinic acid 3- [5-tert-butyl-2-methoxy-3- (propane-1-sulfonylamino) -phenylcarbamoyl] -1H-indazol-5-yl ester;

N- (5-tert-butyl-2-m-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalene -1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalene-1 -Yl] -2-oxo-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (4-morpholin-4-yl-pyrimidin-2-ylamino) -naphthalene- 1-yl] -2-oxo-acetamide;

N- (3-amino-5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide;

1,3,5-triphenyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-cyclohexyl-acetamide;

2- [5-tert-butyl-2- (2-chloro-phenyl) -2H-pyrazol-3-yl] -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

7-cyclohexylmethyl-9-phenyl-2-phenylamino-7,9-dihydro-purin-8-one;

5-tert-butyl-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetyl amino} -thiophene-2-carboxyl Acid methylamides;

5-tert-butyl-N-cyclopropylmethyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino}- Benzamide;

N- [5-tert-butyl-2- (3-methoxy-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-pyrimidine-4- Monoamino) -naphthalen-1-yl] -2-oxo-acetamide;

N '-[1- (5-tert-butyl-3-carbamoyl-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -meth- (Z) -ylidene] -hydrazinecarboxylic acid ethyl ester;

4- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -1- (2,3-dimethyl-phenyl)-[1,2,4] triazolidine-3,5- Diones;

N- (4-Fluoro-3-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide ;

1-benzyl-3-phenyl-5-phenylamino-1,3-dihydro-imidazo [4,5-b] pyridin-2-one;

N- (5-tert-butyl-2-methoxy-phenyl) -2-naphthalen-2-yl-acetamide;

2- [4- (2-Morpholin-4-yl-ethoxy) -naphthalen-1-ylcarbamoyl] -pyrrole-1-carboxylic acid tert-butyl ester;

N- (2,5-di-tert-butyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

2- [4- (2-Morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-N-((1S, 2R) -2-phenyl-cyclopropyl) -acetamide;

2-oxo-2,3-dihydro-benzoimidazol-1-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -amide;

N- (2-methoxy-5-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide ;

N- [2- (4-Bromo-phenyl) -5-tert-butyl-2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide;

1- (5-tert-butyl-2-methoxy-phenyl) -3- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalen-1-yl] -imida Zolidine-2,4,5-trione;

5-tert-butyl-2-methoxy-N-methyl-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino } -Benzamide;

N- (5-tert-butyl-2-methoxy-3-piperidin-1-ylmethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene-1 -Yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-methoxy-phenyl) -2-naphthalen-1-yl-2-oxo-acetamide;

N- (2,5-di-tert-butyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide;

(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -carbamic acid 4-methoxy-phenyl ester;

N- (3-amino-5-tert-butyl-2-methoxy-phenyl) -2-naphthalen-1-yl-2-oxo-acetamide;

5-tert-butyl-N-ethyl-3- {2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -Acetylamino} -2-methoxy-benzamide;

4- {2- [4- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylaminooxalyl) -naphthalen-1-yl] -ethyl} -piperazine-1-car Acid tert-butyl esters;

5-tert-butyl-N-ethyl-2-hydroxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino } -Benzamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-naphthalen-1-yl-acetamide;

N- (5-tert-butyl-2-ethoxy-3-methanesulfonylamino-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide;

N '-[1- (5-tert-butyl-3-ethylcarbamoyl-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -meth- (E) -ylidene] -hydrazinecarboxamide;

2- {4- [2- (4-acetyl-piperazin-1-yl) -ethoxy] -naphthalen-1-yl} -N- (5-tert-butyl-2-p-tolyl-2H-pyra Zol-3-yl) -2-oxo-acetamide;

5-tert-butyl-N-ethyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino } -Benzamide;

5-tert-Butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -benzoic acid;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-hydroxy-2- [4- (2-morpholin-4-yl-ethoxy) -5, 6,7,8-tetrahydro-naphthalen-1-yl] -acetamide;

N- (5-tert-butyl-isoxazol-3-yl) -2- [4- (2-dimethylamino-pyrimidin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetamide ;

5-tert-butyl-3- {2- [4- (2-morpholin-4-yl-pyridin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetylamino} -thiophene- 2-carboxylic acid amides;

2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-N-m-tolyl-acetamide;

5-tert-butyl-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -thiophene-2-carboxyl Acid methyl esters;

N '-[1- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -meth- (Z) -ylidene] -hydrazinecarboxamide;

N- [5-tert-butyl-2- (3-methoxy-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-pyridin-4-yl Amino) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-isopropyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide;

N- (5-tert-butyl-isoxazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (2-benzoyl-5-tert-butyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide;

6-bromo-1H-indazol-3-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -amide;

5-tert-butyl-N-ethyl-3- {2-hydrazono-2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -2- Methoxy-benzamide;

N- (5-tert-butyl-3-ethanesulfonylamino-2-methoxy-phenyl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl -Ethoxy) -naphthalen-1-yl] -acetamide;

N- (3-amino-5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-dimethylamino-pyrimidin-4-ylamino) -naphthalen-1-yl] -2- Oxo-acetamide;

N- (5-tert-butyl-thiophen-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-2- (4-chloro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

N '-[1- (5-tert-butyl-3-carbamoyl-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -meth- (E) -ylidene] -hydrazinecarboxamide;

N- [5-tert-butyl-2- (4-methoxy-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide;

5-tert-butyl-3- {2- [7-chloro-4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -N-cyclo Propyl-2-methoxy-benzamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- {4- [2- (4-methyl-piperazin-1-yl) -ethoxy] -naphthalene -1-yl} -2-oxo-acetamide;

1- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] Imidazolidin-2-one;

N- (5-tert-butyl-thiophen-3-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -acetamide;

5-tert-Butyl-N-cyclopropyl-3- [2-[(Z) -hydroxyimino-2- (4-methoxy-naphthalen-1-yl) -acetylamino] -2-methoxy-benz amides;

N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2- [4- (4-morpholin-4-yl-pyrimidin-2-ylamino) -naphthalene-1 -Yl] -2-oxo-acetamide;

N- [5-tert-butyl-2- (3-methoxy-phenyl) -2H-pyrazol-3-yl] -2-[(Z) -hydroxyimino] -2- [4- (2- Morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetamide;

N- [2-methoxy-5- (1-methyl-1-phenyl-ethyl) -phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

2- [5-tert-butyl-2- (3,4-dimethyl-phenyl) -2H-pyrazol-3-yl] -N- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide;

5-tert-butyl-3- {2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetylamino} -thiophene 2-carboxylic acid amides;

5-tert-butyl-N-isobutyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetyl Amino} -benzamide;

2- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-[(Z) -hydroxyimino] -N- [4- (2-morpholin-4- Mono-ethoxy) -naphthalen-1-yl] -acetamide;

3-tert-butyl-1- (2,3-dichloro-phenyl) -5-phenyl-1,6-dihydro-imidazo [4,5-c] pyrazole;

N- (3,5-di-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo Acetamide;

5-tert-butyl-3- {2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -Thiophene-2-carboxylic acid dimethylamide;

N- (5-tert-butyl-2-methoxy-3-methyl-phenyl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -acetamide;

N '-[1- (5-tert-butyl-3-cyclopropylcarbamoyl-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy) -Naphthalen-1-yl] -meth- (E) -ylidene] -hydrazinecarboxylic acid ethyl ester;

N-indan-5-yl-2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-2- (3-chloro-4-fluoro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-e Methoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-3- (imidazol-1-carbonyl) -2-methoxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

2- (2,5-bis-trifluoromethyl-phenyl) -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acet amides;

N- [5-tert-butyl-2- (2,4-difluoro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -2-oxo-acetamide;

1H-indazol-3-carboxylic acid (5-tert-butyl-2-methoxy-phenyl) -amide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2-4- [2- (5-oxo- [1,4] diazepan-1 -Yl) -ethoxy] -naphthalen-1-yl} -acetamide;

3-tert-butyl-1-p-tolyl-5- (4-trifluoromethyl-phenyl) -1,6-dihydro-imidazo [4,5-c] pyrazole;

N- (5-tert-butyl-3-ethanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide;

3-tert-butyl-5- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -pyrazole-1-carboxyl Acid isopropylamide;

N- (5-tert-butyl- [1,3,4] thiadiazol-2-yl) -2-hydroxy-2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl -Pyrimidin-4-yloxy) -naphthalen-1-yl] -acetamide;

N- [2- (3-Amino-phenyl) -5-tert-butyl-2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

3-tert-butyl-5- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -pyrazole-1-carboxyl Acid phenylamides;

2- (5-tert-butyl-2-methyl-furan-3-yl) -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo- Acetamide;

N- (5-tert-butyl-2-o-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-isoxazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetamide;

N- (5-tert-butyl-2-methoxy-phenyl) -2- (3-methoxy-phenyl) -acetamide;

5-tert-butyl-3- {2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalen-1-yl] -2-oxo-acetylamino} -thiophene 2-carboxylic acid amides;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-hydroxy-2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -acetamide;

N- [5-tert-butyl-2- (2,4-dichloro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-isoxazol-3-yl) -2- [4- (3-hydroxy-propoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (3-tert-butyl-isoxazol-5-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -acetamide;

1H-indole-3-carboxylic acid (5-tert-butyl-2-methoxy-phenyl) -amide;

N- [5-tert-butyl-2-methoxy-3- (propane-1-sulfonylamino) -phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

7-bicyclo [2.2.1] hept-2-yl-9-phenyl-2-phenylamino-7,9-dihydro-purin-8-one;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- (2,4-dichloro-phenyl) -acetamide;

5-tert-butyl-2-methoxy-N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -benzamide;

N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2- [2,3-dimethyl-4- (2-morpholin-4-yl-ethoxy) -phenyl] -2-oxo-acetamide;

N- (5-tert-butyl-2-methoxy-phenyl) -2- (3-fluoro-phenyl) -acetamide;

1- (5-tert-butyl-2-methoxy-3-benzamide) -3- (2,3-dimethylphenyl) -3 '-(carbamic acid ethyl ester) -urea;

2- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2-oxo-N- (3-trifluoromethyl-phenyl) -acetamide;

7-benzyl-9-phenyl-2-phenylamino-7,9-dihydro-purin-8-one;

2,5-dihydro-1H-pyrrole-2-carboxylic acid (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -amide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-oxo-2- {4- [2- (5-oxo- [1,4] diazepan-1 -Yl) -ethoxy] -naphthalen-1-yl} -acetamide;

N- [5-tert-butyl-2- (3-cyano-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-methoxy-3-phenylacetylamino-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide;

2- (2-Chloro-5-trifluoromethyl-phenyl) -N- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalen-1-yl] -2- Oxo-acetamide;

1- (5-tert-butyl-2-methoxy-phenyl) -3- [4- (2-piperidin-1-yl-pyrimidin-4-yloxy) -naphthalen-1-yl] -already Dazolidine-2,4,5-trione;

2- (2-benzyl-5-tert-butyl-2H-pyrazol-3-yl) -2-hydroxy-N- [4- (2-morpholin-4-yl-ethoxy) -naphthalene-1 -Yl] -acetamide;

5-tert-butyl-3- {2- [4- (2-dimethylamino-pyrimidin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetylamino} -thiophen-2-car Acid amides;

N '-[1- (5-tert-butyl-3-ethylcarbamoyl-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -meth- (E) -ylidene] -hydrazinecarboxylic acid ethyl ester;

N- (3-methanesulfonylamino-5-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo- Acetamide;

N- (5-tert-butyl-2-hydroxy-3-piperidin-1-ylmethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene-1 -Yl] -2-oxo-acetamide;

2- (1-methyl-1H-indol-3-yl) -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-2-methoxy-phenyl) -2-oxo-2- {4- [2-((S) -1-phenyl-ethylamino) -pyrimidin-4-ylamino] -Naphthalen-1-yl} -acetamide;

N- [5-tert-butyl-2- (4-cyano-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide;

N '-[1- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -meth- (E) -ylidene] -hydrazinecarboxylic acid ethyl ester;

N- [5-tert-butyl-2- (3-methoxy-phenyl) -2H-pyrazol-3-yl] -2-hydroxy-2- [4- (2-morpholin-4-yl- Ethoxy) -naphthalen-1-yl] -acetamide;

N- (5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -Phenyl) -isobutyramide;

N- [5-tert-butyl-2- (4-methyl-benzoyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-2- (2-chloro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide;

N- [5-tert-butyl-2- (3-chloro-4-methyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -2-oxo-acetamide;

2- (4-Bromo-phenyl) -N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -acetamide;

2- (5-tert-butyl-2-methyl-furan-3-yl) -N- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl]- 2-oxo-acetamide;

4- (4- {4- [2- (5-tert-butyl-2-methyl-furan-3-yl) -2-oxo-acetylamino] -naphthalen-1-ylamino} -phenoxy) -pyridine 2-carboxylic acid methylamide;

N- [5-tert-butyl-2-methoxy-3- (propane-1-sulfonylamino) -phenyl] -2- [4- (2-morpholin-4-yl-pyridin-4-ylamino ) -Naphthalen-1-yl] -2-oxo-acetamide;

5-tert-butyl-N-cyclopropyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-pyridin-4-ylamino) -naphthalen-1-yl] -2 -Oxo-acetylamino} -benzamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-oxo-2- {4- [6- (tetrahydro-pyran-4-ylamino) -pyridine- 3-yl] -naphthalen-1-yl} -acetamide;

3- [2- (4-bromo-naphthalen-1-yl) -2-oxo-acetylamino] -5-tert-butyl-N-cyclopropyl-2-methoxy-benzamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (6-morpholin-4-yl-pyridin-3-yl) -naphthalene-1- Il] -2-oxo-acetamide;

N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (6-morpholin-4-ylethyl-pyridin-3-yl) -naphthalene- 1-yl] -2-oxo-acetamide;

N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-oxo-2- (4-pyridin-3-yl-naphthalen-1-yl) -acetamide;

N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2-oxo-2- (4-pyridin-3-yl-naphthalen-1-yl) -acetamide;

2- (4-Chloro-3-trifluoromethyl-phenyl) -N- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; or

4- {4- [2- (4-Chloro-3-trifluoromethyl-phenyl) -2-oxo-acetylamino] -phenoxy} -pyridine-2-carboxylic acid methylamide.

In another aspect, the invention provides a pharmaceutical composition comprising a compound as described herein (eg, a compound of Formula IA, IB, IC or II) and a pharmaceutically acceptable carrier.

According to a further aspect of the invention there is provided a method of making a cytokine inhibitor of the invention. For example, by reacting G-NH ₂ with QL-Ar-X-OH in the presence of a coupling agent and a base, or by reacting G-NH ₂ with QL-Ar-XX "in the presence of a base, Formula IA compound comprising obtaining a compound wherein variables G, Q, L are as defined in any of the compounds described herein, X is C (O) or C (S), and X "is the active moiety ) Manufacturing method. GXX "and Q-1-Ar-NH ₂ can be used to analogously prepare compounds of formula (IB).

In another aspect of the present invention, the present invention provides a compound of formula II wherein G (NO) -NH-CH ₂ -Ar-1-Q is heated with a suitable organic amine, wherein G, Ar, L, and Q A process for preparing a compound of formula II wherein X 'is NH, comprising obtaining (as defined in formula II).

In another aspect of the invention, the present invention provides a compound of formula III suitable for preparing a compound of the present invention, such as a compound of formula IB.

In compounds of formula III, the pyrazole moiety is substituted with one or more R ¹ , R ² or R ³ at 1-position, 3-position or both;

X "'is OR ^x or an active moiety;

R ^x is H, a substituted or unsubstituted C _{1 -4} alkyl, or substituted or unsubstituted aralkyl group, and;

R ¹ are each independently F, Cl, Br, I, cyano, -C (O) R, -C (O) NR ₂ , -C (O) OR, -OR, -SiR ₃ , -NR ' _{R ', -S (O) m} R, substituted or unsubstituted linear or branched C _{1 -10} alkyl, C _2-10 alkenyl ring, or a C _{2 -10} alkynyl, substituted or unsubstituted C _{3 - 10} cycloalkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl or heterocyclyl Alkyl (containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, S (O) _m ),

R ² are each independently, F, Cl, Br, I, cyano, substituted or unsubstituted linear or branched C _{1 -6-alkyl,} ring substituted or unsubstituted C _{6 -10} aryl, substituted or unsubstituted 5-10 membered heteroaryl, -OR ', -OR ⁶ , -C (O) R', -C (O) OR ', -C (O) NR' ₂ , -NR ' ₂ , -NO ₂ , -S (O) _m R ", NR'SO ₂ R", -NR'C (O) NR'R ', -NR'C (S) NR'R', -NR'C (O) OR ' Or -SO ₂ NR ' ₂ ,

R ^3, independently, is H, a substituted or unsubstituted C _{6 -10} aryl group, a substituted or unsubstituted, saturated or unsaturated 3-11 member heterocyclyl, or heterocyclylalkyl (N, O, S (O) _m independently selected from 1, 2, 3, or 4 also contain a hetero atom), a substituted or unsubstituted C _{3 -12} cycloalkyl, substituted or unsubstituted C _{5 -12} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted linear or branched C _{1 -8} alkyl, R ²⁰ C (O) ring ^{N (R 21) -, R} 22 O-, R 23 R 24 NC (O _{^{) -, R 26 (CH 2}} ) m C (O) N (R 21) -, R 26 C (O) (CH 2) m N (R 21) -, substituted or unsubstituted C _{2 -8} al alkenyl, or substituted or unsubstituted and an unsubstituted C _2-8 alkynyl, said C _{1 -8} alkyl, C _2-8 alkenyl, or C and one or more of the methylene of _2-8 alkynyl group O, NH, or S ( O) is optionally substituted with _m ,

R, R ', R ", R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁶ and m are as defined for any compound described herein.

In another aspect, the invention relates to administering to a subject in need thereof a therapeutically effective amount of a compound as defined herein, eg, a compound of formulas IA, IB, IC and / or II. It provides a method of preventing or treating the disease. The cytokine-mediated diseases include rheumatoid arthritis, osteoarthritis, Crohn's disease, ulcerative colitis, psoriatic arthritis, traumatic arthritis, rubella arthritis, inflammatory bowel disease, multiple sclerosis, psoriasis, graft-versus-host disease, systemic Lupus erythematosus, toxin shock syndrome, irritable bowel syndrome, muscle degeneration, allograft rejection, pancreatitis, insulin salts, glomerulonephritis, diabetic nephropathy, kidney fibrosis, chronic renal failure, gout, leprosy, acute synovitis, Reiter's syndrome syndrom), gouty arthritis, Behcet's disease, spondylitis, endometriosis, non-joint inflammatory symptoms such as intervertebral disc syndrome, bursitis, tendinitis, hay fever or myofascial syndrome; And acute or chronic pain (nerve system pain, neuropathic pain, polyneuropathic pain, diabetes-related polyneuropathic pain, trauma, migraine headaches, tension headaches and cluster headaches, Horton's disease, varicose ulcers) , Neuralgia, musculoskeletal pain, bone-traumatic pain, fracture, painful dysplasia, spondyloarthritis, fibromyalgia, ring pain, back pain, spinal pain, postoperative pain, intervertebral herniation-induced sciatica, cancer-related pain, vascular pain, visceral Sexual pain, labor, or HIV-related pain). Other cytokine-mediated diseases include stroke, chronic heart failure, endotoxemia, reperfusion injury, ischemic reperfusion, myocardial hurdle, restenosis, blood clots, angiogenesis, coronary heart disease, coronary heart disease, acute heart syndrome, Takayasu arteritis ), Heart failure, such as heart failure, cardiomyopathy, myocarditis, vasculitis, vascular restenosis, valve disease or coronary artery bypass; Diseases or conditions associated with hypercholesterolemia, blood clotting or fibrinolysis, such as acute venous thrombus, pulmonary embolism, thrombus during pregnancy, hemorrhagic skin necrosis, acute or chronic disseminated intravascular coagulation (DIC), surgical clot formation, long-term Bed rest or long-term immobilization, venous thrombosis, bleeding meningococcal bacteremia, acute thrombotic stroke, acute heart occlusion, acute peripheral artery occlusion, extensive pulmonary embolism, axillary venous thrombus, extensive intestinal femoral vein thrombus, occlusive arterial or venous intubation , Cardiomyopathy, hepatic venous obstructive disease, hypotension, decreased cardiac output, decreased vascular resistance, pulmonary hypertension, decreased pulmonary purity, leukopenia or thrombocytopenia; Or atherosclerosis. Other diseases include allergic conjunctivitis, uveitis, glaucoma, optic neuritis, retinal ischemia, diabetic retinopathy, laser damage, or proliferative vitreoretinopathy due to surgery or trauma. Cytokine mediated diseases further include allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, emphysema, bronchitis, mucus hypersecretion, silicosis, SARS infection, and respiratory tract inflammation. It also includes psoriasis, eczema, atopic dermatitis, contact dermatitis, or acne. Other cytokine mediated diseases include Guillain-Barre syndrome, Parkinson's disease, Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis and other demyelinating diseases, Viral and bacterial meningitis, CNS trauma, spinal cord injury, seizures, convulsions, olive cerebellar atrophy, AIDS dementia complications, MERRF and MELAS syndromes, Leber's disease, Wernicke's encephalophathy, Rett Syndrome, homocysteineuria, hyperprolinemia, hyperhomocysteinemia, non-ketone hyperglycinemia, hydroxybutyr aminouria, sulfite oxidase deficiency, complex system disease, encephalopathy, Tourette syndrome, hepatic encephalopathy, drug addiction , Drug resistance, drug dependence, depression, anxiety and schizophrenia, aneurysm or epilepsy. In another aspect of the invention cytokine mediated diseases include bone resorption diseases, osteoporosis, osteoporosis or osteoarthritis. It also includes secondary cachexia for diabetes mellitus, systemic cachexia, infection or malignancy, secondary cachexia for acquired immunodeficiency syndrome (AIDS), obesity, anorexia or neurophagia. In addition, cytokine-mediated diseases include sepsis, HIV, HCV, malaria, infectious arthritis, Lyshumania, Lyme disease, cancer (breast cancer, colon cancer, lung cancer, prostate cancer, multiple myeloma, acute myeloid leukemia, myelodysplastic syndrome, non Hodgkin's lymphoma, or vesicle lymphoma, Castleman's disease, or drug resistance.

In another aspect, the invention relates to administering to a subject in need thereof a therapeutically effective amount of a compound as described herein (including a compound of Formulas IA, IB, IC, and / or II). Including a method of treating the disease, wherein the neutrophil mediated disease is bronchial asthma, rhinitis, influenza, stroke, myocardial infarction, heat injury, adult respiratory distress syndrome (ARDS), secondary multiple organ injury to trauma, acute glomeruli Nephritis, dermatitis with acute inflammatory components, acute purulent meningitis, hemodialysis, leukocytosis, granulocyte transfusion related syndromes, or necrotizing colitis.

Combination therapies with cytokine inhibitors have beneficial therapeutic effects, in particular additive or additive effects, or reduce treatment side effects as a whole. This beneficial therapeutic effect is desirable for the treatment of cytokine mediated diseases described herein, specifically for the treatment of rheumatoid arthritis, Crohn's disease and psoriasis. As such, in another aspect, the invention provides a method of administering one or more, typically one, active ingredient (hereinafter referred to as A) described herein in combination with one or more, typically one or more, cytokine inhibitors of the invention. It provides a method of treating cytokine-mediated diseases, including. The additive or additive-above effects of the pharmaceutical combinations according to the invention provide for reduced doses, reduced side effects and / or longer intervals compared to the individual compounds and A and cytokine inhibitors used in monotherapy in the usual manner. The above-mentioned effects are observed both in the case of simultaneous administration of two active substances in a single active substance formulation and in the case of successive administration of them in separate formulations. For injectable A, in particular biological agents, other advantages may be seen for adding cytokine inhibitors. Cost savings, for example by reducing intervals and / or dosages.

Various active ingredients A are contemplated for use in the combinations of the present invention. For example, non-steroidal anti-inflammatory drugs (NSAIDs; widely used to treat inflammation, pain and fever) can be used. The NSAIDs include acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodollac, phenopropene calcium, flurbiprofen, indomethacin, ketoprofen, Carpropene, Indopropene, Ketorolac Tromethamine, Magnesium Salicylate, Meclofenamate Sodium, Mephenamic Acid, Oxaprozin, Pyroxycam, Sodium Salicylate, Sulindac, Tolmetin, Meloxycam , Lofecoxib, celecoxib, etoricoxib, valdecoxib, nabumethone, naproxen, romoxicam, nimesulide, indopropene, remifenzone, salsalate, thiapropenic acid, flosulfide, etc. Include.

Angiogenesis inhibitors can provide as A for example compounds for VEGF, Taxol, Pentoxifylline and Thalidomide.

A biological agent is to be understood as meaning any natural or artificial / synthetic biomolecule or fragment thereof known in the art, such as antibodies, proteins, fusion proteins, receptors, nucleic acids, lipids, carbohydrates and the like. Accordingly, active ingredient A may be a biological agent such as etanercept, infliximab, alefacept, adalimumab, efalizumab, anakinra, IL-1RA, alpha-interferon, interferon beta 1-B, CTLA- 4, and other antibodies or receptor constructs against TNF-alpha, IL1-6, LFA-1 and C5.

For active ingredient A steroids such as glucocorticoids, and vitamin D3 and analogs thereof (cholecalciferol) are present within the scope of the present invention alone or in combination (the latter mostly used for psoriasis). Steroids include budesonide, dexamethasone, fluorosinide, hydrocortisone, betamethasone, halobetasol (ullobetasol), methylprednisolone, prednisolone, clobetason, deplazacort, fluorinonelone acetonide, fluticasone, triamcinolone Acetonide, mometasone and diflucortolone. Among the vitamin D3 derivatives are calcipotriol, tacalcitol, vaxacalcitol, and tacalitol, anticalcium hormone, 1α, 2,5-dihydroxyvitamin D3, and parathyroid hormone-related peptides.

Many types of immunomodulatory drugs, immunosuppressive drugs or cytostatic drugs can be combined with cytokine inhibitors. Exemplary agents include hydroxychloroquine, D-phenicamine, sulfasalazine, auranopine, gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, sirolimus, Pimecrolimus, mycophenolate mofetil, cyclosporin, leflunomide, methotrexate, azathioprine, cyclopospamide, macrolide, ascomycin, hydroxyurea, 6-thioguanine, (Orfanos C E., 1999, Cutis 64 (5): 347-53]); Alefacept, leflunomide, infliximab, etanercept, efalizumab, anti-CD4, anti-CD25, peptide T, LFA3TIP, ICAM-1 ISIS 2302, DAB ₃₈₉ , CTLA-4Ig, anti- CD80 such as IDEC-114 or ABX-IL8, DAB-IL-2, IL-10, anti-TAC, basiliximab and daclizumab. Also suitable as active ingredient A are agents or therapeutic agents that act on other targets, or immune mediated products. These include, for example, inhibitors of protein tyrosine kinase (PTK), such as epidermal growth factor receptor (EGFR), E-selectin inhibitors, and therapeutic agents widely used in psoriasis, such as anthraline, coal tar, medium wavelength ultraviolet light ( phototherapy, including ultraviolet B; UVB) or psoralen ultraviolet A (PUVA), photodynamic therapy, and laser therapy.

Retinoid therapeutics can also be used as active ingredient A. As such, for example bexarotene, excitretin, etretinate and tazarotene, and hydroxyurea, 6-thioguanine and phototherapy are suitable active ingredients. (Orfanos C E., 1999, Cutis 64 (5): 347-53); see also Saurat J H., 1999, J. Am. Acad. Derm. 41 (3 Pt 2): S2-6 ] Reference).

Active ingredient A useful in the present invention further includes small molecule inhibitors for enzymes involved in signaling pathways or cell adhesion molecules such as LFA-1 or ICAM-1.

In another aspect, there is provided the aforementioned pharmaceutical combination for use as a pharmaceutical composition having anti-cytokine activity, which typically comprises a therapeutically effective amount of A and a cytokine inhibitor. Moreover, combinations comprising A and cytokine inhibitors can be used to prepare pharmaceutical compositions for the treatment and / or prophylaxis of cytokine mediated diseases or conditions. Pharmaceutical formulations containing one or more compound combinations comprising A and cytokine inhibitors as active substances further comprise pharmaceutically acceptable derivatives thereof, and may optionally be combined with conventional excipients and / or carriers.

For treatment, the pharmaceutical combination of A and a cytokine inhibitor according to the invention can be administered in any conventional manner, including any route described herein. As such, routes of administration include, but are not limited to, intravenous, intramuscular, subcutaneous, intravaginal, infusion, sublingual, transdermal, oral, topical, and inhalation. Typical modes of administration are oral, topical or intravenous administration.

Pharmaceutical combinations of A and cytokine inhibitors according to the invention can be isolated or enhance the stability of the inhibitor or facilitate the administration of pharmaceutical compositions containing them, increase dissolution or dispersion, increase inhibitor activity or adjuvant Or in combination with other active ingredients or adjuvants that provide similar benefits. Such combination therapy typically avoids possible toxicity and side effects that occur when less conventional treatments are administered and when these agents are used alone. Thus, pharmaceutical combinations of A and cytokine inhibitors may be physically combined with conventional therapeutics or other adjuvants in a single pharmaceutical composition. The active ingredient A and / or cytokine inhibitors can be used in combination as salts, solvates, tautomers and / or prodrugs or as a mixture of stereoisomers, including single stereoisomers or racemates.

The proportion at which the two active substances, A and cytokine inhibitors, can be used in the combination according to the invention is variable. Active substance A and cytokine inhibitors are optionally present in the form of their solvates or hydrates. Depending on the choice of Compound A and cytokine inhibitors, the weight ratios that can be used within the scope of the present invention vary based on the different molecular weights of the various compounds and their different efficacy. Determination of the weight ratio depends in particular on the active ingredient A and cytokine inhibitors.

In the case of psoriasis, known combination therapies are used as effective and circulatory therapies to maintain palliation or as a combination therapy when refractory to conventional systemic products. Most combinations work in different ways to improve efficacy or reduce side effects by decreasing dosage. See Van de Kerkhof, P. 1997 Clinics in Dermatology, 15: 831-834, which has suggested topical steroids or vitamin D of interest and systemic agents. Two widely accepted combinations include medium wavelength ultraviolet (UVB) or soralene long wavelength ultraviolet (PUVA) plus retinoids; Methotrexate, or a combination of cyclosporin and retinoid.

Typical combinations for the treatment of psoriasis include cytokine inhibitor compounds and cyclosporine, pimecrolimus, tacrolimus, ascomycin, anti-CD4, anti-CD25, peptide T, LFA3TIP, DAB ₃₈₉ , CTLA-4Ig, E- Selectin inhibitors, alefacept, infliximab, etanercept, efalizumab, and those disclosed in Griffiths, Christopher EM, 1998 Hospital Medicine, Vol 59 No 7, and their apparent variants Immunotherapy drugs, including. Another common combination for treating psoriasis is a cytokine inhibitor compound and methotrexate (MTX). The combination will be effective because of the good tolerability of MTX in the short term, and the tolerability when a relieved maintenance is obtained with good quality over a sustained period. Another typical combination for the treatment of psoriasis is cytokine inhibitors and cyclosporin, especially because of the efficacy of cyclosporin on inducing remission. Another embodiment of the present invention comprises administering in the following order: induction with cytokine inhibitors and cyclosporine, followed by a reduced dose to sustain the cytokine inhibitors and stop the cyclosporin. Another typical combination for treating psoriasis is a cytokine inhibitor compound and a retinoid. Retinoids provide minimal efficacy with the risk of potential Cyt P450 interactions and terogenicity, which will be alleviated by continuous treatment with cytokine inhibitors. Another typical combination for the treatment of psoriasis is a topically active ingredient A selected from cytokine inhibitors and glucocorticoids, vitamin D derivatives, topical retinoids and ditianol. More typical combinations for the treatment of psoriasis are cytokine inhibitor compounds and vitamin D derivatives (most typically portolol or tacalcitol). Another typical combination for the treatment of psoriasis is cytokine inhibitors and macrolides (most typically topically ascomycin analogs, and even more typically orally available such as pimecrolimus). Another typical combination for treating psoriasis is cytokine inhibitors and cell adhesion molecule inhibitors (eg anti LFA3 and anti LFA1). This includes blocking adhesion molecules by alefacept, recombinant fusion proteins such as anti LFA3-IgCl or anti-CD11 monoclonal antibodies, efalizumab, and their apparent variants. Cell adhesion molecule inhibitors appear to present limited tolerability problems with acceptable reaction rates. Combination with cytokine inhibitors often avoids the drawbacks of their injectable forms with CAM inhibitors used occasionally. Another embodiment of the invention comprises administration in the following order: induction with cytokine inhibitors and CAM inhibitors, followed by maintenance of the cytokine inhibitors alone and treatment with CAM inhibitors in case of significant relapse.

Another typical combination for treating psoriasis is a cytokine inhibitor compound and another anti-TNF-alpha active ingredient. Typical embodiments are those wherein the other anti-TNF-alpha active ingredient is selected from infliximab or etanercept and is typically infliximab. Infliximab is believed to have a higher rate of response for induction of remission, which has recently been shown to persist over time. It is within the scope of the present invention to use topical or general antisense inhibitors of TNF alpha, such as ICAM-1 ISIS 2302 with cytokine inhibitor compounds. Another typical combination for treating psoriasis is a cytokine inhibitor compound with an anti-CD4, anti-CD80 (EDC-114 or ABX-IL8), DAB IL-2, DAB ₃₈₉ IL-2, CTLA4-Ig, IL10, IL2 receptor inhibitors. Such as daclizumab (anti-TAC), basiliximab. Tutron, WD, 2001, Biologic Therapy for Psoriasis vol 68; Tutron, WD, 2001, Biologic Therapy for Psoriasis vol 68; Ben-Bassat, H. 2001 Current Opinion in Investigational Drugs Vol 2 No 11 See Salim, A. et al, 2001 Current Opinion in Investigational Drugs Vol 2 No 11).

Any of the above-mentioned combinations within the scope of the present invention can be tested with animal models known in the art. See, for example, Schon, Michael P. 1999 Animal models of Psoriasis--What can we learn from them, The Society for Investigative Dermatology--Reviews, Vol 112. 4,405-410.

In the case of rheumatoid arthritis, the combination of immunosuppressive drugs or immunomodulatory drug agonists is a well-established therapeutic paradigm. Combination patterns are prevalent from various therapeutic entities. Their identification is based on experimental data or well-defined modes of action supported by deriving from knowledge of the underlying mechanisms. These agents are generally referred to as disease modifying antirheumatic drugs (DMARDs) or slow acting antirheumatic drugs (SAARDs). Apart from the combinations listed below, combinations of cytokine inhibitors with one or more agents classified as DMARD / SAARD or NSAID and / or corticosteroids are contemplated herein.

Typical combinations for the treatment of rheumatoid arthritis include one or more of the following immunosuppressive drugs, immunomodulatory drugs, or cytostatic drugs such as, for example, hydroxychloroquine, D-phenicylamine, sulfasalazine, aurapine, Gold sodium thiomalate, minocycline, dapsone, chlorambucil, mercaptopurine, tacrolimus, sirolimus, mycophenolate mofetil, cyclosporine, leflunomide, methotrexate, azathioprine and Cytokine inhibitor compounds in combination with cyclophosphamide. Another typical combination for the treatment of rheumatoid arthritis is an cytokine inhibitor compound in combination with an angiogenesis inhibitor, such as a compound for VEGF, taxol, pentoxifylline, thalidomide, interferon beta-1B and alpha-interferon. Another typical combination for the treatment of rheumatoid arthritis is a cytokine inhibitor compound and a cell adhesion inhibitor such as a FA-1 or ICAM-1 inhibitor.

More typical combinations for the treatment of rheumatoid arthritis include anti-TNF antibodies or TNF-receptor antagonists such as etanercept, infliximab, adalimumab (D2E7), or biological agents such as CTLA-4, or CD-4. , Cytokine inhibitor compounds in combination with biological agents for LFA-1, IL-6, ICAM-1 and C5. In another embodiment, the cytokine inhibitor is combined with infliximab and methotrexate. Another typical combination for the treatment of rheumatoid arthritis is a cytokine inhibitor compound and a receptor antagonist (eg, Kineret). Another typical combination for the treatment of rheumatoid arthritis is a non-steroidal anti-inflammatory drug (NSAID) (acetaminophen, aspirin, ibuprofen, choline magnesium salicylate, choline salicylate, diclofenac, diflunisal, etodollac , Phenopropene calcium, flubiprofen, indomethacin, ketoprofen, carpropene, indopropene, ketorolac tromethamine, magnesium salicylate, meclofenamate sodium, mephenamic acid, oxa Prozin, Pyroxycham, Sodium Salicylate, Sulindac, Tolmetin, Meloxycham, Rofecoxib, Celecoxib, Erytocoxib, Valdecoxib, Nabumetone, Naproxen, Romoxicam, Nimesul Cytokine inhibitor compounds in combination with reed, indopropene, remifenzone, salsalate, thiapropenoic acid, flosulfide and the like. Another typical combination for the treatment of rheumatoid arthritis is a cytokine inhibitor compound in combination with a glucocorticosteroid (eg, betamethasone, dexamethasone, methylprednisolone, prednisolone, and deplazacort).

Any of the above-mentioned combinations within the scope of the present invention can be tested with animal models known in the art. (Wooley, PH 1998, Animal models of arthritis, in Klippel JH, Dieppe, PA, (eds.) Rheumatology, second edition, 5.8.1-5.8.6.Mosby, London, Philadelphia, St. Louis, Sydney, Tokio].

For Crohn's disease, the following groups of drugs in combination with cytokine inhibitors can be effective: steroids such as budesonide, mesalamine-like 5-ASA drugs, immunosuppressants, biological agents and adhesion molecule inhibitors. Typical combinations for treating Crohn's disease are cytokine inhibitor compounds and one or more of the following substances: steroids, 5-ASA, methotrexate and azathioprine, including all listed herein. Another typical combination for the treatment of Crohn's disease is a cytokine inhibitor compound in combination with an IL-1 receptor antagonist (eg, kineret). Another typical combination for treating Crohn's disease is a cytokine inhibitor compound and an anti-TNF antibody or TNF-receptor antagonist such as etanercept, infliximab, adalimumab (D2E7), or a biological agent (eg CTLA- 4) or a biological agent against a target such as CD-4, LFA-1, IL-6, ICAM-1 and C5. In another embodiment, the cytokine inhibitor is combined with infliximab and methotrexate. More typically, cytokine inhibitors are combined with infliximab. Another typical combination for treating Crohn's disease is a cytokine inhibitor compound in combination with IL-10, ISIS 2302 (anti ICAM 1), or Antegren (VCAM receptor antagonist).

Cytokine inhibitors have an inhibitory effect on the procoagulant and profibrinolytic response of human endotoxin. Accordingly, the present invention provides a method of anticoagulant and fibrinolysis for a disease or condition comprising administering to a patient in need thereof a disease or condition relating to blood coagulation or fibrinolysis. . Such administration may be prophylactically beneficial to patients at risk of developing complications associated with these routes or therapeutically to affected patients.

Also within the scope of the invention are combination therapies of cytokine inhibitors and one or more other anticoagulants or fibrinolytic agents. These include recombinant tissue plasminogen activators (rtPA), streptokinase (SK), urokinase (UK), proUK, heparin, enoxoparin, dalteparin, coumarin anticoagulant, aspirin, dipyrimidamol, agrenox, Ticlopidine, clopidogrel (Plavix), absiksimab, Rheopro, integrinin, agrestat, and the like. Certain dosages, formulations, and methods of administration, alone or in combination, exist in the art.

The following terms are used as generally defined below.

In general, reference to a specific element, such as hydrogen or H, is meant to include all isotopes of that element. For example, where the R group is defined to include hydrogen or H, it also includes deuterium and tritium. Thus, isotopically labeled compounds are within the scope of the present invention.

The term "unsubstituted alkyl" refers to an alkyl group that does not contain heteroatoms. Thus, the term includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The term also includes branched chain isomers of straight chain alkyl groups, for example -CH (CH ₃ ) ₂ , -CH (CH ₃ ) (CH ₂ CH ₃ ), -CH (CH ₂ CH ₃ ) ₂ , -C ( CH ₃ ) ₃ , -C (CH ₂ CH ₃ ) ₃ , -CH ₂ CH (CH ₃ ) ₂ , -CH ₂ CH (CH ₃ ) (CH ₂ CH ₃ ), -CH ₂ CH (CH ₂ CH ₃ ) ₂ , -CH ₂ C (CH ₃ ) ₃ , -CH ₂ C (CH ₂ CH ₃ ) ₃ , -CH (CH ₃ ) CH (CH ₃ ) (CH ₂ CH ₃ ), -CH ₂ CH ₂ CH (CH ₃ ) ₂ , -CH ₂ CH ₂ CH (CH ₃ ) (CH ₂ CH ₃ ), -CH ₂ CH ₂ CH (CH ₂ CH ₃ ) ₂ , -CH ₂ CH ₂ C (CH ₃ ) ₃ , -CH ₂ CH ₂ C (CH ₂ CH ₃ ) ₃ , -CH (CH ₃ ) CH ₂ CH (CH ₃ ) ₂ , -CH (CH ₃ ) CH (CH ₃ ) CH (CH ₃ ) ₂ , -CH (CH ₂ CH ₃ ) CH (CH ₃ ) CH (CH ₃ ) (CH ₂ CH ₃ ), and the like, but is not limited thereto. The term also includes cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and rings substituted with straight and branched chain alkyl groups as defined above. The term also includes polycyclic alkyl groups such as, for example, adamantyl, norbornyl and bicyclo [2.2.2] octyl (but not limited to), and rings substituted with straight and branched chain alkyl groups as defined above. Included. Thus, the term unsubstituted alkyl group includes primary alkyl groups, secondary alkyl groups and tertiary alkyl groups. Unsubstituted alkyl groups may be bonded to one or more carbon atom (s), oxygen atom (s), nitrogen atom (s) and / or sulfur atom (s) in the parent compound. Typical unsubstituted alkyl groups include straight and branched chain alkyl groups and cyclic alkyl groups of 1 to 20 carbon atoms, and more typical such groups have 1 to 10 carbon atoms. Even more typical such groups, also known as unsubstituted lower alkyl, have from 1 to 5 carbon atoms. Typically, unsubstituted alkyl groups include straight and branched chain alkyl groups of 1 to 3 carbon atoms and include methyl, ethyl, propyl and -CH (CH ₃ ) ₂ .

The term "substituted alkyl" means that one or more bonds to carbon (s) or hydrogen (s) may be selected from non-hydrogen and non-carbon atoms, such as halogen atoms such as F, Cl, Br and I; Oxygen atoms in groups such as hydroxyl groups, alkoxy groups, aryloxy groups and ester groups; Sulfur atoms in groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl groups and sulfoxide groups; Nitrogen atoms in groups such as in amines, amides, alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides, and enamines; Silicon atoms in groups such as in trialkylsilyl groups, dialkylarylsilyl groups, alkyldiarylsilyl groups and triarylsilyl groups; And unsubstituted alkyl groups as defined above, which are substituted with other heteroatoms in, but not limited to, various other groups. Substituted alkyl groups also include one or more bonds to carbon (s) or hydrogen (s) atoms, such as oxygen in groups such as heteroatoms such as carbonyl, carboxyl and esters; Groups substituted with nitrogen in groups such as imines, oximes, hydrazones and nitriles. Preferred substituted alkyl groups include, among others, alkyl groups in which one or more bonds to carbon or hydrogen atoms have been replaced by one or more bonds to fluorine atoms. One example of a substituted alkyl group is a trifluoromethyl group and another alkyl group containing a trifluoromethyl group. Other alkyl groups include those in which one or more bonds to carbon or hydrogen atoms are replaced with bonds to oxygen atoms such that the substituted alkyl group contains a hydroxyl, alkoxyl, aryloxy group or heterocyclyloxy group. Other alkyl groups include amines, alkylamines, dialkylamines, arylamines, (alkyl) (aryl) amines, diarylamines, heterocyclylamines, (alkyl) (heterocyclyl) amines, (aryl) (heterocycles And an alkyl group having a aryl) amine or a diheterocyclyl amine group.

The term "alkylene" typically refers to a saturated divalent straight or branched chain hydrocarbyl group in the range of about 2 to about 20 carbon atoms or less, and "substituted alkylene" is one or more as described above. It refers to the alkylene group which further has a substituent.

The term "unsubstituted aryl" refers to an aryl group that does not contain heteroatoms. Thus, the term includes, but is not limited to, for example, groups such as phenyl, biphenyl, anthracenyl, naphthyl. The term "unsubstituted aryl" includes groups containing a condensed ring, such as naphthalene, but since aryl groups, such as tolyl, are considered to be substituted aryl groups as described herein below, they are bonded to one of the ring members. Aryl groups having other groups, such as alkyl or halo groups, are not included. Typical unsubstituted aryl groups are phenyl. However, unsubstituted aryl groups may be bonded to one or more carbon atom (s), oxygen atom (s), nitrogen atom (s) and / or sulfur atom (s) of the parent compound.

The term "substituted aryl group" has the same meaning for an unsubstituted aryl group as having a substituted alkyl group for an unsubstituted alkyl group. However, substituted aryl groups also include aryl groups in which one of the aromatic carbons is bonded to one of the non-carbon or non-hydrogen atoms described above, and wherein at least one aromatic carbon of the aryl group is substituted as defined herein. And aryl groups bonded to unsubstituted and / or unsubstituted alkyl (including cycloalkyl), alkenyl, alkynyl, aralkyl, heterocyclyl or heterocyclylalkyl groups. This includes a bonding arrangement in which two carbon atoms of the aryl group are bonded to two atoms of an alkyl, alkenyl or alkynyl group to define a fused ring system (eg dihydronaphthyl or tetrahydronaphthyl). Moreover, substituted aryl groups include unsubstituted aryl or aryl groups bonded to aryl substituted with one or more aromatic carbons of the aryl group with any of the groups described above except for another aryl. Thus, the term "substituted aryl" includes, but is not limited to, tolyl and hydroxyphenyl, among others.

The term "unsubstituted alkenyl" refers to straight and branched and cyclic chains, such as those described for unsubstituted alkyl groups as defined above, except that one or more double bonds are present between two carbon atoms. Refer to the group. Examples include vinyl, -CH = CH (CH ₃ ), -CH = C (CH ₃ ) ₂ , -C (CH ₃ ) = CH ₂ , -C (CH ₃ ) = CH (CH ₃ ), among others. -C (CH ₂ CH ₃ ) = CH ₂ , cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl and hexadienyl.

The term "substituted alkenyl" has the same meaning for an unsubstituted alkenyl group as the substituted alkyl group has for an unsubstituted alkyl group. Substituted alkenyl groups include alkenyl groups in which a non-carbon or non-hydrogen atom is carbon double bonded to another carbon and one of the non-carbon or non-hydrogen atoms is bonded to a carbon not associated with a double bond to another carbon. Included. Typically, unsubstituted alkenyl groups have 2 to 20 carbons, and in some embodiments such groups have 2 to 10 carbons.

The term "alkenylene" refers to a divalent straight or branched chain hydrocarbyl group having one or more carbon-carbon double bonds, typically in the range of about 2-20 carbon atoms or less, "substituted alkenylene" It refers to an alkenylene group further having one or more substituents as described above.

The term "unsubstituted alkynyl" refers to straight and branched chain groups, such as those described for unsubstituted alkyl groups as defined above, except that one or more triple bonds are present between two carbon atoms. Examples include -C≡CH, -C≡C (CH ₃ ), -C≡C (CH ₂ CH ₃ ), -CH ₂ C≡CH, -CH ₂ C≡C (CH ₃ ), and- CH ₂ C≡C (CH ₂ CH ₃ ), but is not limited thereto. Typically, unsubstituted alkynyl groups have 2 to 20 carbons, and in some embodiments such groups have 2 to 10 carbons.

The term "substituted alkynyl" has the same meaning for an unsubstituted alkynyl group as the substituted alkyl group has for an unsubstituted alkyl group. Substituted alkynyl groups include alkynyl groups in which a non-carbon or non-hydrogen atom is triple bonded to another carbon and one of the non-carbon or non-hydrogen atoms bonded to a carbon that is not associated with triple bonds to another carbon. Things are included.

The term "unsubstituted aralkyl" refers to an unsubstituted alkyl group as defined above wherein the hydrogen or carbon bond of the unsubstituted alkyl group is replaced with a bond to an aryl group as defined above. For example, methyl (-CH ₃ ) is an unsubstituted alkyl group. When the hydrogen atom of a methyl group is replaced by a bond to a phenyl group, for example when carbon of methyl is bonded to carbon of benzene, this compound is an unsubstituted aralkyl group (ie benzyl group). Thus, the term includes, but is not limited to, groups such as benzyl, diphenylmethyl and 1-phenylethyl (-CH (C ₆ H ₅ ) (CH ₃ )), among others.

The term "substituted aralkyl" has the same meaning for an unsubstituted aralkyl group as the substituted aryl group has for an unsubstituted aryl group. However, substituted arylalkyl groups also include groups in which the carbon or hydrogen bond of the alkyl portion of the group is replaced by a bond to a non-carbon or non-hydrogen atom. Examples of unsubstituted aralkyl groups include, but are not limited to, —CH ₂ C (═O) (C ₆ H ₅ ) and —CH ₂ (2-methylphenyl).

The term "unsubstituted heterocyclyl" refers to monocyclic, bicyclic and polycyclic containing at least three ring members wherein at least one of the ring members is a heteroatom such as, but not limited to, N, O and S. It refers to both aromatic and nonaromatic ring compounds, including ring compounds. The term "unsubstituted heterocyclyl" includes condensed heterocyclic rings, such as benzimidazolyl, but since compounds such as 2-methylbenzimidazolyl are substituted heterocyclyl groups, these include Heterocyclyl groups having other groups, such as alkyl or halo groups, bonded to one of them are not included. Examples of heterocyclyl groups are unsaturated 3 to 8 membered rings containing 1 to 4 nitrogen atoms, for example pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridinyl, dihydropyridinyl, pyri Midyl, pyrazinyl, pyridazinyl, triazolyl (eg 4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), Tetrazolyl (eg 1H-tetrazolyl, 2H-tetrazolyl, etc.); 3 to 8 membered rings containing 1 to 4 nitrogen atoms such as, but not limited to, pyrrolidinyl, imidazolidinyl, piperidinyl, piperazinyl; Condensed unsaturated heterocyclic groups containing 1 to 4 nitrogen atoms, for example indolyl, isoindoleyl, indolinyl, indolinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, Benzotriazolyl (but not limited to); Unsaturated 3-8 membered rings containing 1-2 oxygen atoms, for example oxazolyl, isoxazolyl, oxdiazolyl (eg 1,2,4-oxadiazolyl, 1,3,4- Oxadiazolyl, 1,2,5-oxadiazolyl, and the like); Saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such as but not limited to morpholinyl; Unsaturated condensed heterocyclic groups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example benzoxazolyl, benzoxadiazolyl, benzoxazinyl (eg 2H-1,4- Benzoxazinyl and the like) (but not limited to); Unsaturated 3 to 8 membered rings containing 1 to 3 sulfur atoms and 1 to 3 nitrogen atoms, for example thiazolyl, isothiazolyl, thiadiazolyl (eg 1,2,3-thiadiazolyl , 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl and the like); Saturated 3-8 membered rings containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such as but not limited to thiazolodinyl; Saturated and unsaturated 3 to 8 membered rings containing 1 to 2 sulfur atoms such as but not limited to thienyl, dihydrodithiyl, dihydrodithionyl, tetrahydrothiophene, tetrahydrothiopyran ; Unsaturated condensed heterocyclic groups containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example benzothiazolyl, benzothiadiazolyl, benzothiazinyl (eg 2H-1,4- Benzothiazinyl and the like), dihydrobenzothiazinyl (eg, 2H-3,4-dihydrobenzothiazinyl and the like); Unsaturated 3-8 membered rings containing oxygen atoms, such as but not limited to furyl; Unsaturated condensed heterocyclic rings containing 1 to 2 oxygen atoms, such as, but not limited to, benzodioxolyl (eg, 1,3-benzodioxolyl, etc.); Unsaturated 3 to 8 membered rings containing one oxygen atom and one to two sulfur atoms, such as, but not limited to, dihydrooxatiinyl; Saturated 3 to 8 membered rings containing 1 to 2 oxygen atoms and 1 to 2 sulfur atoms, such as, but not limited to, 1,4-oxatian; Unsaturated condensed rings containing 1 to 2 sulfur atoms such as but not limited to benzothienyl, benzodithiinyl; And unsaturated condensed heterocyclic rings containing 1 to 2 oxygen atoms, such as, but not limited to, benzoxathyinyl. Heterocyclyl groups also include those described above wherein one or more S atoms in the ring are double bonded to one or two oxygen atoms (sulfoxide and sulfone). For example, heterocyclyl groups include tetrahydrothiophene oxide and tetrahydrothiophene 1,1-dioxide. Typical heterocyclyl groups contain 5 or 6 ring members. Exemplary heterocyclyl groups include morpholine, piperazine, piperidine, pyrrolidine, imidazole, pyrazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, thiophene , Thiomorpholine, thiomorpholine, wherein the S atom of thiomorpholine is bonded to one or more O atoms, pyrrole, homopiperazin, oxazolidin-2-one, pyrrolidin-2-one, oxa Sol, quinuclidin, thiazole, isoxazole, furan and tetrahydrofuran.

The term "substituted heterocyclyl" refers to an unsubstituted heterocyclyl group as defined above wherein one or more ring members are bonded to a non-hydrogen atom as described above for the substituted alkyl group and the substituted aryl group. . Examples include 2-methylbenzimidazolyl, 5-methylbenzimidazolyl, 5-chlorobenzthiazolyl, 1-methyl piperazinyl, 2-phenoxy-thiophene and 2-chloropyridinyl, among others. But it is not limited thereto. In addition, substituted heterocyclyl groups include a bond to a non-hydrogen atom, substituted and unsubstituted aryl, substituted and unsubstituted, wherein the substituents include any of those described above except for another heterocyclyl group. Also included are heterocyclyl groups that are bonded to a carbon atom that is part of an aralkyl, unsubstituted heterocyclyl or substituted heterocyclyl. Examples include 1-benzylpiperidinyl, 3-phenylthiomorpholinyl, 3- (pyrrolidin-1-yl) -pyrrolidinyl and 4- (piperidin-1-yl) -piperidinyl But it is not limited thereto.

The term "unsubstituted heterocyclylalkyl" refers to an unsubstituted alkyl group as defined above wherein the hydrogen or carbon bond of the unsubstituted alkyl group is replaced by a bond to a heterocyclyl group as defined above. For example, methyl (-CH ₃ ) is an unsubstituted alkyl group. When the hydrogen atom of the methyl group is replaced by a bond to a heterocyclyl group, for example when carbon of methyl is bonded to carbon 2 of pyridine (one of the carbons is bonded to N of pyridine) or carbon 3 or 4 of pyridine, This compound is an unsubstituted heterocyclylalkyl group.

The term "substituted heterocyclylalkyl" has the same meaning for an unsubstituted heterocyclylalkyl group as the substituted aralkyl group has for an unsubstituted aralkyl group. However, substituted heterocyclylalkyl groups also have a non-hydrogen atom bonded to a heteroatom in the heterocyclyl group of the heterocyclylalkyl group, for example, but not limited to, a nitrogen atom in the piperidine ring of the piperidinylalkyl group. The group can be mentioned. In addition, substituted heterocyclylalkyl groups also include groups in which the carbon bond or hydrogen bond of the alkyl portion of the group is replaced by a bond to substituted and unsubstituted aryl or substituted and unsubstituted aralkyl groups. Examples include, but are not limited to, phenyl- (piperidin-1-yl) -methyl and phenyl- (morpholin-4-yl) -methyl.

The term “unsubstituted alkoxy” refers to a hydroxyl group (—OH) in which a bond to a hydrogen atom is replaced with a bond to a carbon atom of another unsubstituted alkyl group as defined above.

The term “substituted alkoxy” refers to a hydroxyl group (—OH) in which a bond to a hydrogen atom is replaced with a bond to a carbon atom of an otherwise substituted alkyl group as defined above.

The term "protected" for hydroxyl, amine and sulfhydryl groups is described in Protective Groups in Organic Synthesis, Greene, T. W .; Wuts, PGM, John Wiley & Sons, New York, NY, (3rd Edition, 1999)] are undesirable, which may be added or removed using the procedures described herein using protecting groups known to those skilled in the art. Refers to the form of the functional group protected from the reaction. Examples of protected hydroxyl groups include those obtained by the reaction of hydroxyl groups with reagents such as, but not limited to, t-butyldimethyl-chlorosilane, trimethylchlorosilane, triisopropylchlorosilane, triethylchlorosilane Silyl ethers such as those; Substituted methyl and ethyl ethers such as methoxymethyl ether, methylthiomethyl ether, benzyloxymethyl ether, t-butoxymethyl ether, 2-methoxyethoxymethyl ether, tetrahydropyranyl ether, 1- to Oxyethyl ether, allyl ether, benzyl ether, including but not limited to; Esters such as, but not limited to, benzoylformate, formate, acetate, trichloroacetate and trifluoroacetate. Examples of protected amine groups include amides such as formamide, acetamide, trifluoroacetamide and benzamide; Imides such as phthalimide and dithiosuccinimide; Carbamates such as, but not limited to, t-butyl carbamate (Boc), fluorenylmethyl carbamate (Fmoc) and benzyl carbamate (Cbz), and the like. Examples of protected sulfhydryl groups include thioethers such as S-t-butyl thioether, S-benzyl thioether and S-4-picolinyl thioether; Substituted S-methyl derivatives such as, but not limited to, hemithio, dithio and aminothio acetals.

“Pharmaceutically acceptable salts” include salts with inorganic bases, organic bases, inorganic acids, organic acids, or basic or acidic amino acids. As salts of inorganic bases, the present invention includes, for example, alkali metals such as sodium or potassium; Alkaline earth metals such as calcium and magnesium or aluminum; And ammonia. As salts of organic bases, the present invention includes, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine and triethanolamine. As salts of inorganic acids, the present invention includes, for example, hydrochloric acid, hydroboric acid, nitric acid, sulfuric acid and phosphoric acid. As salts of organic acids, the present invention includes, for example, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid. As salts of basic amino acids, the present invention includes, for example, arginine, lysine and ornithine. Acidic amino acids include, for example, aspartic acid and glutamic acid.

Certain compounds within the scope of Formulas IA, IB, IC and II are derivatives referred to as prodrugs. The expression “prodrug” is a derivative of known direct functional drugs, eg esters and amides, in which the derivative has enhanced delivery properties and therapeutic properties relative to the drug, and is converted to the active drug by enzymatic or chemical processes. (See, eg, Notari, RE, "Theory and Practice of Prodrug Kinetics," Methods in Enzymology 112 : 309-323 (1985)); Bod, N., "Novel Approaches in Prodrug Design," Drugs of the Future 6 : 165-182 (1981); and Bungaard, H., "Design of Prodrugs: Bioreversible-Derivatives for Various Functional Groups and Chemical Entities," in Design of Prodrugs (H. Bundgaard, ed.), Elsevier, New York (1985), Goodman and Gilmans, The Pharmacological Basis of Therapeutics , 8th ed., McGraw-Hill, Int. Ed. 1992). The above references and all references listed herein are hereby incorporated by reference in their entirety.

Tautomers refer to isomeric forms of compounds that are in equilibrium with each other. The concentration of the isomeric form will depend on the environment in which the compound is found, and can be different depending on, for example, whether the compound is a solid or an organic solution or an aqueous solution. For example, in aqueous solution, the ketone is typically in equilibrium with its enol form. Thus, ketones and their enols are referred to as tautomers of each other. As will be readily appreciated by those skilled in the art, a wide variety of functional groups and other structures may exhibit tautomerism, and all tautomers of the compounds of Formulas IA, IB, and IC are within the scope of the present invention.

Compounds of the present invention include optical isomers enriched or cleaved at any or all asymmetric carbons as will be apparent from the description. Both racemic and diastereomeric mixtures, and individual optical isomers, can be isolated or synthesized substantially free of their enantiomeric or diastereomeric partners, all of which are within the scope of the present invention.

"Treatment" within the context of the present invention may, in whole or in part, alleviate a symptom associated with a disorder or disease, or stop further progression or exacerbation of the symptom, or prevention or prophylaxis of the disease or disorder. it means. Similarly, as used herein, a "therapeutically effective amount" of a compound of the present invention, in whole or in part, alleviates symptoms associated with a disorder or disease, or stops further progression or exacerbation of such symptoms, , Or an amount of a compound that prevents or provides prophylaxis for a disease or disorder. Treatment can also include administering a pharmaceutical formulation of a compound of the invention in combination with other therapies. For example, the compounds and pharmaceutical formulations of the present invention may be administered before, during or after surgical procedures and / or radiation treatment. Alternatively, the compounds of the present invention can also be administered in combination with anti-inflammatory agents, anticancer agents and other agents described herein.

Compounds of the present invention can be readily synthesized by techniques well known to those skilled in the art. For example, compounds of formula (IA) wherein X is C (O) can be prepared by coupling an amine-containing G component with a carboxyl-containing Ar-LQ component. Coupling can be performed, for example, by use of typical amide-binding-forming reagents such as EDC, PyBOP, or the like, or by the formation of acyl halides or active esters. Ie, Bodanszky, M. and Bodanszky, A., The Practice of Peptide Synthesis , Springer-Verlag (1984); Or Jones, J. Amino Acid and Peptide Synthesis Ed. Any suitable amide-bond formation method can be used, such as described in Steven G. Davies, Oxford Science (1992). Vulcanization of the resulting amides can be carried out, for example, using Lawesson reagent or the like to give thioamides of the formula IA or IB (C = S). Similarly, compounds of formula (IB) wherein X is C (O) can be prepared starting with, for example, an amine-containing Ar-LQ component and a carboxyl containing G. Ketoamides of formula IA or IB (coupling of G-NH ₂ with HOOC-C (O) -Ar-LQ, or NH ₂ -Ar-LQ and G'-C (O) -COOH by the method described above Each obtained by coupling of can be converted to the corresponding oxime (Y is C (= NOH)) by treatment with hydroxylamine.

By way of example, Scheme 1 below shows the synthesis of compounds of the invention wherein G is substituted pyrazole.

That is, substituted phenyl hydrazine hydrochloride is heated with beta-ketonitrile in a suitable solvent such as benzene, toluene or the like to obtain substituted phenyl aminopyrazole as shown. The carboxyl-Ar-LQ component is then coupled to the free amine, typically in the presence of a suitable base such as DIEA, using a coupling agent such as EDC, PyBOP and the like. The coupling reaction can be carried out in any suitable solvent such as methylene chloride, DMF, ethyl acetate, THF / water and the like. Alternatively, the carboxyl component can be converted to an acid halide such as an acid chloride by exposure to oxalyl chloride, thionyl chloride or POCl ₃ , among others. The coupled product is an example of a compound of formula (IA) as shown and may be further modified to form other compounds of the invention.

Compounds of formula II wherein X 'is N can be readily prepared. The amide bonds of the compounds of formulas IA and IB, wherein X is C (O), can be reduced with any suitable hydride, such as LAH, and the resulting compounds can be converted to nitroso derivatives by exposure to BuCNO. have. Cyclization of the nitroso derivatives affords a compound of formula II having a structure of formula IIA. Cyclization can be carried out by heating the nitroso compound with a suitable base such as pyridine or the like.

을 가지며, 문헌에 기재된 것과 유사한 절차에 따라 제조될 수 있다. 예를 들어, 유형 A1의 피라졸-아미드 중간체 (반응식 2, 방법 A에 기재된 합성법)은 문헌에 기재된 방법에 따라 브롬 또는 N-브로모숙신이미드를 사용하여 브롬화시켜 유형 A2의 브롬화된 유사체를 수득할 수 있다 ([Justus Liebigs Ann. Chem. 1955, 593:179-199]; [J. Chem. Soc., 1956, 4974-4977]; [Bioorg. Med. Chem. Lett. 11, 22, 2001, 2979-2982]; [J. Chem. Soc. Perkin Trans. 2, 10, 2000, 2049-2053]; 및 [Bioorg. Med. Chem. 4, 2, 1996, 227-238]). Compound of formula II wherein X 'is S

And can be prepared according to procedures similar to those described in the literature. For example, pyrazole-amide intermediates of the type A1 (synthesis described in Scheme 2, Method A) can be brominated with bromine or N-bromosuccinimide according to the method described in the literature to form brominated analogs of type A2. (Justus Liebigs Ann. Chem. 1955, 593: 179-199; J. Chem. Soc., 1956, 4974-4977); Bioorg. Med. Chem. Lett. 11, 22, 2001 , 2979-2982; J. Chem. Soc. Perkin Trans. 2, 10, 2000, 2049-2053; and Bioorg. Med. Chem. 4, 2, 1996, 227-238).

The resulting intermediate A2 can be treated with P ₂ S ₅ using heat under conditions similar to those described in the literature to obtain bicyclic thiazole intermediates of type A3 (Chem. Heterocycl. Compd. 10, 1974, 813 -815].

Alternatively, as shown in Scheme 3 below, intermediate A2 may be treated with a base such as n-butyl lithium (n-BuLi), followed by addition of dibenzyl-disulfane to obtain S-benzyl intermediate A4. Debenzylation of thioethers with HF in Anisole (Bull. Chem. Soc. Jpn., 40, 1967, 2164) or debenzylation of thioethers with cresol-thiocresol-HF mixture ([ Int. J. Pept. Protein res. 28, 1986, 498], can be obtained and cyclized again to form a bicyclic thiazole system (Chem. Soc. Jpn., 58, 1985). , 785-786].

를 가지며, 문헌에 기재된 것과 유사한 절차에 따라 제조될 수 있다. 상기 기재된 유형 A2의 브롬화된 고리, 예를 들어 피라졸을 메탄올 중 나트륨 메톡시드로 처리하여 메톡시 중간체 A5를 수득할 수 있다 ([J. Chem. Soc. Perkin Trans. 1, 1984, 63-67]). Compound of formula II, wherein X 'is O

And can be prepared according to procedures similar to those described in the literature. Brominated rings of the type A2 described above, for example pyrazole, can be treated with sodium methoxide in methanol to afford methoxy intermediate A5 (J. Chem. Soc. Perkin Trans. 1, 1984, 63-67). ]).

As shown in Scheme 4, methoxy intermediate A5 can be converted to the corresponding alcohol A6 using any of a number of methods described in the literature (J. Org. Chem. 1974, 39, 1427; Synthesis, 1989). , 287], J. Am. Chem. Soc. 1981, 103, 7007). Alternatively, bromo intermediate A2 can be converted directly to alcohol A6 using copper bromide and aqueous sodium carbonate (Chem. Heterocycl. Compd. 22, 3, 1986, 265-267). The resulting alcoholic intermediates are described as being directly cyclized under heating conditions, and thus can provide the desired bicyclic oxazole system directly without isolation (Heterocycles, 22, 10, 1984, 2309-2311).

According to one aspect of the present invention, a method for preparing the cytokine inhibitor of the present invention is provided. For example, the process for the preparation of compounds of formula (IA) may react G-NH ₂ with QL-Ar-X-OH in the presence of a coupling agent and a base, or G-NH ₂ in the presence of a base QL-Ar-XX Reacted with a compound of formula (IA) wherein the variable groups G, Q and L are as defined in any of the compounds described herein, X is C (O) or C (S), and X is an activating moiety ) Is obtained. The activating moiety is typically F, Cl, Br, I, -N ₃ , N-hydroxysuccinimide, 1-hydroxybenzotriazole, pentafluorophenol, pentachlorophenol, para-nitrophenol or -OC ( O) -OR ^y , where R ^y is lower alkyl. Suitable bases include sodium bicarbonate or suitable organic amines such as pyridine, N-methylmorpholine, diisopropylethylamine or triethylamine. In one aspect of the invention, a compound of formula (IA), wherein Ar is-(Y) -naphthyl-, Y is -CH (OH)-or -CH _2- , and G is phenyl, pyridinyl, pyrazolyl , Selected from pyrrolyl, imidazolyl, oxazolyl, isoxazolyl or thienyl). Alternatively, of formula IA, wherein Ar is -C (O) -naphthyl-, G is phenyl, pyridinyl, pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl or thienyl A manufacturing method is provided. Furthermore, this compound of formula IA, wherein Y is -C (O)-, is treated with NH ₂ 0R in the presence of a second base to give compound IA, where Y is -C (NOR)-. A method is provided. Typically, the second base is a pyridine or acetate salt. Typically, the reaction is carried out in pure pyridine, in a pyridine / alcohol mixture, or in ethanol in the presence of sodium acetate, and the reaction mixture is heated to a temperature in the range of about 40 ° C to about 80 ° C. Accordingly, the present invention relates to compounds of formula IA wherein Ar is -C (= NOH) -naphthyl- and G is phenyl, pyridinyl, pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl or Selected from thienyl).

In another aspect, the invention relates to compounds of Formula IA, wherein Ar is-(Y) -phenyl-, Y is -C (O)-, G is cyclopropyl, pyrazolyl, pyrrolyl, pyrrolidinyl , Imidazolyl, imidazolonyl, oxazolyl, isoxazolyl, furanyl or thienyl). Furthermore, a process for treating such a compound, wherein Y is -C (O)-, with NH ₂ 0R in the presence of a second base to provide compound IA, wherein Y is -C (NOR)-, Wherein the second base and reaction conditions are as described above. Thus, the present invention relates to compounds of formula (IA) wherein Ar is -C (= NOH) -phenyl- and G is pyrazolyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl Selected) is provided.

Formulas also include reacting GX-OH with QL-Ar-NH _{2 in} the presence of a coupling agent and a base, or reacting QL-Ar-NH ₂ with GXX ″ in the presence of a base to obtain the compound. Provided are methods for the preparation of compounds of IB wherein the variable groups Ar, G, Q and L are as defined herein, X is C (O) or C (S) and X ″ is an active moiety. In one aspect, a compound of Formula (IB) wherein Ar is-(Y) -naphthyl-, Y is -CH (OH)-or -CH _2- , and G is phenyl, pyridinyl, pyrazolyl, pyrrolyl , Imidazolyl, oxazolyl, isoxazolyl or thienyl). In another aspect, a compound of Formula (IB) wherein Ar is -naphthyl-, G is G '-(Y)-, Y is -C (O)-, and G' is phenyl, pyridinyl, pyra Also provided is a process for the preparation of zolyl, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, furanyl or thienyl). Furthermore, this compound of formula IB, wherein Y is -C (O)-, is treated with NH ₂ 0R in the presence of a second base to give compound IB, wherein Y is -C (NOR)-. A method is provided wherein the second base and reaction conditions are as described above. Thus, compounds of formula (IB) wherein Ar is -naphthyl-, G is G'-C (= NOH)-and G 'is phenyl, pyridinyl, pyrazolyl, pyrrolyl, imidazolyl, oxazolyl , Isoxazolyl, furanyl or thienyl).

In another aspect, the invention provides compounds of formula IB wherein Ar is -phenyl-, G is G '-(Y)-, Y is -C (O)-, G' is pyrazolyl, isoxazolyl Or selected from furanyl). Furthermore, this compound of formula IB, wherein Y is -C (O)-, is treated with NH ₂ 0R in the presence of a second base to yield compound IB, wherein Y is -C (NOR)-. A method is provided wherein the second base and reaction conditions are as described above. Thus, there is provided a process for the preparation of a compound of formula IB wherein Ar is -phenyl-, G is G'-C (= NOH)-and G 'is selected from pyrazolyl, isoxazolyl or furanyl. .

In another aspect, the invention comprises reacting G-NHNHC (O) O-Et with QL-Ar-NCO in an aprotic solvent and cyclizing the resulting intermediate in the presence of a base to yield a compound. , A compound of formula IC, wherein the ring is triazolidine dione and G, Ar, L and Q are as defined above. Typically, the aprotic solvent is DCM, chloroform or THF and the base is an inorganic base selected from NaOH, LiOH and K ₂ CO ₃ , or an organic base selected from DBU, DIEA and TEA. Typically, the reaction mixture is maintained at a temperature in the range of about 0 ° C to 60 ° C.

In another aspect, the present invention relates to heating G (NO) —NH—CH ₂ —Ar-LQ, wherein G, Ar, L, and Q are as defined above, together with an organic amine to obtain a compound. There is provided a process for the preparation of a compound of formula II, wherein X 'is NH. Suitable organic amines include pyridine and the like. Typically, the reaction mixture is heated at a temperature in the range of about 80 ° C to about 160 ° C, more typically about 100 ° C to about 140 ° C.

In another aspect of the invention, there is provided a compound of formula III.

<Formula III>

Where

Pyrazole residues are substituted with one or more R ¹ , R ² or R ³ at 1-position, 3-position, or both;

X "'is OR ^x or an activating moiety;

R ^x is H, a substituted or unsubstituted C _{1 -4} alkyl, or substituted or unsubstituted aralkyl group, and;

R ¹ are each independently F, Cl, Br, I, cyano, -C (O) R, -C (O) NR ₂ , -C (O) OR, -OR, -SiR ₃ , -NR'R _{', -S (O) m R} , substituted or unsubstituted linear or branched unsubstituted C _{1 -10} alkyl, C _2-10 alkenyl, or C _{2 -10} alkenyl, a substituted or unsubstituted C _{3 -10} cyclo alkyl, substituted or unsubstituted C _{5 -8} cycloalkenyl, substituted or unsubstituted C _{7 -20} aralkyl, N, O, S (O) independently selected from _m 1, 2, 3 or 4 Substituted or unsubstituted saturated or unsaturated 3 to 11 membered heterocyclyl or heterocyclylalkyl containing a heteroatom;

R ² are each independently F, Cl, Br, I, cyano, substituted or unsubstituted linear or branched C _{1 -6} alkyl, or unsubstituted C _{6 -10} alkyl, substituted or unsubstituted ring optionally substituted ring C _{6 -10} aryl group, a substituted or unsubstituted 5 to 10 membered ^{heteroaryl, -OR ', -OR 6, -C} (O) R', -C (O) oR ', -C (O) NR' ₂ , -NR ' ₂ , -NO ₂ , -S (O) _m R ", -NR'SO ₂ R", -NR'C (O) NR'R', -NR'C (S) NR'R ', -NR'C (O) OR' or -SO ₂ NR '₂;

R ³ are each independently selected from H, substituted or unsubstituted C _{6 -10} aryl, N, O, S substituted or unsubstituted independently selected containing one, two, three or four heteroatoms from the (O) _m with a C _{3 -12} cycloalkyl, or unsubstituted C _{5 -12} cycloalkenyl, a substituted or unsubstituted ring optionally substituted saturated or unsaturated 3- to 11-membered heterocyclyl or heterocyclylalkyl, substituted or unsubstituted C _{7 -20} aralkyl group, a substituted or unsubstituted linear or branched C _{1 -8} ^{alkyl, 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 26 C (O) (CH 2) m N (R 21) -, a substituted or unsubstituted C _{2 -8} alkenyl, or a substituted or unsubstituted C _{2 -8} alkynyl, wherein optionally a C _{1 -8} alkyl, C ₂ alkenyl or C _{2 -8 -8} least one methylene group is O, NH or S (O) alkynyl of _m Replaced;

R, R ', R ", R ²⁰ , R ²¹ , R ²³ , R ²⁴ , R ²⁶ and m are as defined for any compound described herein.

Activation residues are those residues that activate adjacent carbonyls for addition by nucleophiles such as amines, thiols, alcohols and the like. Exemplary activating moieties include F, Cl, Br or I, substituted or unsubstituted aryloxy groups, substituted or unsubstituted heterocyclooxy groups, and oxyacylalkoxy groups, which form mixed anhydrides, It is not limited to this. Typically, the activating moiety is F, Cl, Br, I, -N ₃ , N-hydroxysuccinimide, 1-hydroxybenzotriazole, pentafluorophenol, pentachlorophenol, para-nitrophenol or -OC (O) -OR ^y , where R ^y is lower alkyl.

The invention also provides one or more compounds of Formulas IA, IB and IC or II, prodrugs thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, tautomers thereof, or solvates thereof, in a pharmaceutically acceptable carrier, excipient, binder Provided are pharmaceutical compositions for the prevention and treatment of disorders associated with excessive cytokine production, which can be prepared by mixing with diluents and the like. The compositions of the present invention can be used to treat a variety of disorders associated with excessive cytokine production, such as diseases and pathological conditions associated with inflammation. Such compositions may, for example, be in the form of granules, powders, tablets, capsules, syrups, suppositories, injections, emulsions, elixirs, suspensions or solutions. The compositions of the present invention can be formulated in a variety of routes of administration, for example oral, parenteral, topical, rectal, intranasal, intravaginal, or implanted reservoirs. Parenteral or systemic administration may include, but is not limited to, subcutaneous, intravenous, intraperitoneal, intramuscular, intraarterial, intravaginal, intracostal, intrathecal, intralesional, and intracranial injections. The following dosage forms are given by way of example and should not be taken as limiting the invention.

For oral, buccal and sublingual administration, powders, suspensions, granules, tablets, pills, capsules, gelcaps and caplets are acceptable as solid dosage forms. It may be prepared, for example, by mixing one or more compounds of the invention, or pharmaceutically acceptable salts or tautomers thereof, with one or more additives, such as starch or other additives. Suitable additives are sucrose, lactose, cellulose sugar, mannitol, maltitol, dextran, starch, agar, alginate, chitin, chitosan, pectin, tragacanth gum, gum arabic, gelatin, collagen, casein, albumin, synthetic or half Synthetic polymers or glycerides. Optionally, oral dosage forms may be inert diluents, or lubricants such as magnesium stearate, or preservatives such as parabens or sorbic acid, antioxidants such as ascorbic acid, tocopherol or cysteine, disintegrants, binders, thickeners, buffers, sweeteners, flavoring agents. Or other ingredients that aid in administration, such as fragrances. Tablets and pills can be further treated with suitable coating materials known in the art.

Liquid dosage forms for oral administration may be in the form of pharmaceutically acceptable emulsions, syrups, elixirs, suspensions and solutions which may contain inert diluents such as water. Pharmaceutical formulations and medicaments may be prepared as liquid suspensions or solutions using sterile liquids such as, but not limited to, oils, water, alcohols, and combinations thereof. Pharmaceutically suitable surfactants, suspending agents, emulsifiers may be added for oral or parenteral administration.

As specified above, the suspending agent may comprise an oil. Such oils include, but are not limited to, peanut oil, sesame seed oil, cottonseed oil, corn oil and olive oil. Suspension formulations may also contain esters of fatty acids such as ethyl oleate, isopropyl myristate, fatty acid glycerides and acetylated fatty acid glycerides. Suspension formulations may include, but are not limited to, alcohols such as ethanol, isopropyl alcohol, hexadecyl alcohol, glycerol and propylene glycol. Ethers such as, but not limited to, poly (ethyleneglycol), petroleum hydrocarbons such as mineral oil and petroleum; And water can also be used in suspension formulations.

Injectable dosage forms generally include aqueous suspensions or oily suspensions, which may be prepared using suitable dispersing or wetting agents and suspending agents. Injectable forms may be in solution, prepared in solvent or diluent, or in the form of a suspension. Other solvents or vehicles include sterile water, Ringer's solution or isotonic saline solution. Alternatively, sterile oils can be used as solvents or suspending agents. Typically, oils and fatty acids are non-volatile and include natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.

For injection, the pharmaceutical preparations and / or medicaments may be powders suitable for reconstitution with suitable solutions as described above. Examples thereof include, but are not limited to, lyophilized, rotary dried or spray dried powders, amorphous powders, granules, precipitates or particulates. For injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers, and combinations thereof.

For rectal administration, the pharmaceutical compositions and medicaments may be in the form of suppositories, ointments, enemas, tablets or creams for intestinal, S-colonal flexion and / or rectal compound release. Rectal suppositories are present in one or more compounds of the invention, or pharmaceutically acceptable salts or tautomers thereof, in the solid phase at normal storage temperatures and in the liquid phase at a temperature suitable for release of the drug in the body, such as in the rectum. It can be prepared by mixing with a suitable vehicle, for example cocoa butter or polyethylene glycol. Oils can also be used in the preparation of the formulations of the soft gelatin type and suppositories. Water, saline, aqueous dextrose and related sugar solutions, and glycerol can also be used in the preparation of suppository agents containing pectin, carbamer, methyl cellulose, hydroxypropyl cellulose or carboxymethyl cellulose, and buffers and preservatives. Can be.

The compounds of the present invention can be administered to the lungs by inhalation through the nose or mouth. Pharmaceutical formulations suitable for inhalation include solutions containing any suitable solvent and optionally other compounds such as, but not limited to, stabilizers, antimicrobials, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations thereof. Agent, a spray, a dry powder or an aerosol. Formulations for inhalation administration may contain excipients such as lactose, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate. Aqueous and nonaqueous aerosols are typically used for delivery of the present invention by inhalation.

Typically, aqueous aerosols are prepared by formulating an aqueous solution or suspension of the compound with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary depending on the requirements of the particular compound, but typically are nonionic surfactants (Tween, Pluronic or polyethylene glycol), innocuous proteins such as serum albumin, sorbitan esters, oleic acid Amino acids, such as lecithin, glycine, buffers, salts, sugars or sugar alcohols. Aerosols are generally prepared from isotonic solutions. Non-aqueous suspensions (eg in fluorocarbon propellants) can also be used to deliver the compounds of the invention.

Aerosols containing compounds for use according to the invention are conveniently inhalers, nebulizers, pressurized packs or nebulizers and suitable propellants such as but not limited to pressurized dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra It is conveniently delivered using fluoroethane, nitrogen, air or carbon dioxide. In the case of a pressurized aerosol, the dosage unit can be controlled by providing a valve to deliver a metered amount. Capsules and cartridges of eg gelatin for use in an inhaler or insufflator may be formulated containing a compound and powder mix of a suitable powder base such as lactose or starch. Delivery of the aerosol of the present invention using an acoustic nebulizer is advantageous because it minimizes the exposure of the agent to which the nebulizer shears, leading to disintegration of the compound.

For intranasal administration, pharmaceutical formulations and medicaments are sprays containing suitable solvent (s) and optionally other compounds such as stabilizers, antimicrobials, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations thereof, Nasal droplets or aerosols. For administration in the form of nasal droplets, the compounds may be formulated as an oily solution or gel. For administration of nasal aerosols, any suitable propellant may be used including compressed air, nitrogen, carbon dioxide or hydrocarbon based low boiling solvents.

Dosage forms for topical (including buccal and buccal) or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions and patches. The active ingredient may be mixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and any preservatives or buffers that may be necessary. Powders and sprays may be prepared with excipients such as, for example, lactose, talc, silicic acid, aluminum hydroxide, calcium silicate and polyamide powders, or mixtures of these materials. Ointments, pastes, creams and gels are also excipients such as animal and vegetable fats, oils, waxes, paraffins, starches, tragacanths, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acids, talc and zinc oxide, or mixtures thereof. It may contain.

Transdermal patches have the added advantage of providing controlled delivery of a compound of the invention in the body. Such dosage forms can be made by dissolving or dispersing the agent in the proper medium. Absorption enhancers can also be used to increase the flux of the compounds of the invention through the skin. The rate of this flow can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

Ophthalmic formulations, eye ointments, powders, solutions and the like are also contemplated as being within the scope of this invention. The compounds of the present invention can be incorporated into various forms of ophthalmic agents for delivery to the eye (eg, topically, anteriorly, or through an implant). The compound is typically incorporated into topical ophthalmic formulations for delivery to the eye. The compound may be combined with an ophthalmically acceptable preservative, viscosity enhancer, permeation enhancer, buffer, sodium chloride and water to form an aqueous, sterile ophthalmic suspension or solution. Ophthalmic solution formulations may be prepared by dissolving the compound in a physiologically acceptable isotonic aqueous buffer. In addition, the ophthalmic solution may comprise an ophthalmically acceptable surfactant that aids in dissolution of the compound. Ophthalmic solutions also contain agents that enhance viscosity, such as hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, polyvinylpyrrolidone, and the like, to retain the preparation of the agent in the conjunctival sac. Can be improved. Gelling agents can also be used, including but not limited to gellan and xanthan gum. To prepare sterile ophthalmic ointment formulations, the active ingredient is combined with a preservative in a suitable vehicle, for example mineral oil, liquid lanolin or white oil. Sterile ophthalmic gel formulations can be prepared by suspending the active ingredient in a hydrophilic base prepared from a combination of eg Carbopol-974 and the like according to the published formulations for analogous ophthalmic formulations. Preservatives and osmotic agents may be incorporated.

Intradural administration via bolus administration or constant infusion allows for topical administration of the compound to an area of the spinal cord, such as the dorsal area, delivering the compound directly to the subarachnoid space containing CSF (cerebrospinal fluid).

Central delivery to the spinal cord region may also be performed by epidural injection into the region of the spinal cord outside the arachnoid. Enhancement of the permeation of the active compound through the meninges can be achieved by using a hyperosmotic dosage solution that increases the permeability of the meninges, or by the addition of permeation enhancers such as, but not limited to, liposome encapsulation, surfactants or ion-pairing agents. Can be achieved.

In addition to the representative dosage forms described above, pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in the present invention. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciences" Mack Pub. Co., New Jersey (1991), which is incorporated herein by reference.

The formulations of the present invention may be designed to be short-acting, immediate release, long-acting and sustained release as described below. That is, pharmaceutical formulations may also be formulated for controlled release or for slow release.

Compositions of the present invention may also include, for example, micelles or liposomes, or some other encapsulated form, or are administered in extended release form to provide extended storage and / or delivery effects. Thus, pharmaceutical formulations and medicaments may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneously into implants such as depot injections or splints. Such implants may use known inert materials such as silicones and biodegradable polymers.

Specific dosages can be adjusted according to the disease state, age, body weight, general state of health, sex and diet, interval of administration, route of administration, route of excretion, and drug of the subject. Any such dosage form containing an effective amount is within the scope of conventional experiments and therefore is within the scope of the present invention.

The therapeutically effective amount of a compound of the present invention may vary depending on the route of administration and the dosage form. An effective amount of a compound of the present invention is typically in the range of about 0.001 to 100 mg / kg / day, more typically in the range of about 0.05 to 10 mg / kg / day. Typically, the compound or compounds of the present invention are selected to provide an agent that exhibits a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects and can be expressed as the ratio between LD ₅₀ and ED ₅₀ . LD ₅₀ is the dose that kills 50% of the population and ED ₅₀ is the therapeutically effective dose in 50% of the population. LD ₅₀ and ED ₅₀ are determined by standard pharmaceutical procedures in animal cell culture or experimental animals.

All publications, patent applications, issued patents, and other documents mentioned in the above detailed description are herein incorporated by reference as if each individual publication, patent application, issued patent, or other document was specifically and individually incorporated by reference in its entirety. Is introduced. The definitions in the literature incorporated by reference are excluded to the extent that they conflict with the definitions in the disclosure of the present invention.

The present invention will be more readily understood with reference to the following examples, which are thus generally described, which are provided by way of example and are not intended to limit the invention.

The following abbreviations are used in chemical terms during application.

AcOH or HOAc: acetic acid

Boc: N-tert-butoxycarbonyl

Bn: Benzyl

Cbz: carbobenzyloxy

dba: dibenzylidene acetone

DIEA: diisopropylethylamine

DCM: Dichloromethane

DMF: N, N-dimethylformamide

EDC or EDCI: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride

EtOAc: ethyl acetate

EtOH: Ethanol

Fmoc: 9-fluorenylmethyloxycarbonyl

HPLC: High Pressure Liquid Chromatography

IC ₅₀ value: concentration of inhibitor causing a 50% decrease in measurement activity

LAH: lithium aluminum hydride

MeCN or AcN: acetonitrile

MeOH: Methanol

mL: milliliters

μL: microliters

PyBOP: Benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate

rt: room temperature

THF: tetrahydrofuran

Example  One: Indazole Carboxamide  Synthesis of derivatives

3-amino-5- tert -butyl-2- tolyl -2H- pyrazole (1). A solution of tolyl hydrazine hydrochloride (8.0 g, 50 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (6.3 g, 50 mmol) in toluene (30 mL) was heated to reflux overnight. The residue provided by removal of volatiles under vacuum was purified by silica gel chromatography using 30% ethyl acetate in hexane as eluent. Concentration in vacuo gave 3-amino-5-tert-butyl-2-tolyl-2H-pyrazole as a brown solid (10.5 g, 92%). LC-MS analysis of the compounds confirmed that the desired product was present in greater than 99% purity. Mass calculated = 229. Mass found = 230.

1H- indazol- 3 -carboxylic acid (5- tert -butyl-2-p- tolyl -2H- pyrazol- 3-yl) -amide (2). In a solution of indazole-3-carboxylic acid (28 mg, 0.17 mmol), EDC (50 mg, 0.26 mmol) and diisopropylethylamine (61 μL, 0.35 mmol) in CH ₂ Cl ₂ (3.5 mL) -Amino-5-tert-butyl-2-tolyl-2H-pyrazole (46 mg, 0.20 mmol) was added. After stirring for 14 h at rt, the mixture was diluted with water (10 mL) and extracted with CH ₂ Cl ₂ (2 × 10 mL). The combined organic layers were washed with brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by preparative HPLC (MeCN / H ₂ O) provided 25 mg (40%) of indazolopyrazole. LC-MS: mass calcd = 373. Mass found = 374.

Indazole -3- Carboxylic acid  General Procedure for Manufacturing

5 -methoxy- 1H- indazole- 3 -carboxylic acid (3). To a 1 L round bottom three-necked flask equipped with a mechanical stirrer, thermometer and funnel, 110 mL of water and 6 mL of concentrated sulfuric acid were added at -5 ° C. To the cooled solution was added a solution of 10 g of 5-methoxy isatin, 3.9 g of sodium nitrite and 2.6 g of sodium hydroxide in 65 mL of water. After stirring for 15 minutes, the reaction mixture was warmed up to 0 ° C. and a solution of SnCl ₂ (35 g in 50 mL concentrated HCl) was added dropwise. Stirring was continued for 1 hour at room temperature, then the precipitate was collected and crystallized in EtOH to give 3 g of the product ready for use in the next step. LC-MS: mass calcd = 192. Mass found = 193.

Example  2 - Imidazolopyrazole  Synthesis of derivatives

2-alkyl (aryl) imidazolopyrazole was prepared from 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (Compound 1 above).

Method A

Aminopyrazole  N- Acylation  General procedure for

Two different procedures were used for Scheme 5 and acylated aminopyrazoles as described below.

N- (5- tert -Butyl-2-p- Tolyl -2H- Pyrazole -3 days)- Benzamide  (4)

Of aminopyrazole in ethyl acetate / water Acylation . 2-aminopyrazole (115 mg, 0.5 mmol) was dissolved in 2.5 mL EtOAc and a solution of NaHCO ₃ (46 mg, 0.55 mmol) in 1 mL water was added. To this vigorously stirred mixture was added a solution of benzoyl chloride (57.5 μL, 0.5 mmol) in 1.5 mL of ethyl acetate at room temperature. The resulting mixture was stirred at 60 ° C. for 4 hours. After cooling to room temperature, ethyl acetate was added. The organic phase was washed again with 5% Na ₂ CO ₃ , water, 1 N HCl, and finally with water. The organic phase was dried over Na ₂ S0 ₄ and concentrated to give 115 mg (69% yield) of NMR pure product. LC-MS: mass calcd. 333. Mass found = 334.

Among the pyridine-aminopyrazole Acylation : A solution of 2-aminopyrazole (115 mg, 0.5 mmol), benzoyl chloride (63.3 μL, 0.55 mmol) and DMAP (3 mg, 0.025 mmol, 5 mol%) in 2 mL pyridine overnight at 85 ° C. ( 15 hours). After evaporation and co-evaporation with toluene, the solid residue is dissolved in 2 mL of DCM and then to ISCO purification (4 g column, 0-40% B; A = PCM, B = 10% MeOH in DCM). Applied. Fractions containing product were evaporated to give 134 mg of pure material. Yield 80%. Mass calculated = 333. Mass found = 334.

Amide With lithium aluminum hydride  General procedure for reaction

Benzyl- (5- tert -butyl-2-p- tolyl -2H- pyrazol- 3-yl) -amine ( 5 ). Starting amide (167 mg, 0.5 mmol) was dissolved in 0.5 mL of dry THF. To this solution was added 1.5 mL of 1 M LAH in THF (1.5 mmol) at 4 ° C. The resulting solution was shaken at 60 ° C. for 7 hours. After cooling with ice water, the reaction mixture was basified with aqueous KOH (pH 9-10). The suspension was filtered through Celite and washed with THF. The filtrate was concentrated and the residue was dissolved in ethyl acetate and washed with water. The organic phase was dried over Na ₂ SO ₄ , filtered and evaporated to dryness to give 156 mg of brown oil. The compound was analyzed by LC-MS and NMR. Yield 89%. Mass calculated = 319. Mass found = 320.

N- Of alkylaminopyrazoles Nitrosylated  General procedure for

Benzyl- (3- nitroso- 5- tert -butyl-2-p- tolyl -2H- pyrazol- 3-yl) -amine ( 6 ). Two drops of concentrated HCl and two drops of H ₂ O were added to 1 mL of ethanol followed by BuONO (270 μL, 2.3 mmol, 5 equiv). The solution was added dropwise at 4 ° C. to a solution of N-alkylaminopyrazole (148 mg, 0.46 mmol) in 1 mL of ethanol. The reaction mixture was then stirred at 4 ° C. for 30 minutes and then at room temperature for 2 hours. After concentration, the solid residue was dissolved in 2 mL of DCM and then subjected to column purification (12 g column, 0-40% B; A = DCM; B = 10% MeOH in DCM). Yield: 48%, 76.9 mg. LC-MS: mass calcd. 348. Mass found = 349.

General procedure for cyclization

3- tert -butyl-5- phenyl- 1-p- tolyl- 1,6 -dihydro - imidazo [4,5-c] pyrazole ( 7 ). A solution of nitroso compound (76 mg, 0.21 mmol) in 3 mL of pyridine was heated by microwave at 120 ° C. for 20 minutes. The reaction mixture was cooled to rt and the solvent was co-evaporated with toluene. The residue was dissolved in 3 mL of dichloromethane and subjected to column purification to give 46.9 mg of product. Yield = 68%. LC-MS: mass calcd = 330. Mass found = 331.

Method B

4-hydroxy-1- Arylaldehyde  General Procedure for O-Alkylation

4- (morpholin-4-yl- ethyloxy ) -1 -naphthylaldehyde ( 8 ). 4-hydroxy-1-naphthaldehyde (258 mg, 1.5 mmol), N- (2-chloroethyl) morpholine hydrochloride (307 mg, 1.65 mmol, 1.1 equiv) and K ₂ CO _{3 in} 12 mL acetonitrile (915 mg, 6.6 mmol, 4 equiv) was stirred vigorously at 80 ° C. for 7 h. After filtration, the dark blue filtrate was concentrated to slowly crystallize the provided dark green oil. TLC: (silica) R _f = 0.18 in ethyl acetate. The compound was analyzed by LC-MS. The crude product was used directly in the next step reaction. Mass calculated = 285. Mass found = 286.

Aminopyrazole  Reducing Amination  General procedure for

(5- tert -butyl-2-p- tolyl -2H- pyrazol - 3 - yl)-[4- (2-morpholin-4-yl- ethoxy ) -naphthalen -1-ylmethyl] -amine ( 9 ). Aminopyrazole (344 mg, 1.5 mmol) and the aldehyde from this step (1.5 mmol, 1 equiv) were dissolved in 4 mL of EtOH and 80 μL of HOAc was added. The resulting solution was shaken at 80 ° C. for 5 hours. After cooling to room temperature, sodium cyanoborohydride (282 mg, 3 equiv) was added. The resulting solution was shaken overnight (15 hours) at room temperature. After evaporation, the residue was dissolved in ethyl acetate and washed with aqueous NaHCO ₃ followed by water. The organic phase was concentrated and the residue dissolved in DCM and subjected to column purification to give 540 mg of foam. Yield: 72.3%. LC-MS: mass calcd = 498. Mass found = 499.

3- tert -butyl-5- [4- (2-morpholin-4-yl- ethoxy ) -naphthalen-1-yl] -1-p- tolyl- 1,6-dihydro-imidazo [4, 5-c] pyrazole ( 10 ). The title compound was prepared using the general procedure for cyclization as described above. Mass calculated = 509. Mass found = 510.

Example  3-alpha Ketoamide  synthesis

Method A: via naphthalen-1-yl-oxo-acetic acid

4- [2- (naphthalen-1- yloxy ) -ethyl] -morpholine ( 11 ). 2-hydroxy-naphthylene (1.0 g, 5.37 mmol) was dissolved in acetonitrile (50 mL). To this solution was added cesium carbonate (4.0 g, 12.3 mmol) or potassium carbonate (2.97 g, 21.5 mmol) followed by 2-chloroethylmorpholine (0.774 g, 5.37 mmol). The mixture was stirred at 80 ° C. overnight and then cooled to room temperature. The resulting mixture was filtered, diluted with EtOAc, extracted three times with saturated NaHCO ₃ , once with 0.1 M NaOH, washed with brine, dried over MgSO ₄ , filtered and the solvent removed under reduced pressure to a crude brown color. Oil was provided. The oil was purified by column chromatography to give the desired compound 11 in 64% to 83% yield as a pale yellow oil. Mass calculated = 257. Mass found = 258.

[4- (2-Morpholin-4-yl- ethoxy ) -naphthalen-1-yl] -oxo-acetic acid methyl ester ( 12 ). To the round bottom flask was added CH ₂ Cl ₂ (100 mL) followed by AlCl ₃ (2.2 g, 16.3 mmol). The suspension was stirred at rt for 5 min, methylchloroglyoxylate (1.66 mL, 17.88 mmol) was added, stirred for an additional 5 min and then Compound ( 11 ) (0.841 g, 3.27 mmol). The mixture was stirred at rt overnight, quenched with water, neutralized with NaHCO ₃ and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over MgSO ₄ , filtered and the solvent removed to give a brown oil. The material was purified by column chromatography (0-5% MeOH / CH ₂ Cl ₂ ) to give compound ( 12 ) as 1.08 g (97%) of a yellow solid. LC-MS: mass calcd = 343. Mass found = 344.

N- (5- tert -butyl-2-p- tolyl -2H- pyrazol - 3 - yl) -2- [4- (2-morpholin-4-yl- ethoxy -naphthalen-1-yl]- 2-oxo-acetamide, ( 13. ) Compound 12 (0.224 g, 0.653 mmol) was dissolved in THF (20 mL) To the solution was added 1 N LiOH (3 equiv, 1.96 mmol). The solution was stirred for 2 hours, neutralized with 4 N HCl in dioxane and the solvent was evaporated to give a white solid, The residue was dried at 80 ° C. for 30 minutes under high vacuum, then CH ₂ Cl ₂ (50 To the suspension was added oxalyl chloride (0.56 mL, 6.53 mmol) and a few drops of DMF The suspension was stirred at rt for 2 h and then the solvent was evaporated The resulting solid was ethyl acetate (20). mL), 5-amino-3-t-butyl-1- (4-methylphenyl) pyrazole ( 1 ) (0.159 g) dissolved in ethyl acetate (20 mL) and 50% NaHCO ₃ solution (10 mL) , 0.663 mmol) It was added, and the mixture was stirred overnight at 60 ℃. The mixture was diluted with ethyl acetate and extracted with NaHCO _3. The combined organic layers were washed with brine, dried over MgSO _4, filtered, and the solvent provided a brown oil The material was purified by column chromatography (50-100% EtOAc / hexanes) or (0-5% methanol / DCM) to give 0.346 g (98%) of the desired compound as a yellow solid. Mass calculated = 540. Mass found = 541.

General method for the manufacture of additional building blocks and their introduction

N- (3-amino-5- tert -butyl-2 -methoxy - phenyl ) -methanesulfonamide ( 14 ). 150 mL of DCM was added to a 250 mL round bottom flask containing 5.0 g (25.73 mmol) of 5-tert-butyl-2-methoxy-benzene-1,3-diamine, oven dried. After cooling the reaction mixture to 0 ° C., triethylamine (5.0 mL, 36.0 mmol) was added followed by the dropwise addition of methylsulfonyl chloride (1.99 mL, 25.7 mmol). The reaction was stirred at 0 ° C for 30 minutes. Warm to room temperature and stir for an additional 2 hours. The reaction mixture was poured into a saturated solution of sodium bicarbonate (100 mL) and the layers separated. The aqueous layer was washed two more times with 50 mL of dichloromethane, the combined organic layers were dried over magnesium sulfate and concentrated in vacuo to afford the crude oil obtained by flash chromatography (silica gel, 1: 1 EtOAc: Hex). This gave 6.1 g (87%) of the desired product. Mass calculated = 272. Mass found = 273

N- (5- tert -butyl-3- methanesulfonylamino- 2 -methoxy - phenyl ) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide ( 15 ). The title compound was prepared starting from compound ( 12 ) and compound ( 14 ) by the same method described for compound ( 13 ). Mass calculated = 583. Mass found = 584.

(4-hydroxy-naphthalen-1-yl) -oxo-acetic acid methyl ester. To a suspension of AlCl ₃ (1.11 g, 8.3 mmol) in 50 mL of DCM was added methylchloroglyoxylate (1.02 g, 8.3 mmol). The resulting solution was stirred for 5 minutes before naphthalen-1-ol (1 g, 6.9 mmol) was added. After stirring at room temperature for 2 hours, water was added, the phases were separated and the organic layer was washed with water and dried over MgSO ₄ . The residue obtained after evaporation of the organic solvent was purified by column chromatography (10-30% EtOAc / Hex) to give the target compound in 38% yield. Mass calculated = 230. Mass found = 231.

[4- (5- Bromo- 2- chloro -pyrimidin-4-yl- oxy ) -naphthalen-1-yl] -oxo-acetic acid methyl ester. The compound (1.37 g, 6 mmol) obtained in the above reaction was dissolved in 30 mL of acetone. 5-bromo-2,4-dichloro-pyrimidine (1.36 g, 6 mmol) and K ₂ CO ₃ (2.05 g, 14.8 mmol) were added and the reaction stirred at 60 ° C. for 5 hours. Acetone was evaporated, the residue was dissolved in DCM and the solution was purified through a silica gel bed. After evaporation of the solvent a white solid was obtained in 75% yield. Mass calculated = 421. Mass found = 422.

[4- (5- Bromo- 2-morpholin-4-yl-pyrimidin-4- yloxy ) -naphthalen-1-yl] -oxo-acetic acid methyl ester. The compound (0.50 g, 1.19 mmol) obtained as described above was dissolved in THF / toluene 8/2. Morpholine (0.124 mL, 2.97 mmol) and DIEA (0.5 mL, 2.97 mmol) were added and the solution was stirred overnight at 80 ° C. Acetone was evaporated and the residue was purified by column chromatography (10-30% EtOAc / Hex) to afford 80% of the target compound. Mass calculated = 472. Mass found = 473.

[4- (2-Morpholin-4-yl-pyrimidin-4-yl- oxy ) -naphthalen-1-yl] -oxo-acetic acid methyl ester. The compound obtained above (108 mg, 0.228 mmol) was dissolved in MeOH / DCM 3/1, 10% Pd / C (30 mg) was added and the compound was hydrogenated at H ₂ 1 atm for 50 minutes. The reaction mixture was filtered and concentrated in vacuo. The resulting residue was dissolved in DCM and purified by column chromatography (10-30% EtOAc / Hex) to give 67% of the target product. Mass calculated = 393. Mass found = 394.

[4- (2-Morpholin-4-yl-pyrimidin-4-yl- oxy ) -naphthalen-1-yl] -oxo-acetic acid ( 16 ). The product from the previous reaction (66 mg, 0.168 mmol) was dissolved in DCM and cooled to 0 ° C. BBr ₃ (0.2 mL, 0.202 mmol) of a 1 M solution in DCM was added and the reaction was allowed to warm up to room temperature over 10 minutes. Water was added to the mixture and the product was extracted with EtOAc. The organic layer was dried over MgSO ₄ , evaporated and the residue triturated with hexane to give the target product quantitatively. Mass calculated = 379. Mass found = 380.

N- (5- tert -butyl-3- methanesulfonylamino- 2 -methoxy - phenyl ) -2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalene- 1-yl] -2-oxo-acetamide ( 17 ). [4- (2-Morpholin-4-yl-pyrimidin-4-yl-oxy) -naphthalen-1-yl] -oxo-acetic acid ( 16 ) (36 mg, 0.095 mmol) obtained above was prepared using DCM 2 Dissolve in mL and add oxalyl chloride (0.08 mL, 0.949 mmol) followed by catalytic DMF. The reaction mixture was stirred at rt and then N- (3-amino-5-tert-butyl-2-methoxy-phenyl) -methanesulfonamide ( 14 ) (26 mg, 0.096 mmol) and DIEA (0.05 mL, 0.284 mmol ) Was added and stirring was continued for 12 hours. The reaction mixture was concentrated in vacuo and the residue was purified by LC / MS (10-100% AcN / H ₂ O over 8.5 minutes). Mass calculated = 444. Mass found = 444.

(4- bromo- naphthalen-1-yl) -oxo-acetic acid methyl ester (18). To a suspension of AlCl ₃ (3.20 g, 24 mmol) in 100 mL of DCM at 0 ° C. was added methylchloroglyoxylate (2.2 mL, 24 mmol). The resulting solution was stirred for 5 minutes, then 1-bromo-naphthalene (5 g, 24 mmol) was added. After stirring at room temperature for 2 hours, water was added, the phases were separated and the organic layer was washed with water and dried over MgSO ₄ . The residue obtained after evaporation of the organic solvent was purified by column chromatography (0-30% EtOAc / Hex) to give 2.6 g of the target compound.

2-chloro-pyrimidyl-4-yl-amine. 2,4-Dichloro-pyrimidine (7.45 g, 50 mmol) was stirred overnight in 150 mL aqueous NH ₄ OH. Chloroform was added to the mixture and the organic and aqueous solvents were separated. The organic layer was washed with water and dried over MgSO ₄ . The residue obtained after evaporation of the organic solvent was purified by column chromatography (0-100% EtOAc / Hex) to give 1.5 g of the target compound and 2 g of the rotamers. Mass calculated = 129. Mass found = 130.

2-morpholin-4-yl-pyrimidin-4- ylamine . The compound (166 mg, 1.286 mmol) obtained in the reaction was dissolved in 2 mL of THF. DIEA (0.1 mL) and morpholine (134 mg, 1.5 mmol) were added and the reaction stirred at 75 ° C. overnight. The solvent was removed under reduced pressure and the residue was dissolved in DCM and purified by column chromatography (50-100% EtOAc / Hex) to give the target product in 88% yield. Mass calculated = 180. Mass found = 181.

[4- (2-Morpholin-4-yl-pyrimidin-4- ylamino ) -naphthalen-1-yl] -oxo-acetic acid methyl ester. 2-Morpholin-4-yl-pyrimidin-4-ylamine (140 mg, 0.77 mmol) and (4-bromo-naphthalen-1-yl) -oxo-acetic acid methyl ester ( 18 ) (228 mg, 0.77 mmol) was suspended in 5 mL of toluene and Pd (OAc) ₂ (5 mg, 3 mol%), BINAP (24 mg, 5 mol%) and CS ₂ CO ₃ (753 mg, 2031 mmol) were added. The reaction mixture was stirred at 100 ° C for 24 h. The cooled mixture was purified by column chromatography (0-100% EtOAc / Hex) to give 169 mg of the target product.

[4- (2-Morpholin-4-yl-pyrimidin-4- ylamino ) -naphthalen-1-yl] -oxo-acetic acid. The product from the previous reaction (170 mg, 0.433 mmol) was dissolved in DCM and cooled to 0 ° C. BBr ₃ (0.52 mL, 0.52 mmol) of a 1 M solution in DCM was added and the reaction stirred for 35 minutes. Water was added to the mixture and the solvent was evaporated to yield 160 mg of crude target product, which was used in the coupling reaction.

General procedure for the coupling of G- NH ₂ with [4- (2-morpholin-4-yl-pyrimidin-4- ylamino ) -naphthalen-1-yl] -oxo-acetic acid. The product from the previous reaction (17 mg, 0.44 mmol) was dissolved in 1.5 mL of DMF, followed by the amine component G-NH ₂ (2 equiv, 0.88 mmol) followed by PyBOP (46 mg, 0.088 mmol), HOBt (14 mg, 0.088 mmol) and DIEA (0.02 mg, 0.088 mmol) were added. The reaction was stirred overnight and the crude mixture was purified by LC / MS (10-100% AcN) to afford the final compound. The described method was applied to yield the compound as illustrated in Table 1.

4- (5- Bromo- pyridin-2- ylmethyl ) -morpholine. Thionyl chloride (0.57 g, 5 mmol) in DCM (2 mL) was cooled to 0 ° C. with (5-bromo-pyridin-2-yl) -methanol (0.3 mg, 1.59 mmol) in DCM (5 mL). It was added dropwise to the stirred solution. The mixture was allowed to warm up to room temperature and evaporated to small volume under vacuum. The residue was dissolved in CHCl ₃ and a solution of morpholine (0.41 mg, 5 mmol) in CHCl ₃ was added at 0 ° C. After 3 hours, the reaction was complete. The solvent was evaporated and ether was added to give the target compound (85%) as a white solid. Mass calculated = 257. Mass found = 258.

4- (5-Tri- butylstannanyl -pyridin-2- ylmethyl ) -morpholine. To a solution of the compound obtained above in anhydrous THF while cooling to -78 ° C was added a solution of 1.7 M tert-Buli (1.7 mL, 2.2 equiv). After 10 minutes ClSnBu ₃ (2.2 equiv, 1.2 g) was added at the same temperature and the reaction mixture was stirred for 15 minutes. Then K ₂ HPO ₄ / KH ₂ PO ₄ buffer at pH 7 was added and the residue was extracted with EtOAc and dried with MgSO ₄ to give the target compound in 81% yield. Mass calculated = 467. Mass found = 469.

[4- (6-Morpholin-4- ylmethyl -pyridin-3-yl) -naphthalen-1-yl] -oxo-acetic acid (20). 4- (5-Tri-butylstannanyl-pyridin-2-ylmethyl) -morpholine (0.47 mg, 1.59 mmol) and (4-bromo-naphthalen-1-yl) -oxo-acetic acid methyl ester ( 18 ) (0.6 g, 1.3 mmol) and catalytic tetrakis (triphenylphosphine) palladium (0) were dissolved in 2 mL of anhydrous 2,4-dioxane under nitrogen atmosphere. The tube was heated at 150 ° C. for 10 minutes under microwave irradiation. After cooling to rt, the mixture was diluted with EtOAc and KF 40% solution was added. The organic phase was separated and the aqueous layer was evaporated and purified by LC-MS to give the target product in 54% yield. Mass calculated = 376. Mass found = 376.

N- (5- tert -Butyl-3- Methanesulfonylamino -2- Methoxy - Phenyl ) -2- [4- (6-morpholine-4- Yl methyl -Pyridin-3-yl) -naphthalen-1-yl] -2-oxo-acetamide ( 302 ).

The target compound ( 302 ) is obtained via acid chloride formation and coupling with a compound of formula 1b as described above. Mass calculated = 631. Mass found = 631.

4- (4-nitro-pyridin-2-yl) -morpholine. To a solution of 2-chloro, 4-nitropyridine (0.6 g, 1.3 mmol) in THF (3 mL) was added morpholine (328 mg, 38.1 mmol). The reaction was heated to 80 ° C. and stirred overnight. The solvent was evaporated and the residue was purified by column chromatography (2/1 Hex / EtOAc) to give 150 mg of the target compound.

2-morpholin-4-yl-pyridin-4- ylamine . The compound obtained above (40 mg, 0.86 mmol) was dissolved in MeOH / DCM 5/2, 10% Pd / C (40 mg) was added and the compound was hydrogenated at H ₂ 1 atm for 5 hours. The reaction mixture was filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (1/2 EtOAc / Hex) to give 157 mg of target product.

[4- (2-Morpholin-4-yl-pyridin-4- ylamino ) -naphthalen-1-yl] -oxo-acetic acid methyl ester ( 21 ). 2-morpholin-4-yl-pyrimidin-4-ylamine (159 mg, 0.88 mmol) and (4-bromo-naphthalen-1-yl) -oxo-acetic acid methyl ester ( 18 ) (260 mg, 0.89 mmol) is suspended in 6 mL of toluene / dioxane 1/1, Pd (OAc) ₂ (6 mg, 3 mol%), BINAP (27 mg, 5 mol%) and CS ₂ CO ₃ (858 mg, 2.64 mmol) ) Was added. The reaction mixture was stirred at 80 ° C over 18 hours. The cooled mixture was purified by column chromatography (0-100% EtOAc / Hex) to give 140 mg of product. The product was subjected to the method described above to give the final compound of interest.

4- tert -butyl-2-morpholin-4- ylmethyl -6-nitro-phenol. A solution of 4-t-butyl-2-nitro-phenol (980 mg, 5 mmol), morpholine (50 mmol) and paraformaldehyde (1.5 g, 50 mmol) in 20 mL of ethanol at 95 ° C. in a sealed container. Heated for 6 hours. After removal of solvent and morpholine, the residue was purified via silica gel column chromatography to yield 1.75 g of the target compound as a yellow solid.

2-amino-4- tert -butyl-6-morpholin-4- ylmethyl -phenol. The compound (294 mg, 1 mmol) obtained as described above was heated with tin (II) chloride dihydrate (1.36 g, 6 mmol) in 2 mL concentrated HCl at 90 ° C. for 2 h. After cooling, the reaction mixture was diluted with water and diethyl ether was added. Solid K ₂ CO ₃ was added to neutralize the reaction mixture to pH = 9. Extraction was performed with diethyl ether and the combined organic phases were dried over sodium sulfate. Evaporation gave 222 mg of pure product as a white solid.

N- (5- tert -Butyl-2-hydroxy-3-morpholine-4- Yl methyl - Phenyl ) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide ( 22 ).

Acid chloride (obtained as described above) (0.5 mmol) was added to a solution of the obtained product (66 mg, 0.25 mmol) and DIEA (87 μl, 0.5 mmol) in 5 mL of DCM. The resulting mixture was stirred at rt overnight. After workup with aqueous sodium bicarbonate, silica gel column purification was performed to give the final product in 59.8 mg yield. Mass calculated = 575.7. Mass Found: 575.7

4- tert -butyl-2- methyl -6-nitro-phenol. 4-tert-butyl-2-methyl-phenol (1.64 g, 10 mmol) was dissolved in 15 mL of acetic acid, fuming nitric acid (0.47 mL, 10 mmol) was added and the resulting solution was stirred at rt overnight. The reaction mixture was then poured onto crushed ice and extracted with chloroform. The organic phase was washed with water and dried over sodium sulfate. Evaporation gave 2.02 g of nitrification product as red oil.

N- (5- tert -butyl-2-hydroxy-3- methyl - phenyl ) -2- [4- (2-morpholin-4-yl- ethoxy ) -naphthalen-1-yl] -2-oxo Acetamide ( 23 ). The resulting nitro-compound (31 mg) was reduced with Pd / C and H ₂ in 3 mL of MeOH at room temperature for 2 hours. After filtration and removal of solvent, the residue was dissolved in 2 mL of DCM, DIEA (0.25 mmol) was added and then [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- Oxo-acetyl chloride (0.1 mmol) was added. Stirring was continued at rt overnight. The residue obtained after evaporation of the solvent was purified by LC / MS to give 9.5 mg of the final product. Mass calculated = 491. Mass found = 491.

5- tert -butyl-2 -methoxy -1- methyl- 3-nitro-benzene. 4-tert-butyl-2-methyl-6-nitro-phenol (209 mg, 1 mmol) was dissolved in 3 mL of acetone. 552 mg (4 equiv) of K2C03 was added followed by MeI (0.33 mL, 5 mmol). The reaction mixture was stirred vigorously overnight at 60 ° C. After removal of acetone, the residue was shaken with DCM. Filtration and evaporation of the solution gave 221 mg of product, which was used as follows.

N- (5- tert -butyl-2 -methoxy- 3- methyl - phenyl ) -2- [4- (2-morpholin-4-yl- ethoxy ) -naphthalen-1-yl] -2-oxo Acetamide ( 24 ). The product obtained above (56 mg, 0.25 mmol) was reduced with Pd / C and H ₂ in 5 mL of MeOH at room temperature for 5 hours. After filtration and removal of the solvent, the residue was dissolved in 4 mL of DCM. DIEA (0.5 mmol) was added followed by acid chloride (0.2 mmol). The reaction was continued at room temperature overnight. After workup with aqueous sodium bicarbonate and silica gel column chromatography, the final product was obtained in 46.8 mg yield. Mass calculated = 505. Mass found = 505.

4- tert -butyl-2- chloro -phenol. 4-tert-butyl-phenol (2.64 g, 17.5 mmol) was dissolved in SO ₂ Cl ₂ (17.5 mL, 17.5 mmol) in a 1 M solution in DCM and MeOH (0.71 mL, 17.5 mmol) was added. The reaction was stirred at rt and the progress was monitored. Further 1 m SO ₂ Cl ₂ / DCM (10 mL) and MeOH (0.36 mL) were added. The reaction mixture was concentrated in vacuo to afford the target compound. Mass calculated = 186. Mass found = 187.

4- tert -butyl-2- chloro -6-nitro-phenol. The product obtained above (0.585 g, 3.17 mmol) was dissolved in 6 mL of AcOH, cooled to 0 ° C and HNO ₃ (0.16 mL, 3.5 mmol) was added. The reaction was allowed to warm to room temperature then water was added and the compound extracted with EtOAc. The organic layer was dried over MgSO ₄ , the solution was concentrated and the concentrate was filtered through silica gel to give 0.306 g of the target compound. Mass calculated = 209. Mass found = 210

5- tert -butyl-1 -chloro- 2 -methoxy- 3-nitro-benzene. 4-tert-butyl-2-chloro-6-nitro-phenol (0.214 g, 0.934 mmol) is dissolved in 3 mL of acetone, K ₂ CO ₃ (0.65 g, 4.7 mmol) and MeI (0.58 mL, 9.3 mmol) ) Was added. The reaction was stirred at 65 ° C. overnight and then the solvent was removed under reduced pressure. The residue was dissolved in DCM and the organic layer was washed with water, dried over MgSO ₄ and concentrated to give 0.15 g of the target product.

5- tert -butyl-3 -chloro- 2 -methoxy - phenylamine ( 25 ). 5-tert-butyl-1-chloro-2-methoxy-3-nitro-benzene (157 mg, 0.646 mmol) was dissolved in 3 mL of concentrated HCl and SnCl ₂ H ₂ O (0.874 g, 3.87 mmol) was dissolved in Added. The reaction was stirred at 90 ° C. for 2 hours and then water was added and the product extracted with diethyl ether. The organic layer was dried over MgSO ₄ and concentrated. The residue was purified by column chromatography (2/1 Hex / EtOAc) to give 100 mg of final product. Mass Calculated = 213. Mass Found = 214

N- (5- tert -butyl-3 -chloro- 2 -methoxy - phenyl ) -2- [4- (2-morpholin-4-yl- ethoxy ) -naphthalen-1-yl] -2-oxo Acetamide ( 26 ). 5-tert-butyl-3-chloro-2-methoxy-phenylamine ( 25 ) (77 mg, 0.36 mmol) was dissolved in 10 mL of DCM. [4- (2-Morpholin-4-yl-ethoxy) -naphthalen-1-yl] -oxo-acetyl chloride (0.54 mmol) (prepared as described above) and DIEA (0.37 mL, 1.44 mmol) Addition and stirring of the reaction was continued. The reaction mixture was evaporated and the residue was purified by LC / MS (10-100% AcN). Mass calculated = 524. Mass found = 525.

4- tert -butyl-2 -trifluoromethyl -phenol. 2-trifluoromethyl-phenol (2.98 g, 18.3 mmol) was dissolved in 12 mL of TFA and t-butanol (1.43 g, 19.3 mmol) and H ₂ SO ₄ (0.24 mL) were added. The reaction was stirred at rt for 48 h and then water was added and the compound extracted with DCM. The organic layer was dried over MgSO ₄ and concentrated in vacuo. The residue was purified by column chromatography (2/1 Hex / EtOAc) to give 2.01 g of target compound.

4- tert -butyl-2 -trifluoromethyl- 6-nitro-phenol. 4-tert-butyl-2-trifluoromethyl-phenol (70 mg, 0.32 mmol) was dissolved in 3 mL of AcOH / 1.5 mL of water and cooled to 0 ° C. HNO ₃ (1.5 mL) and catalytic H ₂ SO ₄ were added and the reaction was allowed to warm to room temperature. Stirring was continued overnight then water was added and the compound extracted with EtOAc. The organic layer was dried over MgSO ₄ and concentrated to give 34 mg of the final compound. Mass calculated = 263. Mass found = 264.

5- tert -butyl-2 -methoxy -1 -trifluoromethyl- 3-nitro-benzene. The compound obtained above (34 mg, 0.163 mmol) was dissolved in 3 mL of acetone, and K ₂ CO ₃ (112 mg, 0.81 mmol) and MeI (0.1 mL, 1.63 mmol) were added. The reaction was stirred at 75 ° C. The mixture was concentrated and the residue was dissolved in DCM. The organic layer was filtered, dried over MgSO ₄ and concentrated. The residue was purified by column chromatography (10-30% EtOAc / Hex) to give 30 mg of the target compound. Mass calculated = 277. Mass found = 278.

5- tert -butyl-2 -methoxy- 3 -trifluoromethyl - phenylamine ( 27 ). The compound obtained above (100 mg, 0.036 mmol) was dissolved in MeOH, 10% Pd / C (50 mg) was added and the compound was hydrogenated at H ₂ 1 atm. The reaction mixture was filtered and concentrated in vacuo. The resulting residue was dissolved in DCM and purified by column chromatography (4/1 EtOAc / Hex) to give 72 mg of target product. Mass calculated = 247. Mass found = 248.

N- (5- tert -butyl-2 -methoxy- 3 -trifluoromethyl - phenyl ) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide ( 28 ). 5-tert-butyl-2-methoxy-3-trifluoromethyl-phenylamine (32 mg, 0.165 mmol) was dissolved in 2 mL of DCM. [4- (2-Morpholin-4-yl-ethoxy) -naphthalen-1-yl] -oxo-acetyl chloride (0.232 mmol) (prepared as described above) and DIEA (0.02 mL, 0.50 mmol) Was added and stirring of the reaction was continued. The reaction mixture was evaporated and the residue was purified by LC / MS (10-100% AcN). Mass calculated = 558. Mass found = 559.

4- [2- (6 -Chloro -naphthalen-1- yloxy ) -ethyl] -morpholine. To a suspension of amine (1.0 g, 3.67 mmol) in 6 M HCl (1.8 mL, 11.01 mmol) was added NaNO ₂ (253 mg, 3.67 mmol) and the reaction stirred at 0 ° C. for 1 h. CuCl (363 mg, 3.67 mmol) was added to the mixture, which caused gas evolution. The reaction was heated to 100 ° C and stirred for 1 hour. The mixture was extracted with DCM and the organic layer was dried and evaporated to give 9% of the target product. Mass calculated = 291. Mass found = 291.

[7 -Chloro- 4- (2-morpholin - 4-yl- ethoxy ) -naphthalen-1-yl] -oxo-acetic acid methyl ester. To a suspension of AlCl ₃ (430 mg, 3.30 mmol) in DCM was added methylchloroacetate (0.30 mL, 3.30 mmol), followed by dissolution of AlCl ₃ . To the solution was added dropwise 4- [2- (6-chloro-naphthalen-1-yloxy) -ethyl] -morpholine (95 mg, 0.33 mmol). The mixture was stirred at rt overnight. The mixture was diluted with DCM and the organic layer was washed with water, dried over MgSO ₄ and evaporated to give 83% of target material. Mass calculated = 378. Mass found = 378.

N- (5- tert -butyl-2-p- tolyl -2H- pyrazol - 3 - yl) -2- [7 -chloro- 4- (2-morpholin - 4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide ( 29 ). To a solution of 5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylamine (50 mg, 0.22 mmol) in 1 mL of dioxane is added BuLi (0.11 mL, 2 M in cHex), The mixture was allowed to stand for 10 minutes. To the mixture was added a solution of ester (83 mg, 0.22 mmol) in 1 mL of DMF and the resulting mixture was heated with microwave at 150 ° C. for 5 minutes. The mixture was washed with water, dried over MgSO ₄ and evaporated. The residue was purified by LC / MS to give 12% of the desired product. Mass calculated = 575. Mass found = 575.

Amido- Anisidine  General Procedure for the Synthesis of Derivatives

Method a.

5-t-butyl-2 -methoxy- 3- nitrobenzoic acid . A catalytic amount (about 5 drops) of concentrated sulfuric acid was added to a solution of 5-t-butyl-2-methoxybenzoic acid (5.5 g, 26 mmol) in 30 mL of AcOH and 30 mL of acetic anhydride. The resulting reaction was stirred at rt overnight. After the reaction, the reaction mixture was poured into about 1.2 L of ice water. A white precipitate formed which was filtered off and washed with water. After drying at 80 ° C. under vacuum, 5.98 g (91%) of pure product was obtained as a white solid as measured by NMR.

5- tert -butyl-N- cyclopropyl -2 -methoxy- 3-nitro- benzamide . To a solution of 5-t-butyl-2-methoxy-3-nitrobenzoic acid (759 mg, 3 mmol) in 18 mL DCM was added oxalyl chloride (1.8 mL, 15 mmol). After stirring for 2 hours at room temperature the reaction mixture was concentrated to dryness. The resulting acid chloride was dissolved in 30 mL of DCM and DIEA (2.6 mL, 15 mmol) and cyclopropyl amine (0.83 mL, 12 mmol) were added. Stirring was continued at rt overnight before DCM was added to the reaction mixture. After workup with aqueous sodium bicarbonate, column chromatography purification was performed on ISCO Oprix (silica gel column 3 × 12 g) using DCM. 678 mg of pure product was isolated as a pale yellow solid. Mass calculated = 292. Mass found = 295.

5- tert -butyl-N- cyclopropyl -2 -methoxy- 3- {2- [4- (2-morpholin-4-yl- ethoxy ) -naphthalen-1-yl] 2-oxo-acetylamino } -Benzamide ( 30 ). The compound (584 mg, 2 mmol) obtained in the above step was reduced with Pd / C and H ₂ in 30 mL of MeOH at room temperature for 3 hours. After filtration, the methanol was removed and the crude reduced intermediate was dissolved in 25 mL of DCM. DIEA (1.0 mL, 6 mmol) was added followed by acid chloride (2 mmol). The resulting suspension was stirred at rt overnight then DCM was added to the reaction. The organic layer was washed with aqueous sodium bicarbonate and water. The organic phase was dried over sodium sulfate, concentrated and the residue was purified by silica gel column (ISCO Optix column 7 x 12 g) to give 948 mg (yield: 82.6%) of product as pale yellow foam. Mass calculated = 574. Mass found = 574.

Method b

3-Amino-5- tert -butyl-2 -methoxy -benzoic acid. 5-t-butyl-2-methoxy-3-nitrobenzoic acid (1.5 mmol) was reduced with Pd / C and H ₂ in MeOH and the amine obtained was coupled with acid chloride (1.5 mmol). The reaction was worked up as described above and column purified (3 × 12 g silica gel) to give 211 mg of the target compound.

N- [5- tert -butyl-2 -methoxy- 3- (piperidine-1-carbonyl) -phenyl ] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide (31) Reaction of 26 mg (0.049 mmol) of the compound obtained above with oxalyl chloride (54 μl, 0.5 mmol) in 0.5 mL of DCM in a catalytic amount of DMF (room temperature, 2 hours) to acid chloride. After removing the solvent, the crude acid chloride was dissolved in 1 mL of DCM. DIEA (0.2 mmol) was added followed by piperidine (0.1 mmol). The resulting mixture was stirred at rt overnight. Aqueous workup and purification by LC-MS gave 7.6 mg of pure product. Mass calculated = 602. Mass found = 602

5- tert -Butyl-2-hydroxy-3- {2- [4- (2-morpholin-4-el- ethoxy ) -naphthalen-1-yl] -2-oxo-acetylamino} -benzoic acid ( 32 ). Starting material (11 mg, 0.02 mmol) was dissolved in 1 mL of DCM. A solution of BBr ₃ in DCM (0.1 mL, 1 M solution) was added at 0 ° C. and the reaction was continued for 2 hours at the same temperature and then quenched with water. Work up with aqueous sodium bicarbonate and purify with LC-MS to give 3.6 mg of the target compound. Mass calculated = 521. Mass found = 521.

Containing compound Pyrazolyl Derivatization  General procedure for

N- (5- tert -butyl-2H- pyrazol- 3-yl) -2- [4- (2-morpholin-4-yl- ethoxy ) -naphthalen-1-yl] -2-oxo-acet amides. To a solution of acid chloride (prepared as above) (695 mg, 2 mmol) in 10 mL EtOAc in 5-tert-butyl-2H-pyrazol-3-ylamine (278 mg, 2 mmol in 2.5 mL H ₂ O). ) And NaHCO ₃ (504 mg, 6 mmol) were added. The solution was stirred at 60 ° C for 15 h. The layers were separated and the organic layer was purified by column chromatography (0-6% MeOH / DCM). The target compound was obtained as a pale yellow oil in 51% yield. Mass calculated = 450. Mass found = 451.

N- (5- tert -butyl-2H- pyrazol- 3-yl) -2- [4- (2-morpholin-4-yl- ethoxy ) -naphthalen-1-yl] -2-oxo-acet Amide ( 33 ). The compound (17 mg, 0.038 mmol) obtained in this reaction was treated with phenylsulfonyl chloride (9.8 μL, 0.076 mmol) in pyridine (1 mL) in the presence of DMAP (2 mg) at 60 ° C. for 15 hours. The crude reaction mixture was purified by preparative LC / MS to give 3.1 mg of target material. Mass calculated = 591. Mass found = 591.

Further derivatives such as amide and urea derivatives were synthesized by essentially the same method.

Alpha- Ketoamide  synthesis

Method B: 2H- Pyrazole Via 3-yl-oxo-acetic acid

5- tert -butyl-2-p- tolyl -2H- pyrazole- 3 -carboxylic acid ethyl ester (R = Me). Pyridine (0.95 mL, 11.7 mmol), p-tolylborone in a round-bottom flask containing stirred 5-tert-butyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.5 g, 2.6 mmol) in 25 mL of DCM Acid (1.1 g, 8.1 mmol), Cu (OAc) 2 (0.75 g, 4.1 mmol) and 4 mm molecular sieve (0.75 g) were added. The reaction was stirred for 14 h at room temperature under air. The resulting mixture was filtered through a pad of diatomaceous earth and the filtrate was concentrated in vacuo to yield a pale green solid. The crude material was purified by flash chromatography (0-50% EtOAc: hexanes on silica gel) to afford the desired product (0.64 g, 83%) as a clear oil. Mass estimate = 286. Mass found = 287.

(5- tert -butyl-2-p- tolyl -2H- pyrazol- 3-yl) -methanol (R = Me). To an oven dried, round bottom flask containing 5-tert-butyl-2-p-tolyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.64 g, 2.2 mmol) was added dry THF (20 mL) and DIBAL-H (0.96 mL, 4.9 mmol) was then added dropwise under nitrogen. After stirring for 30 minutes at room temperature the reaction was diluted with 100 mL of diethyl ether and quenched with 5 mL of methanol with stirring for an additional 30 minutes at room temperature. The resulting slurry was treated with 5 g of MgSO ₄ and filtered through a pad of diatomaceous earth. The filter cake was washed with 3 x 75 mL portions of ether and the combined filtrates were concentrated in vacuo to afford the desired alcohol as a clear oil (0.515 g, 96%). No further purification was necessary. Mass estimate = 244. Mass found = 245.

5- tert -butyl-2-p- tolyl -2H- pyrazole- 3 -carbaldehyde (R = Me). In a scintillation vial containing (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -methanol (0.515 g, 2.1 mmol) 15 mL of DCM followed by Dess-Martin Periodinan (1.1 g, 2.52 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes and poured into a separatory funnel containing 30 mL of water. The layers were separated and the aqueous layer was extracted two more times with 50 mL of DCM. The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo to afford crude aldehyde. The crude material was purified by flash chromatography (0-50% EtOAc: hexanes, silica gel) to give the desired product as a clear oil (0.5 g, 97%). Mass estimate = 242. Mass found = 243.

(5- tert -butyl-2-p- tolyl -2H- pyrazol - 3 - yl) -trimethylsilanyloxy - acetonitrile (R = Me). Purely in an oven-dried flask containing 5-tert-butyl-2-p-tolyl-2H-pyrazole-3-carbaldehyde (0.5 g, 2.0 mmol) stirred in dry THF at 0 ° C. under nitrogen. Trimethylsilyl cyanide (0.29 mL, 2.2 mmol) was added followed by 1 drop of n-butyllithium (2.0 M in hexane). The mixture was stirred at 0 ° C. for 1 h and then warmed to rt and stirred overnight. The reaction mixture was concentrated in vacuo to afford the product as a thick oil. No further purification was necessary. Mass estimate = 341. Mass found = 342.

(5- tert -butyl-2-p- tolyl -2H- pyrazol - 3 - yl) -hydroxy-acetic acid (R = Me). 100 mL of concentrated HCl was added to a round bottom flask containing (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -trimethylsilanyloxy-acetonitrile and heated to 80 ° C. After heating overnight, the reaction was diluted with 150 mL of water and extracted with DCM (3 × 100 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was then redissolved in about 75 mL of methanol, then KOH (0.45 g, 8 mmol) was added and the solution was refluxed for 2 hours. The reaction mixture was then cooled to rt and concentrated in vacuo. Several pieces of crushed ice were added to the flask with the reaction residue and acidified with 1 N HCl. The mixture was then diluted with 100 mL of water and extracted with DCM (3 × 100 mL). The organic layer was washed with brine, dried over MgSO ₄ and concentrated in vacuo to afford 0.35 g (60%) of the desired product. No further purification was necessary. Mass estimate = 288. Mass found = 289.

(5- tert -butyl-2-p- tolyl -2H- pyrazol - 3 - yl) -oxo-acetic acid (34, R = Me). In a scintillation vial containing (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -hydroxy-acetic acid (0.35 g, 1.2 mmol), 15 mL of DCM followed by des-martin periodi Egg (0.61 g, 1.44 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes and poured into a separatory funnel containing 30 mL of 0.5 M HCl. The layers were separated and the aqueous layer was extracted two more times with 50 mL DCM. The combined organic layers were washed with brine, dried over MgSO ₄ and concentrated in vacuo to afford the desired product (more than 80% purity by NMR). No further purification was necessary. Mass estimate = 286. Mass found = 287.

2- (5- tert -butyl-2-p- tolyl -2H- pyrazol - 3 - yl) -N- [4- (2-morpholin-4-yl- ethoxy ) naphthalen-1-yl]- 2-oxo-acetamide ( 35 , R = Me): crude (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -oxo-acetic acid in a 40 mL scintillation vial ( 34 ) To (0.4 g, 1.4 mmol) was added oxalyl chloride (5 mL) and 1 drop of DMF. The suspension was stirred at rt for 1 h and concentrated in vacuo. The resulting solid was dissolved in EtOAc (10 mL) and 4- (2-morpholin-4-yl-ethoxy) -naphthalene-1- dissolved in EtOAc (10 mL) / 50% NaHCO ₃ (10 mL). To amine (0.45 g, 1.2 mmol) was added and stirred at rt overnight. The mixture was diluted with EtOAc and extracted with NaHCO ₃ . The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and the solvent removed to give a dark brown oil. The material was purified by column chromatography (50-100% EtOAc / hexanes) to give 0.357 g (57%) of the desired compound as a yellow solid. Mass estimate = 540. Mass found = 541.

α- Ketoamide  synthesis

Method C: 2H- Pyrazole -3-yl-3-oxo-2- ( Triphenyl -λ5- Phosphanilidene ) - Propionitrile  After

5- tert -butyl-2-p- tolyl -2H- pyrazole- 3 -carboxylic acid . To 5 tert-butyl-2-p-tolyl-2H-pyrazole-3-carboxylic acid ethyl ester (0.5 g, 1.75 mmol) in 40 mL of scintillation vial was added 2 mL of THF and 2 mL of 1 N LiOH. . The reaction was heated at 50 ° C. for 1 h and then the reaction mixture was concentrated in vacuo and the crude residue was diluted with 5 mL of 1 N HCl. The reaction slurry was then extracted with DCM (3 × 25 mL) and the combined organic layers were washed with brine (10 mL) and dried over MgSO ₄ . The resulting solution was concentrated in vacuo to give the desired product (0.432 g, 96%) greater than 95% purity. Isolated material was used without further purification.

3- (5- tert -butyl-2-p- tolyl -2H- pyrazol - 3 - yl) -3-oxo-2- ( triphenyl- λ5- phosphanilidene ) -propionitrile. In a round bottom flask containing 5-tert-butyl-2-p-tolyl-2H-pyrazole-3-carboxylic acid (0.432 g, 1.67 mmol), 50 mL of DCM was followed by (triphenyl-λ5-phosphanilidene). ) -Acetonitrile (0.635 g, 2.0 mmol), EDCI (0.394 g, 2.0 mmol) and DMAP (0.024 g, 0.2 mmol) were added. The reaction mixture was stirred at rt for 16 h and then concentrated in vacuo. The crude residue was purified by flash chromatography (on silica gel, 0-20% EtOAc: DCM) to afford the desired product as a white powder (0.722 g, 81%).

(5- tert -butyl-2-p- tolyl -2H- pyrazol - 3 - yl) -oxo-acetic acid methyl ester: 3- (5-tert-butyl-2-p-tolyl-2H-pyrazole-3 25 mL of DCM and 25 mL of methanol were added into a 100 mL round bottom flask containing -yl) -3-oxo-2- (triphenyl-λ5-phosphanilidene) -propionitrile (0.722 g, 1.3 mmol) It was. The starting material was completely dissolved in the solvent mixture and then dimethyl dioxirane (25 mL, 0.1 M in acetone) was added to the reaction. The resulting solution was stirred at room temperature for 30 minutes and then the reaction mixture was concentrated in vacuo and the crude material purified by flash chromatography (0-20% EtOAc: DCM on silica gel) to give a white solid (0.359 g, 92%). ) To obtain the desired keto-ester.

2- (5- tert -butyl-2-p- tolyl -2H- pyrazol - 3 - yl) -N- [4- (2-morpholin-4-yl- ethoxy ) -naphthalen-1-yl] -2-oxo-acetamide ( 35 , R = Me). 2 mL of THF and 1 N LiOH 2 in (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -oxoacetic acid methyl ester (0.359 g, 1.19 mmol) in 40 mL of scintillation vials mL was added. The reaction was heated at 50 ° C. for 1 h and then the reaction mixture was concentrated in vacuo and the crude residue diluted with 5 mL of 1 N HCl. The reaction slurry was then extracted with DCM (3 × 25 mL) and the combined organic layers were washed with brine (10 mL) and dried over MgSO ₄ . The resulting solution was concentrated in vacuo to afford the desired acid.

The pure acid was then dissolved in a minimum amount of about 2 mL of DCM and oxalyl chloride (5 mL) was added followed by 1 drop of DMF. The suspension was stirred at rt for 1 h and then concentrated in vacuo. The resulting solid was dissolved in EtOAc (10 mL) and 4- (2-morpholin-4-yl-ethoxy) -naphthalene-1- dissolved in EtOAc (10 mL) / 50% NaHCO ₃ (10 mL). Add to amine (0.41 g, 1.2 mmol) and stir overnight at room temperature. The mixture was diluted with EtOAc and washed with NaHCO ₃ . The aqueous layer was extracted two more times with 30 mL of EtOAc, the combined organic layers were washed with brine, dried over MgSO ₄ , filtered and the solvent removed in vacuo to give a dark brown oil. The material was purified by column chromatography (0-100% EtOAc / DCM) to give 0.250 g (47%) of the desired compound as a yellow solid.

6- Boc -amino-naphthalen-1-ol. 6-amino-naphthalen-1-ol (5 g, 31.4 mmol) was suspended in 50 mL of 0.5 N NaHCO _{3 and} 50 mL of EtOAc. Boc ₂ O (6.85 g, 31.4 mmol) was added and the reaction mixture was stirred at 60 ° C. overnight. The starting material was completely converted. The solvent layer was separated and the organic layer was washed with water, dried over MgSO ₄ and evaporated to afford the target material.

[6- (2-Morpholin-4-yl- ethoxy ) -naphthalen-1-yl] -carbamic acid tert -butyl ester . The compound obtained above (8.14 g, 31.4 mmol) was dissolved in 100 mL of AcN, 4- (2-chloro-ethyl) -morpholine (5.80 g, 34.5 mmol) and K ₂ CO ₃ (15.6 g, 0.11 mol) ) Was added. The reaction was stirred at 75 ° C overnight. The mixture was filtered, the solvent was evaporated and the residue was purified by silica gel chromatography (DCM / MeOH: 15/1) to give 0.51 g of the target product. Mass calculated = 372. Mass found = 372.

6- (2-Morpholin-4-yl- ethoxy ) -naphthalen-1-yl- Boc -amine (36). Boc protected material (1 g, 2.7 mmol) was stirred for several days at room temperature in 95% TFA / DCM / Et ₃ SiH. After evaporation the target material was obtained. Mass calculated = 272. Mass found = 272.

Example  4 - Imidazoloneopyridine  And Of imidazoloneopyrimidine  synthesis

As shown in the above scheme and as described in Methods A and B, 2,6-dichloro-nitro-pyridine or 2,4-dichloropyrimidine is in microwave (dioxane, 180 ° C., 10 minutes) in the presence of DIEA or Coupling was carried out calmly with various amines at room temperature (THF, 70 hours).

Method A:

(6 -Chloro- 3-nitro-pyridin-2-yl) -phenyl -amine. A mixture of 2,6-dichloro-3-nitropyridine (386 mg, 2 mmol), aniline (182 μL, 2 mmol) and DIEA (419 μL, 2.4 mmol) in 3 mL of dioxane was incubated at 180 ° C. for 10 min. Was stirred. After removal of the solvent, the residue was dissolved in 3 mL of DCM and subjected to silica gel column purification to give 308 mg (6-1.7% yield) of (6-chloro-3-nitro-pyridin-2-yl) -phenyl-amine. It was. Mass calculated = 249. Mass found = 250.

Method B:

(6 -Chloro- 3-nitro-pyridin-2-yl) -phenyl -amine. A mixture of 2,6-dichloro-3-nitropyridine (772 mg, 4 mmol), aniline (364 μL, 4 mmol) and DIEA (838 μL, 24.8 mmol) in 10 mL THF was stirred at room temperature for 70 hours. After removal of the solvent, the residue was dissolved in DCM and subjected to silica gel column purification to give 735 mg (74% yield) of the title compound. LC-MS: mass calcd = 249. Mass found = 250.

3-Amino - 6- chloro -pyridin-2-yl-p- tolyl -amine. A mixture of 6-chloro-3-nitro-pyridin-2-yl-p-tolyl-amine (527 mg, 2 mmol) and tin chloride (II) dihydrate (2.72 g, 12 mmol) in 4 mL concentrated HCl was added. Heat at C for 2 h. After cooling the yellow suspension was diluted with ethyl acetate and treated to pH 10 with aqueous K ₂ CO ₃ with vigorous stirring at 0 ° C. The emulsion was extracted with 5 x 30 mL of EtOAc. The combined organic phases were dried over Na ₂ SO ₄ . Evaporation gave 479 mg (yield: quantitation) of the title compound, which appeared to be pure by LC-MS and used for further reaction without any purification. Mass calculated = 233. Mass found = 234.

5- Chloro -3-p- Tolyl -1,3- Dihydro - Imidazo [4,5-b] pyridine 2-one ( 37 ).

A mixture of 3-amino-6-chloro-pyridin-2-yl-p-tolyl-amine (470 mg, 2 mmol) and DSC (768 mg, 3 mmol) in 10 mL DMF was heated at 80 ° C. for 15 hours. . After cooling the red solution was diluted with EtOAc and washed 2x with saturated sodium bicarbonate solution and 2x with water. The organic phase was dried over sodium sulfate and extracted to give 540 mg (quantitative yield) of a pink solid. TLC showed single spot (Rf = 0.32 in DCM / MeOH (15: 1)). LC-MS analysis showed the compound to be pure and used in the next step. Mass calculated = 259. Mass found = 260.

1 -bicyclo [2.21] hept - 2 -yl-5 -chloro- 3-p- tolyl -1,3 -dihydro - imidazo [4,5-b] pyridin - 2 -one ( 38 ) and 2- ( Bicyclo [2.2.1] hept - 2 - yloxy ) -5 -chloro- 3-p- tolyl- 3H-imidazo [4,5-b] pyridine ( 39 ). 5-chloro-3-p-tolyl-1,3-dihydro-imidazo [4,5-b] pyridin-2-one (52 mg, 0.2 mmol) in 1.5 mL DMF, exo-2-bromonor A mixture of bornane (103 μL, 0.8 mmol) and CS ₂ CO ₃ (195 mg, 0.6 mmol) was heated in microwave at 200 ° C. for 20 minutes. After filtration, the filtrate was diluted with EtOAc and washed with water. The organic phase is concentrated and the residue is dissolved in a minimal amount of DCM and subjected to silica gel column purification to give 1-bicyclo [2.2.1] hept-2-yl-5-chloro-3-p-tolyl-1, 21.2 mg of 3-dihydro-imidazo [4,5-b] pyridin-2-one (yield: 30%) (Rf = 0.60 in DCM) and 2- (bicyclo [2.2.1] hept-2-yljade C) -5-chloro-3-p-tolyl-3H-imidazo [4,5-b] pyridine was given 6.2 mg (yield: 9%) (Rf = 0.49 in DCM). Mass calculated = 353. Mass found = 354.

1 -bicyclo [2.2.1] hept - 2 -yl-5- phenylamino- 3-p- tolyl -1,3 -dihydro - imidazo [4,5-b] pyridin - 2 -one (40) . 1-bicyclo [2.2.1] hept-2-yl-5-chloro-3-p-tolyl-1,3-dihydro-imidazo [4,5-b] pyridine-2- in 1 mL dioxane Of (19 mg, 0.054 mmol), 15 μL (0.16 mmol) of aniline, ligand (5.1 mg, 0.015 mmol), Pd2 (dba) 3 (6.9 mg, 0.0075 mmol), t-BuOK (56 mg, 0.162 mmol) The mixture was heated at 100 ° C for 6 h. Preparative LC-MS gave 3.2 mg of TFA salt of the title compound. Mass calculated = 410. Mass found = 411.

2,6- bis (p- tolylamino ) -3-nitro-pyridine (X = C). A mixture of 2,6-dichloro-3-nitropyridine (193 mg, 1 mmol), p-tolylamine (236 mg, 2.2 mmol) and DIEA (524 μL, 3 mmol) in 3 mL of dioxane was incubated at 200 ° C. in microwave Stir at 20 min. After removal of the solvent, the residue was dissolved in and subjected to chloroform and silica gel column purification to give 291 mg (yield: 87%) of the title compound. Mass calculated = 334. Mass found = 335.

2,6- bis (p- tolylamino ) -3-nitro-pyrimidine (X = N). A microwave mixture of 2,6-dichloro-3-nitropyrimidine (194 mg, 1 mmol), p-tolylamine (236 mg, 2.2 mmol) and DIEA (524 μL, 3 mmol) in 3 mL dioxane Stir at 200 ° C. for 20 minutes. After removal of the solvent, the residue was dissolved in and subjected to chloroform and silica gel column purification to give 319 mg (yield: 95%) of the title compound. Mass calculated = 335. Mass found = 336.

3-amino-2,6- ( bis -p- tolylamino ) -pyridine. A mixture of 2,6-bis (p-tolylamino) -3-nitro-pyridine (288 mg, 0.86 mmol) and tin (II) chloride dihydrate (1.25 g, 5.5 mmol) in 3 mL concentrated HCl was added at 90 ° C. Heated for 2 hours. After cooling the suspension was diluted with ethyl acetate and treated to pH 10 with aqueous K2C03 with vigorous stirring at 0 ° C. The emulsion was extracted with 5 x 30 mL of EtOAc. The combined organic phases were dried over Na ₂ SO ₄ . Evaporation gave 254 mg (yield: 97%) of the title compound, which appeared to be pure by LC-MS and was used for further reaction without any purification. Mass calculated = 304. Mass found = 305.

3-amino-2,6- ( bis -p- tolylamino ) -pyrimidine. 2,6-bis (p-tolylamino) -3-nitro-pyrimidine was treated as described in the procedure above to afford the title compound, which was shown to be pure by LC-MS and subjected to further reaction without any purification. Used. Mass calculated = 305. Mass found = 306.

3-p- tolyl- 5-p- tolylamino- 1,3 -dihydro - imidazo [4,5-b] pyridin - 2 -one ( 41 ). A mixture of 3-amino-2,6- (bis-p-tolylamino) -pyridine (254 mg, 0.84 mmol) and DSC (323 mg, 1.26 mmol) in 6 mL DMF was heated at 80 ° C. for 20 hours. After cooling the red solution was diluted with EtOAc and washed 2x with saturated sodium bicarbonate solution and 2x with water. The organic phase was dried over sodium sulfate, concentrated and subjected to silica gel column purification to give 266 mg (yield: 96%) of the title compound. LC-MS: mass calcd = 330. Mass found = 331.

1 -bicyclo [2.2.1] hept - 2 -yl-3-p- tolyl- 5-p- tolylamino- 1,3 -dihydro - imidazo [4,5-b] pyridin - 2 -one ( 42 ) and [2- ( bicyclo [2.2.1] hept - 2 - yloxy ) -3-p- tolyl- 3H -imidazo [4,5-b] pyridin -5-yl] -p-tolyl- Amines ( 43 ). 3-p-tolyl-5-p-tolylamino-1,3-dihydro-imidazo [4,5-b] pyridin-2-one (33 mg, 0.1 mmol) in 0.5 mL DMF, exo-2 A mixture of bromonorbornane (19 μL, 0.15 mmol) and Cs 2 CO 3 (65 mg, 0.2 mmol) was heated at 180 ° C. for 3 hours. After cooling, EtOAc was added and the organic layer was washed with water. The organic phase is concentrated, the residue is dissolved in and applied to a minimum amount of DCM and silica gel column purification to give 1-bicyclo [2.2.1] hept-2-yl-3-p-tolyl-5-p-tolylamino 13.4 mg -1,3-dihydro-imidazo [4,5-b] pyridin-2-one (yield: 32%) (Rf = 0.44 in DCM) and [2- (bicyclo [2.2.1] hept 4.8 mg (yield: 11%) of 2--2-yloxy) -3-p-tolyl-3H-imidazo [4,5-b] pyridin-5-yl] -p-tolyl-amine (Rf = 0.27 in DCM) ).

Example  5: Difluoro General Procedure for Acetic Acid Derivatives

Difluoro- 4-(2-morpholin-4-yl- ethoxy ) -naphthalen-1-yl] -acetic acid methyl ester ( 44 ). To a solution of keto-ethyl ester ( 12 ) (0.618 g, 1.80 mmol) in CH ₂ Cl ₂ (20 mL) was added diethylaminosulfur trifluoride (1.70 mL, 13.8 mmol) and EtOH (3 drops). . The solution was stirred for 3 days at room temperature. The mixture was neutralized with saturated NaHCO ₃ and extracted with CH ₂ Cl ₂ (3 × 20 mL). The combined organic layers were washed with brine, dried over MgSO ₄ , filtered and the solvent removed. The crude material was purified by preparative LCMS to give 70 mg (10% yield) as an oil. Mass estimate = 365. Mass found = 366.

N- (5- tert -butyl-2-p- tolyl -2H- pyrazol - 3 - yl) -2,2 -difluoro- 2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -acetamide (45). Difluoro methyl ester 44 was saponified, converted to acid chloride, and coupled as described above. Mass estimate = 562. Mass found = 563.

Example  6: Diamide  Synthesis of derivatives

N-naphthalen-1-yl- oxalic acid Methyl ester. In a round bottom flask containing 1-naphthyl amine (0.1 g, 0.68 mmol) stirred in DCM (5 mL) was charged DIEA (0.18 mL, 1.02 mmol) and chloro-oxo-acetic acid methyl ester (0.068 mL, 0.748 mmol). Added. The mixture was stirred at rt for 1 h. The reaction mixture was poured into saturated sodium bicarbonate and the layers separated. The aqueous layer was extracted two more times with DCM 3 x 15 mL. The combined organics were washed with brine, dried over MgSO ₄ and concentrated in vacuo to give a brown solid. The crude material was purified by flash chromatography (0-50% EtOAc: hexanes on silica gel) to afford the desired product (0.14 g, 90%) as an off-white solid. Mass estimate = 229. Mass found = 230.

N-naphthalen-l-yl- oxalic acid . To a stirred N-naphthalen-1-yl-oxalamic acid methyl ester (0.14 g, 0.61 mmol) in THF (2 mL) was added 2 mL of a 1 N lithium hydroxide solution. The reaction was heated to 50 ° C and stirred for 2 hours. The resulting mixture was concentrated in vacuo to afford a yellow residue, which was acidified with 1 N HCl. The resulting mixture was extracted with DCM (3 × 50 mL), dried over MgSO ₄ and concentrated in vacuo to afford the crude product. The crude material was purified by flash chromatography (silica gel, 0-20% MeOH: DCM) to give the desired product (0.128 g, 98%) as a thick oil. Mass estimate = 215. Mass found = 216.

N- (5- tert -butyl-2-p- tolyl -2H- pyrazol - 3 - yl) -N'-naphthalen-1-yl- oxalamide ( 46 ). Diisopropylcarbodiimide (0.09 g, 0.72 mmol) and DIEA (0.19 mL) in a round bottom flask containing N-naphthalen-1-yl-oxalamic acid (0.128 g, 0.6 mmol) stirred in DCM (5 mL) , 1.08 mmol) was added. The reaction was stirred at rt overnight and quenched with 10 mL saturated NaHCO ₃ . The layers were separated and the aqueous layer was extracted twice more with 2 × 25 mL of DCM. The combined organics were washed with brine, dried over MgSO ₄ and concentrated in vacuo to give a brown oil. The crude mixture was purified by flash chromatography (50-100 EtOAc: hexanes, silica gel) to give the desired product (184 g, 72%) as off-white solid. Mass estimate = 426. Mass found = 427.

Example  7: Oxime  General procedure for derivative formation

N- (5- tert -butyl-2-p- tolyl -2H- pyrazol - 3 - yl) -2 -hydroxyimino- 2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -acetamide ( 47 ). Compound ( 13 ) (10 mg, 0.018 mmol) and hydroxylamine hydrochloride (50 equiv, 0.92 mmol, 64 mg) were dissolved in 2 mL EtOH. Pyridine (0.1 mL) was added and the mixture was stirred at 45 ° C for 12 h. The solvent was then removed under vacuum and the crude solid was purified via LCMS to give 6 mg (58% yield; mixture of isomers) of white solid. Mass estimate = 555. Mass found = 556.

N- (5- tert -butyl-2-p- tolyl -2H- pyrazol - 3 - yl) -2 -methoxyimino- 2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -acetamide ( 48 ). Compound ( 13 ) (10 mg, 0.018 mmol) and methoxyamine hydrochloride (50 equiv, 0.92 mmol, 77 mg) were dissolved in 2 mL EtOH. Pyridine (0.1 mL) was added and the mixture was stirred at 45 ° C for 12 h. The solvent was then removed in vacuo and the crude solid was purified via LCMS to give 8 mg (76% yield; mixture of isomers) of white solid. Mass estimate = 569. Mass found = 570.

Example  8

4- (morpholin-4-yl- ethyloxy ) -1 -naphthylepoxide . To a suspension of NaH (24 mg, 1.0 mmol) in DMSO (1 mL) was added trimethylsulfonium iodide (220 mg, 1.0 mmol). After H ₂ evolution ceased, a solution of aldehyde ( 8 ) (285 mg, 1.0 mmol) in DMSO (0.5 mL) was added and the mixture was stirred at 20 ° C. for 12 h. The mixture was diluted with H ₂ O, extracted with Et ₂ O, the combined organic layers were dried (MgSO ₄ ) and rotary evaporated to give a yellow oil which was used in the next step without any further purification. Mass estimate = 299. Mass found = 300.

N- (5- tert -butyl-2-p- tolyl -2H- pyrazol - 3 - yl-2-hydroxy-2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -ethylamine ( 49 ) 5-amino-3-t-butyl-1- (4-methylphenyl) pyrazole ( 1 ) (50 mg, 0.2 mmol in 1,4-dioxane (2 mL) N-BuLi (0.1 mL, 0.2 mmol, 2.0 M in cyclohexane) was added under N2 at 20 ° C. A solution of the compound obtained in the reaction in DMF (1 mL) was added and the brown mixture was Heat in microwave for 5 minutes at 150 ° C. The mixture was diluted with CH ₂ Cl ₂ , washed with water, the organic layer was dried (MgSO ₄ ) and rotary evaporated to give a brown oil which was purified LC-MS. Purification by gave the title compound (8.3 mg, 8%) as a yellow waxy solid: Mass calculated = 528. Mass found = 529.

Example  9 - Triazolidine - Dion  Synthesis of derivatives

Path A:

N '-(3- tert -butyl- phenyl ) -hydrazinecarboxylic acid ethyl ester. 3-t-butylhydrazine hydrochloride (600 mg, 3 mmol) was dissolved in 15 mL of DCM, followed by DIEA (1.7 mL, 10 mmol) followed by ethyl chloroformate (3 mmol). The reaction mixture was stirred overnight at room temperature and then worked up with aqueous sodium bicarbonate. The organic phase was dried over Na ₂ SO ₄ , concentrated and subjected to ISCO column (4 × 12 g) purification to give 437 mg of product as a brown oil.

1- (3- tert -butyl- phenyl ) -4- [4- (2-morpholin-4-yl- ethoxy ) -naphthalen-1-yl]-[1, 2,4] triazolidine-3 , 5-dione ( 50 ). 4- (2-N-morpholinoethoxy) naphthylamine dihydrochloride (70 mg, 0.2 mmol) was dissolved in a cooled (0 ° C) mixture of 4 mL of DCM and 4 mL of saturated NaHCO ₃ solution. Agitation was stopped. 0.36 mL of about 20% phosphine in toluene was added to the DCM layer and vigorous stirring was resumed. The reaction was continued for 30 minutes at 0 ° C. The organic layer was separated and the aqueous layer was extracted once with DCM. The combined organic layers were evaporated. A solution of N '-(3-tert-butyl-phenyl) -hydrazinecarboxylic acid ethyl ester (47 mg, 0.2 mmol) in 1 mL of DCM was added to the crude isocyanate. The reaction mixture was stirred overnight at room temperature. After removal of the solvent, the residue was dissolved in DMSO and subjected to preparative LC-MS purification to give 8.4 mg of the target compound. The compound (8.4 mg, 0.016 mmol) obtained in the above step was dissolved in 1 mL of EtOH and a solution of NaOH (2 mg, 0.05 mmol) in 0.2 mL of water was added. The resulting mixture was stirred at rt for 2 h and then neutralized to pH 4 with concentrated HCl. Purification of the crude material was carried out by preparative LC-MS to give 6 mg of final product.

Path B:

1- tert -butyl-3-isocyanate-benzene. 3-t-butyl-aniline (150 mg, 1 mmol) was converted to isocyanate as described above and then dissolved in 4 mL of DCM. Hydrazate (104 mg, 1 mmol) was added and the reaction continued at room temperature overnight. Preparative LCMS purification gave 181 mg of the target compound as a white solid.

Ethyl 2-[( tolylamino ) carbonyl] hydrazinecarboxylate . NBS (121 mg, 0.68 mmol) was added to a stirred suspension of 1-tert-butyl-3-isocyanate-benzene (181 mg, 0.65 mmol) in 3 mL of DCM and 105 μl of pyridine at room temperature. After stirring for an additional 2 hours, 2 mL of water was added followed by 1 mL of concentrated HCl. The organic phase was separated and washed with a solution of Na 2 S203 (65 mg) in 3 mL water, saturated NaHCO ₃ and water. The organic phase was dried over Na ₂ SO ₄ and concentrated to yield 182 mg of the target compound as a pale red thick oil.

4- (3- tert Butyl Phenyl ) -1- [4- (2-morpholin-4-yl- Ethoxy ) -Naphthalen-1-yl]-[1, 2,4] triazolidine-3,5-dione (51).

A cold solution of the compound obtained above (55 mg, 0.2 mmol) and 1- (2-morpholinoethoxy) -naphthalene (51 mg, 0.2 mmol) in 1.5 mL of DCM was stirred with ZrCl ₄ in 0.5 mL of DCM. Added to suspension. The reaction was continued at −30 ° C. for 45 minutes, then warmed to room temperature, and 1 mL of water was added to quench the reaction. Neutralized with saturated NaHCO ₃ . The organic phase was separated and the aqueous phase extracted with DCM. The combined organic phases were dried over Na ₂ SO ₄ , concentrated and subjected to preparative LC-MS purification to give 22.8 mg of the target compound.

The compound obtained above (22.8 mg, 0.43 mmol) was dissolved in 2 mL of EtOH. A solution of NaOH (4 mg, 1 mmol) in 0.4 mL of water was added. After stirring for 2 hours at room temperature, the reaction mixture was neutralized with concentrated HCl (to pH = 4) and applied directly to preparative LC-MS purification to give 7 mg of final product.

Example  10

N- (5- tert -butyl-3- methanesulfonylamino- 2 -methoxy - phenyl ) -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- Succinic acid methyl ester ( 52 ). To stirred keto-amide ( 13b ) (250 mg, 0.43 mmol) in toluene was added two drops of illi (156 mg, 0.52 mmol) and diisopropylethyl amine. The reaction was sealed and heated to 100 ° C overnight. The reaction was cooled to rt and concentrated in vacuo. The crude residue was purified by LCMS to give two isomers isolated independently as white solid (105 mg, 84%). Both isomers were used in the next step.

N- (5- tert -butyl-3- methanesulfonylamino- 2 -methoxy - phenyl ) -3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- Succinic acid methyl ester ( 53 ). A 50 mL round bottom flask containing ethyl acetate and the succinic acid (75 mg, 0.12 mmol) obtained in the reaction was sparged with nitrogen for 5 minutes. The resulting solution was left under nitrogen and treated with 10% Pd / C (10 mole%). The atmosphere was then exchanged with hydrogen through a balloon and the reaction stirred at room temperature for 16 hours. The resulting solution was filtered through a pad of celite and the filtrate was concentrated in vacuo to afford the crude product. The crude was purified by flash chromatography to give the desired product in 87% yield as a white solid (65 mg).

N- (5- tert -butyl-2 -methoxy- 3- {3- [4- (2-morpholin-4-yl- ethoxy ) -naphthalen-1-yl] -2,5-oxo-2 , 5-dihydro-pyrrole-1-yl} -phenyl) -methanesulfonamide ( 54 ). In a 40 mL scintillation vial 3- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl) -3- [4- (2-morpholin-4-yl- Ethoxy) -naphthalen-1-yl] -acrylic acid methyl ester ( 51 ) (25 mg, 0.04 mmol), DIEA (13.6 mL, 0.08 mmol) and 5 mL of THF were placed. The reaction was heated to 80 ° C with stirring for 16 h. The resulting reaction mixture was concentrated in vacuo and the crude residue was purified by reverse phase preparative LC-MS to give the desired compound (10.2 mg, 39%). Mass calculated = 607. Mass found = 608.

N- (5- tert -butyl-2 -methoxy- 3- {3- [4- (2-morpholin-4-yl- ethoxy ) -naphthalen-1-yl] -2,5-dioxo- Pyrrolidin-1-yl} -phenyl) -methanesulfonamide ( 55 ). In 20 mL scintillation vial N- (5-tert-butyl-2-methoxy-3-3- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2, 5-oxo-2,5-dihydro-pyrrole-1-yl} -phenyl) -methanesulfonamide (28 mg, 0.046 mmol), 5 mL of ethanol and Pd / C (15 mg, 10 mole%) were placed. . The vial was sealed with a septum and the reaction mixture was sparged with house nitrogen for 10 minutes. The resulting solution was then sparged through the balloon for 5 minutes with hydrogen gas. After charging the balloon with hydrogen gas again, the reaction was stirred at room temperature for 2 hours. The resulting solution was filtered through a pad of celite and concentrated in vacuo to afford the desired product (27 mg, 100%). Mass calculated = 610. Mass found = 611.

Example  11

Hydroxy- [4- (2-morpholin-4-yl- ethoxy ) -naphthalen-1-yl] -acetic acid methyl ester. To a solution of compound 12 (1 g, 2.9 mmol) in MeOH (10 mL) was added Pd / C (10 wt.%) And the mixture was stirred at room temperature under H ₂ atmosphere. Upon completion of the reaction (monitored by LCMS) the mixture was filtered through celite and the filtrate was evaporated to give a yellow oil which solidified upon standing. Mass calculated = 345. Mass found = 345.

[4- (2-Morpholin-4-yl- ethoxy ) -naphthalen-1-yl] -acetic acid. Yellow solid (0.5 g) was dissolved in CH ₂ Cl ₂ (10 mL). TFA (10 mL) and Et ₃ SiH (10 equiv, 30 mmol) were added to the solution, and the mixture was allowed to stand until the reaction was complete (after adding 10 equivalents of Et ₃ SiH as shown by LCMS). Stirred at. The solvent was evaporated and the residue was triturated with hexanes. The precipitated product was filtered off, washed with hexanes, dried under vacuum and dissolved in MeOH / THF (1: 1, 10 mL). 2 M NaOH (2.2 mL) was added to the solution and the mixture was stirred at rt for 4 h. The mixture was neutralized with 6 M HCl and evaporated to give a brown residue. The residue was repeatedly dissolved in a minimum amount of MeOH and filtered from residual NaCl. The solvent was evaporated and the acid dried at 50 ° C. under vacuum. Mass calculated = 315. Mass found = 315.

N- (5- tert -butyl-3- methanesulfonylamino- 2 -methoxy - phenyl ) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- Acetamide ( 56 ). To a suspension of acid in CH ₂ Cl ₂ (5 mL) was added oxalyl chloride (10 equiv) and 1 drop of DMF. The mixture was rapidly cleared under gas evolution and stirred at room temperature for 4 hours. The solvent was evaporated to give an effervescent residue which was dried under vacuum and again dissolved in CH ₂ Cl ₂ (5 mL). To the solution was added DIEA (3 equiv) and Compound ( 14 ) (1.2 equiv) and the mixture was stirred at rt for 60 h. The brown solution was washed with H ₂ O, dried (MgSO ₄ ) and evaporated. The brown residue was purified by column chromatography on silica using EtOAc as eluent to give the final product as a pale yellow solid. Mass calculated = 569. Mass found = 569.

Example  12

N '-{(5- tert -butyl-3-sec- butylcarbamoyl- 2 -methoxy - phenylcarbamoyl )-[4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -methylene} -hydrazinecarboxylic acid ethyl ester. Compound ( 30 ) (44 mg, 0.077 mmol) was dissolved in EtOH (1 mL) and hydrazinecarboxylic acid ethyl ester (24 mg, 0.231 mmol) and 1 drop of AcOH were added. The reaction mixture was stirred at 120 ° C. for 15 hours and then the crude mixture was purified by LC / MS. Isomers were separated and the desired isomer was used in the next step. Mass calculated = 660. Mass found = 660.

5- tert -butyl-N- cyclopropyl -2 -methoxy- 3- {6- [4- (2-morpholin-4-yl- ethoxy ) -naphthalen-1-yl] -3,5-di Oxo-2,5-dihydro-3H-1,2,4-triazin-4-yl} -benzamide ( 57 ). The compound obtained in this step (about 8 mg, 0.1 mmol) was dissolved in EtOH and DIEA (0.1 ml, 0.6 mmol) was added. The mixture was stirred at 120 ° C. overnight and then purified by LC / MS to give 2.5 mg of target product. Mass calculated = 614. Mass found = 614.

Example  13: THP  In the cell TNFα  Suppression of production

Inhibition of cytokine production could be observed by measuring inhibition of TNFα in lipopolysaccharide-stimulated THP-1 cells (see Richett et al. J. Inflammation, 1995, 45 , 97). THP-1 cells (ATCC TIB 202, American Type Culture Collection, Rockville, MD) were treated with 10% fetal bovine serum, 10 mM Hepes, 1 mM sodium pyruvate, 4.5 g / L glucose as presented by ATCC. And RPMI 1640 medium containing 0.05 mM 2-mercaptoethanol at 37 ° C., 5% CO ₂ . For analysis, cells and compounds were diluted with the medium (analytical medium) above without 1% fetal bovine serum. Test compound stocks in DMSO were diluted to 6 × final assay concentrations containing 0.3% final DMSO concentration when analyzed using assay media. THP-1 cells were plated at 1 × 10 ⁵ cells / well in 96 well tissue culture plates. Diluted compound (or DMSO control) was added and pre-incubated with the cells at 37 ° C., 5% CO ₂ for 30 minutes and then LPS (Sigma) was added to a final concentration of 1 μg / mL. The cells were then incubated at 37 ° C./5% CO ₂ for 18-20 hours. The assay was terminated by centrifuging the plate for 10 minutes at room temperature. The supernatant was removed to clean the culture plates and aliquots were removed for TNFα analysis with a commercial ELISA kit (R & D Systems # DY210, Minneapolis, MN). Data was analyzed by non-linear regression using Graphpad Software (San Diego, Calif.). The calculated IC ₅₀ is the concentration of the test compound that reduces the maximum TNFα production by 50%.

Example  14

Table 1 lists the compounds of the present invention prepared using the methods of Examples 1-13. Each compound was analyzed by LC-MS and showed predicted molecular ions. Each compound in Table 1 was tested by the TNFα ELISA assay (Example 13) and found to have its activity against certain compounds having an IC ₅₀ of 10 μM or less in this assay.

As will be appreciated by those skilled in the art, for any and all purposes, in particular for providing the described description, all ranges described herein also include any and all possible subranges and combinations of subranges thereof. It will be readily appreciated that any listed range is sufficient to describe and enable the same range, which is classified at least equal to two, three, four, five, ten, and the like. By way of non-limiting example, each range discussed herein can be easily classified into lower thirds, middle thirds, upper thirds, and the like. In addition, as will be understood by those skilled in the art, all terms such as "less than", "greater than", "greater than", "less than" and the like encompass the stated number and mean a range that can be classified later into subranges as discussed above. do. Finally, as those skilled in the art will understand, certain ranges include each individual number. Thus, for example, a group having 1 to 3 atoms means a group having 1, 2 or 3 atoms. Similarly, a group having from 1 to 5 atoms is meant to mean a group having 1, 2, 3, 4 or 5 atoms, and the like.

While particular embodiments have been illustrated and described, it should be understood that changes and modifications may be made herein by those skilled in the art without departing from the invention in its broader aspects as defined in the following claims.

Claims (93)

A compound of formula (IA), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. <Formula IA>

Where X is C (O), G is phenyl or pyrazolyl, substituted with one or more R ¹ , R ² or R ³ , Ar is-(Y)-(C _0-3 alkyl)-(bicyclic aryl), optionally substituted with one or more R ⁴ or R ⁵ , wherein the bicyclic aryl is naphthyl, tetrahydronaphthyl, dihydronaph Butyl, indenyl, indanyl or azulenyl, but not 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthyl, Y is -C (O)-, L is a covalent bond, C ₁ -C ₉ alkoxy, —C (O) O—, —NH— or —O—, m is each independently 0, 1 or 2, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl, optionally substituted with one or more R ²⁷ , Each R ′ is independently hydrogen, C _1-8 alkyl, (C _0-4 alkyl)-(C _6-10 aryl) or (C _0-4 alkyl)-(5-10 membered heterocyclyl), Each R ¹ is independently linear or branched C _1-10 alkyl, R ² , R ⁴ , and R ⁵ are each independently F, Cl, Br, I, cyano, linear or branched C _1-6 alkyl, C _6-10 aryl, 5-10 membered heteroaryl, -OR ' , -OR ⁶ , -C (O) R ', -C (O) OR', -C (O) NR ' ₂ , -NR' ₂ , -NO ₂ , -S (O) _m R ", -NR 'SO ₂ R " _, -NR'C (O) NR'R', -NR'C (S) NR'R ', -NR'C (O) OR' or -SO ₂ NR ' ₂ , Each R ″ is independently C _1-8 alkyl, C _0-4 alkyl-C _6-10 aryl or (C _0-4 alkyl)-(5-10 membered heterocyclyl), R ³ are each independently R ²³ R ²⁴ NC (O)-, R ²⁰ -C (O) -NR ²¹ , or OR ²² , R ⁶ is each C _1-6 branched or unbranched alkyl, optionally partially or completely halogenated, and optionally substituted with R ²⁶ , Each R ²⁶ is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or optionally partially or fully halogenated mono- or di- (C _{0- 4} alkyl) amino, R ²⁰ is C _1-10 alkyl, C _0-6 alkyl-phenyl, C _0-6 alkyl- (5-10 membered heterocyclyl), OR 'or NR' ₂ , R ²¹ is hydrogen or optionally partially or fully halogenated C _1-4 branched or unbranched alkyl, R ²² , R ²³ and R ²⁴ are each independently hydrogen, C _1-10 alkyl (C _1-10 alkyl optionally interrupts one or more O, N or S), C _0-6 alkyl-phenyl, C _{0- 6} alkyl- (5-10 membered heterocyclyl), or R ²³ and R ²⁴ together optionally form a 5-10 membered heterocyclic or heteroaryl ring, R ²⁷ are each independently F, Cl, Br, I, cyano, -C (O) R ', -C (O) NR' ₂ , -C (O) OR ', -OR', -NR'R ', -SiR' ₃ , -S (O) _m R ', linear or branched C _1-10 alkyl, C _2-10 alkenyl or C _2-10 alkynyl, C _3-10 cycloalkyl, C _5- 1, 2, 3 or 4 heteroatoms independently selected from ₈ cycloalkenyl, C _7-20 aralkyl, or 3-11 membered heterocyclyl or heterocyclylalkyl (N, O, S (O) _m Containing), Provided that when Ar is-(Y)-(bicyclic aryl) and G is N- (phenyl) -pyrazolyl, pyrazolyl is further substituted with one or more R ¹ , R ² or R ³ , Compound of formula (IA) is N- (4-chloro-3-methyl-isothiazol-5-yl) -2- [2- (2,2-dimethyl-propyl) -benzooxazol-5-yl] -2 It is not oxo-acetamide. delete delete delete delete delete delete delete A compound of formula (IA), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. <Formula IA>

Where X is C (O), G is phenyl or pyrazolyl, substituted with one or more R ¹ , R ² or R ³ , Ar is-(Y)-(C _0-3 alkyl)-(bicyclic aryl), optionally substituted with one or more R ⁴ or R ⁵ , wherein the bicyclic aryl is naphthyl, tetrahydronaphthyl, dihydronaph Butyl, indenyl, indanyl or azulenyl, but not 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthyl, Y is -C (O)-, L is a covalent bond, C ₁ -C ₉ alkoxy, —C (O) O—, —NH— or —O—, m is each independently 0, 1 or 2, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl, optionally substituted with one or more R ²⁷ , Each R ′ is independently hydrogen, C _1-8 alkyl, (C _0-4 alkyl)-(C _6-10 aryl) or (C _0-4 alkyl)-(5-10 membered heterocyclyl), Each R ¹ is independently, optionally partially or fully halogenated, and 1 to 3 C _3-10 cycloalkyl, hydroxy phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, Imidazolyl, pyrazolyl, thienyl, furyl, isoxazolyl or isothiazolyl, each of which is 1-5 halogen, optionally partially or fully halogenated C _1-6 branched or unbranched alkyl, C _3-8 Cycloalkyl, C _5-8 cycloalkenyl, hydroxy, cyano, optionally partially or fully halogenated C _1-3 alkoxy and NH ₂ C (O) or mono- or di- (C _1-3 alkyl) amino C _3-10 branched or unbranched alkyl optionally substituted with carbonyl), R ² , R ⁴ , and R ⁵ are each independently F, Cl, Br, I, cyano, linear or branched C _1-6 alkyl, C _6-10 aryl, 5-10 membered heteroaryl, -OR ' , -OR ⁶ , -C (O) R ', -C (O) OR', -C (O) NR ' ₂ , -NR' ₂ , -NO ₂ , -S (O) _m R ", -NR 'SO ₂ R " _, -NR'C (O) NR'R', -NR'C (S) NR'R ', -NR'C (O) OR' or -SO ₂ NR ' ₂ , Each R ″ is independently C _1-8 alkyl, C _0-4 alkyl-C _6-10 aryl or (C _0-4 alkyl)-(5-10 membered heterocyclyl), R ³ are each independently R ²³ R ²⁴ NC (O)-, R ²⁰ -C (O) -NR ²¹ , or OR ²² , R ⁶ is each C _1-6 branched or unbranched alkyl, optionally partially or completely halogenated, and optionally substituted with R ²⁶ , Each R ²⁶ is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or optionally partially or fully halogenated mono- or di- (C _{0- 4} alkyl) amino, R ²⁰ is C _1-10 alkyl, C _0-6 alkyl-phenyl, C _0-6 alkyl- (5-10 membered heterocyclyl), OR 'or NR' ₂ , R ²¹ is hydrogen or optionally partially or fully halogenated C _1-4 branched or unbranched alkyl, R ²² , R ²³ and R ²⁴ are each independently hydrogen, C _1-10 alkyl (C _1-10 alkyl optionally interrupts one or more O, N or S), C _0-6 alkyl-phenyl, C _{0- 6} alkyl- (5-10 membered heterocyclyl), or R ²³ and R ²⁴ together optionally form a 5-10 membered heterocyclic or heteroaryl ring, R ²⁷ are each independently F, Cl, Br, I, cyano, -C (O) R ', -C (O) NR' ₂ , -C (O) OR ', -OR', -NR'R ', -SiR' ₃ , -S (O) _m R ', linear or branched C _1-10 alkyl, C _2-10 alkenyl or C _2-10 alkynyl, C _3-10 cycloalkyl, C _5- 1, 2, 3 or 4 heteroatoms independently selected from ₈ cycloalkenyl, C _7-20 aralkyl, or 3-11 membered heterocyclyl or heterocyclylalkyl (N, O, S (O) _m Containing), Provided that when Ar is-(Y)-(bicyclic aryl) and G is N- (phenyl) -pyrazolyl, pyrazolyl is further substituted with one or more R ¹ , R ² or R ³ , Compound of formula (IA) is N- (4-chloro-3-methyl-isothiazol-5-yl) -2- [2- (2,2-dimethyl-propyl) -benzooxazol-5-yl] -2 It is not oxo-acetamide. delete delete delete delete delete delete delete The compound of claim 1, wherein each R ² is independently —NR′SO ₂ R ″, —Cl, —Br, —F, —C (O) —NR ′ ₂ , linear or branched C _1-6 alkyl, — NR ' ₂ or -OR'. delete delete A compound of formula (IA), or a stereoisomer, tautomer or pharmaceutically acceptable salt thereof. <Formula IA>

Where X is C (O), G is phenyl or pyrazolyl, substituted with one or more R ¹ , R ² or R ³ , Ar is-(Y)-(C _0-3 alkyl)-(bicyclic aryl), optionally substituted with one or more R ⁴ or R ⁵ , wherein the bicyclic aryl is naphthyl, tetrahydronaphthyl, dihydronaph Butyl, indenyl, indanyl or azulenyl, but not 1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthyl, Y is -C (O)-, L is a covalent bond, C ₁ -C ₉ alkoxy, —C (O) O—, —NH— or —O—, m is each independently 0, 1 or 2, Q is morpholino, piperazinyl, pyrimidinyl or pyridinyl, optionally substituted with one or more R ²⁷ , Each R ′ is independently hydrogen, C _1-8 alkyl, (C _0-4 alkyl)-(C _6-10 aryl) or (C _0-4 alkyl)-(5-10 membered heterocyclyl), Each R ¹ is independently linear or branched C _1-10 alkyl, R ² , R ⁴ , and R ⁵ are each independently F, Cl, Br, I, cyano, linear or branched C _1-6 alkyl, C _6-10 aryl, 5-10 membered heteroaryl, -OR ' , -OR ⁶ , -C (O) R ', -C (O) OR', -C (O) NR ' ₂ , -NR' ₂ , -NO ₂ , -S (O) _m R ", -NR 'SO ₂ R " _, -NR'C (O) NR'R', -NR'C (S) NR'R ', -NR'C (O) OR' or -SO ₂ NR ' ₂ , Each R ″ is independently C _1-8 alkyl, C _0-4 alkyl-C _6-10 aryl or (C _0-4 alkyl)-(5-10 membered heterocyclyl), Each R ³ is independently phenyl or pyridinyl optionally substituted with 1, 2 or 3 -F, -Cl, C _1-6 branched or unbranched alkyl or C _1-4 alkoxy, R ⁶ is each C _1-6 branched or unbranched alkyl, optionally partially or completely halogenated, and optionally substituted with R ²⁶ , Each R ²⁶ is independently cyano, morpholino, piperidinyl, piperazinyl, imidazolyl, phenyl, pyridinyl, tetrazolyl, or optionally partially or fully halogenated mono- or di- (C _{0- 4} alkyl) amino, R ²⁷ are each independently F, Cl, Br, I, cyano, -C (O) R ', -C (O) NR' ₂ , -C (O) OR ', -OR', -NR'R ', -SiR' ₃ , -S (O) _m R ', linear or branched C _1-10 alkyl, C _2-10 alkenyl or C _2-10 alkynyl, C _3-10 cycloalkyl, C _5- 1, 2, 3 or 4 heteroatoms independently selected from ₈ cycloalkenyl, C _7-20 aralkyl, or 3-11 membered heterocyclyl or heterocyclylalkyl (N, O, S (O) _m Containing), Provided that when Ar is-(Y)-(bicyclic aryl) and G is N- (phenyl) -pyrazolyl, pyrazolyl is further substituted with one or more R ¹ , R ² or R ³ , Compound of formula (IA) is N- (4-chloro-3-methyl-isothiazol-5-yl) -2- [2- (2,2-dimethyl-propyl) -benzooxazol-5-yl] -2 It is not oxo-acetamide. delete delete delete delete delete N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalene- 1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-hydroxy-3-morpholin-4-ylmethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene-1- Il] -2-oxo-acetamide; N- (5-tert-butyl-2-hydroxy-3-methyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo Acetamide; N- (5-tert-butyl-2-methoxy-3-methyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo Acetamide; N- (5-tert-butyl-3-chloro-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo Acetamide; N- (5-tert-butyl-2-methoxy-3-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [7-chloro-4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; 5-tert-butyl-N-cyclopropyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetyl Amino} -benzamide; N- [5-tert-butyl-2-methoxy-3- (piperidine-1-carbonyl) -phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide; 5-tert-Butyl-2-hydroxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -benzoic acid; N- (2-benzenesulfonyl-5-tert-butyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4- Mono-ethoxy) -naphthalen-1-yl] -acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-[(Z) -methoxyimino] -2- [4- (2-morpholine-4- Mono-ethoxy) -naphthalen-1-yl] -acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-oxo-2- [4- (2-piperidin-1-yl-pyrimidin-4-yljade C) -naphthalen-1-yl] -acetamide; N- [5-tert-butyl-2- (2,5-difluoro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetamide; N- [5-tert-butyl-2- (3-chloro-benzoyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (3-methanesulfonyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide; N- [3- (benzenesulfonyl-carbamoylmethyl-amino) -5-tert-butyl-2-methoxy-phenyl] -2-naphthalen-1-yl-2-oxo-acetamide; N- (3-tert-butyl-isoxazol-5-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalene -1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (4-sulfamoyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide; 2- (4-bromo-naphthalen-1-yl) -N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2-oxo-acetamide; 5-tert-butyl-2-hydroxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -benzamide ; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1 -Yl] -2-oxo-acetamide; N- (5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-methylamino-pyrimidin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetamide ; N- (5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-dimethylamino-pyrimidin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetamide ; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2- {4- [2- (1-oxo-1λ ⁴ -thiomorpholine- ⁴ -Yl) -ethoxy] -naphthalen-1-yl} -acetamide; 5-tert-butyl-3- {2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -Thiophene-2-carboxylic acid methyl ester; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- {4- [2-((2R, 6R) -2,6-dimethyl-morpholine-4 -Yl) -ethoxy] -naphthalen-1-yl} -2-oxo-acetamide; N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene-1- Il] -2-oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [7-chloro-4- (2-morpholin-4-yl-ethoxy) -naphthalene-1 -Yl] -2-oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl -Ethoxy) -naphthalen-1-yl] -acetamide; N- (5-tert-butyl-2-methoxy-phenyl) -2- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -2-oxo Acetamide; 5-tert-butyl-N-cyclopropyl-2-methoxy-3- [2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetylamino] -benzamide; N- (2-acetyl-5-tert-butyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide; 5-tert-butyl-N-cyclopropyl-3- {2-hydrazono-2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -2 Methoxy-benzamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-hydrazono-2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -acetamide; N- (3,4-Dimethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-cyclohexyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide; N- (5-tert-butyl-2-methoxy-phenyl) -2-oxo-2- (4-pyridin-3-yl-naphthalen-1-yl) -acetamide; N- (5-tert-butyl-isoxazol-3-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-diethylamino-ethoxy) -naphthalen-1-yl] -2-oxo Acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2- {4- [2- (3-oxo- [1,4] diazepan- 1-yl) -ethyl] -naphthalen-1-yl} -acetamide; 5-tert-butyl-N-ethyl-2-methoxy-3- [2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetylamino] -benzamide; N- (5-tert-butyl-2-methoxy-phenyl) -2-oxo-2- {4- [6- (tetrahydro-pyran-4-ylamino) -pyridin-3-yl] -naphthalene- 1-yl} -acetamide; N- (2,5-dimethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; Pyrrolidine-1-carboxylic acid (5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetylamino} -phenyl) -amide; N- (3-amino-5-tert-butyl-2-methoxy-phenyl) -2-oxo-2- {4- [2-((S) -1-phenyl-ethylamino) -pyrimidine-4 -Ylamino] -naphthalen-1-yl} -acetamide; 5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -benzamide ; N- (5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -Phenyl) -benzamide; N- (3,5-di-tert-butyl-2-methoxy-phenyl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -acetamide; N '-[1- (5-tert-butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -meth- (E) -ylidene] -hydrazinecarboxamide; 5-tert-butyl-3- {2-[(Z) -methoxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -Thiophene-2-carboxylic acid amide; 5-tert-butyl-N-cyclopropylmethyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo- Acetylamino} -benzamide; N- [5-tert-butyl-2-methoxy-3- (2-methoxy-acetylamino) -phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-isopropoxy-3-methanesulfonylamino-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (3,4-dimethyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2- [4- (2-thiomorpholin-4-yl-ethoxy) -naphthalene -1-yl] -acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-dimethylamino-pyrimidin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetamide; 1- (2-Amino-4-tert-butyl-6- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino}- Phenyl) -pyridinium; N- (5-tert-butyl-2-isopropoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide ; N- (5-tert-butyl-2-m-tolyl-2H-pyrazol-3-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholine-4- Mono-ethoxy) -naphthalen-1-yl] -acetamide; 5-tert-butyl-2-methoxy-3- [2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetylamino] -benzamide; 5-tert-butyl-2-methoxy-N- (2-methoxy-ethyl) -3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -benzamide; N- (5-tert-butyl-isoxazol-3-yl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalen-1-yl] -2- Oxo-acetamide; (5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -phenyl ) -Carbamic acid methyl ester; 3-tert-butyl-5- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -pyrazole-1-carboxyl Acid adamantan-1-ylamide; 5-tert-butyl-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -thiophene-2-carboxyl Acid amides; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- {4- [2- (2,6-dimethyl-morpholin-4-yl) -ethyl] -Naphthalen-1-yl} -2-oxo-acetamide; N- (5-tert-butyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acet amides; 3-tert-butyl-5- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -pyrazole-1-carboxyl Acid tert-butylamide; 3-tert-butyl-5- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -pyrazole-1-carboxyl Acid amides; N-allyl-5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino } -Benzamide; N- (5-tert-butyl-isoxazol-3-yl) -2-[(Z) -methoxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -acetamide; N- (3-acetylamino-5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2- Oxo-acetamide; 5-tert-butyl-3- {2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalen-1-yl ] -Acetylamino} -thiophene-2-carboxylic acid amide; N- [3- (4-acetyl-piperazin-1-carbonyl) -5-tert-butyl-2-methoxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-4-methyl-2-p-tolyl-2H-pyrazol-3-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-mor Folin-4-yl-ethoxy) -naphthalen-1-yl] -acetamide; 2- [4- (2-Morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-N- (2-phenyl-cyclopropyl) -acetamide; N- (5-tert-butyl-isoxazol-3-yl) -2- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalen-1-yl] -2-oxo Acetamide; N- (5-tert-butyl-2,3-dimethoxy-phenyl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- {4- [2- (4-methyl-piperazin-1-yl) -ethyl] -naphthalene -1-yl} -2-oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- (1H-indol-3-yl) -2-oxo-acetamide; N- (5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-pyridin-4-ylamino) -naphthalen-1-yl] -2-oxo Acetamide; N- (4-tert-butyl-6-trifluoromethyl-pyrimidin-2-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide; 5-tert-butyl-3- {2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -Thiophene-2-carboxylic acid methylamide; N- [5-tert-butyl-2- (3,5-dichloro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- {4- [2-((2R, 6S) -2,6-dimethyl-morpholine-4 -Yl) -ethoxy] -naphthalen-1-yl} -2-oxo-acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2-imidazol-1-yl-ethyl) -naphthalen-1-yl]- 2-oxo-acetamide; N- (5-tert-butyl-2-methoxy-3-phenylmethanesulfonylamino-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2- [4- (2-pyridin-4-yl-ethoxy) -naphthalene-1 -Yl] -acetamide; N- [5-tert-butyl-2- (3-chloro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (6-chloro-pyridazin-3-yl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-e Methoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-m-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; 5-tert-Butyl-N-cyclopropyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalen-1-yl]- 2-oxo-acetylamino} -benzamide; [(5-tert-Butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino}- Phenyl) -methanesulfonyl-amino] -acetic acid ethyl ester; N- (5-tert-butyl-4-methyl-2-m-tolyl-2H-pyrazol-3-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-mor Folin-4-yl-ethoxy) -naphthalen-1-yl] -acetamide; N- [5-tert-butyl-2- (2,5-dichloro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2- [1,4] oxazepan-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide; N- (2-Bromo-5-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide ; 5-tert-butyl-N-cyclopentyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetyl Amino} -benzamide; N- [5-tert-butyl-2- (morpholin-4-carbonyl) -thiophen-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalen-1-yl] -2- Oxo-acetamide; 5-tert-butyl-N-cyclopropylmethyl-2-methoxy-3- [2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetylamino] -benzamide; N- [5-tert-butyl-3- (3,3-diethyl-ureido) -2-methoxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (4-fluoro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide; N- (2-benzyl-5-tert-butyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-oxo-2- [4- (2-piperazin-1-yl-ethoxy) -naphthalene-1 -Yl] -acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-pyridin-4-ylamino) -naphthalene-1 -Yl] -2-oxo-acetamide; (5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -phenyl ) -Carbamic acid isopropyl ester; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalene- 1-yl] -2-oxo-acetamide; N- [3- (3-allyl-ureido) -5-tert-butyl-2-methoxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene-1 -Yl] -2-oxo-acetamide; 5-tert-butyl-N, N-diethyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo -Acetylamino} -benzamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2- [1,4] oxazepan-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; N- (3-tert-butyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (6-methyl-pyridin-3-yl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (4-ureido-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-m-tolyl-2H-pyrazol-3-yl) -2- [4- (2-dimethylamino-ethoxy) -naphthalen-1-yl] -2-oxo Acetamide; N- (5-tert-butyl-2-methoxy-phenyl) -2-oxo-2- [4- (2-piperidin-1-yl-pyrimidin-4-yloxy) -naphthalene-1- General] -acetamide; N- [5-tert-butyl-2- (3-fluoro-4-methyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-e Methoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- [3,5-bis- (1,1-dimethyl-propyl) -2-methoxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene-1- Il] -2-oxo-acetamide; 4- {2- [4- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylaminooxalyl) -naphthalen-1-yloxy] -ethyl} -piperazine-1-car Acid ethyl esters; N- (3-amino-5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalen-1-yl ] -2-oxo-acetamide; N- [5-tert-butyl-3- (2-dimethylamino-acetylamino) -2-methoxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-dimethylamino-ethoxy) -naphthalen-1-yl] -2-oxo- Acetamide; N- (5-tert-butyl- [1,3,4] thiadiazol-2-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholine-4- Mono-ethoxy) -naphthalen-1-yl] -acetamide; N- (5-tert-butyl-2-ethoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; (5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -phenyl ) -Carbamic acid 2-methoxy-ethyl ester; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2-imidazol-1-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- (4-Bromo-3-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide ; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [8-chloro-4- (2-morpholin-4-yl-ethoxy) -naphthalene-1 -Yl] -2-oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-chloro-ethoxy) -naphthalen-1-yl] -2-oxo-acet amides; 5-tert-butyl-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -thiophene-2-carboxyl Acid dimethylamide; N- (4-Chloro-3-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N '-[1- (5-tert-butyl-3-ethylcarbamoyl-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -meth- (Z) -ylidene] -hydrazinecarboxylic acid ethyl ester; N- [5-tert-butyl-2- (3-chloro-benzenesulfonyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-diethylamino-3-methanesulfonylamino-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2-methoxy-3- (propane-1-sulfonylamino) -phenyl] -2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetamide ; 2- [4- (2-Morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-N- (3-trifluoromethyl-phenyl) -acetamide; N- [5-tert-butyl-2- (4-trifluoromethyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -Naphthalen-1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2-methoxy-3- (propane-1-sulfonylamino) -phenyl] -2- [4- (2-dimethylamino-pyrimidin-4-ylamino) -naphthalene -1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2-methoxy-3- (propane-1-sulfonylamino) -phenyl] -2- [4- (2-morpholin-4-yl-pyrimidin-4-yljade C) -naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- {4- [2- (2,6-dimethyl-morpholin-4-yl) -ethoxy] -Naphthalen-1-yl} -2-oxo-acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2- {4- [2- (3-oxo-piperazin-1-yl)- Ethyl] -naphthalen-1-yl} -acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2- [4- (3-pyridin-4-yl-propoxy) -naphthalene-1 -Yl] -acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl -Ethoxy) -5,6,7,8-tetrahydro-naphthalen-1-yl] -acetamide; N- [5-tert-butyl-2- (4-methanesulfonyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-imidazol-1-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide; N- [5-tert-butyl-2- (3,5-dimethyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-pyridin-4-ylamino) -naphthalene- 1-yl] -2-oxo-acetamide; N- {5-tert-butyl-3- [carbamoylmethyl- (propane-1-sulfonyl) -amino] -2-methoxy-phenyl} -2-naphthalen-1-yl-2-oxo-acet amides; N '-[1- (5-tert-butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -meth- (Z) -ylidene] -hydrazinecarboxylic acid ethyl ester; N- [5-tert-butyl-2- (3-nitro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [3-chloro-4- (2-morpholin-4-yl-ethoxy) -phenyl] -2-oxo-acetamide; N- (3-benzenesulfonylamino-5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide; 3-tert-butyl-5- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -pyrazole-1-carboxyl Acid cyclohexylamide; N- [5-tert-butyl-2-methoxy-3- (2,2,2-trifluoro-ethanesulfonylamino) -phenyl] -2- [4- (2-morpholin-4-yl -Ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N '-[1- (5-tert-butyl-3-carbamoyl-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -meth- (E) -ylidene] -hydrazinecarboxylic acid ethyl ester; (5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -phenyl ) -Carbamic acid 2-dimethylamino-ethyl ester; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [7-fluoro-4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; N- (5-tert-butyl-isoxazol-3-yl) -2- [4- (2-morpholin-4-yl-pyridin-4-ylamino) -naphthalen-1-yl] -2-oxo Acetamide; N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetamide; N- (5-tert-butyl-isoxazol-3-yl) -2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetamide; N- [5-tert-butyl-2- (3-methoxy-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-dimethylamino-pyrimidin-4-ylamino)- Naphthalen-1-yl] -2-oxo-acetamide; N- (2-Chloro-5-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- (3-methanesulfonylamino-2-methoxy-5-methyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2- Oxo-acetamide; 4- {2- [4- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylaminooxalyl) -naphthalen-1-yl] -ethyl} -piperazine-1-car Acid ethyl esters; N- (3,5-di-tert-butyl-2-hydroxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo Acetamide; N- (5-tert-butyl-2-naphthalen-1-yl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene-1- Il] -2-oxo-acetamide; N- (5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalen-1-yl] -2- Oxo-acetamide; 4- {2- [4- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylaminooxalyl) -naphthalen-1-yloxy] -ethyl} -piperazine-1- Carboxylic acid ethyl esters; 5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetyl Amino} -benzamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- (1-methyl-1H-indol-3-yl) -2-oxo-acetamide; N- [2- (4-acetyl-phenyl) -5-tert-butyl-2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; N- [5-tert-butyl-3- (carbamoylmethyl-methanesulfonyl-amino) -2-methoxy-phenyl] -2-naphthalen-1-yl-2-oxo-acetamide; N- [2- (4-Amino-phenyl) -5-tert-butyl-2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; (5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -phenyl ) -Carbamic acid phenyl ester; N- (5-tert-butyl-2-isobutoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- (4-tert-butyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (3-methyl-benzoyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; 5-tert-butyl-3- {2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -Thiophene-2-carboxylic acid amide; N- [5-tert-butyl-2- (2,3-dimethyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (4-nitro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; 2-[(Z) -hydroxyimino] -N- (3-methanesulfonylamino-2-methoxy-5-methyl-phenyl) -2- [4- (2-morpholin-4-yl- Methoxy) -naphthalen-1-yl] -acetamide; N- [5-tert-butyl-2- (morpholin-4-carbonyl) -thiophen-3-yl] -2-[(Z) -hydroxyimino] -2- [4- (2-mor Folin-4-yl-ethoxy) -naphthalen-1-yl] -acetamide; N- (5-tert-butyl-2-phenyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide; N '-[1- (5-tert-butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -meth- (E) -ylidene] -hydrazinecarboxylic acid ethyl ester; N '-[1- (5-tert-butyl-2-methyl-2H-pyrazol-3-ylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -meth- (Z) -ylidene] -hydrazinecarboxamide; N- [5-tert-butyl-2- (3-methoxy-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide; 5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -N- Pyridin-2-yl-benzamide; N- [5-tert-butyl-3- (3,3-dimethyl-ureido) -2-methoxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide; 5-tert-butyl-3- {2- [7-chloro-4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -2-meth Oxy-benzamide; 2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-N-quinolin-3-yl-acetamide; N- [5-tert-butyl-2-methoxy-3- (morpholine-4-carbonyl) -phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; N- [5-tert-butyl-3- (3-isopropyl-ureido) -2-methoxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; N- (3-Amino-5-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalene-1 -Yl] -2-oxo-acetamide; 2- {4- [2- (4-acetyl-piperazin-1-yl) -ethoxy] -naphthalen-1-yl} -N- (5-tert-butyl-3-methanesulfonylamino-2- Methoxy-phenyl) -2-oxo-acetamide; N- [5-tert-butyl-2- (3-fluoro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (3,4-dichloro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-isoxazol-3-yl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalen-1-yl] -2- Oxo-acetamide; N- [5-tert-butyl-2- (2,5-dimethyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -5,6,7,8 -Tetrahydro-naphthalen-1-yl] -2-oxo-acetamide; N- (4-Chloro-3-trifluoromethyl-phenyl) -2- (4-methoxy-naphthalen-1-yl) -2-oxo-acetamide; N- [5- (1,1-Dimethyl-butyl) -2-p-tolyl-2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide; N '-[1- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -meth- (E) -ylidene] -hydrazinecarboxamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-methylamino-pyrimidin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-m-tolyl-2H-pyrazol-3-yl) -2-[(Z) -methoxyimino] -2- [4- (2-morpholine-4- Mono-ethoxy) -naphthalen-1-yl] -acetamide; 5-tert-Butyl-N-cyclopropyl-3- [2-[(E) -hydroxyimino] -2- (4-methoxy-naphthalen-1-yl) -acetylamino] -2-methoxy- Benzamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- {4- [2- (2,6-dimethyl-morpholin-4-yl) -ethoxy ] -Naphthalen-1-yl} -2-oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [8-fluoro-4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; 5-tert-butyl-N-furan-2-ylmethyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 -Oxo-acetylamino} -benzamide; N- [5-tert-butyl-2- (3-trifluoromethyl-benzoyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -Naphthalen-1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2-methoxy-3- (propane-1-sulfonylamino) -phenyl] -2- [4- (2-morpholin-4-yl-pyrimidin-4-yl Amino) -naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-oxo-2- {4- [2- (3-oxo-piperazin-1-yl)- Methoxy] -naphthalen-1-yl} -acetamide; 2- {4- [2- (4-acetyl-piperazin-1-yl) -ethyl] -naphthalen-1-yl} -N- (5-tert-butyl-2-p-tolyl-2H-pyrazole -3-yl) -2-oxo-acetamide; N- (5-tert-butyl-2-phenylacetyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2- {4- [2- (3-oxo-piperazin-1-yl)- Ethoxy] -naphthalen-1-yl} -acetamide; N- [5-tert-butyl-2- (3-ureido-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-[(Z) -methoxyimino] -2- [4- (2-morpholin-4-yl -Pyrimidin-4-yloxy) -naphthalen-1-yl] -acetamide; N- [5-tert-butyl-2-methoxy-3- (3-oxo-piperazine-1-carbonyl) -phenyl] -2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -2-oxo-acetamide; 3-tert-butyl-5- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -pyrazole-1-carboxyl Acid propylamides; 5-tert-butyl-N-cyclopropyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalen-1-yl]- 2-oxo-acetylamino} -benzamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- {4- [2- (4-methyl-piperazin-1-yl) -ethoxy]- Naphthalen-1-yl} -2-oxo-acetamide; N- (3-Amino-5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalen-1-yl ] -2-oxo-acetamide; 5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -N- Propyl-benzamide; N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl- Ethoxy) -naphthalen-1-yl] -acetamide; N- (5-Isopropyl-2-methyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; (5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -phenyl ) -Carbamic acid pyridin-3-ylmethyl ester; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-ethylamino-ethoxy) -naphthalen-1-yl] -2-oxo- Acetamide; N- (3,5-di-tert-butyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- (3-Amino-5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-methylamino-pyrimidin-4-ylamino) -naphthalen-1-yl] -2- Oxo-acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalene -1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (2,3-dichloro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide; N- [3,5-bis- (1,1-dimethyl-propyl) -2-hydroxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene-1- Il] -2-oxo-acetamide; 4- {2- [4- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylaminooxalyl) -naphthalen-1-yloxy] -ethyl} -piperazine-1-car Acid tert-butyl esters; 5-tert-butyl-N-isopropyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetyl Amino} -benzamide; N- (5-tert-butyl-3-diethylaminomethyl-2-hydroxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide; N- (5-tert-butyl-2-m-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalene -1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalene-1 -Yl] -2-oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (4-morpholin-4-yl-pyrimidin-2-ylamino) -naphthalene- 1-yl] -2-oxo-acetamide; N- (3-amino-5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo Acetamide; 5-tert-butyl-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -thiophene-2-carboxyl Acid methylamides; N- [5-tert-butyl-2- (3-methoxy-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-pyrimidine-4- Monoamino) -naphthalen-1-yl] -2-oxo-acetamide; N '-[1- (5-tert-butyl-3-carbamoyl-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -meth- (Z) -ylidene] -hydrazinecarboxylic acid ethyl ester; N- (4-Fluoro-3-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide ; N- (2,5-di-tert-butyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; 2- [4- (2-Morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-N-((1S, 2R) -2-phenyl-cyclopropyl) -acetamide; N- (2-methoxy-5-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide ; N- [2- (4-Bromo-phenyl) -5-tert-butyl-2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide; 5-tert-butyl-2-methoxy-N-methyl-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino } -Benzamide; N- (5-tert-butyl-2-methoxy-3-piperidin-1-ylmethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene-1 -Yl] -2-oxo-acetamide; N- (5-tert-butyl-2-methoxy-phenyl) -2-naphthalen-1-yl-2-oxo-acetamide; N- (2,5-di-tert-butyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide; N- (3-amino-5-tert-butyl-2-methoxy-phenyl) -2-naphthalen-1-yl-2-oxo-acetamide; 5-tert-butyl-N-ethyl-3- {2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -Acetylamino} -2-methoxy-benzamide; 4- {2- [4- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-ylaminooxalyl) -naphthalen-1-yl] -ethyl} -piperazine-1-car Acid tert-butyl esters; 5-tert-butyl-N-ethyl-2-hydroxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino } -Benzamide; N- (5-tert-butyl-2-ethoxy-3-methanesulfonylamino-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide; N '-[1- (5-tert-butyl-3-ethylcarbamoyl-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -meth- (E) -ylidene] -hydrazinecarboxamide; 2- {4- [2- (4-acetyl-piperazin-1-yl) -ethoxy] -naphthalen-1-yl} -N- (5-tert-butyl-2-p-tolyl-2H-pyra Zol-3-yl) -2-oxo-acetamide; 5-tert-butyl-N-ethyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino } -Benzamide; 5-tert-Butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -benzoic acid; N- (5-tert-butyl-isoxazol-3-yl) -2- [4- (2-dimethylamino-pyrimidin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetamide ; 5-tert-butyl-3- {2- [4- (2-morpholin-4-yl-pyridin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetylamino} -thiophene- 2-carboxylic acid amides; 2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-N-m-tolyl-acetamide; 5-tert-butyl-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -thiophene-2-carboxyl Acid methyl esters; N '-[1- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -meth- (Z) -ylidene] -hydrazinecarboxamide; N- [5-tert-butyl-2- (3-methoxy-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-pyridin-4-yl Amino) -naphthalen-1-yl] -2-oxo-acetamide; N- (5-isopropyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide; N- (5-tert-butyl-isoxazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- (2-benzoyl-5-tert-butyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide; 5-tert-butyl-N-ethyl-3- {2-hydrazono-2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -2- Methoxy-benzamide; N- (5-tert-butyl-3-ethanesulfonylamino-2-methoxy-phenyl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl -Ethoxy) -naphthalen-1-yl] -acetamide; N- (3-amino-5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-dimethylamino-pyrimidin-4-ylamino) -naphthalen-1-yl] -2- Oxo-acetamide; N- (5-tert-butyl-thiophen-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (4-chloro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; N '-[1- (5-tert-butyl-3-carbamoyl-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -meth- (E) -ylidene] -hydrazinecarboxamide; N- [5-tert-butyl-2- (4-methoxy-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide; 5-tert-butyl-3- {2- [7-chloro-4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -N-cyclo Propyl-2-methoxy-benzamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- {4- [2- (4-methyl-piperazin-1-yl) -ethoxy] -naphthalene -1-yl} -2-oxo-acetamide; N- (5-tert-butyl-thiophen-3-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -acetamide; 5-tert-Butyl-N-cyclopropyl-3- [2-[(Z) -hydroxyimino] -2- (4-methoxy-naphthalen-1-yl) -acetylamino] -2-methoxy- Benzamide; N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2- [4- (4-morpholin-4-yl-pyrimidin-2-ylamino) -naphthalene-1 -Yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (3-methoxy-phenyl) -2H-pyrazol-3-yl] -2-[(Z) -hydroxyimino] -2- [4- (2- Morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetamide; N- [2-methoxy-5- (1-methyl-1-phenyl-ethyl) -phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; 5-tert-butyl-3- {2- [4- (2-morpholin-4-yl-pyrimidin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetylamino} -thiophene 2-carboxylic acid amides; 5-tert-butyl-N-isobutyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetyl Amino} -benzamide; N- (3,5-di-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo Acetamide; 5-tert-butyl-3- {2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -acetylamino} -Thiophene-2-carboxylic acid dimethylamide; N- (5-tert-butyl-2-methoxy-3-methyl-phenyl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -acetamide; N '-[1- (5-tert-butyl-3-cyclopropylcarbamoyl-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy) -Naphthalen-1-yl] -meth- (E) -ylidene] -hydrazinecarboxylic acid ethyl ester; N-indan-5-yl-2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (3-chloro-4-fluoro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-e Methoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- [5-tert-butyl-3- (imidazol-1-carbonyl) -2-methoxy-phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (2,4-difluoro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2-oxo-2- {4- [2- (5-oxo- [1,4] diazepan- 1-yl) -ethoxy] -naphthalen-1-yl} -acetamide; N- (5-tert-butyl-3-ethanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl]- 2-oxo-acetamide; 3-tert-butyl-5- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -pyrazole-1-carboxyl Acid isopropylamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl -Pyrimidin-4-yloxy) -naphthalen-1-yl] -acetamide; N- [2- (3-Amino-phenyl) -5-tert-butyl-2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; 3-tert-butyl-5- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -pyrazole-1-carboxyl Acid phenylamides; N- (5-tert-butyl-2-o-tolyl-2H-pyrazol-3-yl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetamide; 5-tert-butyl-3- {2- [4- (2-morpholin-4-yl-pyrimidin-4-yloxy) -naphthalen-1-yl] -2-oxo-acetylamino} -thiophene 2-carboxylic acid amides; N- [5-tert-butyl-2- (2,4-dichloro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -2-oxo-acetamide; N- (5-tert-butyl-isoxazol-3-yl) -2- [4- (3-hydroxy-propoxy) -naphthalen-1-yl] -2-oxo-acetamide; N- (3-tert-butyl-isoxazol-5-yl) -2-[(Z) -hydroxyimino] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -acetamide; N- [5-tert-butyl-2-methoxy-3- (propane-1-sulfonylamino) -phenyl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-oxo-2- {4- [2- (5-oxo- [1,4] diazepan-1 -Yl) -ethoxy] -naphthalen-1-yl} -acetamide; N- [5-tert-butyl-2- (3-cyano-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide; N- (5-tert-butyl-2-methoxy-3-phenylacetylamino-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide; 5-tert-butyl-3- {2- [4- (2-dimethylamino-pyrimidin-4-ylamino) -naphthalen-1-yl] -2-oxo-acetylamino} -thiophen-2-car Acid amides; N '-[1- (5-tert-butyl-3-ethylcarbamoyl-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -meth- (E) -ylidene] -hydrazinecarboxylic acid ethyl ester; N- (3-methanesulfonylamino-5-trifluoromethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo- Acetamide; N- (5-tert-butyl-2-hydroxy-3-piperidin-1-ylmethyl-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene-1 -Yl] -2-oxo-acetamide; N- (5-tert-butyl-2-methoxy-phenyl) -2-oxo-2- {4- [2-((S) -1-phenyl-ethylamino) -pyrimidin-4-ylamino] -Naphthalen-1-yl} -acetamide; N- [5-tert-butyl-2- (4-cyano-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide; N '-[1- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenylcarbamoyl) -1- [4- (2-morpholin-4-yl-ethoxy)- Naphthalen-1-yl] -meth- (E) -ylidene] -hydrazinecarboxylic acid ethyl ester; N- (5-tert-butyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2-oxo-acetylamino} -Phenyl) -isobutyramide; N- [5-tert-butyl-2- (4-methyl-benzoyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (2-chloro-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene- 1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2- (3-chloro-4-methyl-phenyl) -2H-pyrazol-3-yl] -2- [4- (2-morpholin-4-yl-ethoxy ) -Naphthalen-1-yl] -2-oxo-acetamide; N- [5-tert-butyl-2-methoxy-3- (propane-1-sulfonylamino) -phenyl] -2- [4- (2-morpholin-4-yl-pyridin-4-ylamino ) -Naphthalen-1-yl] -2-oxo-acetamide; 5-tert-butyl-N-cyclopropyl-2-methoxy-3- {2- [4- (2-morpholin-4-yl-pyridin-4-ylamino) -naphthalen-1-yl] -2 -Oxo-acetylamino} -benzamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-oxo-2- {4- [6- (tetrahydro-pyran-4-ylamino) -pyridine- 3-yl] -naphthalen-1-yl} -acetamide; 3- [2- (4-bromo-naphthalen-1-yl) -2-oxo-acetylamino] -5-tert-butyl-N-cyclopropyl-2-methoxy-benzamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (6-morpholin-4-yl-pyridin-3-yl) -naphthalene-1- Il] -2-oxo-acetamide; N- (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl) -2- [4- (6-morpholin-4-ylmethyl-pyridin-3-yl) -naphthalene- 1-yl] -2-oxo-acetamide; N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2-oxo-2- (4-pyridin-3-yl-naphthalen-1-yl) -acetamide; And N- (5-tert-butyl-2-methyl-2H-pyrazol-3-yl) -2-oxo-2- (4-pyridin-3-yl-naphthalen-1-yl) -acetamide . The compound of claim 1, wherein N- (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalene -1-yl] -2-oxo-acetamide. The compound of claim 1, wherein N- (5-tert-butyl-2-methoxy-phenyl) -2- [4- (2-morpholin-4-yl-ethoxy) -naphthalen-1-yl] -2 Oxo-acetamide. delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete delete