CN1878769A - Cytokine inhibitors - Google Patents

Cytokine inhibitors Download PDF

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Publication number
CN1878769A
CN1878769A CNA2004800330557A CN200480033055A CN1878769A CN 1878769 A CN1878769 A CN 1878769A CN A2004800330557 A CNA2004800330557 A CN A2004800330557A CN 200480033055 A CN200480033055 A CN 200480033055A CN 1878769 A CN1878769 A CN 1878769A
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base
butyl
tert
naphthalene
phenyl
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Inventor
E·博曼
S·C·塞德
R·达尔
N·G·J·德拉埃特
J·厄恩斯特
A·G·蒙塔尔班
J·D·卡尔
C·拉森
S·米勒
H·中西
E·罗伯茨
E·萨亚
R·沙利文
Z·王
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iTherX Pharmaceuticals Inc
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Kemia Inc
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

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

Description

Cytokine inhibitor
Cross reference with related application
[0001] the application requires following U.S. Provisional Application No.: the U.S. Provisional Application of submitting on September 11st, 2003 number 60/502,569; The U.S. Provisional Application of submitting on December 18th, 2003 number 60/531,234; The U.S. Provisional Application of submitting on May 28th, 2004 number 60/575,704; The U.S. Provisional Application 60/585,012 that on July 2nd, 2004 submitted to; The full content of these provisional application is incorporated herein by reference.
Invention field
[0002] the present invention relates to can be used as low-molecular-weight compound and the composition and their preparation of cytokine inhibitor.The invention still further relates to the method for preventing and treating cytokine mediated disease.
Background of invention
[0003] tumor necrosis factor-alpha (TNF-α) and interleukin 1 (IL-1) are pro-inflammatory cytokines, its mediation and infective agent (infectious agent) and the relevant inflammatory response of other cellular stress (cellular stress).The excessive generation of cytokine such as IL-1 and TNF-α is considered to the basis of many diseases associated with inflammation progress (progression), described diseases associated with inflammation comprises other diseases (Dinarello such as rheumatoid arthritis (rheumatoid arthritis (RA)), Crohn disease, inflammatory bowel, multiple sclerosis, endotoxin shock (endotoxin shock), osteoporosis, Alzheimer's, congestive heart failure and psoriasis, C.A.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).It is to reduce pro-inflammatory cytokine that potential medicine in these situations is interfered a kind of acceptable methods of treatment of (intervention), such as TNF-α (being also referred to as TNFa) and interleukin-1 ' beta ' (IL-1b).
[0004] the protein antagonist of nearest clinical testing data support use cytokine, soluble TNF a receptor fusion protein (etanercept (etanercept)) (Moreland et al. for example, Ann.Intern.Med.1999,130:478-486) or mono-clonal TNFa antibody (Enbrel), be used for the treatment of rheumatoid arthritis, Crohn disease, juvenile chronic arthritis and arthritic psoriasis (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).Therefore, suppress or antagonism cytokine such as TNFa and or the small molecules of the effect of IL-1b be expected to help treating rheumatoid arthritis, Crohn disease, juvenile chronic arthritis and arthritic psoriasis.
[0005] Il-1 is detected in the patient's who suffers from osteoarthritis synovia and cartilage matrix joint.In various experiment arthritis models, the IL-1 antagonist demonstrated the degraded that can reduce the cartilage matrix composition (Chevalier, Biomed Pharmacother.1997,51:58).
[0006] the Il-1 receptor antagonist evaluated in the mankind (Bresnihan et al., Arthritis Rheum.1998,41:2196-2204).Demonstrated to the treatment rheumatoid arthritis have effect (Antril, Amgen).The IL-1 receptor antagonist also shows the mortality ratio that can reduce in patient's group of suffering from the septic shock syndromes, and (Dinarello, Nutrition 1995,11:492).
[0007] cytokine such as IL-1 and TNFa are the potent stimulator that nitrogen protoxide (NO) produces.NO is the medium of cardiovascular homeostasis (cardiovascular homeostasis), neurotransmission, immunologic function, also be that bone is built the medium of (bone remodeling) again, to sclerocyte and osteoclast have effect (van ' t Hof, Immunology 2001,103 (3): 255-61 Evans, et al., J.Bone Miner.Res.1996,11:300).
[0008] IL-1 is also relevant with beta cell destruction (beta-cell destruction), and it is one of mark of insulin-dependent diabetes mellitus that beta cell destroys.Although other factors also may mediate beta cell damage, Il-1 act on epoxidase II (COX-2) and inductible NO-synthase by it and interrelate with this process (McDaniel et al., Proc SocExp Biol Med.1996,211:24).
[0009] IL-1 has also demonstrated the uveitis that can bring out mouse, and the mouse uveitis can suppress with the IL-1 retarding agent.(Xuan et al.，J.Ocular Pharmacol.and Ther.1998，14：31)。The cytokine that comprises IL-1, TNFa and GM-CSF demonstrated stimulate the acute myelogenous leukemia proliferation of cells (Bruserud, Leukemia Res.1996,20:65).The development that IL-1 demonstrates for pungency and irritated contact dermatitis is essential.Before using at the epidermis of anaphylactogen, resist-the IL-1 monoclonal antibody, the epidermis sensitization can by the prevention (Muller, et al., Am J Contact Dernat.1996,7:177).The data presentation that obtains from the mouse of rejecting IL-1 this cytokine be heating vital participant (Kluger et al., Clin ExpPharmacol Physiol.1998,25:141).Comprise that the various cytokines of TNFa, IL-1, IL-6 and IL-8 cause the reaction in acute-stage, the feature of the reaction in this acute-stage is heating, discomfort, myalgia, headache, cell metabolism is hyperfunction and multiple internal secretion and enzyme are replied (Beisel, Am J Clin Nutr.1995,62:813).These struvite cytokines produce rapidly after damage or the invasion of pathogenic organism body.
[0010] rhinovirus causes the various releasing and activity of inflammatory cytokines of urging, and mainly is IL-8, its cause symptomatic disease such as acute rhinitis (Winther et al., Am J Rhinol.1998,12:17).
[0011] cytokine inhibitor also is expected to suppress induction type COX-2, this induction type COX-2 be the enzyme that participates in inflammation (M.K.O ' Banion et al., Proc.Natl.Acad.Sci.USA 1992,89:4888).Cytokine inhibitor such as IL-1 receptor antagonist (IL-1ra) be expected to use cox 2 inhibitor (such as NSAIDs) obstacle demonstrate effect.These obstacles include but not limited to diseases associated with inflammation, chronic pain and cardiovascular disorder.
Know that [0012] some cytokines are enhanced in inflammatory bowel (IBD) situation.Imbalance between IL-1 and the IL-1ra has been described among the patient who suffers from IBD.The inadequate generation of IL-1ra may be at least in part the pathogenetic reason of IBD place (Cominelli, et al.Aliment Pharmacol.Ther.1996,10:49).
[0013] in the person with Alzheimer's disease, has been observed and in whole hippocampus (hippocampalregion), had amyloid-beta matter deposition, neurofibrillary tangles and cholinomimetic sexual disorder.The lasting level of cytokine such as IL-1 and/or TNFa may cause at least in part damage in person with Alzheimer's disease's brain (Grammas, Neurobiol.Aging 2001,22 (6): 837-42; Rempel, J.Neurochem.2001,78 (3): 640-645).
[0014] cytokine such as TNFa and Il-1 also infect with human immune deficiency C-type virus C (HIV) and pathogeny relevant (Kreuzer, Clin.Exp.Immunol.1997,109 (1): 54-58 of acute inflammatory incident; Baqui, Immunopharmacol Immunotoxicol 2000,22 (3): 401-421).In the bone marrow supernatants liquid of the HIV-infected patient that is attended by the hematology unusual phenomenon, the concentration of cytokine and acceptor is enhanced, and these concentration show and these patients' clinical parameter has dependency (Dallalio, J.Investig.Med.1999,47 (9): 477-483).
[0015] urge that inflammatory cytokine such as TNFa and IL-1b interleukin-6 (IL-6) are that septic shock, cardio-pulmonary function are unusual, the important medium of adult respiratory distress syndrome (ARDS) and multiple organ failure.Compared the patient who suffers from septicemia who leaves hospital, and suffers from the patient of the non-infectious systemic inflammatory response syndromes (SIRS) of prediction compared with those, the patient who makes a definite diagnosis the septicemia of prediction has the cytokine levels of increase, this shows that in these patients cytokine and subsequently septicemia complication have dependency (Terregino, Ann.Emerg.Med.2000,35 (1): 26-34).
[0016] the cytokine imbalance also relates to and HIV infection related cachexia and muscle deterioration.The serum-concentration of the struvite cytokine (IL-lb, TNFa, IL-6) and the regulatory cell factor (interleukin 12) was studied in ten AIDS emaciation patients, and compared with control group.In patient's group, (Baronzio, In Vivo 1999,13 (6): 499-502) with the remarkable increase of urging inflammatory cytokine (IL-1, IL-6, TNFa) to observe the cytokine imbalance.
[0017] fat relevant with the increase phenomenon of infection, diabetes and cardiovascular disorder.For each above-mentioned condition, have been noted that all unusual phenomenon in TNFa expresses (Loffreda, et al., FASEB J.1998,12:57).The someone points out, the TNFa of elevated levels participates in disorder such as apositia and the disease of eating too much at one meal that other and table manner close.(MedHypotheses 1996,47:423) for Holden, et al. to draw the pathologic, physiologic equity between anorexia nervosa and cancer cachexia.In experimental model, the inhibitor HU-211 that TNFa produces, demonstrate the result that improves closed injury of brain (Shohami, et al., J Neuroimmunol.1997,72:169).
[0018] have basic evidence to show, inflammation works in coronary heart disease (CHD) and coronary artery disease (CAD) development.In suffering from the patient of acute coronary artery syndrome, find the acute phase reactant of rising concentration, such as C-reactive protein (CRP), and the danger of predicting the future in the object of surface health.Cytokine such as TNFa, Il-1 and 11-6 have shown and can promote arteriosclerosis and heart trouble.The feature of patients with coronary heart disease is that the serum-concentration of TNFa increases.Seemingly, the immuno-stimulating effect in the coronary artery patient (TNFa, soluble TNF acceptor 1 and 2 (sTNFR, sTNFR2) is with interleukin-10 (IL-10)) relevant (Mizia-Stec, ActaCardiol.2003,58 (1): 9-15) with serum class lipid level.
[0019] the acute tubulose artery syndromes of big per-cent is the break result of (unstable plaquerupturing) of unsettled plaque, forms thrombus subsequently.The feature of these unsettled plaques is that inflammatory cell (scavenger cell and T lymphocyte) increases.The serum-concentration of CRP (C-reactive protein) can reflect the inflammation number in the atherosclerosis plaque, and therefore measuring the instability of plaque can be provided.Therefore CRP is considered to have predictive value for the plaque disruptive.In addition, have sign to show CRP this has activity in inflammatory process.Numerous studies show that, so-called height-susceptibility CRP (hsCRP) measures the instrument that can be used as the danger of measuring acute coronary syndrome.The anti-inflammatory agent that can reduce the hsCRP level can help to reduce the danger of plaque disruptive (Abjil, Ned Tijdschr Geneeskd 2003,147 (1): 15-20; Branger, J.Immunol.2002,168 (8): 4070-7).
[0020] find that also the TNFa level that raises is relevant with congestive heart failure, the level of cytokine is relevant with severity of disease.In suffering from the patient of cardiac failure, the serum level of TNFa raises, and the heart cell of cardiac muscle and infiltration cell can produce this and urge inflammatory cytokine.Research of Animal Model for Study and clinical study show, pathologic, physiologic result (McTieman, Curr.Cardiol.Rep.2000,2 (3): 189-97) that anti-TNF a treatment can limit congestive heart failure.In addition, cause the significant dosage-dependent form at left ventricular ejection fraction and in building again to be improved with etanercept (soluble TNF acceptor) treatment, and the trend that improvement is arranged on patient's functional status, as measure (Bozkurt, Circulation 2001 Feb 27 by clinical composite score; 103 (8): 1044-7).
[0021] in the patient's who suffers from chronic obstructive pulmonary disease air flue, the TNFa level raises, this may be this disease pathogenetic reason (M.A.Higham et al., Eur.Respiratory J.2000,15:281).Circulation TNFa also may facilitate (N.Takabatake et al., the Amer.J.Resp.﹠amp of losing weight with this disease-related; Crit.Care Med.2000,161 (4 Pt 1): 1179).The TNFa level that also has been found that rising is relevant with congestive heart failure, and this level relevant with severity of disease (A.M.Feldman et al., J.Amer.College ofCardiology 2000,35:537).In addition, TNFa with at lung (Borjesson et al., Amer.J.Physiol.2000,278:L3-12), kidney (Lemay et al., Transplantation 2000,69:959) and neural system (844:192) reperfusion injury in (reperfusion injury) is relevant for Mitsui et al., Brain Res.1999.Also known, urge inflammatory cytokine in the ischemia reperfusion injury (ischemia-reperfusioninjury) of heart, kidney, small intestine, skin and liver, to play a role.For example, TNFa and IL-1 β demonstrate the development that can help regulation and control ischemia of lung-reperfusion injury.They seem and can urge the expression of inflammatory and anti--inflammatory cytokine to promote damage by change.During animals received anti-TNF a and anti--IL-1 β; replenish and the gathering of lung neutrophilic granulocyte of neutrophilic granulocyte are significantly reduced; they unite to blockade and given bigger protection (Krishnadasan, J.Thorac.Cardiovasc.Surg.2003,12 (2): 261-72).In brain injury, with the pretreat that intravenously anti-TNF a antibody carries out, reduced damage under cortex and the cortex, strengthen again the cerebrum blood between flush phase and flowed, and improved neural result.This has supported such argument, and promptly TNFa is deleterious cytokine in apoplexy, yet can protect brain to exempt from reperfusion injury (Lavine, J.Cereb.Blood FlowMetab.1998,18 (1): 52-8 at the circulating antibody of TNF-α; Mitsui, Brain Res.1999,844 (1-2): 192-5).TNFa also is considered to produce at the kidney ischemia reperfusion injury and replys and to be released from kidney, and with pathogeny relevant (Donnahoo, J.Urol.1999,162 (1): 196-203) of kidney ischemia reperfusion injury.
[0022] bone mass is kept by cell that absorbs bone again (osteoclast) and the balance that forms between the cell (sclerocyte) of bone.Nearest observation is verified, the member of the TNF family of part and acceptor is the crucial instrumentality (Horowitz that osteoclast generates, Cytokine Growth Factor Rev 2001,12 (1): 9-18), and show that cytokine such as TNFa and IL-1 α may play an important role in the pathology bone resorption.The viewpoint that the data support is such, be that the osteoclast of sclerotin between breaking-in period generated and bone resorption around TNFa critically participated in artificial limb, and show that the TNFa inhibitor can relate to the treatment of diseases agent (Childs of bone resorption as treatment, J.Bone Miner.Res.2001,16 (2): 338-47; Abu-Amer, J.Biol.Chem.2000,275 (35): 27307-10).
[0023] periodontopathy is the major reason of adult tooth loss, it is characterized in that the change and the permanent damage of dark periodontal tissue.Studies show that IL-1 and TNF antagonist significantly reduce the loss of reticular tissue annex (attachment) and the loss of phatnoma bone height.This shows that the loss of reticular tissue annex and the process of periodontopathy can delay (Delima, J.Clin.Periodontol.2001,28 (3): 233-40) with the antagonist at cytokine such as IL-1.
[0024] TNFa plays a role aspect glomerulonephritis progress many.Studies show that, can effectively prevent acute renal glomerulus inflammation and demilune to the inhibition of endogenous TNFa and form (crescent formation) (Karkar, Nephrol.Dial.Transplant 2001,16 (3): 518-24).
[0025] ulcerative colitis (UC) and Crohn disease (CD) comprise a series of inflammatory bowel (IBD), and this disease is produced by the chronic rise of mucomembranous immune system and cytokine such as TNFa, ILl-b and the IL-6 level of rising.Be intended to reduce the strategy of cytokine such as the TNFa level in the patients with inflammatory bowel disease, comprise the sharp former times monoclonal antibody (infliximab) of mouse/people's chimeric mAb English, humanized monoclonal antibody CDP571, human soluble TNF p55 acceptor onercept, human monoclonal antibodies D2E7 (adalimumab (adalimumab)), anti-TNF people's monoclonal antibody ' fragment-polyoxyethylene glycol (PEG) conjugate CDP870 and small molecules Thalidomide and CNI-1493MAP-kinase inhibitor (Escher et al., Inflamm.Bowel.Dis.2003 Jan; 9 (1): 34-58; Sandbor etal., Best Pract.Res.Clin.Gastroenterol.2003,17 (1): 105-17).
It is believed that [0026] abnormal immune response plays a role in hypertension incidence mechanism.Studies show that when whole blood stimulated with lipopolysaccharides in vivo, IL-1 and IL-6 that the hyperpietic has increase produced ability (Peeters, Eur.J.Clin.Invest.2001, (1): 31-6).Show that the inducible nitric oxide synthase (iNOS) that is present in the vascular smooth muscle cell (VSMC) plays a role in the generation of vessel wall intracellular nitric oxide (NO), thereby regulate the blood vessel coordination in the normal and hypertension of pressure.IL-1 β demonstrates control iNOS genetic expression on transcriptional level, and ((9): 867-77), this shows that the reagent that suppresses cytokine can be used to treat hypertension such as the IL-1 inhibitor for Singh, Am.J.Hypertens.1996.
[0027] disease that is caused by IL-8 comprises myocardial ischemia and perfusion again, inflammatory bowel and many other diseases.
[0017] it is relevant to urge inflammatory cytokine IL-6 and acute phase to reply.IL-6 is the somatomedin in many tumor diseases, comprise multiple myeloma and relevant plasma cell dyscrasia (Treon, et al., Current Opinion inHematology 1998,5:42).It also shows it is the important medium of inflammation in the central nervous system.High-caliber IL-6 is found in some nervous disorders, comprise AIDS dementia, Alzheimer, multiple sclerosis, systemic lupus erythematous, CNS damage and viral and bacterial meningitis (Gruol, et al., Molecular Neurobiology 1997,15:307).IL-6 also plays a significant role in osteoporosis.In mouse model, it demonstrated cause bone resorption and induce osteoclast activity (Ershler et al., Development and Comparative Immunol.1997,21:487).Significant cytokine difference, such as the IL-6 level, be present in vivo between the osteoclast of normal bone and page's disease patient's the osteoclast of bone (Mills, et al., Calcif Tissue Int.1997,61:16).Many cytokines have demonstrated and have participated in cancer foul disease matter.By with anti-IL-6 antibodies or with IL-6 receptor antagonist treatment, the seriousness of the key parameter of this foul disease matter can be reduced (Strassmann, et al., Cytokins Mol Ther.1995,1:107).Some communicable diseases, such as influenza, show IL-6 and IFN α be symptom form and the key factor of host in resisting (Hayden, et al., JClin Invest.1998,101:643).Expressing excessively of IL-6 is relevant with the pathology of numerous disease, these diseases comprise multiple myeloma, rheumatoid arthritis, Castleman ' s disease, psoriasis and post-menopausal osteoporosis (Simpson, et al., Protein Sci.1997,6:929).The interference cell factor comprise compound that IL-6 and TNFa produce can block effectively passivity in the mouse allergic (Scholz et al., J.Med.Chem.1998,41:1050).
[0018] GM-CSF is another relevant with many treatment diseases inflammatory cytokine of urging.It not only influences propagation and the differentiation of stem cell, also regulates and control other cells of some participation acute and chronic inflammations.Attempted being used for the numerous disease state with the GM-CSF treatment, mucositis (the Masucci that brings out with radiation treatment that comprises that bone-recovery is closed, dermatoplasty is disappeared (skin-graft resolution) and suppress cell, Medical Oncology 1996,13:149).In the cell of the scavenger cell pedigree relevant with AIDS treatment, GM-CSF also seem and in the duplicating of human immune deficiency C-type virus C (HIV), play a role (Crowe et al., Journal of Leukocyte Biology 1997,62:41).The feature of bronchial asthma is the inflammatory processes of lung.Related cytokine comprise GM-CSF and other cytokines (Lee, J R Coll Physicians Lond 1998,32:56).
[0019] interferon-(IFN-γ) is relevant with numerous disease.The collagen deposition of interferon-and increase is relevant, the collagen deposition be graft-vs.-host disease main histopathology feature (Parkman, Curr OpinHematol.1998,5:22).After the renal transplantation, the patient is diagnosed with acute myelogenous leukemia.The retrospective analysis of the peripheral blood cells factor (Retrospective analysis) has disclosed the GM-CSF and the IFN-γ of elevated levels.The level of these risings conform to the rising of peripheral white blood cell amount (Burke, et al., LeukLymphoma.1995,19:173).The development of Regular Insulin-dependent diabetes (1 type) may be relevant with the accumulation of the islet cells of the T-cell that produces IFN-γ (Ablumunits, et al., J Autoimmun.1998,11:73).For disease such as multiple sclerosis (MS) and AIDS dementia, before development damages in central nervous system, IFN-γ and TNFa, IL-2 and IL-6 cause activating most peripheral t-cell (Martino et al., AnnNeurol.1998,43:340).Atherosclerotic lesions causes artery disease, and this disease can cause cardiac infarction and cerebral infarction.Many active immne cells are present in these damages, mainly are T-cell and scavenger cell.These cells produce a large amount of inflammatory cytokines of urging, such as TNFa, IL-1 and IFN-γ.It is believed that these cytokines participate in promoting the apoptosis or the apoptosis of surrounding blood vessel smooth muscle cell, thereby cause atherosclerotic lesions (Geng, Heart Vessels 1997, Suppl 12:76).After attacking with the Vespula venom, allergic patients produce to IFN-γ have specific mRNA (Bonay, et al., Clin Exp Immunol.1997,109:342).Delayed hypersensitivity (delayed type hypersensitivity reaction) afterwards, many cytokines, comprise that IFN-γ demonstrates expression and increases, thereby show the effect (Szepietowski of IFN-γ in the irritated dermatitis of heredity, et al., Br J Dermatol.1997,137:195).In fatal encephalic malaria, carry out histopathology and immunohistology research.Observe the IFN-γ of elevated levels and the evidence of other cytokines, this show they in this disease, have effect (Udomsangpetch et al., Am J Trop Med Hyg.1997,57:501).Established the importance of free free radical material in the pathogeny of various communicable diseases.In to infectious the replying of carrying some virus, urge inflammatory cytokine such as IFN-γ by inducing, the nitrogen protoxide route of synthesis be activated (Akaike, et al., Proc Soc Exp Biol Med.1998,217:64).Infecting lentamente has the patient of hepatitis B virus (HBV) may develop sclerosis and hepatocellular carcinoma.Viral gene expression and duplicating in the HBV transgenic mouse, can be suppressed by the back mechanism of transcribing by IFN-γ, TNFa and IL-2 mediation (Chisari, et al., Springer Semin Immunopathol.1995,17:261).IFN-γ can optionally suppress the bone resorption of cytokine induction.As if this finishes by intermediate nitrogen protoxide (NO), and nitrogen protoxide is the important modulability molecule that bone is built again.NO may participate in osteopathy as medium, osteopathy such as rheumatoid arthritis, with the relevant osteolysis of tumour and postclimacteric osteoporosis (Evans, et al., J Bone Miner Res.1996,11:300).To studies have shown that of gene defection type mouse, it is the key of the early stage parasitic growth of control that the IL-12 dependent form of IFN-γ produces.Although this process is independent of nitrogen protoxide, to the control of chronic infection really seemingly NO dependent (Alexander et al., Philos Trans R Soc Lond B Biol Sci 1997,352:1355).NO is the important vessel expander, believable evidence because of it exist in cardiovascular shock (cardiovascular shock) effect (Kilboum, et al., Dis Mon.1997,43:277).IFN-γ is that the progress of chronic intestinal inflammations disease is needed, in such as Crohn disease and inflammatory bowel (IBD), mainly by intermediate CD4 +Lymphocyte may be that the THI phenotype realizes (Sartor, Aliment Pharmacol Ther.1996,10 Suppl 2:43).The SERUM IgE of improving the standard is relevant with the irritated dermatitis of heredity with various heredity anaphylactic diseases such as bronchial asthma.IFN-γ level and SERUM IgE form inverse relation, this expression IFN-γ the heredity allergy patient have effect (Teramotoet al., Clin Exp Allergy 1998,28:74).
[0020] shows recently, cytokine passage (the Proc Natl Acad Sci USA.2004 that in embryonic stem cell (ES cell) produces and keeps, plays a role, 101:6027), this show cytokine inhibitor with the combined action of stem-cell therapy in have the potential applicability.
[0020] WO 01/01986 discloses unique compound, and this compound it is said to have the ability that suppresses TNFa.Disclosed specific inhibitor is structurally different with the novel cpd described among following the application disclosed herein.Being disclosed in some compound among the WO 01/01986 expresses and can treat following disease effectively: infect relevant dementia with HIV, glaucoma, look-neuropathy, optic neuritis, retinal ischemia, laser induced look infringement (laser induced optic damage), operation or the proliferative vitreoretinopathy that damages-bring out, cerebral ischemia, anoxic-ischemic, hypoglycemia, domoic acid is poisoned, anoxia, carbon monoxide or manganese or cyanide poisoning, Huntington Chorea, Alzheimer, the Ba Jinsen disease, meningitis, multiple sclerosis and other demyelinating diseases, amyotrophic lateral sclerosis, head and Spinal injury, epileptic seizures, spasm, olivopontocerebellar atrophy, the neuropathic pain syndromes, diabetic neuropathy, the neuropathy that HIV-is relevant, MERRF and MELAS syndromes, leber disease, wernicke encephalopathy, the special syndrome of thunder, homocystinuria, hyper prolinemia, hyperhomocysteinemiainjury, non-ketone hyperglycinemia, hydroxyl fourth amino acid uria (hydroxybutyricaminoaciduria), sulfite oxidase deficiency, the system ensemble disease, lead encephalopathy, Tourette's syndrome, hepatogenic encephalopathy, drug habit, resistance, drug dependence, dysthymia disorders, anxiety disorder and schizophrenia.WO 02/32862 discloses short-inflammatory cytokine and has comprised the inhibitor of TNFa, and this inhibitor it is said and can be used for treating by sucking lung's acute and chronic inflammation that cigarette such as cigarette causes.The TNFa antagonist obviously also can be used for the treatment of endometriosis, referring to EP 1022027 A1.English monoclonal antibody of sharp former times is used for RA in clinical experiment, shown to be used for the treatment of various diseases associated with inflammation, comprises Behcet ' s disease, uveitis and ankylosing spondylitis.Pancreatitis also can produce (J Surg Res 2000,90 (2): 95-101 by inflammatory mediator; Shock1998,10 (3): 160-75).
[0028] known in the art, anti--scorching compound such as cytokine inhibitor can be used in combination with other active ingredients, is used for the treatment of disease and pathologic state.For example, cytokine inhibitor is used in combination with anti--choline medicament, is used for the treatment of respiratory tract disease (referring to WO 03/084539 and corresponding U. S. application 2003/0225089 and WO 2004/004725 and corresponding U. S. application 2004/0044020).Be disclosed in the U.S. Patent application 2004/0110755 with the combined therapy of cytokine inhibitor and various other active ingredients.
[0029] demand to new treatment is even more important in arthritis disease.The primary incapabitated effect that makes of osteoarthritis, rheumatoid arthritis and suppurative arthritis is the loss of carrying out property of joint cartilage, and therefore causes the carrying out property loss of normal function of joint.
[0030] TNFa is in many cell types, to outside stimulus, plays important effect such as in the replying of infection, damage or mitogen in mediation.
[0031] therefore, exist can be used for treating the needs of cytokine mediated treatment of diseases agent.Although developed some protein therapeutic agent, they suffer from the problem of bioavailability and stability.Especially, need to suppress the low-molecular-weight compound of TNFa and/or IL-1b generation.
Summary of the invention
[0032] the invention provides low-molecular-weight compound and pharmaceutical composition thereof.Especially, compound of the present invention can be used as the release of cytokines inhibitor.The present invention also provides the method for preparing this compounds preventing or treating by the purposes in the cytokine mediated various diseases with them.
[0033] therefore, according to an aspect of the present invention, provide cytokine inhibitor, having comprised:
Targeting moiety (targeting moiety), TM comprises an amide group that contains amide NH at least, this targeting moiety can form one or more hydrogen bonds with target protein, and wherein said targeting moiety is not a urea group;
Bag-expansion (pocket-expanding moiety), PEM, it directly is attached on the targeting moiety, bag-expansion comprises the planar section on the on-plane surface hydrophobic part that is attached to large volume (bulky), wherein said non--planar section can form hydrophobic interaction with target protein;
Bearing portion (orienting moiety), OM, comprise the plane hydrophobic part, and be attached on the targeting moiety, adhere on the atom inequality with bag-expansion, wherein, bearing portion can form the fragrance interaction (aromatic interaction) of π-π or limit-right-face (edge-to-face) with target protein.
[0034] in this aspect of the invention, cytokine inhibitor has structure PEM-TM-OM.Under concentration 10 μ M, this compounds is general to be suppressed bringing out property TNFa-from cell and discharges about 50% or greater than 50%.
[0035] targeting moiety can form hydrogen bond with the residue on the binding site of target protein, and can comprise extra hydrogen bond donor or the acceptor groups that also forms hydrogen bond with target protein.Targeting moiety comprises acid amides and thioamides group, methyl nitrosourea and thioamides group, carbamate, methylol amide, alpha-keto amide, diamide and analogue.The ring-type targeting moiety also is considered, such as imidazolone, imidazolinedione and triketone.
[0036] bag-expansion has enough sizes, and occurred conformation changes in target protein to impel, thereby produces the binding pocket (expanded binding pocket) of expansion therein.This type of part for example comprises, pyrazolyl, _ azoles base, phenyl or similar group, each in them is replaced by jumbo part.Compared with for example methyl group, jumbo part is full of the space of large volume, and comprises group such as t-butyl, bornyl (norbornyl) and similar group.
[0037] for cytokine inhibitor is attached on its target protein, bearing portion provides targeting moiety and bag-expansion correct orientation by being attached on the hydrophobic pocket on the target protein.The plane hydrophobic part that constitutes bearing portion has less polar group or does not have polar group.This type of part comprises for example phenyl, naphthyl, indyl and analogue.
[0038] in other embodiments, cytokine inhibitor also comprises having the hydrophilic segment that at least one is selected from following functionality: hydrogen-key donor, hydrogen-key acceptor, alkaline heteroatoms or acid heteroatoms, wherein, hydrophilic segment is attached to hydrophobic bearing portion indirectly, and can form hydrogen bond with proteinic body frame.Usually, hydrophilic segment is attached on the bearing portion by the about 2 connection chain atoms (linker chain of atoms) to about 10 dusts length.Hydrophilic parts is combined in the ATP-binding pocket on the target protein or near the ATP-binding pocket, thereby forms at least one hydrogen bond with the residue of ATP-binding pocket.Hydrophilic segment comprises morpholinyl, piperazinyl and pyrimidyl group and other groups.This type of part can be attached to bearing portion by for example oxo, ethylidene, inferior methoxyl group (methyleneoxy) and vinyloxy group (ethyleneoxy) chain.
[0039] in some embodiment of cytokine inhibitor of the present invention, if cytokine inhibitor is PEM-CHR " C (O) NH-OM, wherein R " be H or randomly by partially or completely halogenated C 1-6Alkyl, bag-expansion is not the 5-unit heterocycle that replaces so.In other embodiments, targeting moiety is not the tricyclic heterocyclic of the nitrogen-atoms ring members with the amidocarbonylation that is attached to targeting moiety of replacement.
[0040] according to a further aspect in the invention, provide first group of compound with formula IA,
Figure A20048003305500661
Its steric isomer, its tautomer, its solvate, its prodrug and its pharmacy acceptable salt, wherein:
X is C (O), C (S) or CH 2
G is C 3-10Carbocylic radical, 5-8 unit's monocyclic heterocycles base or 8-11 unit bicyclic heterocycles base, it contains one or more heteroatomss that is selected from O, N or S; Wherein, G is by R 1, R 2Or R 3In one or more replacements;
Ar is an indazolyl, indyl, pseudoindoyl, imidazolyl, benzimidazolyl-(benzimidazolyl), pyrazolyl, pyrazolinyl, pyrryl, pyrrolinyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, indolinyl, benzisoxa _ azoles base (benzoisoxazolyl), dihydrobenzo is different _ azoles base (dihydrobenzoisoxazolyl), dihydro-iso indolyl (dihydroisoindolyl), benzisothiazole base (benzoisothiazolyl), benzisothiazole base dioxide (benzoisothiazolyl dioxide), C 6-10Aryl ,-(C 1-3Alkyl)-(C 6-10Aryl) ,-(Y)-(C 0-3Alkyl)-(C 6-10Aryl) or-(Y)-(C 0-3Alkyl)-(5-10 unit heteroaryl), each in them is randomly used R 4Or R 5In one or more replacements;
Each Y is independently-CHZ-,-CZ 2-,-CHR-,-O-,-C (=CHR)-,-C (=C-CO 2R)-;
Each Z be independently F, Cl ,-OR ,-NR 2,-SR ,-NHCONHR or-NHCOR;
L is a covalent linkage, saturated or undersaturated side chain or unbranched C 1-10Carbochain, wherein, optional O, NR and the S (O) of being selected from independently of one or more methylene groups mHeteroatoms substitute; Wherein L is randomly by 0-2 oxo group (oxo group) and one or more C 1-4Side chain or unbranched alkyl replace, described C 1-4Side chain or unbranched alkyl are randomly replaced by one or more F, Cl, Br or I;
Each m is 0,1 or 2 independently;
Q be hydrogen ,-NR ' R ', cycloalkyl, aryl, heterocyclic radical (heterocyclyl), C 1-6Alkoxyl group, C 1-6Alkyl-S (O) m, or phenyl-S (O) m, wherein cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) mEach randomly uses one or more R 27Replace;
Each R independently is C hydrogen or replacement or unsubstituted 1-6Alkyl;
Each R ' is C hydrogen, replacement or unsubstituted independently 1-8(C alkyl, replacement or unsubstituted 0-4Alkyl)-(C 6-10Aryl) or that replace or unsubstituted (C 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-OR ,-NR ' R ' ,-SiR 3,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2, R 4And R 5Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
Each R " be that replace or unsubstituted C independently 1-8C alkyl, replacement or unsubstituted 0-4Alkyl-C 6-10(C aryl or replacement or unsubstituted 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 3Be that replace or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace.
Each R 6Be C 1-6Side chain or unbranched alkyl, it is randomly by part or all of halogenation, and randomly uses R 26Replace;
Each R 26Be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by part or all of halogenation;
R 20Be that replace or unsubstituted C 1-10C alkyl, replacement or unsubstituted 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical, OR ' or NR ' 2
R 21Be hydrogen or C 1-4Side chain or unbranched alkyl, it is randomly by part or all of halogenation; With
R 22, R 23And R 24In each be C hydrogen, replacement or unsubstituted independently 1-10Alkyl, wherein C 1-10Alkyl is randomly interrupted (interrupt), replace or unsubstituted C by one or more O, N or S 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical; Or R 23And R 24Randomly form heterocycle or hetero-aromatic ring together;
Each R 27Be independently F, Cl, Br, I, cyano group ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR ' ,-OR ' ,-NR ' R ' ,-SiR ' 3,-S (O) mR ', replace or unsubstituted straight or branched C 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-203-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and independently is selected from N, O, S (O) mHeteroatoms;
Yet, if when Ar be-(Y)-(C 6-10Aryl), when G was N-(phenyl replacement or unsubstituted)-pyrazolyl, pyrazolyl was used one or more R extraly 1, R 2Or R 3Replace; And IA is not N-(5-tert-butyl-2-phenyl-2H-pyrazole-3-yl)-2-(4-chloro-phenyl)-ethanamide.
[0041] in some embodiment of first group of compound of formula IA, the compound of 10 μ M concentration suppresses bringing out property TNFa-from cell and discharges about 50% or greater than 50%.
[0042] in some embodiment of first group of compound of formula IA, G is
Phenyl, naphthyl, benzocyclobutane base (benzocyclobutanyl), dihydro naphthyl (dihydronaphthyl), tetralyl, benzocyclohepta base (benzocycloheptanyl), benzocyclohepta thiazolinyl (benzocycloheptenyl), 2,3-indanyl (indanyl), indenyl, cumarone-3-ketone;
Pyrazolyl, pyrryl, imidazolyl, the imidazoles ketone group, thiazolyl, _ azoles base, different _ the azoles base, furyl, thienyl, pyridyl, pyriconyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group (tetrahydroquinoyl), isoquinolyl, tetrahydro isoquinolyl (tetrahydroisoquinoyl), pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzofuryl, the benzo thiophenyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thiophenyl, benzo _ oxazolone base, 4H-benzo [1,4] _ piperazine-3-ketone group (4H-benzo[1,4] oxazine-3-only), benzo dioxolyl (benzodioxolyl), benzo [1,3] dioxole-2-ketone group (benzo[1,3] dioxol-2-onyl), tetrahydro benzo pyranyl (tetrahydrobenzopyranyl), indyl, indolinyl, the indoles ketone group, dihydroindole ketone group (indolinonyl), phthalimide-based (phthalimidyl);
Pyrrolidyl, tetrahydrofuran base, the tetrahydrochysene thiophenyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, two _ alkyl, tetramethylene sulfide sulfuryl (tetramethylene sulfonyl), tetramethylene sulfoxide base (tetramethylene sulfoxidyl), _ azoles quinoline base, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl (homopiperidinyl), pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, the Decahydroisoquinolinpreparation base, thio-morpholinyl (thiomorpholinyl), thiazolidyl, dihydro _ piperazine base, dihydro pyranyl, oxocanyl, heptacanyl, thiophene _ alkyl or dithiane base.
[0043] in other embodiment of first group of compound of formula IA, G is phenyl, naphthyl, benzocyclobutane alkyl, dihydro naphthyl, tetralyl, benzocyclohepta base, benzocyclohepta thiazolinyl, 2,3-indanyl (indanyl), indenyl or cumarone-3-ketone.In the embodiment that also has other, G is a pyrazolyl, pyridyl, pyriconyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group (tetrahydroquinoyl), isoquinolyl, tetrahydro isoquinolyl (tetrahydroisoquinoyl), pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzofuryl, the benzo thiophenyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thiophenyl, benzo _ oxazolone base, benzo [1,4] _ piperazine-3-ketone group, the benzo dioxolyl, benzo [1,3] dioxole 2-ketone group, the tetrahydro benzo pyranyl, indyl, indolinyl, the indoles ketone group, the dihydroindole ketone group, or phthalimide-based.Selectively, G be pyrrolidyl, tetrahydrofuran base, tetrahydrochysene thiophenyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, two _ alkyl, tetramethylene sulfide sulfuryl, tetramethylene sulfoxide base, _ azoles quinoline base, different _ azoles quinoline base, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, Decahydroisoquinolinpreparation base, thio-morpholinyl, thiazolidyl, dihydro _ piperazine base, dihydro pyranyl, oxocanyl, heptacanyl, thiophene _ alkyl or dithiane base.In other embodiments, G be phenyl, naphthyl, pyrazolyl, pyrryl, pyrrolidyl, imidazolyl, imidazoles ketone group, thiazolyl, _ azoles base, different _ the azoles base, furyl, thienyl or pyridyl.
[0044] in some embodiment of first group of compound of formula IA, Ar be indazolyl, indyl, pseudoindoyl, imidazolyl, benzimidazolyl-, pyrazolyl, pyrazolinyl, pyrryl, pyrrolinyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, indolinyl, benzisoxa _ azoles base, dihydrobenzo different _ azoles base, dihydro-iso indolyl, benzisothiazole base, benzisothiazole base dioxide or C 6-10Aryl.In some such embodiments, at least one R of Ar 4Or R 5Replace.Selectively, Ar is indazolyl, pseudoindoyl, pyrazolyl, pyrrolinyl, phenyl, naphthyl, dihydro naphthyl, tetralyl, 2,3 indanyls, indenyl or imidazolyl.In also having other these type of embodiments, Ar is indazolyl, phenyl, tetralyl or naphthyl.
[0045] in some embodiment of the compound with formula IA, Ar is-(C 1-3Alkyl)-(C 6-10Aryl) ,-(Y)-(C 0-3Alkyl)-(C 6-10Aryl) or-(Y)-(C 0-3Alkyl)-(5-10 unit heteroaryl).In some such embodiments, at least one R of Ar 4Or R 5Replace.In some such embodiments, Y is-CZ 2-, and each Z be independently F ,-OR or-CHR.For example, Y is-CF 2-.In other embodiments, Y is-CHR or-CHZ-, and Z is-OR.Therefore, for example Y is-CHOH-.Selectively, Y be-O-or-CH 2-.In also having other these type of embodiments, C 6-10Aryl is a phenyl or naphthyl, and/or 5-10 unit heteroaryl is quinolyl, isoquinolyl, phthalazinyl or quinazolyl.In also having other these type of embodiments, Ar is (C 1-3Alkyl)-(C 6-10Aryl).
[0046] in some embodiments of first group of compound of formula IA, one or more methylene groups of L are selected from O, N or S (O) independently mHeteroatoms substitute.In other embodiments, L is covalent linkage, C 1-C 9Alkoxyl group ,-C (O) O-,-NH-or-O-.
[0047] as mentioned above, except-H or-NR ' R ', Q randomly uses R 27Replace.In some embodiment of first group of compound of formula IA, Q is
Phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, imidazolyl, pyrryl, pyrrolidyl, benzimidazolyl-, furyl, thienyl, pyranyl, naphthyl pyridyl (naphthylpyridinyl), pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazyl, pyrazolo [3,4-b] pyrimidyl, fast quinoline base, pyrrolo-[2,3-b] pyridyl, pyrazolo [3,4-b] pyridyl, tubercidin base (tubercidinyl), _ azoles also [4,5-b] pyridyl or imidazo [4,5-b] pyridyl, THP trtrahydropyranyl, tetrahydrofuran base, 1,3-dioxane pentanone, 1,3-two _ alkane ketone (dioxanone), 1,4-two _ alkyl, morpholino, thiomorpholine is for sulfoxide (thiomorpholino sulfoxide), thiomorpholine is for sulfone (thiomorpholino sulfone), piperazinyl, piperidyl, piperidone base (piperidinonyl), the tetrahydropyrimidine ketone group, pimelinketone, hexalin (cyclohexanolol), pentamethylene sulfide (pentamethylene sulfide), encircle penta sulfoxide (pentamethylene sulfoxide), encircle penta sulfone (entamethylene sulfone), tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone, C 1-6Alkoxyl group, secondary amine or tertiary amine, wherein amino nitrogen is covalently bound to C 1-3Alkyl or C 1-5Alkoxyalkyl, phenyl amino; C 1-6Alkyl-S (O) mOr phenyl-S (O) mIn some such embodiments, R 27Be C 1-6Alkyl, C 1-65-10 alkoxyl group, hydroxyl amino, replacement or unsubstituted unit heterocyclic radical, list-or two-(C 1-3Alkyl) amino, single-or two-(phenyl-C 1-3Alkyl) amino, C 1-6Alkyl-S (O) m, phenyl-C 1-3-alkoxyl group or phenylamino, wherein phenyl ring is randomly used one to two halogen, C 1-6Alkyl or C 1-6Alkoxyl group replaces.
[0048] in some other embodiments of first group of compound of formula IA, Q be hydrogen, phenyl, thiomorpholine for sulfoxide, thiomorpholine for sulfone, piperazine ketone group (piperazinonyl), oxazepinyl, diazepinonyl, imidazolyl, pyridyl or morpholino.In other embodiments, Q is morpholino, piperazinyl, pyrimidyl or pyridyl.In some such embodiments, R 27Be-C (O) OR ' ,-NR ' R ', replace or unsubstituted straight or branched C 1-10C alkyl, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl or replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.Selectively, Q is a pyrimidyl, R 27Be-NR ' R ' or replace or unsubstituted saturated or undersaturated 3-11 unit heterocyclic radical, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.In other other this type of embodiment, Q is a pyridyl, R 27Be-NR ' R ', replace or unsubstituted C 1-6Saturated or undersaturated 3-11 unit's heterocyclic radical alkyl or replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.
[0049] in some embodiments of first group of compound of formula IA, works as R 4And R 5When not existing ,-L-Q is not-H.
[0050] in some embodiments of first group of compound of formula IA, each R 1Be independently
C 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, dicyclohexyl or two suberyl, they are randomly by partially or completely halogenation, and randomly replace with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl, or the analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH replace;
C 3-10Side chain or unbranched alkenyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: C 1-5Side chain or unbranched alkyl, phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ the azoles base, isothiazolyl; Aforesaid each randomly by partially or completely halogenation, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl; C wherein 3-10Side chain or unbranched alkenyl are randomly by one or more O, N or S (O) mInterrupt;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls or bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
Cyano group, F, Cl, Br or I;
Methoxycarbonyl, ethoxycarbonyl or the third oxygen carbonyl;
Silyl contains three C 1-4Side chain or unbranched alkyl group independently, it is randomly by partially or completely halogenation;
C 2-6Side chain or unbranched alkyl-C (O), C 2-6Side chain or unbranched-S, C 2-6Side chain or unbranched-S (O), C 2-6Side chain or unbranched-S (O) 2
Randomly by partially or completely halogenated C 2-6Side chain or unbranched alkynyl, wherein one or more methylene groups are randomly replaced by O, NH and S (O) m, and wherein, described alkynyl group is optional to be replaced by following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino.
[0051] in other embodiments of first group of compound of formula IA, each R 1Be C independently 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl.For example, each R 1Be C independently 3-10Side chain or unbranched alkyl.
[0052] in some embodiments of first group of compound of formula IA, each R 2Be independently-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2Selectively, each R 2Be independently-NR ' 2,-NO 2,-C (O) NR ' 2,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or SO 2NR ' 2
[0053] in some embodiments of first group of compound of formula IA, each R 3Be independently
Hydrogen or phenyl, naphthyl or heterocyclic radical, in them each is randomly by halogenation partially or completely, and randomly got: phenyl by 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino (phenylamino), naphthylamine base (naphthylamino), heterocyclic amino group (heterocyclyamino), NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N, carboxyl-list-or two-(C 1-5Alkyl) amino;
The condensed aryl, be selected from the benzocyclobutane alkyl, 2,3 indanyls, indenyl, the dihydro naphthyl, tetralyl, benzocyclohepta base and benzocyclohepta thiazolinyl, or annelated heterocycles, be selected from cyclopenta pyridine (cyclopentenopyridine), hexanaphthene and pyridine (cyclohexanopyridine), pentamethylene and pyrimidine (cyclopentanopyrimidine), hexanaphthene and pyrimidine (cyclohexanopyrimidine), pentamethylene and pyrazine (cyclopentanopyrazine), hexanaphthene and pyrazine (cyclohexanopyrazine), pentamethylene and pyridazine (cyclopentanopyridazine), cyclopentanoindole (cyclopentanoindole), hexanaphthene diindyl (cyclohexanoindole), ring benzoglyoxaline (cyclobenzimidazole), pentamethylene and imidazoles (cyclopentanoimidazole), hexanaphthene and imidazoles (cyclohexanoimidazole), pentamethylene thiophthene (cyclopentanothiophene) and hexanaphthene thiophthene (cyclohexanothiophene); Wherein said condensed aryl or annelated heterocycles be randomly, replaced by 1 to 3 following radicals independently: phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2,5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, isothiazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, heteroaryloxy, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocycle or amino, the NH of assorted virtue 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-4Alkyl-C (O), C 1-5Alkylamino-S (O) 2, single-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, R 12-C 1-5Alkyl, R 13-C 1-5Alkoxyl group, R 14-C (O)-C 1-5Alkyl, R 15-C 1-5Alkyl (R 16) N;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl; The analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls, bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
C 1-4Alkyl or alkylidene group-phenyl-C (O)-C 0-4Alkyl or alkylidene group, C 1-4Alkyl or alkylidene group-C (O)-C 0-4Alkyl or alkylidene group, C 1-4Alkyl or alkylidene group-phenyl-S (O) m-C 0-4Alkyl or alkylidene group;
C 1-6Alkyl or C 1-6Alkoxyl group, each is randomly by partially or completely halogenation, or randomly uses R 17, amino, OR 18, or randomly use R 19The C that replaces 1-5Single-or the replacement of two-alkylamino.
Ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, it is randomly by partially or completely halogenation, and randomly uses one to three: randomly by partially or completely halogenated C 1-3Alkyl group replaces, and wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-6Alkenyl;
C 2-6Side chain or unbranched carbochain alkynyl, it is randomly by partially or completely halogenation, and wherein one or more methylene groups are randomly by O, NH or S (O) mSubstitute, and wherein, described alkynyl group is optional to be replaced with following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino; Or
Benzoyl or naphthoyl; Wherein
R 7, R 8, R 9, R 10, R 12, R 13, R 14, R 15, R 17, R 19And R 25In each be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by partially or completely halogenation;
R 11And R 16In each be hydrogen or C independently 1-4Side chain or unbranched alkyl, it is optional by partially or completely halogenation; With
R 18Be hydrogen or C independently 1-4Side chain or unbranched alkyl, optional independently with oxo or R 25Replace.
[0054] in some such embodiments, each R 3Be phenyl independently, naphthyl or heterocyclic radical, in them each is randomly by partially or completely halogenation, and randomly replace: phenyl with 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two (C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N or carboxyl-list-or two-(C 1-5Alkyl) amino.In other embodiments, each R 3Be phenyl, pyridazinyl or pyridyl independently, each in them is randomly by partially or completely halogenation, and randomly replaces with following radicals: randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, nitro, amino, list-or two-(C 1-3Alkyl) amino; C 1-6Alkyl or C 1-6Alkoxyl group, each is optional by partially or completely halogenation, or randomly replaces with following radicals: R 17, amino, OR 18, randomly use R 19The C that replaces 1-5Single-or two-alkylamino; R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-.R for example 3Can be phenyl or tolyl.
[0055] in some embodiments of first group of compound of formula IA, X is C=O.
[0056] in another aspect of this invention, provide first group of compound with formula IB:
Its steric isomer, its tautomer, its solvate, its prodrug and its pharmacy acceptable salt, wherein:
X is C (O), C (S) or CH 2
G is C 3-10Carbocylic radical, 5-8 unit's monocyclic heterocycles base or 8-11 unit bicyclic heterocycles base, it contains one or more heteroatomss that is selected from O, N or S; Wherein, G is by R 1, R 2Or R 3In one or more replacements;
Ar be indazolyl, indyl, pseudoindoyl, imidazolyl, benzimidazolyl-, pyrazolyl, pyrazolinyl, pyrryl, pyrrolinyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, indolinyl, benzisoxa _ azoles base, dihydrobenzo different _ azoles base, dihydro-iso indolyl, benzisothiazole base, benzisothiazole base dioxide, C 6-10Aryl ,-(C 1-3Alkyl)-(C 6-10Aryl) ,-(Y)-(C 0-3Alkyl)-(C 6-10Aryl) or-(Y)-(C 0-3Alkyl)-(5-10 unit heteroaryl), each in them is randomly used R 4Or R 5In one or more replacements;
Each Y is independently-CHZ-,-CZ 2-,-CHR-,-C (=CHR)-,-C (=C-CO 2R)-;
Each Z be independently F, Cl ,-OR ,-NR 2,-SR ,-NHCONHR or-NHCOR;
L is a covalent linkage, saturated or undersaturated side chain or unbranched C 1-10Carbochain, wherein, optional O, NR and the S (O) of being selected from independently of one or more methylene groups mHeteroatoms substitute; Wherein L is randomly by 0-2 oxo group and one or more C 1-4Side chain or unbranched alkyl replace, described C 1-4Side chain or unbranched alkyl are randomly replaced by one or more F, Cl, Br or I;
Each m is 0,1 or 2 independently;
Q be hydrogen ,-NR ' R ', cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) m, or phenyl-S (O) m, wherein cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) mEach randomly uses one or more R 27Replace; If R 4And R 5Do not exist, so-L-Q is not-H;
Each R independently is C hydrogen or replacement or unsubstituted 1-6Alkyl;
Each R ' is C hydrogen, replacement or unsubstituted independently 1-8(C alkyl, replacement or unsubstituted 0-4Alkyl)-(C 6-10Aryl) or that replace or unsubstituted (C 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-OR ,-NR ' R ' ,-SiR 3,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2, R 4And R 5Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
Each R " be that replace or unsubstituted C independently 1-8C alkyl, replacement or unsubstituted 0-4Alkyl-C 6-10(C aryl or replacement or unsubstituted 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 3Be that replace or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace.
Each R 6Be C 1-6Side chain or unbranched alkyl, it is randomly by part or all of halogenation, and randomly uses R 26Replace;
Each R 26Be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by part or all of halogenation;
R 20Be that replace or unsubstituted C 1-10C alkyl, replacement or unsubstituted 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical, OR ' or NR ' 2
R 21Be hydrogen or C 1-4Side chain or unbranched alkyl, it is randomly by part or all of halogenation; With
R 22, R 23And R 24In each be C hydrogen, replacement or unsubstituted independently 1-10Alkyl, wherein C 1-10Alkyl is randomly interrupted (interrupt), replace or unsubstituted C by one or more O, N or S 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical; Or R 23And R 24Randomly form heterocycle or hetero-aromatic ring together;
Each R 27Be independently F, Cl, Br, I, cyano group ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR ' ,-OR ' ,-NR ' R ' ,-SiR ' 3,-S (O) mR ', replace or unsubstituted straight or branched C 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-203-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and independently is selected from N, O, S (O) mHeteroatoms;
[0057] in some embodiment of first group of compound of formula IB, the compound of 10 μ M concentration suppresses bringing out property TNFa-from cell and discharges about 50% or greater than 50%.
[0058] in some embodiment of first group of compound of formula IB, G is
Phenyl, naphthyl, benzocyclobutane alkyl, dihydro naphthyl, tetralyl, benzocyclohepta base, benzocyclohepta thiazolinyl, 2,3 indanyls, indenyl, cumarone-3-ketone;
Pyrazolyl, pyrryl, imidazolyl, the imidazoles ketone group, thiazolyl, _ azoles base, different _ the azoles base, furyl, thienyl, pyridyl, pyriconyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzofuryl, the benzo thiophenyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thiophenyl, benzo _ oxazolone base, 4H-benzo [1,4] _ piperazine-3-ketone group, the benzo dioxolyl, benzo [1,3] dioxole-2-ketone group, the tetrahydro benzo pyranyl, indyl, indolinyl, the indoles ketone group, the dihydroindole ketone group, phthalimide-based;
Pyrrolidyl, tetrahydrofuran base, tetrahydrochysene thiophenyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, two _ alkyl, tetramethylene sulfide sulfuryl, tetramethylene sulfoxide base, _ azoles quinoline base, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, Decahydroisoquinolinpreparation base, thio-morpholinyl, thiazolidyl, dihydro _ piperazine base, dihydro pyranyl, oxocanyl, heptacanyl, thiophene _ alkyl or dithiane base.
[0059] in other embodiments of first group of compound of formula IB, G is phenyl, naphthyl, benzocyclobutane alkyl, dihydro naphthyl, tetralyl, benzocyclohepta base, benzocyclohepta thiazolinyl, 2,3 indanyls, indenyl or cumarone-3-ketone.Selectively, G is a pyrazolyl, pyridyl, pyriconyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzofuryl, the benzo thiophenyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thiophenyl, benzo _ oxazolone base, benzo [1,4] _ piperazine-3-ketone group, the benzo dioxolyl, benzo [1,3] dioxole-2-ketone group, the tetrahydro benzo pyranyl, indyl, indolinyl, the indoles ketone group, the dihydroindole ketone group, or phthalimide-based.In other embodiments, G be pyrrolidyl, tetrahydrofuran base, tetrahydrochysene thiophenyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, two _ alkyl, tetramethylene sulfide sulfuryl, tetramethylene sulfoxide base, _ azoles quinoline base, different _ azoles quinoline base, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, Decahydroisoquinolinpreparation base, thio-morpholinyl, thiazolidyl, dihydro _ piperazine base, dihydro pyranyl, oxocanyl, heptacanyl, thiophene _ alkyl or dithiane base.In also having other embodiments, G be phenyl, naphthyl, pyrazolyl, pyrryl, pyrrolidyl, imidazolyl, imidazoles ketone group, thiazolyl, _ azoles base, different _ the azoles base, furyl, thienyl or pyridyl.
[0060] in some embodiment of first group of compound of formula IB, Ar be indazolyl, indyl, pseudoindoyl, imidazolyl, benzimidazolyl-, pyrazolyl, pyrazolinyl, pyrryl, pyrrolinyl, pyridyl, piperidyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, indolinyl, benzisoxa _ azoles base, dihydrobenzo different _ azoles base, dihydro-iso indolyl, benzisothiazole base, benzisothiazole base dioxide or C 6-10Aryl.In some such embodiments, at least one R of Ar 4Or R 5Replace.In other embodiments, Ar is indazolyl, pseudoindoyl, pyrazolyl, pyrrolinyl, phenyl, naphthyl, dihydro naphthyl, tetralyl, 2,3 indanyls, indenyl or imidazolyl.For example, Ar is indazolyl, phenyl, naphthyl or tetralyl.In other embodiments, Ar is-(C 1-3Alkyl)-(C 6-10Aryl) ,-(Y)-(C 0-3Alkyl)-(C 6-10Aryl) or-(Y)-(C 0-3Alkyl)-(5-10 unit heteroaryl).In some these type of embodiments, at least one R of Ar 4Or R 5Replace.In other embodiments, Y is-CHR or-CHZ-, and Z is-OR.For example, Y is-CH 2-.In also having other these type of embodiments, C 6-10Aryl is a phenyl or naphthyl, or 5-10 unit heteroaryl is quinolyl, isoquinolyl, phthalazinyl or quinazolyl.Selectively, Ar is-(C 1-3Alkyl)-(C 6-10Aryl).
[0061] in some embodiments of first group of compound of formula IB, one or more methylene groups of L are selected from O, N or S (O) independently mHeteroatoms substitute.Selectively, L is covalent linkage, C 1-C 9Alkoxyl group ,-C (O) O-,-NH-or-O-.
[0062] as mentioned above, except-H or-NR ' R ', Q randomly uses R 27Replace.In some embodiment of first group of compound of formula IB, Q is phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, imidazolyl, pyrryl, pyrrolidyl, benzimidazolyl-, furyl, thienyl, pyranyl, naphthyl pyridyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazyl, pyrazolo [3,4-b] pyrimidyl, fast quinoline base, pyrrolo-[2,3-b] pyridyl, pyrazolo [3,4-b] pyridyl, tubercidin base, _ azoles also [4,5-b] pyridyl or imidazo [4,5-b] pyridyl; THP trtrahydropyranyl, tetrahydrofuran base, 1,3-dioxane pentanone, 1,3-two _ alkane ketone, 1,4-two _ alkyl, morpholino, thiomorpholine for sulfoxide, thiomorpholine for sulfone, piperazinyl, piperidyl, piperidone base, tetrahydropyrimidine ketone group, pimelinketone, hexalin, pentamethylene sulfide, ring penta sulfoxide, ring penta sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone, C 1-6Alkoxyl group, secondary amine or tertiary amine, wherein amino nitrogen is covalently bound to C 1-3Alkyl or C 1-5On the alkoxyalkyl, phenylamino; C 1-6Alkyl-S (O) mOr phenyl-S (O) mIn some such embodiments, R 27Be C 1-6Alkyl, C 1-65-10 alkoxyl group, hydroxyl amino, replacement or unsubstituted unit heterocyclic radical, list-or two-(C 1-3Alkyl) amino, single-or two-(phenyl-C 1-3Alkyl) amino, C 1-6Alkyl-S (O) m, phenyl-C 1-3-alkoxyl group or phenylamino, wherein phenyl ring is randomly used halogen, C 1-6Alkyl or C 1-6One to two replacement in the alkoxyl group.Selectively, Q be hydrogen, phenyl, thiomorpholine for sulfoxide, thiomorpholine for sulfone, piperazine ketone group, oxazepinyl, diazepinonyl, imidazolyl, pyridyl or morpholino.In also having other embodiments, Q is morpholino, piperazinyl, pyrimidyl or pyridyl.In some such embodiments, R 27Be-C (O) OR ' ,-NR ' R ', replace or unsubstituted straight or branched C 1-10C alkyl, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl or replacement or unsubstituted or Heterocyclylalkyl, they contain 1,2,3 or 4 and are independently selected from N, O, S (O) mHeteroatoms.Selectively, Q is a pyrimidyl, R 27Be-NR ' R ' or replace or unsubstituted saturated or undersaturated 3-11 unit heterocyclic radical, they contain 1,2,3 or 4 and are independently selected from N, O, S (O) mHeteroatoms.In this type of embodiment that also has other, Q is a pyridyl, R 27Be-NR ' R ' or that replace or unsubstituted C 1-6Saturated or undersaturated 3-11 unit's heterocyclic radical alkyl or replacement or unsubstituted or Heterocyclylalkyl, they contain 1,2,3 or 4 and are independently selected from N, O, S (O) mHeteroatoms.
[0063] in some embodiments of first group of compound of formula IB, each R 1Be independently
C 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, dicyclohexyl or two suberyl, they are randomly by partially or completely halogenation, and randomly replace with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl, or the analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH replace;
C 3-10Side chain or unbranched alkenyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: C 1-5Side chain or unbranched alkyl, phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ the azoles base, isothiazolyl; Aforesaid each randomly by partially or completely halogenation, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl; C wherein 3-10Side chain or unbranched alkenyl are randomly by one or more O, N or S (O) mInterrupt;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls or bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
Cyano group, F, Cl, Br or I;
Methoxycarbonyl, ethoxycarbonyl or the third oxygen carbonyl;
Silyl contains three C 1-4Side chain or unbranched alkyl group independently, it is randomly by partially or completely halogenation;
C 2-6Side chain or unbranched alkyl-C (O), C 2-6Side chain or unbranched-S, C 2-6Side chain or unbranched-S (O), C 2-6Side chain or unbranched-S (O) 2
Randomly by partially or completely halogenated C 2-6Side chain or unbranched alkynyl, wherein one or more methylene groups are randomly replaced by O, NH and S (O) m, and wherein, described alkynyl group is optional to be replaced by following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino.
[0064] in other embodiments of first group of compound of formula IB, each R 1Be C independently 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl.For example, each R 1Be C independently 3-10Side chain or unbranched alkyl.
[0065] in some embodiments of first group of compound of formula IB, each R 2Be independently-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2In other embodiments, R 2Be independently-NR ' 2,-NO 2,-C (O) NR ' 2,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or SO 2NR ' 2
[0066] in some embodiments of first group of compound of formula IB, each R 3Be independently
Hydrogen or phenyl, naphthyl or heterocyclic radical, in them each is randomly by halogenation partially or completely, and randomly got: phenyl by 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N, carboxyl-list-or two-(C 1-5Alkyl) amino;
The condensed aryl, be selected from benzocyclobutane alkyl, 2,3 indanyls, indenyl, dihydro naphthyl, tetralyl, benzocyclohepta base and benzocyclohepta thiazolinyl, or annelated heterocycles, be selected from cyclopenta pyridine, hexanaphthene and pyridine, pentamethylene and pyrimidine, hexanaphthene and pyrimidine, pentamethylene and pyrazine, hexanaphthene and pyrazine, pentamethylene and pyridazine, cyclopentanoindole, hexanaphthene diindyl, ring benzoglyoxaline, pentamethylene and imidazoles, hexanaphthene and imidazoles, pentamethylene thiophthene and hexanaphthene thiophthene; Wherein said condensed aryl or annelated heterocycles are randomly, replaced by 1 to 3 group independently, described group is selected from: phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2,5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, isothiazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, heteroaryloxy, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocycle or heteroaryl amino, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-4Alkyl-C (O), C 1-5Alkylamino-S (O) 2, single-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, R 12-C 1-5Alkyl, R 13-C 1-5Alkoxyl group, R 14-C (O)-C 1-5Alkyl, R 15-C 1-5Alkyl (R 16) N;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl; The analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls, bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
C 1-4Alkyl or alkylidene group-phenyl-C (O)-C 0-4Alkyl or alkylidene group, C 1-4Alkyl or alkylidene group-C (O)-C 0-4Alkyl or alkylidene group, C 1-4Alkyl or alkylidene group-phenyl-S (O) m-C 0-4Alkyl or alkylidene group;
C 1-6Alkyl or C 1-6Alkoxyl group, each is randomly by partially or completely halogenation, or randomly uses R 17, amino, OR 18, or randomly use R 19The C that replaces 1-5Single-or the replacement of two-alkylamino.
Ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, it is randomly by partially or completely halogenation, and randomly uses one to three randomly by partially or completely halogenated C 1-3Alkyl group replaces, and wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-6Alkenyl;
C 2-6Side chain or unbranched carbochain alkynyl, it is randomly by partially or completely halogenation, and wherein one or more methylene groups are randomly by O, NH or S (O) mSubstitute, and wherein, described alkynyl group is optional to be replaced with following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino; 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, R 25And R 26In each be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by partially or completely halogenation;
R 11And R 16In each be hydrogen or C independently 1-4Side chain or unbranched alkyl, it is optional by partially or completely halogenation; With
R 18Be hydrogen or C independently 1-4Side chain or unbranched alkyl, optional independently with oxo or R 25Replace.
[0067] in some such embodiments, each R 3Be phenyl independently, naphthyl or heterocyclic radical, in them each is randomly by partially or completely halogenation, and randomly replace: phenyl with 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two (C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N or carboxyl-list-or two-(C 1-5Alkyl) amino.In other embodiments, each R 3Be phenyl, pyridazinyl or pyridyl independently, each in them is randomly by partially or completely halogenation, and randomly replaces with following radicals: randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, nitro, amino, list-or two-(C 1-3Alkyl) amino; C 1-6Alkyl or C 1-6Alkoxyl group, each is optional by partially or completely halogenation, or randomly replaces with following radicals: R 17, amino, OR 18, randomly use R 19The C that replaces 1-5Single-or two-alkylamino; R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-.R for example 3Can be phenyl or tolyl.
[0068] in some embodiment of first group of compound of formula IB, X is C=O.
[0069] according to a further aspect in the invention, provide second group of compound with formula IA:
Figure A20048003305500821
Its steric isomer, its tautomer, its solvate, its prodrug and its pharmacy acceptable salt, wherein:
X is C (O) or C (S);
G is C 3-10Carbocylic radical, 5-8 unit's monocyclic heterocycles base or 8-11 unit bicyclic heterocycles base, it contains one or more heteroatomss that is selected from O, N or S; Wherein, G is by R 1, R 2Or R 3In one or more replacements;
Ar is-(Y)-and (C 0-3Alkyl)-(aryl bicyclic) or-(Y)-(C 0-3Alkyl)-(bicyclic heteroaryl), wherein bicyclic heteroaryl is indazolyl, pseudoindoyl, quinolyl, isoquinolyl, phthalazinyl, indolinyl, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, dihydrobenzo different _ azoles base, dihydro-iso indolyl, benzimidazolyl-, benzothienyl, benzothiazolyl, benzisothiazole base or benzisothiazole base dioxide, wherein, Ar randomly uses one or more R 4Or R 5Replace; Yet prerequisite is that aryl bicyclic is not 1,1,4,4-tetramethyl--1,2,3,4-tetrahydrochysene-naphthyl;
Y is-C (O)-,-C (NNRC (O) OR)-,-C (NNRR)-,-C (NNC (O) NRR)-or-C (NOR)-;
L is a covalent linkage, saturated or undersaturated side chain or unbranched C 1-10Carbochain, wherein, optional O, NR and the S (O) of being selected from independently of one or more methylene groups mHeteroatoms substitute; Wherein L is randomly by 0-2 oxo group and one or more C 1-4Side chain or unbranched alkyl replace, described C 1-4Side chain or unbranched alkyl are randomly replaced by one or more F, Cl, Br or I;
Each m is 0,1 or 2 independently;
Q be hydrogen ,-NR ' R ', cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) m, or phenyl-S (O) m, wherein cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) mEach randomly uses one or more R 27Replace; And if R 4And R 5Do not exist, so-L-Q is not-H;
Each R independently is C hydrogen or replacement or unsubstituted 1-6Alkyl;
Each R ' is C hydrogen, replacement or unsubstituted independently 1-8(C alkyl, replacement or unsubstituted 0-4Alkyl)-(C 6-10Aryl) or that replace or unsubstituted (C 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-OR ,-NR ' R ' ,-SiR 3,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl (heterocyclylalkyl), it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2, R 4And R 5Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
Each R " be that replace or unsubstituted C independently 1-8C alkyl, replacement or unsubstituted 0-4Alkyl-C 6-10(C aryl or replacement or unsubstituted 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 3Be hydrogen, replacement or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace.
Each R 6Be C 1-6Side chain or unbranched alkyl, it is randomly by part or all of halogenation, and randomly uses R 26Replace;
Each R 26Be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by part or all of halogenation;
R 20Be that replace or unsubstituted C 1-10C alkyl, replacement or unsubstituted 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical, OR ' or NR ' 2
R 21Be hydrogen or C 1-4Side chain or unbranched alkyl, it is randomly by part or all of halogenation; With
R 22, R 23And R 24In each be C hydrogen, replacement or unsubstituted independently 1-10Alkyl, wherein C 1-10Alkyl randomly by one or more O, N or S interrupt, replace or unsubstituted C 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical; Or R 23And R 24Randomly form heterocycle or hetero-aromatic ring together;
Each R 27Be independently F, Cl, Br, I, cyano group ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR ' ,-OR ' ,-NR ' R ' ,-SiR ' 3,-S (O) mR ', replace or unsubstituted straight or branched C 1-30Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-203-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and independently is selected from N, O, S (O) mHeteroatoms;
Yet, if when Ar be-(Y)-(aryl bicyclic), when G was N-(phenyl replacement or unsubstituted)-pyrazolyl, pyrazolyl was used one or more R extraly 1, R 2Or R 3Replace; And IA is not N-(4-chloro-3-methyl-isothiazole-5-yl)-2-[2-(2,2-dimethyl-propyl group)-benzo _ azoles-5-yl]-2-oxo-ethanamide.
[0070] in some embodiment of the compound of formula IA, the compound of 10 μ M concentration suppresses bringing out property TNFa-from cell and discharges about 50% or greater than 50%.
[0071] in some embodiment of second group of compound of formula IA, G is
Phenyl, naphthyl, benzocyclobutane base, dihydro naphthyl, cyclopropyl, tetralyl, benzocyclohepta base, benzocyclohepta thiazolinyl, 2,3 indanyls, indenyl, cumarone-3-ketone;
Pyrazolyl, pyrryl, imidazolyl, the imidazoles ketone group, thiazolyl, _ azoles base, different _ the azoles base, furyl, thienyl, pyridyl, pyriconyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzofuryl, the benzo thiophenyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thiophenyl, benzo _ oxazolone base, 4H-benzo [1,4] _ piperazine-3-ketone group, the benzo dioxolyl, benzo [1,3] dioxole-2-ketone group, the tetrahydro benzo pyranyl, indyl, indolinyl, the indoles ketone group, the dihydroindole ketone group, phthalimide-based;
Pyrrolidyl, tetrahydrofuran base, tetrahydrochysene thiophenyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, two _ alkyl, tetramethylene sulfide sulfuryl, tetramethylene sulfoxide base, _ azoles quinoline base, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, Decahydroisoquinolinpreparation base, thio-morpholinyl, thiazolidyl, dihydro _ piperazine base, dihydro pyranyl, oxocanyl, heptacanyl, thiophene _ alkyl or dithiane base.
[0072] in other embodiments, G is phenyl, naphthyl, cyclopropyl, benzocyclobutane base, dihydro naphthyl, tetralyl, benzocyclohepta base, benzocyclohepta thiazolinyl, 2,3 indanyls, indenyl or cumarone-3-ketone.Selectively, G is a pyrazolyl, pyridyl, pyriconyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzofuryl, the benzo thiophenyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thiophenyl, benzo _ oxazolone base, benzo [1,4] _ piperazine-3-ketone group, the benzo dioxolyl, benzo [1,3] dioxole-2-ketone group, the tetrahydro benzo pyranyl, indyl, indolinyl, the indoles ketone group, dihydroindole ketone group or phthalimide-based.In other embodiments, G be pyrrolidyl, tetrahydrofuran base, tetrahydrochysene thiophenyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, two _ alkyl, tetramethylene sulfide sulfuryl, tetramethylene sulfoxide base, _ azoles quinoline base, different _ azoles quinoline base, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, Decahydroisoquinolinpreparation base, thio-morpholinyl, thiazolidyl, dihydro _ piperazine base, dihydro pyranyl, oxocanyl, heptacanyl, thiophene _ alkyl or dithiane base.In also having other embodiments, G be phenyl, naphthyl, cyclopropyl, pyrazolyl, pyrryl, pyrrolidyl, imidazolyl, imidazoles ketone group, thiazolyl, _ azoles base, different _ the azoles base, furyl, thienyl or pyridyl.
[0073] in some embodiment of second group of compound of formula IA, Ar is-(Y)-(C 0-3Alkyl)-(aryl bicyclic), and aryl bicyclic be naphthyl, tetralyl, dihydro naphthyl, indenyl, 2,3 indanyls or camomile cyclic group (azulenyl).In some such embodiments, at least one R of Ar 4Or R 5Replace.In other embodiments, Y be-C (O)-,-C (NNRC (O) OR)-or-C (NOR)-.Selectively, Ar is-C (O)-(aryl bicyclic) or-C (NOR)-(aryl bicyclic), and aryl bicyclic can be naphthyl, dihydro naphthyl, tetralyl, 2,3 indanyls, indenyl or camomile cyclic group.In other embodiments, Ar be-(Y)-(C 0-3Alkyl)-(bicyclic heteroaryl).In some such embodiments, Ar R 4Or R 5In at least one replacement.In other embodiments, Y be-C (O)-,-C (NNRC (O) OR)-or-C (NOR)-.In also having other embodiment, Ar is-C (O)-(bicyclic heteroaryl) or-C (NOR)-(bicyclic heteroaryl).For example, bicyclic heteroaryl is quinolyl, isoquinolyl, phthalazinyl or quinazolyl.
[0074] in some embodiment of second group of compound of formula IA, one or more methylene groups of L are selected from O, N or S (O) independently mHeteroatoms substitute.Selectively, L is covalent linkage, C 1-C 9Alkoxyl group ,-C (O) O-,-NH-or-O-.
[0075] in some embodiment of second group of compound of formula IA, Q is hydrogen, phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, imidazolyl, pyrryl, pyrrolidyl, benzimidazolyl-, furyl, thienyl, pyranyl, naphthyl pyridyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazyl, pyrazolo [3,4-b] pyrimidyl, fast quinoline base, pyrrolo-[2,3-b] pyridyl, pyrazolo [3,4-b] pyridyl, tubercidin base, _ azoles also [4,5-b] pyridyl or imidazo [4,5-b] pyridyl; THP trtrahydropyranyl, tetrahydrofuran base, 1,3-dioxane pentanone, 1,3-two _ alkane ketone, 1,4-two _ alkyl, morpholino, thiomorpholine for sulfoxide, thiomorpholine for sulfone, piperazinyl, piperazine ketone group, oxazepinyl, Diazesuberane ketone group (diazepanonyl), piperidyl, piperidone base, tetrahydropyrimidine ketone group, pimelinketone, hexalin, pentamethylene sulfide, ring penta sulfoxide, ring penta sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone; C 1-6Alkoxyl group, secondary amine or tertiary amine, wherein amino nitrogen is covalently bound to C 1-3Alkyl or C 1-5On the alkoxyalkyl, phenylamino; C 1-6Alkyl-S (O) mOr phenyl-S (O) mIn some such embodiments, R 27Be C 1-6Alkyl, C 1-65-10 alkoxyl group, hydroxyl amino, replacement or unsubstituted unit heterocyclic radical, list-or two-(C 1-3Alkyl) amino, single-or two-(phenyl-C 1-3Alkyl) amino, C 1-6Alkyl-S (O) m, phenyl-C 1-3-alkoxyl group or phenylamino, wherein phenyl ring is randomly used halogen, C 1-6Alkyl or C 1-6One to two replacement of alkoxyl group.
[0076] in other embodiments of second group of compound of formula IA, Q be hydrogen, thiomorpholine for sulfoxide, thiomorpholine for sulfone, piperazine ketone group, oxazepinyl, diazepinonyl, imidazolyl, pyridyl or morpholino.In also having other embodiments, Q is morpholino, piperazinyl, pyrimidyl or pyridyl.In some such embodiments, R 27Be-C (O) OR ,-NR ' R ', replace or unsubstituted straight or branched C 1-10C alkyl, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl or replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.For example, Q is a pyrimidyl, R 27Be-NR ' R ' or replace or unsubstituted saturated or undersaturated 3-11 unit heterocyclic radical, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.Selectively, Q is a pyridyl, R 27Be-NR ' R ', replace or unsubstituted C 1-6Saturated or undersaturated 3-11 unit's heterocyclic radical alkyl or replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.
[0077] in some embodiments of second group of compound of formula IA, each R 1Be independently
C 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, dicyclohexyl or two suberyl, they are randomly by partially or completely halogenation, and randomly replace with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl, or the analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH replace;
C 3-10Side chain or unbranched alkenyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: C 1-5Side chain or unbranched alkyl, phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ the azoles base, isothiazolyl; Aforesaid each randomly by partially or completely halogenation, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl; C wherein 3-10Side chain or unbranched alkenyl are randomly by one or more O, N or S (O) mInterrupt;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls or bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
Cyano group, F, Cl, Br or I;
Methoxycarbonyl, ethoxycarbonyl or the third oxygen carbonyl;
Silyl contains three C 1-4Independently side chain or unbranched alkyl group, it is randomly by partially or completely halogenation;
C 2-6Side chain or unbranched alkyl-C (O), C 2-6Side chain or unbranched-S, C 2-6Side chain or unbranched-S (O), C 2-6Side chain or unbranched-S (O) 2
Randomly by partially or completely halogenated C 2-6Side chain or unbranched alkynyl, wherein one or more methylene groups are randomly replaced by O, NH and S (O) m, and wherein, described alkynyl group is optional to be replaced by following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino.Selectively, each R 1Be C independently 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl.For example, each R 1Be C independently 3-10Side chain or unbranched alkyl.
[0078] in some embodiments of second group of compound of formula IA, each R 2Be independently-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2Selectively, R 2Be independently-NR ' 2,-NO 2,-C (O) NR ' 2,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or SO 2NR ' 2
[0079] in some embodiments of second group of compound of formula IA, each R 3Be independently
Hydrogen or phenyl, naphthyl or heterocyclic radical, in them each is randomly by halogenation partially or completely, and randomly got: phenyl by 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N, carboxyl-list-or two-(C 1-5Alkyl) amino;
The condensed aryl, be selected from benzocyclobutane base, 2,3 indanyls, indenyl, dihydro naphthyl, tetralyl, benzocyclohepta base and benzocyclohepta thiazolinyl, or annelated heterocycles, be selected from cyclopenta pyridine, hexanaphthene and pyridine, pentamethylene and pyrimidine, hexanaphthene and pyrimidine, pentamethylene and pyrazine, hexanaphthene and pyrazine, pentamethylene and pyridazine, cyclopentanoindole, hexanaphthene diindyl, ring benzoglyoxaline, pentamethylene and imidazoles, hexanaphthene and imidazoles, pentamethylene thiophthene and hexanaphthene thiophthene; Wherein said condensed aryl or annelated heterocycles are randomly, replaced by 1 to 3 group independently, described group is selected from: phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2,5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, isothiazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, heteroaryloxy, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocycle or amino, the NH of assorted virtue 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-4Alkyl-C (O), C 1-5Alkylamino-S (O) 2, single-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, R 12-C 1-5Alkyl, R 13-C 1-5Alkoxyl group, R 14-C (O)-C 1-5Alkyl, R 15-C 1-5Alkyl (R 16) N;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl; Or the analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls, bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
C 1-4Alkyl or alkylidene group-phenyl-C (O)-C 0-4Alkyl or alkylidene group, C 1-4Alkyl or alkylidene group-C (O)-C 0-4Alkyl or alkylidene group, C 1-4Alkyl or alkylidene group-phenyl-S (O) m-C 0-4Alkyl or alkylidene group;
C 1-6Alkyl or C 1-6Alkoxyl group, each is randomly by partially or completely halogenation, or randomly uses R 17, amino, OR 18, or randomly use R 19The C that replaces 1-5Single-or the replacement of two-alkylamino.
Ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, it is randomly by partially or completely halogenation, and randomly uses one to three randomly by partially or completely halogenated C 1-3Alkyl group replaces, and wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-6Alkenyl;
C 2-6Side chain or unbranched carbochain alkynyl, it is randomly by partially or completely halogenation, and wherein one or more methylene groups are randomly by O, NH or S (O) mSubstitute, and wherein, described alkynyl group is optional to be replaced with following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino; Or
Benzoyl or naphthoyl; Wherein
R 7, R 8, R 9, R 10, R 12, R 13, R 14, R 15, R 17, R 19And R 25In each be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by partially or completely halogenation;
R 11And R 16In each be hydrogen or C independently 1-4Side chain or unbranched alkyl, it is optional by partially or completely halogenation; With
R 18Be hydrogen or C independently 1-4Side chain or unbranched alkyl, optional independently with oxo or R 25Replace.
[0080] in some these type of embodiments of second group of compound of formula IA, each R 3Be phenyl independently, naphthyl or heterocyclic radical, in them each is randomly by partially or completely halogenation, and randomly replace: phenyl with 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two (C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N or carboxyl-list-or two-(C 1-5Alkyl) amino.In other such embodiments, R 3Be phenyl, pyridazinyl or pyridyl independently, each in them is randomly by partially or completely halogenation, and randomly replaces with following radicals: randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, nitro, amino, list-or two-(C 1-3Alkyl) amino; C 1-6Alkyl or C 1-6Alkoxyl group, each is optional by partially or completely halogenation, or randomly replaces with following radicals: R 17, amino, OR 18, randomly use R 19The C that replaces 1-5Single-or two-alkylamino; R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-.
[0081] in some embodiments of second group of compound of formula IA, X is C=O.
[0082] in some embodiment of second group of compound of formula IA, Ar is-(Y)-and naphthyl-, Y is-C (O)-or-C (=NOH)-, G be selected from phenyl, pyridyl, pyrazolyl, pyrryl, imidazolyl, _ azoles base, different _ the azoles base, furyl or thienyl.In other embodiments, Ar is-(Y)-naphthyl-, Y is-C (O)-or-C (=NOH)-, G is phenyl or pyridyl.In some such embodiments, each R 1Be that replace or unsubstituted straight or branched C independently 1-10Alkyl, each R 3Can be R independently 23R 24N-C (O)-, R 20-C (O)-NR 21-or OR 22In some such embodiments, each R 2Be independently-NR ' SO 2R " ,-Cl ,-Br ,-F ,-C (O)-NR ' 2, replace or unsubstituted straight or branched C 1-6Alkyl ,-NR ' 2, or-OR '.
[0083] in other embodiments of second group of compound of formula IA, Ar is-(Y)-naphthyl-, Y is-C (O)-or-C (=NOH)-and G be pyrazolyl, thienyl or different _ azoles base.In some such embodiments, each R 1Be that replace or unsubstituted straight or branched C independently 1-10Alkyl, each R 3Can be phenyl or pyridyl independently, they randomly use one, two or three-F ,-Cl, replacement or unsubstituted C 1-6Side chain or unbranched alkyl or that replace or unsubstituted C 1-4Alkoxyl group replaces.
[0084] according to a further aspect in the invention, provide second group of compound with formula IB:
Figure A20048003305500891
Its steric isomer, its tautomer, its solvate, its prodrug and its pharmacy acceptable salt, wherein:
X is C (O) or C (S);
G be G '-(Y)-, wherein G ' is C 3-10Carbocylic radical, 5-8 unit's monocyclic heterocycles base or the unit of the 8-11 except that indyl bicyclic heterocycles base, it contains one or more heteroatomss that is selected from O, N or S; Wherein, G ' is by R 1, R 2Or R 3In one or more replacements;
Ar is aryl bicyclic or 8-11 unit bicyclic heteroaryl, contains the heteroatoms that one or more are selected from N, O, S, and wherein Ar randomly uses one or more R 4Or R 5Replace;
Y is independently-C (O)-,-C (NNRC (O) OR)-,-C (NNRR)-,-C (NNC (O) NRR) or-C (NOR)-;
L is a covalent linkage, saturated or undersaturated side chain or unbranched C 1-10Carbochain, wherein, optional O, NR and the S (O) of being selected from independently of one or more methylene groups mHeteroatoms substitute; Wherein L is randomly by 0-2 oxo group and one or more C 1-4Side chain or unbranched alkyl replace, described C 1-4Side chain or unbranched alkyl are randomly replaced by one or more F, Cl, Br or I;
Each m is 0,1 or 2 independently;
Q be hydrogen ,-NR ' R ', cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) m, or phenyl-S (O) m, wherein cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) m, or phenyl-S (O) mIn each randomly uses one or more R 27Replace; If R 4And R 5Do not exist, so-L-Q is not-H;
Each R independently is C hydrogen or replacement or unsubstituted 1-6Alkyl;
Each R ' independently is C hydrogen, replacement or unsubstituted 1-8(C alkyl, replacement or unsubstituted 0-4Alkyl)-(C 6-10Aryl) or that replace or unsubstituted (C 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-OR ,-NR ' R ' ,-SiR 3,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2, R 4And R 5Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
Each R " be that replace or unsubstituted C independently 1-8C alkyl, replacement or unsubstituted 0-4Alkyl-C 6-10(C aryl or replacement or unsubstituted 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 3Be that replace or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace.
Each R 6Be C 1-6Side chain or unbranched alkyl, it is randomly by part or all of halogenation, and randomly uses R 26Replace;
Each R 26Be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by part or all of halogenation;
R 20Be that replace or unsubstituted C 1-10C alkyl, replacement or unsubstituted 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical, OR ' or NR ' 2
R 21Be hydrogen or C 1-4Side chain or unbranched alkyl, it is randomly by part or all of halogenation; With
R 22, R 23And R 24In each be C hydrogen, replacement or unsubstituted independently 1-10Alkyl, wherein C 1-10Alkyl randomly by one or more O, N or S interrupt, replace or unsubstituted C 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical; Or R 23And R 24Randomly form heterocycle or hetero-aromatic ring together;
Each R 27Be independently F, Cl, Br, I, cyano group ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR ' ,-OR ' ,-NR ' R ' ,-SiR ' 3,-S (O) mR ', replace or unsubstituted straight or branched C 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-203-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and independently is selected from N, O, S (O) mHeteroatoms;
Yet prerequisite is that IB is not 2-[6-(2-xenyl-4-base-2-oxo-kharophen)-indoles-1-ylmethyl]-phenylformic acid.
[0085] in some embodiment of second group of compound of formula IB, the compound of 10 μ M concentration suppresses bringing out property TNFa-from cell and discharges about 50% or greater than 50%.
[0086] in some embodiments of second group of compound of formula IB, G ' is
Phenyl, naphthyl, cyclopropyl, benzocyclobutane base, dihydro naphthyl, tetralyl, benzocyclohepta base, benzocyclohepta thiazolinyl, 2,3 indanyls, indenyl, cumarone-3-ketone;
Pyrazolyl, pyrryl, imidazolyl, the imidazoles ketone group, thiazolyl, _ azoles base, different _ the azoles base, furyl, thienyl, pyridyl, pyriconyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group (tetrahydroquinoyl), isoquinolyl, tetrahydro isoquinolyl (tetrahydroisoquinoyl), pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzofuryl, the benzo thiophenyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thiophenyl, benzo _ oxazolone base, 4H-benzo [1,4] _ piperazine-3-ketone group, the benzo dioxolyl, benzo [1,3] dioxole-2-ketone group, the tetrahydro benzo pyranyl, indyl, indolinyl, the indoles ketone group, the dihydroindole ketone group, phthalimide-based;
Pyrrolidyl, tetrahydrofuran base, tetrahydrochysene thiophenyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, two _ alkyl, tetramethylene sulfide sulfuryl, tetramethylene sulfoxide base, _ azoles quinoline base, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, Decahydroisoquinolinpreparation base, thio-morpholinyl, thiazolidyl, dihydro _ piperazine base, dihydro pyranyl, oxocanyl, heptacanyl, thiophene _ alkyl or dithiane base.
[0087] in other embodiment of second group of compound of formula IB, G ' is phenyl, naphthyl, cyclopropyl, benzocyclobutane base, dihydro naphthyl, tetralyl, benzocyclohepta base, benzocyclohepta thiazolinyl, 2,3 indanyls, indenyl or cumarone-3-ketone.In other embodiments, G ' is a pyrazolyl, pyridyl, pyriconyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzofuryl, the benzo thiophenyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thiophenyl, benzo _ oxazolone base, benzo [1,4] _ piperazine-3-ketone group, the benzo dioxolyl, benzo [1,3] dioxole-2-ketone group, the tetrahydro benzo pyranyl, indyl, indolinyl, the indoles ketone group, the dihydroindole ketone group, or phthalimide-based.Selectively, G ' be pyrrolidyl, tetrahydrofuran base, tetrahydrochysene thiophenyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, two _ alkyl, tetramethylene sulfide sulfuryl, tetramethylene sulfoxide base, _ azoles quinoline base, different _ azoles quinoline base, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, Decahydroisoquinolinpreparation base, thio-morpholinyl, thiazolidyl, dihydro _ piperazine base, dihydro pyranyl, oxocanyl, heptacanyl, thiophene _ alkyl or dithiane base.In also having other embodiments, G ' be phenyl, naphthyl, pyrazolyl, cyclopropyl, pyrryl, pyrrolidyl, imidazolyl, imidazoles ketone group, thiazolyl, _ azoles base, different _ the azoles base, furyl, thienyl or pyridyl.
[0088] in some embodiment of second group of compound of formula IB, Y is-C (O)-,-C (NNRC (O) OR)-or-C (NOR)-.
[0089] in some embodiment of second group of compound of formula IB, Ar is naphthyl, dihydro naphthyl, tetralyl, indenyl or camomile cyclic group.Selectively, Ar is indazolyl, pseudoindoyl, quinolyl, isoquinolyl, phthalazinyl, indyl, indolinyl, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, dihydrobenzo different _ azoles base, dihydro-iso indolyl, benzimidazolyl-, benzothienyl, benzothiazolyl, benzisothiazole base or benzisothiazole base dioxide.
[0090] in some embodiments of second group of compound of formula IB, one or more methylene groups of L are selected from O, N or S (O) independently mHeteroatoms substitute.Selectively, L is covalent linkage, C 1-C 9Alkoxyl group ,-C (O) O-,-NH-or-O-.
[0091] in some embodiment of second group of compound of formula IB, Q is hydrogen, phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, imidazolyl, pyrryl, pyrrolidyl, benzimidazolyl-, furyl, thienyl, pyranyl, naphthyl pyridyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazyl, pyrazolo [3,4-b] pyrimidyl, fast quinoline base, pyrrolo-[2,3-b] pyridyl, pyrazolo [3,4-b] pyridyl, tubercidin base, _ azoles [4,5-b] pyridyl or imidazo [4,5-b] pyridyl; THP trtrahydropyranyl, tetrahydrofuran base, 1,3-dioxane pentanone, 1,3-two _ alkane ketone, 1,4-two _ alkyl, morpholino, thiomorpholine for sulfoxide, thiomorpholine for sulfone, piperazinyl, piperazine ketone group, oxazepinyl, Diazesuberane ketone group, piperidyl, piperidone base, tetrahydropyrimidine ketone group, pimelinketone, hexalin, pentamethylene sulfide, ring penta sulfoxide, ring penta sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone; C 1-6Alkoxyl group, secondary amine or tertiary amine, wherein amino nitrogen is covalently bound to C 1-3Alkyl or C 1-5On the alkoxyalkyl, phenylamino; C 1-6Alkyl-S (O) mOr phenyl-S (O) mIn some such embodiments, R 27Be C 1-6Alkyl, C 1-65-10 alkoxyl group, hydroxyl amino, replacement or unsubstituted unit heterocyclic radical, list-or two-(C 1-3Alkyl) amino, single-or two-(phenyl-C 1-3Alkyl) amino, C 1-6Alkyl-S (O) m, phenyl-C 1-3-alkoxyl group or phenylamino, wherein phenyl ring is randomly used one to two halogen, C 1-6Alkyl or C 1-6Alkoxyl group replaces.
[0092] in other embodiments of the compound of formula IB, Q be hydrogen, thiomorpholine for sulfoxide, thiomorpholine for sulfone, piperazine ketone group, oxazepinyl, diazepinonyl, imidazolyl, pyridyl or morpholino.In also having other embodiments, Q is morpholino, piperazinyl, pyrimidyl or pyridyl.In some such embodiments, R 27Be-C (O) OR ,-NR ' R ', replace or unsubstituted straight or branched C 1-10C alkyl, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl or replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.For example, Q is a pyrimidyl, R 27Be-NR ' R ' or replace or unsubstituted saturated or undersaturated 3-11 unit heterocyclic radical, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.Selectively, Q is a pyridyl, R 27Be-NR ' R ', replace or unsubstituted C 1-6Saturated or undersaturated 3-11 unit's heterocyclic radical alkyl or replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.
[0093] in some embodiment of second group of compound of formula IB, each R 1Be independently:
C 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, dicyclohexyl or two suberyl, they are randomly by partially or completely halogenation, and randomly replace with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl, or the analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH replace;
C 3-10Side chain or unbranched alkenyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: C 1-5Side chain or unbranched alkyl, phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ the azoles base, isothiazolyl; Aforesaid each randomly by partially or completely halogenation, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl; C wherein 3-10Side chain or unbranched alkenyl are randomly by one or more O, N or S (O) mInterrupt;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls or bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
Cyano group, F, Cl, Br or I;
Methoxycarbonyl, ethoxycarbonyl or the third oxygen carbonyl;
Silyl contains three C 1-4Side chain or unbranched alkyl group independently, it is randomly by partially or completely halogenation;
C 2-6Side chain or unbranched alkyl-C (O), C 2-6Side chain or unbranched-S, C 2-6Side chain or unbranched-S (O), C 2-6Side chain or unbranched-S (O) 2
Randomly by partially or completely halogenated C 2-6Side chain or unbranched alkynyl, wherein one or more methylene groups are randomly by O, NH and S (O) mReplace, and wherein, described alkynyl group is optional to be replaced by following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino.
[0094] in other embodiments, each R 1Be C independently 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl.For example, each R 1Be C independently 3-10Side chain or unbranched alkyl.
[0095] in some embodiments of second group of compound of formula IB, each R 2Be independently-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2In some embodiment, each R 2Be independently-NR ' 2,-NO 2,-C (O) NR ' 2,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or SO 2NR ' 2
[0096] in some embodiments of second group of compound of formula IB, each R 3Be independently:
Hydrogen or phenyl, naphthyl or heterocyclic radical, in them each is randomly by halogenation partially or completely, and randomly got: phenyl by 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-G 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N, carboxyl-list-or two-(C 1-5Alkyl) amino;
Fused-aryl, be selected from benzocyclobutane base, 2,3 indanyls, indenyl, dihydro naphthyl, tetralyl, benzocyclohepta base and benzocyclohepta thiazolinyl, or annelated heterocycles, be selected from cyclopenta pyridine, hexanaphthene and pyridine, pentamethylene and pyrimidine, hexanaphthene and pyrimidine, pentamethylene and pyrazine, hexanaphthene and pyrazine, pentamethylene and pyridazine, cyclopentanoindole, hexanaphthene diindyl, ring benzoglyoxaline, pentamethylene and imidazoles, hexanaphthene and imidazoles, pentamethylene thiophthene and hexanaphthene thiophthene; Wherein said condensed aryl or annelated heterocycles are randomly, replaced by 1 to 3 group independently, be selected from: phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2,5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, isothiazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, heteroaryloxy, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocycle or amino, the NH of assorted virtue 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-4Alkyl-C (O), C 1-5Alkylamino-S (O) 2, single-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, R 12-C 1-5Alkyl, R 13-C 1-5Alkoxyl group, R 14-C (O)-C 1-5Alkyl, R 15-C 1-5Alkyl (R 16) N;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl; The analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls, bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
C 1-4Alkyl or alkylidene group-phenyl-C (O)-C 0-4Alkyl or alkylidene group, C 1-4Alkyl or alkylidene group-C (O)-C 0-4Alkyl or alkylidene group, C 1-4Alkyl or alkylidene group-phenyl-S (O) m-C 0-4Alkyl or alkylidene group;
C 1-6Alkyl or C 1-6Alkoxyl group, each is randomly by partially or completely halogenation, or randomly uses R 17, amino, OR 18, or randomly use R 19The C that replaces 1-5Single-or the replacement of two-alkylamino.
Ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, it is randomly by partially or completely halogenation, and randomly uses one to three: randomly by partially or completely halogenated C 1-3Alkyl group replaces, and wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-6Alkenyl;
C 2-6Side chain or unbranched carbochain alkynyl, it is randomly by partially or completely halogenation, and wherein one or more methylene groups are randomly by O, NH or S (O) mSubstitute, and wherein, described alkynyl group is optional to be replaced with following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino; Or
Benzoyl or naphthoyl; Wherein
R 7, R 8, R 9, R 10, R 12, R 13, R 14, R 15, R 17, R 19And R 25In each be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by partially or completely halogenation;
R 11And R 16In each be hydrogen or C independently 1-4Side chain or unbranched alkyl, it is optional by partially or completely halogenation; With
R 18Be hydrogen or C independently 1-4Side chain or unbranched alkyl, optional independently with oxo or R 25Replace.
[0097] in some these type of embodiments, each R 3Be phenyl independently, naphthyl or heterocyclic radical, in them each is randomly by partially or completely halogenation, and randomly replace: phenyl with 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two (C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N or carboxyl-list-or two-(C 1-5Alkyl) amino.In other these type of embodiments, each R 3Be phenyl, pyridazinyl or pyridyl independently, each in them is randomly by partially or completely halogenation, and randomly replaces with following radicals: randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, nitro, amino, list-or two-(C 1-3Alkyl) amino; C 1-6Alkyl or C 1-6Alkoxyl group, each is optional by partially or completely halogenation, or randomly replaces with following radicals: R 17, amino, OR 18, randomly use R 19The C that replaces 1-5Single-or two-alkylamino, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-.
[0098] in some embodiments of second group of compound of formula IB, X is C=O.
[0099] in some embodiment of second group of compound of formula IB, Ar is a naphthyl, G be G '-(Y)-, Y is-C (O)-or-C (=NOH)-, G ' be selected from phenyl, pyridyl, pyrazolyl, pyrryl, imidazolyl, _ azoles base, different _ the azoles base, furyl or thienyl.In other embodiments, Ar is a naphthyl, G be G '-(Y)-, Y is-C (O)-or-C (=NOH)-, G ' is phenyl or pyridyl, by one or more R 1, R 2Or R 3Replace.In some such embodiments, each R 1Be independently replace or a unsubstituted straight chain or a C 1-10Alkyl.In these embodiments, each R 3Can be R independently 23R 24N-C (O)-, R 20-C (O)-NR 21-or OR 22In other these type of embodiments, each R 2Be independently-NR ' SO 2R " ,-Cl ,-Br ,-F ,-C (O)-NR ' 2, replace or unsubstituted straight or branched C 1-6Alkyl ,-NR ' 2Or-OR '.
[0100] in other embodiments of second group of compound of formula IB, Ar is-naphthyl-, G be G '-(Y)-, wherein Y be selected from-C (O)-and-C (=NOH)-, G ' is pyrazolyl, different _ azoles base or furyl, they are by one or more R 1, R 2Or R 3Replace.In some such embodiments, each R 1Be that replace or unsubstituted straight or branched C independently 1-10Alkyl.In these embodiments, each R 3Can be that replace or unsubstituted C independently 1-6Alkyl, pyridyl or phenyl, they randomly use one to three-F ,-Cl, replacement or unsubstituted C 1-6Side chain or unbranched alkyl or that replace or unsubstituted C 1-3Alkoxyl group replaces.
[0101] according to a further aspect in the invention, provide the 3rd group of compound with formula IA:
Its steric isomer, its tautomer, its solvate, its prodrug and its pharmacy acceptable salt, wherein:
X is C (O), C (S) or CH 2
G is C 3-5Cycloalkyl, pyrazolyl, thiazolyl, _ azoles base, isothiazolyl, thiadiazolyl group, _ di azoly, pyrrolinyl, pyridazinyl, pyrryl, imidazolyl, the imidazoles ketone group, different _ the azoles base, furyl, thienyl, pyriconyl, naphthyl, the dihydro naphthyl, tetralyl, 2,3 indanyls, indenyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzofuryl, the benzo thiophenyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thiophenyl, benzo _ oxazolone base, 4H-benzo [1,4] _ piperazine-3-ketone group, the benzo dioxolyl, benzo [1,3] dioxole-2-ketone group, the tetrahydro benzo pyranyl, indyl, indolinyl, the indoles ketone group, the dihydroindole ketone group, phthalimide-based, pyrrolidyl, tetrahydrofuran base, the tetrahydrochysene thiophenyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, two _ alkyl, the tetramethylene sulfide sulfuryl, the tetramethylene sulfoxide base, _ azoles quinoline base, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, the Decahydroisoquinolinpreparation base, thio-morpholinyl, thiazolidyl, dihydro _ piperazine base, dihydro pyranyl, oxocanyl, heptacanyl, thiophene _ alkyl or dithiane base; Wherein G is by R 1, R 2Or R 3In one or more replacements.
Ar is-(Y)-and (C 0-3Alkyl)-(phenyl) or-(Y)-(C 0-3Alkyl)-(bicyclic heteroaryl), wherein Ar randomly uses R 4Or R 5In one or more replacements;
Y is-C (O)-,-C (NNRC (O) OR)-,-C (NNRR)-,-C (NNC (O) NRR)-or-C (NOR)-;
L is a covalent linkage, saturated or undersaturated side chain or unbranched C 1-10Carbochain, wherein, optional O, NR and the S (O) of being selected from independently of one or more methylene groups mHeteroatoms substitute; Wherein L is randomly by 0-2 oxo group and one or more C 1-4Side chain or unbranched alkyl replace, described C 1-4Side chain or unbranched alkyl are randomly replaced by one or more F, Cl, Br or I;
Each m is 0,1 or 2 independently;
Q be hydrogen ,-NR ' R ', cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) m, or phenyl-S (O) m, wherein cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) mEach randomly uses one or more R 27Replace; If R 4And R 5Do not exist, so-L-Q is not-H;
Each R independently is C hydrogen or replacement or unsubstituted 1-6Alkyl;
Each R ' is C hydrogen, replacement or unsubstituted independently 1-8(C alkyl, replacement or unsubstituted 0-4Alkyl)-(C 6-10Aryl) or that replace or unsubstituted (C 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-OR ,-NR ' R ' ,-SiR 3,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2, R 4And R 5Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
Each R " be that replace or unsubstituted C independently 1-8C alkyl, replacement or unsubstituted 0-4Alkyl-C 6-10(C aryl or replacement or unsubstituted 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 3Be that replace or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace.
Each R 6Be C 1-6Side chain or unbranched alkyl, it is randomly by part or all of halogenation, and randomly uses R 26Replace;
Each R 26Be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by part or all of halogenation;
R 20Be that replace or unsubstituted C 1-10C alkyl, replacement or unsubstituted 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical, OR ' or NR ' 2
R 21Be hydrogen or C 1-4Side chain or unbranched alkyl, it is randomly by part or all of halogenation; With
R 22, R 23And R 24In each be C hydrogen, replacement or unsubstituted independently 1-10Alkyl, wherein C 1-10Alkyl randomly by one or more O, N or S interrupt, replace or unsubstituted C 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical; Or R 23And R 24Randomly form heterocycle or hetero-aromatic ring together;
Each R 27Be independently F, Cl, Br, I, cyano group ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR ' ,-OR ' ,-NR ' R ' ,-SiR ' 3,-S (O) mR ', replace or unsubstituted straight or branched C 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-203-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and independently is selected from N, O, S (O) mHeteroatoms;
Yet, if when Ar be phenyl, when G was N-(phenyl replacement or unsubstituted)-pyrazolyl, pyrazolyl was additionally used R 1, R 2Or R 3In one or more replacements; And IA is not 2-[6-(2-xenyl-4-base-2-oxo-kharophen)-indoles-1-ylmethyl]-phenylformic acid.
[0102] in some embodiment of the 3rd group of compound of formula IA, the compound of 10 μ M concentration suppresses bringing out property TNFa-from cell and discharges about 50% or greater than 50%.
[0103] in some embodiment of the 3rd group of compound of formula IA, G is cyclopropyl, cyclobutyl or cyclopentyl.In other embodiments, G be cyclopropyl, pyrazolyl, pyrryl, pyrrolidyl, imidazolyl, imidazoles ketone group, thiazolyl, _ azoles base, different _ the azoles base, furyl or thienyl.
[0104] in some embodiments of the 3rd group of compound of formula IA, Ar is-(Y)-(C 0-3Alkyl)-(phenyl), Y be-C (O)-,-C (NNRC (O) OR)-or-C (NOR)-.In some such embodiments, Ar is by R 4Or R 5In at least one replacement.In other embodiments, Ar is-C (O)-(phenyl).In also having other embodiments, Ar is-(Y)-(C 0-3Alkyl)-(bicyclic heteroaryl), and bicyclic heteroaryl be pyrazolyl, imidazolyl, pyrazolinyl, pyrryl, pyrrolinyl, pyridyl, pyrimidyl or pyridazinyl.In some such embodiments, Ar is by R 4Or R 5In at least one replacement.Selectively, Y be-C (O)-,-C (NNRC (O) OR)-or-C (NOR)-.In also having other embodiments, Ar is-C (O)-(bicyclic heteroaryl) or-C (NOR)-(bicyclic heteroaryl).For example, bicyclic heteroaryl can be pyrazolyl, imidazolyl, pyrazolinyl, pyrryl, pyrrolinyl, pyridyl, pyrimidine or pyridazinyl.
[0105] in some embodiments of first group of compound of formula IA, one or more methylene groups of L are selected from O, N or S (O) independently mHeteroatoms substitute.In other embodiments, L is covalent linkage, C 1-C 9Alkoxyl group ,-C (O) O-,-NH-or-O-.
[0106] in some embodiment of the 3rd group of compound of formula IA, Q is hydrogen, phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, imidazolyl, pyrryl, pyrrolidyl, benzimidazolyl-, furyl, thienyl, pyranyl, naphthyl pyridyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazyl, pyrazolo [3,4-b] pyrimidyl, fast quinoline base, pyrrolo-[2,3-b] pyridyl, pyrazolo [3,4-b] pyridyl, tubercidin base, _ azoles also [4,5-b] pyridyl or imidazo [4,5-b] pyridyl; THP trtrahydropyranyl, tetrahydrofuran base, 1,3-dioxane pentanone, 1,3-two _ alkane ketone, 1,4-two _ alkyl, morpholino, thiomorpholine for sulfoxide, thiomorpholine for sulfone, piperazinyl, piperazine ketone group, oxazepinyl, Diazesuberane ketone group, piperidyl, piperidone base, tetrahydropyrimidine ketone group, pimelinketone, hexalin, pentamethylene sulfide, ring penta sulfoxide, ring penta sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone; C 1-6Alkoxyl group, secondary amine or tertiary amine, wherein amino nitrogen is covalently bound to C 1-3Alkyl or C 1-5Alkoxyalkyl, phenylamino; C 1-6Alkyl-S (O) mOr phenyl-S (O) mIn some such embodiments, R 27Be C 1-6Alkyl, C 1-65-10 alkoxyl group, hydroxyl amino, replacement or unsubstituted unit heterocyclic radical, list-or two-(C 1-3Alkyl) amino, single-or two-(phenyl-C 1-3Alkyl) amino, C 1-6Alkyl-S (O) m, phenyl-C 1-3-alkoxyl group or phenylamino, wherein phenyl ring is randomly used one to two halogen, C 1-6Alkyl or C 1-6Alkoxyl group replaces.
[0107] in other embodiments, Q be hydrogen, thiomorpholine for sulfoxide, thiomorpholine for sulfone, piperazine ketone group, oxazepinyl, diazepinonyl, imidazolyl, pyridyl or morpholino.In also having other embodiments, Q is morpholino, piperazinyl, pyrimidyl or pyridyl.In some such embodiments, R 27Be-C (O) OR ,-NR ' R ', replace or unsubstituted straight or branched C 1-10C alkyl, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.For example, Q is a pyrimidyl, R 27Be-NR ' R ' or replace or unsubstituted saturated or undersaturated 3-11 unit heterocyclic radical, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.Selectively, Q is a pyridyl, R 27Be-NR ' R ', replace or unsubstituted C 1-6Saturated or undersaturated 3-11 unit's heterocyclic radical alkyl or replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.
[0108] in some embodiment of the 3rd group of compound of formula IA, each R 1Be independently:
C 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, dicyclohexyl or two suberyl, they are randomly by partially or completely halogenation, and randomly replace with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl, or the analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH replace;
C 3-10Side chain or unbranched alkenyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: C 1-5Side chain or unbranched alkyl, phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ the azoles base, isothiazolyl; Aforesaid each randomly by partially or completely halogenation, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl; C wherein 3-10Side chain or unbranched alkenyl are randomly by one or more O, N or S (O) mInterrupt;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls or bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
Cyano group, F, Cl, Br or I;
Methoxycarbonyl, ethoxycarbonyl or the third oxygen carbonyl;
Silyl contains three C 1-4Side chain or unbranched alkyl group independently, it is randomly by partially or completely halogenation;
C 2-6Side chain or unbranched alkyl-C (O), C 2-6Side chain or unbranched-S, C 2-6Side chain or unbranched-S (O), C 2-6Side chain or unbranched-S (O) 2
Randomly by partially or completely halogenated C 2-6Side chain or unbranched alkynyl, wherein one or more methylene groups are randomly by O, NH and S (O) mReplace, and wherein, described alkynyl group is optional to be replaced by following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino.
[0109] in some other embodiments of the 3rd group of compound with formula IA, each R 1Be C independently 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl.For example, each R 1Be C independently 3-10Side chain or unbranched alkyl.
[0110] in some embodiment of the 3rd group of compound of formula IA, each R 2Be independently-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2Selectively, each R 2Be independently-NR ' 2,-NO 2,-C (O) NR ' 2,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or SO 2NR ' 2
[0111] in some embodiments of the 3rd group of compound of formula IA, each R 3Be independently
Hydrogen or phenyl, naphthyl or heterocyclic radical, in them each is randomly by halogenation partially or completely, and randomly got: phenyl by 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N, carboxyl-list-or two-(C 1-5Alkyl) amino;
The condensed aryl, be selected from benzocyclobutane base, 2,3 indanyls, indenyl, dihydro naphthyl, tetralyl, benzocyclohepta base and benzocyclohepta thiazolinyl, or annelated heterocycles, be selected from cyclopenta pyridine, hexanaphthene and pyridine, pentamethylene and pyrimidine, hexanaphthene and pyrimidine, pentamethylene and pyrazine, hexanaphthene and pyrazine, pentamethylene and pyridazine, cyclopentanoindole, hexanaphthene diindyl, ring benzoglyoxaline, pentamethylene and imidazoles, hexanaphthene and imidazoles, pentamethylene thiophthene and hexanaphthene thiophthene; Wherein said condensed aryl or annelated heterocycles are randomly, replaced by 1 to 3 group independently, described group is selected from: phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2,5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, isothiazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, heteroaryloxy, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocycle or amino, the NH of assorted virtue 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-4Alkyl-C (O), C 1-5Alkylamino-S (O) 2, single-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, R 12-C 1-5Alkyl, R 13-C 1-5Alkoxyl group, R 14-C (O)-C 1-5Alkyl, R 15-C 1-5Alkyl (R 16) N;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl; The analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls, bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
C 1-4Alkyl or alkylidene group-phenyl-C (O)-C 0-4Alkyl or alkylidene group, C 1-4Alkyl or alkylidene group-C (O)-C 0-4Alkyl or alkylidene group, C 1-4Alkyl or alkylidene group-phenyl-S (O) m-C 0-4Alkyl or alkylidene group;
C 1-6Alkyl or C 1-6Alkoxyl group, each is randomly by partially or completely halogenation, or randomly uses R 17, amino, OR 18, or randomly use R 19The C that replaces 1-5Single-or the replacement of two-alkylamino.
Ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, it is randomly by partially or completely halogenation, and randomly uses one to three randomly by partially or completely halogenated C 1-3Alkyl group replaces, and wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-6Alkenyl;
C 2-6Side chain or unbranched carbochain alkynyl, it is randomly by partially or completely halogenation, and wherein one or more methylene groups are randomly by O, NH or S (O) mSubstitute, and wherein, described alkynyl group is optional to be replaced with following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino; Or
Benzoyl or naphthoyl; Wherein
R 7, R 8, R 9, R 10, R 12, R 13, R 14, R 15, R 17, R 19And R 25In each be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by partially or completely halogenation;
R 11And R 16In each be hydrogen or C independently 1-4Side chain or unbranched alkyl, it is optional by partially or completely halogenation; With
R 18Be hydrogen or C independently 1-4Side chain or unbranched alkyl, optional independently with oxo or R 25Replace.
[0112] in some these type of embodiments of the 3rd group of compound of formula IA, each R 3Be phenyl independently, naphthyl or heterocyclic radical, in them each is randomly by partially or completely halogenation, and randomly replace: phenyl with 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two (C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N or carboxyl-list-or two-(C 1-5Alkyl) amino.In other embodiments, R 3Be phenyl, pyridazinyl or pyridyl, each in them is randomly by partially or completely halogenation, and randomly replaces with following radicals: randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, nitro, amino or list-or two-(C 1-3Alkyl) amino; C 1-6Alkyl or C 1-6Alkoxyl group, each is optional by partially or completely halogenation, or randomly replaces with following radicals: R 17, amino, OR 18, randomly use R 19The C that replaces 1-5Single-or two-alkylamino; R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-.
[0113] in some embodiments of the 3rd group of compound of formula IA, X is C=O.
[0114] in some embodiment of the 3rd group of compound of formula IA, Ar is-(Y)-phenyl-, Y is-C (O)-or-C (=NOH)-, G be selected from pyrazolyl, pyrryl, imidazolyl, _ azoles base, different _ the azoles base, furyl or thienyl.In other embodiments, Ar is-(Y)-phenyl-, Y is-C (O)-or-C (=NOH)-, G is pyrazolyl, thienyl or different _ azoles base.In some such embodiments, each R 1Be that replace or unsubstituted straight or branched C independently 1-10Alkyl.In these embodiments, each R 3Can be phenyl or pyridyl independently, they randomly use one, two or three-F ,-Cl, replacement or unsubstituted C 1-6Side chain or unbranched alkyl or replacement or unsubstituted C 1-4Alkoxyl group replaces.
[0115] according to a further aspect in the invention, provide the 3rd group of compound with formula IB:
Figure A20048003305501041
Its steric isomer, its tautomer, its solvate, its prodrug and its pharmacy acceptable salt, wherein:
X is C (O) or C (S);
G be G '-(Y)-, wherein G ' is C 3-10Cycloalkyl, phenyl, naphthyl, remove 1,1,4,4-tetramethyl--1,2,3, tetralyl outside the 4-tetralyl, pyrazolyl, thiazolyl, pyridyl, _ azoles base, different _ the azoles base, isothiazolyl, thiadiazolyl group, _ di azoly, pyridazinyl, imidazolyl, the furyl except that furans-2-base, the thienyl except that thiophene-2-base, dihydro naphthyl, 2,3 indanyls, indenyl, quinolyl, isoquinolyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzopyrazoles base or homopiperidinyl; Wherein G ' is by R 1, R 2Or R 3In one or more replacements.
Ar be phenyl, pyrimidyl, pyrazolyl, thiazolyl, thiadiazolyl group, _ the azoles base, different _ the azoles base, _ di azoly, isothiazolyl, pyrrolinyl, pyridazinyl, pyrryl, imidazolyl, furyl, thienyl, pyrimidyl, pyrazinyl; Wherein Ar is optional by R 4Or R 5In one or more replacements.
Y is independently-C (O)-,-C (NNRC (O) OR)-,-C (NNRR)-,-C (NNC (O) NRR)-or-C (NOR)-;
L is a covalent linkage, saturated or undersaturated side chain or unbranched C 1-10Carbochain, wherein, optional O, NR and the S (O) of being selected from independently of one or more methylene groups mHeteroatoms substitute; Wherein L is randomly by 0-2 oxo group and one or more C 1-4Side chain or unbranched alkyl replace, described C 1-4Side chain or unbranched alkyl are randomly replaced by one or more F, Cl, Br or I;
Each m is 0,1 or 2 independently;
Q be hydrogen ,-NR ' R ', cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) m, wherein cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) mEach randomly uses one or more R 27Replace; And if R 4And R 5Do not exist ,-L-Q is not a hydrogen;
Each R is C hydrogen or replacement or unsubstituted independently 1-6Alkyl;
Each R ' independently is C hydrogen, replacement or unsubstituted 1-8(C alkyl, replacement or unsubstituted 0-4Alkyl)-(C 6-10Aryl) or that replace or unsubstituted (C 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-NR ' R ' ,-OR ,-SiR 3,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2, R 4And R 5Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
Each R " be that replace or unsubstituted C independently 1-8C alkyl, replacement or unsubstituted 0-4Alkyl-C 6-10(C aryl or replacement or unsubstituted 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 3Be that replace or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace.
Each R 6Be C 1-6Side chain or unbranched alkyl, it is randomly by part or all of halogenation, and randomly uses R 26Replace;
Each R 26Be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by part or all of halogenation;
R 20Be that replace or unsubstituted C 1-10C alkyl, replacement or unsubstituted 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical, OR ' or NR ' 2
R 21Be hydrogen or C 1-4Side chain or unbranched alkyl, it is randomly by part or all of halogenation; With
R 22, R 23And R 24In each be C hydrogen, replacement or unsubstituted independently 1-10Alkyl, wherein C 1-10Alkyl randomly by one or more O, N or S interrupt, replace or unsubstituted C 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical; Or R 23And R 24Randomly form heterocycle or hetero-aromatic ring together;
Each R 27Be independently F, Cl, Br, I, cyano group ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR ' ,-OR ' ,-NR ' R ' ,-SiR ' 3,-S (O) mR ', replace or unsubstituted straight or branched C 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-203-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and independently is selected from N, O, S (O) mHeteroatoms;
Yet, if work as Ar-L-Q being-N-(phenyl replacement or unsubstituted)-pyrazolyl, G is phenyl, naphthyl, 2,3 indanyls or tetralyl, pyrazolyl is used R extraly 4Or R 5In one or more replacements; With IB be not N-{2-chloro-4-[2-(3,5-dimethyl-1-phenyl-1H-pyrazoles-4-yl)-2-oxo-kharophen]-5-hydroxyl-phenyl-2-(3-pentadecyl-benzenesulfonyl)-butyramide or 5-(4-oxyethyl group-phenyl)-1-be right-tolyl-4-is right-tolyl oxamyl-1H-pyrazoles-3-carboxylate methyl ester.
[0116] in some embodiment of the 3rd group of compound of formula IB, the compound of 10 μ M concentration suppresses bringing out property TNFa-from cell and discharges about 50% or greater than 50%.
[0117] in some embodiment of the 3rd group of compound of formula IB, G ' be phenyl, naphthyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetralyl, pyrazolyl, thiazolyl, pyridyl, _ azoles base, different _ the azoles base, isothiazolyl, thiadiazolyl group, _ di azoly, pyridazinyl, imidazolyl, furyl, thienyl, dihydro naphthyl, 2,3 indanyls, indenyl, quinolyl, isoquinolyl, pyrimidyl or pyrazinyl.In other embodiments, G ' be phenyl, naphthyl, pyrazolyl, cyclopropyl, imidazolyl, thiazolyl, _ azoles base, different _ the azoles base, furyl, thienyl or pyridyl.
[0118] in some embodiment of the 3rd group of compound of formula IB, Y is-C (O)-,-C (NNRC (O) OR)-or-C (NOR)-.
[0119] in some embodiments of the 3rd group of compound of formula IB, Ar is phenyl, pyrazolyl, imidazolyl, pyrazolinyl, pyrryl, pyrrolinyl, pyridyl or pyrimidyl.
[0120] in some other embodiments of the 3rd group of compound of formula IB, one or more methylene groups of L are selected from O, N or S (O) independently mHeteroatoms substitute.Selectively, L is covalent linkage, C 1-C 9Alkoxyl group ,-C (O) O-,-NH-or-O-.
[0121] in some embodiment of the 3rd group of compound of formula IB, Q is hydrogen, phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, imidazolyl, pyrryl, pyrrolidyl, benzimidazolyl-, furyl, thienyl, pyranyl, naphthyl pyridyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazyl, pyrazolo [3,4-b] pyrimidyl, fast quinoline base, pyrrolo-[2,3-b] pyridyl, pyrazolo [3,4-b] pyridyl, tubercidin base, _ azoles also [4,5-b] pyridyl or imidazo [4,5-b] pyridyl; THP trtrahydropyranyl, tetrahydrofuran base, 1,3-dioxane pentanone, 1,3-two _ alkane ketone, 1,4-two _ alkyl, morpholino, thiomorpholine for sulfoxide, thiomorpholine for sulfone, piperazinyl, piperazine ketone group, oxazepinyl, Diazesuberane ketone group, piperidyl, piperidone base, tetrahydropyrimidine ketone group, pimelinketone, hexalin, pentamethylene sulfide, ring penta sulfoxide, ring penta sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone; C 1-6Alkoxyl group, secondary amine or tertiary amine, wherein amino nitrogen is covalently bound to C 1-3Alkyl or C 1-5On the alkoxyalkyl, phenylamino; C 1-6Alkyl-S (O) or phenyl-S (O) mIn some such embodiments, R 27Be C 1-6Alkyl, C 1-65-10 alkoxyl group, hydroxyl amino, replacement or unsubstituted unit heterocyclic radical, list-or two-(C 1-3Alkyl) amino, single-or two-(phenyl-C 1-3Alkyl) amino, C 1-6Alkyl-S (O) m, phenyl-C 1-3-alkoxyl group or phenylamino, wherein phenyl ring is randomly used one or more halogens, C 1-6Alkyl or C 1-6Alkoxyl group replaces.
[0122] in some other embodiments of the 3rd group of compound of formula IB, Q be hydrogen, thiomorpholine for sulfoxide, thiomorpholine for sulfone, piperazine ketone group, oxazepinyl, diazepinonyl, imidazolyl, pyridyl or morpholino.In also having other embodiments, Q is morpholinyl, piperazinyl, pyrimidyl or pyridyl.In some such embodiments, R 27Be-C (O) OR ,-NR ' R ', replace or unsubstituted straight or branched C 1-10C alkyl, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.For example, Q is a pyrimidyl, R 27Be-NR ' R ' or replace or unsubstituted saturated or undersaturated 3-11 unit heterocyclic radical, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.Selectively, Q is a pyridyl, and R 27Be-NR ' R ' or that replace or unsubstituted C 1-6Saturated or undersaturated 3-11 unit's heterocyclic radical alkyl or replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.
[0123] in some embodiment of the 3rd group of compound of formula IB, each R 1Be independently
C 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, dicyclohexyl or two suberyl, they are randomly by partially or completely halogenation, and randomly replace with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl, or the analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH replace;
C 3-10Side chain or unbranched alkenyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: C 1-5Side chain or unbranched alkyl, phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ the azoles base, isothiazolyl; Aforesaid each randomly by partially or completely halogenation, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl; C wherein 3-10Side chain or unbranched alkenyl are randomly by one or more O, N or S (O) mInterrupt;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls or bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
Cyano group, F, Cl, Br or I;
Methoxycarbonyl, ethoxycarbonyl or the third oxygen carbonyl;
Silyl contains three C 1-4Independently side chain or unbranched alkyl group, it is randomly by partially or completely halogenation;
C 2-6Side chain or unbranched alkyl-C (O), C 2-6Side chain or unbranched-S, C 2-6Side chain or unbranched-S (O), C 2-6Side chain or unbranched-S (O) 2
Randomly by partially or completely halogenated C 2-6Side chain or unbranched alkynyl, wherein one or more methylene groups are randomly replaced by O, NH and S (O) m, and wherein, described alkynyl group is optional to be replaced by following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino.
[0124] in some other embodiments of the 3rd group of compound of formula IB, each R 1Be C independently 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl.For example, each R 1Be C independently 3-10Side chain or unbranched alkyl.
[0125] in some embodiment of the 3rd group of compound of formula IB, each R 2Be independently-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2Selectively, each R 2Be independently-NR ' 2,-NO 2,-C (O) NR ' 2,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or SO 2NR ' 2
[0126] in some embodiment of the 3rd group of compound of formula IB, each R 3Be independently
Hydrogen or phenyl, naphthyl or heterocyclic radical, in them each is randomly by halogenation partially or completely, and randomly got: phenyl by 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N, carboxyl-list-or two-(C 1-5Alkyl) amino;
Fused-aryl, be selected from benzocyclobutane base, 2,3 indanyls, indenyl, dihydro naphthyl, tetralyl, benzocyclohepta base and benzocyclohepta thiazolinyl, or annelated heterocycles, be selected from cyclopenta pyridine, hexanaphthene and pyridine, pentamethylene and pyrimidine, hexanaphthene and pyrimidine, pentamethylene and pyrazine, hexanaphthene and pyrazine, pentamethylene and pyridazine, cyclopentanoindole, hexanaphthene diindyl, ring benzoglyoxaline, pentamethylene and imidazoles, hexanaphthene and imidazoles, pentamethylene thiophthene and hexanaphthene thiophthene; Wherein said fused-aryl or annelated heterocycles are randomly, replaced by 1 to 3 group independently, described group is selected from: phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2,5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, isothiazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, heteroaryloxy, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocycle or amino, the NH of assorted virtue 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-4Alkyl-C (O), C 1-5Alkylamino-S (O) 2, single-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, R 12-C 1-5Alkyl, R 13-C 1-5Alkoxyl group, R 14-C (O)-C 1-5Alkyl, R 15-C 1-5Alkyl (R 16) N;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl; The analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls, bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
C 1-4Alkyl or alkylidene group-phenyl-C (O)-C 0-4Alkyl or alkylidene group, C 1-4Alkyl or alkylidene group-C (O)-C 0-4Alkyl or alkylidene group, C 1-4Alkyl or alkylidene group-phenyl-S (O) m-C 0-4Alkyl or alkylidene group;
C 1-6Alkyl or C 1-6Alkoxyl group, each is randomly by partially or completely halogenation, or randomly uses R 17, amino, OR 18, or randomly use R 19The C that replaces 1-5Single-or the replacement of two-alkylamino.
Ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, it is randomly by partially or completely halogenation, and randomly uses one to three: randomly by partially or completely halogenated C 1-3Alkyl group replaces, and wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-6Alkenyl;
C 2-6Side chain or unbranched carbochain alkynyl, it is randomly by partially or completely halogenation, and wherein one or more methylene groups are randomly by O, NH or S (O) mSubstitute, and wherein, described alkynyl group is optional to be replaced with following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino; Or
Benzoyl or naphthoyl; Wherein
R 7, R 8, R 9, R 10, R 12, R 13, R 14, R 15, R 17, R 19And R 25In each be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by partially or completely halogenation;
R 11And R 16In each be hydrogen or C independently 1-4Side chain or unbranched alkyl, it is optional by partially or completely halogenation; With
R 18Be hydrogen or C independently 1-4Side chain or unbranched alkyl, optional independently with oxo or R 25Replace.
[0127] in some these type of embodiments of the 3rd group of compound of formula IB, each R 3Be phenyl independently, naphthyl or heterocyclic radical, in them each is randomly by partially or completely halogenation, and randomly replace: phenyl with 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzoxazolyl group, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl oxygen generation, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two (C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N or carboxyl-list-or two-(C 1-5Alkyl) amino.In other such embodiments, R 3Be phenyl, pyridazinyl or pyridyl independently, each in them is randomly by partially or completely halogenation, and randomly replaces with following radicals: randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, nitro, amino or list-or two-(C 1-3Alkyl) amino; C 1-6Alkyl or C 1-6Alkoxyl group, each is optional by partially or completely halogenation, or randomly replaces with following radicals: R 17, amino, OR 18, randomly use R 19The C that replaces 1-5Single-or two-alkylamino, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-.
[0128] in some embodiment of the 3rd group of compound of formula IB, X is C=O.
[0129] in some embodiments of the 3rd group of compound of formula IB, Ar is a phenyl, G be G '-(Y)-, Y is-C (O)-or-C (=NOH)-, G ' be selected from phenyl, pyridyl, pyrazolyl, imidazolyl, _ azoles base, different _ the azoles base, furyl or thienyl.In other embodiments, Ar is a phenyl, G be G '-(Y)-, Y is-C (O)-or-C (=NOH)-, G ' is phenyl or pyridyl, it is by R 1, R 2Or R 3In one or more replacements.In some such embodiments, each R 1Be that replace or unsubstituted straight or branched C independently 1-10Alkyl.In these embodiments, each R 3Be R independently 23R 24N-C (O)-, R 20-C (O)-NR 21-or OR 22Selectively, each R 2Be independently-NR ' SO 2R " ,-Cl ,-Br ,-F ,-C (O)-NR ' 2, replace or unsubstituted straight or branched C 1-6Alkyl ,-NR ' 2Or-OR '.
[0130] in other embodiments of the 3rd group of compound of formula IB, Ar is a phenyl, G be G '-(Y)-, wherein Y be selected from-C (O)-and-C (=NOH)-, and G ' is pyrazolyl, different _ azoles base or furyl, it is by R 1, R 2Or R 3In one or more replacements.In some such embodiments, each R 1Be that replace or unsubstituted straight or branched C independently 1-10Alkyl.In these embodiments, each R 3Be that replace or unsubstituted C independently 1-6Alkyl, pyridyl or phenyl, it randomly replaces with one to three following radicals :-F ,-Cl, replacement or unsubstituted C 1-6Side chain or unbranched alkyl, replacement or unsubstituted C 1-3Alkoxyl group.
[0131] according to a further aspect in the invention, provide compound with formula IC,
G-ring-Ar-L-Q
IC
Its steric isomer, its tautomer, its solvate, its prodrug and its pharmacy acceptable salt, wherein:
Ring is maleimide, succinimide, imidazolidone, imidazolidine-diketone, imidazolidine-triketone, triazolidine-diketone or triazine-diketone;
G is C 3-10Carbocylic radical, C 4-12Carbocyclic ring alkyl, 5-8 unit's monocyclic heterocycles base or Heterocyclylalkyl or 8-11 unit's bicyclic heterocycles base or Heterocyclylalkyl, wherein said heterocycle contains one or more heteroatomss that is selected from O, N or S; G is by R 1, R 2Or R 3In one or more replacements;
Ar be indazolyl, indyl, pseudoindoyl, imidazolyl, benzimidazolyl-, pyrazolyl, pyrazolinyl, pyrryl, pyrrolinyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, indolinyl, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, dihydrobenzo different _ azoles base, dihydro-iso indolyl, benzothiazolyl, benzisothiazole base, benzisothiazole base dioxide, C 6-10Aryl or-(C 1-3Alkyl)-(C 6-10Aryl), wherein Ar randomly uses R 4Or R 5In one or more replacements.
L is a covalent linkage, saturated or undersaturated side chain or unbranched C 1-10Carbochain, wherein, optional O, NR and the S (O) of being selected from independently of one or more methylene groups mHeteroatoms substitute; Wherein L is randomly by 0-2 oxo group and one or more C 1-4Side chain or unbranched alkyl replace, described C 1-4Side chain or unbranched alkyl are randomly replaced by one or more F, Cl, Br or I;
Each m is 0,1 or 2 independently;
Q be hydrogen ,-NR ' R ', cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) m, or phenyl-S (O) m, wherein cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) mEach randomly uses one or more R 27Replace; If R 4And R 5Do not exist, then-L-Q is not-H;
Each R independently is C hydrogen or replacement or unsubstituted 1-6Alkyl;
Each R ' is C hydrogen, replacement or unsubstituted independently 1-8(C alkyl, replacement or unsubstituted 0-4Alkyl)-(C 6-10Aryl) or that replace or unsubstituted (C 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-OR ,-NR ' R ' ,-SiR 3,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2, R 4And R 5Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
Each R " be that replace or unsubstituted C independently 1-8C alkyl, replacement or unsubstituted 0-4Alkyl-C 6-10(C aryl or replacement or unsubstituted 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 3Be that replace or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace.
Each R 6Be C 1-6Side chain or unbranched alkyl, it is randomly by part or all of halogenation, and randomly uses R 26Replace;
Each R 26Be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by part or all of halogenation;
R 20Be that replace or unsubstituted C 1-10C alkyl, replacement or unsubstituted 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical, OR ' or NR ' 2
R 21Be hydrogen or C 1-4Side chain or unbranched alkyl, it is randomly by part or all of halogenation; With
R 22, R 23And R 24In each be C hydrogen, replacement or unsubstituted independently 1-10Alkyl, wherein C 1-10Alkyl randomly by one or more O, N or S interrupt, replace or unsubstituted C 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical; Or R 23And R 24Randomly form heterocycle or hetero-aromatic ring together; With
Each R 27Be independently F, Cl, Br, I, cyano group ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR ' ,-OR ' ,-NR ' R ' ,-SiR ' 3,-S (O) mR ', replace or unsubstituted straight or branched C 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-203-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and independently is selected from N, O, S (O) mHeteroatoms.
[0132] in some embodiment of the compound of formula IC, the compound of 10 μ M concentration suppresses bringing out property TNFa-from cell and discharges about 50% or greater than 50%.
[0133] in some embodiment of the compound of formula IC, G is
Phenyl, naphthyl, benzocyclobutane base, dihydro naphthyl, cyclopropyl, tetralyl, benzocyclohepta base, benzocyclohepta thiazolinyl, 2,3 indanyls, indenyl, cumarone-3-ketone;
Pyrazolyl, pyrryl, imidazolyl, the imidazoles ketone group, thiazolyl, _ azoles base, different _ the azoles base, furyl, thienyl, pyridyl, pyriconyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzofuryl, the benzo thiophenyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thiophenyl, benzo _ oxazolone base, 4H-benzo [1,4] _ piperazine-3-ketone group, the benzo dioxolyl, benzo [1,3] dioxole-2-ketone group, the tetrahydro benzo pyranyl, indyl, indolinyl, the indoles ketone group, the dihydroindole ketone group, phthalimide-based;
Pyrrolidyl, tetrahydrofuran base, tetrahydrochysene thiophenyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, two _ alkyl, tetramethylene sulfide sulfuryl, tetramethylene sulfoxide base, _ azoles quinoline base, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, Decahydroisoquinolinpreparation base, thio-morpholinyl, thiazolidyl, dihydro _ piperazine base, dihydro pyranyl, oxocanyl, heptacanyl, thiophene _ alkyl or dithiane base.
[0134] in other embodiments of the compound of formula IC, G is phenyl, naphthyl, cyclopropyl, benzocyclobutane base, dihydro naphthyl, tetralyl, benzocyclohepta base, benzocyclohepta thiazolinyl, 2,3 indanyls, indenyl or cumarone-3-ketone.In also having other embodiments, G is a pyrazolyl, pyridyl, pyriconyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzofuryl, the benzo thiophenyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thiophenyl, benzo _ oxazolone base, benzo [1,4] _ piperazine-3-ketone group, the benzo dioxolyl, benzo [1,3] dioxole-2-ketone group, the tetrahydro benzo pyranyl, indyl, indolinyl, the indoles ketone group, the dihydroindole ketone group, or phthalimide-based.In also having other embodiments, G be pyrrolidyl, tetrahydrofuran base, tetrahydrochysene thiophenyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, two _ alkyl, tetramethylene sulfide sulfuryl, tetramethylene sulfoxide base, _ azoles quinoline base, different _ azoles quinoline base, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, Decahydroisoquinolinpreparation base, thio-morpholinyl, thiazolidyl, dihydro _ piperazine base, dihydro pyranyl, oxocanyl, heptacanyl, thiophene _ alkyl or dithiane base.For example G be phenyl, naphthyl, cyclopropyl, pyrazolyl, pyrryl, pyrrolidyl, imidazolyl, imidazoles ketone group, thiazolyl, _ azoles base, different _ the azoles base, furyl, thienyl or pyridyl.
[0135] in some embodiment of the compound of formula IC, Ar be indazolyl, indyl, pseudoindoyl, imidazolyl, benzimidazolyl-, pyrazolyl, pyrazolinyl, pyrryl, pyrrolinyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, indolinyl, benzisoxa _ azoles base, dihydrobenzo different _ azoles base, dihydro-iso indolyl, benzisothiazole base, benzisothiazole base dioxide, C 6-10Aryl.In some such embodiments, at least one R of Ar 4Or R 5Replace.Selectively, Ar is indazolyl, pseudoindoyl, pyrazolyl, pyrrolinyl, phenyl, naphthyl, tetralyl, dihydro naphthyl, 2,3 indanyls, indenyl or imidazolyl.For example, Ar is an indazolyl, phenyl, naphthyl or tetralyl.
[0136] in some embodiments of the compound of formula IC, one or more methylene groups of L are selected from O, N or S (O) independently mHeteroatoms substitute.Selectively, L is covalent linkage, C 1-C 9Alkoxyl group ,-C (O) O-,-NH-or-O-.
[0137] in some embodiment of the compound of formula IC, Q is hydrogen, phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, imidazolyl, pyrryl, pyrrolidyl, benzimidazolyl-, furyl, thienyl, pyranyl, naphthyl pyridyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazyl, pyrazolo [3,4-b] pyrimidyl, fast quinoline base, pyrrolo-[2,3-b] pyridyl, pyrazolo [3,4-b] pyridyl, tubercidin base, _ azoles also [4,5-b] pyridyl or imidazo [4,5-b] pyridyl; THP trtrahydropyranyl, tetrahydrofuran base, 1,3-dioxolane ketone, 1,3-two _ alkane ketone, 1,4-two _ alkyl, morpholino, thiomorpholine for sulfoxide, thiomorpholine for sulfone, piperazinyl, piperazine ketone group, oxazepinyl, Diazesuberane ketone group, piperidyl, piperidone base, tetrahydropyrimidine ketone group, pimelinketone, hexalin, pentamethylene sulfide, ring penta sulfoxide, ring penta sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone; C 1-6Alkoxyl group, secondary amine or tertiary amine, wherein amino nitrogen is covalently bound to C 1-3Alkyl or C 1-5On the alkoxyalkyl, phenylamino; C 1-6Alkyl-S (O) mOr phenyl-S (O) mIn some such embodiments, R 27Be C 1-6Alkyl, C 1-65-10 alkoxyl group, hydroxyl amino, replacement or unsubstituted unit heterocyclic radical, list-or two-(C 1-3Alkyl) amino, single-or two-(phenyl-C 1-3Alkyl) amino, C 1-6Alkyl-S (O) m, phenyl-C 1-3-alkoxyl group or phenylamino, wherein phenyl ring is randomly used one to two halogen, C 1-6Alkyl or C 1-6Alkoxyl group replaces.
[0138] in other embodiments of the compound of formula IC, Q be hydrogen, thiomorpholine for sulfoxide, thiomorpholine for sulfone, piperazine ketone group, oxazepinyl, diazepinonyl, imidazolyl, pyridyl or morpholino.In also having other embodiments, Q is morpholino, piperazinyl, pyrimidyl or pyridyl.In some such embodiments, R 27Be-C (O) OR ,-NR ' R ', replace or unsubstituted straight or branched C 1-10C alkyl, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl or replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.For example, Q is a pyrimidyl, R 27Be-NR ' R ' or replace or unsubstituted saturated or undersaturated 3-11 unit heterocyclic radical, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.Selectively, Q is a pyridyl, and R is-NR " R ', replace or unsubstituted C 1-6Saturated or undersaturated 3-11 unit's heterocyclic radical alkyl or replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.
[0139] in some embodiment of the compound of formula IC, each R 1Be independently:
C 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, dicyclohexyl or two suberyl, they are randomly by partially or completely halogenation, and randomly replace with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl, or the analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH replace;
C 3-10Side chain or unbranched alkenyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: C 1-5Side chain or unbranched alkyl, phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ the azoles base, isothiazolyl; Aforesaid each randomly by partially or completely halogenation, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl; C wherein 3-10Side chain or unbranched alkenyl are randomly by one or more O, N or S (O) mInterrupt;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls or bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
Cyano group, F, Cl, Br or I;
Methoxycarbonyl, ethoxycarbonyl or the third oxygen carbonyl;
Silyl contains three C 1-4Side chain or unbranched alkyl group independently, it is randomly by partially or completely halogenation;
C 2-6Side chain or unbranched alkyl-C (O), C 2-6Side chain or unbranched-S, C 2-6Side chain or unbranched-S (O), C 2-6Side chain or unbranched-S (O) 2
Randomly by partially or completely halogenated C 2-6Side chain or unbranched alkynyl, wherein one or more methylene groups are randomly by O, NH and S (O) mReplace, and wherein, described alkynyl group is optional to be replaced by following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino.
[0140] in other embodiments of the compound with formula IC, each R 1Be C independently 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl.For example, each R 1Be C independently 3-10Side chain or unbranched alkyl.
[0141] in some embodiment of the compound of formula IC, each R 2Be independently-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2Selectively, each R 2Be independently-NR ' 2,-NO 2,-C (O) NR ' 2,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or SO 2NR ' 2
[0142] in some embodiment of the compound of formula IC, each R 3Be independently
Hydrogen or phenyl, naphthyl or heterocyclic radical, in them each is randomly by halogenation partially or completely, and randomly got: phenyl by 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N, carboxyl-list-or two-(C 1-5Alkyl) amino;
Fused-aryl, be selected from benzocyclobutane base, 2,3 indanyls, indenyl, dihydro naphthyl, tetralyl, benzocyclohepta base and benzocyclohepta thiazolinyl, or annelated heterocycles, be selected from cyclopenta pyridine, hexanaphthene and pyridine, pentamethylene and pyrimidine, hexanaphthene and pyrimidine, pentamethylene and pyrazine, hexanaphthene and pyrazine, pentamethylene and pyridazine, cyclopentanoindole, hexanaphthene diindyl, ring benzoglyoxaline, pentamethylene and imidazoles, hexanaphthene and imidazoles, pentamethylene thiophthene and hexanaphthene thiophthene; Wherein said fused-aryl or annelated heterocycles are randomly, replaced by 1 to 3 group independently, described group is selected from: phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2,5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, isothiazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, heteroaryloxy, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocycle or amino, the NH of assorted virtue 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-4Alkyl-C (O), C 1-5Alkylamino-S (O) 2, single-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, R 12-C 1-5Alkyl, R 13-C 1-5Alkoxyl group, R 14-C (O)-C 1-5Alkyl, R 15-C 1-5Alkyl (R 16) N;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl; The analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls, bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
C 1-4Alkyl or alkylidene group-phenyl-C (O)-C 0-4Alkyl or alkylidene group, C 1-4Alkyl or alkylidene group-C (O)-C 0-4Alkyl or alkylidene group, C 1-4Alkyl or alkylidene group-phenyl-S (O) m-C 0-4Alkyl or alkylidene group;
C 1-6Alkyl or C 1-6Alkoxyl group, each is randomly by partially or completely halogenation, or randomly uses R 17, amino, OR 18, or randomly use R 19The C that replaces 1-5Single-or the replacement of two-alkylamino.
Ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, it is randomly by partially or completely halogenation, and randomly uses one to three randomly by partially or completely halogenated C 1-3Alkyl group replaces, and wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-6Alkenyl;
C 2-6Side chain or unbranched carbochain alkynyl, it is randomly by partially or completely halogenation, and wherein one or more methylene groups are randomly by O, NH or S (O) mSubstitute, and wherein, described alkynyl group is optional to be replaced with following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino; Or
Benzoyl or naphthoyl; Wherein
R 7, R 8, R 9, R 10, R 12, R 13, R 14, R 15, R 17, R 19And R 25In each be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by partially or completely halogenation;
R 11And R 16In each be hydrogen or C independently 1-4Side chain or unbranched alkyl, it is optional by partially or completely halogenation; With
R 18Be hydrogen or C independently 1-4Side chain or unbranched alkyl, optional independently with oxo or R 25Replace.
[0143] in some such embodiments of formula IC compound, each R 3Be phenyl independently, naphthyl or heterocyclic radical, in them each is randomly by partially or completely halogenation, and randomly replace: phenyl with 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two (C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N or carboxyl-list-or two-(C 1-5Alkyl) amino.In other such embodiments, each R 3Be phenyl, pyridazinyl or pyridyl independently, each in them is randomly by partially or completely halogenation, and randomly replaces with following radicals: randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, nitro, amino or list-or two-(C 1-3Alkyl) amino; C 1-6Alkyl or C 1-6Alkoxyl group, each is optional by partially or completely halogenation, or randomly replaces with following radicals: R 17, amino, OR 18, randomly use R 19The C that replaces 1-5Single-or two-alkylamino; R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-.
[0144] in some embodiment of the compound of formula IC, ring is maleimide, succinimide or triazine-diketone.In other embodiments, ring is a succinimide-1,4-two bases, maleimide-1,4-two bases, imidazolidin-2-one-1,3-two bases, imidazolidine-2,4,5-triketone-1,3-two bases, [1,2,4] triazolidine-3,5-diketone-1,4-two bases or 2H-[1,2,4] triazine-3,5-diketone-4,6-two bases.
[0145] in another aspect of this invention, provide compound with formula II,
Its steric isomer, its tautomer, its solvate, its prodrug and its pharmacy acceptable salt, wherein:
G is C 3-10Carbocylic radical, 5-8 unit's monocyclic heterocycles base or 8-11 unit bicyclic heterocycles base, it contains one or more heteroatomss that is selected from O, N or S; Wherein, G is by R 1, R 2Or R 3In one or more replacements;
X ' is CR '=CR ', CR '=N, NR ', CR ' 2, O or S;
Ar is phenyl, naphthyl, quinoline, isoquinoline 99.9, tetralyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, tetrahydroquinoline, tetrahydroisoquinoline, benzoglyoxaline, cumarone, 2,3 indanyls, indenyl, indoles or structure-(Y ')-(C 0-3Alkyl)-(C 6-10Aryl), each in them is randomly used one or more R 4Group replaces;
Y ' do not exist or-O-or-NH-;
L is a covalent linkage, saturated or undersaturated side chain or unbranched C 1-10Carbochain, wherein, optional O, NR and the S (O) of being selected from independently of one or more methylene groups mHeteroatoms substitute; Wherein L is randomly by 0-2 oxo group and one or more C 1-4Side chain or unbranched alkyl replace, described C 1-4Side chain or unbranched alkyl are randomly replaced by one or more F, Cl, Br or I;
Each m is O, 1 or 2 independently;
Q be hydrogen ,-NR ' R ', cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) m, or phenyl-S (O) m, wherein cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) mEach randomly uses one or more R 27Replace;
Each R independently is C hydrogen or replacement or unsubstituted 1-6Alkyl;
Each R ' is C hydrogen, replacement or unsubstituted independently 1-8(C alkyl, replacement or unsubstituted 0-4Alkyl)-(C 6-10Aryl) or that replace or unsubstituted (C 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-NR ' R ' ,-OR ,-SiR 3,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2And R 4Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
Each R " be that replace or unsubstituted C independently 1-8C alkyl, replacement or unsubstituted 0-4Alkyl-C 6-10(C aryl or replacement or unsubstituted 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 3Be H, replacement or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace.
Each R 6Be C 1-6Side chain or unbranched alkyl, it is randomly by part or all of halogenation, and randomly uses R 26Replace;
Each R 26Be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by part or all of halogenation;
R 20By partially or completely halogenated C randomly 1-10Side chain or do not have alkyl, phenyl, pyridine, OR ' or the NR ' of straight chain 2
R 21Be hydrogen or C 1-4Side chain or unbranched alkyl, it is randomly by part or all of halogenation; With
R 22, R 23And R 24In each be hydrogen, C independently 1-6Side chain or unbranched alkyl, it is randomly by carbonyl amino-list-or two-C 1-3Alkyl or amino-list or two-C 1-3Alkyl replaces or wherein said C 1-6Alkyl is randomly by part or all of halogenation, and randomly interrupted by one or more following radicals: O, N or S, phenyl, pyridine, randomly by part or all of halogenated list-or two-C 0-4Side chain or unbranched alkyl and alkylamino; Or R 23And R 24Randomly form heterocycle or hetero-aromatic ring together;
Each R 27Be independently F, Cl, Br, I, cyano group ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR ' ,-OR ' ,-NR ' R ' ,-SiR ' 3,-S (O) mR ', replace or unsubstituted straight or branched C 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-203-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and independently is selected from N, O, S (O) mHeteroatoms.
[0146] in some embodiment of formula II compound, the compound of 10 μ M concentration suppresses bringing out property TNFa-from cell and discharges about 50% or greater than 50%.
[0147] in some embodiment of formula II compound, G is
Phenyl, naphthyl, benzocyclobutane base, dihydro naphthyl, tetralyl, benzocyclohepta base, benzocyclohepta thiazolinyl, 2,3 indanyls, indenyl, cumarone-3-ketone;
Pyrazolyl, pyrryl, imidazolyl, the imidazoles ketone group, thiazolyl, _ azoles base, different _ the azoles base, furyl, thienyl, pyridyl, pyriconyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzofuryl, the benzo thiophenyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thiophenyl, benzo _ oxazolone base, 4H-benzo [1,4] _ piperazine-3-ketone group, the benzo dioxolyl, benzo [1,3] dioxole-2-ketone group, the tetrahydro benzo pyranyl, indyl, indolinyl, the indoles ketone group, the dihydroindole ketone group, phthalimide-based;
Pyrrolidyl, tetrahydrofuran base, tetrahydrochysene thiophenyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, two _ alkyl, tetramethylene sulfide sulfuryl, tetramethylene sulfoxide base, _ azoles quinoline base, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, Decahydroisoquinolinpreparation base, thio-morpholinyl, thiazolidyl, dihydro _ piperazine base, dihydro pyranyl, oxocanyl, heptacanyl, thiophene _ alkyl or dithiane base.
[0148] in other embodiment of formula II compound, G is phenyl, naphthyl, benzocyclobutane base, dihydro naphthyl, tetralyl, benzocyclohepta base, benzocyclohepta thiazolinyl, 2,3 indanyls, indenyl, cumarone-3-ketone or 4H-benzo [1,4] _ piperazine-3-ketone.In also having other embodiments, G is a pyrazolyl, pyridyl, pyriconyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzofuryl, the benzo thiophenyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thiophenyl, benzo _ oxazolone base, benzo [1,4] _ piperazine-3-ketone group, the benzo dioxolyl, benzo [1,3] dioxole-2-ketone group, the tetrahydro benzo pyranyl, indyl, indolinyl, the indoles ketone group, the dihydroindole ketone group, or phthalimide-based.In also having other embodiments, G be pyrrolidyl, tetrahydrofuran base, tetrahydrochysene thiophenyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, two _ alkyl, tetramethylene sulfide sulfuryl, tetramethylene sulfoxide base, _ azoles quinoline base, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, Decahydroisoquinolinpreparation base, thio-morpholinyl, thiazolidyl, dihydro _ piperazine base, dihydro pyranyl, oxocanyl, heptacanyl, thiophene _ alkyl or dithiane base.In certain embodiments, G be phenyl, pyrazolyl, pyrryl, pyrrolidyl, imidazolyl, imidazoles ketone group, thiazolyl, _ azoles base, different _ the azoles base, furyl, thienyl or pyridyl.
[0149] in some embodiment of formula II compound, Ar is indazolyl, pseudoindoyl, pyrazolyl, imidazolyl or imidazoles ketone group.In some such embodiments, at least one R of Ar 4Replace.Selectively, Ar is an indazolyl, and it randomly uses one or more R 4Replace.In also having other embodiments, Ar is a phenyl or naphthyl.At some in this type of the embodiment, at least one R of Ar 4Replace.
[0150] in the embodiment that also has other of formula II compound, Ar is-(Y ')-(C 0-3Alkyl)-(C 6-10Aryl).In some such embodiments, at least one R of Ar 4Replace.In other embodiments, C 6-10Aryl is a phenyl or naphthyl.Selectively, Y ' is-NH-.
[0151] in some embodiment of formula II compound, one or more methylene groups of L are selected from O, N or S (O) independently mHeteroatoms substitute.In other embodiments, L is covalent linkage, C 1-C 9Alkoxyl group ,-C (O) O-,-NH-or-O-.
[0152] in some embodiment of formula II compound, Q is hydrogen, phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, imidazolyl, pyrryl, pyrrolidyl, benzimidazolyl-, furyl, thienyl, pyranyl, naphthyl pyridyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazyl, pyrazolo [3,4-b] pyrimidyl, fast quinoline base, pyrrolo-[2,3-b] pyridyl, pyrazolo [3,4-b] batch pyridine base, tubercidin base, _ azoles also [4,5-b] pyridyl or imidazo [4,5-b] pyridyl; THP trtrahydropyranyl, tetrahydrofuran base, 1,3-dioxane pentanone, 1,3-two _ alkane ketone, 1,4-two _ alkyl, morpholino, thio-morpholinyl sulfoxide, thio-morpholinyl sulfone, piperazinyl, piperidyl, piperidone base, tetrahydropyrimidine ketone group, pimelinketone, hexalin, pentamethylene sulfide, ring penta sulfoxide, ring penta sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone; C 1-6Alkoxyl group, secondary amine or tertiary amine, wherein amino nitrogen is covalently bound to C 1-3Alkyl or C 1-5Alkoxyalkyl, phenylamino; C 1-6Alkyl-S (O) mOr phenyl-S (O) mIn some such embodiments, R 27Be C 1-6Alkyl, C 1-65-10 alkoxyl group, hydroxyl amino, replacement or unsubstituted unit heterocyclic radical, list-or two-(C 1-3Alkyl) amino, single-or two-(phenyl-C 1-3Alkyl) amino, C 1-6Alkyl-S (O) m, phenyl-C 1-3-alkoxyl group or phenylamino, wherein phenyl ring is randomly used one to two halogen, C 1-6Alkyl or C 1-6Alkoxyl group replaces.
[0153] in other embodiments of formula II compound, Q is that hydrogen, thio-morpholinyl sulfoxide, thiomorpholine are for sulfone, piperazine ketone group, oxazepinyl, diazepinonyl, imidazolyl, pyridyl or morpholino.In also having other embodiments, Q is morpholino, piperazinyl, pyrimidyl or pyridyl.In some such embodiments, R 27Be-C (O) OR ,-NR ' R ', replace or unsubstituted straight or branched C 1-10C alkyl, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl or replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.For example, Q is a pyrimidyl, R 27Be-NR ' R ' or replace or unsubstituted saturated or undersaturated 3-11 unit heterocyclic radical, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.Selectively, Q is a pyridyl, R 27Be-NR ' R ', replace or unsubstituted C 1-6Saturated or undersaturated 3-11 unit's heterocyclic radical alkyl or replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.
[0154] in some embodiment of formula II compound, each R 1Be independently
C 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, dicyclohexyl or two suberyl, they are randomly by partially or completely halogenation, and randomly replace with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl; Or the analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH replace;
C 3-10Side chain or unbranched alkenyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: C 1-5Side chain or unbranched alkyl, phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, thienyl, furyl, different _ the azoles base, isothiazolyl; Aforesaid each randomly by partially or completely halogenation, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl; C 3-10Side chain or unbranched alkenyl are randomly by one or more O, N or S (O) mInterrupt;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls or bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
Cyano group, F, Cl, Br or I;
Methoxycarbonyl, ethoxycarbonyl or the third oxygen carbonyl;
Silyl contains three C 1-4Independently side chain or unbranched alkyl group, it is randomly by partially or completely halogenation;
C 2-6Side chain or unbranched alkyl-C (O), C 2-6Side chain or unbranched-S, C 2-6Side chain or unbranched-S (O), C 2-6Side chain or unbranched-S (O) 2
Randomly by partially or completely halogenated C 2-6Side chain or unbranched carbochain alkynyl, wherein one or more methylene groups are randomly by partially or completely halogenation, wherein one or more methylene groups are randomly replaced by O, NH and S (O) m, and wherein, described alkynyl group is optional to be replaced by following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino.
[0155] in other embodiments of formula II compound, each R 1Be C independently 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl.For example, each R 1Be C independently 3-10Side chain or unbranched alkyl.
[0156] in some embodiment of formula II compound, each R 3Be independently
Hydrogen or phenyl, naphthyl or heterocyclic radical, in them each is randomly by halogenation partially or completely, and randomly replaced: phenyl by 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N, carboxyl-list-or two-(C 1-5Alkyl) amino;
Fused-aryl, be selected from benzocyclobutane base, 2,3 indanyls, indenyl, dihydro naphthyl, tetralyl, benzocyclohepta base and benzocyclohepta thiazolinyl, or annelated heterocycles, be selected from cyclopenta pyridine, hexanaphthene and pyridine, pentamethylene and pyrimidine, hexanaphthene and pyrimidine, pentamethylene and pyrazine, hexanaphthene and pyrazine, pentamethylene and pyridazine, cyclopentanoindole, hexanaphthene diindyl, ring benzoglyoxaline, pentamethylene and imidazoles, hexanaphthene and imidazoles, pentamethylene thiophthene and hexanaphthene thiophthene; Wherein said fused-aryl or annelated heterocycles are randomly, replaced by 1 to 3 group independently, described group is selected from: phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2,5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, isothiazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, heteroaryloxy, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocycle or amino, the NH of assorted virtue 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-4Alkyl-C (O), C 1-5Alkylamino-S (O) 2, single-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, R 12-C 1-5Alkyl, R 13-C 1-5Alkoxyl group, R 14-C (O)-C 1-5Alkyl, R 15-C 1-5Alkyl (R 16) N;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl; The analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls, bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
C 1-4Side chain or unbranched alkyl-phenyl-C (O)-C 0-4Side chain or unbranched alkyl, C 1-4Side chain or unbranched alkyl-C (O)-C 0-4Side chain or unbranched alkyl, C 1-4Side chain or unbranched alkyl-phenyl-S (O) m-C 0-4Side chain or unbranched alkyl;
C 1-6Side chain or unbranched alkyl or C 1-60Side chain or unbranched alkoxyl group, each is randomly by partially or completely halogenation, or the optional R that uses 17Replace;
C 1-6Side chain or unbranched alkyl, it randomly uses OR 18Replace; Amino or C 1-C 5Side chain or unbranched list-or two-alkylamino, it randomly uses R 19Replace;
Ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, it is randomly by partially or completely halogenation, and randomly uses one to three: randomly by partially or completely halogenated C 1-3Alkyl group replaces, and wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-6Alkenyl;
C 2-6Side chain or unbranched carbochain alkynyl, it is randomly by partially or completely halogenation, and wherein one or more methylene groups are randomly by partially or completely halogenation, and wherein one or more methylene groups are randomly by O, NH and S (O) mOr S substitutes, and wherein, described alkynyl group is optional to be replaced with following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino; Or
Benzoyl or naphthoyl; Wherein
R 7, R 8, R 9, R 10, R 12, R 13, R 14, R 15, R 17, R 19And R 25In each be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by partially or completely halogenation;
R 11And R 16In each be hydrogen or C independently 1-4Side chain or unbranched alkyl, it is optional by partially or completely halogenation; With
R 18Be hydrogen or C independently 1-4Side chain or unbranched alkyl, optional independently with oxo or R 25Replace.
[0157] in some such embodiments of formula II compound, each R 3Be phenyl independently, naphthyl or heterocyclic radical, in them each is randomly by partially or completely halogenation, and randomly replace: phenyl with 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two (C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N or carboxyl-list-or two-(C 1-5Alkyl) amino.In other embodiments, R 3Be phenyl, pyridazinyl or pyridyl independently, each in them is randomly by partially or completely halogenation, and randomly replaces with following radicals: randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, nitro, amino or list-or two-(C 1-3Alkyl) amino; C 1-6Alkyl or C 1-6Alkoxyl group, each is optional by partially or completely halogenation, or randomly replaces with following radicals: R 17, amino, OR 18, randomly use R 19The C that replaces 1-5Single-or two-alkylamino; R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-.R for example 3Can be phenyl or tolyl.
[0158] in some embodiment of formula II compound, X ' is NR ', CR '=N or CR '=CR '.
[0159] according to a further aspect of the invention, provide following compound, comprised the representative example of the compound of formula IA, IB, IC and II:
1H-indazole-3-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
3-tert-butyl-5-phenyl-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido (methanesulfonylamino)-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-hydroxyl-3-morpholine-4-ylmethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-hydroxy-3-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-3-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-chloro-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-3-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[7-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-[5-tert-butyl-2-methoxyl group-3-(piperidines-1-carbonyl)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-2-hydroxyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenylformic acid;
N-(2-benzenesulfonyl-5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-N-[4-(2-morpholine 4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1-two ring [2.2.1] heptan-2-base-5-phenylamino-3-is right-tolyl-1, and the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones also; 3-is right-and tolyl-5-is right-tolyl amino-1, the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones also;
1-two ring [2.2.1] heptan-2-base-3-is right-and tolyl-5-is right-tolyl amino-1, the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones also;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2,2-two fluoro-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-N '-naphthalene-1-base-oxamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl amino)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanol;
1-(3-tert-butyl-phenyl)-4-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-[1,2,4] triazolidine-3, the 5-diketone;
4-(3-tert-butyl-phenyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-[1,2,4] triazolidine-3, the 5-diketone;
(E)-3-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylcarbamoyl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-methyl acrylate;
N-(5-tert-butyl-2-methoxyl group-3-{3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,5-dioxo-2,5-dihydro-pyrroles-1-yl }-phenyl)-Toluidrin (methanesulfonamide);
N-(5-tert-butyl-2-methoxyl group-3-{3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,5-dioxo-tetramethyleneimine-1-yl }-phenyl)-Toluidrin;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-[4-(2-piperidines-1-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-ethanamide;
3-tert-butyl-1-is right-tolyl-5-(3-trifluoromethyl-phenyl)-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
1-(2-morpholine-4-base-ethyl)-1H-indazole-3-carboxylic acid (5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-acid amides;
N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-2-(2,4,6-trimethylammonium-phenyl)-ethanamide;
1-phenyl-cyclopropane-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
N-[5-tert-butyl-2-(2,5-two fluoro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3-chloro-benzoyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3-methylsulfonyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
4-[(5-tert-butyl-2-is right-tolyl-2H-pyrazole-3-yl formamyl)-methyl]-piperidines-1-carboxylic acid tert-butyl ester;
N-[3-(benzenesulfonyl-carbamyl ylmethyl-amino)-5-tert-butyl-2-methoxyl group-phenyl]-2-naphthalene-1-base-2-oxo-ethanamide;
N-(3-tert-butyl-different _ azoles-5-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-ethanesulfonamido (ethanesulfonylamino)-2-methoxyl group-phenyl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-the succinamic acid methyl esters;
2-(2-benzyl-5-tert-butyl-2H-pyrazole-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-2-(3-chloro-phenyl)-2H-pyrazoles-3-carboxylic acid [4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-acid amides;
2-(3-bromo-4-methoxyl group-phenyl)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[3-fluoro-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-ethanamide;
(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-(2,2-dimethyl-propyl group)-amine;
2-(4-benzyloxy-phenyl)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-(4-sulphonamide-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-base-2-oxo-ethanamide;
5-tert-butyl-2-methoxyl group-3-(1-naphthalene-1-base-3,5-dioxo-[1,2,4] triazolidine-4-yl)-benzamide;
2-(4-bromo-naphthalene-1-yl)-N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-oxo-ethanamide;
5-tert-butyl-2-hydroxyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-(4-methoxyl group-naphthalene-1-yl)-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-methylamino--pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-{4-[2-(I-oxo-1 λ 4-thiomorpholine-4-yl)-oxyethyl group]-naphthalene-1-yl }-ethanamide;
The 5-tert-butyl-3-{2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid methyl esters;
N-[5-tert-butyl-2-(3-methylsulfonyl-phenyl)-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-{4-[2-((2R, 6R)-2,6-dimethyl-morpholine-4-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[7-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-[2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-kharophen]-benzamide;
4-tert-butyl-N-[4-(2-piperidines-1-base-oxyethyl group)-naphthalene-1-yl]-benzamide;
N-(2-ethanoyl-5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-N-cyclopropyl-3-{2-hydrazono--2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-2-methoxyl group-benzamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-hydroxyl-2-(4-methoxyl group-naphthalene-1-yl)-propionic acid amide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-phenyl-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-hydrazono--2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
2,3-dihydro-indoles-1-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
N-(3,4-dimethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-cyclohexyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(3,5-two fluoro-phenyl)-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-oxo-2-(4-pyridin-3-yl-naphthalene-1-yl)-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-diethylin-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-{4-[2-(3-oxo-[1,4] Diazesuberane (diazepan)-1-yl)-ethyl]-naphthalene-1-yl }-ethanamide;
5-tert-butyl-N-ethyl-2-methoxyl group-3-[2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-kharophen]-benzamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-oxo-2-{4-[6-(tetrahydrochysene-pyrans-4-base is amino)-pyridin-3-yl]-naphthalene-1-yl }-ethanamide;
5-tert-butyl-3-ethanesulfonamido-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-benzamide;
Between 2-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-oxo-N--tolyl-ethanamide;
N-(2,5-dimethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
Tetramethyleneimine-1-carboxylic acid (5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-acid amides;
2-(4-bromo-phenyl)-N-(5-tert-butyl-2-methoxyl group-phenyl)-ethanamide;
N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-oxo-2-{4-[2-((S)-1-phenyl-ethylamino)-pyrimidine-4-base is amino]-naphthalene-1-yl }-ethanamide;
5-tert-butyl-3-[1-(2,3-dimethyl-phenyl)-3,5-dioxo-[1,2,4] triazolidine-4-yl]-2-methoxyl group-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-naphthalene-2-base-ethanamide;
5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-methoxyl group-2-(4-methoxyl group-naphthalene-1-yl)-propionic acid amide;
5-tert-butyl-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-ylmethyl]-3-nitro-benzamide;
N-(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2,5-two fluoro-phenyl)-ethanamide;
N-(3,5-two-tert-butyl-2-methoxyl group-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N '-[1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl formamyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical (meth-(E)-yliden)]-Hydrazinecarboxamidederivatives (hydrazinecarboxamide);
N-[2-(4-amino-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
The 5-tert-butyl-3-{2-[(Z)-methoxyimino]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid acid amides;
Ethyl sulfonic acid (5-tert-butyl-2-methoxyl group-3-{3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,5-dioxo-2,5-dihydro-pyrroles-1-yl }-phenyl)-acid amides;
5-tert-butyl-N-cyclopropyl methyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
5-fluoro-1H-indazole-3-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
N-[5-tert-butyl-2-methoxyl group-3-(2-methoxyl group-kharophen)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
7-two ring [2.2.1] heptan-2-base-9-is right-and tolyl-2-is right-tolyl amino-7,9-dihydro-fast quinoline-8-ketone;
N-(5-tert-butyl-2-isopropoxy-3-methanesulfonamido-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-1-(3,4-two chloro-phenyl)-5-phenyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-[4-(2-thiomorpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
5-nitro-1H-pyrazoles-3-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
1-(2-amino-4-tert-butyl-6-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-pyridine;
N-(5-tert-butyl-2-isopropoxy-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,5-pair-trifluoromethyl-benzamide;
2-(tert-butyl-dimethyl-silicon alkoxyl group (silanyloxy))-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(4-methoxyl group-phenyl)-ethanamide;
N-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
5-tert-butyl-2-methoxyl group-3-[2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-kharophen]-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-phenyl-ethanamide;
5-tert-butyl-2-methoxyl group N-(2-methoxyl group-ethyl)-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
(E)-3-(5-tert-butyl-3-ethanesulfonamido-2-methoxyl group-phenylcarbamoyl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-methyl acrylate;
1-sec.-propyl-3-phenyl-5-phenylamino-1,3-dihydro-imidazol-be [4,5-b] pyridin-2-ones also;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(2-benzyl-5-tert-butyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
2-(5-tert-butyl-2-methoxyl group-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2,4-dimethoxy-phenyl)-ethanamide;
(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-Urethylane;
3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid diamantane-1-base acid amides;
3-tert-butyl-5-phenyl-1-(4-trifluoromethyl-phenyl)-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-methoxyl group-3-{3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,4,5-trioxy--imidazolidine-1-yl }-phenyl)-Toluidrin;
3-tert-butyl-1-(3-chloro-phenyl)-5-phenyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
5-tert-butyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid acid amides;
2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxy-n-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-{4-[2-(2,6-dimethyl-morpholine-4-yl)-ethyl]-naphthalene-1-yl }-2-oxo-ethanamide;
N-(5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid t-butyl carboxamide;
1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-3-(2, the 3-dichlorophenyl)-3 '-(urethanum)-urea;
2-(3,5-two fluoro-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid amide;
N-allyl group-5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
3-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-pyrroles-2, the 5-diketone;
2-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
3-tert-butyl-5-neighbour-tolyl-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[(E)-oximido]-2-phenyl-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-hydroxyl-2-phenyl-ethanamide;
N-(3-acetylaminohydroxyphenylarsonic acid 5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1H-indazole-3-carboxylic acid (5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-acid amides;
5-tert-butyl-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-3-nitro-benzamide;
The 5-tert-butyl-3-{2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid acid amides;
N-[3-(4-ethanoyl-piperazine-1-carbonyl)-5-tert-butyl-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-N-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-4-methyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-N-(2-phenyl-cyclopropyl)-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2,3-dimethoxy-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2-chloro-phenyl)-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-{4-[2-(4-methyl-piperazine-1-yl)-ethyl]-naphthalene-1-yl }-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-(1H-indol-3-yl)-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(4-tert-butyl-6-trifluoromethyl-pyrimidine-2-base)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-neighbour-tolyl-ethanamide;
The 5-tert-butyl-3-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid methane amide;
N-[5-tert-butyl-2-(3,5-two chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-{4-[2-((2R, 6S)-2,6-dimethyl-morpholine-4-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide;
3-tert-butyl-1,5-xenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-imidazoles-1-base-ethyl)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-5-(3-chloro-phenyl)-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-methoxyl group-3-phenyl methanesulfonamide amido-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-[4-(2-pyridin-4-yl-oxyethyl group)-naphthalene-1-yl]-ethanamide;
1-(5-tert-butyl-2-methoxyl group-phenyl)-3-(4-{2-[(pyridine-2-ylmethyl)-amino]-pyrimidine-4-base oxygen }-naphthalene-1-yl)-imidazolidine-2,4, the 5-triketone;
N-[5-tert-butyl-2-(3-chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-methoxyl group-1H-indazole-3-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
N-[5-tert-butyl-2-(6-chloro-pyridazine-3-yl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2-methoxyl group-phenyl)-ethanamide;
5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
[(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-methylsulfonyl-amino]-ethyl acetate;
N-(between 5-tert-butyl-4-methyl-2--tolyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-(2,5-two chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine 4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-[1,4] oxazepan-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1-(5-tert-butyl-2-methoxyl group-3-benzamide)-3-(4-methoxyl group-phenyl)-3 '-(urethanum)-urea;
N-[5-tert-butyl-2-(4-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-(4-methoxyl group-naphthalene-1-yl)-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-4-chloro-benzamide;
N-(2-bromo-5-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
3-sec.-propyl-5-phenyl-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
3,5-two-tert-butyl-1-is right-tolyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
5-tert-butyl-N-cyclopentyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
2-[5-tert-butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazole-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(4-methoxyl group-phenyl)-2-oxo-ethanamide;
1,3-two-tert-butyl-5-phenyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
4-(4-bromo-naphthalene-1-yl)-1-(3-tert-butyl-phenyl)-[1,2,4] triazolidine-3, the 5-diketone;
N-[5-tert-butyl-2-(morpholine-4-carbonyl)-thiene-3-yl-]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-5-(3-methoxyl group-phenyl)-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
1-tert-butyl-5-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-base is amino]-3-is right-tolyl-1, and the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones also;
2-[5-tert-butyl-2-(3-fluoro-phenyl)-2H-pyrazole-3-yl]-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
5-tert-butyl-2-is right-tolyl-2H-pyrazoles-3-carboxylic acid [4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-ylmethyl]-acid amides;
2-[5-tert-butyl-2-(3-fluoro-phenyl)-2H-pyrazole-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl }-2-oxo-ethanamide;
5-tert-butyl N-cyclopropyl methyl-2-methoxyl group-3-[2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-kharophen]-benzamide;
N-[5-tert-butyl-3-(3,3-diethyl-urea groups)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(4-fluoro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(2-benzyl-5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-[4-(2-piperazine-1-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide;
(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-the carboxylamine isopropyl esters;
1-(5-tert-butyl-2-methoxyl group-phenyl)-3-[4-(2-dimethylamino-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
4-(3-tert-butyl-1-is right-tolyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles-5-yl also)-2-methoxyl group-phenol;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(3,4-two chloro-phenyl)-ethanamide;
N-[3-(3-allyl group-urea groups)-5-tert-butyl-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-N, N-diethyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-[1,4] oxazepan-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(3-tert-butyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-N-ethyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-benzamide;
N-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(4-urea groups-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[4-(2-dimethylamino-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-oxo-2-[4-(2-piperidines-1-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
Indazole-1-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
N-[3,5-pair-(1,1-dimethyl-propyl group)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1-benzyl-3-tert-butyl-5-phenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also;
2-(5-tert-butyl-2-methoxyl group-3-nitro-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
4-{2-[4-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylamino oxalyl)-naphthalene-1-base oxygen base]-ethyl }-piperazine-1-carboxylic acid, ethyl ester;
2-hydroxy-n-(5-sec.-propyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
In 1-two ring [2.2.1] heptan-2-base-3-phenyl-5-phenylamino-1, the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones also;
N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-3-(2-dimethylamino-kharophen)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-3-{6-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-3,5-dioxo-2,5-dihydro-3H-[1,2,4] triazine-4-yl }-phenyl)-Toluidrin;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
(R)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-phenyl-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-dimethylamino-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[2-(3-amino-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
2-[5-tert-butyl-2-(3-chloro-phenyl)-2H-pyrazole-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1,5-xenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also;
N-(5-tert-butyl-[1,3,4] thiadiazoles-2-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-3-{2-hydroxyl-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-ethylamino }-2-methoxyl group-phenyl)-Toluidrin;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-4-chloro-benzamide;
N-(5-tert-butyl-2-oxyethyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-carboxylamine 2-methoxyl group-ethyl ester;
(R)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-methoxyl group-2-phenyl-ethanamide;
2-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-hydroxy-n-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
2-amino-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-naphthalene-1-base-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-acrylamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-imidazoles-1-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(4-bromo-3-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
4-(4-benzyloxy-phenyl)-1-(3-tert-butyl-phenyl)-[1,2,4] triazolidine-3, the 5-diketone;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[8-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-chloro-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid dimethylformamide;
1-(5-tert-butyl-different _ azoles-3-yl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
N-(4-chloro-3-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1-benzoyl-3-(5-tert-butyl-2-methoxyl group-phenyl)-urea;
N '-[1-(5-tert-butyl-3-ethylamino formyl radical-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(Z)-methylene radical (meth-(Z)-ylidene)]-hydrazine carboxylic acid's ethyl ester;
3-tert-butyl-5-(3-fluoro-phenyl)-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
2-[3-bromo-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-ethanamide;
2-(2-chloro-5-trifluoromethyl-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3-chloro-benzenesulfonyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-carboxylamine is right-the tolyl ester;
N-(5-tert-butyl-2-diethylin-3-methanesulfonamido-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-ethanamide;
Propane-1-sulfonic acid (5-tert-butyl-2-methoxyl group-3-{4-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-base-3,5-dioxo-[1,2,4] triazolidine-1-yl }-phenyl)-acid amides;
3-amino-5-tert-butyl-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-ylmethyl]-benzamide;
2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-N-(3-trifluoromethyl-phenyl)-ethanamide;
4-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-6-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2H-[1,2,4] triazine-3, the 5-diketone;
N-[5-tert-butyl-2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-phenyl-ethanamide;
N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-{4-[2-(2,6-dimethyl-morpholine-4-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(4-methoxyl group-naphthalene-1-yl)-ethanamide;
3-tert-butyl-1-cyclohexyl-5-phenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also;
3-tert-butyl-5-(4-fluoro-phenyl)-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-methoxyl group-3-{4-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-3,5-dioxo-[1,2,4] triazolidine-1-yl }-phenyl)-Toluidrin;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-{4-[2-(3-oxo-piperazine-1-yl)-ethyl]-naphthalene-1-yl }-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-[4-(3-pyridin-4-yl-propoxy-)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-(4-methylsulfonyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl formamyl)-2,5-dihydro-pyrroles-1-carboxylic acid tert-butyl ester;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-imidazoles-1-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3,5-dimethyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-{5-tert-butyl-3-[carbamyl ylmethyl-(propane-1-alkylsulfonyl)-amino]-2-methoxyl group-phenyl }-2-naphthalene-1-base-2-oxo-ethanamide;
N '-[1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl formamyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(Z)-methylene radical]-hydrazine carboxylic acid's ethyl ester;
5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-benzamide;
N-[5-tert-butyl-2-(3-nitro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[3-chloro-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-2-oxo-ethanamide;
N-(3-benzenesulfonyl amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid cyclohexyl amide;
N-[5-tert-butyl-2-methoxyl group-3-(2,2,2-three fluoro-ethanesulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N '-[1-(5-tert-butyl-3-formamyl-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-hydrazine carboxylic acid's ethyl ester;
5-tert-butyl-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-3-(propane-1-sulfonamido)-benzamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-hydroxyl-2-(4-methoxyl group-naphthalene-1-yl)-ethanamide;
(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-carboxylamine 2-dimethylamino-ethyl ester;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[7-fluoro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-1-(4-chloro-phenyl)-5-phenyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-ethanamide;
2-[5-tert-butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazole-3-yl]-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-ethanamide;
N-[5-(1,1-dimethyl-propyl group)-2-is right-tolyl-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(2-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[2,3-two chloro-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-2-oxo-ethanamide;
N-(3-methanesulfonamido-2-methoxyl group-5-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
4-{2-[4-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl oxamyl)-naphthalene-1-yl]-ethyl }-piperazine-1-carboxylic acid, ethyl ester;
(1-benzyl-1H-benzimidazolyl-2 radicals-yl)-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-amine;
N-(3,5-two-tert-butyl-2-hydroxyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-naphthalene-1-base-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
4-{2-[4-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl oxamyl)-naphthalene-1-base oxygen base]-ethyl }-piperazine-1-carboxylic acid, ethyl ester;
5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-(1-Methyl-1H-indole-3-yl)-2-oxo-ethanamide;
4-phenyl-piperidines-4-carboxylic acid (5-tert-butyl-2-methoxyl group-phenyl)-acid amides;
5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-benzamide;
N-[2-(4-ethanoyl-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2,3-two fluoro-phenyl)-ethanamide;
N-[5-tert-butyl-3-(carbamyl ylmethyl-methylsulfonyl-amino)-2-methoxyl group-phenyl]-2-naphthalene-1-base-2-oxo-ethanamide;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[2-methyl-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-2-oxo-ethanamide;
N-[2-(4-amino-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-phenyl carbamate;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-isobutoxy-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(4-tert-butyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3-methyl-benzoyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
The 5-tert-butyl-3-{2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid acid amides;
1-(5-tert-butyl-2-methoxyl group-phenyl)-3-[4-(2-chloro-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
(S)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-phenyl-ethanamide;
N-[5-tert-butyl-2-(2,3-dimethyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(4-nitro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-[(Z)-oximido]-N-(3-methanesulfonamido-2-methoxyl group-5-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-(morpholine-4-carbonyl)-thiene-3-yl-]-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-phenyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N '-[1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl formamyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-hydrazine carboxylic acid's ethyl ester;
N '-[1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl formamyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(Z)-methylene radical]-Hydrazinecarboxamidederivatives;
N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-N-pyridine-2-base-benzamide;
N-[5-tert-butyl-3-(3,3-dimethyl-urea groups)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-3-{2-[7-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-2-methoxyl group-benzamide;
Between N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2--tolyl-ethanamide;
1-(5-tert-butyl-2-methoxyl group-phenyl)-3-[4-(2-tetramethyleneimine-1-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-phenyl-propionic acid amide;
2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-N-quinoline-3-base-ethanamide;
1-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-(3-trifluoromethyl-benzyl)-amine;
N-[5-tert-butyl-2-methoxyl group-3-(morpholine-4-carbonyl)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-3-(3-sec.-propyl-urea groups)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-methoxyl group-2-(4-methoxyl group-naphthalene-1-yl)-ethanamide;
N-(3-amino-5-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
3-methyl isophthalic acid, 5-xenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also;
N-(5-tert-butyl-different _ azoles-3-yl)-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-2-(2-phenyl-cyclopropyl)-ethanamide;
2-{4-[2-(4-ethanoyl-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-ethanamide;
2-(1H-indol-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3-fluoro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3,4-two chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(2,5-dimethyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-2-oxo-ethanamide;
1H-indazole-3-carboxylic acid (5-tert-butyl-2-pyridine-2-base-2H-pyrazole-3-yl)-acid amides;
N-(4-chloro-3-trifluoromethyl-phenyl)-2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-ethanamide;
N-[5-(1,1-dimethyl-butyl)-2-is right-tolyl-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1H-indazole-3-carboxylic acid [5-tert-butyl-2-(4-methoxyl group-phenyl)-2H-pyrazole-3-yl]-acid amides;
1H-indazole-3-carboxylic acid [5-tert-butyl-2-(4-hydroxyl-phenyl)-2H-pyrazole-3-yl]-acid amides;
N '-[1-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-Hydrazinecarboxamidederivatives;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-N '-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-oxamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-methylamino--pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
5-tert-butyl-N-cyclopropyl-3-[2-[(E)-oximido]-2-(4-methoxyl group-naphthalene-1-yl)-kharophen]-2-methoxyl group-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-{4-[2-(2,6-dimethyl-morpholine-4-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[8-fluoro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(3-fluoro-phenyl)-ethanamide;
5-tert-butyl-N-furans-2-ylmethyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-[5-tert-butyl-2-(3-trifluoromethyl-benzoyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
1-(5-tert-butyl-different _ azoles-3-yl)-3-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-3 '-(urethanum)-urea;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-4-[2-(3-oxo-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-ethanamide;
2-{4-[2-(4-ethanoyl-piperazine-1-yl)-ethyl]-naphthalene-1-yl }-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-ethanamide;
N-(5-tert-butyl-2-phenylacetyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-{4-[2-(3-oxo-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-ethanamide;
2-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-(3-urea groups-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-methoxyl group-3-(3-oxo-piperazine-1-carbonyl)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid propionic acid amide;
5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-{4-[2-(4-methyl-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide;
N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-N-propyl group-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-(4-methoxyl group-phenyl)-ethanamide;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(3-phenoxy group-phenyl)-ethanamide;
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N-(5-sec.-propyl-2-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
7-sec.-propyl-9-phenyl-2-phenylamino-7,9-dihydro-fast quinoline-8-ketone;
(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-anginin-3-base methyl esters;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-ethylamino-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(3,5-two-tert-butyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-amino-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-naphthalene-2-base-ethanamide;
N-[5-tert-butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
2-[5-tert-butyl-2-(3,4-two fluoro-phenyl)-2H-pyrazole-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-methylamino--pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(2,3-two chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[3,5-pair-(1,1-dimethyl-propyl group)-2-hydroxyl-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-base-2-oxo-ethanamide;
4-{2-[4-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylamino oxalyl)-naphthalene-1-base oxygen base]-ethyl }-piperazine-1-carboxylic acid tert-butyl ester;
3-tert-butyl-1-naphthalene-2-base-5-phenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also;
2-xenyl-4-base-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-ethanamide;
5-tert-butyl-N-sec.-propyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-3-diethylin methyl-2-hydroxyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
6-hydroxyl-nicotinic acid 3-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenylcarbamoyl]-1H-indazole-5-base ester;
N-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(4-morpholine-4-base-pyrimidine-2--amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1,3,5-triphenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-cyclohexyl-ethanamide;
2-[5-tert-butyl-2-(2-chloro-phenyl)-2H-pyrazole-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
7-cyclohexyl methyl-9-phenyl-2-phenylamino-7,9-dihydro-fast quinoline-8-ketone;
5-tert-butyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid methyl nitrosourea;
5-tert-butyl-N-cyclopropyl methyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-benzamide;
N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N '-[1-(5-tert-butyl-3-formamyl-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(Z)-methylene radical]-hydrazine carboxylic acid's ethyl ester;
4-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-1-(2,3-dimethyl-phenyl)-[1,2,4] triazolidine-3, the 5-diketone;
N-(4-fluoro-3-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1-benzyl-3-phenyl-5-phenylamino-1,3-dihydro-imidazol-be [4,5-b] pyridin-2-ones also;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-naphthalene-2-base-ethanamide;
2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-base formamyl]-pyrroles-1-carboxylic acid tert-butyl ester;
N-(2,5-two-tert-butyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-N-((1S, 2R)-2-phenyl-cyclopropyl)-ethanamide;
2-oxo-2,3-dihydro-benzoglyoxaline-1-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
N-(2-methoxyl group-5-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[2-(4-bromo-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1-(5-tert-butyl-2-methoxyl group-phenyl)-3-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
5-tert-butyl-2-methoxyl group-N-methyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-2-methoxyl group-3-piperidines-1-ylmethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-naphthalene-1-base-2-oxo-ethanamide;
N-(2,5-two-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-carboxylamine 4-methoxyl group-phenyl ester; N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-naphthalene-1-base-2-oxo-ethanamide;
5-tert-butyl-N-ethyl-3-{2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-2-methoxyl group-benzamide;
4-{2-[4-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl oxamyl)-naphthalene-1-yl]-ethyl }-piperazine-1-carboxylic acid tert-butyl ester;
5-tert-butyl-N-ethyl-2-hydroxyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-naphthalene-1-base-ethanamide;
N-(5-tert-butyl-2-oxyethyl group-3-methanesulfonamido-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N '-[1-(5-tert-butyl-3-ethylamino formyl radical-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-Hydrazinecarboxamidederivatives;
2-{4-[2-(4-ethanoyl-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-ethanamide;
5-tert-butyl-N-ethyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenylformic acid;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-3-{2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid acid amides;
2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-N-between-tolyl-ethanamide;
5-tert-butyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid methyl esters;
N '-[1-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(Z)-methylene radical]-Hydrazinecarboxamidederivatives;
N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-sec.-propyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(2-benzoyl-5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
6-bromo-1H-indazole-3-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
5-tert-butyl-N-ethyl-3-{2-hydrazono--2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-2-methoxyl group-benzamide;
N-(5-tert-butyl-3-ethanesulfonamido-2-methoxyl group-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-thiene-3-yl-)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(4-chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N '-[1-(5-tert-butyl-3-formamyl-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-Hydrazinecarboxamidederivatives;
N-[5-tert-butyl-2-(4-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-3-{2-[7-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-N-cyclopropyl-2-methoxyl group-benzamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-{4-[2-(4-methyl-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide;
1-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-imidazolidin-2-one;
N-(5-tert-butyl-thiene-3-yl-)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
5-tert-butyl-N-cyclopropyl-3-[2-[(Z)-oximido]-2-(4-methoxyl group-naphthalene-1-yl)-kharophen]-2-methoxyl group-benzamide;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(4-morpholine-4-base-pyrimidine-2--amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[2-methoxyl group-5-(1-methyl isophthalic acid-phenyl-ethyl)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-[5-tert-butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazole-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-3-{2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid acid amides;
5-tert-butyl-N-isobutyl--2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
3-tert-butyl-1-(2,3-two chloro-phenyl)-5-phenyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(3,5-two-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
The 5-tert-butyl-3-{2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid dimethylformamide;
N-(5-tert-butyl-2-methoxyl group-3-methyl-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N '-[1-(5-tert-butyl-3-cyclopropyl formamyl-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-hydrazine carboxylic acid's ethyl ester;
N-indane-5-base-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3-chloro-4-fluoro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-3-(imidazoles-1-carbonyl)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(2,5-couple-trifluoromethyl-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(2,4-two fluoro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1H-indazole-3-carboxylic acid (5-tert-butyl-2-methoxyl group-phenyl)-acid amides;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-4-[2-(5-oxo-[1,4] Diazesuberane-1-yl)-oxyethyl group]-naphthalene-1-yl }-ethanamide;
3-tert-butyl-1-is right-tolyl-5-(4-trifluoromethyl-phenyl)-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(5-tert-butyl-3-ethanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid sec.-propyl acid amides;
N-(5-tert-butyl-[1,3,4] thiadiazoles-2-yl)-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-ethanamide;
N-[2-(3-amino-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid phenyl acid amides;
2-(5-tert-butyl-2-methyl-furans-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-neighbour-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide; N-(5-tert-butyl-2-methoxyl group-phenyl)-2-(3-methoxyl group-phenyl)-ethanamide;
5-tert-butyl-3-{2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid acid amides;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-(2,4-two chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(3-hydroxyl-propoxy-)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(3-tert-butyl-different _ azoles-5-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
1H-Indole-3-Carboxylic Acid (5-tert-butyl-2-methoxyl group-phenyl)-acid amides;
N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
7-two ring [2.2.1] heptan-2-base-9-phenyl-2-phenylamino-7,9-dihydro-fast quinoline-8-ketone;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2,4-two chloro-phenyl)-ethanamide;
5-tert-butyl-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-benzamide;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[2,3-dimethyl-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-(3-fluoro-phenyl)-ethanamide;
1-(5-tert-butyl-2-methoxyl group-3-benzamide)-3-(2, the 3-3,5-dimethylphenyl)-3 '-(urethanum)-urea;
2-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-oxo-N-(3-trifluoromethyl-phenyl)-ethanamide;
7-benzyl-9-phenyl-2-phenylamino-7,9-dihydro-fast quinoline-8-ketone;
2,5-dihydro-1H-pyrroles-2-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-{4-[2-(5-oxo-[1,4] Diazesuberane-1-yl)-oxyethyl group]-naphthalene-1-yl }-ethanamide;
N-[5-tert-butyl-2-(3-cyano group-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-3-phenylacetylamino-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(2-chloro-5-trifluoromethyl-phenyl)-N-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
1-(5-tert-butyl-2-methoxyl group-phenyl)-3-[4-(2-piperidines-1-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
2-(2-benzyl-5-tert-butyl-2H-pyrazole-3-yl)-2-hydroxy-n-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
5-tert-butyl-3-{2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid acid amides;
N '-[l-(5-tert-butyl-3-ethylamino formyl radical-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-hydrazine carboxylic acid's ethyl ester;
N-(3-methanesulfonamido-5-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-hydroxyl-3-piperidines-1-ylmethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(1-Methyl-1H-indole-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-oxo-2-{4-[2-((S)-1-phenyl-ethylamino)-pyrimidine-4-base is amino]-naphthalene-1-yl }-ethanamide;
N-[5-tert-butyl-2-(4-cyano group-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N '-[1-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-hydrazine carboxylic acid's ethyl ester;
N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-isobutyramide;
N-[5-tert-butyl-2-(4-methyl-benzoyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(2-chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3-chloro-4-methyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(4-bromo-phenyl)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-ethanamide;
2-(5-tert-butyl-2-methyl-furans-3-yl)-N-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide;
4-(4-{4-[2-(5-tert-butyl-2-methyl-furans-3-yl)-2-oxo-kharophen]-naphthalene-1-base is amino }-phenoxy group)-the pyridine-2-carboxylic acids methyl nitrosourea;
N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-{4-[6-(tetrahydrochysene-pyrans-4-base is amino)-pyridin-3-yl]-naphthalene-1-yl }-ethanamide;
3-[2-(4-bromo-naphthalene-1-yl)-2-oxo-kharophen]-5-tert-butyl-N-cyclopropyl-2-methoxyl group-benzamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(6-morpholine-4-base-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-(4-pyridin-3-yl-naphthalene-1-yl)-ethanamide;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-oxo-2-(4-pyridin-3-yl-naphthalene-1-yl)-ethanamide;
2-(4-chloro-3-trifluoromethyl-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide; Or
4-{4-[2-(4-chloro-3-trifluoromethyl-phenyl)-2-oxo-kharophen]-phenoxy group }-the pyridine-2-carboxylic acids methane amide.
[0160] also have other aspect, the invention provides pharmaceutical composition, this pharmaceutical composition comprises compound (for example compound of formula IA, IB, IC or II) and the pharmaceutically acceptable carrier of describing herein.
[0161] the other aspect according to the present invention provides the method for preparing cytokine inhibitor of the present invention.For example, the method for the compound of preparation formula IA comprises: with G-NH 2React in the presence of coupling agent and alkali with Q-L-Ar-X-OH, or with G-NH 2With Q-L-Ar-X-X " reaction in the presence of alkali, the compound of production IA, wherein, variable G, Q, L institute's definition in any compound of describing herein, X is C (O) or C (S), X " be activation partly (activating moiety).The compound of formula IB can use G-X-X " and Q-L-Ar-NH 2, by similar method preparation.
[0162] also has aspect another of the present invention, the method for the compound---wherein X ' is NH---of preparation formula II is provided, comprise with suitable organic amine (organoamine) and heat G (NO)-NH-CH 2-Ar-L-Q, with production II compound, wherein G, Ar, L and Q are suc as formula defining among the II.
[0163] in another aspect of the present invention, the formula III compound is provided, this compound is suitable for preparing compound of the present invention, and is all suc as formula the IB compound.
In the formula III compound, in the 1-position, 3-position or on two, the pyrazoles part is by R 1, R 2Or R 3In one or more replacements.
X " be OR xOr activation part;
R xBe H, replacement or unsubstituted C 1-4Alkyl or that replace or unsubstituted aralkyl;
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-OR ,-SiR 3,-NR ' R ' ,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2With
Each R 3Be H, replacement or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace; With
R, R ', R ", R 20, R 21, R 23, R 24, R 26With m in any compound described herein definition.
[0164] on the other hand, the invention provides prevention or treatment method by cytokine mediated disease, this method comprises the compound described herein of significant quantity on the patient treatment that needs this kind treatment, for example compound of formula IA, IB, IC and/or II.The disease of this kind cytokine-mediation comprises: rheumatoid arthritis, osteoarthritis, Crohn disease, ulcerative colitis, arthritic psoriasis, traumatic arthritis, rubella arthritis, inflammatory bowel, multiple sclerosis, psoriasis, graft versus host disease (GVH disease), systemic lupus erythematous, toxic shock syndrome, irritable bowel syndrome, muscle deterioration, allograft rejection, pancreatitis, insulitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, leprosy, acute synovitis, rely special syndrome, urarthritis, Behcet ' s disease, spondylitis, endometriosis, non--joint property inflammatory conditions (non-articular inflammatory conditions) is such as intervertebral disk syndromes state (intervertbral disk syndrome conditions), bursitis, tendinitis, tenosynovitis or fibromyalgia syndrome; With acute or chronic pain, include but not limited to neuropathic pain, neuropathy, polyneuropathy, diabetes-relevant polyneuropathy, wound, migraine, tonus pain and burst headache (cluster headache), horton's disease, varicose ulcer, neurodynia, flesh-skeleton pain, bone-traumatic pain (osteo-traumatic pain), fracture, nutritional trouble, arthritis vertebralis, fibromyalgia disease, phantom limb pain, have a back ache, vertebra is painful, post-operative pain, the sciatica of prolapse of intervertebral disc-bring out, cancer-ache related, vascular pain, visceral pain, the pain that childbirth or HIV-are relevant.Other cytokine mediated diseases are apoplexy, chronic heart failure, toxaemia, reperfusion injury, ischemia-reperfusion, myocardial ischemia, restenosis, thrombosis, blood vessel generation, coronary heart disease, coronary artery disease, acute coronary syndrome, aortic arch syndrome, in heart failure such as cardiac failure, myocardosis, myocarditis, vasculitis, vascular restenosis, valvulopathy or coronary artery bypass (coronary artery bypass); Hypercholesterolemia, with coagulation of blood or fibrinolysis diseases associated or state, such as for example acute phlebothrombosis disease, pulmonary infarction, the thrombosis of gestation time, the hemorrhagic gangrene of skin, acute or chronic disseminated intravascular coagulation (DIC), form by condensing of causing of operation, CBR or extended immobilization (long bed rest or long periods of immobilization), phlebothrombosis disease, explosive meningococcemia, acute thrombotic apoplexy, acute coronary occlusion, acute periphery artery occlusion, Massive pulmonary embolism, the axillary vein thrombosis, bulk femoral vein thrombosis, occlusive artery or venous cannula, myocardosis, the venous occlusive disease of liver, ypotension, the cardiac output that reduces, the vascular resistance that reduces, pulmonary hypertension, the lung compliance that reduces, leukopenia or thrombocytopenia; Or arteriosclerosis.The disease that also has other is looking infringement (laser induced optic damage) or performing the operation or damage-inductive proliferative vitreoretinopathy of anaphylaxis conjunctivitis, uveitis, glaucoma, optic neuritis, retinal ischemia, diabetic retinopathy, induced with laser.Cytokine mediated disease also comprises: allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, pulmonary emphysema, bronchitis, Polyblennia (mucus hypersecretion), silicosis, SARS infect and respiratory inflammation.Also comprise psoriasis, eczema, the irritated dermatitis of heredity, contact dermatitis or acne.Other cytokine mediated diseases are Ge-Ba two syndromes, the Ba Jinsen disease, Huntington Chorea, Alzheimer, amyotrophic lateral sclerosis, multiple sclerosis and other demyelinating diseases, viral and bacterial meningitis, the CNS wound, Spinal injury, epilepsy, spasm, olivopontocerebellar atrophy, aids dementia complex, MERRF and MELAS syndromes, leber disease, wernicke encephalopathy, the special syndrome of thunder, homocystinuria, hyper prolinemia, hyperhomocysteinemiainjury, non-ketone hyperglycinemia, hydroxyl fourth amino acid uria, sulfite oxidase deficiency, system ensemble disease (combined systems disease), lead encephalopathy, Tourette's syndrome, hepatogenic encephalopathy, drug habit, resistance, drug dependence, depressed, anxiety disorder and schizophrenia, aneurysma or epilepsy.In another aspect of this invention, cytokine mediated disease comprises bone-resorbing disease (boneresorption diseases), osteopetrosis, osteoporosis or osteoarthritis.Also comprise the emaciation (cachexia secondary to infection or malignancy) of diabetes, general emaciation, infection or pernicious secondary, emaciation, obesity, apositia or the disease of eating too much at one meal of acquired immune deficiency syndrome (AIDS) (AIDS) secondary.In addition, cytokine mediated disease can be pyemia, HIV, HCV, malaria, infective arthritis, leishmaniasis, Lyme disease, cancer, includes, but are not limited to mammary cancer, colorectal carcinoma, lung cancer, prostate cancer, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non--He Jiejin lymphomas or follicular lymphoma, Castleman ' s disease or resistance.
[0165] on the other hand, the invention provides the method for the disease of treatment neutrophilic granulocyte mediation, this method comprises the compound described herein of significant quantity on the patient treatment that needs this kind treatment, comprise formula IA, IB, the compound of IC and/or II, the disease of wherein said neutrophilic granulocyte mediation is: bronchial asthma, rhinitis, influenza, apoplexy, myocardial infarction, thermal damage, adult respiratory distress syndrome (ARDS), the multiple organ damage of wound secondary, acute glomerulonephritis, be attended by the tetter (dermatoses withacute inflammatory components) of acute inflammation composition, acute purulent meningitis, hemodialysis, leucopheresis, relevant syndromes (granulocyte transfusion associated syndromes) of granulocyte blood transfusion or necrotizing enterocolitis.
[0166] combined therapy with cytokine inhibitor provides useful result of treatment, particularly add up or super-additive effect (over-additive effect), or the side effect of treatment reduces comprehensively.The result of treatment that this kind is useful is gratifying in the cytokine mediated disease that treatment is described herein, particularly in treatment rheumatoid arthritis, Crohn disease and psoriasis.Therefore, another aspect of the present invention provides the method for the treatment of cytokine mediated disease, comprise giving one or more normally a kind of active ingredient described herein (being called A after this) and one or more, normally a kind of cytokine inhibitor of the present invention.When comparing with the mode of routine, the individualized compound that is used for monotherapy and A and cytokine inhibitor, drug regimen of the present invention add up or super-additive effect provides the effect that dosage reduces, side effect reduces and/or prolongs at interval.When two kinds of active substances in the single-activity material formula during administration simultaneously, and, all observe above-mentioned effect when in the prescription that they are separating in succession during administration.At A is under the situation injectable, particularly biological reagent, also can observe other the benefit that adds that cytokine inhibitor produced.For example, the cost of following interval and/or dosage to reduce reduces.
[0167] many active ingredient A are considered in the combination of the present invention.For example, can use NSAID (non-steroidal anti-inflammatory drug) (NSAIDs), this medicine is widely used in treating inflammation, pain and heating.This type of NSAIDS comprises acamol, Asprin, Ibuprofen BP/EP, choline salicylate magnesium (choline magnesium salicylate), choline salicylate, diclofenac, diflunisal, R-ETODOLAC, fenoprofen calcium, flurbiprofen, indomethacin, Ketoprofen, carprofen, indoprofen, ketorolac tromethamine, magnesium salicylate, that sour sodium of first chlorophenol, mefenamic acid, _ promazine, piroxicam, sodium salicylate, sulindac, Tolmetin, meloxicam, rofecoxib (rofecoxib), Sai Lekao former times (celecoxib), Ai Tuolikao former times (etoricoxib), valdecoxib (valdecoxib), nabumetone, naproxen, lornoxicam (lomoxicam), nimesulide, indoprofen, auspicious fragrant ancestor (remifenzone), salsalate, tiaprofenic acid, Flosulide and analogue.
[0168] angiogenesis inhibitor can serve as A, such as compound, taxol, pentoxifylline (pentoxyfylline) and the Thalidomide at VEGF.
[0169] biological reagent be appreciated that refer to known in the art any natural or artificial/synthetic biomolecules or its fragment, such as antibody, protein, fused protein, acceptor, nucleic acid, lipoid, carbohydrate and analogue.Therefore, active ingredient A comprises biological reagent, such as the sharp former times monoclonal antibody (infliximab) of etanercept, English, A Le bill anti-(alefacept), adalimumab (adalimumab), pearl monoclonal antibody (efalizumab), Kineret (anakinra), IL-1RA, alpha-interferon, interferon beta 1-B, CTLA-4 and at other antibody or the receptor structure thing of TNF-α, IL1-6, LFA-1 and C5 in accordance with the law.
[0170] being also included within the active ingredient A scope of the present invention is steroid, such as glucocorticosteroid and Vitamin D3 500,000 I.U/GM and their analogue (vitamins D 3), use (latter is mainly used in psoriasis) separately or unite use.Steroid comprise budesonide, dexamethasone, fluocinonide, hydrocortisone, Betamethasone Valerate, halogen doubly his rope (halobetasol) (ulobetasol), methylprednisolone, prednisolone, clobetasone, fluorine can the spy, fluocinolone acetonide, fluticasone, Triamcinolone Acetonide, Mometasone and diflucortolone.Vitamins D 3Derivative calcipotriol, Tacalcitol, Ma Shaka alcohol (maxacalcitol) and tacalitol, solid calcium sexual hormoue, 1 α, 2,5-dihydroxy vitamin d3 and Rat parathyroid hormone 1-34-relevant peptide are arranged.
[0171] immunoregulation druge of many types, immunosuppressive drug or cytostatic medicament can be used in combination with cytokine inhibitor.Exemplary reagent comprises Oxychloroquine, Beracilline, sulfasalazine, auranofin, disodium aurothiomalate, Minocycline HCl, dapsone, Chlorambucil, purinethol, tacrolimus, sirolimus, pimecrolimus, mycophenolic acid morpholine ethyl ester (mycophenolate mofetil), ciclosporin, leflunomide, methotrexate, azathioprine, endoxan, macrolide, ascosin (ascomycin), hydroxyurea, 6-Tioguanine (Orfanos C E., 1999, Cutis 64 (5): 347-53); The A Le bill is anti-, leflunomide, English monoclonal antibody of sharp former times, etanercept, pearl monoclonal antibody, anti--CD4, anti--CD25, peptide T, LFA3TIP, ICAM-1 ISIS 2302, DAB389, CTLA-4Ig, anti--CD80, for example IDEC-114 or ABX-IL8, DAB-IL-2, IL-10, anti--TAC, Bali Xidan anti-(basiliximab) and daclizumab (daclizumab) in accordance with the law.In addition, reagent or the therapeutical agent that acts on other targets or immune-mediated product also is suitable as active ingredient A.These comprise for example inhibitor of protein tyrosine kinase (PTKs), select plain inhibitor and be widely used in the psoriasis treatment agent such as EGF-R ELISA (EGFR), E-, such as anthraline, coal tar, light treatment, comprise UV-B (UVB) or psoralene ultraviolet ray (psoralen ultraviolet) A (PUVA), photodynamic therapy (photodynamictherapy) and laser therapy (laser therapy).
[0172] the retinoids therapy also can be used as active ingredient A.Therefore, for example, bexarotene (bexarotene), Etretin, etretinate and Ta Zhaluoting (tazarotene) and hydroxyurea, 6-Tioguanine and light treatment be suitable active ingredient (Orfanos C E., 1999, Cutis 64 (5): 347-53; Also referring to Saurat J H., 1999, J.Am.Acad.Derm.41 (3Pt 2): S2-6).
[0173] be applicable to that active ingredient A of the present invention also comprises micromolecular inhibitor, this micromolecular inhibitor is at the enzyme that participates in signal transduction pathway, or at cell adhesion molecule such as LFA-1 or ICAM-1.
[0174] on the other hand, provide the said medicine combination, this drug regimen comprises A and cytokine inhibitor, and its amount normally treatment goes up effective dosage, as having the active pharmaceutical composition of anti-cytokine.In addition, comprise the combination of A and cytokine inhibitor, can be used for pharmaceutical compositions, be used for the treatment of and/or prevent cytokine mediated disease or state.Pharmaceutical preparation---contain active substance, and one or more comprises compounds combination of A and cytokine inhibitor---and also comprises its pharmaceutically acceptable derivates, and can be randomly and conventional excipients and/or carrier combinations.
[0175] for therepic use, the drug regimen of A and cytokine inhibitor of the present invention can with any usual manner administration, comprise any approach of describing herein with any regular dosage form.Therefore, route of administration include, but are not limited in intravenously, intramuscular, subcutaneous, the synovia, by inculcate, the hypogloeeis, through skin, mouth, part with pass through inhalation.Common administering mode is mouth, part or intravenous administration.
[0176] drug regimen of A and cytokine inhibitor of the present invention can independent administration, or with other active ingredients or adjuvant form administration with combination formula (combination formulation), these other active ingredients or adjuvant can strengthen the stability of inhibitor, conveniently contain the administration of their pharmaceutical composition, the solvability that increase is provided or dispersiveness, increase suppresses active, assisting therapy is provided, or confers similar advantages is provided.This kind combined therapy usually utilizes the conventional treatment agent than low dosage, and avoids the possible toxicity and the disadvantageous side effect that produce when those reagent is used for monotherapy.Therefore, the drug regimen of A and cytokine inhibitor can be combined into the single medicine composition with method physically with conventional treatment agent or other adjuvants.Active ingredient A and/or cytokine inhibitor can be used as salt, solvate, tautomer and/or prodrug and as the mixture of single stereoisomers or steric isomer, comprise the racemize acid esters and are used in combination.
[0177] according to the present invention, two kinds of active substances, the ratio that A and cytokine inhibitor can be used in combination is variable.Active substance A and cytostatics randomly exist with their solvate or the form of hydrate.According to choosing of compd A and cytokine inhibitor, the weight ratio that can use within the scope of the present invention is according to the variation of tiring of the different molecular weight of all cpds and their difference.The given activity component and the cytokine inhibitor of determining to depend on A of weight ratio, and in the art technology scope.
[0178] in psoriasis, known combined therapy is effectively, and as keeping rotation [radiation] treatment that psoriasis is alleviated, if perhaps Chang Gui general product refractory is used as combined therapy.Most combination has the different modes of action, perhaps for effect is provided, perhaps in order to reduce side effect by reducing dosage.Referring to Van de Kerkhof, Clinics in Dermatology P.1997,15:831-834, the document shows as the steroid of the locality of general medicament or the interest of vitamins D.Two combinations of extensively being approved comprise that UV-B (UVB) or ultraviolet light,long wave add psoralene (PUVA); Methotrexate, or the combination of S-Neoral and retinoids.
[0179] the psoriasic typical combination of treatment is cytokine inhibitor compound and immunotherapy medicaments, and immunotherapy medicaments comprises S-Neoral, pimecrolimus, tacrolimus, ascosin, anti--CD4, anti--CD25, peptide T, LFA3TIP, DAB 389, CTLA-4Ig, E-select plain inhibitor, A Faxipu, English monoclonal antibody of sharp former times, etanercept, pearl monoclonal antibody in accordance with the law, be disclosed in Griffiths with those, Christopher E.M., 1998HospitalMedicine, medicine among Vol 59 No 7, with and tangible variant.Treating psoriasic another typical combination is cytokine inhibitor compound and methotrexate (MTX).Because MTX has the cause of good tolerability in a short time, and if alleviate and to be maintained and to have acceptable cause when having good quality of life, combination is expected to have effect.Treating psoriasic another typical combination is cytokine inhibitor compound and ciclosporin, particularly because ciclosporin effectively brings out the cause that psoriasis is alleviated.Another embodiment of the present invention comprises administration in the following sequence: induce with cytokine inhibitor and ciclosporin, after ciclosporin dosage reduces and stops, continuing to give cytokine inhibitor.Treating psoriasic another typical combination is cytokine inhibitor compound and retinoids combination.Retinoids provides minimum effect, and the CytP450 with possibility interacts and teratogenecity danger, and this will alleviate by carrying out continued treatment with cytokine inhibitor.Also have another to treat the combination that psoriasic typical combination is the active ingredient A of cytokine inhibitor compound and locality, this A is selected from glucocorticosteroid, vitamin D-derivatives, locality retinoids and dithiane alcohol (dithianol).It is cytokine inhibitor compound and vitamin D-derivatives that the treatment psoriasis comparatively typically makes up, and most typical is calcipotriol or Tacalcitol.Another the typical combination of treatment psoriasis is the combination of cytokine inhibitor compound and macrolide, most typical be partly with the combination of ascosin analogue, more be typically and combination that can be oral such as pimecrolimus.Treating psoriasic another typical combination is the combination of cytokine inhibitor compound and cell adhesion molecule inhibitor such as anti-LFA3, anti-LFA1.This comprises by recombinant fusion protein such as A Faxipu, anti-LFA3-IgCl, or by anti--CD11 monoclonal antibody, the adhesion molecule retardance (blockage) carried out of pearl monoclonal antibody and their conspicuous variants in accordance with the law.As if the cell adhesion molecule inhibitor provides acceptable response speed, and has limited problem of resistance.Can avoid the shortcoming of their injectable forms with the combination of cytokine inhibitor, the CAM inhibitor is intermittently used simultaneously.Another embodiment of the present invention comprises administration in the following sequence: induce with cytokine inhibitor and CAM inhibitor, keep treatment with cytokine inhibitor separately then, if significantly recurrence is treated once more with the CAM inhibitor.
[0180] psoriasic another typical combination of treatment is cytokine inhibitor compound and another anti-TNF-alpha active composition.Typical embodiment is such, and wherein other anti-TNF-alpha active composition is selected from English monoclonal antibody of sharp former times or etanercept, normally English monoclonal antibody of sharp former times.English monoclonal antibody of sharp former times is considered to have higher speed of reaction for inducing psoriasis to alleviate, and it shows recently by long term maintenance.Within the scope of the present invention be to use locality or general TNF α antisense inhibitor, such as ICAM-1 ISIS 2302 and cytokine inhibitor combination of compounds.Treating psoriasic another typical combination is cytokine inhibitor compound and anti--CD4, anti-CD80 (EDC-114 or ABX-IL8), DAB IL-2, DAB 389IL-2, CTLA4-Ig, IL10, IL2 acceptor inhibitor such as daclizumab (anti--TAC), the Bali Xidan is anti-.(referring to Tutrone, W.D., 2001, Biologic Therapy forPsoriasis vol 68; Tutrone, W.D., 2001, Biologic Therapy for Psoriasis vol 68; Ben-Bassat, H.2001 Current Opinion in Investigational Drugs Vol 2 No 11; Salim, A.etal, 2001 Current Opinion in Investigational Drugs Vol, 2 No 11).
[0181] any aforesaid combination in the scope of the invention can be by animal model test known in the art.In this, can be with reference to Schon, Michael is Animal models of Psoriasis--What can we learnfrom them P.1999, The Society for Investigative Dermatology--Reviews, Vol 112.No.4,405-410.
[0182] in rheumatoid arthritis, the combination of immunosuppressor or immunomodulator is long and has obtained the treatment example confirmed.Combined partner capable is from various treatment entities.Their evaluation or based on rule of thumb data, these data obtain the progressivity knowledge support of basic mechanism, perhaps based on the clear and definite mode of action.These reagent are commonly called Disease Modifying Antirheumatic Drugs (DMARDs) or Slow ActingAntirheumatic Drugs (SAARDs).Except the combination of listing below, the combination that cytokine inhibitor and one or more are classified as DMARD/SAARD or NSAID and/or reflunomide is considered in the present invention.
[0183] typical combination of treatment rheumatoid arthritis is one or more combinations in cytokine inhibitor compound and following immunosuppressor, immunomodulator or the cytostatic medicament, such as Oxychloroquine, Beracilline, sulfasalazine, auranofin, disodium aurothiomalate, Minocycline HCl, dapsone, Chlorambucil, purinethol, tacrolimus, sirolimus, mycophenolic acid morpholine ethyl ester, ciclosporin, leflunomide, methotrexate, azathioprine and endoxan.Another typical combination of treatment rheumatoid arthritis is the combination of cytokine inhibitor compound and angiogenesis inhibitor, and angiogenesis inhibitor is such as compound, taxol, pentoxifylline, Thalidomide, interferon beta-1B and alpha-interferon at VEGF.Another typical combination in addition of treatment rheumatoid arthritis is cytokine inhibitor compound and cell adhension inhibitors, such as LFA-1 or the combination of ICAM-1 inhibitor.
[0184] more typically make up be the cytokine inhibitor compound and following substances makes up to the treatment rheumatoid arthritis: anti-TNF antibody or TNF-receptor antagonist such as etanercept, English profit former times monoclonal antibody, adalimumab (D2E7) or biological reagent be such as CTLA-4, or at the biological reagent of target such as CD-4, LFA-1, IL-6, ICAM-1 and C5.In another embodiment, cytokine inhibitor and English monoclonal antibody of sharp former times and methotrexate combination.Another typical combination of treatment rheumatoid arthritis is that cytokine inhibitor compound and IL-1 receptor antagonist make up such as Kineret.It is cytokine inhibitor compound and NSAID (non-steroidal anti-inflammatory drug) (NSAIDs) combination that the treatment rheumatoid arthritis also has another typical combination, and NSAID (non-steroidal anti-inflammatory drug) comprises acamol, Asprin, Ibuprofen BP/EP, choline salicylate magnesium, choline salicylate, diclofenac, diflunisal, R-ETODOLAC, fenoprofen calcium, flurbiprofen, indomethacin, Ketoprofen, carprofen, indoprofen, ketorolac tromethamine, magnesium salicylate, that sour sodium of first chlorophenol, mefenamic acid, _ promazine, piroxicam, sodium salicylate, sulindac, Tolmetin, meloxicam, rofecoxib, Sai Lekao former times, Ai Tuolikao former times, valdecoxib, nabumetone, naproxen, lornoxicam, nimesulide, indoprofen, auspicious fragrant ancestor, salsalate, tiaprofenic acid, Flosulide and analogue.The typical combination of another of treatment rheumatoid arthritis is cytokine inhibitor compound and glucocorticosteroid, can special make up such as Betamethasone Valerate, dexamethasone, methylprednisolone, prednisolone and ground fluorine.
[0185] any aforesaid combination in the scope of the invention can test with animal model known in the art (referring to Wooley, P.H.1998, Animal models of arthritis, in Klippel J.H., Dieppe, P.A., (eds.) Rheumatology, second edition, 5.8.1-5.8.6.Mosby, London, Philadelphia, St.Louis, Sydney, Tokio).
[0186] in Crohn disease, with medicine in the following group of cytokine inhibitor combination can be effective: the pine of steroid such as cloth, 5-ASA medicine such as U.S. salad are bright, immunosuppressor, biological reagent and adhesion molecule inhibitor.The typical combination of treatment Crohn disease is one or more in cytokine inhibitor compound and the following substances: steroid comprises those materials, 5-ASA, methotrexate and the azathioprine that all are listed in this article.The typical combination of another of treatment Crohn disease is that cytokine inhibitor compound and IL-1 receptor antagonist make up such as Kineret.Another typical combination that also has of treatment Crohn disease is cytokine inhibitor compound and following substances combination: anti-TNF antibody or TNF-receptor antagonist, such as etanercept, English monoclonal antibody of sharp former times, adalimumab (D2E7), or biological reagent is such as CTLA-4, or at the biological reagent of target such as CD-4, LFA-1, IL-6, ICAM-1 and C5.In another embodiment, cytokine inhibitor and English monoclonal antibody of sharp former times and methotrexate combination.More typically, cytokine inhibitor and English monoclonal antibody of sharp former times combination.Another typical combination of treatment Crohn disease is cytokine inhibitor compound and IL-10, ISIS 2302 (anti-ICAM 1) or Antegren (VCAM receptor antagonist) combination.
Have been found that during people's toxaemia that [0187] cytokine inhibitor has urging the inhibition effect that blood coagulation and proplasmin (profibrinolytic) are replied.The present invention therefore provide at the disease of coagulation of blood or plasmin decorrelation and the resist coagulation and the fibrinolytic therapy of state, this method comprises the patient's cytokine inhibitor of significant quantity pharmaceutically that needs them.If the patient in the danger is had prophylactic action, or the patient who suffers from these reaction path complications associated with arterial system is had therapeutic effect, this administration effect can be useful so.
[0188] also within the scope of the present invention be the combined therapy of cytokine inhibitor and one or more other resist coagulation or fibrinolytic agent.These materials comprise that recombinant tissue plasminogen activator (rtPA), streptokinase (SK), urokinase (UK), proUK, heparin, enoxaparin (enoxoparin), its heparin of moral (dalteparin), tonka bean camphor anti-coagulant, Asprin, dipyrimidamole, aggrennox, plug chlorine are fixed, clopidogrel (Plavix), ReoPro, RheoPro, according to drenching (integrilin), aggrestath and analogue for lattice.Concrete dosage, prescription and the method for administration alone or in combination are within the scope of the invention.
Invent auspicious stating
[0189] Xia Mian term runs through and applies to be defined as follows herein.
[0190] usually, when mentioning some element such as hydrogen or H, be intended to comprise all isotropic substances of the sort of element.For example, if the R group is defined as comprising hydrogen or H, it also comprises deuterium and tritium.Therefore, isotope-labeled compound within the scope of the invention.
[0191] term " unsubstituted alkyl (unsubstituted alkyl) " refers to not contain heteroatomic alkyl group.Therefore, this word comprises straight chained alkyl group such as methyl, ethyl, propyl group, butyl, amyl group, hexyl, heptyl, octyl group, nonyl, decyl, undecyl, dodecyl and similar group.This word also comprises the branched chain isomer of straight chained alkyl group, includes but not limited to the following group that provides in the mode of example :-CH (CH 3) 2,-CH (CH 3) (CH 2CH 3) ,-CH (CH 2CH 3) 2,-C (CH 3) 3,-C (CH 2CH 3) 3,-CH 2CH (CH 3) 2,-CH 2CH (CH 3) (CH 2CH 3) ,-CH 2CH (CH 2CH 3) 2,-CH 2C (CH 3) 3,-CH 2C (CH 2CH 3) 3,-CH (CH 3) CH (CH 3) (CH 2CH 3) ,-CH 2CH 2CH (CH 3) 2,-CH 2CH 2CH (CH 3) (CH 2CH 3) ,-CH 2CH 2CH (CH 2CH 3) 2,-CH 2CH 2C (CH 3) 3,-CH 2CH 2C (CH 2CH 3) 3,-CH (CH 3) CH 2CH (CH 3) 2,-CH (CH 3) CH (CH 3) CH (CH 3) 2,-CH (CH 2CH 3) CH (CH 3) CH (CH 3) (CH 2CH 3) and other groups.This word also comprises group of naphthene base such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group and this type of ring that replaces with the straight chain of above-mentioned definition and branched alkyl group.This word also comprises multi-ring alkyl group such as, but this type of ring that is not limited to adamantyl (adamantyl), bornyl (norbornyl) and dicyclo [2.2.2] octyl group and replaces with the straight chain of above-mentioned definition and branched alkyl group.Therefore, word unsubstituted alkyl group comprises primary alkyl group, secondary alkyl group and tertiary alkyl groups.The unsubstituted alkyl group can be incorporated on one or more carbon atoms, Sauerstoffatom, nitrogen-atoms and/or the sulphur atom in the parent compound.Typical unsubstituted alkyl group comprises straight chain and branched alkyl group and the group of naphthene base with 1 to 20 carbon atom, more typically, has this type of group of 1 to 10 carbon atom.More typical this type of group also is known unsubstituted low-grade alkyl group, has 1 to 5 carbon atom.Typically, the unsubstituted alkyl group comprises straight chain and the branched alkyl group with 1 to 3 carbon atom, comprise methyl, ethyl, propyl group and-CH (CH 3) 2
[0192] word " alkyl of replacement (substituted alkyl) " is meant unsubstituted alkyl group defined above, wherein the one or more keys with carbon or hydrogen evolution are substituted by the key with non--hydrogen and non--carbon atom formation, and non--hydrogen and non--carbon atom are such as still being not limited to: halogen atom such as F, Cl, Br and I; Sauerstoffatom in various groups such as oh group, alkoxy base, aryloxy and the ester group; Sulphur atom in various groups such as thiol group, alkyl and aromatic yl sulfide group, alkylsulfonyl group, sulfinyl group and sulfoxide radicals; Nitrogen-atoms in various groups such as amine, acid amides, alkylamine, dialkylamine, arylamines, alkylarylamine (alkylarylamines), diarylamine (diarylamines), N-oxide compound, imino-(imide) and enamine; Siliciumatom in various groups such as trialkylsilkl (trialkylsilyl) group, di alkylaryl silyl-group (dialkylarylsilyl), alkyl diaryl silyl (alkyldiarylsilyl) group, diarye silyl (triarylsilyl) group; And other heteroatomss in various other groups.The alkyl group that replaces also comprises such group, and therein, the one or more keys with carbon or hydrogen atom form are replaced by the key with other heteroatomss formation, and wherein heteroatoms is such as the oxygen in group such as carbonyl, carboxyl and ester; Nitrogen-atoms in group such as imines, oxime, hydrazone and nitrile.In addition, the preferred alkyl group that replaces comprises such alkyl group, and one or more keys that form with carbon or hydrogen atom are wherein substituted by the one or more keys that form with fluorine atom.An example of the alkyl group that replaces is trifluoromethyl group and other alkyl groups that contain trifluoromethyl group.Other alkyl groups comprise those groups, substitute with carbon atom or hydrogen atom one or more keys quilts that form and the key that Sauerstoffatom forms therein, and the alkyl group of Qu Daiing contains hydroxyl, alkoxyl group, aryloxy group or heterocyclic oxy group group like this.Also have other alkyl group to comprise alkyl group: amine, alkylamine, dialkylamine, arylamines, (alkyl) (aryl) amine, diarylamine, heterocyclic radical amine, (alkyl) (heterocyclic radical) amine, (aryl) (heterocyclic radical) amine or two heterocyclic radical amine groups with following groups.
[0193] term " alkylidene group (alkylene) " refers to saturated, divalence straight or branched hydrocarbyl group, has about 2 usually to about 20 carbon atoms, and " alkylidene group of replacement " refers to also have one or more above-mentioned substituent alkylidene groups.
[0194] word ' unsubstituted aryl (unsubstituted aryl) " refers to not contain heteroatomic aromatic yl group.Therefore, in the mode of example, this word includes but not limited to group such as phenyl, xenyl, anthracene nucleus base (anthracenyl), the naphthyl by example.Although word " unsubstituting aromatic yl " comprises the group that contains condensed ring such as naphthalene, it does not comprise the aromatic yl group with other groups, described other groups are such as the alkyl or the halogen group that are attached to one of them ring members (ringmember), this is because aromatic yl group such as tolyl is considered to the aromatic yl group that replaces in this article, and is as described below.Typical unsubstituting aromatic yl group is a phenyl.Yet unsubstituted aromatic yl group can be incorporated on one or more carbon atoms, Sauerstoffatom, nitrogen-atoms and/or the sulphur atom in the parent compound.
[0195] word " aromatic yl group of replacement (substituted aryl group) " with alkyl group that replaces pair and unsubstituted alkyl group, has same implication for unsubstituted aromatic yl group.Yet the aromatic yl group of replacement also comprises such aromatic yl group, and one of them aromatic carbon is attached on above-mentioned one of them non--carbon or non--hydrogen atom; And also comprise such aromatic yl group, therein one or more aromatic carbons of aromatic yl group be incorporated into replacement and/or unsubstituted alkyl (comprising cycloalkyl), alkenyl, alkynyl, aralkyl, heterocyclic radical or heterocycloalkyl on, as definition herein.This comprises that wherein two of aromatic yl group carbon atoms are incorporated on two atoms of alkyl, alkenyl or alkynyl group in conjunction with arranging (bonding arrangements), with definition condensed ring system (for example dihydro naphthyl or tetralyl).Also have, the aromatic yl group of replacement comprises such aromatic yl group, and wherein, one or more aromatic carbons of aromatic yl group are incorporated on the unsubstituted aryl or on the aryl with above-mentioned any group replacement except that another aryl.Therefore, word " aryl of replacement (substituted aryl) " includes but not limited to tolyl, hydroxy phenyl etc.
[0196] word " unsubstituted alkenyl (unsubstituted alkenyl) " refers to straight chain and side chain and cyclic group, such as those groups of describing according to unsubstituted alkyl group defined above, except at least one two key is present between two carbon atoms.Example include but not limited to vinyl ,-CH=CH (CH 3) ,-CH=C (CH 3) 2,-C (CH 3)=CH 2,-C (CH 3)=CH (CH 3) ,-C (CH 2CH 3)=CH 2, cyclohexenyl, cyclopentenyl, cyclohexadienyl, butadienyl, pentadienyl and hexadienyl and other groups.
[0197] word " alkenyl of replacement (substituted alkenyl) " has same implication with the alkyl group that replaces for the unsubstituted alkyl group for unsubstituted kiki alkenyl group.The kiki alkenyl group that replaces comprises such kiki alkenyl group, and wherein, non--carbon or non--hydrogen atom are attached to another carbon atom and form on the carbon atom of two keys; And comprise that such kiki alkenyl group, one of them non--carbon or non--hydrogen atom are attached to and do not participate in forming on the carbon atom of two keys with another carbon.Normally, unsubstituted kiki alkenyl group has 2 to 20 carbon, and in some embodiments, this type of group has 2 to 10 carbon.
[0198] term " alkenylene (alkenylene) " refers to have the divalence straight or branched alkyl of at least one carbon-to-carbon double bond, typically have about 2 to 20 carbon atoms, " alkenylene of replacement (substituted alkenylene) " refers to also have one or more above-mentioned substituent alkenylene groups.
[0199] word " unsubstituted alkynyl (unsubstituted alkynyl) " refers to straight chain and branched group, such as those groups of describing according to unsubstituted alkyl group defined above, except at least one triple bond is present between two carbon atoms.Example includes but not limited to-C ≡ CH ,-C ≡ C (CH 3) ,-C ≡-C (CH 2CH 3) ,-CH 2C ≡ CH ,-CH 2C ≡ C (CH 3) and-CH 2C ≡ C (CH 2CH 3) etc.Typically, unsubstituted alkynyl group has 2 to 20 carbon, and in some embodiments, this type of group has 2 to 10 carbon.
[0200] word " alkynyl of replacement (substituted alkynyl) " has same implication with the alkyl group that replaces for the unsubstituted alkyl group for unsubstituted alkynyl group.The alkynyl group that replaces comprises such alkynyl group, and therein, non--carbon or non--hydrogen atom are attached to another carbon atom and form on the triple-linked carbon atom; And comprise such alkynyl group, therein, non--carbon or non--hydrogen atom are attached to and do not participate in forming on the triple-linked carbon atom with another carbon.
[0201] " unsubstituted aralkyl (unsubstituted aralkyl) " refers to unsubstituted alkyl group defined above, and the hydrogen of unsubstituted alkyl group or carbon bond are substituted by the key that forms with aromatic yl group as defined above therein.For example, methyl (CH 3) be the unsubstituted alkyl group.If the hydrogen atom of methyl group is substituted by the key with phenyl group formation, if be attached on the carbon of benzene such as the carbon of methyl, this compound is unsubstituted aromatic alkyl group (a for example benzyl group) so.Therefore, this word includes but not limited to group such as benzyl, Biphenylmethyl and 1-styroyl (CH (C 6H 5) (CH 3)) and other groups etc.
[0202] word " aralkyl of replacement (substituted aralkyl) " has same implication with the aromatic yl group that replaces for unsubstituted aromatic yl group for unsubstituted aromatic alkyl group.Yet the aromatic alkyl group of replacement also comprises such group, and therein, the carbon of the moieties of group or hydrogen bond are replaced by the key with non--carbon or non--hydrogen atom formation.The example of the aromatic alkyl group that replaces includes but not limited to-CH 2C (=O) (C 6H 5) and-CH 2( 2-aminomethyl phenyl) and other groups etc.
[0203] word " unsubstituted heterocyclic (unsubstituted heterocyclyl) " refers to aromatic ring and non-aromatic ring compound, comprise monocycle, two rings and contain the polynuclear compound of 3 or a plurality of ring memberses, wherein one or more ring memberses are heteroatomss, such as, but not limited to N, O and S.Although word " unsubstituted heterocyclic " comprises that annelated heterocycles is such as benzimidazolyl-, it does not comprise having other groups, such as being attached to the alkyl on one of them ring members or the heterocyclic radical group of halogen group, because compound such as 2-tolimidazole base is the heterocyclic radical group that replaces.The example of heterocyclic radical group includes but not limited to: unsaturated 3 to the 8 yuan of rings that contain 1 to 4 nitrogen-atoms such as, but be not limited to pyrryl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridine base, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (4H-1 for example, 24-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.), tetrazyl (for example 1H-tetrazyl, 2H-tetrazyl etc.); Saturated 3 to the 8 yuan of rings that contain 1 to 4 nitrogen-atoms such as, but be not limited to pyrrolidyl, imidazolidyl, piperidyl, piperazinyl; Have 1 to 4 nitrogen-atoms condense unsaturated heterocycle such as, but be not limited to indyl, pseudoindoyl, indolinyl, indolizine base (indolizinly), benzimidazolyl-, quinolyl, isoquinolyl, indazolyl, benzotriazole base; Unsaturated 3 to the 8 yuan of rings that contain 1 to 2 Sauerstoffatom and 1 to 3 nitrogen-atoms such as, but be not limited to _ the azoles base, different _ the azoles base, _ di azoly (for example 1,2,4-_ di azoly, 1,3,4-_ di azoly, 1,2,5-_ di azoly etc.); Saturated 3 to the 8 yuan of rings that contain 1 to 2 Sauerstoffatom and 1 to 3 nitrogen-atoms such as, but be not limited to morpholinyl; The unsaturated annelated heterocycles group that contains 1 to 2 Sauerstoffatom and 1 to 3 nitrogen-atoms, for example benzo _ azoles base, benzo _ di azoly, benzo _ piperazine base (for example 2H-1,4-benzo _ piperazine base etc.); Unsaturated 3 to the 8 yuan of rings that contain 1 to 3 sulphur atom and 1 to 3 nitrogen-atoms such as, but be not limited to thiazolyl, isothiazolyl, thiadiazolyl group (for example 1,2,3-thiadiazolyl group, 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,5-thiadiazolyl group etc.); Saturated 3 to the 8 yuan of rings that contain 1 to 2 sulphur atom and 1 to 3 nitrogen-atoms such as, but be not limited to thiazolidyl (thiazolodinyl); Saturated and unsaturated 3 to the 8 yuan of rings that contain 1 to 2 sulphur atom such as, but be not limited to thienyl, dihydrodithiinyl, dihydro two sulfinyls (dihydrodithionyl), tetramethylene sulfide, tetrahydric thiapyran; The unsaturated annelated heterocycles that contains 1 to 2 sulphur atom and 1 to 3 nitrogen-atoms such as, but be not limited to benzothiazolyl, diazosulfide base, benzothiazine base (2H-1 for example, 4-benzothiazine base etc.), dihydrobenzo thiazinyl (for example 2H-3,4-dihydrobenzo thiazinyl etc.); Unsaturated 3 to the 8 yuan of rings that contain Sauerstoffatom such as, but be not limited to furyl; Unsaturated annelated heterocycles such as the benzo dioxolyl (for example 1,3-benzo dioxolyl etc.) that contains 1 to 2 Sauerstoffatom; Unsaturated 3 to the 8 yuan of rings that contain Sauerstoffatom and 1 to 2 sulphur atom such as, but be not limited to dihydro oxathiin base (Dihydrooxathiinyl); Saturated 3 to the 8 yuan of rings that contain 1 to 2 Sauerstoffatom and 1 to 2 sulphur atom such as, but be not limited to 1, the 4-oxathiane; Unsaturated condensed ring such as the benzothienyl, the benzodithiinyl that contain 1 to 2 sulphur atom; The unsaturated annelated heterocycles that contains Sauerstoffatom and 1 to 2 Sauerstoffatom is such as benzo oxathiin base (benzoxathiinyl).The heterocyclic radical group also comprises those above-described groups, and therein, the one or more S atoms in the ring combine (sulfoxide and sulfone) with two keys with one or two Sauerstoffatom.For example, the heterocyclic radical group comprises oxidation tetramethylene sulfide (tetrahydrothiopheneoxide) and 1, and (tetradrothiophene 1,1-dioxide) for 1-titanium dioxide tetramethylene sulfide.Typical heterocyclic radical contains 5 and 6 ring memberses.Exemplary heterocyclic radical group comprises morpholine, piperazine, piperidines, tetramethyleneimine, imidazoles, pyrazoles, 1,2,3-triazole, 1,2,4-triazole, tetrazolium, thiophene, thiomorpholine, thiomorpholine, therein, the S atom of thiomorpholine be attached on one and a plurality of O atoms, pyrroles, high piperazine (homopiperazine), _ azoles alkane-2-ketone, pyrrolidin-2-one, _ azoles, quinoline rather ring, thiazole, different _ azoles, furans and tetrahydrofuran (THF).
[0204] word " heterocyclic radical of replacement (substituted heterocyclyl) " refers to unsubstituted heterocyclic group defined above, one and a plurality of ring memberses are attached on non--hydrogen atom therein, such as on regard to that the aromatic yl group of the alkyl group of replacement and replacement describes.Example includes, but are not limited to other group such as 2-tolimidazole base, 5-tolimidazole base, 5-chloro benzothiazole base, 1-methylpiperazine base, 2-phenoxy group-thiophene and 2-chloropyridine base.In addition, the heterocyclic radical group that replaces also comprises such heterocyclic radical group, the key that forms with non--hydrogen atom is the key that forms with carbon atom, it is that replace and part unsubstituted aryl, replacement and heterocyclic radical unsubstituted aralkyl, unsubstituted heterocyclic or replacement, therein, substituting group comprises above-mentioned those any substituting groups except another heterocyclic radical group.Example includes, but are not limited to 1-benzyl piepridine base, 3-phenyl thio-morpholinyl, 3-(tetramethyleneimine-1-yl)-pyrrolidyl and 4-(piperidines-1-yl)-piperidyl.
[0205] word " unsubstituted Heterocyclylalkyl (unsubstituted heterocyclylalkyl) " refers to unsubstituted alkyl group defined above, therein, the hydrogen of unsubstituted alkyl group or carbon bond are replaced by the key with heterocyclic radical group formation defined above.For example, methyl (CH 3) be the unsubstituted alkyl group.If the hydrogen atom of methyl group is replaced by the key that forms with heterocyclic radical, if be incorporated into such as the carbon of methyl on the carbon 3 or 4 of the carbon 2 (one of them carbon is attached on the N of pyridine) of pyridine or pyridine, compound is unsubstituted heterocycloalkyl so.
[0206] word " Heterocyclylalkyl of replacement (substituted heterocyclylalkyl) " has same implication with the aromatic alkyl group that replaces for unsubstituted aromatic alkyl group for unsubstituted heterocycloalkyl.Yet unsubstituted heterocycloalkyl also comprises such group, and therein, non--hydrogen atom is attached on the heteroatoms of heterocyclic radical group of heterocycloalkyl, such as, but not limited to the piperidines ring nitrogen of piperidines alkyl group.In addition, the Heterocyclylalkyl of replacement also comprises such group, and therein, the carbon bond of the moieties of group or hydrogen bond are replaced with the key with unsubstituted aromatic alkyl group formation unsubstituted aryl or replacement with that replace.Example includes but not limited to phenyl-(piperidines-1-yl)-methyl and phenyl-(morpholine-4-yl)-methyl.
[0207] word " unsubstituted alkoxyl group (unsubstituted alkoxy) " refer to such oh group (OH), therein, with the key of hydrogen atom by with as the key that forms of the carbon atom of other unsubstituted alkyl group defined above replace.
[0208] word " alkoxyl group of replacement (substituted alkoxy) " refer to such oh group (OH), therein, with the key of hydrogen atom by with as the key that forms of the carbon atom of the alkyl group of other replacement defined above replace.
[0209] term " protected (protected) " relevant with oh group, amine groups and mercapto groups refers to the form of these functionality, they are protected in order to avoid suffer adverse effect with the protecting group that those skilled in the art will know that, such as Protective Groups in Organic Synthesis, Greene, T.W.; Wuts, P.G.M., John Wiley﹠amp; Sons, New York, NY, those protecting groups of being set forth in (3rd Edition, 1999), they can or be removed with the step adding of describing in the document.The example of protected hydroxyl group includes but not limited to silyl ether, such as those by with the acquisition of oh group and following reagent react: such as, but not limited to tertiary butyl dimethyl-chlorosilane, trimethylchlorosilane, tri isopropyl chlorosilane, chlorotriethyl silane; Methyl that replaces and ethyl ether are such as, but not limited to methoxymethyl ether, methylthio group methyl ether (methythiomethyl ether), benzyloxy methyl ether (benzyloxymethyl ether), tert.-butoxy methyl ether, 2-methoxy ethoxy methyl ether (methoxyethoxymethylether), THP trtrahydropyranyl ether, 1-ethoxyethylether, allyl ether, dibenzyl ether; Ester is such as, but not limited to benzoyl formiate, manthanoate, acetic ester, trichloroacetic esters and tetrafluoro acetic ester.The example of protected amine groups includes but not limited to acid amides, such as methane amide, ethanamide, trifluoroacetamide and benzamide; Imide such as phthalic imidine, dithiosuccinimide; Carbamate such as uncle-butyl carbamate (Boc), carboxylamine fluorenyl methyl esters (fluorenylmethyl carbamate) are (Fmoc) and benzyl carbamate (Cbz); And other.The example of protected mercapto groups includes, but are not limited to thioether such as S-tertiary butyl thioether, S-benzyl thioether and S-4-picolyl thioether (S-4-picolyl thioether); S-methyl-derivatives such as half sulfenyl (hemithio), disulfide group and the amino sulfenyl acetal that replace; And other.
[0210] " pharmacy acceptable salt (pharmaceutically acceptable salt) " comprises the salt that forms with mineral alkali, organic bases, mineral acid or organic acid or alkalescence or acidic amino acid.As for the salt of mineral alkali, the present invention includes for example an alkali metal salt such as sodium or sylvite; Alkaline earth salt is such as calcium and magnesium or aluminium; And ammonia.As for the salt of organic bases, the present invention includes for example Trimethylamine 99, triethylamine, pyridine, picoline (picoline), thanomin, diethanolamine and trolamine.As for the salt of mineral acid, the present invention includes for example salt of hydrochloric acid, hydrogen borate (hydroboricacid), nitric acid, sulfuric acid and phosphoric acid.As for organic acid salt, the present invention includes for example formic acid, acetate, trifluoroacetic acid, FUMARIC ACID TECH GRADE, oxalic acid, tartrate, toxilic acid, citric acid, succsinic acid, oxysuccinic acid, methylsulfonic acid, Phenylsulfonic acid and right-toluenesulphonic acids.As for the salt of basic aminoacids, the present invention includes for example arginine, Methionin and ornithine.Acidic amino acid comprises for example aspartic acid and L-glutamic acid.
[0211] some compound in formula IA, IB, IC and II scope is a derivative, is called prodrug.The derivative of the direct acting medicine that oneself knows is represented in statement " prodrug (prodrug) ", for example ester and acid amides, compared with medicine, this derivative has enhanced transfer characteristic and therapeutic value, and it is converted into active medicine by enzyme or chemical process.Referring to Notari, R.E., " Theory and Practice of Prodrug Kinetics, " Methodsin Enzymology 112:309-323 (1985); Bodor, N., " Novel Approaches in Prodrug Design, " Drugs of the Future 6:165-182 (1981); And Bundgaard, H., " Design of Prodrugs:Bioreversible-Derivatives for Various Functional Groups and Chemical Entities, " inDesign of Prodrugs (H.Bundgaard, ed.), Elsevier, New York (1985), Goodman andGilmans, The Pharmacological Basis of Therapeutics, 8th ed., McGraw-Hill, Int.Ed.1992.Aforementioned reference and all reference of listing are herein incorporated this paper into by reference in its entirety.
[0212] tautomer refers to the isomeric forms of mutual compound in equilibrium.The concentration of each isomeric form will depend on the environment of finding compound, and can be according to for example whether compound is solid or changes to some extent not in organic or aqueous solution.For example, in aqueous solution, ketone usually and their enol form balance.Therefore, ketone and their enol are called as mutual tautomer.Understand ground easily as those skilled in the art institute, many functional groups and other structures can demonstrate tautomerism, and have formula IA, IB and IC compound all tautomers within the scope of the invention.
[0213] compound of the present invention is included in (resolved) optically active isomer enrichment or that split on any or all asymmetric atom, and this is conspicuous from specification sheets.Racemize and diastereomeric compound, and single optical isomer can separate or synthetic, so that separate with their enantiomer or diastereomer companion fully, and these are within the scope of the present invention.
[0214] " treatment (treatment) " within the scope of the present invention refers to whole or in part, the symptom of alleviation and obstacle or disease-related, or stop to further develop or worsening of these symptoms, or prevent or ward off disease or obstacle.Similarly, as used herein, " in the treatment (the therapeuticallyeffective amount) of significant quantity " of compound of the present invention refers to such compound quantity, this amount whole or in part, the symptom of alleviation and obstacle or disease-related, or stop to further develop or worsening of these symptoms, or prevention or ward off disease or obstacle.Treatment also can comprise with other treatment and gives pharmaceutical preparation of the present invention.For example, compound of the present invention and pharmaceutical preparation can be before operative procedure and/or radiation therapies, during or administration afterwards.Selectively, compound of the present invention also can with other anti--scorching agent, antineoplastic agent and other agent combination administrations described herein.
[0215] compound of the present invention can be easily synthetic by technology well known to those skilled in the art.For example, formula IA compound---wherein X is C (O)---can get by the G component that will carry amine and the Ar-1-Q component coupling preparation of carrying carboxyl.Coupling can realize by for example using typical amido linkage formation reagent such as EDC, PyBOP and analogue, maybe can realize by forming carboxylic acid halides or active ester.Therefore, can use any suitable amide key to form step, be described in step in the following document such as those: Bodanszky, M.and Bodanszky, A., The Practice of Peptide Synthesis, Springer-Verlag (1984); Or Jones, J.Amino Acid and Peptide Synthesis Ed.Steven G.Davies, OxfordScience (1992).Can carry out sulfuration (Thionation) to the acid amides of gained, for example use Lawesson ' s reagent or analogue, with the thioamides (being C=S) that formula IA or IB are provided.Similarly, formula IB compound---wherein X is C (O)---is also passable, for example gets with carrying the initial preparation of G of carboxyl with the Ar-L-Q component of carrying amine.The keto-amide of formula IA or IB (respectively by aforesaid method with G-NH 2With HOOC-C (O)-Ar-L-Q coupling, or with NH 2-Ar-L-Q and G '-C (O)-COOH coupling and obtain), can be converted into corresponding oxime (Y is C (=NOH)) by handling with oxyamine.
[0216] as an example, scheme 1 shows the synthetic of The compounds of this invention, and wherein G is the pyrazoles that replaces.
Scheme 1
[0217] therefore, in suitable solvent such as benzene, toluene or analogue, the phenylhydrazine hydrochloride that replaces is heated the phenyl amino pyrazoles that replaces shown in providing with ss-ketonitriles (beta-ketonitrile).With carboxyl-Ar-L-Q component and unhindered amina coupling, use coupling agent such as EDC, PyBOP and analogue usually then, in the presence of suitable alkali such as DIEA and other alkali, carry out.Linked reaction can be implemented in any suitable solvent, suitable solvent such as ethylene dichloride, DMF, ethyl acetate, THF/ water and similar solvent.Selectively, carboxyl group can be converted into acyl halide such as chloride of acid, and this is by being exposed to oxalyl chloride, thionyl chloride or POCl 3And other materials carry out.The example of the formula IA compound of link coupled product shown in being, and can further modify, to form other compounds of the present invention.
[0218] formula II compound---wherein X ' is N---can easily be prepared.The amido linkage of the compound of formula IA and IB (wherein X is C (O)) can reduce such as LAH with any suitable hydride, and the compound of gained can be converted into nitroso-derivative by being exposed to BuCNO.The cyclic action of nitroso-derivative produces the compound of the formula II with structure I IA.By with suitable alkali such as pyridine or analogue heating nitroso compound, can implement cyclic action.
[0219] compound of formula II---wherein X ' is S---has following formula,
And can use to document in the similar following program preparation described.For example the pyrazoles of type A1-acid amides intermediate product is (as in scheme 2, that describes among the method A is synthetic) can be according to the method for describing in the document, use bromine or N-bromo-succinimide bromination, produce bromination analogue (Justus Liebigs Ann.Chem.1955, the 593:179-199 of type A2; 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; Bioorg.Med.Chem.4,2,1996,227-238).
Scheme 2
[0220] gained intermediate product A2 can be by heating P 2S 5Handle, produce the two ring thiazole intermediate products of type A3, describe in used condition and the document similar (Chem.Heterocycl.Compd.10,1974,813-815).
[0221] selectively, shown in scheme 3, intermediate product A2 can handle with alkali such as n-Butyl Lithium (n-BuLi), adds dibenzyl-two sulphurs (disulfane) again, produces S-benzyl intermediate A 4.Be used in HF (Bull.Chem.Soc.Jpn., 40,1967 in the methyl-phenoxide, 2164), or use cresols-thiophenol-HF mixture (Int.J.Pept.Proteinres.28,1986,498), thioether is carried out debenzylation, produce free mercaptan, itself then can cyclisation and form two ring thiazole system (Chem.Soc.Jpn., 58,1985,785-786).
Scheme 3
Figure A20048003305501682
[0222] wherein X ' is that the formula II compound of O has following formula,
And can use to document in the similar following program preparation described.The ring of the bromination of the above-mentioned type A2, such as pyrazoles, the sodium methylate that can be used for methyl alcohol is handled, with provide methoxyl group intermediate A 5 (J.Chem.Soc.PerkinTrans.1,1984,63-67).
Scheme 4
[0223] as shown in scheme 4, methoxyl group intermediate A 5 can be converted into corresponding pure A6, and this implements (J.Org.Chem.1974,39,1427 by using any method in the no counting method of describing in the document; Synthesis, 1989,287, J.Am.Chem.Soc.1981,103,7007).Selectively, bromine intermediate A 2 can be used cupric bromide and aqueous carbonic acid sodium, be converted into pure A6 (Chem.Heterocycl.Compd.22,3,1986,265-267).Describe, the alcohols intermediate product of gained is directly cyclisation under heating condition, and therefore needn't separate, directly provide the two ring _ azoles systems wanted (Heterocycles, 22,10,1984,2309-2311).
[0224] according to an aspect of the present invention, provide the method for preparing cytokine inhibitor of the present invention.For example, the compound method of preparation formula IA comprises G-NH 2React in the presence of coupling agent and alkali with Q-L-Ar-X-OH, or with G-NH 2With Q-L-Ar-X-X " reaction in the presence of alkali, with the compound of production IA, wherein, define in any as described in this article compound of variable G, Q and L, X is C (O) or C (S), X " be to activate part.Activate part normally F, Cl, Br, I ,-N 3, N-hydroxy-succinamide, l-hydroxybenzotriazole, Pentafluorophenol, pentachlorophenol, right-Acylphenol or-O-C (O)-OR y, R wherein yIt is low alkyl group.Suitable alkali comprises sodium bicarbonate or suitable organic amine such as pyridine, N-methylmorpholine, diisopropylethylamine or triethylamine.In one aspect of the invention, provide the method for preparation formula IA compound, wherein, Ar is-(Y)-naphthyl-, Y is-CH (OH)-or-CH 2-, G be selected from phenyl, pyridyl, pyrazolyl, pyrryl, imidazolyl, _ azoles base, different _ azoles base or thienyl.On the other hand, the invention provides the method for preparation formula IA compound, wherein Ar be C (O)-naphthyl-, G be phenyl, pyridyl, pyrazolyl, pyrryl, imidazolyl, _ azoles base, different _ azoles base or thienyl.Also provide in the presence of second kind of alkali and used NH 2OR handles wherein, and Y is-C (O)-this type of formula IA compound Y is to provide wherein-method of the Compound I A of C (NOR).Usually, second kind of alkali is pyridine or acetate.Usually be reflected in the pure pyridine, in pyridine/alcohol mixture, or in ethanol, in the presence of sodium acetate, carry out, and with reaction mixture be heated to about 40 ℃ to about 80 ℃ temperature range.Therefore, the invention provides the method for preparation formula IA compound, wherein Ar be-C (=NOH)-naphthyl-, G be selected from phenyl, pyridyl, pyrazolyl, pyrryl, imidazolyl, _ azoles base, different _ azoles base or thienyl.
[0225] also having on the other hand, the invention provides the method for preparation formula IA compound, wherein Ar be-(Y)-phenyl-, Y is-C (O)-, and G be selected from cyclopropyl, pyrazolyl, pyrryl, pyrrolidyl, imidazolyl, imidazoles ketone group, _ azoles base, different _ the azoles base, furyl or thienyl.Also provide in the presence of second kind of alkali, used NH 2OR handles wherein, and Y is-C (O)-this compounds Y is to provide wherein-method of the formula IA compound of C (NOR), wherein second kind of alkali and reaction conditions are as top description.Therefore, the invention provides the method for preparation formula IA compound, wherein Ar be-C (=NOH)-phenyl-, G be selected from pyrazolyl, pyrryl, imidazolyl, _ azoles base, different _ the azoles base, furyl or thienyl.
[0226] also provide preparation to have the method for the compound of formula IB, this method comprises G-X-OH and Q-L-Ar-NH 2There is reaction at coupling agent and alkali, or with Q-L-Ar-NH 2With G-X-X " reaction in the presence of alkali, obtain described compound, wherein variables A r, G, Q and L as defined herein, X is C (O) or C (S), X " be to activate part.In one aspect, provide the method for preparation formula IB compound, wherein, Ar is-(Y)-naphthyl-, Y is-CH (OH)-or-CH 2-, G be selected from phenyl, pyridyl, pyrazolyl, pyrryl, imidazolyl, _ azoles base, different _ azoles base or thienyl.On the other hand, provide the method for preparation formula IB compound, wherein, Ar is-naphthyl-, G be G '-(Y)-, Y is-C (O)-, G ' be selected from phenyl, pyridyl, pyrazolyl, pyrryl, imidazolyl, _ azoles base, different _ the azoles base, furyl or thienyl.Also provide in the presence of second kind of alkali, used NH 2OR handles wherein, and Y is-C (O)-this kind formula IB compound Y is to provide wherein-C (NOR)-the method for formula IB compound, second kind of alkali and described above the reaction conditions institute wherein.Therefore, provide preparation formula IB compound method, wherein Ar be-naphthyl-, G be G '-C (=NOH)-, G ' be selected from phenyl, pyridyl, pyrazolyl, pyrryl, imidazolyl, _ azoles base, different _ the azoles base, furyl or thienyl.
[0227] also having on the other hand, the invention provides the method for preparation formula IB compound, wherein Ar be-phenyl-, G be G '-(Y)-, Y is-C (O)-, G ' is selected from pyrazolyl, different _ azoles base or furyl.Also provide in the presence of second kind of alkali, used NH 2OR handles wherein, and Y is-Y is to provide wherein for this kind formula IB compound of C (O)-C (NOR)-the method for formula IB compound, wherein second kind of alkali and reaction conditions are as described in above the institute.Therefore, provide preparation formula IB compound method, wherein Ar be-naphthyl-, G be G '-C (=NOH)-, G ' is selected from pyrazolyl, different _ azoles base or furyl.
[0228] on the other hand, the invention provides the method for preparation formula IC compound, wherein ring is the triazolidine diketone, this method comprises reacts G-NHNHC (O) O-Et and Q-L-Ar-NCO in aprotic solvent, and in the presence of alkali, the intermediate of cyclisation gained produces described compound, and wherein G, Ar, L and Q are as previously described.Usually, aprotic solvent is DCM, chloroform or THF, and alkali is to be selected from NaOH, LiOH and K 2CO 3Mineral alkali, or be selected from the organic bases of DBU, DIEA and TEA.Usually, reaction mixture maintains under the temperature in about 0 ℃ to 60 ℃ scope.
[0229] on the other hand, the invention provides the method for preparation formula II compound, wherein X ' is NH, and this method comprises G (NO)-NH-CH 2-Ar-L-Q and organic amine heating produce described compound, and wherein G, Ar, L and Q such as front define.Suitable organic amine comprises pyridine and analogue.Usually, reaction mixture is heated to the temperature in about 80 ℃ to 160 ℃ scopes, more generally, is heated to about 100 ℃ to about 140 ℃.
[0230] in another aspect of the present invention, the formula III compound is provided,
Wherein, the pyrazoles part is on 1-position, 3-position or this two positions, by one or more R 1, R 2Or R 3Replace;
X " be OR xOr activation part;
R xBe H, replacement or unsubstituted C 1-4Aralkyl alkyl or replacement or unsubstituted;
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-OR ,-SiR 3,-NR ' R ' ,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 individual independently N, O, the S (O) of being selected from mHeteroatoms;
Each R 2Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2With
Each R 3Be H, replacement or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight chain aralkyl, replacement or unsubstituted or a C 1-8Alkyl, R 20(O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups of alkynyl are randomly by O, NH or S (O) mReplace;
R, R ', R ", R 20, R 21, R 23, R 24, R 26With m as described in this article any compound define.
[0231] activating part is such group, and this group activates contiguous carbonyl, with the addition nucleophilic reagent, such as amine, mercaptan, alcohol or analogue.Exemplary activation partly includes but not limited to heterocyclic oxy group group aryloxy group F, Cl, Br or I, replacement or unsubstituted, replacement or unsubstituted, oxygen acyl alkoxyl group (oxyacylalkoxy) group, and it forms the blended acid anhydride.Usually, activate part be F, Cl, Br, I ,-N 3, N-hydroxy-succinamide, I-hydroxybenzotriazole, Pentafluorophenol, pentachlorophenol, right-nitrophenols or-O-C (O)-OR y, R wherein yIt is low alkyl group.
[0232] the present invention also provides pharmaceutical composition, this pharmaceutical composition can pass through following one or more materials: the compound of formula IA, IB and IC or II, its prodrug, its pharmacy acceptable salt, its steric isomer, its tautomer or its solvate, be mixed with and get with pharmaceutically acceptable carrier, vehicle, tackiness agent, thinner or analogue, with prevention and the relevant obstacle of the excessive generation of treatment and cytokine.Composition of the present invention can be used for producing prescription, with prevention or the treatment various obstacles relevant with the excessive generation of cytokine, for example relates to the disease and the pathological conditions of inflammation.This kind composition can be such form, for example particle, powder, tablet, capsule, syrup, suppository, injection, emulsion, elixir, suspension agent or solution.This composition can be mixed with and be used for various route of administration, for example, and through port, parenteral, part, rectum, nose, vagina administration, or by implantable container (implanted reservoir) administration.Parenteral or general administration include, but are not limited to, in subcutaneous, intravenously, intraperitoneal, intramuscular, intraarticular, the synovia, in the breastbone, in the sheath, in the damage and injection in the head.Following formulation gives in the mode of example, and should not be considered to limit the present invention.
[0233] for mouth, oral cavity and sublingual administration, powder, suspension agent, particle, tablet, pill, capsule, granular capsule (gelcaps) and capsule sheet are acceptable solid dosages.These formulations can be mixed with and get with at least a additive such as starch or other additives for example by with one or more compounds of the present invention or its pharmacy acceptable salt or its tautomer.Suitable additive is sucrose, lactose, cellulose sugar, seminose, maltose alcohol, dextran, starch, agarose, alginates, chitin, chitosan, pectin, tragacanth, gum arabic, gel, collagen, casein, white protein, synthetic or semisynthetic polymkeric substance or glyceryl ester.Randomly, the per os formulation can contain other components to help administration, such as thinner or lubricant such as Magnesium Stearate or sanitas such as parabens (paraben) or Sorbic Acid or antioxidant such as xitix, tocopherol or halfcystine, decomposition agent, tackiness agent, thickening material, damping fluid, sweeting agent, sweetener or the perfume compound of non-activity.Tablet and pill can further be handled with suitable coating material known in the art.
[0234] being used for peroral administration liquid dosage form can be pharmaceutically acceptable emulsion, syrup, elixir, suspension and solution form, and its thinner that can contain non-activity is such as water.Formula of medicine and medicament can be used sterile liquid, such as, but not limited to the combination of oil, water, pure and mild these materials, are prepared into liquid suspension or solution.Pharmaceutically suitable tensio-active agent, suspension agent, emulsifying agent can be added into, to be used for per os or administered parenterally.
[0235] as mentioned above, suspension can comprise oil.This kind oil includes but not limited to peanut oil, sesame oil, oleum gossypii seminis, Semen Maydis oil and sweet oil.Suspension formulation also can contain the ester of lipid acid, such as ethyl oleate, Isopropyl myristate, glycerol fatty acid ester and acetylated glycerol fatty acid esters.Suspension formulation can comprise alcohols, such as, but not limited to ethanol, Virahol, cetene-1-alcohol, glycerine and propylene glycol.Ether is such as, but not limited to poly-(ethylene glycol), petroleum hydrocarbon such as mineral oil and paraffin; Also can be used for suspension formulation with water.
[0236] injectable dosage formulations generally comprises aqeous suspension, or oil suspension, and it can and get with suitable dispersion agent or wetting agent and suspension agent preparation.Injectable forms can be with solution phase (solution phase) or form of suspension, and it prepares with solvent or thinner.Acceptable solvent or carrier comprise aqua sterilisa, Ringer ' s solution or isoosmotic pressure aqueous salt solution.Selectively, aseptic oil can be used as solvent or suspension agent.Normally, oil or lipid acid right and wrong-volatile comprise natural or synthetic is oily, lipid acid, monoglyceride, triglyceride or triglyceride level.
[0237] for injection, pharmaceutical preparation and/or medicament can be powder, and this powder is suitable for above-described suitable solution reconstruct.The example of these powder includes, but are not limited to cryodesiccated, Rotary drying or spray-dired powder, amorphous powder, particle, throw out or particulate.For injection, preparation can randomly contain the combination of stablizer, pH regulator modifier, tensio-active agent, bioavailability modifier (bioavailabilitymodifier) and these materials.
[0238] for rectal administration, pharmaceutical preparation and medicament can be suppository, ointment, enema, tablet or emulsion form, to discharge compound at intestines, sigmoid colon and/or internal rectum.Rectal suppository is by the tautomer with one or more compounds of the present invention or pharmacy acceptable salt or compound, with acceptable carrier, for example theobroma oil or polyoxyethylene glycol are mixed with and get, it exists with solid phase in normal storing temp, be suitable in vivo, such as existing with liquid phase under the temperature that discharges medicine in the rectum.Oil also can be used to prepare the preparation and the suppository of soft gel type.Water, salt solution, moisture dextrose and associated sugars solution and glycerol can be used to prepare suspension formulation, this suspension formulation also can comprise suspension agent such as pectin, carbomer (carbomers), methylcellulose gum, hydroxypropylcellulose or carboxymethyl cellulose, and damping fluid and sanitas.
[0239] compound of the present invention can suck by nose or mouth and give lung.The suitable pharmaceutical preparation that is used to suck comprises solution, spraying, dry powder or aerosol, it contains any suitable solvent and other compounds randomly, such as but be not limited to the combination that stablizer, biocide, antioxidant, pH regulator agent, tensio-active agent, biology can utilize modifier and these materials.The preparation that is used for inhalation contains vehicle, for example lactose, polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate salt.Moisture and water-free aerosol is normally used for transmitting compound of the present invention by sucking.
[0240] generally, aqueous aerosol is by formulated with the pharmaceutically acceptable carrier and the stablizer of routine with the aqueous solution or the suspension of compound.Carrier and stablizer change along with the demand of specific compound, but generally comprise nonionogenic tenside (Tweens, Pluronics or polyoxyethylene glycol), nontoxic protein matter such as serum albumin, Isosorbide Dinitrate, oleic acid, Yelkin TTS, amino acid such as glycine, damping fluid, salt, sugar or sugar alcohol.Aerosol is generally got by the isotonic solution preparation.Non-aqueous suspension (for example carbon fluorine propelling agent) also can be used to transmit compound of the present invention.
[0241] aerosol that contains the compound that is useful on purposes of the present invention passes through to use the following substances transmission traditionally: sucker, atomizer, compression wrap (pressurized pack) or atomizer and suitable propelling agent, for example without restriction, the methyl chlorofluoride of pressurization, trichlorofluoromethane, dichloro tetrafluoro ethane, nitrogen, air or carbonic acid gas.Under the situation of these pressurised aerosols, dose unit can be controlled by valve is provided, to transmit metered amounts (metered amount).Capsule and cartridge (cartridge) for example are used in the capsule of the gel in sucker or the insufflator and cartridge and can be mixed with and contain compound and suitable powder-base such as the lactose or the powdered mixture of starch.It is favourable using sound wave atomizer (sonic nebulizers) to transmit aerosol of the present invention, and this is because atomizer makes reagent stand minimum shearing force, and shearing force can degradation compound.
[0242] for nose administration, pharmaceutical preparation and medicament can be sprays, nasal drop or aerosol, they contain suitable solvent and other compounds randomly, can utilize the combination of modifier and these materials such as, but not limited to stablizer, biocide, antioxidant, pH regulator agent, tensio-active agent, biology.For the administration of nasal drop form, compound can be used as oily solution or prepares as colloid.For the nose aerosol drug delivery, can use any suitable propelling agent, comprise low boil-off dose of pressurized air, nitrogen, carbonic acid gas or hydrocarbon-based.
[0243] formulation that is used for part (comprising oral cavity and hypogloeeis) or transdermal administration The compounds of this invention comprises powder, spraying, cream, paste, breast, lotion, glue, solution and paster (patch).Active ingredient can be under aseptic condition with pharmaceutically acceptable carrier and mixed with excipients and with any may be that sanitas or the damping fluid that needs mixes.Powder and sprays can for example be used the mixture preparation of vehicle such as lactose, mica, silicic acid, aluminium hydroxide, Calucium Silicate powder and polyamide powder or these materials.Ointment, paste, emulsion and glue also can contain vehicle, such as the mixture of animal and plant fat, oil, wax, paraffin, starch, tragacanth, derivatived cellulose, polyoxyethylene glycol, silicone resin, wilkinite, silicic acid, mica and zinc oxide or these materials.
[0244] have the advantage of increase through the skin patch, promptly may command compound of the present invention is delivered to health.This kind formulation can be by preparing agent dissolves with being dispersed in the suitable medium.Absorption enhancer also can be used to increase the The compounds of this invention skin of flowing through.This flow velocity or can control by the speed control film is provided perhaps can be controlled by compound is dispersed in polymeric matrix and the glue.
[0245] ophthalmic preparation, eye ointment, powder, solution and analogue also are considered within the scope of the invention.Compound of the present invention can be incorporated in various types of ophthalmic preparation, to pass to eyes (for example partly, in the anterior eye or by implanting).Compound is incorporated in the topical ophthalmic usually, to pass to eyes.Compound can combine with the acceptable sanitas of ophthalmology, viscosity-increasing agent, penetration enhancers, damping fluid, sodium-chlor and water, forms aqueous, aseptic eye with suspension or solution.Ophthalmic solution formulations can get by compound dissolution is prepared in physiologically acceptable isoosmotic pressure water-containing buffering liquid.Also have, ophthalmic solution can comprise acceptable surfactant on the ophthalmology, to help dissolved compound.In addition, ophthalmic solution can contain reagent, to increase viscosity, such as Walocel MT 20.000PV, Natvosol, Vltra tears, methylcellulose gum, polyvinylpyrrolidone or analogue, to increase the hold-time of preparation in conjunctival sac.Also gelifying agent be can use, Gellan and xanthan gum included, but are not limited to.In order to prepare aseptic eye ointment preparation, active ingredient is mixed in suitable carriers such as mineral oil, liquid lanolin or white vaseline with sanitas.According to the prescription of disclosed similar ophthalmic preparation, aseptic eye glue preparation can preparation gets in the hydrophilic basic thing (hydrophilic base) by active ingredient is suspended in, and hydrophilic basic thing gets by the combined preparation of for example kappa general-974 or analogue.Can mix sanitas and tonicity agents (tonicity agent).
[0246] intrathecal drug delivery is undertaken by bolus quantities or SE, makes to give the spinal cord zone partly with compound, such as the dorsal horn zone, simultaneously compound is directly delivered to the subarachnoid space that contains CSF (celiolymph).
[0247], also can be passed to the spinal cord zone by the enforcement maincenter by the spinal cord zone of epidural injection to arachnoid membrane.Increase meninx infiltrative hypertonic pressure dosage solution (hypertonic dosing solutions) by using, or by adding penetration enhancers such as, but not limited to liposome encapsulation, tensio-active agent or ion-pairing agent, can enhanced activity compound infiltration passing through meninx.
[0248] except above-mentioned those representational formulations, pharmaceutically acceptable vehicle and carrier generally are known to those skilled in the art, and therefore are included in the present invention.Vehicle and carrier are described in, " Remingtons Pharmaceutical Sciences " Mack Pub.Co. for example, and among the New Jersey (1991), the document is by with reference to incorporating this paper into.
[0249] preparation of the present invention also is designed to fugitive type (short-acting), quick-release (fast-releasing), (long-acting), (sustained-releasing) of sustained releasing type of long-acting type, and is as described below.Therefore, pharmaceutical preparation also can be mixed with controllable release or slow releasing pattern.
[0250] this composition also can comprise other packing forms of micelle for example or liposome or some, or can be to prolong the form administration that discharges, with storage and/or the transmission effect that prolongation is provided.Therefore, pharmaceutical preparation and medicament can be compressed into ball or cylinder, and as storage injected material (depot injections) or as graft such as support intramuscular or subcutaneous implantation.This kind graft can utilize known inert material such as silicone resin and biodegradable polymer.
[0251] concrete dosage can be adjusted according to disease condition, age, body weight, general health situation, sex, patient's diet, spacing of doses, route of administration, discharge rate and these factors of drug regimen.Any above-mentioned formulation that contains significant quantity is fully in the normal experiment scope, therefore fully within the scope of the invention.
[0252] pharmaceutically the compound of the present invention of significant quantity can change according to route of administration and formulation.The The compounds of this invention of significant quantity usually in about 0.001 to 100mg/kg/ day scope, more generally, in about 0.05 to 10mg/kg/ day scope.Usually, perhaps the polyvoltine compound is selected so that the preparation that shows high therapeutic index to be provided for compound of the present invention.Therapeutic index is the dosage ratio between toxic effect and the result of treatment, and this index can be expressed as LD 50And ED 50Between ratio.LD 50Be 50% the lethal dosage of colony, ED 50Be the dosage that there is result of treatment in 50% colony.LD 50And ED 50Pharmacy program by standard in animal cell culture or laboratory animal is measured.
[0253] patent of the publication of all this specification sheets references, patent application, publication and other documents be all by with reference to incorporating this paper into, even if patent and other documents of the independent publication of each piece, patent application, publication are incorporated this paper into by showing specifically and individually on the reference in its entirety.If by contradicting with definition in the disclosure, just get rid of outside scope with reference to the definition that is included in herein.
[0254] by with reference to following embodiment, the present invention---is described in mode synoptically---that easier quilt is understood, and these embodiment provide in the mode of demonstrating, and are not intended to limit the present invention.
Embodiment
[0255] following abbreviation about the technical term of chemistry is applied in the whole application:
AcOH or HOAc: Acetate
Boc： Uncle N--butoxy carbonyl
Bn： Benzyl
Cbz： Carbobenzoxy-(Cbz) (Carbobenzyloxy)
dba： Dibenzalacetone (Dibenzylidene acetone)
DIEA： Diisopropylethylamine
DCM： Methylene dichloride
DMF： N, dinethylformamide
EDC or EDCI: 1-(3-dimethylamino-propyl)-3-ethyl-carbodiimide hydrochloride (1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)
EtOAc： Ethyl acetate
EtOH： Ethanol
Fmoc： 9-fluorenylmethyloxycarbonyl
HPLC： High pressure liquid chromatography
IC 50Value The feasible concentration of measuring the inhibitor of active minimizing 50%
LAH： Lithium aluminum hydride
MeCN or AcN: Acetonitrile
MeOH： Methyl alcohol
mL： Milliliter (s)
μL： Microlitre (s)
PyBOP： Phosphofluoric acid benzotriazole-1-base-oxygen tripyrrole alkyl _ (benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate)
rt： Room temperature
THF： Tetrahydrofuran (THF)
Embodiment 1: Indazolecarboxamides derivative synthetic
Figure A20048003305501761
[0256] 3-amino-5-tert-butyl-2-tolyl-2H-pyrazoles (1).(8.0g, 50mmol) and 4,4-dimethyl-3-oxo-valeronitrile (6.3g, spend the night by vlil 50mmol) will to be in tolyl hydrazine hydrochloride (tolyl hydrazine hydrochloride) in the toluene (30mL).Remove volatile matter in a vacuum, obtain residue, use the ethyl acetate that is dissolved in 30% in the hexane as elutriant, by this residue of silica gel chromatography purifying.Concentrate in the vacuum and obtain brown solid 3-amino-5-tert-butyl-2-tolyl-2H-pyrazoles (10.5g, 92%).Compound is carried out the LC-MS analysis revealed, and the product that needs exists with＞99% purity.Quality=229 of calculating.Quality=230 of observation.
Figure A20048003305501771
[0257] 1H-indazole-3-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides (2).To being dissolved in CH 2Cl 2Indazole (3.5mL)-3-carboxylic acid (28mg, 0.17mmol), EDC (50mg, 0.26mmol) and diisopropylethylamine (61 μ L, solution 0.35mmol), add 3-amino-5-tert-butyl-2-tolyl-2H-pyrazoles (46mg, 0.20mmol).Behind stirring at room 14h,, and use CH with mixture water (10mL) dilution 2Cl 2(2 * 10mL) extractions.The organic layer that merges is washed with salt, with (MgSO 4) drying, concentrate in a vacuum.Via preparation HPLC (MeCN/H 2O) purifying provides indazole and the pyrazoles (indazolopyrazole) (40%) of 25mg.LC-MS: the quality of calculating=373.Quality=374 of observation.
The general procedure of preparation indazole-3-carboxylic acid
[0258] 5-methoxyl group-1H-indazole-3-carboxylic acid (3).At-5 ℃, in the three-necked round bottom flask of the 1L that is equipped with mechanical stirrer, thermometer and funnel, add the water of 110mL, the vitriol oil of 6mL.To refrigerative solution, add the solution of sodium hydroxide of SODIUMNITRATE, the 2.6g of the 5-methoxyl group isatin be dissolved in the 10g in the 65mL water, 3.9g.After stirring 15 minutes, make reaction mixture be warmed up to 0 ℃, dropwise add SnCl 2Solution (35g is in the dense HCl of 50mL).Continue in the room temperature to stir 1 hour, the collecting precipitation thing is used the EtOH crystallization then, obtains the 3g product, prepares to be used for next step.LC-MS: the quality of calculating=192.Quality=193 of observation.
Synthesizing of embodiment 2-imidazolopyrazole derivatives
[0259] by 5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl amine (top compound 1) preparation 2-alkyl (aryl) imidazolopyrazole.
Scheme 5
Method A
The general procedure of the N-acetylizing of amino-pyrazol
[0260] have two kinds of different programs to be used for amino-pyrazol is carried out acetylizing, as scheme 5 and following as described in.
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-benzamide (4)
[0261] in ethyl acetate/water, amino-pyrazol is carried out acetylizing.(115mg 0.5mmol) is dissolved among the EtOAc of 2.5mL, and adds the NaHCO that is dissolved in the 1mL water with the 2-amino-pyrazol 3(46mg, 0.55mmol) solution.At room temperature, add Benzoyl chloride (57.5uL, 0.5mmol) solution in the ethyl acetate that is dissolved in 1.5mL to the mixture of this vigorous stirring.The mixture of gained stirred 4 hours at 60 ℃.After being cooled to room temperature, add ethyl acetate.Organic phase 5%Na 2CO 3, water, 1N HCl washing, last water washs once more.Organic phase is passed through Na 2SO 4Drying concentrates and provides 115mg NMR pure products (yield: 69%).LC-MS: the quality of calculating=333.Quality=334 of observation.
[0262] in pyridine, amino-pyrazol is carried out acetylizing: at-85 ℃, will in the 2-amino-pyrazol in the 2mL pyridine (115mg, 0.5mmol), Benzoyl chloride (63.3 μ L, 0.55mmol) and DMAP (3mg, 0.025mmol, 5mol%) shaken overnight.Evaporation and with toluene altogether-evaporation after, solid residue is dissolved among the 2mLDCM, carry out successive ISCO purifying (4g post, 0-40% B; A=PCM, B=10% MeOH is in DCM).The part evaporation that will contain product obtains the pure substance of 134mg.Yield: 80%.Quality=333 of calculating.Quality=334 of observation.
General procedure with the lithium aluminium hydride reduction acid amides
[0263] benzyl-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-amine (5).(167mg 0.5mmol) is dissolved among the anhydrous THF of 0.5mL with initial acid amides.At 4 ℃, in this solution, add the 1.5mL 1M LAH that is dissolved among the THF (1.5mmol).With the solution of gained at 60 ℃ of vibration 7h.After ice-water cooling, reaction mixture is alkalized with anhydrous K OH (pH 9-10).Suspension is filtered with diatomite (Celite), wash with THF.Concentrated filtrate is dissolved in residue in the ethyl acetate, and washes with water.Organic phase is through Na 2SO 4Drying is filtered and be evaporated to drying, obtains the 156mg brown oil.Compound is analyzed with LC-MS and NMR.Yield: 89%.Quality=319 of calculating.Quality=320 of observation.
The general procedure that N-alkylamino pyrazoles is carried out nitrosylation
[0264] benzyl-(3-nitroso-group-5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-amine (6).Add two dense HCl and 2 H to 1mL ethanol 2O, add then BuONO (270 μ L, 2.3mmol, 5eq).At 4 ℃, this solution is dropwise joined N-alkylamino pyrazoles (148mg, 0.46mmol) solution that is dissolved in the 1mL ethanol.Reaction mixture was stirred 30 minutes at 4 ℃, stir 2h then at room temperature.After concentrating, solid residue is dissolved among the DCM of 2mL, and carries out order column purification (sequential columnpurification) (12g post, 0-40%B; A=DCM; B=10%MeOH is in DCM).Yield: 48%, 76.9mg.LC-MS: the quality of calculating=348.Quality=349 of observation.
The crystalline general procedure
[0265] 3-tert-butyl-5-phenyl-1-right-tolyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles (7) also.At 120 ℃, (76mg, solution 0.21mmol) heated in microwave 20 minutes will to be dissolved in nitroso compound in the 3mL pyridine.With the reaction mixture cool to room temperature, with solvent and toluene coevaporation.Residue is dissolved in the methylene dichloride of 3mL, carries out the column chromatography purifying, obtain the product of 46.9mg.Yield=68%.LC-MS: the quality of calculating=330.Quality=331 of observation.
Scheme 6
Figure A20048003305501791
Method B
The general procedure of the O-alkylating of 4-hydroxyl-1-aromatic aldehyde
[0266] 4-(morpholine-4-base-oxyethyl group)-1-naphthaldehyde (8).To be dissolved in 4-hydroxyl-1-naphthaldehyde in the 12mL acetonitrile (258mg, 1.5mmol), N-(2-chloroethyl) morpholine hydrochloride (morpholine hydrochloride) (307mg, 1.65mmol, 1.1eq) and K 2CO 3(mixture 4eq) is at 80 ℃ of vigorous stirring 7h for 915mg, 6.6mmol.After the filtration, concentrate navy blue filtrate, obtain bottle-green oil, its slow crystallization.TLC:(silicon-dioxide) R f=0.18, in ethyl acetate.Compound is analyzed with LC-MS.This crude product is directly carried out next step reaction.Quality=285 of calculating.Quality=286 of observation.
Amino-pyrazol is carried out the general procedure of reductive amination
[0267] (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-ylmethyl]-amine (9).With amino-pyrazol (344mg, 1.5mmol) and the aldehyde of preceding step (1.5mmol 1eq) is dissolved among the 4mL EtOH, adds 80 μ L HOAc.With the solution of gained at 80 ℃ of vibration 5h.Be cooled to after the room temperature, and the adding sodium cyanoborohydride (282mg, 3eq).With the solution of gained at room temperature shaken overnight (15h).After the evaporation, residue is dissolved in the ethyl acetate, uses moisture NaHCO 3Washing washes with water then.Organic phase is concentrated, and residue is dissolved among the DCM, carry out column purification then, obtain the foam of 540mg.Yield: 72.3%.LC-MS: the quality of calculating=498.Quality=499 of observation.
[0268] 3-tert-butyl-5-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles (10) also.Use above-mentioned crystalline general procedure to prepare title compound.Quality=509 of calculating.Quality=510 of observation.
Synthesizing of embodiment 3-alpha-keto amide
Method A: by naphthalene-1-base-oxo-acetic acids
[0269] 4-[2-(naphthalene-1-base oxygen)-ethyl]-morpholine (11).(1.0g 5.37mmol) is dissolved in the acetonitrile (50mL) with 2-hydroxyl-naphthalene.To this solution add cesium carbonate (4.0g, 12.3mmol) or salt of wormwood (2.97g, 21.5mmol), add then 2-chloroethyl morpholine (chloroethylmorpholine) (0.774g, 5.37mmol).Mixture is spent the night, then cool to room temperature 80 ℃ of stirrings.The mixture of gained is filtered,, and use saturated NaHCO with the EtOAc dilution 3Extract 3 times, with 0.1M NaOH extraction once, use the salt water washing, use MgSO 4Drying is filtered, and under reduced pressure removes and desolvates, and obtains thick brown oil.By column chromatography purifying oil, the compound 11 that obtains wanting is lurid oil, yield 64% to 83%.Quality=257 of calculating.Quality=258 of observation.
[0270] [4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-oxo-acetic acids methyl esters (12).Add CH to round-bottomed flask 2Cl 2(100mL), add AlCl again 3(2.2g, 16.3mmol).Suspension was stirred 5 minutes at room temperature, add methyl chloride oxoethanoic acid (methylchloroglyoxylate) (1.66mL, 17.88mmol), restir 5 minutes, add 11 then (0.841g, 3.27mmol).Mixture stirred at room temperature spend the night, water finishes reaction (quench), uses NaHCO 3Neutralization is extracted three times with EtOAc.With the organic extraction salt water washing that merges, use MgSO 4Drying is filtered, and removing desolvates obtains the oil of brown.The gained material is by column chromatography (0-5%MeOH/CH 2Cl 2) purifying, obtain the yellow solid 12 (97%) of 1.08g.LC-MS: the quality of calculating=343.Quality=344 of observation.
[0271] N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide, (13).(0.224g 0.653mmol) is dissolved among the THF (20mL) with compound 12.To this solution add 1N LiOH (3eq, 1.96mmol).Make solution stirring 2 hours, and with the 4N HCl neutralization that is dissolved in two _ alkane, solvent evaporation was obtained white solid then.In 80 ℃, under high vacuum, dried residue 30 minutes is suspended in CH then 2Cl 2(50mL).To suspension add oxalyl chloride (0.56mL, 6.53mmol) and a little drip DMF.Suspension stirring at room 2 hours, is fallen solvent evaporation then.The solid suspension of gained in ethyl acetate (20mL), and is joined it and is dissolved in ethyl acetate (20mL) and 50%NaHCO 3(0.159g's 5-amino-3-tert-butyl-1-(4-aminomethyl phenyl) pyrazoles (1) in the solution (10mL) 0.663mmol), spends the night 60 ℃ of stirrings.Mixture dilutes with ethyl acetate, uses NaHCO 3Extract.MgSO is used in the organic layer salt water washing that merges 4Drying is filtered, and removing desolvates obtains brown oil.This material is by column chromatography purifying (50-100%EtOAc/ hexane) or (0-5% methyl alcohol/DCM), obtain the compound of wanting of 0.346g (98%) is yellow solid.LC-MS: the quality of calculating=540.Quality=541 of observation.
[0272] preparation of extra tectonic element (building blocks) is mixed the general method of (incorporation) with them
Figure A20048003305501821
[0273] N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-Toluidrin (14).To containing 5.0g (25.73mmol) 5-tert-butyl-2-methoxyl group-benzene-1, the 250mL round-bottomed flask of the oven drying of 3-diamines adds 150mL DCM.Reaction mixture is cooled to 0 ℃, afterwards, add triethylamine (5.0mL, 36.0mmol), dropwise add then methylsulfonyl chloride (1.99mL, 25.7mmol).Reactant was stirred 30 minutes at 0 ℃, heat to room temperature restir 2h then.Reaction-ure mixture is poured on the saturated sodium bicarbonate solution (100mL), and separating layer.50mL washed with dichloromethane twice is used in the waterbearing stratum again, and mixing organic layer dried over mgso concentrates in a vacuum and obtains thick oil, this thick oil flash chromatography (silica gel, 1: 1 EtOAc: Hex) purifying, the product of wanting (87%) of generation 6.1g.Quality=272 of calculating.Quality=273 of observation.
[0274] N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide (15).Initial by compound 12 and compound 14, by preparing title compound with the same method of describing for compound 13.Quality=583 of calculating.Quality=584 of observation.
Figure A20048003305501831
[0275] (4-hydroxyl-naphthalene-1-yl)-oxo-acetic acids methyl esters.AlCl in being dissolved in 50mL DCM 3(1.11g, 8.3mmol) suspension, adding methyl chloride oxoethanoic acid (1.02g, 8.3mmol).With the solution stirring 5min of gained, afterwards, adding naphthalene-1-alcohol (1g, 6.9mmol).Under the room temperature, stir 2h, add entry, separate phase, afterwards, organic phase washes with water, uses MgSO 4Dry.The residue that obtains after the organic solvent evaporation by column chromatography (10-30%EtOAc/Hex) purifying, obtains target compound, and yield is 38%.Quality=230 of calculating.Quality=231 of observation.
[0276] [4-(5-bromo-2-chloro-pyrimidine-4-base-oxygen)-naphthalene-1-yl]-oxo-acetic acids methyl esters.(1.37g 6mmol) is dissolved in the 30mL acetone with the compound that obtains in the reaction in front.Add 5-bromo-2, and 4-two chloro-pyrimidines (1.36g, 6mmol) and K 2CO 3(2.05g 14.8mmol), and will be reflected at 60 ℃ of stirring 5h.Evaporate acetone, residue is absorbed into DCM, the silica gel bed is passed through in the solution operation.After the solvent evaporated, obtain yield and be 75% white solid.Quality=421 of calculating.Quality=422 of observation.
[0277] [4-(5-bromo-2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-oxo-acetic acids methyl esters.(0.50g 1.19mmol) is dissolved in the THF/ toluene 8/2 with the compound that obtains as mentioned above.Add morpholine (0.124mL, 2.97mmol) and DIEA (0.5mL 2.97mmol), and spends the night solution 80 ℃ of stirrings.Evaporate acetone, residue produces 80% target compound by column chromatography (10-30%EtOAc/Hex) purifying.Quality=472 of calculating.Quality=473 of observation.
[0278] [4-(2-morpholine-4-base-pyrimidine-4-base-oxygen)-naphthalene-1-yl]-oxo-acetic acids methyl esters.(108mg 0.228mmol) is dissolved among the MeOH/DCM 3/1, adds 10%Pd/C (30mg), and at 1atm H with the compound of above-mentioned acquisition 2, with hydrogenation of compounds 50min.Reaction mixture is filtered, concentrate in the vacuum.The residue of gained is dissolved among the DCM,, produces 67% target product by column chromatography (10-30%EtOAc/Hex) purifying.Quality=393 of calculating.Quality=394 of observation.
[0279] [4-(2-morpholine-4-base-pyrimidine-4-base-oxygen)-naphthalene-1-yl]-oxo-acetic acids (16).Will (66mg 0.168mmol) be dissolved among the DCM, and is cooled to 0 ℃ from the product that reacts previously.Add and be dissolved in DCM (0.2mL, 0.202mmol) BBr of the 1M in 3Solution, and make to be reflected in 10 minutes and be warmed to room temperature.Water is joined in the mixture, and product is extracted among the EtOAc.Organic layer MgSO 4Drying, evaporation, residue grinds with hexane, obtains target product quantitatively.Quality=379 of calculating.Quality=380 of observation.
[0280] N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide (17).(36mg 0.095mmol) is dissolved among the 2mL DCM, and (0.08mL 0.949mmol), adds the DMF of catalytic again to add people's oxalyl chloride with [4-(2-morpholine-4-base-pyrimidine-4-base-oxygen)-naphthalene-1-yl]-oxo-acetic acids (16) of obtaining above.Reaction mixture is stirred at room temperature, afterwards, add N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-Toluidrin (14) (26mg, 0.096mmol) and DIEA (0.05mL 0.284mmol), continues stirring 12h.Concentrated reaction mixture in the vacuum is by LC/MS (10-100%AcN/H 2O, 8.5min) purifying residue.Quality=444 of calculating.Quality=444 of observation.
Figure A20048003305501842
[0281] (4-bromo-naphthalene-1-yl)-oxo-acetic acids methyl esters (18).At 1 ℃, the AlCl in being dissolved in 100mL DCM 3(3.20g, suspension 24mmol), adding methyl chloride oxoethanoic acid (2.2mL, 24mmol).With the solution stirring 5min. of gained, afterwards, adding 1-bromo-naphthalene (5g, 24mmol).After stirring 2h at room temperature, add entry, and separate each phase, afterwards, organic phase washes with water, uses MgSO 4Dry.The residue that obtains after the organic solvent evaporation is passed through column chromatography (0-30%EtOAc/Hex) purifying, obtain the target compound of 2.6g. 1HNMR(CDCl 3)：8.92(1H，d，J＝9.3Hz，H-arom)；8.31(1H，d，J＝9.3Hz，H-arom)；7.82(1H，d，J＝8.8Hz，H-arom)；7.72(1H，d，J＝8.8Hz，H-arom)；7.57-7.68(2H，m，H-arom)；3.94(3H，s，OMe)。
[0282] 2-chloro-pyrimidyl-4-base-amine.With 2, (7.45g is 50mmol) at the moisture NH of 150mL for 4-two chloro-pyrimidines 4Stir among the OH and spend the night.Chloroform is joined in the mixture, separate organic and water-containing solvent.Organic layer washes with water, and uses MgSO 4Dry.The residue that obtains after the organic solvent evaporation obtains the target compound of 1.5g and the isomer of 2g by column chromatography (0-100%EtOAc/Hex) purifying.Quality=129 of calculating.Quality=130 of observation.
[0283] 2-morpholine-4-base-pyrimidine-4-base amine.(166mg 1.286mmol) is dissolved among the 2mL THF with obtaining compound in the reaction of front.(134mg 1.5mmol), and will be reflected at 75 ℃ of stirrings and spend the night to add DIEA (0.1mL) and morpholine.Decompression removes and desolvates down, and residue is dissolved among the DCM, and by column chromatography (50-100%EtOAc/Hex) purifying, the generation yield is 88% target product.Quality=180 of calculating.Quality=181 of observation.
[0284] [4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-oxo-acetic acids methyl esters.(140mg, 0.77mmol) (228mg 0.77mmol) is suspended in the 5mL toluene, and adds Pd (OAc) with (4-bromo-naphthalene-1-yl)-oxo-acetic acids methyl esters (18) with 2-morpholine-4-base-pyrimidine-4-base amine 2(5mg, 3mol%), BINAP (24mg, 5mol5) and CS 2CO 3(753mg, 2031mmol).Reaction mixture is stirred 24hr at 100 ℃.The refrigerative mixture produces the target product of 169mg by column chromatography (0-100%EtOAc/Hex) purifying.
[0285] [4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-oxo-acetic acids.(170mg 0.433mmol) is dissolved among the DCM, and is cooled to 0 ℃ with the product of previous reaction.Add and be dissolved in DCM (0.52mL, 0.52mmol) BBr of the 1M in 3Solution, and will react and stir 35min.Water is joined in the mixture, solvent evaporated, the thick target product of generation 160mg, like this, this crude product is used to linked reaction.
[0286] coupling G-NH 2The general procedure of [4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-oxo-acetic acids.Will (17mg 0.044mmol) be dissolved among the 1.5mL DMF, and adds amine component G-NH from the product that reacts previously 2(2eq., 0.88mmol), add again PyBOP (46mg, 0.088mmol), HOBt (14mg, 0.088mmol) and DIEA (0.02mL, 0.088mmol).To react to stir and spend the night, crude mixture obtains final compound by LC/MS (10-100%AcN) purifying.Described method is applied to the compound of giving an example in the generation table 1.
Figure A20048003305501861
[0287] 4-(5-bromo-pyridine-2-ylmethyl)-morpholine.(0.57g, (0.3g 1.59mmol) in the stirred solution, is cooled to 0 ℃ simultaneously 5mmol) dropwise to join (5-bromo-pyridine-2-the yl)-methyl alcohol that is dissolved among the DCM (5mL) will to be dissolved in thionyl chloride among the DCM (2mL).Mixture is warmed to room temperature, and after 1 hour, is evaporated to low volume in a vacuum.Residue is dissolved in CHCl 3In, be dissolved in CHCl 0 ℃ of adding 3In morpholine (0.41g, 5mmol) solution.Behind the 3h, reaction is finished.With solvent evaporation, add ether and obtain target compound (85%), be white solid.Quality=257 of calculating.Quality=258 of observation.
[0288] 4-(5-three-butyl tin alkyl-pyridine-2-ylmethyl) morpholine.((1.7mL, 2.2eq) solution are cooled to-78 ℃ to the compound that is obtaining above doing among the THF simultaneously to add tert-butyl lithium 1.7M for 0.35g, solution 1.3mmol).After 10 minutes, in same temperature, add ClSnBu 3(2.2eq 1.2g), stirs reaction mixture 15 minutes.Add pH 7K then 2HPO 4/ KH 2PO 4Damping fluid, residue extracts with EtOAc, uses MgSO 4Drying obtains the target compound of 81% yield.Quality=467 of calculating.Quality=469 of observation.
[0289] [4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-oxo-acetic acids (20).Under nitrogen atmosphere, with 4-(5-three-butyl tin alkyl-pyridine-2-ylmethyl)-morpholine (0.47g, 1.59mmol) and (4-bromo-naphthalene-1-yl)-oxo-acetic acids methyl esters (18) (0.6g, 1.3mmol) and catalysis four (triphenylphosphine) close palladium (0) to be dissolved in 2mL anhydrous 2, in 4-two _ alkane.At 150 ℃, pipe was heated 10 minutes under microwave radiation.After the cool to room temperature, mixture dilutes with EtOAc, adds the solution of KF 40%.Separate organic phase, evaporate the waterbearing stratum,, obtain yield and be 54% target product by the LC-MS purifying.Quality=376 of calculating.Quality=376 of observation.
[0290] N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide (302).Target compound 302 forms by chloride of acid and obtains with above-mentioned (1b) coupling.Quality=631 of calculating.Quality=631 of observation.
Figure A20048003305501871
[0291] 4-(4-nitro-pyridine-2-yl)-morpholine.To the 2-chlorine in THF (3mL), the 4-nitropyridine (0.2g, 1.27mmol) solution add morpholine (328mg, 38.1mmol).Reaction is heated to 80 ℃, and stirs and spend the night.Evaporating solvent, residue produce the target compound of 150mg by column chromatography (2/1 Hex/EtOAc) purifying.
[0292] 2-morpholine-4-base-pyridin-4-yl amine.With the compound that obtains above (40mg 0.86mmol) is dissolved among the MeOH/DCM 5/2, adds 10%Pd/C (40mg), and with compound at 1atm H 2Following hydrogenation 5hr.Reaction mixture is filtered, and concentrate in a vacuum.The residue of gained obtains the target product of 157mg by column chromatography (1/2 EtOAc/Hex) purifying.
[0293] [4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-oxo-acetic acids methyl esters (21).(159mg, 0.88mmol) (260mg 0.89mmol) is suspended in 6mL toluene/two _ alkane 1/1, adds Pd (OAc) with (4-bromo-naphthalene-1-yl)-oxo-acetic acids methyl esters (18) with 2-morpholine-4-base-pyridin-4-yl amine 2(6mg, 3mol%), BINAP (27mg, 5mol%) and CS 2CO 3(858mg, 2.64mmol).Reaction mixture was stirred 18 hours by 80 ℃ to 80 ℃.The refrigerative mixture produces the 140mg product by column chromatography (0-100%EtOAc/Hex) purifying.This product is carried out previously described method, to obtain interested final compound.
[0294] 4-tert-butyl-2-morpholine-4-ylmethyl-6-nitro-phenol.To be dissolved in 4-tert-butyl-2-nitro-phenol in the 20mL ethanol (980mg, 5mmol), (1.5g, solution 50mmol) are in air-tight bottle, in 95 ℃ of heating 6 hours for morpholine (50mmol) and paraformaldehyde.Remove desolvate and morpholine after, residue obtains the target compound of 1.75g by the silica gel column chromatography purifying, is yellow solid.
[0295] 2-amino-4-tert-butyl-6-morpholine-4-ylmethyl-phenol.In the dense HCl of 2mL, in 90 ℃, with compound (294mg, 1mmol) usefulness tin chloride dihydrate (II) (1.36g, 6mmol) the heating 2hr that obtains as mentioned above.After cooling down, the reaction mixture dilute with water, and add diethyl ether.By adding solid K 2CO 3Make pH=9, the neutralization reaction mixture.Extract the organic phase dried over sodium sulfate of merging with diethyl ether.Evaporation obtains the 222mg pure products, is white solid.
[0296] N-(5-tert-butyl-2-hydroxyl-3-morpholine-4-ylmethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide (22).The product of the acquisition in being dissolved in 5mL DCM (66mg, 0.25mmol) and DIEA (87 μ l, solution 0.5mmol) add chloride of acid (as described above and obtain) (0.5mmol).The mixture of gained is in stirred overnight at room temperature.After aqueous carbonic acid hydrogen sodium is checked (work-up) and silica gel column chromatography, obtain the final product of 59.8mg output.Quality=575.7 of calculating.Quality=575.723 of observation.
Figure A20048003305501881
[0297] 4-tert-butyl-2-methyl-6-nitro-phenol.(1.64g 10mmol) is dissolved in the 15mL acetate, and (0.47mL, 10mmol), the solution of gained is in stirred overnight at room temperature to add nitrosonitric acid with 4-tert-butyl-2-methyl-phenol.Then reaction mixture is poured on trash ice, use chloroform extraction.Organic phase washes with water, uses dried over sodium sulfate.Evaporation provides the nitration product of 2.02g, is reddish oil.
[0298] N-(tert-butyl-2-hydroxy-3-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide (23).At room temperature, the nitro-compound of acquisition (31mg) is Pd/C and the H among the 3mL MeOH 2Reductase 12 hr.Filter and, residue is dissolved among the 2mL DCM, add DIEA (0.25mmol), add [4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-oxo-Acetyl Chloride 98Min. (0.1mmol) again except that after desolvating.In the room temperature, lasting stirring is spent the night.The residue that obtains after the solvent evaporation obtains the 9.5mg final product by the LC-MS purifying.Quality=491 of calculating.Quality=491 of observation.
[0299] 5-tert-butyl-2-methoxyl group-1-methyl-3-nitro-benzene.(209mg 1mmol) is dissolved in the 3mL acetone with 4-tert-butyl-2-methyl-6-nitro-phenol.Add 552mg K 2CO 3(4eq), add again MeI (0.33mL, 5mmol).Reaction mixture is spent the night 60 ℃ of vigorous stirring.Remove after the acetone, residue vibrates with DCM.Solution filters and evaporation produces the 221mg product afterwards, and this product just can use.
[0300] N-(5-tert-butyl-2-methoxyl group-3-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide (24).At room temperature, (56mg 0.25mmol) uses Pd/C and H to the product that obtains above in 5mL MeOH 2Reduction 5hr.Filter and, residue is dissolved among the 4mL DCM except that after desolvating.Add DIEA (0.5mmol), add chloride of acid (0.2mmol) again.Reaction continues to spend the night at room temperature.After inspection of aqueous carbonic acid hydrogen sodium and the silica gel column chromatography, obtain final product, output is 46.8mg.Quality=505 of calculating.Quality=505 of observation.
Figure A20048003305501892
[0301] 4-tert-butyl-2-chloro-phenol.(2.64g 17.5mmol) is dissolved in and is dissolved in DCM (17.5mL, 17.5mmol) SO of the 1M in 4-tert-butyl-phenol 2Cl 2Solution, and adding MeOH (0.71mL, 17.5mmol).Reaction is stirred at room temperature, monitoring process.Add extra 1M SO 2Cl 2/ DCM (10mL) and MeOH (0.36mL).Concentrated reaction mixture in the vacuum produces target compound.Quality=186 of calculating.Quality=187 of observation.
[0302] 4-tert-butyl-2-chloro-6-nitro-phenol.(0.585g 3.17mmol) is dissolved among the 6mL AcOH, is cooled to 0 ℃, and adds HNO with the product that obtains above 3(0.16mL, 3.5mmol).Reaction is warmed to room temperature, afterwards, adds entry, and compound is extracted among the EtOAc.Organic layer MgSO 4Drying with solution concentration, is filtered by silica gel enriched material to produce the target compound of 0.306g.Quality=209 of calculating.Quality=210 of observation.
[0303] 5-tert-butyl-1-chloro-2-methoxyl group-3-nitro-benzene.(0.214g 0.934mmol) is dissolved in the 3mL acetone, and adds K with 4-tert-butyl-2-chloro-6-nitro-phenol 2CO 3(0.65g, 4.7mmol) and MeI (0.58mL, 9.3mmol).To be reflected at 65 ℃ of stirrings and spend the night, and after this, under reduced pressure remove and desolvate.Residue is absorbed into DCM, and organic layer washes with water, uses MgSO 4Drying concentrates the target product that produces 0.15g.
[0304] 5-tert-butyl-3-chloro-2-methoxyl group-aniline (25).(157mg 0.646mmol) is dissolved among the dense HCl of 3mL, and adds SnCl with 5-tert-butyl-1-chloro-2-methoxyl group-3-nitro-benzene 2.2H 2O (0.874g, 3.87mmol).To be reflected at 90 ℃ and stir 2 hours, and after this, add entry, and product is extracted in the diethyl ether.Organic layer MgSO 4Drying, and concentrate.Residue produces the 100mg final product by column chromatography (2/1 Hex/EtOAc) purifying.Quality=213 of calculating.Quality=214 of observation.
Figure A20048003305501901
[0305] N-(5-tert-butyl-3-chloro-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-acetic acids amine (26).(77mg 0.36mmol) is dissolved among the 10mL DCM with 5-tert-butyl-3-chloro-2-methoxyl group-aniline (25).(0.37mL 1.44mmol), and continues stirring reaction for [4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-oxo-Acetyl Chloride 98Min. (0.54mmol) that adding prepares as previously described and DIEA.Reaction mixture is evaporated, and residue is by LC/MS (10-100% AcN) purifying.Quality=524 of calculating.Quality=525 of observation.
Figure A20048003305501902
[0306] 4-tert-butyl-2-trifluoromethyl-phenol.With 2-trifluoromethyl-phenol (2.98g 18.3mmol) is dissolved among the 12mL TFA, add the t-butanols (1.43g, 19.3mmol) and H 2SO 4(0.24mL).To react and at room temperature stir 48hr, and after this, add entry, and compound is extracted among the DCM.Organic phase MgSO 4Drying concentrates in the vacuum.Residue produces the target compound of 2.01g by column chromatography (2/1 Hex/EtOAc) purifying.
[0307] 4-tert-butyl-2-trifluoromethyl-6-nitro-phenol.(70mg 0.32mmol) is dissolved in the 3mLAcOH/1.5mL water, and is cooled to 0 ℃ with 4-tert-butyl-2-trifluoromethyl-phenol.Add HNO 3(1.5mL) with catalysis H 2SO 4, and allow reaction to be warmed to room temperature.Continue to stir and spend the night, after this, add entry, compound is extracted among the EtOAc.Organic layer MgSO 4Drying concentrates, and produces the final compound of 34mg.Quality=263 of calculating.Quality=264 of observation.
[0308] 5-tert-butyl-2-methoxyl group-1-trifluoromethyl-3-nitro-benzene.(34mg 0.163mmol) is dissolved in the 3mL acetone, and adds K with the compound that obtains above 2CO 3(112mg, 0.81mmol) and MeI (0.1mL, 1.63mmol).Be reflected in 75 ℃ and stir.Mixture is concentrated, and residue is dissolved among the DCM.Filter organic layer, through MgSO 4Drying, and concentrate.Residue produces the target compound of 30mg by column chromatography (10-30%EtOAc/Hex) purifying.Quality=277 of calculating.Quality=278 of observation.
[0309] 5-tert-butyl-2-methoxyl group-3-trifluoromethyl-aniline (27).(100mg 0.0.36mmol) is dissolved in MeOH, adds 10%Pd/C (50mg), at 1atm H with the compound that obtains above 2, with hydrogenation of compounds.Reaction mixture is filtered, and concentrate in a vacuum.The residue of gained is dissolved among the DCM, and, produces the target product of 72mg by column chromatography (4/1EtOAc/Hex) purifying.Quality=247 of calculating.Quality=248 of observation.
Figure A20048003305501911
[0310] N-(5-tert-butyl-2-methoxyl group-3-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide (28).(32mg 0.165mmol) is dissolved among the 2mL DCM with 5-tert-butyl-2-methoxyl group-3-trifluoromethyl-aniline.(0.02mL 0.50mmol), and continues stirring reaction as describing before prepared [4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-oxo-Acetyl Chloride 98Min. (0.232mmol) and DIEA in adding.With the reaction mixture evaporation, residue is by LC/MS (10-100%AcN) purifying.Quality=558 of calculating.Quality=559 of observation.
Figure A20048003305501921
[0311] 4-[2-(6-chloro-naphthalene-1-base oxygen)-ethyl]-morpholine.(1.8mL, 11.01mmol) (1.0g, 3.67mmol) solution add NaNO to the amine in to being dissolved in 6M HCl 2(253mg 3.67mmol), and will be reflected at 0 ℃ of stirring 1hr.(363mg 3.67mmol), thereby produces (evolve) gas to add CuCl to this mixture.Reaction is heated to 100 ℃, and stirred 1 hour.Mixture extracts with DCM, dry organic layer, and evaporation provides 9% target product.Quality=291 of calculating.Quality=291 of observation.
[0312] [7-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-oxo-acetic acids methyl esters.AlCl in being dissolved in DCM 3(430mg, 3.30mmol) suspension, the adding methyl chloroacetate (0.30mL, 3.30mmol), thus AlCl 3Dissolved.Dropwise add 4-[2-(6-chloro-naphthalene-1-base oxygen)-ethyl to this solution]-morpholine (95mg, 0.33mmol).Mixture stirred at room temperature spend the night.Mixture dilutes with DCM, and organic layer washes with water, through MgSO 4Drying, evaporation produces 83% target substance.Quality=378 of calculating.Quality=378 of observation.
[0313] N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[7-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide (29).5-in being dissolved in 1mL two _ alkane (tert-butyl-2-is right-and (50mg 0.22mmol), adds butyllithium (BuLi) (0.11mL, 2M is in cHex), and mixture is left standstill 10min tolyl-2H-pyrazole-3-yl amine.To this mixture add the ester that is dissolved among the 1mL DMF (83mg, 0.22mmol) solution, and with the mixture of gained in microwave, in 150 ℃ of heating 5min.Mixture washes with water, uses MgSO 4Drying, and evaporation.Residue produces 12% the product of wanting by the LC/MS purifying.Quality=575 of calculating.Quality=575 of observation.
Amide group-aminobenzoic ether derivant synthetic general procedure
Method a.
Figure A20048003305501931
[0314] 5-tert-butyl-2-methoxyl group-3-nitrobenzoic acid.5-tert-butyl-O-Anisic Acid in being dissolved in 30mL AcOH and 30mL diacetyl oxide (5.5g, 26mmol) solution, (ca.5 drips) vitriol oil of adding catalytic amount.The reaction of gained stirred at room temperature spend the night.After the reaction, reaction mixture is poured in the ca.1.2L frozen water.White precipitate forms, and this white precipitate is filtered, and washes with water.Under vacuum, after 80 ℃ of dryings, measure acquisition 5.98g (91%) pure products through NMR, be white solid. 1H NMR(500MHz，CDCl 3)：1.39(s，9H)，4.08(s，3H)，8.02(s，1H)，8.32(s，1H)。
[0315] 5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-nitro-benzamide.5-tert-butyl in being dissolved in 18mL DCM-2-methoxyl group-3-nitrobenzoic acid (759mg, 3mmol) solution, the adding oxalyl chloride (1.8mL, 15mmol).After stirring 2 hours at room temperature, reaction mixture is concentrated into drying.The chloride of acid of gained is dissolved among the 30mL DCM, and add DIEA (2.6mL, 15mmol) and cyclopropylamine (0.83mL, 12mmol).In the room temperature, lasting stirring is spent the night, and after this, DCM is joined in the reaction mixture.After the inspection of aqueous carbonic acid hydrogen sodium, use DCM on ISCO Optix (3 * 12g silicagel column), to carry out the column chromatography purifying.Separate obtaining the 678mg pure products, be light yellow solid.Quality=292 of calculating.Quality=295 of observation.
[0316] 5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl] 2-oxo-kharophen }-benzamide (30).At room temperature, (584mg is 2mmol) in 30mL MeOH, with Pd/C and H for the compound that will obtain in abovementioned steps 2Reduction 3hr.After the filtration, remove methyl alcohol, and thick reductive intermediate product is dissolved among the 25mL DCM.(1.0mL 6mmol), adds chloride of acid (2mmol) again to add DIEA.The suspension of gained stirred at room temperature spend the night, after this, DCM is joined reaction.Organic layer aqueous carbonic acid hydrogen sodium and water washing.The organic phase dried over sodium sulfate concentrates, and residue obtains the product of 948mg by silicagel column purification process (ISCO Optix 7 * 12 gram posts) purifying, is weak yellow foam (yield: 82.6%).Quality=574 of calculating.Quality=574 of observation.
Method b
Figure A20048003305501941
[0317] 3-amino-5-tert-butyl-2-methoxyl group-phenylformic acid.5-tert-butyl-2-methoxyl group-3-nitrobenzoic acid (1.5mmol) in MeOH, is used Pd/C and H 2Reduction, and with the amine and chloride of acid (1.5mmol) coupling of gained.React ground as described above and check that like that column purification (3 * 12 silica gel) obtains the target compound of 211mg.
[0318] N-[5-tert-butyl-2-methoxyl group-3-(piperidines-1-carbonyl)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide (31).(rt 2h) exists down, in 0.5mL DCM, by (54 μ l, 0.5mmol) reaction are converted into chloride of acid with the compound that obtains above of 26mg (0.049mmol) with oxalyl chloride at the DMF of catalytic quantity.Except that after desolvating, thick chloride of acid is dissolved among the 1mL DCM.Add DIEA (0.2mmol), add piperidines (0.1mmol) again.The mixture of gained stirs at room temperature and spends the night.Moisture inspection, and the pure products that produces 7.6mg by the LC-MS purifying.Quality=602 of calculating.Quality=602 of observation.
Figure A20048003305501942
[0319] 5-tert-butyl-2-hydroxyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenylformic acid (32).(11mg 0.02mmol) is dissolved among the 1mL DCM with initial substance.At 0 ℃, add the BBr that is dissolved among the DCM (0.1mL, 1M solution) 3Solution, before water finishes reaction, make to be reflected to continue 2hr in the same temperature.Aqueous carbonic acid hydrogen sodium is checked and by the LC-MS purifying, is produced the 3.6mg target compound.Quality=521 of calculating.Quality=521 of observation.
The general procedure of the compound deriving effect of pyrazolyl containing
[0320] N-(5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide.((adding is dissolved in 2.5mL H to chloride of acid in being dissolved in 10mL EtOAc for 695mg, 2mmol) solution as the front preparation 25-tert-butyl among the O-2H-pyrazole-3-yl amine (278mg, 2mmol) and NaHCO 3(504mg, 6mmol).Solution stirs 15hr at 60 ℃.Separating layer, organic layer is by column chromatography (0-6%MeOH/DCM) purifying.Obtain the target compound of 51% yield, be light yellow oil.Quality=450 of calculating.Quality=451 of observation.
N-(5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide (33).In the presence of DMAP (2mg), in pyrimidine (1mL), (17mg, 0.038mmol) (9.8 μ L 0.076mmol) handled 16 hours in 60 ℃ the compound that obtains in the reaction of front with benzene sulfonyl chloride.Thick mixture produces the target substance of 3.1mg by preparation type LC/MS purifying.Quality=591 of calculating.Quality=591 of observation.
[0321] other derivative, such as acid amides and urea derivative, synthetic by same basically method.
Synthesizing of alpha-keto amide
Method B: by 2H-pyrazole-3-yl-oxo-acetic acids
[0322] 5-tert-butyl-2-right-tolyl-2H-pyrazoles-3-carboxylic acid, ethyl ester (R=Me).To contain be dissolved in 5-tert-butyl-2H-pyrazoles-3-carboxylic acid, ethyl ester of stirring among the 25mLDCM (0.5g, round-bottomed flask 2.6mmol), add pyridine (0.95mL, 11.7mmol), right-tolyl boric acid (1.1g, 8.1mmol), Cu (OAc) 2(0.75g is 4.1mmol) with 4A molecular sieve (0.75g).Reaction is stirred 14h at room temperature in air.The mixture of gained filters by Celite pad (pad), and filtrate is concentrated in a vacuum, obtains the light green solid.Thick material provides the product of wanting (0.64g, 83%) by the flash chromatography purifying, is limpid oil (0-50%EtOAc: hexane, on silica gel).Forecast quality=286.Quality=287 of observation.
[0323] (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-methyl alcohol (R=Me).To contain 5-tert-butyl-2-right-tolyl-2H-pyrazoles-3-carboxylic acid, ethyl ester (0.64g, the round-bottomed flask of oven drying 2.2mmol) add anhydrous THF (20mL), again in nitrogen atmosphere, dropwise add DIBAL-H (0.96mL, 4.9mmol).After stirring at room temperature 30 minutes, reaction is with the dilution of the diethyl ether of 100mL, and finishes to react with 5mL methyl alcohol, then restir 30 minutes at room temperature.The slurry of gained 5g MgSO 4Handle, and filter and pass through Celite pad.Filter cake concentrates the filtrate that merges in a vacuum with the washing of 3 * 75mL part ether, and the alcohol that obtains wanting is limpid oil (0.515g, 96%).Need not to be further purified.Prospective quality=244.Quality=245 of observation.
[0324] 5-tert-butyl-2-right-tolyl-2H-pyrazoles-3-formaldehyde (carbaldehyde) (R=Me).To contain (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-methyl alcohol (0.515g, scintillation vial 2.1mmol) add 15mLDCM, add again Dess-Martin cross iodine alkane (periodinane) (1.1g, 2.52mmol).Make reaction mixture stir 20 minutes at room temperature, and be poured in the separating funnel that contains 30mL water.Separating layer, the waterbearing stratum is extracted more than 2 times with 50mL DCM.MgSO is used in the organic layer salt water washing that merges 4Drying concentrates in the vacuum, obtains thick aldehyde.Thick material produces the product of wanting by flash chromatography (0-50%EtOAc: hexane, silica gel) purifying, is limpid oil (0.5g, 97%).Prospective quality=242.Quality=243 of observation.
[0325] (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-trimethyl silicane alcoxyl base-acetonitrile (R=Me).To contain 5-tert-butyl-2-right-tolyl-2H-pyrazoles-3-formaldehyde (0.5g, 2.0mmol)---it is just under nitrogen, in 0 ℃, in anhydrous THF, stir---with the flask of oven drying, add pure trimethylsilyl cyanide (0.29mL, 2.2mmol), add a n-butyllithium (2.0M is in hexane) again.Mixture is stirred 1h at 0 ℃ to the room temperature heating, and then stir and spend the night.Concentrated reaction mixture under the vacuum obtains product, is thick oil.Need not further purifying.Prospective quality=341.Quality=342 of observation.
[0326] (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-hydroxyl-acetate (R=Me).To the round-bottomed flask that contains (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-trimethyl silicane alcoxyl base-acetonitrile, add the dense HCl of 100mL, and be heated to 80 ℃.Spend the night after the heating, reaction is diluted with 150mL water, and (3 * 100mL) extract with DCM.Dried over sodium sulfate is used in organic layer salt water washing, concentrates in the vacuum.Residue and then-be dissolved in about 75mL methyl alcohol, add then KOH (0.45g, 8mmol), with the solution 2h that refluxes.With the reaction mixture cool to room temperature, concentrate under the vacuum then.Some trash ices are joined in the flask that contains reaction residue, and with 1N HCl acidifying.Mixture dilutes with 100mL water then, and (3 * 100mL) extract with DCM.MgSO is used in organic layer salt water washing 4Drying concentrates under the vacuum, produces the product that 0.35g (60%) wants.Need not further purifying.Prospective quality=288.Quality=289 of observation.
[0327] (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-oxo-acetic acids (34, R=Me).To contain (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-hydroxyl-acetate (0.35g, scintillation vial 1.2mmol) add 15mLDCM, add again Dai Si-Martin cross iodine alkane (Dess-Martin periodinane) (0.61g, 1.44mmol).Make reaction mixture stir 20 fens kinds at room temperature, and pour into the separating funnel that contains 30mL 0.5M HCl.Separating layer, and extract 2 time or more with 50mL DCM the waterbearing stratum.MgSO is used in the organic layer salt water washing that merges 4Drying, and concentrate the product that obtains wanting (purity＞80% is analyzed through NMR) in a vacuum.Need not further purifying.Prospective quality=286.Quality=287 of observation.
Figure A20048003305501971
[0328] 2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl) N-[4-(2-morpholine-4-base-oxyethyl group) naphthalene-1-yl]-2-oxo-ethanamide (35, R=Me): to thick (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-oxo-acetic acids 34 (0.4g in the 40mL scintillation vial, 1.4mmol), add oxalyl chloride (5mL) and a DMF.Suspension is stirred 1h at room temperature, concentrate under the vacuum.The solid of gained is dissolved among the EtOAc (10mL), and joins and be dissolved in EtOAc (10mL)/50%NaHCO 34-(10mL) (2-morpholine-4-base-oxyethyl group)-naphthalene-1-base amine (0.45g, 1.2mmol) in, stir in the room temperature and spend the night.Mixture dilutes with EtOAc, and uses NaHCO 3Extract.MgSO is used in the organic layer salt water washing that merges 4Drying is filtered, and removes and desolvate, and obtains auburn oil.This material obtains the compound that 0.357g (57%) wants by column chromatography (50-100%EtOAc/ hexane) purifying, is the xanchromatic solid.Prospective quality=540.Quality=541 of observation.
Synthesizing of alpha-keto amide
Method C: by 2H-pyrazole-3-yl-3-oxo-2-(triphenyl-λ 5-phosphanylidene)-propionitrile
[0329] 5-tert-butyl-2-right-tolyl-2H-pyrazoles-3-carboxylic acid.To the 5-tert-butyl-2-in the 40mL scintillation vial right-(0.5g 1.75mmol), adds 2mL THF and 2mL 1NLiOH to tolyl-2H-pyrazoles-3-carboxylic acid, ethyl ester.Be reflected at 50 ℃ of heating 1hr, after this, reaction mixture concentrates in a vacuum, and thick residue dilutes with 5mL1N HCl.(3 * 25mL) extract reaction slurry, and the organic layer of merging is with the water washing of (10mL) salt, and use MgSO with DCM then 4Dry.The solution of gained concentrates under vacuum, produces the product of wanting (0.432g, 96%),＞95% purity.Isolating material need not to be further purified and to use.
[0330] 3-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-3-oxo-2-(triphenyl-λ 5-phosphanylidene)-propionitrile.To contain 5-tert-butyl-2-right-tolyl-2H-pyrazoles-3-carboxylic acid (0.432g, 1.67mmol) round-bottomed flask, add 50mL DCM, and then add (triphenyl-15-phosphanylidene)-acetonitrile (0.635g, 2.0mmol), EDCI (0.394g, 2.0mmol) and DMAP (0.024g, 0.2mmol).Make reaction mixture stir 16hr at room temperature, under vacuum, concentrate then.Thick residue produces the product of wanting, white powder (0.722g, 81%) by flash chromatography (0-20%EtOAc:DCM is on silica gel) purifying.
[0331] (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-oxo-acetic acids methyl esters: to containing 3-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-3-oxo-2-(triphenyl-15-phosphanylidene)-propionitrile (0.722g, 1.3mmol) the 100mL round-bottomed flask, add 25mL DCM and 25mL methyl alcohol.Initial substance fully is dissolved in the solvent mixture, and after this, (25mL, 0.1M is in acetone) joins in the reaction with dimethyldioxirane (dimethyl dioxirane).The solution of gained was stirred 30 minutes at room temperature, after this, reaction mixture is concentrated under vacuum, thick material is by flash chromatography (0-20% EtOAc:DCM is on silica gel) purifying, the ketone-ester that obtains wanting (keto-ester), be white solid (0.359g, 92%).
[0332] 2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide (35, R=Me).(0.359g 1.19mmol), adds 2mL THF and 2mL 1N LiOH to (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl) in the 40mL scintillation vial-oxo-acetic acids methyl esters.Be reflected at 50 ℃ of heating 1hr, after this, concentrated reaction mixture under the vacuum, crude product dilutes with 5mL 1N HCl.(3 * 25mL) extract, and the organic layer of merging passes through MgSO with salt solution (10mL) washing with DCM with reaction slurry then 4Dry.The solution of gained concentrates under vacuum, the acid that obtains wanting.
[0333] then pure acid is dissolved among the DCM of minimum quantity ,～2mL, and add oxalyl chloride (5mL), add a DMF again.Suspension is stirred 1hr at room temperature, under vacuum, concentrate then.The solid of gained is dissolved among the EtOAc (10mL), and joins and be dissolved in EtOAc (10mL)/50%NaHCO 34-(10mL) (2-morpholine-4-base-oxyethyl group)-naphthalene-1-base amine (0.41g, 1.2mmol) in, and stir and spend the night.Mixture dilutes with EtOAc, and uses NaHCO 3Washing.The waterbearing stratum extracts twice again with 30mL EtOAc, and the salt water washing of the organic layer of merging is through MgSO 4Drying is filtered, and removes under vacuum and desolvates, and obtains Vandyke brown oil.This material produces the compound of wanting of 0.250g (47%) by column chromatography (0-100%EtOAc/DCM) purifying, is the xanchromatic solid.
[0334] 6-Boc-amino-naphthalene-1-alcohol.(5g 31.4mmol) is suspended in 50mL 0.5NNaHCO with 6-amino-naphthalene-1-alcohol 3In 50mL EtOAc.Add Boc 2(6.85g's O 31.4mmol), and spends the night reaction mixture 60 ℃ of stirrings.Initial substance transforms fully.Separate solvent layer, organic layer washes with water, through MgSO 4Drying, evaporation produces target substance.
[0335] [(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-t-butyl carbamate.With the compound that obtains above (8.14g 31.4mmol) is dissolved among the 100mL AcN, and add 4-(2-chloro-ethyl)-morpholine (5.80g, 34.5mmol) and K 2CO 3(15.6g, 0.11mol).Being reflected at 75 ℃ of stirrings spends the night.Mixture is filtered, solvent evaporated, residue produces the target product of 0.51g by silica gel chromatography (DCM/MeOH:15/1) purifying.Quality=372 of calculating.Quality=372 of observation.
[0336] 6-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-base-Boc-amine (36).At room temperature, (1g is 2.7mmol) in 95%TFA/DCM/Et for the material that Boc is protected 3SiH stirred some days.After the evaporation, obtain target substance.Quality=272 of calculating.Quality=272 of observation.
Synthesizing of embodiment 4-imidazopyridine and imidazopyrimidine
[0337] in the presence of DIEA, perhaps in microwave (two _ alkane, 180 ℃, 10min), perhaps at room temperature (THF, 70h), with 2,6-two chloro-nitro-pyridines or 2,4-dichloro pyrimidine and the steady coupling of various amine, as be illustrated in the top scheme, and be described among method A and the method B.
Method A:
[0338] (6-chloro-3-nitro-pyridine-2-yl)-phenyl-amine.Will be in 3mL two _ alkane 2,6-two chloro-3-nitropyridines (386mg, 2mmol), aniline (182 μ L, 2mmol) and DIEA (419 μ L, mixture 2.4mmol) heats 10min at 180 ℃ in microwave.Except that after desolvating, residue is dissolved among the 3mL DCM, carry out the silicagel column purifying, obtain 308mg (yield 61.7%) (6-chloro-3-nitro-pyridine-2-yl)-phenyl-amine.Quality=249 of calculating.Quality=250 of observation.
Method B:
[0339] (6-chloro-3-nitro-pyridine-2-yl)-phenyl-amine.Will be in 10mL THF 2,6-two chloro-3-nitropyridines (772mg, 4mmol), aniline (364 μ L, 4mmol) and DIEA (838 μ L, mixture 24.8mmol) stirs 70h at room temperature.Except that after desolvating, residue is dissolved in DCM, carry out the silicagel column purifying, obtain the title compound of 735mg (yield 74%), LC-MS: the quality of calculating=249.Quality=250 of observation.
[0340] 3-amino-6-chloro-pyridine-2-base-right-tolyl-amine.Will in the 6-chloro-3-nitro-pyridine-2-base-right-tolyl-amine among the dense HCl of 4mL (527mg, 2mmol) and tin chloride dihydrate (II) (2.72g, mixture 12mmol), 90 ℃ the heating 2h.After the cooling, yellow suspension is diluted with ethyl acetate,, use moisture K at 0 ℃ 2CO 3Under vigorous stirring, handle pH regulator to 10.Milk sap extracts with 5 * 30mL EtOA.The organic phase of combination is through Na 2SO 4Dry.Evaporation obtains 479mg (output: quantitative) title compound, and this compound need not any purifying and just is used for next step reaction by the LC-MS purifying.Quality=233 of calculating.Quality=234 of observation.
[0341] 5-chloro-3-right-tolyl-1, the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones (37) also.Will the amino of the 3-among the 10mL DMF-6-chloro-pyridine-2-base-right-tolyl-amine (470mg, 2mmol) and DSC (768mg, mixture 3mmol) in 80 ℃ the heating 15h.After cooling down, red solution dilutes with EtOAc, with saturated sodium bicarbonate solution washing 2 times, washes with water 2 times.Organic phase dried over sodium sulfate, evaporation obtain 540mg (quantitatively output) pink solid.TLC shows a single point (R f=0.32, in DCM/MeOH (15: 1)).LC-MS analysis revealed compound is pure, is used for next step.Quality=259 of calculating.Quality=260 of observation.
Figure A20048003305502012
[0342] 1-two ring [2.2.1] heptan-2-base-5-chloro-3-right-tolyl-1, the 3-dihydro-imidazol-also [4,5-b] pyridin-2-ones (38) and 2-(two rings [2.2.1] heptan-the basic oxygen of 2-)-5-chloro-3-right-tolyl-3H-imidazo [4,5-b] pyridines (39).Will-tolyl-1 right in the 5-chloro-3-among the 1.5mL DMF, the 3-dihydro-imidazol-also [4,5-b] pyridin-2-ones (52mg, 0.2mmol), outer-2-bromine norbornane (103 μ L, 0.8mmol) and Cs 2CO 3(195mg, mixture 0.6mmol) heat 20min at 200 ℃ in microwave.After the filtration, filtrate is diluted with EtOAc, washes with water.Concentrate organic phase, residue is dissolved among the DCM of minimum quantity, carry out the silicagel column purifying, obtain 21.2mg (yield: 30%) 1-two ring [2.2.1] heptan-2-base-5-chloro-3-right-tolyl-1, the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones (Rf=0.60 also, in DCM), and 6.2mg (yield: 9%) 2-(two rings [2.2.1] heptan-2-base oxygen)-5-chloro-3-right-tolyl-3H-imidazo [4,5-b] pyridine (Rf=0.49 is in DCM).Quality=353 of calculating.Quality=354 of observation.
Figure A20048003305502021
[0343] 1-two ring [2.2.1] heptan-2-base-5-phenylamino-3-right-tolyl-1, the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones (40) also.Will-tolyl-1 right in the 1-in 1mL two _ alkane two ring [2.2.1] heptan-2-base-5-chloro-3-, the 3-dihydro-imidazol-also [4,5-b] pyridin-2-ones (19mg, 0.054mmol), 15 μ L (0.16mmol) aniline, part (5.1mg, 0.015mmol), Pd 2(dba) 3(6.9mg, 0.0075mmol), t-BuOK (56mg, mixture 0.162mmol), 100 ℃ the heating 6h.Preparation LC-MS provides the tfa salt of the title compound of 3.2mg.Quality=410 of calculating.Quality=411 of observation.
Figure A20048003305502022
[0344] 2,6-two (right-tolyl amino)-3-nitro-pyridine (X=C).Will be in 3mL two _ alkane 2,6-two chloro-3-nitropyridines (193mg, 1mmol), right-tolyl amine (236mg, 2.2mmol) and DIEA (524pL, mixture 3mmol) stir 20min in 200 ℃ in microwave.Except that after desolvating, residue is dissolved in the chloroform, carry out the silicagel column purifying, obtain 291mg (yield: title compound 87%).Quality=334 of calculating.Quality=335 of observation.
[0345] 2,6-two (right-tolyl amino)-3-nitro-pyrimidine (X=N).Will be in 3mL two _ alkane 2,6-two chloro-3-nitro-pyrimidines (194mg, 1mmol), right-tolyl amine (236mg, 2.2mmol) and DIEA (524 μ L, mixture 3mmol) stir 20min in 200 ℃ in microwave.Except that after desolvating, residue is dissolved in the chloroform, carry out the silicagel column purifying, obtain 319mg (yield: title compound 95%).Quality=335 of calculating.Quality=336 of observation.
Figure A20048003305502031
[0346] 3-amino-2,6-(two-right-tolyl amino)-pyridine.Will be in the dense HCl of 3mL 2,6-two (right-tolyl amino)-3-nitro-pyridine (288mg, 0.86mmol) and tin chloride dihydrate (II) (1.25g, 5.5mmol), at 90 ℃ of heating 2h.After cooling down, suspension is diluted with ethyl acetate,, under vigorous stirring, use moisture K at 0 ℃ 2CO 3Handle, to pH 10.Milk sap extracts with 5 * 30mL EtOAc.Blended organic phase Na 2SO 4Dry.Evaporation, (yield: title compound 97%), through the LC-MS analysis, this compound is pure, need not any purifying, just is used for further reaction to obtain 254mg.Quality=304 of calculating.Quality=305 of observation.
[0347] 3-amino-2,6-(two-right-tolyl amino)-pyrimidine.With 2,6-two (right-tolyl amino)-3-nitro-pyrimidine is handled with previously described method, produces title compound, analyzes through LC-MS, and this compound is pure, need not any purifying, just is used for further reaction.Quality=305 of calculating.Quality=306 of observation.
Figure A20048003305502033
[0348] 3-right-tolyl-5-is right-tolyl amino-1, the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones (41) also.Will be in the 3-amino-2 among the 6mL DMF, 6-(two-right-tolyl amino)-pyridine (254mg, 0.84mmol) and DSC (323mg, mixture 1.26mmol) 80 ℃ the heating 20h.After cooling down, red solution dilutes with EtOAc, with saturated sodium bicarbonate solution washing 2 times, washes with water 2 times.The organic phase dried over sodium sulfate concentrates, and carries out the silicagel column purifying, obtains 266mg (yield: title compound 96%).LC-MS: the quality of calculating=330.Quality=331 of observation.
[0349] 1-two ring [2.2.1] heptan-2-base-3-right-tolyl-5-is right-tolyl amino-1,3-dihydro-imidazol-also [4,5-b] pyridin-2-ones (42) and [2-(two rings [2.2.1] heptan-2-base oxygen)-3-right-tolyl-3H-imidazo [4,5-b] pyridine-5-yl]-right-tolyl-amine (43).Will-tolyl-5-right right-tolyl amino-1 in the 3-among the 0.5mL DMF, the 3-dihydro-imidazol-also [4,5-b] pyridin-2-ones (33mg, 0.1mmol), outer-2-bromine norbornane (19 μ L, 0.15mmol) and Cs 2CO 3(65mg, mixture 0.2mmol) is at 180 ℃ of heating 3h.After cooling down, add EtOAc, organic layer washes with water.Concentrate organic phase, residue is dissolved among the DCM of minimum quantity, carry out the silicagel column purifying, obtain 13.4mg (yield: 32%) 1-two ring [2.2.1] heptan-2-base-3-right-tolyl-5-is right-tolyl amino-1,3-dihydro-imidazol-also [4,5-b] pyridin-2-ones (Rf=0.44, in DCM), and 4.8mg (yield: 11%) [2-(two rings [2.2.1] heptan-2-base oxygen)-3-is right-tolyl-3H-imidazo [4,5-b] pyridine-5-yl]-right-tolyl-amine (R 0.27, in DCM).
The general procedure of 5: two fluoro-acetogenins of embodiment
[0350] two fluoro-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-methyl acetate (44).To being dissolved in CH 2Cl 2Ketone-ethyl ester 12 (20mL) (0.618g, 1.80mmol) solution, add diethylaminosulfur trifluoride (1.70mL, 13.8mmol) and EtOH (3).Solution was stirred 3 days at room temperature.The saturated NaHCO of mixture 3CH is used in neutralization 2Cl 2(3 * 20mL) extract.MgSO is used in the organic layer salt water washing that merges 4Drying is filtered, and removes and desolvate.By the thick material of preparation LCMS purifying, produce the oil of 70mg (10% yield).Prospective quality=365.Quality=366 of observation.
Figure A20048003305502051
[0351] N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2,2-two fluoro-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide (45).With 44 saponification of difluoro methyl esters, be converted into chloride of acid, and according to the preceding method coupling.Prospective quality=562.Quality=563 of observation.
Embodiment 6: diamide derivatives synthetic
Figure A20048003305502052
[0352] N-naphthalene-1-base-oxaminic acid methyl esters (oxalamic acid methyl ester).The naphthalidine that contains in DCM (5mL) and just stirring (0.1g, round-bottomed flask 0.68mmol), add DIEA (0.18mL, 1.02mmol) and chloro-oxo-acetic acids methyl esters (0.068mL, 0.748mmol).Make mixture at stirring at room 1h.Reaction mixture is poured into saturated sodium bicarbonate, and separating layer.The waterbearing stratum is with more than 3 * 15mL DCM washed twice.The organic layer salt water washing that merges is through MgSO 4Drying concentrates in the vacuum, obtains brown solid.Thick material flash chromatography (0-50%EtOAc: hexane, on silica gel) purifying.Thick material is purified, produces the product of wanting (0.14g, 90%), is pale solid.Prospective quality=229.Quality=230 of observation.
[0353] N-naphthalene-1-base-oxaminic acid (oxalamic acid).(0.14g 0.61mmol), adds the lithium hydroxide solution of 2mL to the N-naphthalene that is stirring in THF (2mL)-1-base-oxaminic acid methyl esters.Reaction is heated to 50 ℃, and stirs 2h.With concentrating in the mixture vacuum of gained, obtain yellow residue, the 1N HC acidifying of this residue.(3 * 50mL) extract the mixture of gained, through MgSO with DCM 4Drying concentrates in the vacuum, obtains crude product.Crude product flash chromatography (0-20%MeOH:DCM, silica gel) purifying, the product that obtains wanting (0.128g, 98%) is thick oil.Prospective quality=215.Quality=216 of observation.
[0354] N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-N '-naphthalene-1-base-oxamide (46).Contain in DCM (5mL) N-naphthalene-1-base-oxaminic acid of stirring (0.128g, in round-bottomed flask 0.6mmol), add DIC (0.09g, 0.72mmol) and DIEA (0.19mL, 1.08mmol).Reaction is stirred at room temperature spend the night, with the saturated NaHCO of 10mL 3Termination reaction.Separate each layer, extract third time with 2 * 25mL DCM in the waterbearing stratum again.The organic layer salt water washing that merges is through MgSO 4Drying concentrates under vacuum, obtains brown oil.Crude mixture flash chromatography (50-100 EtOAc: hexane, silica gel) purifying, the product that obtains wanting (184g, 72%) is pale solid.Prospective quality=426.Quality=427 of observation.
Embodiment 7: the general procedure that 9 oxime derivate forms
Figure A20048003305502061
[0355] N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oximido-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide (47).(10mg, 0.018mmol) (50eqv., 0.92mmol 64mg) are dissolved among the EtOH of 2mL with the hydrochloric acid oxyamine with compound 13.Add pyridine (0.1mL), mixture stirs 12h at 45 ℃.Remove in the vacuum then and desolvate, thick solid produces white solid (58% yield of 6mg through the LCMS purifying; Isomer mixture).Prospective quality=555.Quality=556 of observation.
Figure A20048003305502062
[0356] N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-methoxyimino-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide (48).With compound 13 (10mg, 0.018mmol) and methoxy-amine hydrochloride (50eqv., 0.92mmol 77mg) are dissolved among the EtOH of 2mL.Add pyridine (0.1mL), mixture stirs 12h at 45 ℃.Remove in a vacuum then and desolvate, thick solid produces white solid (76% yield of 8mg by the LCMS purifying; Mixture of isomers).Prospective quality=569.Quality=570 of observation.
Embodiment 8
Figure A20048003305502071
[0357] 4-(morpholine-4-base-oxyethyl group)-1-naphthyl epoxide (naphthylepoxide).To the NaH in DMSO (1mL) (24mg, in suspension 1.0mmol), add Trimethylsulfoxonium Iodide (trimethylsulfoxoniumiodide) (220mg, 1.0mmol).Stop to produce H 2Afterwards, (mixture stirs 12h at 20 ℃ for 285mg, 1.0mmol) solution to add the aldehyde 8 that is dissolved among the DMSO (0.5mL).Mixture H 2Et is used in the O dilution 2O extracts, the dry organic layer (MgSO that merges 4), rotary evaporation obtains yellow oil, and this oil need not any further purifying and just is used for next step.Prospective quality=299.Quality=300 of observation.
[0358] N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethamine (49).At 20 ℃, in N 2Down, to being dissolved in 1, (50mg 0.2mmol) in the solution, adds n-Butyl Lithium (n-BuLi) (2.0M is in hexanaphthene for 0.1mL, 0.2mmol) to 5-amino-3-tert-butyl-1-(4 aminomethyl phenyl) pyrazoles (1) in 4-two _ alkane (2mL).The solution that adds the compound that obtains in the previous reaction that is dissolved among the DMF (1mL), and at 150 ℃, in microwave, heating brown mixture 5min.Mixture CH 2Cl 2Dilution washes dry organic layer (MgSO with water 4), rotary evaporation obtains brown oil, and this oil obtains title compound (8.3mg, 8%) by preparation type LC-MS purifying, is yellow waxy solid: the quality of calculating=528.Quality=529 of observation.
Synthesizing of embodiment 9-triazolidine-derovatives
Approach A:
[0359] N '-(3-tert-butyl-phenyl)-hydrazine carboxylic acid's ethyl ester.(600mg 3mmol) is dissolved among the 15mL DCM, and (1.7mL 10mmol), adds Vinyl chloroformate (3mmol) again to add DIEA with 3-tertiary butyl hydrazine hydrogenchloride (3-t-Butylhydrazinehydrochloride).Reaction mixture stirs at room temperature and spends the night, and checks by aqueous carbonic acid hydrogen sodium again.Organic phase is through Na 2SO 4Drying concentrates, and (4 * 12g) purifying obtain the 437mg product, are brown oil to carry out the ISCO post.
[0360] 1-(3-tert-butyl-phenyl)-4-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-[1,2,4] triazolidine-3,5-diketone (50).(70mg 0.2mmol) is dissolved in (0 ℃) 4mL DCM and the saturated NaHCO of 4mL with 4-(2-N-morpholino oxyethyl group) naphthylamines dichloride hydrogen (naphthyamine dihydrochloride) 3In cold (0 ℃) mixture of solution.Stop to stir.After the ca.20% phosgene of 0.36mL that will be in toluene joins the DCM layer, continue violent stirring.Be reflected at 0 ℃ of lasting 30min.Separate organic layer, extract once with DCM in the waterbearing stratum.With the organic layer evaporation that merges.(47mg, 0.2mmol) solution joins in the thick isocyanic ester will to be dissolved in N '-(3-tert-butyl-phenyl)-hydrazine carboxylic acid's ethyl ester among the 1mL DCM.Reaction mixture stirs at room temperature and spends the night.Remove and desolvate, residue is dissolved among the DMSO, and is prepared the LC-MS purifying, obtain the target compound of 8.4mg.(8.4mg 0.016mmol) is dissolved among the 1mL EtOH compound that will obtain in abovementioned steps, adds the NaOH (2mg, 0.05mmol) solution that are dissolved in the 0.2mL water.The mixture of gained stirs 2hr at room temperature, then with the dense HCL pH4 that neutralizes.The purifying of thick material is finished by preparation LC-MS, obtains the 6mg final product.
Approach B
Figure A20048003305502091
[0361] 1-tert-butyl-3-isocyanato-benzene.(150mg 1mmol) is converted into isocyanic ester, as mentioned above, and is dissolved among the 4mL DCM with 3-tert-butyl-aniline.(104mg, 1mmol), reaction continues to spend the night at room temperature to add Hydrazate.Through preparation LC-MS purifying, obtain the target compound of 181mg, be white solid.
[0362] carbonyl ethyl 2-[(tolyl amino)] hydrazinecarboxylate (hydrazinecarboxylate).At room temperature, (121mg 0.68mmol) joins 1-tert-butyl-3-isocyanato-benzene (181mg, stirred suspension 0.65mmol) in 3mL DCM and 105 μ l pyridines with NBS.Behind the restir 2hr, add the water of 2mL, add the dense HCl of 1mL again.Separate organic phase, and with the Na that is dissolved in the 3mL water 2S 2O 3(65mg) solution, saturated NaHCO 3And water washing.Organic phase is through Na 2SO 4Drying concentrates, and obtains the target compound of 182mg, is ruddy viscous crude.
[0363] 4-(3-tert-butyl-phenyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-[1,2,4] triazolidine-3,5-diketone (51).At-30 ℃, will be dissolved in the compound that obtains above among the 1.5mL DCM (55mg, 0.2mmol) and 1-(2-morpholino oxyethyl group)-(51mg, cold soln 0.2mmol) dropwise join the ZrCl in 0.5mL DCM to naphthalene 4Stirred suspension in.Be reflected at-30 ℃ of lasting 45min, then it be warming up to room temperature, add the water of 1mL, to finish reaction.Use saturated NaHCO 3Neutralize.Separate organic phase, contain water and extract with DCM.The organic phase that merges is through Na 2SO 4Drying concentrates, and is prepared the LC-MS purifying, obtains the target compound of 22.8mg.
[0364] (22.8mg 0.43mmol) is dissolved among the 2mL EtOH with the compound that obtains above.Add the NaOH (4mg, 1mmol) solution that are dissolved in the 0.4mL water.After stirring 2hr in the room temperature, reaction mixture neutralizes (to pH=4) with dense HCl, directly is prepared the LC-MS purifying, obtains the 7mg final product.
Embodiment 10
Figure A20048003305502101
[0365] N-(5-tert-butyl-3-sulfonyloxy methyl amino-2-methoxyl group-phenyl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-succinamic acid methyl esters (52).(250mg, 0.43mmol), (156mg is 0.52mmol) with two diisopropylethylamine to add ylide to the ketone-acid amides that is stirring in toluene (13b).To react sealing, and be heated to 100 ℃ and spend the night.To react cool to room temperature, and under vacuum, concentrate.Crude product produces two kinds of isomer of independent separate by the LCMS purifying, is white solid (105mg, 84%).Two kinds of isomer all are used for next step.
[0366] N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-succinamic acid methyl esters (53).(75mg, the round-bottomed flask of 50mL 0.12mmol) is with nitrogen jet (sparge) 5min will to contain the succinamic acid that obtains in ethyl acetate and the superincumbent reaction.The solution of gained places under the nitrogen, and handles with 10%Pd/C (10 moles of %).Make air and hydrogen exchange by balloon then, and will be reflected at stirring at room 16h.The solution of gained filters by Celite pad (pad of celite), and concentrated filtrate produces crude product in a vacuum.This thick material produces the product of wanting by the flash chromatography purifying, is white solid (65mg) that yield is 87%.
[0367] N-(5-tert-butyl-2-methoxyl group-3-{3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,5-dioxo-2,5-dihydro-pyrroles-1-yl }-phenyl)-sulfonyloxy methyl amine (54).In the 40mL scintillation vial, place 3-(5-tert-butyl-3-sulfonyloxy methyl amino-2-methoxyl group-phenylcarbamoyl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-methyl acrylate 51 (25mg, 0.04mmol), DIEA (13.6mL, 0.08mmol) and 5mL THF.Reaction is heated to 80 ℃, stirs 16 hours.Concentrate the reaction mixture of gained in a vacuum, thick residue obtains the compound that (10.2mg, 39%) is wanted by anti-phase preparation LC-MS purifying.Quality=607 of calculating.Quality=608 of observation.
[0368] N-(5-tert-butyl-2-methoxyl group-3-{3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,5-dioxo-tetramethyleneimine-1-yl }-phenyl)-sulfonyloxy methyl amine (55).In the 20mL scintillation vial, place (28mg, 0.046mmol) N-(5-tert-butyl-2-methoxyl group-3-{3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,5-dioxo-2,5-dihydro-pyrroles-1-yl }-phenyl)-sulfonyloxy methyl amine, 5mL ethanol and Pd/C (15mg, 10 moles of %).The scintillation vial diaphragm seal, reaction mixture sprayed 10 minutes with indoor nitrogen (house nitrogen).Solution with gained sprayed 5 minutes by balloon with hydrogen then.Balloon is reloaded after the hydrogen, and reaction was stirred 2 hours at room temperature.The solution of gained filters by Celite pad, and concentrates the product that obtains wanting (27mg, 100%) in a vacuum.Quality=610 of calculating.Quality=611 of observation.
Embodiment 11
[0369] hydroxyl-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-methyl acetate.12 solution in being dissolved in MeOH (10mL) (1g 2.9mmol), adds Pd/C (10wt%), and at room temperature, at H 2Under the atmosphere, stir the mixture.In case (by the LCMS monitoring) finished in reaction, and mixture is filtered by diatomite, with the filtrate evaporation, obtains xanchromatic oil, just solidifies during stagnation.Quality=345 of calculating.Quality=345 of observation.
[0370] [4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-acetate.(0.5g) is dissolved in CH with yellow solid 2Cl 2(10mL).Add TFA (10mL) and Et to this solution 3(10eq. 30mmol), stirs mixture SiH at room temperature, finishes (at the Et that adds 10eq. again up to reaction 3Behind the SiH, shown in LCMS).Evaporating solvent, residue grinds with hexane.Sedimentary product is filtered, use hexane wash, drying in the vacuum, and be absorbed into MeOH/THF (1: 1,10mL).Add 2M NaOH (2.2mL) to this solution, and with mixture at stirring at room 4h.Mixture evaporates with 6M HCl neutralization, provides the brown residue.Residue absorbs repeatedly with the MeOH of minimum quantity, and is filtered by residual NaCl.Solvent evaporated, acid are in a vacuum in 50 ℃ of dryings.Quality=315 of calculating.Quality=315 of observation.
[0371] N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide (56).To in CH 2Cl 2Sour suspension (5mL) adds oxalyl chloride (10eq) and a DMF.Mixture is Rapid Cleaning under the situation that produces gas, and stirs 4h at room temperature.Evaporating solvent provides foam residue, and this foam residue is dry in a vacuum, and uses CH once more 2Cl 2Handle (take up) (5mL).Add DIEA (3eq) and 14 (1.2eq) to this solution, mixture is stirred 60h at room temperature.Brown solution H 2The O washing, dry (MgSO 4) and evaporation.The brown residue as elutriant, obtains final product with EtOA by column chromatography purifying on silicon-dioxide, is light yellow solid.Quality=569 of calculating.Quality=569 of observation.
Embodiment 12
Figure A20048003305502121
[372] N '-(5-tert-butyl-3-second month in a season the-butyl formamyl-2-methoxyl group-aniline carbonyl)-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-methylene radical }-hydrazine carboxylic acid's ethyl ester.(44mg 0.077mmol) is dissolved among the EtOH (1mL), and (24mg is 0.231mmol) with 1 AcOH to add hydrazine carboxylic acid's ethyl ester with compound 30.At 120 ℃, reaction mixture is stirred 15hr, after this, crude mixture is by the LC/MS purifying.The separating isomerism body, and the isomer that will want is used for next step.Quality=660 of calculating.Quality=660 of observation.
[0373] 5-tert-butyl N-cyclopropyl-2-methoxyl group-3-{6-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-3,5-dioxo-2,5-dihydro-3H-1,2,4-triazole-4-yl }-benzamide (57).With the compound that obtains in the step in front (～8mg 0.1mmol) is dissolved among the EtOH, add DIEA (0.1ml, 0.6mmol).Mixture spends the night 120 ℃ of stirrings, then by the LC/MS purifying, obtains the target product of 2.5mg.Quality=614 of calculating.Quality=614 of observation.
Embodiment 13: the inhibition that TNFa produces in the THP cell.
[0374] inhibition of pair cell factor generation can be observed (referring to Prichett et al.J.Inflammation, 1995,45,97) to the inhibition of TNFa by measuring in the THP-1 of lipopolysaccharides-stimulation cell.(Rockville MD) is maintained at 37 ℃ to the THP-1 cell, the 5%CO of RPMI 1640 substratum for ATCC TIB 202, American Type Culture Collection 2Down, RPMI 1640 substratum contain 10% foetal calf serum, 10mMHepes, 1mM Sodium.alpha.-ketopropionate, 4.5g/L glucose and 0.05mM 2 mercapto ethanol, and are indicated as ATCC.For mensuration, cell and compound dilute with above-mentioned substratum, except with (mensuration substratum) 1% foetal calf serum.Test compounds stock in DMSO is diluted into the mensuration substratum, is 6 * finally to measure concentration, and the final DMSO concentration in the mensuration is 0.3%.With the THP-1 cell with 1 * 10 5/ hole is layered in the 96 hole tissue culturing plates.Add the compound (or DMSO contrast) of dilution, before LPS (Sigma) is added to ultimate density 1 μ g/mL, allow at 37 ℃ 5%CO 2In with cell preincubation 30 minutes.Cell is then at 37C/5%CO 2The middle 18-20h that cultivates.Stopped in 10 minutes measuring by centrifugal plate at room temperature.Remove supernatant liquor with the cleaning culture plate, and duplicate samples such as shift out, be used for by commercially available ELISA test kit (R﹠amp; D Systems#DY210, Minneapolis MN) analyzes TNFa.(San Diego, PRISM 4 softwares CA) are by non--linear regression method analytical data from Graphpad Software in use.The IC that calculates 50Be to cause that maximum TNFa produces the concentration of the test compounds of minimizing 50%.
Embodiment 14
[0375] table 1 has been listed the compound of the present invention with the method preparation of embodiment 1-13.Each compound is all analyzed with LC-MS, and has showed the molion (molecular ion) of expection.Each compound in the table 1 is tested in TNFaELISA measuring method (embodiment 13), has activity in the concurrent present mensuration, the IC of some compounds in this is measured 50Be lower than 10 μ M.
Table 1
Compound number The compound title Calculate MW
2 1H-indazole-3-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazoles-3-yl)-acid amides 373
7 3-tert-butyl-5-phenyl-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also 330
13 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 541
15 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 584
17 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide 634
22 N-(5-tert-butyl-2-hydroxyl-3-morpholine-4-ylmethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 576
23 N-(5-tert-butyl-2-hydroxy-3-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 491
24 N-(5-tert-butyl-2-methoxyl group-3-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 505
26 N-(5-tert-butyl-3-chloro-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 525
28 N-(5-tert-butyl-2-methoxyl group-3-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 559
29 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[7-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 575
30 5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 574
31 N-[5-tert-butyl-2-methoxyl group-3-(piperidines-1-carbonyl)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 602
32 5-tert-butyl-2-hydroxyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenylformic acid 521
33 N-(2-benzenesulfonyl-5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 591
35 2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 541
40 1-two ring [2.2.1] heptan-2-base-5-phenylamino-3-is right-tolyl-1, and the 3-dihydro- 411
Compound number The compound title Calculate MW
Imidazo [4,5-b] pyridin-2-ones
41 3-is right-and tolyl-5-is right-tolyl amino-1, the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones also 330
42 1-two ring [2.2.1] heptan-2-base-3-is right-and tolyl-5-is right-tolyl amino-1, the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones also 425
45 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2,2-two fluoro-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 563
46 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-N '-naphthalene-1-base-oxamide 427
47 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 556
48 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 570
49 2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl amino)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanol 529
50 1-(3-tert-butyl-phenyl)-4-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-[1,2,4] triazolidine-3, the 5-diketone 489
51 4-(3-tert-butyl-phenyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-[1,2,4] triazolidine-3, the 5-diketone 489
52 (E)-3-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylcarbamoyl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-methyl acrylate 640
54 N-(5-tert-butyl-2-methoxyl group-3-{3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,5-dioxo-2,5-dihydro-pyrroles-1-yl }-phenyl)-Toluidrin 608
55 N-(5-tert-butyl-2-methoxyl group-3-{3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,5-dioxo-tetramethyleneimine-1-yl }-phenyl)-Toluidrin 610
56 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 570
57 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-[4-(2-piperidines-1-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-ethanamide 632
58 3-tert-butyl-1-is right-tolyl-5-(3-trifluoromethyl-phenyl)-1, and 6-dihydro-imidazo [4,5-c] pyrazoles 398
59 1-(2-morpholine-4-base-ethyl)-1H-indazole-3-carboxylic acid (5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-acid amides; 530
Compound number The compound title Calculate MW
60 N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-2-(2,4,6-trimethylammonium-phenyl)-ethanamide 447
61 1-phenyl-cyclopropane-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazoles-3-yl)-acid amides 373
62 N-[5-tert-butyl-2-(2,5-two fluoro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 563
63 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 491
64 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-ethanamide 485
65 N-[5-tert-butyl-2-(3-chloro-benzoyl group)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 589
66 N-[5-tert-butyl-2-(3-methylsulfonyl-phenyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 605
67 4-[(5-tert-butyl-2-is right-tolyl-2H-pyrazole-3-yl formamyl)-methyl]-piperidines-1-carboxylic acid tert-butyl ester 455
68 N-[3-(benzenesulfonyl-carbamyl ylmethyl-amino)-5-tert-butyl-2-methoxyl group-phenyl]-2-naphthalene-1-base-2-oxo-ethanamide 574
69 N-(3-tert-butyl-different _ azoles-5-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 452
70 N-(5-tert-butyl-3-ethanesulfonamido-2-methoxyl group-phenyl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-the succinamic acid methyl esters 656
71 2-(2-benzyl-5-tert-butyl-2H-pyrazole-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 541
72 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 590
73 5-tert-butyl-2-(3-chloro-phenyl)-2H-pyrazoles-3-carboxylic acid [4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-acid amides 533
74 2-(3-bromo-4-methoxyl group-phenyl)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-ethanamide 456
75 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[3-fluoro-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-ethanamide 495
76 (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-(2,2-dimethyl-propyl group)-amine 299
Compound number The compound title Calculate MW
77 2-(4-benzyloxy-phenyl)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-ethanamide 454
78 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 543
79 N-[5-tert-butyl-2-(4-sulphonamide-phenyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-base-2-oxo-ethanamide 606
80 5-tert-butyl-2-methoxyl group-3-(1-naphthalene-1-base-3,5-dioxo-[1,2,4] triazolidine-4-yl)-benzamide 432
81 2-(4-bromo-naphthalene-1-yl)-N-(5-tert-butyl-2-methyl-2H-pyrazoles-3-yl)-2-oxo-ethanamide 414
82 5-tert-butyl-2-hydroxyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 520
83 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-(4-methoxyl group-naphthalene-1-yl)-ethanamide 444
84 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide 631
85 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-methylamino--pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 484
86 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 498
87 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-{4-[2-(I-oxo-1 λ 4-thiomorpholine-4-yl)-oxyethyl group]-naphthalene-1-yl }-ethanamide 573
88 The 5-tert-butyl-3-{2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid methyl esters 540
89 N-[5-tert-butyl-2-(3-methylsulfonyl-phenyl)-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 607
90 N-(5-tert-butyl-2-right-tolyl-2H-pyrazoles-3-yl)-2-{4-[2-((2R, 6R)-2,6-dimethyl-morpholine-4-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide 569
91 N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide 512
92 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[7-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 618
Compound number The compound title Calculate MW
93 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 599
94 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide 538
95 5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-[2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-kharophen]-benzamide 475
96 4-tert-butyl-N-[4-(2-piperidines-1-base-oxyethyl group)-naphthalene-1-yl]-benzamide 431
97 N-(2-ethanoyl-5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 493
98 5-tert-butyl-N-cyclopropyl-3-{2-hydrazono--2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-2-methoxyl group-benzamide 588
99 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-hydroxyl-2-(4-methoxyl group-naphthalene-1-yl)-propionic acid amide 408
100 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-phenyl-ethanamide 361
101 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-hydrazono--2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 598
102 2,3-dihydro-indoles-1-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides 374
103 N-(3,4-dimethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 433
104 N-(5-tert-butyl-2-cyclohexyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 533
105 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(3,5-two fluoro-phenyl)-ethanamide 383
106 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-oxo-2-(4-pyridin-3-yl-naphthalene-1-yl)-ethanamide 439
107 N-(5-tert-butyl-different _ azoles-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 467
108 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-diethylin-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 570
109 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-{4-[2-(3-oxo-[1,4] Diazesuberane-1-yl)-ethyl]-naphthalene-1- 552
Compound number The compound title Calculate MW
Base }-ethanamide
110 5-tert-butyl-N-ethyl-2-methoxyl group-3-[2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-kharophen]-benzamide 463
111 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-oxo-2-{4-[6-(tetrahydrochysene-pyrans-4-base is amino)-pyridin-3-yl]-naphthalene-1-yl }-ethanamide 538
112 5-tert-butyl-3-ethanesulfonamido-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-benzamide 570
113 Between 2-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-oxo-N--tolyl-ethanamide 299
114 N-(2,5-dimethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 433
115 Tetramethyleneimine-1-carboxylic acid (5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-acid amides 603
116 2-(4-bromo-phenyl)-N-(5-tert-butyl-2-methoxyl group-phenyl)-ethanamide 376
117 N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-oxo-2-{4-[2-((S)-1-phenyl-ethylamino)-pyrimidine-4-base is amino]-naphthalene-1-yl }-ethanamide 589
118 5-tert-butyl-3-[1-(2,3-dimethyl-phenyl)-3,5-dioxo-[1,2,4] triazolidine-4-yl]-2-methoxyl group-benzamide 410
119 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-naphthalene-2-base-ethanamide 398
120 5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 534
121 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-methoxyl group-2-(4-methoxyl group-naphthalene-1-yl)-propionic acid amide 472
122 5-tert-butyl-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-ylmethyl]-3-nitro-benzamide 522
123 N-(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-benzamide 610
124 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2,5-two fluoro-phenyl)-ethanamide 383
125 N-(3,5-two-tert-butyl-2-methoxyl group-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 562
126 N '-[1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl carbamyl 522
Compound number The compound title Calculate MW
Base)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-Hydrazinecarboxamidederivatives
127 N-[2-(4-amino-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 544
128 The 5-tert-butyl-3-{2-[(Z)-methoxyimino]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid acid amides 539
129 Ethyl sulfonic acid (5-tert-butyl-2-methoxyl group-3-{3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,5-dioxo-2,5-dihydro-pyrroles-1-yl }-phenyl)-acid amides 622
130 5-tert-butyl-N-cyclopropyl methyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 588
131 5-fluoro-1H-indazole-3-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides 391
132 N-[5-tert-butyl-2-methoxyl group-3-(2-methoxyl group-kharophen)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 578
133 7-two ring [2.2.1] heptan-2-base-9-is right-and tolyl-2-is right-tolyl amino-7,9-dihydro-fast quinoline-8-ketone 426
134 N-(5-tert-butyl-2-isopropoxy-3-methanesulfonamido-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 612
135 N-[5-tert-butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 555
136 3-tert-butyl-1-(3,4-two chloro-phenyl)-5-phenyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also 385
137 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-[4-(2-thiomorpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 557
138 5-nitro-1H-pyrazoles-3-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides 368
139 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 591
140 1-(2-amino-4-tert-butyl-6-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-pyridine 554
141 N-(5-tert-butyl-2-isopropoxy-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 519
142 N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,5-pair-trifluoromethyl- 512
Compound number The compound title Calculate MW
Benzamide
143 2-(tert-butyl-dimethyl-silicon alkoxyl group)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(4-methoxyl group-phenyl)-ethanamide 508
144 N-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 556
145 5-tert-butyl-2-methoxyl group-3-[2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-kharophen]-benzamide 434
146 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-phenyl-ethanamide 361
147 5-tert-butyl-2-methoxyl group-N-(2-methoxyl group-ethyl)-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 592
148 (E)-3-(5-tert-butyl-3-ethanesulfonamido-2-methoxyl group-phenylcarbamoyl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-methyl acrylate 654
149 1-sec.-propyl-3-phenyl-5-phenylamino-1,3-dihydro-imidazol-be [4,5-b] pyridin-2-ones also 344
150 N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 501
151 2-(2-benzyl-5-tert-butyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 556
152 2-(5-tert-butyl-2-methoxyl group-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 491
153 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2,4-dimethoxy-phenyl)-ethanamide 408
154 (5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-Urethylane 564
155 3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid diamantane-1-base acid amides 628
156 3-tert-butyl-5-phenyl-1-(4-trifluoromethyl-phenyl)-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also 384
157 N-(5-tert-butyl-2-methoxyl group-3-{3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,4,5-trioxy--imidazolidine-1-yl }-phenyl)-Toluidrin 625
158 3-tert-butyl-1-(3-chloro-phenyl)-5-phenyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also 351
159 5-tert-butyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxygen 510
Compound number The compound title Calculate MW
Generation-kharophen }-the thiophene-2-carboxylic acid acid amides
160 2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxy-n-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 543
161 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-{4-[2-(2,6-dimethyl-morpholine-4-yl)-ethyl]-naphthalene-1-yl }-2-oxo-ethanamide 553
162 N-(5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 451
163 N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 598
164 3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid t-butyl carboxamide 550
165 1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-3-(2, the 3-dichlorophenyl)-3 '-(urethanum)-urea 428
166 2-(3,5-two fluoro-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 440
167 3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid amide 494
168 N-allyl group-5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 574
169 N-(5-tert-butyl-different _ azoles-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 481
170 3-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-cough up-2, the 5-diketone 489
171 2-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 480
172 3-tert-butyl-5-neighbour-tolyl-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also 344
173 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[(E)-oximido]-2-phenyl-ethanamide 376
174 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-hydroxyl-2-phenyl-ethanamide 313
175 N-(3-acetylaminohydroxyphenylarsonic acid 5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 548
176 1H-indazole-3-carboxylic acid (5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-acid amides 417
Compound number The compound title Calculate MW
177 5-tert-butyl-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-3-nitro-benzamide 508
178 The 5-tert-butyl-3-{2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid acid amides 575
179 N-[3-(4-ethanoyl-piperazine-1-carbonyl)-5-tert-butyl-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 645
180 2-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-N-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide 515
181 N-(5-tert-butyl-4-methyl-2-right-tolyl-2H-pyrazoles-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 570
182 2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-N-(2-phenyl-cyclopropyl)-ethanamide 445
183 N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide 499
184 N-(5-tert-butyl-2,3-dimethoxy-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 536
185 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2-chloro-phenyl)-ethanamide 382
186 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-{4-[2-(4-methyl-piperazine-1-yl)-ethyl]-naphthalene-1-yl }-2-oxo-ethanamide 538
187 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-(1H-indol-3-yl)-2-oxo-ethanamide 444
188 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide 539
189 N-(4-tert-butyl-6-trifluoromethyl-pyrimidine-2-base)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 531
190 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-neighbour-tolyl-ethanamide 361
191 The 5-tert-butyl-3-2[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid methane amide 539
192 N-[5-tert-butyl-2-(3,5-two chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 596
193 N-(5-tert-butyl-2-is right-tolyl-2H-pyrazoles-3- 569
Compound number The compound title Calculate MW
Base)-2-{4-[2-((2R, 6S)-2,6-dimethyl-morpholine-4-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide
194 3-tert-butyl-1,5-xenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also 316
195 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-imidazoles-1-base-ethyl)-naphthalene-1-yl]-2-oxo-ethanamide 506
196 3-tert-butyl-5-(3-chloro-phenyl)-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also 365
197 N-(5-tert-butyl-2-methoxyl group-3-phenyl methanesulfonamide amido-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 660
198 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-[4-(2-pyridin-4-yl-oxyethyl group)-naphthalene-1-yl]-ethanamide 533
199 1-(5-tert-butyl-2-methoxyl group-phenyl)-3-(4-{2-[(pyridine-2-ylmethyl)-amino]-pyrimidine-4-base oxygen }-naphthalene-1-yl)-imidazolidine-2,4, the 5-triketone 603
200 N-[5-tert-butyl-2-(3-chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 561
201 5-methoxyl group-1H-indazole-3-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides 403
202 N-[5-tert-butyl-2-(6-chloro-pyridazine-3-yl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 563
203 N-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 541
204 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2-methoxyl group-phenyl)-ethanamide 377
205 5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 623
206 [(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-methylsulfonyl-amino]-ethyl acetate 670
207 N-(between 5-tert-butyl-4-methyl-2--tolyl-2H-pyrazoles-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 570
208 N-[5-tert-butyl-2-(2,5-two chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 596
209 N-(5-tert-butyl-2-is right-tolyl-2H-pyrazoles-3- 555
Compound number The compound title Calculate MW
Base)-2-[4-(2-[1,4] oxazepan-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide
210 1-(5-tert-butyl-2-methoxyl group-3-benzamide)-3-(4-methoxyl group-phenyl)-3 '-(urethanum)-urea 459
211 N-[5-tert-butyl-2-(4-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-(4-methoxyl group-naphthalene-1-yl)-ethanamide 444
212 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-4-chloro-benzamide 368
213 N-(2-bromo-5-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 551
214 3-sec.-propyl-5-phenyl-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also 316
215 3,5-two-tert-butyl-1-is right-tolyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also 310
216 5-tert-butyl-N-cyclopentyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 602
217 2-[5-tert-butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazoles-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 559
218 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(4-methoxyl group-phenyl)-2-oxo-ethanamide 391
219 1,3-two-tert-butyl-5-phenyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also 296
220 4-(4-bromo-naphthalene-1-yl)-1-(3-tert-butyl-phenyl)-[1,2,4] triazolidine-3, the 5-diketone 438
221 N-[5-tert-butyl-2-(morpholine-4-carbonyl)-thiene-3-yl-]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 580
222 3-tert-butyl-5-(3-methoxyl group-phenyl)-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also 360
223 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine 4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide 541
224 1-tert-butyl-5-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-base is amino]-3-is right-tolyl-1, and the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones also 552
225 2-[5-tert-butyl-2-(3-fluoro-phenyl)-2H-pyrazole-3-yl]-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 560
226 5-tert-butyl-2-is right-tolyl-2H-pyrazoles-3-carboxylic acid [4-(2-morpholine-4-base 527
Compound number The compound title Calculate MW
-oxyethyl group)-naphthalene-1-ylmethyl]-acid amides
227 2-[5-tert-butyl-2-(3-fluoro-phenyl)-2H-pyrazole-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 545
228 5-tert-butyl-N-cyclopropyl methyl-2-methoxyl group-3-[2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-kharophen]-benzamide 489
229 N-[5-tert-butyl-3-(3,3-diethyl-urea groups)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 605
230 N-[5-tert-butyl-2-(4-fluoro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 545
231 N-(2-benzyl-5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 541
232 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-[4-(2-piperazine-1-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 583
233 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide 632
234 (5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-the carboxylamine isopropyl esters 592
235 1-(5-tert-butyl-2-methoxyl group-phenyl)-3-[4-(2-dimethylamino-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone 540
236 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 633
237 4-(3-tert-butyl-1-is right-tolyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles-5-yl also)-2-methoxyl group-phenol 376
238 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(3,4-two chloro-phenyl)-ethanamide 416
239 N-[3-(3-allyl group-urea groups)-5-tert-butyl-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 589
240 5-tert-butyl-N, N-diethyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 590
241 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-[1,4] oxazepan-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 598
242 N-(3-tert-butyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 461
Compound number The compound title Calculate MW
243 5-tert-butyl-N-ethyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-benzamide 548
244 N-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 542
245 N-[5-tert-butyl-2-(4-urea groups-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 585
246 N-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[4-(2-dimethylamino-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 499
247 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-oxo-2-[4-(2-piperidines-1-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-ethanamide 539
248 N-[5-tert-butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 559
249 Indazole-1-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides 373
250 N-[3,5-pair-(1,1-dimethyl-propyl group)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 575
251 1-benzyl-3-tert-butyl-5-phenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also 330
252 2-(5-tert-butyl-2-methoxyl group-3-nitro-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 536
253 4-{2-[4-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylamino oxalyl)-naphthalene-1-base oxygen base]-ethyl }-piperazine-1-carboxylic acid, ethyl ester 655
254 2-hydroxy-n-(5-sec.-propyl-2-right-tolyl-2H-pyrazoles-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 529
255 In 1-two ring [2.2.1] heptan-2-base-3-phenyl-5-phenylamino-1, the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones also 396
256 N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 555
257 N-[5-tert-butyl-3-(2-dimethylamino-kharophen)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 591
258 N-(5-tert-butyl-2-methoxyl group-3-{6-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-3,5-dioxo-2,5-dihydro-3H-[1,2,4] triazine-4-yl }-phenyl)-Toluidrin 624
259 N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 465
Compound number The compound title Calculate MW
260 (R)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-phenyl-ethanamide 363
261 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-dimethylamino-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 542
262 2-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 465
263 N-[2-(3-amino-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 544
264 2-[5-tert-butyl-2-(3-chloro-phenyl)-2H-pyrazole-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 561
265 1,5-xenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also 260
266 N-(5-tert-butyl-[1,3,4] thiadiazoles-2-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 484
267 N-(5-tert-butyl-3-{2-hydroxyl-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-ethylamino }-2-methoxyl group-phenyl)-Toluidrin 622
268 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-4-chloro-benzamide 368
269 N-(5-tert-butyl-2-oxyethyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 505
270 (5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-carboxylamine 2-methoxyl group-ethyl ester 608
271 (R)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-methoxyl group-2-phenyl-ethanamide 377
272 2-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-hydroxy-n-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 543
273 2-amino-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-naphthalene-1-base-ethanamide 413
274 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-acrylamide 582
275 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-imidazoles-1-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 522
276 N-(4-bromo-3-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 551
Compound number The compound title Calculate MW
277 4-(4-benzyloxy-phenyl)-1-(3-tert-butyl-phenyl)-[1,2,4] triazolidine-3, the 5-diketone 415
278 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[8-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 618
279 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-chloro-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 533
280 5-tert-butyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid dimethylformamide 538
281 1-(5-tert-butyl-different _ azoles-3-yl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone 493
282 N-(4-chloro-3-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 507
283 1-benzoyl-3-(5-tert-butyl-2-methoxyl group-phenyl)-urea 326
284 N '-[1-(5-tert-butyl-3-ethylamino formyl radical-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(Z)-methylene radical]-hydrazine carboxylic acid's ethyl ester 648
285 3-tert-butyl-5-(3-fluoro-phenyl)-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also 348
286 2-[3-bromo-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-ethanamide 556
287 2-(2-chloro-5-trifluoromethyl-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 507
288 N-[5-tert-butyl-2-(3-chloro-benzenesulfonyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 625
289 (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-carboxylamine p-methylphenyl ester 363
290 N-(5-tert-butyl-2-diethylin-3-methanesulfonamido-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 625
291 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 527
292 N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-ethanamide 513
293 Propane-1-sulfonic acid (5-tert-butyl-2-methoxyl group-3-{4-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-base-3,5-dioxo-[1,2,4] triazolidine-1-yl }-benzene 640
Compound number The compound title Calculate MW
Base]-acid amides
294 3-amino-5-tert-butyl-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-ylmethyl]-benzamide 492
295 2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-N-(3-trifluoromethyl-phenyl)-ethanamide 472
296 4-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-6-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2H-[1,2,4] triazine-3, the 5-diketone 505
297 N-[5-tert-butyl-2-(4-trifluoromethyl-phenyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 595
298 N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 619
299 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-phenyl-ethanamide 347
300 N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide 662
301 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-{4-[2-(2,6-dimethyl-morpholine-4-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide 612
302 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(4-methoxyl group-naphthalene-1-yl)-ethanamide 428
303 3-tert-butyl-1-cyclohexyl-5-phenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also 322
304 3-tert-butyl-5-(4-fluoro-phenyl)-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also 348
305 N-(5-tert-butyl-2-methoxyl group-3-{4-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-3,5-dioxo-[1,2,4] triazolidine-1-yl }-phenyl)-Toluidrin 612
306 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-{4-[2-(3-oxo-piperazine-1-yl)-ethyl]-naphthalene-1-yl }-ethanamide 538
307 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-[4-(3-pyridin-4-yl-propoxy-)-naphthalene-1-yl]-ethanamide 547
308 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-second 603
Compound number The compound title Calculate MW
Acid amides
309 N-[5-tert-butyl-2-(4-methylsulfonyl-phenyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 605
310 2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl formamyl)-2,5-dihydro-pyrroles-1-carboxylic acid tert-butyl ester 425
311 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-imidazoles-1-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 565
312 N-[5-tert-butyl-2-(3,5-dimethyl-phenyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 555
313 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide 589
314 N-{5-tert-butyl-3-[carbamyl ylmethyl-(propane-1-alkylsulfonyl)-amino]-2-methoxyl group-phenyl }-2-naphthalene-1-base-2-oxo-ethanamide 540
315 N '-[1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl formamyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(Z)-methylene radical]-hydrazine carboxylic acid's ethyl ester 551
316 5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-benzamide 560
317 N-[5-tert-butyl-2-(3-nitro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 572
318 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[3-chloro-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-2-oxo-ethanamide 525
319 N-(3-benzenesulfonyl amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 646
320 3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid cyclohexyl amide 576
321 N-[5-tert-butyl-2-methoxyl group-3-(2,2,2-three fluoro-ethanesulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 652
322 N '-[1-(5-tert-butyl-3-formamyl-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-hydrazine carboxylic acid's ethyl ester 620
323 5-tert-butyl-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-3-(propane-1-sulfonamido)-benzamide 584
324 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-hydroxyl-2-(4-methoxyl group-naphthalene 393
Compound number The compound title Calculate MW
-1-yl)-ethanamide
325 (5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-carboxylamine 2-dimethylamino-ethyl ester 621
326 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[7-fluoro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 602
327 N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-morpholine-4-base-pyridine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 500
328 3-tert-butyl-1-(4-chloro-phenyl)-5-phenyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also 351
329 N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-ethanamide 365
330 2-[5-tert-butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazoles-3-yl]-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 570
331 N-(5-tert-butyl-different _ azoles-3-yl)-2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-ethanamide 352
332 N-[5-(1,1-dimethyl-propyl group)-2-is right-tolyl-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 557
333 N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazoles-3-yl]-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 564
334 N-(2-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 507
335 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[2,3-two chloro-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-2-oxo-ethanamide 603
336 N-(3-methanesulfonamido-2-methoxyl group-5-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 542
337 4-{2-[4-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl oxamyl)-naphthalene-1-yl]-ethyl }-piperazine-1-carboxylic acid, ethyl ester 596
338 (1-benzyl-1H-benzimidazolyl-2 radicals-yl)-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-amine 436
339 N-(3,5-two-tert-butyl-2-hydroxyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 533
Compound number The compound title Calculate MW
340 N-(5-tert-butyl-2-naphthalene-1-base-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 577
341 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 540
342 4-{2-[4-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl oxamyl)-naphthalene-1-base oxygen base]-ethyl }-piperazine-1-carboxylic acid, ethyl ester 612
343 5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 583
344 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-(1-Methyl-1H-indole-3-yl)-2-oxo-ethanamide 458
345 4-phenyl-piperidines-4-carboxylic acid (5-tert-butyl-2-methoxyl group-phenyl)-acid amides 367
346 5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-benzamide 520
347 N-[2-(4-ethanoyl-phenyl)-5-tert-butyl-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 569
348 1-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone 582
349 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2,3-two fluoro-phenyl)-ethanamide 383
350 N-[5-tert-butyl-3-(carbamyl ylmethyl-methylsulfonyl-amino)-2-methoxyl group-phenyl]-2-naphthalene-1-base-2-oxo-ethanamide 512
351 N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[2-methyl-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-2-oxo-ethanamide 429
352 N-[2-(4-amino-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 542
353 (5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-phenyl carbamate 626
354 N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 451
355 N-(5-tert-butyl-2-isobutoxy-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 533
356 N-(4-tert-butyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 461
357 N-[5-tert-butyl-2-(3-methyl-benzoyl)-2H-pyrazoles-3- 569
Compound number The compound title Calculate MW
Base]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide
358 The 5-tert-butyl-3-{2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid acid amides 525
359 1-(5-tert-butyl-2-methoxyl group-phenyl)-3-[4-(2-chloro-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone 531
360 (S)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-phenyl-ethanamide 363
361 N-[5-tert-butyl-2-(2,3-dimethyl-phenyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 555
362 N-[5-tert-butyl-2-(4-nitro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 572
363 2-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 541
364 2-[(Z)-oximido]-N-(3-methanesulfonamido-2-methoxyl group-5-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 557
365 N-[5-tert-butyl-2-(morpholine-4-carbonyl)-thiene-3-yl-]-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 595
366 N-(5-tert-butyl-2-phenyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 527
367 N '-[1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl formamyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-hydrazine carboxylic acid's ethyl ester 551
368 N '-[1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl formamyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(Z)-methylene radical]-Hydrazinecarboxamidederivatives 522
369 N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 557
370 5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-N-pyridine-2-base-benzamide 611
371 N-[5-tert-butyl-3-(3,3-dimethyl-urea groups)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 577
372 5-tert-butyl-3-{2-[7-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-2-methoxyl group-benzamide 568
373 Between N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2--tolyl- 361
Compound number The compound title Calculate MW
Ethanamide
374 1-(5-tert-butyl-2-methoxyl group-phenyl)-3-[4-(2-tetramethyleneimine-1-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone 566
375 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-phenyl-propionic acid amide 377
376 2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-N-quinoline-3-base-ethanamide 456
377 1-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone 582
378 (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-(3-trifluoromethyl-benzyl)-amine 387
379 N-[5-tert-butyl-2-methoxyl group-3-(morpholine-4-carbonyl)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 604
380 N-[5-tert-butyl-3-(3-sec.-propyl-urea groups)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 591
381 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-methoxyl group-2-(4-methoxyl group-naphthalene-1-yl)-ethanamide 458
382 N-(3-amino-5-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 487
383 N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide 515
384 3-methyl isophthalic acid, 5-xenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also 274
385 N-(5-tert-butyl-different _ azoles-3-yl)-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 454
386 N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-2-(2-phenyl-cyclopropyl)-ethanamide 445
387 2-{4-[2-(4-ethanoyl-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-ethanamide 625
388 2-(1H-indol-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 444
389 N-[5-tert-butyl-2-(3-fluoro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 545
390 2-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 506
Compound number The compound title Calculate MW
391 N-[5-tert-butyl-2-(3,4-two chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 596
392 N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide 502
393 N-[5-tert-butyl-2-(2,5-dimethyl-phenyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 555
394 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-2-oxo-ethanamide 588
395 1H-indazole-3-carboxylic acid (5-tert-butyl-2-pyridine-2-base-2H-pyrazole-3-yl)-acid amides 360
396 N-(4-chloro-3-trifluoromethyl-phenyl)-2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-ethanamide 408
397 N-[5-(1,1-dimethyl-butyl)-2-is right-tolyl-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 569
398 1H-indazole-3-carboxylic acid [5-tert-butyl-2-(4-methoxyl group-phenyl)-2H-pyrazole-3-yl]-acid amides 389
399 1H-indazole-3-carboxylic acid [5-tert-butyl-2-(4-hydroxyl-phenyl)-2H-pyrazoles-3-yl]-acid amides 375
400 N '-[1-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-Hydrazinecarboxamidederivatives 641
401 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-N '-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-oxamide 556
402 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-methylamino--pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 577
403 N-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 570
404 5-tert-butyl-N-cyclopropyl-3-[2-[(E)-oximido]-2-(4-methoxyl group-naphthalene-1-yl)-kharophen]-2-methoxyl group-benzamide 490
405 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-{4-[2-(2,6-dimethyl-morpholine-4-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide 569
406 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[8-fluoro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 602
407 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(3-fluoro-benzene 365
Compound number The compound title Calculate MW
Base)-ethanamide
408 5-tert-butyl-N-furans-2-ylmethyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 614
409 N-[5-tert-butyl-2-(3-trifluoromethyl-benzoyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 623
410 N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 661
411 1-(5-tert-butyl-different _ azoles-3-yl)-3-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone 543
412 1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-3 '-(urethanum)-urea 539
413 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-4-[2-(3-oxo-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-ethanamide 597
414 2-{4-[2-(4-ethanoyl-piperazine-1-yl)-ethyl]-naphthalene-1-yl }-N-(uncle 5--butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-ethanamide 566
415 N-(5-tert-butyl-2-phenylacetyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 569
416 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-{4-[2-(3-oxo-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-ethanamide 554
417 2-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 556
418 N-[5-tert-butyl-2-(3-urea groups-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 585
419 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-ethanamide 663
420 N-[5-tert-butyl-2-methoxyl group-3-(3-oxo-piperazine-1-carbonyl)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 617
421 3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid propionic acid amide 536
422 5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 624
423 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-{4-[2-(4-first 554
Compound number The compound title Calculate MW
Base-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide
424 N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide 556
425 5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-N-propyl group-benzamide 576
426 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-(4-methoxyl group-phenyl)-ethanamide 393
427 N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 480
428 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(3-phenoxy group-phenyl)-ethanamide 440
429 N-(5-sec.-propyl-2-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 461
430 7-sec.-propyl-9-phenyl-2-phenylamino-7,9-dihydro-fast quinoline-8-ketone 345
431 (5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-anginin-3-base methyl esters 641
432 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-ethylamino-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 542
433 N-(3,5-two-tert-butyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 517
434 2-amino-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-naphthalene-2-base-ethanamide 413
435 N-[5-tert-butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 561
436 2-[5-tert-butyl-2-(3,4-two fluoro-phenyl)-2H-pyrazole-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 563
437 N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-methylamino--pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 499
438 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide 591
439 N-[5-tert-butyl-2-(2,3-two chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 596
440 N-[3,5-pair-(1,1-dimethyl-propyl group)-2-hydroxyl-phenyl]-2-[4-(2-morpholine 561
Compound number The compound title Calculate MW
-4-base-oxyethyl group)-naphthalene-1-base-2-oxo-ethanamide
441 4-{2-[4-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylamino oxalyl)-naphthalene-1-base oxygen base]-ethyl }-piperazine-1-carboxylic acid tert-butyl ester 683
442 3-tert-butyl-1-naphthalene-2-base-5-phenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also 366
443 2-xenyl-4-base-N-(5-tert-butyl-2-right-tolyl-2H-pyrazoles-3-yl)-ethanamide 424
444 5-tert-butyl-N-sec.-propyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 576
445 N-(5-tert-butyl-3-diethylin methyl-2-hydroxyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 562
446 6-hydroxyl-nicotinic acid 3-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenylcarbamoyl]-1H-indazole-5-base ester 582
447 N-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 590
448 N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 514
449 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(4-morpholine-4-base-pyrimidine-2--amino)-naphthalene-1-yl]-2-oxo-ethanamide 633
450 N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 506
451 1,3,5-triphenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also 336
452 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-cyclohexyl-ethanamide 354
453 2-[5-tert-butyl-2-(2-chloro-phenyl)-2H-pyrazole-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 561
454 7-cyclohexyl methyl-9-phenyl-2-phenylamino-7,9-dihydro-fast quinoline-8-ketone 399
455 5-tert-butyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid methyl nitrosourea 524
456 5-tert-butyl-N-cyclopropyl methyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-benzamide 574
457 N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 606
Compound number The compound title Calculate MW
458 N '-[1-(5-tert-butyl-3-formamyl-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(Z)-methylene radical]-hydrazine carboxylic acid's ethyl ester 620
459 4-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-1-(2,3-dimethyl-phenyl)-[1,2,4] triazolidine-3, the 5-diketone 341
460 N-(4-fluoro-3-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 490
461 1-benzyl-3-phenyl-5-phenylamino-1,3-dihydro-imidazol-be [4,5-b] pyridine-2-ketone also 392
462 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-naphthalene-2-base-ethanamide 347
463 2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-base formamyl]-pyrroles-1-carboxylic acid tert-butyl ester 466
464 N-(2,5-two-tert-butyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 517
465 2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-N-((1S, 2R)-2-phenyl-cyclopropyl)-ethanamide 445
466 2-oxo-2,3-dihydro-benzoglyoxaline-1-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides 389
467 N-(2-methoxyl group-5-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 502
468 N-[2-(4-bromo-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 606
469 1-(5-tert-butyl-2-methoxyl group-phenyl)-3-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone 582
470 5-tert-butyl-2-methoxyl group-N-methyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 548
471 N-(5-tert-butyl-2-methoxyl group-3-piperidines-1-ylmethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 588
472 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-naphthalene-1-base-2-oxo-ethanamide 361
473 N-(2,5-two-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 507
474 (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-carboxylamine 4-methoxyl group-phenyl ester; 379
475 N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-naphthalene-1-base-2-oxo 376
Compound number The compound title Calculate MW
-ethanamide
476 5-tert-butyl-N-ethyl-3-{2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-2-methoxyl group-benzamide 577
477 4-{2-[4-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl oxamyl)-naphthalene-1-yl]-ethyl }-piperazine-1-carboxylic acid tert-butyl ester 624
478 5-tert-butyl-N-ethyl-2-hydroxyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 548
479 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-naphthalene-1-base-ethanamide 398
480 N-(5-tert-butyl-2-oxyethyl group-3-methanesulfonamido-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 598
481 N '-[1-(5-tert-butyl-3-ethylamino formyl radical-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-Hydrazinecarboxamidederivatives 619
482 2-{4-[2-(4-ethanoyl-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-ethanamide 582
483 5-tert-butyl-N-ethyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 562
484 5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenylformic acid 535
485 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-ethanamide 590
486 N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 459
487 5-tert-butyl-3-{2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid acid amides 558
488 2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-N-between-tolyl-ethanamide 418
489 5-tert-butyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid methyl esters 525
490 N '-[1-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(Z)-methylene radical]-Hydrazinecarboxamidederivatives 641
Compound number The compound title Calculate MW
491 N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide 605
492 N-(5-sec.-propyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 527
493 N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 452
494 N-(2-benzoyl-5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 555
495 6-bromo-1H-indazole-3-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides 452
496 5-tert-butyl-N-ethyl-3-{2-hydrazono--2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-2-methoxyl group-benzamide 576
497 N-(5-tert-butyl-3-ethanesulfonamido-2-methoxyl group-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 613
498 N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide 513
499 N-(5-tert-butyl-thiene-3-yl-)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 467
500 N-[5-tert-butyl-2-(4-chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 561
501 N '-[1-(5-tert-butyl-3-formamyl-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-Hydrazinecarboxamidederivatives 591
502 N-[5-tert-butyl-2-(4-methoxyl group-phenyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 557
503 5-tert-butyl-3-{2-[7-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-N-cyclopropyl-2-methoxyl group-benzamide 608
504 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-{4-[2-(4-methyl-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide 597
505 1-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-imidazolidin-2-one 554
506 N-(5-tert-butyl-thiene-3-yl-)-2-[(Z)-oximido]-2-[4-(2-morpholine-4- 482
Compound number The compound title Calculate MW
Base-oxyethyl group)-naphthalene-1-yl]-ethanamide
507 5-tert-butyl-N-cyclopropyl-3-[2-[(Z)-oximido]-2-(4-methoxyl group-naphthalene-1-yl)-kharophen]-2-methoxyl group-benzamide 490
508 N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(4-morpholine-4-base-pyrimidine-2--amino)-naphthalene-1-yl]-2-oxo-ethanamide 514
509 N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 572
510 N-[2-methoxyl group-5-(1-methyl isophthalic acid-phenyl-ethyl)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 553
511 2-[5-tert-butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazoles-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 555
512 5-tert-butyl-3-{2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid acid amides 559
513 5-tert-butyl-N-isobutyl--2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 590
514 2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 556
515 3-tert-butyl-1-(2,3-two chloro-phenyl)-5-phenyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also 385
516 N-(3,5-two-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 547
517 The 5-tert-butyl-3-{2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid dimethylformamide 553
518 N-(5-tert-butyl-2-methoxyl group-3-methyl-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 520
519 N '-[1-(5-tert-butyl-3-cyclopropyl formamyl-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-hydrazine carboxylic acid's ethyl ester 660
520 N-indane-5-base-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 445
521 N-[5-tert-butyl-2-(3-chloro-4-fluoro-phenyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 579
522 N-[5-tert-butyl-3-(imidazoles-1-carbonyl)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 585
Compound number The compound title Calculate MW
523 2-(2,5-couple-trifluoromethyl-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 540
524 N-[5-tert-butyl-2-(2,4-two fluoro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 563
525 1H-indazole-3-carboxylic acid (5-tert-butyl-2-methoxyl group-phenyl)-acid amides 323
526 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-4-[2-(5-oxo-[1,4] Diazesuberane-1-yl)-oxyethyl group]-naphthalene-1-yl }-ethanamide 568
527 3-tert-butyl-1-is right-tolyl-5-(4-trifluoromethyl-phenyl)-1, and 6-dihydro-imidazo [4,5-c] pyrazoles 398
528 N-(5-tert-butyl-3-ethanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 598
529 3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid sec.-propyl acid amides 536
530 N-(5-tert-butyl-[1,3,4] thiadiazoles-2-yl)-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 471
531 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-ethanamide 649
532 N-[2-(3-amino-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 542
533 3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid phenyl acid amides 570
534 2-(5-tert-butyl-2-methyl-furans-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 465
535 N-(5-tert-butyl-2-neighbour-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 541
536 N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 438
537 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-(3-methoxyl group-phenyl)-ethanamide 327
538 5-tert-butyl-3-{2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid acid amides 560
539 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 586
Compound number The compound title Calculate MW
540 N-[5-tert-butyl-2-(2,4-two chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 596
541 N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(3-hydroxyl-propoxy-)-naphthalene-1-yl]-2-oxo-ethanamide 396
542 N-(3-tert-butyl-different _ azoles-5-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 467
543 1H-Indole-3-Carboxylic Acid (5-tert-butyl-2-methoxyl group-phenyl)-acid amides 322
544 N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 612
545 7-two ring [2.2.1] heptan-2-base-9-phenyl-2-phenylamino-7,9-dihydro-fast quinoline-8-ketone 397
546 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2,4-two chloro-phenyl)-ethanamide 416
547 5-tert-butyl-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-benzamide 463
548 N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[2,3-dimethyl-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-2-oxo-ethanamide 443
549 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-(3-fluoro-phenyl)-ethanamide 315
550 1-(5-tert-butyl-2-methoxyl group-3-benzamide)-3-(2, the 3-3,5-dimethylphenyl)-3 '-(urethanum)-urea 457
551 2-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-oxo-N-(3-trifluoromethyl-phenyl)-ethanamide 353
552 7-benzyl-9-phenyl-2-phenylamino-7,9-dihydro-fast quinoline-8-ketone 393
553 2,5-dihydro-1H-pyrroles-2-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides 324
554 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-{4-[2-(5-oxo-[1,4] Diazesuberane-1-yl)-oxyethyl group]-naphthalene-1-yl }-ethanamide 611
555 N-[5-tert-butyl-2-(3-cyano group-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 552
556 N-(5-tert-butyl-2-methoxyl group-3-phenylacetylamino-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 624
557 2-(2-chloro-5-trifluoromethyl-phenyl)-N-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide 557
Compound number The compound title Calculate MW
558 1-(5-tert-butyl-2-methoxyl group-phenyl)-3-[4-(2-piperidines-1-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone 580
559 2-(2-benzyl-5-tert-butyl-2H-pyrazole-3-yl)-2-hydroxy-n-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 543
560 5-tert-butyl-3-{2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid acid amides 517
561 N '-[1-(5-tert-butyl-3-ethylamino formyl radical-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-hydrazine carboxylic acid's ethyl ester 648
562 N-(3-methanesulfonamido-5-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 566
563 N-(5-tert-butyl-2-hydroxyl-3-piperidines-1-ylmethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 574
564 2-(1-Methyl-1H-indole-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 458
565 N-(5-tert-butyl-2-methoxyl group-phenyl)-2-oxo-2-{4-[2-((S)-1-phenyl-ethylamino)-pyrimidine-4-base is amino]-naphthalene-1-yl }-ethanamide 574
566 N-[5-tert-butyl-2-(4-cyano group-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 552
567 N '-[1-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-hydrazine carboxylic acid's ethyl ester 670
568 N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide 559
569 N-(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-isobutyramide 576
570 N-[5-tert-butyl-2-(4-methyl-benzoyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 569
571 N-[5-tert-butyl-2-(2-chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 561
572 N-[5-tert-butyl-2-(3-chloro-4-methyl-phenyl)-2H-pyrazoles-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 575
573 2-(4-bromo-phenyl)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazoles-3-yl)-ethanamide 426
Compound number The compound title Calculate MW
574 2-(5-tert-butyl-2-methyl-furans-3-yl)-N-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide 512
575 4-(4-{4-[2-(5-tert-butyl-2-methyl-furans-3-yl)-2-oxo-kharophen]-naphthalene-1-base is amino }-phenoxy group)-the pyridine-2-carboxylic acids methyl nitrosourea 577
576 N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide 660
577 5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide 622
578 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-{4-[6-(tetrahydrochysene-pyrans-4-base is amino)-pyridin-3-yl]-naphthalene-1-yl }-ethanamide 631
579 3-[2-(4-bromo-naphthalene-1-yl)-2-oxo-kharophen]-5-tert-butyl-N-cyclopropyl-2-methoxyl group-benzamide 523
580 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(6-morpholine-4-base-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide 617
581 N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide 588
582 N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-(4-pyridin-3-yl-naphthalene-1-yl)-ethanamide 532
583 N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-oxo-2-(4-pyridin-3-yl-naphthalene-1-yl)-ethanamide 412
584 2-(4-chloro-3-trifluoromethyl-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide 507
585 4-{4-[2-(4-chloro-3-trifluoromethyl-phenyl)-2-oxo-kharophen]-phenoxy group }-the pyridine-2-carboxylic acids methane amide 478
[0376] as meeting is with understanding,, particularly providing aspect the written description that all scopes disclosed herein also comprise the combination of any and all possible inferior scope and these inferior scopes for any and all purposes by those skilled in the art.Any scope of listing can be described and make same scope to be decomposed at least fully to equate by easily recognizing 1/2nd, 1/3rd, 1/4th, 1/5th, ten/first-class.As non--limitative examples, each scope disclosed herein can easily be decomposed into lower 1/3rd, medium 1/3rd and three higher/first-class.As meeting be by those skilled in the art with understanding, all language such as " up to ", " at least ", " greater than ", " being less than " and similar language throughout comprise the number that is described, and refer to can be broken down into subsequently the scope of above-mentioned inferior scope.At last, be that scope comprises each one number by those skilled in the art as meeting with understanding.Therefore, the group that for example has a 1-3 atom refers to have the group of 1,2 or 3 atom.Similarly, the group with 1-5 atom refers to have the group of 1,2,3,4 or 5 atom, and the rest may be inferred.
[0377] although some embodiment is illustrated and describes, should be appreciated that, can change and revise according to the common practise of this area, and can in as the broad aspect that its claim limited, not deviate from the present invention.

Claims (93)

1. cytokine inhibitor comprises:
Targeting moiety, it comprises that at least one contains the amide group of amide NH, described targeting moiety can form one or more hydrogen bonds with target protein, and wherein said targeting moiety is not a urea group;
Bag-expansion, it directly is attached on the described targeting moiety, described bag-expansion comprises the planar section on the on-plane surface hydrophobic part that is attached to large volume, described non--planar section and target protein form hydrophobic interaction;
Bearing portion, it comprises a plane hydrophobic part, and is attached on the described targeting moiety, different with the bag-expansion attachment area atom, described bearing portion can form the fragrance interaction of π-π or limit-right-face with target protein.
2. cytokine inhibitor as claimed in claim 1, wherein said targeting moiety also comprise extra hydrogen bond donor group or hydrogen bond receptor group.
3. cytokine inhibitor as claimed in claim 1, also comprise hydrophilic segment with at least one functionality, described functionality is selected from hydrogen-key donor, hydrogen-key acceptor, alkaline heteroatoms and acid heteroatoms, wherein said hydrophilic segment is attached on the described hydrophobic bearing portion indirectly, and can form hydrogen bond with described proteinic main chain.
4. cytokine inhibitor as claimed in claim 1, wherein said targeting moiety are acid amides or alpha-keto amide group.
5. cytokine inhibitor as claimed in claim 1, wherein said bag-expansion comprise 5-or 6 yuan of fragrance or assorted aromatic nucleus, and it is replaced by the tertiary butyl or bornyl.
6. formula IA compound:
Its steric isomer, its tautomer, its solvate, its prodrug and its pharmacy acceptable salt, wherein:
X is C (O), C (S) or CH 2
G is C 3-10Carbocylic radical, 5-8 unit's monocyclic heterocycles base or 8-11 unit bicyclic heterocycles base, it contains one or more heteroatomss that is selected from O, N or S; Wherein, G is by R 1, R 2Or R 3In one or more replacements;
Ar be indazolyl, indyl, pseudoindoyl, imidazolyl, benzimidazolyl-, pyrazolyl, pyrazolinyl, pyrryl, pyrrolinyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, indolinyl, benzisoxa _ azoles base, dihydrobenzo different _ azoles base, dihydro-iso indolyl, benzisothiazole base, benzisothiazole base dioxide, C 6-10Aryl ,-(C 1-3Alkyl)-(C 6-10Aryl) ,-(Y)-(C 0-3Alkyl)-(C 6-10Aryl) or-(Y)-(C 0-3Alkyl)-(5-10 unit heteroaryl), each in them is randomly used R 4Or R 5In one or more replacements;
Each Y is independently-CHZ-,-CZ 2-,-CHR-,-O-,-C (=CHR)-,-C (=C-CO 2R)-;
Each Z be independently F, Cl ,-OR ,-NR 2,-SR ,-NHCONHR or-NHCOR;
L is a covalent linkage, saturated or undersaturated side chain or unbranched C 1-10Carbochain, wherein, optional O, NR and the S (O) of being selected from independently of one or more methylene groups mHeteroatoms substitute; Wherein L is randomly by 0-2 oxo group and one or more C 1-4Side chain or unbranched alkyl replace, described C 1-4Side chain or unbranched alkyl are randomly replaced by one or more F, Cl, Br or I;
Each m is 0,1 or 2 independently;
Q be hydrogen ,-NR ' R ', cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) m, or phenyl-S (O) m, wherein cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) mEach randomly uses one or more R 27Replace;
Each R independently is C hydrogen or replacement or unsubstituted 1-6Alkyl;
Each R ' is C hydrogen, replacement or unsubstituted independently 1-8(C alkyl, replacement or unsubstituted 0-4Alkyl)-(C 6-10Aryl) or that replace or unsubstituted (C 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-OR ,-NR ' R ' ,-SiR 3,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2, R 4And R 5Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
Each R " be that replace or unsubstituted C independently 1-8C alkyl, replacement or unsubstituted 0-4Alkyl-C 6-10(C aryl or replacement or unsubstituted 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 3Be that replace or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace.
Each R 6Be C 1-6Side chain or unbranched alkyl, it is randomly by part or all of halogenation, and randomly uses R 26Replace;
Each R 26Be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by part or all of halogenation;
R 20Be that replace or unsubstituted C 1-10C alkyl, replacement or unsubstituted 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical, OR ' or NR ' 2
R 21Be hydrogen or C 1-4Side chain or unbranched alkyl, it is randomly by part or all of halogenation; With
R 22, R 23And R 24In each be C hydrogen, replacement or unsubstituted independently 1-10Alkyl, wherein C 1-10Alkyl randomly by one or more O, N or S interrupt, replace or unsubstituted C 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical; Or R 23And R 24Randomly form heterocycle or hetero-aromatic ring together;
Each R 27Be independently F, Cl, Br, I, cyano group ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR ' ,-OR ' ,-NR ' R ' ,-SiR ' 3,-S (O) mR ', replace or unsubstituted straight or branched C 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-203-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and independently is selected from N, O, S (O) mHeteroatoms;
Yet, if when Ar be-(Y)-(C 6-10Aryl), when G was N-(phenyl replacement or unsubstituted)-pyrazolyl, pyrazolyl was used one or more R extraly 1, R 2Or R 3Replace; And
IA is not N-(5-tert-butyl-2-phenyl-2H-pyrazole-3-yl)-2-(4-chloro-phenyl)-ethanamide.
7. compound as claimed in claim 6, wherein, the described compound of 10 μ M concentration suppresses bringing out property TNFa-from cell and discharges about 50% or greater than 50%.
8. compound as claimed in claim 6, wherein G is
Phenyl, naphthyl, benzocyclobutane alkyl, dihydro naphthyl, tetralyl, benzocyclohepta alkyl, benzocyclohepta thiazolinyl, 2,3 indanyls, indenyl, cumarone-3-ketone;
Pyrazolyl, pyrryl, imidazolyl, the imidazoles ketone group, thiazolyl, _ azoles base, different _ the azoles base, furyl, thienyl, pyridyl, pyriconyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzofuryl, the benzo thiophenyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thiophenyl, benzo _ oxazolone base, 4H-benzo [1,4] _ piperazine-3-ketone group, the benzo dioxolyl, benzo [1,3] dioxole-2-ketone group, the tetrahydro benzo pyranyl, indyl, indolinyl, the indoles ketone group, the dihydroindole ketone group, phthalimide-based;
Pyrrolidyl, tetrahydrofuran base, tetrahydrochysene thiophenyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, two _ alkyl, tetramethylene sulfide sulfuryl, tetramethylene sulfoxide base, _ azoles quinoline base, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, Decahydroisoquinolinpreparation base, thio-morpholinyl, thiazolidyl, dihydro _ piperazine base, dihydro pyranyl, oxocanyl, heptacanyl, thiophene _ alkyl or dithiane base.
9. compound as claimed in claim 6, wherein G is phenyl, naphthyl, benzocyclobutane alkyl, dihydro naphthyl, tetralyl, benzocyclohepta alkyl, benzocyclohepta thiazolinyl, 2,3 indanyls, indenyl or cumarone-3-ketone.
10. compound as claimed in claim 6, wherein G is a pyrazolyl, pyridyl, pyriconyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzofuryl, the benzo thiophenyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thiophenyl, benzo _ oxazolone base, benzo [1,4] _ piperazine-3-ketone group, the benzo dioxolyl, benzo [1,3] dioxole-2-ketone group, the tetrahydro benzo pyranyl, indyl, indolinyl, the indoles ketone group, dihydroindole ketone group or phthalimide-based.
11. compound as claimed in claim 6, wherein G be pyrrolidyl, tetrahydrofuran base, tetrahydrochysene thiophenyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, two _ alkyl, tetramethylene sulfide sulfuryl, tetramethylene sulfoxide base, _ azoles quinoline base, different _ azoles quinoline base, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, Decahydroisoquinolinpreparation base, thio-morpholinyl, thiazolidyl, dihydro _ piperazine base, dihydro pyranyl, oxocanyl, heptacanyl, thiophene _ alkyl or dithiane base.
12. compound as claimed in claim 6, wherein G be phenyl, naphthyl, pyrazolyl, pyrryl, pyrrolidyl, imidazolyl, imidazoles ketone group, thiazolyl, _ azoles base, different _ the azoles base, furyl, thienyl or pyridyl.
13. compound as claimed in claim 6, wherein Ar is indazolyl, indyl, pseudoindoyl, imidazolyl, benzimidazolyl-, pyrazolyl, pyrazolinyl, pyrryl, pyrrolinyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, indolinyl, benzisoxa _ azoles base, dihydrobenzo different _ azoles base, dihydro-iso indolyl, benzisothiazole base, titanium dioxide benzo isothiazolyl or C 6-10Aryl.
14. compound as claimed in claim 13, wherein Ar is by R 4Or R 5In at least one replacement.
15. compound as claimed in claim 13, wherein Ar is indazolyl, pseudoindoyl, pyrazolyl, pyrrolinyl, phenyl, naphthyl, dihydro naphthyl, tetralyl, 2,3 indanyls, indenyl or imidazolyl.
16. compound as claimed in claim 13, wherein Ar is indazolyl, phenyl, tetralyl or naphthyl.
17. compound as claimed in claim 6, wherein Ar is-(C 1-3Alkyl)-(C 6-10Aryl) ,-(Y)-(C 0-3Alkyl)-(C 6-10Aryl) or-(Y)-(C 0-3Alkyl)-(5-10 unit heteroaryl).
18. compound as claimed in claim 17, wherein Ar is by R 4Or R 5In at least one replacement.
19. compound as claimed in claim 17, wherein Y is-CZ 2-, each Z be independently F ,-OR or-CHR.
20. compound as claimed in claim 17, wherein Y is-CF 2-.
21. compound as claimed in claim 17, wherein Y is-CHR or CHZ-, and Z is-OR.
22. compound as claimed in claim 17, wherein Y is-CHOH-.
23. compound as claimed in claim 17, wherein Y be-O-or-CH 2-.
24. compound as claimed in claim 17, wherein C 6-10Aryl is a phenyl or naphthyl.
25. compound as claimed in claim 17, wherein 5-10 unit heteroaryl is quinolyl, isoquinolyl, phthalazinyl or quinazolyl.
26. compound as claimed in claim 17, wherein Ar is-(C 1-3Alkyl)-(C 6-10Aryl).
27. compound as claimed in claim 6, wherein one or more methylene groups of L are selected from O, N or S (O) independently mHeteroatoms substitute.
28. compound as claimed in claim 6, wherein L is covalent linkage, C 1-C 9Alkoxyl group ,-C (O) O-,-NH-or-O-.
29. compound as claimed in claim 6, wherein Q is
Phenyl, naphthyl, pyridyl, pyrimidyl, pyridazinyl, imidazolyl, pyrryl, pyrrolidyl, benzimidazolyl-, furyl, thienyl, pyranyl, the naphthyl pyridyl, pyrazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazyl, pyrazolo [3,4-b] pyrimidyl, fast quinoline base, pyrrolo-[2,3-b] pyridyl, pyrazolo [3,4-b] pyridyl, the tubercidin base, _ azoles also [4,5-b] pyridyl, or imidazo [4,5-b] pyridyl, THP trtrahydropyranyl, tetrahydrofuran base, 1,3-dioxane pentanone, 1,3-two _ alkane ketone, 1,4-two _ alkyl, morpholino, the thio-morpholinyl sulfoxide, the thio-morpholinyl sulfone, piperazinyl, piperidyl, piperidone base, the tetrahydropyrimidine ketone group, pimelinketone, hexalin (cyclohexanolol), pentamethylene sulfide, the pentamethylene sulfoxide, the pentamethylene sulfone, tetramethylene sulfide, tetramethylene sulfoxide or tetramethylene sulfone, C 1-6Alkoxyl group, secondary amine or tertiary amine, wherein amino nitrogen is covalently bound to C 1-3Alkyl or C 1-5On the alkoxyalkyl, phenylamino;
C 1-6Alkyl-S (O) mOr phenyl-S (O) m
30. compound as claimed in claim 29, wherein R 27Be C 1-6Alkyl, C 1-65-10 alkoxyl group, hydroxyl amino, replacement or unsubstituted unit heterocyclic radical, list-or two-(C 1-3Alkyl) amino, single-or two-(phenyl-C 1-3Alkyl) amino, C 1-6Alkyl-S (O) m, phenyl-C 1-3-alkoxyl group or phenylamino, wherein said phenyl ring is randomly used one or two halogen, C 1-6Alkyl or C 1-6Alkoxyl group replaces.
31. compound as claimed in claim 6, wherein Q is hydrogen, phenyl, thio-morpholinyl sulfoxide, thio-morpholinyl sulfone, piperazine ketone group, oxazepinyl, diazepinonyl, imidazolyl, pyridyl or morpholino.
32. compound as claimed in claim 6, wherein Q is morpholino, piperazinyl, pyrimidyl or pyridyl.
33. compound as claimed in claim 32, wherein R 27Be-C (O) OR ' ,-NR ' R ', replace or unsubstituted straight or branched C 1-10C alkyl, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl or replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.
34. compound as claimed in claim 32, wherein Q is a pyrimidyl, R 27Be-NR ' R ' or replace or unsubstituted saturated or undersaturated 3-11 unit heterocyclic radical, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.
35. compound as claimed in claim 32, wherein Q is a pyridyl, R 27Be-NR ' R ', replace or unsubstituted C 1-6Saturated or undersaturated 3-11 unit's heterocyclic radical alkyl or replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms.
36. compound as claimed in claim 6 is wherein worked as R 4And R 5When not existing ,-L-Q is not-H.
37. compound as claimed in claim 6, wherein each R 1Be independently
C 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, dicyclohexyl or two suberyl, they are randomly by partially or completely halogenation, and randomly replace with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl, or the analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH replace;
C 3-10Side chain or unbranched alkenyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: C 1-5Side chain or unbranched alkyl, phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ the azoles base, isothiazolyl; Aforesaid each randomly by partially or completely halogenation, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, two cyclopentyl, dicyclohexyl or two suberyl, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl; C wherein 3-10Side chain or unbranched alkenyl are randomly by one or more O, N or S (O) mInterrupt;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls or bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
Cyano group, F, Cl, Br or I;
Methoxycarbonyl, ethoxycarbonyl or the third oxygen carbonyl;
Silyl contains three C 1-4Side chain or unbranched alkyl group independently, it is randomly by partially or completely halogenation;
C 2-6Side chain or unbranched alkyl-C (O), C 2-6Side chain or unbranched-S, C 2-6Side chain or unbranched-S (O), C 2-6Side chain or unbranched-S (O) 2
Randomly by partially or completely halogenated C 2-6Side chain or unbranched alkynyl, wherein one or more methylene groups are randomly replaced by O, NH and S (O) m, and wherein, described alkynyl group is optional to be replaced by following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino.
38. compound as claimed in claim 6, wherein each R 1Be C independently 3-10Side chain or unbranched alkyl, it is randomly by partially or completely halogenation, and is randomly replaced by one to three following radicals: C 3-10Cycloalkyl, hydroxy phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, imidazolyl, pyrazolyl, thienyl, furyl, different _ azoles base or isothiazolyl; In them each randomly replaces with 1 to 5 following radicals: halogen, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, C 3-8Cycloalkyl, C 5-8Cycloalkenyl group, hydroxyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group and NH 2C (O) or list-or two-(C 1-3Alkyl) aminocarbonyl.
39. compound as claimed in claim 38, wherein each R 1Be C independently 3-10Side chain or unbranched alkyl.
40. compound as claimed in claim 6, wherein each R 2Be independently-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
41. compound as claimed in claim 6, one of them R 2Independently-NR ' 2,-NO 2,-C (O) NR ' 2,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
42. compound as claimed in claim 6, wherein each R 3Be independently
Hydrogen or phenyl, naphthyl or heterocyclic radical, in them each is randomly by halogenation partially or completely, and randomly got: phenyl by 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N, carboxyl-list-or two-(C 1-5Alkyl) amino;
Fused-aryl, be selected from benzocyclobutane alkyl, 2,3 indanyls, indenyl, dihydro naphthyl, tetralyl, benzocyclohepta alkyl and benzocyclohepta thiazolinyl, or annelated heterocycles, be selected from cyclopenta pyridine, hexanaphthene and pyridine, pentamethylene and pyrimidine, hexanaphthene and pyrimidine, pentamethylene and pyrazine, hexanaphthene and pyrazine, pentamethylene and pyridazine, cyclopentanoindole, hexanaphthene diindyl, ring benzoglyoxaline, pentamethylene and imidazoles, hexanaphthene and imidazoles, pentamethylene thiophthene and hexanaphthene thiophthene; Wherein said fused-aryl or annelated heterocycles are randomly, replaced by 1 to 3 group independently, described group is selected from: phenyl, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2,5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, isothiazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, heteroaryloxy, nitro, amino, list-or two-(C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocycle or amino, the NH of assorted virtue 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-4Alkyl-C (O), C 1-5Alkylamino-S (O) 2, single-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, R 12-C 1-5Alkyl, R 13-C 1-5Alkoxyl group, R 14-C (O)-C 1-5Alkyl, R 15-C 1-5Alkyl (R 16) N;
Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, it is randomly by partially or completely halogenation, and randomly replaces with one to three following radicals: randomly by partially or completely halogenated C 1-3Alkyl group, cyano group, hydroxyl C 1-3Alkyl or aryl; The analogue of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl or two suberyl, wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
Cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene base, two cyclohexenyls, bicycloheptene base, each randomly uses one to three C 1-3Alkyl group replaces;
C 1-4Alkyl or alkylidene group-phenyl-C (O)-C 0-4Alkyl or alkylidene group, C 1-4Alkyl or alkylidene group-C (O)-C 0-4Alkyl or alkylidene group, C 1-4Alkyl or alkylidene group-phenyl-S (O) m-C 0-4Alkyl or alkylidene group;
C 1-6Alkyl or C 1-6Alkoxyl group, each is randomly by partially or completely halogenation, or randomly uses R 17, amino, OR 18, or randomly use R 19The C that replaces 1-5Single-or the replacement of two-alkylamino.
Ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy, ring oxygen in heptan base, it is randomly by partially or completely halogenation, and randomly uses one to three randomly by partially or completely halogenated C 1-3Alkyl group replaces, and wherein one to three ring methylene group is independently by O, S (O) m, CHOH, C=O, C=S or NH substitute;
R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-;
By R 23R 24The C of NC (O)-replacement 2-6Alkenyl;
C 2-6Side chain or unbranched carbochain alkynyl, it is randomly by partially or completely halogenation, and wherein one or more methylene groups are randomly by O, NH or S (O) mSubstitute, and wherein, described alkynyl group is optional to be replaced with following radicals independently: 0-2 oxo group, pyrrolidyl, pyrryl, one or more C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkyl, nitrile, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or the C that is randomly replaced by one or more halogen atoms 1-4Side chain or unbranched alkylamino; Or
Benzoyl or naphthoyl; Wherein
R 7, R 8, R 9, R 10, R 12, R 13, R 14, R 15, R 17, R 19And R 25In each be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by partially or completely halogenation;
R 11And R 16In each be hydrogen or C independently 1-4Side chain or unbranched alkyl, it is optional by partially or completely halogenation; With
R 18Be hydrogen or C independently 1-4Side chain or unbranched alkyl, optional independently with oxo or R 25Replace.
43. compound as claimed in claim 42, wherein each R 3Be phenyl independently, naphthyl or heterocyclic radical, in them each is randomly by partially or completely halogenation, and randomly replace: phenyl with 1-3 following radicals, naphthyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrryl, pyrrolidyl, 2, the 5-pyrrolidine-2,4-diketo, imidazolyl, pyrazolyl, thienyl, furyl, tetrahydrofuran base, different _ the azoles base, thiazolyl, _ azoles base, triazolyl, tetrazyl, isothiazolyl, quinolyl, isoquinolyl, indyl, benzimidazolyl-, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, the benzopyrazoles base, benzimidazole thiophanate is for furyl, the cinnolines base, pteridyl, phthalazinyl, the naphthyl pyridyl, quinoxalinyl, quinazolyl, fast quinoline base, indazolyl, randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, two cyclopentyl, dicyclohexyl, two suberyl, phenyl C 1-5Alkyl, naphthyl C 1-5Alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, phenoxy group, naphthyloxy, heterocyclic oxy group, nitro, amino, list-or two (C 1-3Alkyl) amino, phenylamino, naphthylamine base, heterocyclic amino group, NH 2C (O), single-or two-(C 1-3Alkyl) aminocarbonyl, C 1-5Alkyl-C (O)-C 1-4Alkyl, amino-C 1-5Alkyl, list-or two-(C 1-3Alkyl) amino-C 1-5Alkyl, amino-S (O) 2, two-(C 1-3Alkyl) amino-S (O) 2, R 7-C 1-5Alkyl, R 8-C 1-5Alkoxyl group, R 9-C (O)-C 1-5Alkyl, R 10-C 1-5Alkyl (R 11) N or carboxyl-list-or two-(C 1-5Alkyl) amino.
44. compound as claimed in claim 42, wherein each R 3Be phenyl, pyridazinyl or pyridyl independently, each in them is randomly by partially or completely halogenation, and randomly replaces with following radicals: randomly by partially or completely halogenated C 1-6Side chain or unbranched alkyl, hydroxyl, oxo, cyano group, randomly by partially or completely halogenated C 1-3Alkoxyl group, nitro, amino, list-or two-(C 1-3Alkyl) amino;
C 1-6Alkyl or C 1-6Alkoxyl group, each is optional by partially or completely halogenation, or randomly replaces with following radicals: R 17, amino, OR 18, randomly use R 19The C that replaces 1-5Single-or two-alkylamino;
R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-or R 26C (O) (CH 2) mN (R 21)-.
45. compound as claimed in claim 43, wherein each R 3Be phenyl or tolyl.
46. compound as claimed in claim 6, wherein X is C=O.
47. the compound of formula IB:
Figure A2004800330550011C1
Its steric isomer, its tautomer, its solvate, its prodrug and its pharmacy acceptable salt, wherein:
X is C (O), C (S) or CH 2
G is C 3-10Carbocylic radical, 5-8 unit's monocyclic heterocycles base or 8-11 unit bicyclic heterocycles base, it contains one or more heteroatomss that is selected from O, N or S; Wherein, G is by R 1, R 2Or R 3In one or more replacements;
Ar be indazolyl, indyl, pseudoindoyl, imidazolyl, benzimidazolyl-, pyrazolyl, pyrazolinyl, pyrryl, pyrrolinyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, indolinyl, benzisoxa _ azoles base, dihydrobenzo different _ azoles base, dihydro-iso indolyl, benzisothiazole base, titanium dioxide benzo isothiazolyl, C 6-10Aryl ,-(C 1-3Alkyl)-(C 6-10Aryl) ,-(Y)-(C 0-3Alkyl)-(C 6-10Aryl) or-(Y)-(C 0-3Alkyl)-(5-10 unit heteroaryl), each in them is randomly used R 4Or R 5In one or more replacements;
Each Y is independently-CHZ-,-CZ 2-,-CHR-,-C (=CHR)-,-C (=C-CO 2R)-;
Each Z be independently F, Cl ,-OR ,-NR 2,-SR ,-NHCONHR or-NHCOR;
L is a covalent linkage, saturated or undersaturated side chain or unbranched C 1-10Carbochain, wherein, optional O, NR and the S (O) of being selected from independently of one or more methylene groups mHeteroatoms substitute; Wherein L is randomly by 0-2 oxo group and one or more C 1-4Side chain or unbranched alkyl replace, described C 1-4Side chain or unbranched alkyl are randomly replaced by one or more F, Cl, Br or I;
Each m is 0,1 or 2 independently;
Q be hydrogen ,-NR ' R ', cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) m, wherein cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) mEach randomly uses one or more R 27Replace; If R 4And R 5Do not exist, so-L-Q is not-H;
Each R independently is C hydrogen or replacement or unsubstituted 1-6Alkyl;
Each R ' is C hydrogen, replacement or unsubstituted independently 1-8(C alkyl, replacement or unsubstituted 0-4Alkyl)-(C 6-10Aryl) or that replace or unsubstituted (C 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-OR ,-NR ' R ' ,-SiR 3,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2, R 4And R 5Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
Each R " be that replace or unsubstituted C independently 1-8C alkyl, replacement or unsubstituted 0-4Alkyl-C 6-10(C aryl or replacement or unsubstituted 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 3Be that replace or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace.
Each R 6Be C 1-6Side chain or unbranched alkyl, it is randomly by part or all of halogenation, and randomly uses R 26Replace;
Each R 26Be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by part or all of halogenation;
R 20Be that replace or unsubstituted C 1-10C alkyl, replacement or unsubstituted 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical, OR ' or NR ' 2
R 21Be hydrogen or C 1-4Side chain or unbranched alkyl, it is randomly by part or all of halogenation; With
R 22, R 23And R 24In each be C hydrogen, replacement or unsubstituted independently 1-10Alkyl, wherein C 1-10Alkyl randomly by one or more O, N or S interrupt, replace or unsubstituted C 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical; Or R 23And R 24Randomly form heterocycle or hetero-aromatic ring together;
Each R 27Be independently F, Cl, Br, I, cyano group ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR ' ,-OR ' ,-NR ' R ' ,-SiR ' 3,-S (O) mR ', replace or unsubstituted straight or branched C 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-203-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and independently is selected from N, O, S (O) mHeteroatoms;
48. have the cytokine inhibitor of formula IA:
Figure A2004800330550013C1
Its steric isomer, its tautomer, its solvate, its prodrug and its pharmacy acceptable salt, wherein:
X is C (O) or C (S);
G is C 3-10Carbocylic radical, 5-8 unit's monocyclic heterocycles base or 8-11 unit bicyclic heterocycles base, it contains one or more heteroatomss that is selected from O, N or S; Wherein, G is by R 1, R 2Or R 3In one or more replacements;
Ar is-(Y)-and (C 0-3Alkyl)-(aryl bicyclic) or-(Y)-(C 0-3Alkyl)-(bicyclic heteroaryl), wherein bicyclic heteroaryl is indazolyl, pseudoindoyl, quinolyl, isoquinolyl, phthalazinyl, indolinyl, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, dihydrobenzo different _ azoles base, dihydro-iso indolyl, benzimidazolyl-, benzothienyl, benzothiazolyl, benzisothiazole base or titanium dioxide benzo isothiazolyl, wherein, Ar randomly uses one or more R 4Or R 5Replace; Yet prerequisite is that aryl bicyclic is not 1,1,4,4-tetramethyl--1,2,3,4-tetrahydrochysene-naphthyl;
Y is-C (O)-,-C (NNRC (O) OR)-,-C (NNRR)-,-C (NNC (O) NRR)-or-C (NOR)-;
L is a covalent linkage, saturated or undersaturated side chain or unbranched C 1-10Carbochain, wherein, optional O, NR and the S (O) of being selected from independently of one or more methylene groups mHeteroatoms substitute; Wherein L is randomly by 0-2 oxo group and one or more C 1-4Side chain or unbranched alkyl replace, described C 1-4Side chain or unbranched alkyl are randomly replaced by one or more F, Cl, Br or I;
Each m is 0,1 or 2 independently;
Q be hydrogen ,-NR ' R ', cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) m, or phenyl-S (O) m, wherein cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) mEach randomly uses one or more R 27Replace; And if R 4And R 5Do not exist, so-L-Q is not-H;
Each R independently is C hydrogen or replacement or unsubstituted 1-6Alkyl;
Each R ' is C hydrogen, replacement or unsubstituted independently 1-8(C alkyl, replacement or unsubstituted 0-4Alkyl)-(C 6-10Aryl) or that replace or unsubstituted (C 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-OR ,-NR ' R ' ,-SiR 3,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocycle aralkyl, replacement or unsubstituted or Heterocyclylalkyl (heterocyclic radical alkyl), it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2, R 4And R 5Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
Each R " be that replace or unsubstituted C independently 1-8C alkyl, replacement or unsubstituted 0-4Alkyl-C 6-10(C aryl or replacement or unsubstituted 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 3Be hydrogen, replacement or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace.
Each R 6Be C 1-6Side chain or unbranched alkyl, it is randomly by part or all of halogenation, and randomly uses R 26Replace;
Each R 26Be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by part or all of halogenation;
R 20Be that replace or unsubstituted C 1-10C alkyl, replacement or unsubstituted 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical, OR ' or NR ' 2
R 21Be hydrogen or C 1-4Side chain or unbranched alkyl, it is randomly by part or all of halogenation; With
R 22, R 23And R 24In each be C hydrogen, replacement or unsubstituted independently 1-10Alkyl, wherein C 1-10Alkyl randomly by one or more O, N or S interrupt, replace or unsubstituted C 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical; Or R 23And R 24Randomly form heterocycle or hetero-aromatic ring together;
Each R 27Be independently F, Cl, Br, I, cyano group ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR ' ,-OR ' ,-NR ' R ' ,-SiR ' 3,-S (O) mR ', replace or unsubstituted straight or branched C 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-203-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and independently is selected from N, O, S (O) mHeteroatoms;
Yet, if when Ar be-(Y)-(aryl bicyclic), when G was N-(phenyl replacement or unsubstituted)-pyrazolyl, pyrazolyl was used one or more R extraly 1, R 2Or R 3Replace; With
IA is not N-(4-chloro-3-methyl-isothiazole-5-yl)-2-[2-(2,2-dimethyl-propyl group)-benzo _ azoles-5-yl]-2-oxo-ethanamide.
49. the compound of formula IB:
Its steric isomer, its tautomer, its solvate, its prodrug and its pharmacy acceptable salt, wherein:
X is C (O) or C (S);
G be G '-(Y)-, wherein G ' is C 3-10Carbocylic radical, 5-8 unit's monocyclic heterocycles base or the unit of the 8-11 except that indyl bicyclic heterocycles base, it contains one or more heteroatomss that is selected from O, N or S; Wherein, G ' is by R 1, R 2Or R 3In one or more replacements;
Ar is aryl bicyclic or 8-11 unit bicyclic heteroaryl, contains the heteroatoms that one or more are selected from N, O, S, and wherein Ar randomly uses one or more R 4Or R 5Replace;
Y is independently-C (O)-,-C (NNRC (O) OR)-,-C (NNRR)-,-C (NNC (O) NRR) or-C (NOR)-;
L is a covalent linkage, saturated or undersaturated side chain or unbranched C 1-10Carbochain, wherein, optional O, NR and the S (O) of being selected from independently of one or more methylene groups mHeteroatoms substitute; Wherein L is randomly by 0-2 oxo group and one or more C 1-4Side chain or unbranched alkyl replace, described C 1-4Side chain or unbranched alkyl are randomly replaced by one or more F, Cl, Br or I;
Each m is 0,1 or 2 independently;
Q be hydrogen ,-NR ' R ', cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) m, or phenyl-S (O) m, wherein cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) mIn each randomly uses one or more R 27Replace; If R 4And R 5Do not exist, so-L-Q is not-H;
Each R independently is C hydrogen or replacement or unsubstituted 1-6Alkyl;
Each R ' independently is C hydrogen, replacement or unsubstituted 1-8(C alkyl, replacement or unsubstituted 0-4Alkyl)-(C 6-10Aryl) or that replace or unsubstituted (C 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-OR ,-NR ' R ' ,-SiR 3,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2, R 4And R 5Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
Each R " be that replace or unsubstituted C independently 1-8C alkyl, replacement or unsubstituted 0-4Alkyl-C 6-10(C aryl or replacement or unsubstituted 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 3Be that replace or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace.
Each R 6Be C 1-6Side chain or unbranched alkyl, it is randomly by part or all of halogenation, and randomly uses R 26Replace;
Each R 26Be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by part or all of halogenation;
R 20Be that replace or unsubstituted C 1-10C alkyl, replacement or unsubstituted 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical, OR ' or NR ' 2
R 21Be hydrogen or C 1-4Side chain or unbranched alkyl, it is randomly by part or all of halogenation; With
R 22, R 23And R 24In each be C hydrogen, replacement or unsubstituted independently 1-10Alkyl, wherein C 1-10Alkyl randomly by one or more O, N or S interrupt, replace or unsubstituted C 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical; Or R 23And R 24Randomly form heterocycle or hetero-aromatic ring together;
Each R 27Be independently F, Cl, Br, I, cyano group ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR ' ,-OR ' ,-NR ' R ' ,-SiR ' 3,-S (O) mR ', replace or unsubstituted straight or branched C 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-203-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and independently is selected from N, O, S (O) mHeteroatoms;
Yet prerequisite is that IB is not 2-[6-(2-xenyl-4-base-2-oxo-kharophen)-indoles-1-ylmethyl]-phenylformic acid.
50. have the cytokine inhibitor of formula IA:
Its steric isomer, its tautomer, its solvate, its prodrug and its pharmacy acceptable salt, wherein:
X be C (O) or C (S) or;
G is C 3-5Cycloalkyl, pyrazolyl, thiazolyl, _ azoles base, isothiazolyl, thiadiazolyl group, _ di azoly, pyrrolinyl, pyridazinyl, pyrryl, imidazolyl, the imidazoles ketone group, different _ the azoles base, furyl, thienyl, pyriconyl, naphthyl, the dihydro naphthyl, tetralyl, 2,3 indanyls, indenyl, quinolyl, the dihydroquinoline base, tetrahydric quinoline group, isoquinolyl, tetrahydro isoquinolyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzofuryl, the benzo thiophenyl, the benzopyrazoles base, dihydro benzo furyl, the dihydrobenzo thiophenyl, benzo _ oxazolone base, 4H-benzo [1,4] _ piperazine-3-ketone group, the benzo dioxolyl, benzo [1,3] dioxole-2-ketone group, the tetrahydro benzo pyranyl, indyl, indolinyl, the indoles ketone group, the dihydroindole ketone group, phthalimide-based, pyrrolidyl, tetrahydrofuran base, the tetrahydrochysene thiophenyl, piperidyl, piperazinyl, morpholinyl, THP trtrahydropyranyl, two _ alkyl, the tetramethylene sulfide sulfuryl, the tetramethylene sulfoxide base, _ azoles quinoline base, thiazolinyl, imidazolinyl, tetrahydro pyridyl, homopiperidinyl, pyrrolinyl, tetrahydro-pyrimidine base, decahydroquinolyl, the Decahydroisoquinolinpreparation base, thio-morpholinyl, thiazolidyl, dihydro _ piperazine base, dihydro pyranyl, oxocanyl, heptacanyl, thiophene _ alkyl or dithiane base; Wherein G is by R 1, R 2Or R 3In one or more replacements.
Ar is-(Y)-and (C 0-3Alkyl)-(phenyl) or-(Y)-(C 0-3Alkyl)-(bicyclic heteroaryl), wherein Ar randomly uses R 4Or R 5In one or more replacements;
Y is-C (O)-,-C (NNRC (O) OR)-,-C (NNRR)-,-C (NNC (O) NRR)-or-C (NOR)-;
L is a covalent linkage, saturated or undersaturated side chain or unbranched C 1-10Carbochain, wherein, optional O, NR and the S (O) of being selected from independently of one or more methylene groups mHeteroatoms substitute; Wherein L is randomly by 0-2 oxo group and one or more C 1-4Side chain or unbranched alkyl replace, described C 1-4Side chain or unbranched alkyl are randomly replaced by one or more F, Cl, Br or I;
Each m is 0,1 or 2 independently;
Q be hydrogen ,-NR ' R ', cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) m, or phenyl-S (O) m, wherein cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) mEach randomly uses one or more R 27Replace; If R 4And R 5Do not exist, so-L-Q is not-H;
Each R independently is C hydrogen or replacement or unsubstituted 1-6Alkyl;
Each R ' is C hydrogen, replacement or unsubstituted independently 1-8(C alkyl, replacement or unsubstituted 0-4Alkyl)-(C 6-10Aryl) or that replace or unsubstituted (C 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-OR ,-NR ' R ' ,-SiR 3,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2, R 4And R 5Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
Each R " be that replace or unsubstituted C independently 1-8C alkyl, replacement or unsubstituted 0-4Alkyl-C 6-10(C aryl or replacement or unsubstituted 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 3Be that replace or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace.
Each R 6Be C 1-6Side chain or unbranched alkyl, it is randomly by part or all of halogenation, and randomly uses R 26Replace;
Each R 26Be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by part or all of halogenation;
R 20Be that replace or unsubstituted C 1-10C alkyl, replacement or unsubstituted 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical, OR ' or NR ' 2
R 21Be hydrogen or C 1-4Side chain or unbranched alkyl, it is randomly by part or all of halogenation; With
R 22, R 23And R 24In each be C hydrogen, replacement or unsubstituted independently 1-10Alkyl, wherein C 1-10Alkyl randomly by one or more O, N or S interrupt, replace or unsubstituted C 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical; Or R 23And R 24Randomly form heterocycle or hetero-aromatic ring together;
Each R 27Be independently F, Cl, Br, I, cyano group ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR ' ,-OR ' ,-NR ' R ' ,-SiR ' 3,-S (O) mR ', replace or unsubstituted straight or branched C 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-203-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and independently is selected from N, O, S (O) mHeteroatoms;
Yet, if when Ar be phenyl, when G was N-(phenyl replacement or unsubstituted)-pyrazolyl, pyrazolyl was used R extraly 1, R 2Or R 3In one or more replacements; And
IA is not 2-[6-(2-xenyl-4-base-2-oxo-kharophen)-indoles-1-ylmethyl]-phenylformic acid.
51. the compound of formula IB:
Figure A2004800330550019C1
Its steric isomer, its tautomer, its solvate, its prodrug and its pharmacy acceptable salt, wherein:
X is C (O) or C (S);
G be G '-(Y)-, wherein G ' is C 3-10Cycloalkyl, phenyl, naphthyl, remove 1,1,4,4-tetramethyl--1,2,3, tetralyl outside the 4-tetralyl, pyrazolyl, thiazolyl, pyridyl, _ azoles base, different _ the azoles base, isothiazolyl, thiadiazolyl group, _ di azoly, pyridazinyl, imidazolyl, the furyl except that furans-2-base, the thienyl except that thiophene-2-base, dihydro naphthyl, 2,3 indanyls, indenyl, quinolyl, isoquinolyl, pyrimidyl, pyrazinyl, benzimidazolyl-, benzothiazolyl, benzo _ azoles base, benzopyrazoles base or homopiperidinyl; Wherein
G ' is by R 1, R 2Or R 3In one or more replacements.
Ar be phenyl, pyrimidyl, pyrazolyl, thiazolyl, thiadiazolyl group, _ the azoles base, different _ the azoles base, _ di azoly, isothiazolyl, pyrrolinyl, pyridazinyl, pyrryl, imidazolyl, furyl, thienyl, pyrimidyl, pyrazinyl; Wherein Ar is optional by R 4Or R 5In one or more replacements.
Y is independently-C (O)-,-C (NNRC (O) OR)-,-C (NNRR)-,-C (NNC (O) NRR)-or-C (NOR)-;
L is a covalent linkage, saturated or undersaturated side chain or unbranched C 1-10Carbochain, wherein, optional O, NR and the S (O) of being selected from independently of one or more methylene groups mHeteroatoms substitute; Wherein L is randomly by 0-2 oxo group and one or more C 1-4Side chain or unbranched alkyl replace, described C 1-4Side chain or unbranched alkyl are randomly replaced by one or more F, Cl, Br or I;
Each m is 0,1 or 2 independently;
Q be hydrogen ,-NR ' R ', cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) m, wherein cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) mEach randomly uses one or more R 27Replace; And if R 4And R 5Do not exist ,-L-Q is not a hydrogen;
Each R is C hydrogen or replacement or unsubstituted independently 1-6Alkyl;
Each R ' independently is C hydrogen, replacement or unsubstituted 1-8(C alkyl, replacement or unsubstituted 0-4Alkyl)-(C 6-10Aryl) or that replace or unsubstituted (C 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-NR ' R ' ,-OR ,-SiR 3,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2, R 4And R 5Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
Each R " be that replace or unsubstituted C independently 1-8C alkyl, replacement or unsubstituted 0-4Alkyl-C 6-10(C aryl or replacement or unsubstituted 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 3Be that replace or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace.
Each R 6Be C 1-6Side chain or unbranched alkyl, it is randomly by part or all of halogenation, and randomly uses R 26Replace;
Each R 26Be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by part or all of halogenation;
R 20Be that replace or unsubstituted C 1-10C alkyl, replacement or unsubstituted 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical, OR ' or NR ' 2
R 21Be hydrogen or C 1-4Side chain or unbranched alkyl, it is randomly by part or all of halogenation; With
R 22, R 23And R 24In each be C hydrogen, replacement or unsubstituted independently 1-10Alkyl, wherein C 1-10Alkyl randomly by one or more O, N or S interrupt, replace or unsubstituted C 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical; Or R 23And R 24Randomly form heterocycle or hetero-aromatic ring together;
Each R 27Be independently F, Cl, Br, I, cyano group ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR ' ,-OR ' ,-NR ' R ' ,-SiR ' 3,-S (O) mR ', replace or unsubstituted straight or branched C 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-203-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and independently is selected from N, O, S (O) mHeteroatoms;
Yet, if work as Ar-L-Q being-N-(phenyl replacement or unsubstituted)-pyrazolyl, G is phenyl, naphthyl, 2,3 indanyls or tetralyl, pyrazolyl is used R extraly 4Or R 5In one or more replacements; With
IB is not N-{2-chloro-4-[2-(3,5-dimethyl-1-phenyl-1H-pyrazoles-4-yl)-2-oxo-kharophen]-5-hydroxyl-phenyl }-2-(3-pentadecyl-benzenesulfonyl)-butyramide or 5-(4-oxyethyl group-phenyl)-1-be right-and tolyl-4-is right-tolyl oxamyl-1H-pyrazoles-3-carboxylate methyl ester.
52. the compound of formula IC,
G-encircles an Ar-L-Q
IC
Its steric isomer, its tautomer, its solvate, its prodrug and its pharmacy acceptable salt, wherein:
Ring is maleimide, succinimide, imidazolidone, imidazolidine-diketone, imidazolidine-triketone, triazolidine-diketone or triazine-diketone;
G is C 3-10Carbocylic radical, C 4-12Carbocyclic ring alkyl, 5-8 unit's monocyclic heterocycles base or Heterocyclylalkyl or 8-11 unit's bicyclic heterocycles base or Heterocyclylalkyl, wherein said heterocycle contains one or more heteroatomss that is selected from O, N or S; G ' is by R 1, R 2Or R 3In one or more replacements;
Ar be indazolyl, indyl, pseudoindoyl, imidazolyl, benzimidazolyl-, pyrazolyl, pyrazolinyl, pyrryl, pyrrolinyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, indolinyl, benzofuryl, benzo _ azoles base, benzisoxa _ azoles base, dihydrobenzo different _ azoles base, dihydro-iso indolyl, benzothiazolyl, benzisothiazole base, titanium dioxide benzo isothiazolyl, C 6-10Aryl or-(C 1-3Alkyl)-(C 6-10Aryl), wherein Ar randomly uses R 4Or R 5In one or more replacements.
L is a covalent linkage, saturated or undersaturated side chain or unbranched C 1-10Carbochain, wherein, optional O, NR and the S (O) of being selected from independently of one or more methylene groups mHeteroatoms substitute; Wherein L is randomly by 0-2 oxo group and one or more C 1-4Side chain or unbranched alkyl replace, described C 1-4Side chain or unbranched alkyl are randomly replaced by one or more F, Cl, Br or I;
Each m is 0,1 or 2 independently;
Q be hydrogen ,-NR ' R ', cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) m, or phenyl-S (O) m, wherein cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) mEach randomly uses one or more R 27Replace; If R 4And R 5Do not exist, then-L-Q is not-H;
Each R independently is C hydrogen or replacement or unsubstituted 1-6Alkyl;
Each R ' is C hydrogen, replacement or unsubstituted independently 1-8(C alkyl, replacement or unsubstituted 0-4Alkyl)-(C 6-10Aryl) or that replace or unsubstituted (C 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-OR ,-NR ' R ' ,-SiR 3,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2, R 4And R 5Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
Each R " be that replace or unsubstituted C independently 1-8C alkyl, replacement or unsubstituted 0-4Alkyl-C 6-10(C aryl or replacement or unsubstituted 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 3Be that replace or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace.
Each R 6Be C 1-6Side chain or unbranched alkyl, it is randomly by part or all of halogenation, and randomly uses R 26Replace;
Each R 26Be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by part or all of halogenation;
R 20Be that replace or unsubstituted C 1-10C alkyl, replacement or unsubstituted 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical, OR ' or NR ' 2
R 21Be hydrogen or C 1-4Side chain or unbranched alkyl, it is randomly by part or all of halogenation; With
R 22, R 23And R 24In each be C hydrogen, replacement or unsubstituted independently 1-10Alkyl, wherein C 1-10Alkyl randomly by one or more O, N or S interrupt, replace or unsubstituted C 0-6C alkyl-phenyl, replacement or unsubstituted 0-6Alkyl-heterocyclic radical; Or R 23And R 24Randomly form heterocycle or hetero-aromatic ring together; With
Each R 27Be independently F, Cl, Br, I, cyano group ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR ' ,-OR ' ,-NR ' R ' ,-SiR ' 3,-S (O) mR ', replace or unsubstituted straight or branched C 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-203-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and independently is selected from N, O, S (O) mHeteroatoms.
53. have the compound of formula II
Figure A2004800330550023C1
Its steric isomer, its tautomer, its solvate, its prodrug and its pharmacy acceptable salt, wherein:
G is C 3-10Carbocylic radical, 5-8 unit's monocyclic heterocycles base or 8-11 unit bicyclic heterocycles base, it contains one or more heteroatomss that is selected from O, N or S; Wherein, G is by R 1, R 2Or R 3In one or more replacements;
X ' is CR '=CR ', CR '=N, NR ', CR ' 2, O or S;
Ar is phenyl, naphthyl, quinoline, isoquinoline 99.9, tetralyl, pyridyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, tetrahydroquinoline, tetrahydroisoquinoline, benzoglyoxaline, cumarone, 2,3 indanyls, indenyl, indoles or structure-(Y ')-(C 0-3Alkyl)-(C 6-10Aryl), each in them is randomly used one or more R 4Group replaces;
Y ' do not exist or-O-or-NH-;
L is a covalent linkage, saturated or undersaturated side chain or unbranched C 1-10Carbochain, wherein, optional O, NR and the S (O) of being selected from independently of one or more methylene groups mHeteroatoms substitute; Wherein L is randomly by 0-2 oxo group and one or more C 1-4Side chain or unbranched alkyl replace, described C 1-4Side chain or unbranched alkyl are randomly replaced by one or more F, Cl, Br or I;
Each m is 0,1 or 2 independently;
Q be hydrogen ,-NR ' R ', cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) m, or phenyl-S (O) m, wherein cycloalkyl, aryl, heterocyclic radical, C 1-6Alkoxyl group, C 1-6Alkyl-S (O) mOr phenyl-S (O) mEach randomly uses one or more R 27Replace;
Each R independently is C hydrogen or replacement or unsubstituted 1-6Alkyl;
Each R ' is C hydrogen, replacement or unsubstituted independently 1-8(C alkyl, replacement or unsubstituted 0-4Alkyl)-(C 6-10Aryl) or that replace or unsubstituted (C 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 1Be independently F, Cl, Br, I, cyano group ,-C (O) R ,-C (O) NR 2,-C (O) OR ,-NR ' R ' ,-OR ,-SiR 3,-S (O) mStraight or branched C R, replacement or unsubstituted 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-20Saturated or undersaturated 3-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms;
Each R 2And R 4Be F, Cl, Br, I, cyano group, replacement or unsubstituted straight or branched C independently 1-6C alkyl, replacement or unsubstituted 6-10The first heteroaryl of 5-10 aryl, replacement or unsubstituted ,-OR ' ,-OR 6,-C (O) R ' ,-C (O) OR ' ,-C (O) NR ' 2,-NR ' 2,-NO 2,-S (O) mR " ,-NR ' SO 2R " ,-NR ' C (O) NR ' R ' ,-NR ' C (S) NR ' R ' ,-NR ' C (O) OR ' or-SO 2NR ' 2
Each R " be that replace or unsubstituted C independently 1-8C alkyl, replacement or unsubstituted 0-4Alkyl-C 6-10(C aryl or replacement or unsubstituted 0-4Alkyl)-(5-10 unit heterocyclic radical);
Each R 3Be H, replacement or unsubstituted C independently 6-10Saturated or undersaturated 3-11 unit's heterocyclic radical aryl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and is independently selected from N, O, S (O) mHeteroatoms, replacement or unsubstituted C 3-12C cycloalkyl, replacement or unsubstituted 5-12C cycloalkenyl group, replacement or unsubstituted 7-20Straight or branched C aralkyl, replacement or unsubstituted 1-8Alkyl, R 20C (O) N (R 21)-, R 22O-, R 23R 24NC (O)-, R 26(CH 2) mC (O) N (R 21)-, R 26C (O) (CH 2) mN (R 21That replace)-, or unsubstituted C 2-8Alkenyl or that replace or unsubstituted C 2-8Alkynyl, wherein, C 1-8Alkyl, C 2-8Alkenyl or C 2-8One or more methylene groups in the alkynyl are randomly by O, NH or S (O) mReplace.
Each R 6Be C 1-6Side chain or unbranched alkyl, it is randomly by part or all of halogenation, and randomly uses R 26Replace;
Each R 26Be cyano group, morpholino, piperidyl, piperazinyl, imidazolyl, phenyl, pyridyl, tetrazyl or single or two-(C independently 0-4Alkyl) amino, it is randomly by part or all of halogenation;
R 20By partially or completely halogenated C randomly 1-10Side chain or do not have alkyl, phenyl, pyridine, OR ' or the NR ' of straight chain 2
R 21Be hydrogen or C 1-4Side chain or unbranched alkyl, it is randomly by part or all of halogenation; With
R 22, R 23And R 24In each be hydrogen, C independently 1-6Side chain or unbranched alkyl, it is randomly by carbonyl amino-list-or two-C 1-3Alkyl or amino-list or two-C 1-3Alkyl replaces or wherein said C 1-6Alkyl is randomly by part or all of halogenation, and randomly interrupted by one or more following radicals: O, N or S, phenyl, pyridine, randomly by part or all of halogenated list-or two-C 0-4Side chain or unbranched alkyl and alkylamino; Or R 23And R 24Randomly form heterocycle or hetero-aromatic ring together;
Each R 27Be independently F, Cl, Br, I, cyano group ,-C (O) R ' ,-C (O) NR ' 2,-C (O) OR ' ,-OR ' ,-NR ' R ' ,-SiR ' 3,-S (O) mR ', replace or unsubstituted straight or branched C 1-10Alkyl, C 2-10Alkenyl or C 2-10C alkynyl, replacement or unsubstituted 3-10C cycloalkyl, replacement or unsubstituted 5-8C cycloalkenyl group, replacement or unsubstituted 7-203-11 unit's heterocyclic radical aralkyl, replacement or unsubstituted or Heterocyclylalkyl, it contains 1,2,3 or 4 and independently is selected from N, O, S (O) mHeteroatoms;
54. pharmaceutical composition comprises described compound of claim 6 and pharmaceutically acceptable carrier.
55. a treatment is by the method for cytokine mediated disease, this method comprises the described compound of the claim 6 of significant quantity on the patient treatment that needs this kind treatment.
56. according to the described method of claim 55, the disease of wherein said cytokine-mediation is a rheumatoid arthritis, osteoarthritis, Crohn disease, ulcerative colitis, arthritic psoriasis, traumatic arthritis, rubella arthritis, inflammatory bowel, multiple sclerosis, graft versus host disease (GVH disease), systemic lupus erythematous, toxic shock syndrome, irritable bowel syndrome, muscle worsens, allograft rejection, pancreatitis, insulitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, leprosy, acute synovitis, rely special syndrome, urarthritis, Behcet ' s disease, spondylitis, endometriosis, non--joint property inflammatory conditions, acute or chronic pain, apoplexy, chronic heart failure, toxaemia, reperfusion injury, ischemia-reperfusion, myocardial ischemia, restenosis, thrombosis, blood vessel takes place, coronary heart disease, coronary artery disease, acute coronary syndrome, aortic arch syndrome, in heart failure, hypercholesterolemia, with coagulation of blood or fibrinolysis diseases associated or state, arteriosclerosis, anaphylaxis conjunctivitis, uveitis, glaucoma, look-neuritis, retinal ischemia, diabetic retinopathy, induced with laser look infringement, operation or damage-inductive proliferative vitreoretinopathy, allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, pulmonary emphysema, bronchitis, Polyblennia, silicosis, SARS infects, respiratory inflammation, psoriasis, eczema, the irritated dermatitis of heredity, contact dermatitis, acne, Ge-Ba two syndromes, the Ba Jinsen disease, Huntington Chorea, Alzheimer, amyotrophic lateral sclerosis, multiple sclerosis and other demyelinating diseases, viral and bacterial meningitis, the CNS wound, Spinal injury, epileptic seizures, spasm, olivopontocerebellar atrophy, aids dementia complex, MERRF and MELAS syndromes, leber disease, wernicke encephalopathy, the special syndrome of thunder, homocystinuria, hyper prolinemia, hyperhomocysteinemiainjury, non-ketone hyperglycinemia, hydroxyl fourth amino acid uria, sulfite oxidase deficiency, the system ensemble disease, lead encephalopathy, Tourette's syndrome, hepatogenic encephalopathy, drug habit, resistance, drug dependence, depressed, anxiety disorder and schizophrenia, aneurysma, epilepsy, diabetes, the general emaciation, the emaciation of infection or pernicious secondary, the emaciation of acquired immune deficiency syndrome (AIDS) secondary, fat, apositia and disease of eating too much at one meal, bone-resorbing disease, osteopetrosis, osteoporosis, pyemia, HIV, HCV, malaria, infective arthritis, leishmaniasis, Lyme disease, cancer, Castleman ' s disease, stem-cell therapy target or resistance.
57. according to the described method of claim 56, wherein said cancer is mammary cancer, colorectal carcinoma, lung cancer, prostate cancer, multiple myeloma, acute myelogenous leukemia, myelodysplastic syndrome, non--He Jiejin lymphomas or follicular lymphoma.
58. according to the described method of claim 56, wherein said non--property inflammatory conditions in joint is intervertebral disk syndromes state, bursitis, tendinitis, tenosynovitis or fibromyalgia syndrome.
59. according to the described method of claim 56, wherein said heart failure is cardiac failure, myocardosis, myocarditis, vasculitis, vascular restenosis, valvulopathy or coronary artery bypass.
60. according to the described method of claim 56, the wherein said and disease plasmin decorrelation is acute phlebothrombosis disease, pulmonary infarction, the thrombosis of gestation time, the hemorrhagic gangrene of skin, acute or chronic disseminated intravascular coagulation, form by condensing of causing of operation, CBR or extended immobilization, phlebothrombosis disease, explosive meningococcemia, acute thrombotic apoplexy, acute coronary occlusion, acute periphery artery occlusion, Massive pulmonary embolism, the axillary vein thrombosis, bulk femoral vein thrombosis, occlusive artery or venous cannula, myocardosis, the venous occlusive disease of liver, ypotension, the cardiac output that reduces, the vascular resistance that reduces, lung's hypertension, the lung compliance that reduces, leukopenia or thrombocytopenia.
61. according to the described method of claim 56, wherein said pain is neuropathic pain, neuropathy, polyneuropathy, diabetes-relevant polyneuropathy, wound, migraine, tonus pain and burst headache, horton's disease, varicose ulcer, neurodynia, flesh-skeleton pain, bone-traumatic pain, fracture, nutritional trouble, arthritis vertebralis, fibromyalgia disease, phantom limb pain, have a back ache, vertebra is painful, the sciatica of prolapse of intervertebral disc-bring out, post-operative pain, cancer-ache related, blood vessel pain, visceral pain, the pain that childbirth or HIV-are relevant.
62. according to the described method of claim 56, wherein said cytokine mediated disease is a rheumatoid arthritis, osteoarthritis, Crohn disease, ulcerative colitis, arthritic psoriasis, traumatic arthritis, rubella arthritis, inflammatory bowel, multiple sclerosis, psoriasis, graft versus host disease (GVH disease), systemic lupus erythematous, toxic shock syndrome, irritable bowel syndrome, muscle deterioration, allograft rejection, pancreatitis, insulitis, glomerulonephritis, diabetic nephropathy, renal fibrosis, chronic renal failure, gout, acute synovitis, rely special syndrome, urarthritis, Behcet ' s disease, spondylitis, endometriosis, non--joint property inflammatory conditions, acute or chronic pain.
63. according to the described method of claim 56, wherein said cytokine mediated disease is apoplexy, chronic heart failure, toxaemia, reperfusion injury, ischemia-reperfusion, myocardial ischemia, restenosis, thrombosis, blood vessel generation, coronary heart disease, coronary artery disease, acute coronary syndrome, aortic arch syndrome, heart failure, hypercholesterolemia, follows coagulation of blood or fibrinolysis diseases associated or state or arteriosclerosis.
64. according to the described method of claim 56, wherein said cytokine mediated disease is anaphylaxis conjunctivitis, uveitis, glaucoma, look-neuritis, retinal ischemia, diabetic retinopathy, induced with laser look infringement or operation or damage-inductive proliferative vitreoretinopathy.
65. according to the described method of claim 56, wherein said cytokine mediated disease is allergic rhinitis, asthma, adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, pulmonary emphysema, asthma, bronchitis, Polyblennia, SARS infection, silicosis or respiratory inflammation.
66. according to the described method of claim 56, wherein said cytokine mediated disease is psoriasis, eczema, the irritated dermatitis of heredity, contact dermatitis or acne.
67. according to the described method of claim 56, wherein said cytokine mediated disease is Ge-Ba two syndromes, the Ba Jinsen disease, Huntington Chorea, Alzheimer, amyotrophic lateral sclerosis, multiple sclerosis and other demyelinating diseases, viral and bacterial meningitis, the CNS wound, Spinal injury, epileptic seizures, spasm, olivopontocerebellar atrophy, aids dementia complex, MERRF and MELAS syndromes, leber disease, wernicke encephalopathy, the special syndrome of thunder, homocystinuria, hyper prolinemia, hyperhomocysteinemiainjury, non-ketone hyperglycinemia, hydroxyl fourth amino acid uria, sulfite oxidase deficiency, the system ensemble disease, lead encephalopathy, Tourette's syndrome, hepatogenic encephalopathy, drug habit, resistance, drug dependence, depressed, anxiety disorder and schizophrenia, aneurysma or epilepsy.
68. according to the described method of claim 56, wherein said cytokine mediated disease is bone-resorbing disease, osteopetrosis, osteoporosis or osteoarthritis.
69. according to the described method of claim 56, wherein said cytokine mediated disease is the emaciation of diabetes, general emaciation, infection or pernicious secondary, emaciation, obesity, apositia or the disease of eating too much at one meal of acquired immune deficiency syndrome (AIDS) secondary.
70. according to the described method of claim 56, wherein said cytokine mediated disease is pyemia, HIV, HCV, malaria, infective arthritis, leishmaniasis, Lyme disease, cancer, Castleman ' s disease or resistance.
71. a method for the treatment of the disease of neutrophilic granulocyte-mediation, this method comprise the described compound of the claim 6 of significant quantity on the patient treatment that needs this kind treatment.
72. as the described method of claim 71, the disease of wherein said neutrophilic granulocyte-mediation is bronchial asthma, rhinitis, influenza, apoplexy, myocardial infarction, thermal damage, adult respiratory distress syndrome (ARDS), multiple organ damage, the acute glomerulonephritis of wound secondary, the tetter that is attended by the acute inflammation composition, acute purulent meningitis, hemodialysis, leucopheresis, the relevant syndromes of granulocyte blood transfusion or necrotizing enterocolitis.
73. pharmaceutical composition, comprise the described compound of claim 6 and one or more active ingredients A, wherein A is the inhibitor of NSAID, immunosuppression medicament, immunomodulatory medicament, cytostatic agent, angiogenesis inhibitor, biological reagent, steroid, Vitamin D3 500,000 I.U/GM or its analogue, retinoids or cell adhesion molecule LFA-1 or ICAM.
74., also comprise pharmaceutically acceptable carrier or vehicle as the described pharmaceutical composition of claim 73.
75. as the described pharmaceutical composition of claim 73, wherein A be Bu Desong, Vitamin D3 500,000 I.U/GM, 5-ASA medicine, glucocorticosteroid, Betamethasone Valerate, dexamethasone, methylprednisolone, prednisolone, fluorine can the spy, methotrexate, fluocinonide, hydrocortisone, halogen doubly his rope, clobetasone, fluocinolone acetonide, fluticasone, Triamcinolone Acetonide, Mometasone, diflucortolone, calcipotriol, Tacalcitol, Maxacalcitol, his Cali's alcohol, calcium torrid zone hormone 1 α, 2,5-dihydroxy vitamin D 3And Rat parathyroid hormone 1-34-related peptides, pimecrolimus, tacrolimus, macrolide, ascosin, daclizumab, anti--CD4, anti--CD80, anti--CD25, peptide T, LFA3TIP, DAB 389, anti-LFA3-IgCl, CTLA-4Ig, protein tyrosine kinase inhibitors, E-select plain inhibitor, A Faxipu, English monoclonal antibody of sharp former times, Kineret, IL-1-RA, at the antibody of TNF-α, I1-6, LFA-1 and C5 or receptor structure thing, etanercept, pearl monoclonal antibody, ICAM-1 ISIS 2302, DAB IL-2, DAB in accordance with the law 389IL-2, Bali Xidan are anti-, ciclosporin, azathioprine, hydroxyurea, 6-Tioguanine, anti--TAC, Oxychloroquine, Beracilline, sulfasalazine, auranofin, disodium aurothiomalate, Minocycline HCl, dapsone, Chlorambucil, purinethol, sirolimus, mycophenolic acid morpholine ethyl ester, leflunomide, endoxan; Compound at VEGF, taxol, pentoxifylline, Thalidomide, interferon beta-1B, alpha-interferon, adalimumab, the IL-1 receptor antagonist, acamol, Asprin, Ibuprofen BP/EP, choline salicylate magnesium, choline salicylate, diclofenac, diflunisal, R-ETODOLAC, fenoprofen calcium, flurbiprofen, indomethacin, Ketoprofen, carprofen, indoprofen, ketorolac tromethamine, magnesium salicylate, that sour sodium of first chlorophenol, mefenamic acid, _ promazine, piroxicam, sodium salicylate, sulindac, Tolmetin, meloxicam, rofecoxib, Sai Lekao former times, Ai Tuolikao former times, valdecoxib, nabumetone, naproxen, lornoxicam, nimesulide, indoprofen, auspicious fragrant ancestor, salsalate, tiaprofenic acid or Flosulide.
76. according to the described composition of claim 73, wherein A is methotrexate, English monoclonal antibody of sharp former times, leflunomide or their combination.
77. method for the treatment of rheumatoid arthritis, this method comprises the composition of significant quantity on the patient treatment that needs this kind treatment, described composition comprises the described compound of claim 6, with one or many middle active ingredient A, wherein said A is the inhibitor of NSAID, immunosuppression medicament, immunomodulatory medicament, cytostatic agent, angiogenesis inhibitor, biological reagent, glucocorticosteroid or cell adhesion molecule LFA-1 or ICAM-1.
78. according to the described method of claim 76, wherein said A is Oxychloroquine, Beracilline, sulfasalazine, auranofin, disodium aurothiomalate, Minocycline HCl, dapsone, Chlorambucil, purinethol, tacrolimus, sirolimus, mycophenolic acid morpholine ethyl ester, ciclosporin, leflunomide, methotrexate, azathioprine and endoxan; VEGF inhibitor, taxol, pentoxifylline, Thalidomide, interferon beta-1B and alpha-interferon; Etanercept, English monoclonal antibody of sharp former times, adalimumab (D2E7), CTLA-4, at the biological reagent of CD-4, LFA-1, IL-6, ICAM-1 or C5 and IL-1 acceptor; Acamol, Asprin, Ibuprofen BP/EP, choline salicylate magnesium, choline salicylate, diclofenac, diflunisal, R-ETODOLAC, fenoprofen calcium, flurbiprofen, indomethacin, Ketoprofen, carprofen, indoprofen, ketorolac tromethamine, magnesium salicylate, that sour sodium of first chlorophenol, mefenamic acid, _ promazine, piroxicam, sodium salicylate, sulindac, Tolmetin, meloxicam, rofecoxib, Sai Lekao former times, Ai Tuolikao former times, valdecoxib, nabumetone, naproxen, lornoxicam, nimesulide, indoprofen, auspicious fragrant ancestor, salsalate, tiaprofenic acid and Flosulide; Betamethasone Valerate, dexamethasone, methylprednisolone, prednisolone and ground fluorine can be special.
79. according to the described method of claim 78, wherein A is the English monoclonal antibody of sharp former times, makes up separately or with methotrexate.
80. psoriasic method of treatment, this method comprises the composition of significant quantity on the patient treatment that needs this kind treatment, described composition comprises the described compound of claim 6, with one or various active composition A, it is randomly united with conventional excipients and/or carrier, and wherein said A is selected from one or more following substances: retinoids, immunosuppression medicament, immunomodulatory medicament, biological reagent, steroid, novel vitamin D analogues and cell adhesion molecule inhibitor; Or A is selected from the therapy that UV-B (UVB), ultraviolet light,long wave add psoralene (PUVA), and each in them randomly gives with combining of retinoids, methotrexate or S-Neoral and retinoids.
81. 0 described method according to Claim 8, wherein A be that S-Neoral, pimecrolimus, tacrolimus, ascus are mould, anti--CD4, anti-CD80, anti--CD25, peptide T, LFA3TIP, anti-LFA3-IgCl, anti--CD11, DAB 389, CTLA-4Ig, E-select plain inhibitor, A Faxipu, English monoclonal antibody of sharp former times, etanercept, in accordance with the law pearl monoclonal antibody, methotrexate, retinoids, dithiane alcohol, calcipotriol, Tacalcitol, ICAM-1 ISIS 2302, IL10, daclizumab (anti--TAC) and the Bali Xidan anti-; Or A is selected from the therapy that UV-B (UVB), ultraviolet light,long wave add psoralene (PUVA), and each in them randomly gives with combining of retinoids, methotrexate or S-Neoral and retinoids.
82. method for the treatment of Crohn disease, this method comprises the composition of significant quantity on the patient treatment that needs this kind treatment, described composition comprises the described compound of claim 6 and one or more active ingredients, it is randomly united with traditional vehicle or carrier, and wherein said A is selected from one or more following substances: steroid, 5-ASA medicine, immunosuppressor, antiviral agent, biological reagent and adhesion molecule inhibitor.
83. 2 described methods according to Claim 8, wherein said A is selected from one or more following substances: 5-ASA, methotrexate, azathioprine, Bu Desong, IL-1 receptor antagonist, etanercept, English monoclonal antibody of sharp former times, adalimumab (D2E7), CTLA-4, at biological reagent or the antegren of target CD-4, LFA-1, IL-6, ICAM-1 and C5, IL-10, ISIS 2302.
84. a treatment and the disease of coagulation of blood or plasmin decorrelation and the method for state, this method comprises the described compound of the claim 6 of significant quantity on the patient treatment that needs this kind treatment and one or more anti-agglomerating agents or fibrinolytic agent.
85. 4 described methods according to Claim 8, wherein said disease or state are caused by grumeleuse, thrombosis or embolism.
86. 4 described methods according to Claim 8, wherein said disease or state are selected from: acute phlebothrombosis disease, pulmonary infarction, the thrombosis of gestation time, the hemorrhagic gangrene of skin, acute or chronic disseminated intravascular coagulation (DIC), form by condensing of causing of operation, CBR or extended immobilization, phlebothrombosis disease, explosive meningococcemia, acute thrombotic apoplexy, acute coronary occlusion, acute periphery artery occlusion, Massive pulmonary embolism, the axillary vein thrombosis, bulk femoral vein thrombosis, occlusive artery or venous cannula, myocardosis, the venous occlusive disease of liver, ypotension, the cardiac output that reduces, the vascular resistance that reduces, lung's hypertension, the lung compliance that reduces, leukopenia and thrombocytopenia.
87. 6 described methods according to Claim 8, wherein said other anti-agglomerating agents or fibrinolytic agent are selected from: recombinant tissue plasminogen activator (rtPA), streptokinase (SK), urokinase (UK), proUK, heparin, enoxaparin, its heparin of moral, tonka bean camphor anti-coagulant, Asprin, dipyrimidamole, aggrennox, plug chlorine are fixed, clopidogrel (Plavix), ReoPro, RheoPro, according to drenching and aggrestat for lattice.
88. a method for preparing the described compound of claim 6 with formula IA, described method comprises: with G-NH 2React in the presence of coupling agent and alkali with Q-L-Ar-X-OH, or with G-NH 2With Q-L-Ar-X-X " reaction in the presence of alkali, produce described compound, wherein, G, Ar, Q and L such as front define, X is C (O) or C (S), X " be to activate part.
89. as the described method of claim 88, wherein said activation partly be F, Cl, Br, I ,-N 3, N-hydroxy-succinamide, I-hydroxybenzotriazole, Pentafluorophenol, pentachlorophenol, right-nitrophenols or-O-C (O)-OR y, R wherein yIt is low alkyl group.
90. as the described method of claim 88, wherein said alkali is sodium bicarbonate or organic amine.
91. as the described method of claim 90, wherein said organic amine is pyridine, N-methylmorpholine, diisopropylethylamine or triethylamine.
92. as the described method of claim 88, wherein Ar be-(Y)-naphthyl-, Y is-CH (OH)-or-CH 2-, G be selected from phenyl, pyridyl, pyrazolyl, pyrryl, imidazolyl, _ azoles base, different _ azoles base or thienyl.
93. compound is selected from:
1H-indazole-3-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
3-tert-butyl-5-phenyl-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-hydroxyl-3-morpholine-4-ylmethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-hydroxy-3-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-3-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-chloro-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-3-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[7-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-[5-tert-butyl-2-methoxyl group-3-(piperidines-1-carbonyl)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-2-hydroxyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenylformic acid;
N-(2-benzenesulfonyl-5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1-two ring [2.2.1] heptan-2-base-5-phenylamino-3-is right-tolyl-1, and the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones also;
3-is right-and tolyl-5-is right-tolyl amino-1, the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones also;
1-two ring [2.2.1] heptan-2-base-3-is right-and tolyl-5-is right-tolyl amino-1, the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones also;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2,2-two fluoro-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-N '-naphthalene-1-base-oxamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl amino)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanol;
1-(3-tert-butyl-phenyl)-4-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-[1,2,4] triazolidine-3, the 5-diketone; 4-(3-tert-butyl-phenyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-[1,2,4] triazolidine-3, the 5-diketone;
(E)-3-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylcarbamoyl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-methyl acrylate;
N-(5-tert-butyl-2-methoxyl group-3-{3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,5-dioxo-2,5-dihydro-pyrroles-1-yl }-phenyl)-Toluidrin;
N-(5-tert-butyl-2-methoxyl group-3-{3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,5-dioxo-tetramethyleneimine-1-yl }-phenyl)-Toluidrin;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-[4-(2-piperidines-1-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-ethanamide;
3-tert-butyl-1-is right-tolyl-5-(3-trifluoromethyl-phenyl)-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
1-(2-morpholine-4-base-ethyl)-1H-indazole-3-carboxylic acid (5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-acid amides;
N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-2-(2,4,6-trimethylammonium-phenyl)-ethanamide;
1-phenyl-cyclopropane-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
N-[5-tert-butyl-2-(2,5-two fluoro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3-chloro-benzoyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3-methylsulfonyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
4-[(5-tert-butyl-2-is right-tolyl-2H-pyrazole-3-yl formamyl)-methyl]-piperidines-1-carboxylic acid tert-butyl ester;
N-[3-(benzenesulfonyl-carbamyl ylmethyl-amino)-5-tert-butyl-2-methoxyl group-phenyl]-2-naphthalene-1-base-2-oxo-ethanamide;
N-(3-tert-butyl-different _ azoles-5-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-ethanesulfonamido-2-methoxyl group-phenyl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-the succinamic acid methyl esters;
2-(2-benzyl-5-tert-butyl-2H-pyrazole-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-2-(3-chloro-phenyl)-2H-pyrazoles-3-carboxylic acid [4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-acid amides;
2-(3-bromo-4-methoxyl group-phenyl)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[3-fluoro-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-ethanamide;
(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-(2,2-dimethyl-propyl group)-amine;
2-(4-benzyloxy-phenyl)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-(4-sulphonamide-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-base-2-oxo-ethanamide;
5-tert-butyl-2-methoxyl group-3-(1-naphthalene-1-base-3,5-dioxo-[1,2,4] triazolidine-4-yl)-benzamide; 2-(4-bromo-naphthalene-1-yl)-N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-oxo-ethanamide;
5-tert-butyl-2-hydroxyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-(4-methoxyl group-naphthalene-1-yl)-ethanamide; N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-methylamino--pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-{4-[2-(I-oxo-1 λ 4-thiomorpholine-4-yl)-oxyethyl group]-naphthalene-1-yl }-ethanamide;
The 5-tert-butyl-3-{2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid methyl esters;
N-[5-tert-butyl-2-(3-methylsulfonyl-phenyl)-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-{4-[2-((2R, 6R)-2,6-dimethyl-morpholine-4-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[7-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-[2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-kharophen]-benzamide;
4-tert-butyl-N-[4-(2-piperidines-1-base-oxyethyl group)-naphthalene-1-yl]-benzamide;
N-(2-ethanoyl-5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-N-cyclopropyl-3-{2-hydrazono--2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-2-methoxyl group-benzamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-hydroxyl-2-(4-methoxyl group-naphthalene-1-yl)-propionic acid amide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-phenyl-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-hydrazono--2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
2,3-dihydro-indoles-1-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
N-(3,4-dimethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-cyclohexyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(3,5-two fluoro-phenyl)-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-oxo-2-(4-pyridin-3-yl-naphthalene-1-yl)-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-diethylin-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-{4-[2-(3-oxo-[1,4] Diazesuberane-1-yl)-ethyl]-naphthalene-1-yl }-ethanamide;
5-tert-butyl-N-ethyl-2-methoxyl group-3-[2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-kharophen]-benzamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-oxo-2-{4-[6-(tetrahydrochysene-pyrans-4-base is amino)-pyridin-3-yl]-naphthalene-1-yl }-ethanamide;
5-tert-butyl-3-ethanesulfonamido-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-benzamide;
Between 2-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-oxo-N--tolyl-ethanamide;
N-(2,5-dimethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
Tetramethyleneimine-1-carboxylic acid (5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-acid amides;
2-(4-bromo-phenyl)-N-(5-tert-butyl-2-methoxyl group-phenyl)-ethanamide;
N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-oxo-2-{4-[2-((S)-1-phenyl-ethylamino)-pyrimidine-4-base is amino]-naphthalene-1-yl }-ethanamide;
5-tert-butyl-3-[1-(2,3-dimethyl-phenyl)-3,5-dioxo-[1,2,4] triazolidine-4-yl]-2-methoxyl group-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-naphthalene-2-base-ethanamide;
5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-methoxyl group-2-(4-methoxyl group-naphthalene-1-yl)-propionic acid amide;
5-tert-butyl-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-ylmethyl]-3-nitro-benzamide;
N-(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2,5-two fluoro-phenyl)-ethanamide;
N-(3,5-two-tert-butyl-2-methoxyl group-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N '-[1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl formamyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-Hydrazinecarboxamidederivatives;
N-[2-(4-amino-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
The 5-tert-butyl-3-{2-[(Z)-methoxyimino]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid acid amides;
Ethyl sulfonic acid (5-tert-butyl-2-methoxyl group-3-{3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,5-dioxo-2,5-dihydro-pyrroles-1-yl }-phenyl)-acid amides;
5-tert-butyl-N-cyclopropyl methyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
5-fluoro-1H-indazole-3-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
N-[5-tert-butyl-2-methoxyl group-3-(2-methoxyl group-kharophen)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
7-two ring [2.2.1] heptan-2-base-9-is right-and tolyl-2-is right-tolyl amino-7,9-dihydro-fast quinoline-8-ketone;
N-(5-tert-butyl-2-isopropoxy-3-methanesulfonamido-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-1-(3,4-two chloro-phenyl)-5-phenyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-[4-(2-thiomorpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
5-nitro-1H-pyrazoles-3-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
1-(2-amino-4-tert-butyl-6-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-pyridine;
N-(5-tert-butyl-2-isopropoxy-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,5-pair-trifluoromethyl-benzamide;
2-(tert-butyl-dimethyl-silicon alkoxyl group)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(4-methoxyl group-phenyl)-ethanamide;
N-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
5-tert-butyl-2-methoxyl group-3-[2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-kharophen]-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-phenyl-ethanamide;
5-tert-butyl-2-methoxyl group-N-(2-methoxyl group-ethyl)-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
(E)-3-(5-tert-butyl-3-ethanesulfonamido-2-methoxyl group-phenylcarbamoyl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-methyl acrylate;
1-sec.-propyl-3-phenyl-5-phenylamino-1,3-dihydro-imidazol-be [4,5-b] pyridin-2-ones also;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(2-benzyl-5-tert-butyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
2-(5-tert-butyl-2-methoxyl group-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2,4-dimethoxy-phenyl)-ethanamide;
(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-Urethylane;
3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid diamantane-1-base acid amides;
3-tert-butyl-5-phenyl-1-(4-trifluoromethyl-phenyl)-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-methoxyl group-3-{3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2,4,5-trioxy--imidazolidine-1-yl }-phenyl)-Toluidrin;
3-tert-butyl-1-(3-chloro-phenyl)-5-phenyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
5-tert-butyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid acid amides;
2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxy-n-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-{4-[2-(2,6-dimethyl-morpholine-4-yl)-ethyl]-naphthalene-1-yl }-2-oxo-ethanamide;
N-(5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid t-butyl carboxamide;
1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-3-(2, the 3-dichlorophenyl)-3 '-(urethanum)-urea;
2-(3,5-two fluoro-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid amide;
N-allyl group-5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
3-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-pyrroles-2, the 5-diketone;
2-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
3-tert-butyl-5-neighbour-tolyl-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[(E)-oximido]-2-phenyl-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-hydroxyl-2-phenyl-ethanamide;
N-(3-acetylaminohydroxyphenylarsonic acid 5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1H-indazole-3-carboxylic acid (5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-acid amides;
5-tert-butyl-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-3-nitro-benzamide;
The 5-tert-butyl-3-{2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid acid amides;
N-[3-(4-ethanoyl-piperazine-1-carbonyl)-5-tert-butyl-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-N-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-4-methyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-N-(2-phenyl-cyclopropyl)-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2,3-dimethoxy-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2-chloro-phenyl)-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-{4-[2-(4-methyl-piperazine-1-yl)-ethyl]-naphthalene-1-yl }-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-(1H-indol-3-yl)-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(4-tert-butyl-6-trifluoromethyl-pyrimidine-2-base)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-neighbour-tolyl-ethanamide;
The 5-tert-butyl-3-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid methane amide;
N-[5-tert-butyl-2-(3,5-two chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-{4-[2-((2R, 6S)-2,6-dimethyl-morpholine-4-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide;
3-tert-butyl-1,5-xenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-imidazoles-1-base-ethyl)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-5-(3-chloro-phenyl)-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-methoxyl group-3-phenyl methanesulfonamide amido-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-[4-(2-pyridin-4-yl-oxyethyl group)-naphthalene-1-yl]-ethanamide;
1-(5-tert-butyl-2-methoxyl group-phenyl)-3-(4-{2-[(pyridine-2-ylmethyl)-amino]-pyrimidine-4-base oxygen }-naphthalene-1-yl)-imidazolidine-2,4, the 5-triketone;
N-[5-tert-butyl-2-(3-chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-methoxyl group-1H-indazole-3-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
N-[5-tert-butyl-2-(6-chloro-pyridazine-3-yl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2-methoxyl group-phenyl)-ethanamide;
5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
[(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-methylsulfonyl-amino]-ethyl acetate;
N-(between 5-tert-butyl-4-methyl-2--tolyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-(2,5-two chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-[1,4] oxazepan-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1-(5-tert-butyl-2-methoxyl group-3-benzamide)-3-(4-methoxyl group-phenyl)-3 '-(urethanum)-urea;
N-[5-tert-butyl-2-(4-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-(4-methoxyl group-naphthalene-1-yl)-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-4-chloro-benzamide;
N-(2-bromo-5-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
3-sec.-propyl-5-phenyl-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
3,5-two-tert-butyl-1-is right-tolyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
5-tert-butyl-N-cyclopentyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
2-[5-tert-butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazole-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(4-methoxyl group-phenyl)-2-oxo-ethanamide;
1,3-two-tert-butyl-5-phenyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
4-(4-bromo-naphthalene-1-yl)-1-(3-tert-butyl-phenyl)-[1,2,4] triazolidine-3, the 5-diketone;
N-[5-tert-butyl-2-(morpholine-4-carbonyl)-thiene-3-yl-]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-5-(3-methoxyl group-phenyl)-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
1-tert-butyl-5-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-base is amino]-3-is right-tolyl-1, and the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones also;
2-[5-tert-butyl-2-(3-fluoro-phenyl)-2H-pyrazole-3-yl]-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
5-tert-butyl-2-is right-tolyl-2H-pyrazoles-3-carboxylic acid [4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-ylmethyl]-acid amides;
2-[5-tert-butyl-2-(3-fluoro-phenyl)-2H-pyrazole-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl }-2-oxo-ethanamide;
5-tert-butyl-N-cyclopropyl methyl-2-methoxyl group-3-[2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-kharophen]-benzamide;
N-[5-tert-butyl-3-(3,3-diethyl-urea groups)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(4-fluoro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(2-benzyl-5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-[4-(2-piperazine-1-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide;
(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-the carboxylamine isopropyl esters;
1-(5-tert-butyl-2-methoxyl group-phenyl)-3-[4-(2-dimethylamino-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
4-(3-tert-butyl-1-is right-tolyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles-5-yl also)-2-methoxyl group-phenol;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(3,4-two chloro-phenyl)-ethanamide;
N-[3-(3-allyl group-urea groups)-5-tert-butyl-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-N, N-diethyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-[1,4] oxazepan-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(3-tert-butyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-N-ethyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-benzamide;
N-[5-tert-butyl-2-(6-methyl-pyridin-3-yl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(4-urea groups-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[4-(2-dimethylamino-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-oxo-2-[4-(2-piperidines-1-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
Indazole-1-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
N-[3,5-pair-(1,1-dimethyl-propyl group)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1-benzyl-3-tert-butyl-5-phenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also;
2-(5-tert-butyl-2-methoxyl group-3-nitro-phenyl) N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
4-{2-[4-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylamino oxalyl)-naphthalene-1-base oxygen base]-ethyl }-piperazine-1-carboxylic acid, ethyl ester;
2-hydroxyl N-(5-sec.-propyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
In 1-two ring [2.2.1] heptan-2-base-3-phenyl-5-phenylamino-1, the 3-dihydro-imidazol-is [4,5-b] pyridin-2-ones also;
N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-3-(2-dimethylamino-kharophen)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-3-{6-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-3,5-dioxo-2,5-dihydro-3H-[1,2,4] triazine-4-yl }-phenyl)-Toluidrin;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
(R)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-phenyl-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-dimethylamino-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[2-(3-amino-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
2-[5-tert-butyl-2-(3-chloro-phenyl)-2H-pyrazole-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1,5-xenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also;
N-(5-tert-butyl-[1,3,4] thiadiazoles-2-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-3-{2-hydroxyl-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-ethylamino }-2-methoxyl group-phenyl)-Toluidrin;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-4-chloro-benzamide;
N-(5-tert-butyl-2-oxyethyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-carboxylamine 2-methoxyl group-ethyl ester;
(R)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-methoxyl group-2-phenyl-ethanamide;
2-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-hydroxy-n-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
2-amino-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-naphthalene-1-base-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-acrylamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-imidazoles-1-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(4-bromo-3-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
4-(4-benzyloxy-phenyl)-1-(3-tert-butyl-phenyl)-[1,2,4] triazolidine-3, the 5-diketone;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[8-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-chloro-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid dimethylformamide;
1-(5-tert-butyl-different _ azoles-3-yl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
N-(4-chloro-3-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1-benzoyl-3-(5-tert-butyl-2-methoxyl group-phenyl)-urea;
N '-[1-(5-tert-butyl-3-ethylamino formyl radical-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(Z)-methylene radical]-hydrazine carboxylic acid's ethyl ester;
3-tert-butyl-5-(3-fluoro-phenyl)-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
2-[3-bromo-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-ethanamide;
2-(2-chloro-5-trifluoromethyl-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3-chloro-benzenesulfonyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-carboxylamine is right-the tolyl ester;
N-(5-tert-butyl-2-diethylin-3-methanesulfonamido-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-ethanamide;
Propane-1-sulfonic acid (5-tert-butyl-2-methoxyl group-3-{4-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-base-3,5-dioxo-[1,2,4] triazolidine-1-yl }-phenyl)-acid amides;
3-amino-5-tert-butyl-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-ylmethyl]-benzamide;
2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-N-(3-trifluoromethyl-phenyl)-ethanamide;
4-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-6-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2H-[1,2,4] triazine-3, the 5-diketone;
N-[5-tert-butyl-2-(4-trifluoromethyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-phenyl-ethanamide;
N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-{4-[2-(2,6-dimethyl-morpholine-4-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(4-methoxyl group-naphthalene-1-yl)-ethanamide;
3-tert-butyl-1-cyclohexyl-5-phenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also;
3-tert-butyl-5-(4-fluoro-phenyl)-1-is right-tolyl-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-methoxyl group-3-{4-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-3,5-dioxo-[1,2,4] triazolidine-1-yl }-phenyl)-Toluidrin;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-{4-[2-(3-oxo-piperazine-1-yl)-ethyl]-naphthalene-1-yl }-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-[4-(3-pyridin-4-yl-propoxy-)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-(4-methylsulfonyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl formamyl)-2,5-dihydro-pyrroles-1-carboxylic acid tert-butyl ester;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-imidazoles-1-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3,5-dimethyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-{5-tert-butyl-3-[carbamyl ylmethyl-(propane-1-alkylsulfonyl)-amino]-2-methoxyl group-phenyl }-2-naphthalene-1-base-2-oxo-ethanamide;
N '-[1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl formamyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(Z)-methylene radical]-hydrazine carboxylic acid's ethyl ester;
5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-benzamide;
N-[5-tert-butyl-2-(3-nitro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[3-chloro-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-2-oxo-ethanamide;
N-(3-benzenesulfonyl amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid cyclohexyl amide;
N-[5-tert-butyl-2-methoxyl group-3-(2,2,2-three fluoro-ethanesulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N '-[1-(5-tert-butyl-3-formamyl-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-hydrazine carboxylic acid's ethyl ester;
5-tert-butyl-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-3-(propane-1-sulfonamido)-benzamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-hydroxyl-2-(4-methoxyl group-naphthalene-1-yl)-ethanamide;
(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-carboxylamine 2-dimethylamino-ethyl ester;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[7-fluoro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-1-(4-chloro-phenyl)-5-phenyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-ethanamide;
2-[5-tert-butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazole-3-yl]-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-ethanamide;
N-[5-(1,1-dimethyl-propyl group)-2-is right-tolyl-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(2-chloro-5-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[2,3-two chloro-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-2-oxo-ethanamide;
N-(3-methanesulfonamido-2-methoxyl group-5-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
4-{2-[4-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl oxamyl)-naphthalene-1-yl]-ethyl) piperazine-1-carboxylic acid, ethyl ester;
(1-benzyl-1H-benzimidazolyl-2 radicals-yl)-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-amine;
N-(3,5-two-tert-butyl-2-hydroxyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-naphthalene-1-base-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
4-{2-[4-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl oxamyl)-naphthalene-1-base oxygen base]-ethyl }-piperazine-1-carboxylic acid, ethyl ester;
5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-(1-Methyl-1H-indole-3-yl)-2-oxo-ethanamide;
4-phenyl-piperidines-4-carboxylic acid (5-tert-butyl-2-methoxyl group-phenyl)-acid amides;
5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-benzamide;
N-[2-(4-ethanoyl-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2,3-two fluoro-phenyl)-ethanamide;
N-[5-tert-butyl-3-(carbamyl ylmethyl-methylsulfonyl-amino)-2-methoxyl group-phenyl]-2-naphthalene-1-base-2-oxo-ethanamide;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[2-methyl-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-2-oxo-ethanamide;
N-[2-(4-amino-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-phenyl carbamate;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-isobutoxy-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(4-tert-butyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3-methyl-benzoyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
The 5-tert-butyl-3-{2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid acid amides;
1-(5-tert-butyl-2-methoxyl group-phenyl)-3-[4-(2-chloro-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
(S)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-phenyl-ethanamide;
N-[5-tert-butyl-2-(2,3-dimethyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(4-nitro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-[(Z)-oximido]-N-(3-methanesulfonamido-2-methoxyl group-5-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-(morpholine-4-carbonyl)-thiene-3-yl-]-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-phenyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N '-[1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl formamyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-hydrazine carboxylic acid's ethyl ester;
N '-[1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl formamyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(Z)-methylene radical]-Hydrazinecarboxamidederivatives;
N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-N-pyridine-2-base-benzamide;
N-[5-tert-butyl-3-(3,3-dimethyl-urea groups)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-3-{2-[7-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-2-methoxyl group-benzamide;
Between N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2--tolyl-ethanamide;
1-(5-tert-butyl-2-methoxyl group-phenyl)-3-[4-(2-tetramethyleneimine-1-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-phenyl-propionic acid amide;
2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-N-quinoline-3-base-ethanamide;
1-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-(3-trifluoromethyl-benzyl)-amine;
N-[5-tert-butyl-2-methoxyl group-3-(morpholine-4-carbonyl)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-3-(3-sec.-propyl-urea groups)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-methoxyl group-2-(4-methoxyl group-naphthalene-1-yl)-ethanamide;
N-(3-amino-5-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
3-methyl isophthalic acid, 5-xenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also;
N-(5-tert-butyl-different _ azoles-3-yl)-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-2-(2-phenyl-cyclopropyl)-ethanamide;
2-{4-[2-(4-ethanoyl-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-ethanamide;
2-(1H-indol-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3-fluoro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3,4-two chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(2,5-dimethyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-2-oxo-ethanamide;
1H-indazole-3-carboxylic acid (5-tert-butyl-2-pyridine-2-base-2H-pyrazole-3-yl)-acid amides;
N-(4-chloro-3-trifluoromethyl-phenyl)-2-(4-methoxyl group-naphthalene-1-yl)-2-oxo-ethanamide;
N-[5-(1,1-dimethyl-butyl)-2-is right-tolyl-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1H-indazole-3-carboxylic acid [5-tert-butyl-2-(4-methoxyl group-phenyl)-2H-pyrazole-3-yl]-acid amides;
1H-indazole-3-carboxylic acid [5-tert-butyl-2-(4-hydroxyl-phenyl)-2H-pyrazole-3-yl]-acid amides;
N '-[1-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-Hydrazinecarboxamidederivatives;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-N '-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-oxamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-methylamino--pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
5-tert-butyl-N-cyclopropyl-3-[2-[(E)-oximido]-2-(4-methoxyl group-naphthalene-1-yl)-kharophen]-2-methoxyl group-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-{4-[2-(2,6-dimethyl-morpholine-4-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[8-fluoro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(3-fluoro-phenyl)-ethanamide;
5-tert-butyl-N-furans-2-ylmethyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-[5-tert-butyl-2-(3-trifluoromethyl-benzoyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
1-(5-tert-butyl-different _ azoles-3-yl)-3-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
1-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-3 '-(urethanum)-urea;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-4-[2-(3-oxo-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-ethanamide;
2-{4-[2-(4-ethanoyl-piperazine-1-yl)-ethyl]-naphthalene-1-yl }-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-ethanamide;
N-(5-tert-butyl-2-phenylacetyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-{4-[2-(3-oxo-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-ethanamide;
2-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-(3-urea groups-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[(Z)-methoxyimino]-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-methoxyl group-3-(3-oxo-piperazine-1-carbonyl)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid propionic acid amide;
5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-{4-[2-(4-methyl-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide;
N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-N-propyl group-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-hydroxyl-2-(4-methoxyl group-phenyl)-ethanamide;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(3-phenoxy group-phenyl)-ethanamide;
N-(5-sec.-propyl-2-methyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
7-sec.-propyl-9-phenyl-2-phenylamino-7,9-dihydro-fast quinoline-8-ketone;
(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-anginin-3-base methyl esters;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-ethylamino-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(3,5-two-tert-butyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-amino-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-naphthalene-2-base-ethanamide;
N-[5-tert-butyl-2-(3-fluoro-4-methyl-phenyl)-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
2-[5-tert-butyl-2-(3,4-two fluoro-phenyl)-2H-pyrazole-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-methylamino--pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(2,3-two chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[3,5-pair-(1,1-dimethyl-propyl group)-2-hydroxyl-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-base-2-oxo-ethanamide;
4-{2-[4-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylamino oxalyl)-naphthalene-1-base oxygen base]-ethyl }-piperazine-1-carboxylic acid tert-butyl ester;
3-tert-butyl-1-naphthalene-2-base-5-phenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also;
2-xenyl-4-base-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-ethanamide;
5-tert-butyl-N-sec.-propyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-3-diethylin methyl-2-hydroxyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
6-hydroxyl-nicotinic acid 3-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenylcarbamoyl]-1H-indazole-5-base ester;
N-(between 5-tert-butyl-2--tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(4-morpholine-4-base-pyrimidine-2--amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1,3,5-triphenyl-1,6-dihydro-imidazol-be [4,5-c] pyrazoles also;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-cyclohexyl-ethanamide;
2-[5-tert-butyl-2-(2-chloro-phenyl)-2H-pyrazole-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
7-cyclohexyl methyl-9-phenyl-2-phenylamino-7,9-dihydro-fast quinoline-8-ketone;
5-tert-butyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid methyl nitrosourea;
5-tert-butyl-N-cyclopropyl methyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-benzamide;
N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N '-[1-(5-tert-butyl-3-formamyl-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(Z)-methylene radical]-hydrazine carboxylic acid's ethyl ester;
4-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-1-(2,3-dimethyl-phenyl)-[1,2,4] triazolidine-3, the 5-diketone;
N-(4-fluoro-3-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1-benzyl-3-phenyl-5-phenylamino-1,3-dihydro-imidazol-be [4,5-b] pyridin-2-ones also;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-naphthalene-2-base-ethanamide;
2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-base formamyl]-pyrroles-1-carboxylic acid tert-butyl ester;
N-(2,5-two-tert-butyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-N-((1S, 2R)-2-phenyl-cyclopropyl)-ethanamide;
2-oxo-2,3-dihydro-benzoglyoxaline-1-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
N-(2-methoxyl group-5-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[2-(4-bromo-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1-(5-tert-butyl-2-methoxyl group-phenyl)-3-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
5-tert-butyl-2-methoxyl group-N-methyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-2-methoxyl group-3-piperidines-1-ylmethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-naphthalene-1-base-2-oxo-ethanamide;
N-(2,5-two-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-carboxylamine 4-methoxyl group-phenyl ester; N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-naphthalene-1-base-2-oxo-ethanamide;
5-tert-butyl-N-ethyl-3-{2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-2-methoxyl group-benzamide;
4-{2-[4-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl oxamyl)-naphthalene-1-yl]-ethyl }-piperazine-1-carboxylic acid tert-butyl ester;
5-tert-butyl-N-ethyl-2-hydroxyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-naphthalene-1-base-ethanamide;
N-(5-tert-butyl-2-oxyethyl group-3-methanesulfonamido-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N '-[1-(5-tert-butyl-3-ethylamino formyl radical-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-Hydrazinecarboxamidederivatives;
2-{4-[2-(4-ethanoyl-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-ethanamide;
5-tert-butyl-N-ethyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenylformic acid;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-5,6,7,8-tetrahydrochysene-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-3-{2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid acid amides;
2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-N-between-tolyl-ethanamide;
5-tert-butyl-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid methyl esters;
N '-[1-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(Z)-methylene radical]-Hydrazinecarboxamidederivatives;
N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-sec.-propyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(2-benzoyl-5-tert-butyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
6-bromo-1H-indazole-3-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
5-tert-butyl-N-ethyl-3-{2-hydrazono--2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-2-methoxyl group-benzamide;
N-(5-tert-butyl-3-ethanesulfonamido-2-methoxyl group-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(3-amino-5-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-thiene-3-yl-)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(4-chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N '-[1-(5-tert-butyl-3-formamyl-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-Hydrazinecarboxamidederivatives;
N-[5-tert-butyl-2-(4-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-3-{2-[7-chloro-4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-N-cyclopropyl-2-methoxyl group-benzamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-{4-[2-(4-methyl-piperazine-1-yl)-oxyethyl group]-naphthalene-1-yl }-2-oxo-ethanamide;
1-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-3-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-imidazolidin-2-one;
N-(5-tert-butyl-thiene-3-yl-)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide; 5-tert-butyl-N-cyclopropyl-3-[2-[(Z)-oximido]-2-(4-methoxyl group-naphthalene-1-yl)-kharophen]-2-methoxyl group-benzamide;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[4-(4-morpholine-4-base-pyrimidine-2--amino)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[2-methoxyl group-5-(1-methyl isophthalic acid-phenyl-ethyl)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-[5-tert-butyl-2-(3,4-dimethyl-phenyl)-2H-pyrazole-3-yl]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-3-{2-[4-(2-morpholine-4-base-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid acid amides;
5-tert-butyl-N-isobutyl--2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
2-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[(Z)-oximido]-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
3-tert-butyl-1-(2,3-two chloro-phenyl)-5-phenyl-1, the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(3,5-two-tert-butyl-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
The 5-tert-butyl-3-{2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-kharophen }-the thiophene-2-carboxylic acid dimethylformamide;
N-(5-tert-butyl-2-methoxyl group-3-methyl-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N '-[1-(5-tert-butyl-3-cyclopropyl formamyl-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-hydrazine carboxylic acid's ethyl ester;
N-indane-5-base-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3-chloro-4-fluoro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-3-(imidazoles-1-carbonyl)-2-methoxyl group-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(2,5-couple-trifluoromethyl-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(2,4-two fluoro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
1H-indazole-3-carboxylic acid (5-tert-butyl-2-methoxyl group-phenyl)-acid amides;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-oxo-2-4-[2-(5-oxo-[1,4] Diazesuberane-1-yl)-oxyethyl group]-naphthalene-1-yl }-ethanamide;
3-tert-butyl-1-is right-tolyl-5-(4-trifluoromethyl-phenyl)-1, and the 6-dihydro-imidazol-is [4,5-c] pyrazoles also;
N-(5-tert-butyl-3-ethanesulfonamido-2-methoxyl group-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid sec.-propyl acid amides;
N-(5-tert-butyl-[1,3,4] thiadiazoles-2-yl)-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-ethanamide;
N-[2-(3-amino-phenyl)-5-tert-butyl-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
3-tert-butyl-5-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-pyrazoles-1-carboxylic acid phenyl acid amides;
2-(5-tert-butyl-2-methyl-furans-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-neighbour-tolyl-2H-pyrazole-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide; N-(5-tert-butyl-2-methoxyl group-phenyl)-2-(3-methoxyl group-phenyl)-ethanamide;
5-tert-butyl-3-{2-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid acid amides;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-[5-tert-butyl-2-(2,4-two chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-different _ azoles-3-yl)-2-[4-(3-hydroxyl-propoxy-)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(3-tert-butyl-different _ azoles-5-yl)-2-[(Z)-oximido]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
1H-Indole-3-Carboxylic Acid (5-tert-butyl-2-methoxyl group-phenyl)-acid amides;
N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
7-two ring [2.2.1] heptan-2-base-9-phenyl-2-phenylamino-7,9-dihydro-fast quinoline-8-ketone;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-(2,4-two chloro-phenyl)-ethanamide;
5-tert-butyl-2-methoxyl group-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-benzamide;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-[2,3-dimethyl-4-(2-morpholine-4-base-oxyethyl group)-phenyl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-(3-fluoro-phenyl)-ethanamide;
1-(5-tert-butyl-2-methoxyl group-3-benzamide)-3-(2, the 3-3,5-dimethylphenyl)-3 '-(urethanum)-urea;
2-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-oxo-N-(3-trifluoromethyl-phenyl)-ethanamide;
7-benzyl-9-phenyl-2-phenylamino-7,9-dihydro-fast quinoline-8-ketone;
2,5-dihydro-1H-pyrroles-2-carboxylic acid (5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-acid amides;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-{4-[2-(5-oxo-[1,4] Diazesuberane-1-yl)-oxyethyl group]-naphthalene-1-yl }-ethanamide;
N-[5-tert-butyl-2-(3-cyano group-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-3-phenylacetylamino-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(2-chloro-5-trifluoromethyl-phenyl)-N-[4-(2-morpholine-4-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-2-oxo-ethanamide;
1-(5-tert-butyl-2-methoxyl group-phenyl)-3-[4-(2-piperidines-1-base-pyrimidine-4-base oxygen)-naphthalene-1-yl]-imidazolidine-2,4, the 5-triketone;
2-(2-benzyl-5-tert-butyl-2H-pyrazole-3-yl)-2-hydroxy-n-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
5-tert-butyl-3-{2-[4-(2-dimethylamino-pyrimidine-4-base is amino)-naphthalene-1-yl]-2-oxo-kharophen }-the thiophene-2-carboxylic acid acid amides;
N '-[1-(5-tert-butyl-3-ethylamino formyl radical-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-hydrazine carboxylic acid's ethyl ester;
N-(3-methanesulfonamido-5-trifluoromethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-hydroxyl-3-piperidines-1-ylmethyl-phenyl)-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(1-Methyl-1H-indole-3-yl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-methoxyl group-phenyl)-2-oxo-2-{4-[2-((S)-1-phenyl-ethylamino)-pyrimidine-4-base is amino]-naphthalene-1-yl }-ethanamide;
N-[5-tert-butyl-2-(4-cyano group-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N '-[1-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenylcarbamoyl)-1-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-(E)-methylene radical]-hydrazine carboxylic acid's ethyl ester;
N-[5-tert-butyl-2-(3-methoxyl group-phenyl)-2H-pyrazole-3-yl]-2-hydroxyl-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-ethanamide;
N-(5-tert-butyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-kharophen }-phenyl)-isobutyramide;
N-[5-tert-butyl-2-(4-methyl-benzoyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(2-chloro-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
N-[5-tert-butyl-2-(3-chloro-4-methyl-phenyl)-2H-pyrazole-3-yl]-2-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide;
2-(4-bromo-phenyl)-N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-ethanamide;
2-(5-tert-butyl-2-methyl-furans-3-yl)-N-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide;
4-(4-{4-[2-(5-tert-butyl-2-methyl-furans-3-yl)-2-oxo-kharophen]-naphthalene-1-base is amino }-phenoxy group)-the pyridine-2-carboxylic acids methyl nitrosourea;
N-[5-tert-butyl-2-methoxyl group-3-(propane-1-sulfonamido)-phenyl]-2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-ethanamide;
5-tert-butyl-N-cyclopropyl-2-methoxyl group-3-{2-[4-(2-morpholine-4-base-pyridin-4-yl amino)-naphthalene-1-yl]-2-oxo-kharophen }-benzamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-{4-[6-(tetrahydrochysene-pyrans-4-base is amino)-pyridin-3-yl]-naphthalene-1-yl }-ethanamide;
3-[2-(4-bromo-naphthalene-1-yl)-2-oxo-kharophen]-5-tert-butyl-N-cyclopropyl-2-methoxyl group-benzamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-[4-(6-morpholine-4-base-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-2-right-tolyl-2H-pyrazole-3-yl)-2-[4-(6-morpholine-4-ylmethyl-pyridin-3-yl)-naphthalene-1-yl]-2-oxo-ethanamide;
N-(5-tert-butyl-3-methanesulfonamido-2-methoxyl group-phenyl)-2-oxo-2-(4-pyridin-3-yl-naphthalene-1-yl)-ethanamide;
N-(5-tert-butyl-2-methyl-2H-pyrazole-3-yl)-2-oxo-2-(4-pyridin-3-yl-naphthalene-1-yl)-ethanamide;
2-(4-chloro-3-trifluoromethyl-phenyl)-N-[4-(2-morpholine-4-base-oxyethyl group)-naphthalene-1-yl]-2-oxo-ethanamide; Or
4-{4-[2-(4-chloro-3-trifluoromethyl-phenyl)-2-oxo-kharophen]-phenoxy group }-the pyridine-2-carboxylic acids methane amide.
CNA2004800330557A 2003-09-11 2004-09-10 Cytokine inhibitors Pending CN1878769A (en)

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WO2009049492A1 (en) * 2007-10-12 2009-04-23 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China N-substituted aromatic hydrocarbon aniline and multi-substituted diarylether compounds, the preparation and the use of antitumor thereof
CN103864792A (en) * 2012-12-12 2014-06-18 山东亨利医药科技有限责任公司 Heterocyclic nitrogen compound acting as tyrosine kinase inhibitor
CN105418527A (en) * 2015-12-28 2016-03-23 青岛友诚高新技术有限公司 Compound with ductal breast cancer prevention activity, and preparation method and use thereof
CN107382909A (en) * 2016-05-16 2017-11-24 复旦大学 Selective ER beta receptors conditioning agent and its pharmaceutical usage
CN108701171A (en) * 2015-10-22 2018-10-23 马古苏托科技大学 In pharmacophore, the Compounds and methods for by inhibiting that there is application in CYP17A1 and CYP19A1 treating cancers
US10266488B2 (en) 2013-10-10 2019-04-23 Eastern Virginia Medical School 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase
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* Cited by examiner, † Cited by third party
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WO2009049492A1 (en) * 2007-10-12 2009-04-23 Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A. China N-substituted aromatic hydrocarbon aniline and multi-substituted diarylether compounds, the preparation and the use of antitumor thereof
CN103864792B (en) * 2012-12-12 2017-01-18 山东亨利医药科技有限责任公司 Heterocyclic nitrogen compound acting as tyrosine kinase inhibitor
CN103864792A (en) * 2012-12-12 2014-06-18 山东亨利医药科技有限责任公司 Heterocyclic nitrogen compound acting as tyrosine kinase inhibitor
US10266488B2 (en) 2013-10-10 2019-04-23 Eastern Virginia Medical School 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase
US10752581B2 (en) 2013-10-10 2020-08-25 Eastern Virginia Medical School 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase
US11274077B2 (en) 2013-10-10 2022-03-15 Eastern Virginia Medical School 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase
CN108701171A (en) * 2015-10-22 2018-10-23 马古苏托科技大学 In pharmacophore, the Compounds and methods for by inhibiting that there is application in CYP17A1 and CYP19A1 treating cancers
CN108701171B (en) * 2015-10-22 2022-06-10 马古苏托科技大学 Pharmacophores, compounds and methods having application in the treatment of cancer by inhibition of CYP17a1 and CYP19a1
CN105418527A (en) * 2015-12-28 2016-03-23 青岛友诚高新技术有限公司 Compound with ductal breast cancer prevention activity, and preparation method and use thereof
CN107382909A (en) * 2016-05-16 2017-11-24 复旦大学 Selective ER beta receptors conditioning agent and its pharmaceutical usage
CN110305036A (en) * 2019-01-15 2019-10-08 江南大学 A kind of nitrogen mustards anti-tumor predrug and preparation method thereof of hydrogen peroxide response
CN110305036B (en) * 2019-01-15 2020-09-04 江南大学 Hydrogen peroxide-responsive nitrogen mustard antitumor prodrug and preparation method thereof
CN113289018A (en) * 2020-02-21 2021-08-24 中国科学院上海药物研究所 Application of old medicine such as auranofin and composition thereof in resisting single positive strand RNA virus
CN113289018B (en) * 2020-02-21 2023-08-25 中国科学院上海药物研究所 Application of old medicines such as auranofin and the like and compositions thereof in resisting single positive strand RNA viruses

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