CN1264377A - Substituted pyrazoles as P38 kinase inhabitors - Google Patents

Substituted pyrazoles as P38 kinase inhabitors Download PDF

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CN1264377A
CN1264377A CN98807369A CN98807369A CN1264377A CN 1264377 A CN1264377 A CN 1264377A CN 98807369 A CN98807369 A CN 98807369A CN 98807369 A CN98807369 A CN 98807369A CN 1264377 A CN1264377 A CN 1264377A
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alkyl
group
amino
heterocyclic radical
carbonyl
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阿绍克·安南塔纳拉扬
迈克尔·克莱尔
波尔·W·科林斯
约斯·佐夫·克里奇
拉耶什·代弗拉
达尼尔·L·弗灵
力枫·耿
冈纳·J·汉森
弗兰基斯·J·科斯兹克
书远·廖
理查德·A·帕蒂斯
沙希德哈·N·劳
尚·拉·塞尔内斯
迈克尔·S·绍斯
迈克尔·A·斯蒂尔
理查德·M·韦
向东·徐
义·于
伊斯克·克汉纳
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GD Searle LLC
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Abstract

A class of pyrazole derivatives is described for use in treating p38 kinase mediated disorders. Compounds of particular interest are defined by Formula (I) wherein R<1>, R<2>, R<3> and R<4> are as described in the specification.

Description

Be used as the pyrazole compound of the replacement of p38 kinase inhibitor
The cross reference of mutual application
The application requires the right of priority of the U.S. Provisional Application sequence number 60/047,570 submitted on May 22nd, 1997. Invention field
The present invention relates to be used for the treatment of one group of new pyrazole compound, composition and method of the disease that the p38 kinases mediated. Background of invention
Mitogen-activated protein kinase (MAP) is the serine/threonine kinase that gang is oriented to proline(Pro) (proline-directed), and this kinases activates its substrate by dual phosphorylation.This kinases is by multiple signal activation, comprise nutrition with infiltration stress, UV-light, somatomedin, intracellular toxin and inflammatory cytokine.P38 map kinase group is the family of various isoform MAP, comprises p38 α, p38 β and p38 γ, and it is responsible for the phosphorylation and the activation of transcription factor (for example ATF2, CHOP and MEF2C) and other kinases (for example MAPKAP-2 and MAPKAP-3).The p38 isoform can by bacteria lipopolysaccharide, physiology and chemistry stress and pro-inflammatory cytokine comprise that tumour necrosis factor (TNF-α) and interleukin 1 (IL-1) activate.The product transmitting inflammation production of cytokines of p38 phosphorylation comprises TNF, IL-1 and cyclo-oxygenase.
TNF-α is a kind of cytokine that is mainly produced by activated monocyte and scavenger cell.TNF excessive or out of control produces can cause multiple disease potentially.Nearest studies show that, TNF is the reason of rheumatoid arthritis morbidity.Other studies show that, suppresses TNF and have wide application in treatment inflammation, inflammatory bowel disease, multiple sclerosis and asthma.
TNF is also relevant with virus infection, for example HIV; Influenza virus; Simplexvirus comprises herpes simplex types 1 virus (HSV-1), herpes simplex types 2 virus (HSV-2), cytomegalovirus (CMV), varicella zoster virus (VZV), Epstein-Barr virus, herpes virus hominis-6 (HHV-6), herpes virus hominis-7 (HHV-7), herpes virus hominis-8 (HHV-8); Pseudorabies and rhinotracheitis etc.
IL-8 is another kind of pro-inflammatory cytokine, and it is produced by monocyte, inoblast, endotheliocyte and keratinocyte, and is relevant with disease such as inflammation.
IL-1 is produced by activated monocyte and scavenger cell, with struvite reply relevant.IL-1 works in many physiopathology are replied, and comprises the reduction of rheumatoid arthritis, fever and bone resorption.
TNF, IL-1 and IL-8 can influence various kinds of cell and tissue, and are the important inflammatory mediators of multiple disease.Suppressing these cytokines by inhibition p38 kinases is useful for controlling, weakening and alleviate multiple disease.
Put down in writing multiple pyrazole compound.United States Patent (USP) NO.4,000,281 (Beiler and Binon) have put down in writing all has 4 of antiviral activity, the pyrazole compound that the 5-aryl/hetaryl replaces to the various viruses in RNA and dna virus such as myxovirus, adenovirus, rhinovirus and the simplexvirus group.WO 92/19615 (on November 12nd, 1992 is open) has put down in writing the pyrazole compound as novel mycocide.United States Patent (USP) NO.3,984,431 (Cueremy and Renault) have put down in writing the pyrazoles-5-acetogenin with anti-inflammatory activity.[1-isobutyl--3,4-phenylbenzene-1H-pyrazoles-5-yl] acetate is wherein specifically disclosed.United States Patent (USP) 3,245,093 (Hinsgen etc.) have put down in writing the method for preparing pyrazole compound.WO83/00330 (February 3 nineteen eighty-three is open) has put down in writing preparation phenylbenzene-3, the novel method of 4-methyl-5-pyrazole derivatives.WO 95/06036 (March 2 nineteen ninety-five is open) has put down in writing the method for preparing pyrazole derivatives.United States Patent (USP) 5,589,439 (T.Goto etc.) have been put down in writing terazole derivatives and as the purposes of weedicide.EP 515,041 has put down in writing the pyrazole derivatives as the pyrimidyl replacement of novel agricultural mycocide.Japanese Patent 4,145,081 has put down in writing the pyrazole carboxylic acid derivative as weedicide.Japanese Patent 5,345,772 have put down in writing the novel pyrazole derivative that is used for acetylcholine esterase inhibition.
Put down in writing the purposes of pyrazole compound in the treatment inflammation.Japanese Patent 5,017,470 have put down in writing synthetic as the pyrazole derivatives of anti-inflammatory, wind resistance diseases caused by dampness, antibiotic and antiviral.EP 115640 (December 30 nineteen eighty-three is open) has put down in writing the 4-imidazolyl-pyrazole derivatives as the thromboxane synthetic inhibitor.3-(4-sec.-propyl-1-methyl cyclohexane-1-yl)-4-(imidazoles-1-yl)-1H-pyrazoles is wherein specifically disclosed.WO97/01551 (on January 16th, 1997 is open) has put down in writing the pyrazole compound as adenosine antagonist.4-(3-oxo-2,3-dihydrogen dazin-6-yl)-3-phenylpyrazole is wherein specifically disclosed.United States Patent (USP) NO.5,134,142 (Matsuo etc.) have put down in writing has 1 of anti-inflammatory activity, 5-diaryl pyrazole azole compounds.
United States Patent (USP) NO.5,559,137 (Adams etc.) have put down in writing the new pyrazole compound (1,3,4 ,-replacement) as cytokine inhibitor, and this compound can be used for treating cytokine diseases.Compound 3-(4-fluorophenyl)-1-(4-methylsulfinyl phenyl)-4-(4-pyridyl)-5H-pyrazoles is wherein specifically disclosed.WO 96/03385 (on February 8th, 1996 is open) has put down in writing has 3 of anti-inflammatory activity, the pyrazole compound that 4-replaces.4-[1-ethyl-4-(4 pyridyl)-5-Trifluoromethyl-1 H-pyrazole-3-yl is wherein specifically disclosed) benzsulfamide.
Found pyrazolyl compounds useful as p 38 kinase inhibiting agents of the present invention.Description of the invention
Formula I has defined the pyrazolyl compounds that a class can be used for treating the replacement of the disease that the p38 kinases mediated:
Figure A9880736900911
Wherein
R 1Be selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl group, alkynyl group, aryl, heterocyclic group, the cycloalkyl alkylidene group, the cycloalkenyl group alkylidene group, the heterocyclic radical alkylidene group, haloalkyl, halogenated alkenyl, the halo alkynyl group, hydroxyalkyl, the hydroxyl alkenyl, the hydroxyl alkynyl group, aralkyl, aromatic yl alkenyl, aryl alkynyl chain, the aryl-heterocyclic base, carboxyl, carboxyalkyl, alkoxyalkyl, the alkenyloxy alkyl, the chain oxy-acetylene alkyl, aryloxy alkyl, the heterocyclic oxy group alkyl, the alkoxyl group alkoxyl group, mercaptoalkyl, the alkylthio alkylidene group, alkenyl sulfo-alkylidene group, the alkylthio alkenylene, amino, aminoalkyl group, alkylamino, alkenyl amino, chain alkynyl amino, arylamino, heterocyclic radical amino, alkyl sulphinyl, the alkenyl sulfinyl, the alkynyl group sulfinyl, aryl sulfonyl kia, the heterocyclic radical sulfinyl, alkyl sulphonyl, the alkenyl alkylsulfonyl, the alkynyl group alkylsulfonyl, aryl sulfonyl, the heterocyclic radical alkylsulfonyl, alkylamino alkylene, the alkyl sulphonyl alkylidene group, acyl group, the acyl-oxygen carbonyl, the carbalkoxy alkylidene group, the aryloxy carbonyl alkylidene group, heterocycle oxygen carbonyl alkylen group, the carbalkoxy arylidene, the aryloxy carbonyl arylidene, heterocycle oxygen carbonyl arylidene, the alkyl-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the heterocyclic radical carbonyl alkylen group, the alkyl-carbonyl arylidene, the aryl carbonyl arylidene, heterocyclic radical carbonyl arylidene, alkyl-carbonyl oxygen base alkylidene group, aryl carbonyl oxygen base alkylidene group, heterocyclic radical ketonic oxygen base alkylidene group, alkyl-carbonyl oxygen base arylidene, aryl carbonyl oxygen base arylidene and heterocyclic radical ketonic oxygen base arylidene; Perhaps
R 1Structure with following formula
Wherein:
I is the integer of 0-9;
R 25Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group;
R 26Be selected from hydrogen, alkyl, alkenyl, alkynyl group, cycloalkyl alkylidene group, aralkyl, carbalkoxy alkylidene group and alkylamino alkyl;
R 27Be selected from alkyl, cycloalkyl, alkynyl group, aryl, heterocyclic radical, aralkyl, the cycloalkyl alkylidene group, the cycloalkenyl group alkylidene group, the cycloalkyl arylidene, the cycloalkyl ring alkyl, the heterocyclic radical alkylidene group, alkyl arylene, alkyl aralkyl, the aralkyl arylidene, alkyl heterocyclic, the alkyl heterocyclic alkylidene group, the alkyl heterocyclic arylidene, the aralkyl heterocyclic radical, the alkoxyl group alkylidene group, the alkoxyl group arylidene, the alkoxy aromatic alkyl, the alkoxyl group heterocyclic radical, the alkoxyl group alkoxyalkyl, the alkoxyl group arylidene, the alkoxy aromatic alkyl, the alkoxyl group heterocyclic radical, alkoxyl group alkoxyl group arylidene, the aryloxy arylidene, the aralkoxy arylidene, alkoxyl group heterocyclic radical alkylidene group, aryloxy alcoxyl base arylidene, the carbalkoxy alkylidene group, the carbalkoxy heterocyclic radical, carbalkoxy heterocyclic radical carbonyl alkylen group, aminoalkyl group, alkylamino alkylene, the aromatic yl aminocarbonyl alkylidene group, alkoxy aryl aminocarboxyl alkylidene group, the aminocarboxyl alkylidene group, the aromatic yl aminocarbonyl alkylidene group, the alkyl amino-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the carbalkoxy arylidene, the aryloxy carbonyl arylidene, alkyl aryloxy carbonyl arylidene, the aryl carbonyl arylidene, alkylaryl carbonyl arylidene, carbalkoxy heterocyclic radical arylidene, the alkoxycarbonyl alkoxy arylidene, heterocyclic radical carbonylic alkyl arylidene, the alkylthio alkylidene group, the cycloalkylthio alkylidene group, the alkylthio arylidene, the aromatic alkylthio arylidene, heterocyclic radical sulfo-arylidene, the arylthio alkyl arylidene, the arlysulfonylamino alkylidene group, the alkyl sulphonyl arylidene, the alkyl amino sulfonyl arylidene; Wherein said alkyl, cycloalkyl, aryl, heterocyclic radical, aralkyl, heterocyclic radical alkylidene group, alkyl heterocyclic arylidene, alkoxyl group arylidene, aryloxy arylidene, aromatic yl aminocarbonyl alkylidene group, aryloxy carbonyl arylidene, aryl carbonyl arylidene, alkylthio arylidene, heterocyclic radical sulfo-arylidene, arylthio alkyl arylidene and alkyl sulphonyl arylidene are optionally replaced by one or more group, and described group is independently from each other: alkyl, halogen, haloalkyl, alkoxyl group, ketone group, amino, nitro and cyano group; Perhaps
R 27Be-CHR 28R 29, R wherein 28Be carbalkoxy, R 29Be selected from aralkyl, aralkoxy alkylidene group, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, carbalkoxy alkylidene group, alkylthio alkylidene group and aromatic alkylthio alkylidene group; Wherein said aralkyl and heterocyclic group are optionally replaced by one or more groups that are independently from each other alkyl and nitro; Or
R 26And R 27Form heterocycle together with the nitrogen-atoms that they connected, wherein said heterocycle is optionally replaced by one or more groups that are independently from each other alkyl, aryl, heterocyclic radical, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, aryloxy alkylidene group, alkoxyl group arylidene, alkyl-aryloxy alkylidene group, alkyl-carbonyl, carbalkoxy, aralkoxycarbonyl, alkylamino and alkoxycarbonyl amido; Wherein said aryl, heterocyclic radical alkylidene group and aryloxy alkylidene group are optionally replaced by one or more group, and described group is independently from each other: halogen, alkyl and alkoxyl group;
R 2Be selected from hydrogen, halogen, alkyl, alkenyl, alkynyl group, aryl, heterocyclic radical, haloalkyl, hydroxyalkyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, alkylamino, alkenyl amino, chain alkynyl amino, arylamino, heterocyclic radical amino, the heterocyclic radical alkylamino, aryl alkyl amino, aminoalkyl group, aminoaryl, aminoalkyl group amino, the arylamino alkylidene group, alkylamino alkylene, the arylamino arylidene, the alkylamino arylidene, the alkylamino alkylamino, cycloalkyl, cycloalkenyl group, alkoxyl group, the heterocycle alkoxyl group, alkylthio, arylthio, the heterocyclic radical sulfo-, carboxyl, carboxyalkyl, the carboxyl cycloalkyl, the carboxyl cycloalkenyl group, carboxyalkyl amino, carbalkoxy, the heterocyclic radical carbonyl, alkoxycarbonyl alkyl, the carbalkoxy heterocyclic radical, carbalkoxy heterocyclic radical carbonyl, alkoxyalkyl amino, alkoxycarbonyl amido alkylamino and heterocyclic radical alkylsulfonyl; Aryl wherein, heterocyclic radical, the heterocyclic radical alkyl, cycloalkyl and cycloalkenyl group are optionally by one or more halogens that are independently from each other, ketone group, amino, alkyl, alkenyl, alkynyl group, aryl, heterocyclic radical, aralkyl, the heterocyclic radical alkyl, the epoxy group(ing) alkyl, amino (hydroxyalkyl) carboxyl, alkoxyl group, aryloxy, aralkoxy, haloalkyl, alkylamino, chain alkynyl amino, the alkylamino alkylamino, the heterocyclic radical alkylamino, alkyl-carbonyl, carbalkoxy, alkyl sulphonyl, the group of aryl sulfonyl and aralkyl alkylsulfonyl replaces; Perhaps
R 2Structure with following formula:
Figure A9880736900941
Wherein:
J is the integer of 0-8;
M is 0 or 1;
R 30And R 31Be independently from each other hydrogen, alkyl, aryl, heterocyclic radical, aralkyl, heterocyclic radical alkylidene group, aminoalkyl group, alkylamino alkyl, aminocarboxyl alkyl, alkoxyalkyl and alkyl-carbonyl oxygen base alkyl;
R 32Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group;
R 33Be selected from hydrogen, alkyl ,-C (O) R 35,-C (O) OR 36,-SO 2R 36,-C (O) NR 37R 38With-SO 2NR 39R 40, R wherein 35, R 36, R 37, R 38, R 39And R 40Be independently from each other the hydrocarbon and the heterocyclic radical of hydrocarbon, heteroatoms replacement;
R 34Be selected from hydrogen, alkyl, aminocarboxyl, alkyl amino-carbonyl and aromatic yl aminocarbonyl; Perhaps
R 2Be-CR 41R 42R wherein 41Be aryl, R 42It is hydroxyl;
R 3Be selected from pyridyl, pyrimidyl, quinolyl, purine radicals,
R wherein 43Be selected from hydrogen, alkyl, aminoalkyl group, alkoxyalkyl, alkenyloxy alkyl and aryloxy alkyl;
R wherein 3Pyridyl; pyrimidyl; quinolyl and purine radicals are optionally replaced by one or more group, and described group is independently from each other: halogen; alkyl; aralkyl; aromatic yl alkenyl; the aryl-heterocyclic base; carboxyl; carboxyalkyl; alkoxyl group; aryloxy; alkylthio; arylthio; alkyl sulphinyl; aryl sulfonyl kia; alkyl sulphonyl; aryl sulfonyl; aralkoxy; the heterocyclic radical alkoxyl group; amino; alkylamino; alkenyl amino; chain alkynyl amino; cycloalkyl amino; cycloalkenyl group amino; arylamino; heterocyclic radical amino; aminocarboxyl; cyano group; hydroxyl; hydroxyalkyl; carbalkoxy; aryloxy carbonyl; heterocycle oxygen carbonyl; alkoxycarbonyl amido; the alkoxy aromatic alkylamino; amino sulfinyl; amino-sulfonyl; the alkylamino alkylamino; hydroxyalkyl amino; aryl alkyl amino; the heterocyclic radical alkylamino; aralkyl heterocyclic radical amino; nitro; alkyl amino-carbonyl; alkyl-carbonyl-amino; halosulfonyl groups; aminoalkyl group; haloalkyl; alkyl-carbonyl; diazanyl; the alkyl diazanyl; the aryl diazanyl or-NR 44R 45, R wherein 44Be alkyl-carbonyl or amino, R 45Be alkyl or aralkyl;
R 4Be selected from hydrogen, alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkenyl group, aryl and heterocyclic radical, wherein R 4Optionally replaced by one or more group, described group is independently from each other: halogen, alkyl, alkenyl, alkynyl group, aryl, heterocyclic radical, alkylthio, arylthio, the alkylthio alkylidene group, the arylthio alkylidene group, alkyl sulphinyl, the alkyl sulphinyl alkylidene group, the aryl sulfonyl kia alkylidene group, alkyl sulphonyl, the alkyl sulphonyl alkylidene group, the aryl sulfonyl alkylidene group, alkoxyl group, aryloxy, aralkoxy, aminocarboxyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, carbalkoxy, aryloxy carbonyl, haloalkyl, amino, cyano group, nitro, alkylamino, arylamino, alkylamino alkylene, the arylamino alkylidene group, aminoalkyl group amino and hydroxyl;
Condition is to work as R 4Be to contain the phenyl ring of 2-hydroxyl substituent and work as R 1When being hydrogen, R 3It or not the 2-pyridyl; Another condition is to work as R 4When being hydrogen, R 2Be selected from aryl, heterocyclic radical, unsubstituted cycloalkyl and cycloalkenyl group; Another condition is R 4It or not the methyl sulphonyl phenyl; Perhaps its pharmacologically acceptable salt or tautomer.
Formula I compound can be used for (but being not limited only to) and treats in people or other Mammals because described Mammals TNF or p38 kinases excessive or out of control produced caused various diseases.Therefore, the invention provides the method for the treatment disease that cytokine mediated, this method comprises the formula I compound or pharmaceutically acceptable salt thereof of using interference cell factor significant quantity.
Formula I compound can be used for (but being not limited only to) treatment inflammation, and treats fever as antipyretic.Compound of the present invention can be used for treatment of arthritis, includes but are not limited to rheumatoid arthritis, spondyloarthropathy, urarthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis,juvenile chronic arthritis,juvenile rheumatoid arthritis, osteoarthritis, urarthritis and other sacroiliitis.Described compound can be used for treating lung disease or pneumonia, comprises adult respiratory distress syndrome, sarcoidosis of lung, asthma, silicosis and chronic pneumonia.This compound also can be used for treating virus and infectation of bacteria, comprise Sepsis, septic shock, gram negative sepsis, malaria, meningitis, owing to infect or emaciation that malignant tumour causes, emaciation, AIDS, ARC (AIDS dependency syndrome), pneumonia and simplexvirus, this compound of being caused by acquired immune deficiency syndrome (AIDS) (AIDS) also can be owing to treatment bone resorption disease, for example osteoporosis; Endotoxin shock; Toxic shock syndrome; Reperfusion injury; Autoimmune disease comprises reaction and the homograft rejection of graft to the host; Cardiovascular disorder comprises atherosclerosis, thrombosis, congestive heart failure and heart reperfusion injury; Renal reperfusion injury; Hepatic diseases and ephritis, and owing to infect the myalgia that causes.This compound compound also can be used for treating influenza, multiple sclerosis, cancer, diabetes, systemic lupus erythematosus (SLE), forms with skin diseases associated such as psoriasis, eczema, burn, dermatitis, keloid, scar tissue forms and angiogenic disease.Compound of the present invention also can be used for treating gastrointestinal illness, for example inflammatory bowel disease, Crohn disease, gastritis, Anaphylaxis enteritis and ulcerative colitis.This compound also can be used for treating ophthalmic diseases, for example the retinitis, retinopathy, uveitis, eye photophobia and the damage of acute ocular tissue.Compound of the present invention also can be used for treating vasculogenesis, comprises tumorigenesis; Tumor metastasis; Ophthalmic diseases such as corneal graft rejection, eye neovascularization, retina neovascularization comprise damage or metainfective neovascularization, diabetic retinopathy, retrolental fibroplasia and neovascular glaucoma; Ulcer disease such as stomach ulcer; Pathologic state (nonmalignant) is as the no angionecrosis of vascular tumor (comprising the invantile vascular tumor), nasopharyngeal fibrohemangioma and bone; Diabetic nephropathy and myocardosis; Female repro ductive system disease such as endometriosis.Compound of the present invention also can be used for preventing the generation of cyclooxygenase-2.
Except the treatment that can be used for the people, these compounds also can be used for pet, unusual animal and farm-animals, comprise that Mammals, rodent etc. treat.Preferred animal comprises horse, dog and cat.
Compound of the present invention also can be used for Synergistic treatment, be used for partially or completely replacing other conventional anti-inflammatory agent, for example use with steroidal compounds, cyclooxygenase-2 inhibitor, DMARD ' s, immunosuppressor, NSAID, 5-lipoxidase inhibitor, LTB4 antagonist and LTA4 hydrolase inhibitor.
Term used herein " TNF mediation disease " is meant work therein all diseases of (no matter being by control TNF itself, still is the release that causes another kind of monokine (for example but be not limited only to IL-1, IL-6 or IL-8) by TNF) of TNF.For example, be main component and its generation or effect therein for IL-1 since respond that TNF aggravates or the disease that disappears to be interpreted as be the disease that TNF mediates.
Term used herein " p38 mediation disease " is meant work therein all diseases of (no matter being by control p38 itself, still is the release that causes the another kind of factor (for example but be not limited only to IL1, IL-6 or IL-8) by p38) of p38.For example, be main component and its generation or effect therein for IL-1 since respond that p38 aggravates or the disease that disappears to be interpreted as be the disease that p38 mediates.
Because TNF-β and the close structural homology of TNF-α (being also referred to as cachectin), and since they all induce similar biological answer-reply and with identical cell receptor combination, the synthetic inhibition that all is subjected to The compounds of this invention of TNF-α and TNF-β, therefore this paper is referred to as it " TNF " except as otherwise noted.
Preferred compound is by forming as shown in the formula I compound or pharmaceutically acceptable salt thereof or tautomer, wherein:
R 1Be selected from hydrogen, low alkyl group, low-grade cycloalkyl, low-grade alkenyl, alkynyl of low-grade chain, rudimentary heterocyclic radical, low-grade cycloalkyl alkylidene group, low-grade halogenated alkyl, rudimentary hydroxyalkyl, rudimentary aralkyl, low-grade alkoxy alkyl, rudimentary mercaptoalkyl, lower alkylthio alkylidene group, amino, low-grade alkyl amino, lower aryl amino, low-grade alkyl amino alkylidene group and rudimentary heterocyclic radical alkylidene group; Perhaps
R 1Structure with following formula:
Figure A9880736900981
Wherein:
I is 0,1 or 2;
R 25Be to be selected from hydrogen, low alkyl group, rudimentary phenylalkyl, rudimentary heterocyclic radical alkyl, lower alkoxy alkylidene group, rudimentary phenoxy group alkylidene group, rudimentary aminoalkyl group, low-grade alkyl amino alkyl, rudimentary phenoxy group aminoalkyl group, lower alkylcarbonyl alkylidene group, rudimentary carbobenzoxy alkylidene group and rudimentary heterocyclic radical carbonylamino alkylidene group;
R 26Be selected from hydrogen, low alkyl group, low-grade alkenyl, alkynyl of low-grade chain, low-grade cycloalkyl alkylidene group, rudimentary phenylalkyl, lower alkoxycarbonyl alkylidene group and low-grade alkyl amino alkyl;
R 27Be selected from low alkyl group, low-grade cycloalkyl, alkynyl of low-grade chain, be selected from phenyl, the aryl of xenyl and naphthyl, rudimentary heterocyclic radical, rudimentary phenylalkyl, the low-grade cycloalkyl alkylidene group, the lower alkenyl ring alkylidene group, the low-grade cycloalkyl arylidene, the low-grade cycloalkyl cycloalkyl, rudimentary heterocyclic radical alkylidene group, the low alkyl group phenylene, the low alkyl group phenylalkyl, rudimentary phenylalkyl phenylene, the low alkyl group heterocyclic radical, low alkyl group heterocyclic radical alkylidene group, low alkyl group heterocyclic radical phenylene, rudimentary phenylalkyl heterocyclic radical, the lower alkoxy alkylidene group, the lower alkoxy phenylene, the lower alkoxyphenyl alkyl, the lower alkoxy heterocyclic radical, lower alkoxy alkoxyl group phenylene, rudimentary phenoxy group phenylene, rudimentary phenyl alkoxyl group phenylene, lower alkoxy heterocyclic radical alkylidene group, rudimentary phenoxy alkoxy phenylene, the lower alkoxycarbonyl alkylidene group, the lower alkoxycarbonyl heterocyclic radical, lower alkoxycarbonyl heterocyclic radical carbonyl alkylen group, rudimentary aminoalkyl group, the low-grade alkyl amino alkylidene group, rudimentary phenyl amino carbonyl alkylen group, lower alkoxyphenyl aminocarboxyl alkylidene group, rudimentary aminocarboxyl alkylidene group, the aromatic yl aminocarbonyl alkylidene group, the low-grade alkyl amino carbonylic alkylidene group, rudimentary phenylcarbonyl group alkylidene group, the lower alkoxycarbonyl phenylene, rudimentary carbobenzoxy phenylene, low alkyl group carbobenzoxy phenylene, rudimentary phenylcarbonyl group phenylene, low alkyl group phenylcarbonyl group phenylene, lower alkoxycarbonyl heterocyclic radical phenylene, lower alkoxycarbonyl alkoxyl group phenylene, rudimentary heterocyclic radical carbonylic alkyl phenylene, the lower alkylthio alkylidene group, the cycloalkylthio alkylidene group, the lower alkylthio phenylene, rudimentary octadecyloxy phenyl sulfenyl phenylene, rudimentary heterocyclic radical sulfo-phenylene, rudimentary phenyl alkylthio phenylene, rudimentary phenyl sulfonyl amino alkylidene group, low alkyl group alkylsulfonyl phenylene, low-grade alkyl amino alkylsulfonyl phenylene; Wherein said low alkyl group, low-grade cycloalkyl, be selected from phenyl, the aryl of xenyl and naphthyl, rudimentary heterocyclic radical, rudimentary phenylalkyl, rudimentary heterocyclic radical alkylidene group, low alkyl group heterocyclic radical phenylene, the lower alkoxy phenylene, rudimentary phenoxy group phenylene, rudimentary phenyl amino carbonyl alkylen group, rudimentary carbobenzoxy phenylene, rudimentary phenylcarbonyl group phenylene, the lower alkylthio phenylene, rudimentary heterocyclic radical sulfo-phenylene, rudimentary phenyl alkylthio phenylene and low alkyl group alkylsulfonyl phenylene are optionally replaced by one or more group, and described group is independently from each other: low alkyl group, halogen, low-grade halogenated alkyl, lower alkoxy, ketone group, amino, nitro and cyano group; Perhaps
R 27Be-CHR 46R 47, R wherein 46Be lower alkoxycarbonyl, R 47Be selected from rudimentary phenylalkyl, rudimentary phenyl alkoxyl group alkylidene group, rudimentary heterocyclic radical alkylidene group, low alkyl group heterocyclic radical alkylidene group, lower alkoxycarbonyl alkylidene group, lower alkylthio alkylidene group and rudimentary octadecyloxy phenyl sulfenyl alkylidene group; Wherein said phenylalkyl and heterocyclic group are optionally replaced by one or more groups that are independently from each other low alkyl group and nitro; Perhaps
R 26And R 27The nitrogen-atoms that is connected with them lumps together the heterocycle that forms 4-8 unit, wherein said heterocycle is optionally replaced by one or more group, and described group is independently from each other: low alkyl group, the aryl that is selected from phenyl, xenyl and naphthyl, heterocyclic radical, heterocyclic radical alkylidene group, low alkyl group heterocyclic radical alkylidene group, rudimentary phenoxy group alkylidene group, lower alkoxy phenylene, low alkyl group phenoxy group alkylidene group, lower alkylcarbonyl, lower alkoxycarbonyl, rudimentary phenyl carbalkoxy, low-grade alkyl amino and lower alkoxycarbonyl amino; The wherein said aryl of phenyl, xenyl and naphthyl, rudimentary heterocyclic radical alkylidene group and the rudimentary phenoxy group alkylidene group of being selected from optionally replaced by one or more groups that are independently from each other halogen, low alkyl group and lower alkoxy;
R 2Be selected from hydrogen, halogen, low alkyl group, be selected from phenyl, the aryl of xenyl and naphthyl, low-grade halogenated alkyl, rudimentary hydroxyalkyl, the heterocyclic radical of 5-or 6-unit, the low alkyl group heterocyclic radical, rudimentary heterocyclic radical alkyl, low-grade alkyl amino, alkynyl of low-grade chain amino, phenyl amino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkylamino, rudimentary Phenylalkylamino, rudimentary aminoalkyl group, rudimentary aminoalkyl group amino, the low-grade alkyl amino alkylamino, low-grade cycloalkyl, low-grade alkenyl, the lower alkoxycarbonyl alkyl, lower alkenyl ring, rudimentary carboxyalkyl amino, lower alkoxycarbonyl, rudimentary heterocyclic radical carbonyl, the lower alkoxycarbonyl heterocyclic radical, lower alkoxycarbonyl heterocyclic radical carbonyl, alkoxycarbonyl alkyl, low-grade alkoxy alkyl amino, lower alkoxycarbonyl aminoalkyl group amino, rudimentary heterocyclic radical alkylsulfonyl, rudimentary heterocycle alkoxyl group and rudimentary heterocyclic radical sulfo-; Aryl wherein, heterocyclic radical, the heterocyclic radical alkyl, cycloalkyl and cycloalkenyl group are optionally replaced by one or more group, and described group is independently from each other: halogen, ketone group, low alkyl group, alkynyl of low-grade chain, phenyl, the heterocyclic radical of 5-or 6-unit, rudimentary phenylalkyl, rudimentary heterocyclic radical alkyl, rudimentary epoxy group(ing) alkyl, carboxyl, lower alkoxy, rudimentary aryloxy, rudimentary phenyl alkoxyl group, low-grade halogenated alkyl, low-grade alkyl amino, the low-grade alkyl amino alkylamino, alkynyl of low-grade chain amino, rudimentary amino (hydroxyalkyl), rudimentary heterocyclic radical alkylamino, lower alkylcarbonyl, lower alkoxycarbonyl, the low alkyl group alkylsulfonyl, rudimentary phenylalkyl alkylsulfonyl and phenyl sulfonyl; Perhaps
R 2Structure with following formula:
Figure A9880736901001
Wherein:
J is 0,1 or 2;
M is 0;
R 30And R 31Be independently from each other hydrogen, alkyl, aryl, heterocyclic radical, aralkyl, heterocyclic radical alkylidene group, aminoalkyl group, alkylamino alkyl, aminocarboxyl alkyl, alkoxyalkyl and alkyl-carbonyl oxygen base alkyl;
R 32Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group;
R33 be selected from hydrogen, alkyl ,-C (O) R 35,-C (O) OR 35,-SO 2R 36,-C (O) NR 37R 38With-SO 2NR 39R 40
R wherein 35Be selected from alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclic radical, aralkyl, cycloalkyl aryl, the cycloalkenyl group alkylidene group, the heterocyclic radical alkylidene group, alkyl arylene, alkyl heterocyclic, the aryl arylidene, the aryl-heterocyclic base, alkoxyl group, alkenyloxy, the alkoxyl group alkylidene group, the alkoxy aromatic alkyl, the alkoxyl group arylidene, the aryloxy alkylidene group, the aralkoxy alkylidene group, the cycloalkyloxy alkylidene group, carbalkoxy, the heterocyclic radical carbonyl, alkyl-carbonyl oxygen base alkylidene group, alkyl-carbonyl oxygen base arylidene, the carbalkoxy alkylidene group, the carbalkoxy arylidene, the aralkoxycarbonyl heterocyclic radical, the alkyl-carbonyl heterocyclic radical, aryl carbonyl oxygen base alkyl arylene and alkylthio alkylidene group; Wherein said aryl, heterocyclic radical, aralkyl, alkyl arylene, aryl-heterocyclic base, alkoxyl group arylidene, aryloxy alkylidene group, cycloalkyloxy alkylidene group, carbalkoxy alkylidene group and alkyl-carbonyl heterocyclic radical are optionally replaced by one or more groups that are independently from each other alkyl, halogen, haloalkyl, alkoxyl group, halogenated alkoxy, ketone group, amino, nitro and cyano group; Perhaps
R 35Be CHR 48R 48, R wherein 48Be arlysulfonylamino or alkylaryl sulfuryl amino, R 49Be selected from aralkyl, amino, alkylamino and aryl alkyl amino; Perhaps
R 35Be-NR 50R 51, R wherein 50Be alkyl, R 51It is aryl;
R wherein 36Be selected from alkyl, haloalkyl, aryl, heterocyclic radical, the cycloalkyl alkylidene group, alkyl arylene, the alkenyl arylidene, the aryl arylidene, aralkyl, aromatic yl alkenyl, the heterocyclic radical heterocyclic radical, the carboxyl arylidene, the alkoxyl group arylidene, the carbalkoxy arylidene, the alkyl-carbonyl-amino arylidene, the alkyl-carbonyl-amino heterocyclic radical, the aryl-amino-carbonyl alkyl heterocyclic, the alkylamino arylidene, alkylamino, the alkylamino arylidene, the alkyl sulphonyl arylidene, alkyl sulphonyl aralkyl and arylsulfonylheterocyamines base; Wherein said aryl, heterocyclic radical, cycloalkyl alkylidene group, aralkyl, alkyl-carbonyl-amino heterocyclic radical and alkyl sulphonyl arylidene are optionally replaced by one or more group, and described group is independently from each other: alkyl, halogen, hydroxyl, haloalkyl, alkoxyl group, halogenated alkoxy, ketone group, amino, nitro and cyano group;
R wherein 37Be selected from hydrogen and alkyl;
R wherein 38Be selected from hydrogen, alkyl, alkenyl, aryl, heterocyclic radical, aralkyl, alkyl arylene, cycloalkyl aryl, the aryl arylidene, the cycloalkyl alkylidene group, the heterocyclic radical alkylidene group, the alkyl heterocyclic alkylidene group, the aralkyl heterocyclic radical, the alkoxyl group alkylidene group, the alkoxyl group arylidene, the aryloxy arylidene, aryl carbonyl, carbalkoxy, the carbalkoxy alkylidene group, the carbalkoxy arylidene, the alkyl-carbonyl carbonyl alkylen group, alkylamino alkylene, the alkylamino aralkyl, the alkyl-carbonyl-amino alkylidene group, the alkylthio arylidene, alkyl sulphonyl aralkyl and amino-sulfonyl aralkyl; Wherein said aryl, heterocyclic radical, aralkyl and heterocyclic radical alkylidene group are optionally replaced by one or more group, and described group is independently from each other: alkyl, halogen, hydroxyl, haloalkyl, alkoxyl group, halogenated alkoxy, ketone group, amino, nitro and cyano group; Perhaps
R 38Be-CR 52R 53, R wherein 52Be carbalkoxy, R 53It is the alkylthio alkylidene group; Perhaps
R 37With 38The nitrogen-atoms that is connected with them lumps together the formation heterocycle;
R 39And R 40Have with claim 1 in R 26And R 27Identical definition; Perhaps
R 2Be-CR 54R 55, R wherein 54Be phenyl, R 55It is hydroxyl; Perhaps
R 2Be selected from as next group group:
Wherein
K is the integer of 0-3;
R 56Be hydrogen or low alkyl group;
R 57Be hydrogen or low alkyl group; Perhaps
R 56And R 57Form the low-grade alkylidene bridge;
R 58Be selected from hydrogen, alkyl, aralkyl, aryl, heterocyclic radical, heterocyclic radical alkyl, carbalkoxy, alkyl sulphonyl, aralkyl alkylsulfonyl, aryl sulfonyl ,-C (O) R 59,-SO 2R 60With-C (O) NHR 61
R wherein 59Be selected from alkyl, haloalkyl, cycloalkyl, aryl, heterocyclic radical, alkyl arylene, aralkyl, alkyl heterocyclic, alkoxyl group, alkenyloxy, aralkoxy, alkoxyl group alkylidene group, alkoxyl group arylidene, alkoxy aromatic alkyl; Wherein said aryl, heterocyclic radical and aralkyl are optionally replaced by one or more group, and described group is independently from each other alkyl, halogen, hydroxyl, haloalkyl, alkoxyl group, halogenated alkoxy, ketone group, amino, nitro and cyano group;
R wherein 60Be selected from alkyl, aryl, heterocyclic radical, alkyl arylene, alkyl heterocyclic, aralkyl, heterocyclic radical heterocyclic radical, alkoxyl group arylidene, alkylamino, alkylamino arylidene, alkyl sulphonyl arylidene and arylsulfonylheterocyamines base; Wherein said aryl, heterocyclic radical and aralkyl are optionally replaced by one or more group, and described group is independently from each other alkyl, halogen, hydroxyl, haloalkyl, alkoxyl group, halogenated alkoxy, ketone group, amino, nitro and cyano group;
R wherein 61Be selected from alkyl, aryl, alkyl arylene and alkoxyl group arylidene; Wherein said aryl is optionally replaced by one or more group, and described group is independently from each other: alkyl, halogen, hydroxyl, haloalkyl, alkoxyl group, halogenated alkoxy, ketone group, amino, nitro and cyano group;
R 3Be selected from pyridyl, pyrimidyl, quinolyl, purine radicals and
Figure A9880736901031
R wherein 43Be selected from hydrogen, low alkyl group, rudimentary aminoalkyl group, low-grade alkoxy alkyl, rudimentary alkenyloxy alkyl and rudimentary aryloxy alkyl;
R wherein 3Pyridyl; pyrimidyl; quinolyl and purine radicals are optionally replaced by one or more group, and described group is independently from each other: lower alkylthio; the low alkyl group alkylsulfonyl; amino-sulfonyl; halogen; low alkyl group; rudimentary aralkyl; rudimentary phenyl alkenyl; rudimentary phenyl heterocycles base; carboxyl; the low alkyl group sulfinyl; cyano group; lower alkoxycarbonyl; aminocarboxyl; lower alkylcarbonyl amino; low-grade halogenated alkyl; hydroxyl; lower alkoxy; amino; low-grade cycloalkyl amino; low-grade alkyl amino; low-grade alkenyl amino; alkynyl of low-grade chain amino; rudimentary aminoalkyl group; arylamino; rudimentary aryl alkyl amino; nitro; halosulfonyl groups; lower alkylcarbonyl; lower alkoxycarbonyl amino; the lower alkoxyphenyl alkylamino; the low-grade alkyl amino alkylamino; rudimentary hydroxyalkyl amino; rudimentary heterocyclic radical amino; rudimentary heterocyclic radical alkylamino; rudimentary phenylalkyl heterocyclic radical amino; low-grade alkyl amino carbonylic; the lower alkoxyphenyl alkylamino; diazanyl; the low alkyl group diazanyl or-NR 62R 63, R wherein 62Be lower alkylcarbonyl or amino, R 63Be low alkyl group or rudimentary phenylalkyl;
R 4Be selected from hydrogen, low-grade cycloalkyl, lower alkenyl ring, the aryl that is selected from phenyl, xenyl and naphthyl and 5-or 6-unit heterocyclic radical; R wherein 4Low-grade cycloalkyl, lower alkenyl ring, aryl and 5-10 unit heterocyclic radical optionally replaced by one or more group, described group is independently from each other lower alkylthio, low alkyl group alkylsulfonyl, low alkyl group sulfinyl, halogen, low alkyl group, alkynyl of low-grade chain, lower alkoxy, rudimentary aryloxy, rudimentary aralkoxy, rudimentary heterocyclic radical, low-grade halogenated alkyl, amino, cyano group, nitro, low-grade alkyl amino and hydroxyl; Perhaps its pharmacologically acceptable salt or tautomer.
In these formulas I compound, one group of particularly preferred compound is, wherein:
R 1Be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, isobutyl-, methyl fluoride, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, three chloroethyls, pentafluoroethyl group, seven fluoropropyls, the difluoro chloromethyl, dichlorofluoromethyl, two fluoro ethyls, two fluoropropyls, Dichloroethyl, two chloropropyls, vinyl, propenyl, ethynyl, propargyl, the 1-proyl, 2-propynyl, piperidyl, piperazinyl, morpholinyl, benzyl, phenylethyl, the morpholinyl methyl, the morpholinyl ethyl, the pyrrolidyl methyl, the piperazinyl methyl, piperidino methyl, pyridylmethyl, thienyl methyl, methoxymethyl, ethoxyl methyl, amino, methylamino, dimethylamino, phenyl amino, the methylamino methyl, dimethylamino methyl, the methylamino ethyl, dimethylaminoethyl, the ethylamino ethyl, diethyllaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexyl methyl, hydroxymethyl, hydroxyethyl, mercapto methyl and methylthiomethyl;
R 2Be selected from hydrogen, chlorine, fluorine, bromine, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, isobutyl-, phenyl, xenyl, methyl fluoride, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl group, seven fluoropropyls, the difluoro chloromethyl, dichlorofluoromethyl, two fluoro ethyls, two fluoropropyls, Dichloroethyl, two chloropropyls, hydroxymethyl, hydroxyethyl, pyridyl, isothiazolyl isoxazolyl, thienyl, thiazolyl oxazolyl, pyrimidyl, quinolyl, isoquinolyl, imidazolyl, benzimidazolyl-, furyl, pyrazinyl, piperidyl, piperazinyl, morpholinyl, the N methyl piperazine base, the methoxycarbonyl ethyl, ethoxycarbonyl-ethyl, the N-methylamino, N, the N-dimethylamino, the N-ethylamino, N, the N-diethylamino, N-n-propyl amino, N, the N-dimethylamino, N-methyl-N-phenyl amino, the N-phenyl amino, piperidyl amino, the N-benzylamino, N-propargyl amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl radical, the cyclobutene base, cyclopentenyl, cyclohexenyl, cyclohexadienyl, amino methyl, amino-ethyl, aminoethylamino, amino propyl amino, N, N-dimethyl aminoethyl amino, N, N-dimethylaminopropyl amino, the morpholinyl ethylamino, morpholinyl propyl amino, the carboxyl methylamino, methoxy ethyl amino, methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, 1, the 1-dimethyl ethoxycarbonyl, 1,1-dimethyl ethoxycarbonyl aminoethylamino, 1,1-dimethyl ethoxycarbonyl amino propyl amino, piperazinyl carbonyl and 1,1-dimethyl ethoxycarbonyl piperazinyl carbonyl; Aryl wherein, heteroaryl, cycloalkyl and cycloalkenyl group are optionally replaced by one or more group, described group is independently from each other fluorine, chlorine, bromine, ketone group, methyl, ethyl, sec.-propyl, the tertiary butyl, isobutyl-, benzyl, carboxyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, methyl fluoride, difluoromethyl, dimethylamino, methoxycarbonyl, ethoxycarbonyl and 1,1-dimethyl ethyl carbonyl; Perhaps
R 2Be-CR 54R 55, R wherein 54Be phenyl, R 56It is hydroxyl;
R 3Be selected from pyridyl, pyrimidyl and purine radicals; R wherein 3Optionally replaced by one or more group; described group is independently from each other: methylthio group; methylsulfinyl; methyl sulphonyl; fluorine; chlorine; bromine; amino-sulfonyl; methyl; ethyl; sec.-propyl; the tertiary butyl; isobutyl-; cyano group; methoxycarbonyl; ethoxycarbonyl; aminocarboxyl; the methyl carbonylamino; trifluoromethyl; difluoromethyl; methyl fluoride; trichloromethyl; dichloromethyl; chloromethyl; hydroxyl; fluorophenyl methyl; the fluorophenyl ethyl; Chlorophenylmethyl; the chloro-phenyl-ethyl; the fluorophenyl vinyl; the chloro-phenyl-vinyl; the fluorophenyl pyrazolyl; the chloro-phenyl-pyrazolyl; carboxyl; methoxyl group; oxyethyl group; propyl group oxygen base; n-butoxy; methylamino; ethylamino; dimethylamino; diethylin; 2-methyl butyl amino; propargyl amino; amino methyl; amino-ethyl; N-methyl-N-phenyl amino; phenyl amino; diphenyl amino; benzylamino; styroyl amino; cyclopropyl amino; nitro; chlorosulfonyl; amino; the methyl carbonyl; methoxycarbonyl amino; ethoxycarbonyl amino; the p-methoxy-phenyl methylamino; N, N-dimethylaminoethyl amino; hydroxypropyl amino; hydroxyethyl amino; the imidazolyl ethylamino; the morpholinyl ethylamino; (1-ethyl-2-hydroxyl) ethylamino; piperidyl amino; pyridylmethyl amino; the phenyl methyl piperidyl amino; phenyl methyl amino; fluorophenyl methyl amino; the fluorophenyl ethylamino; the methylamino carbonyl; the ethylamino carbonyl; the methyl carbonyl; the p-methoxy-phenyl methylamino; diazanyl; 1-methyl diazanyl or-NR 62R 63, R wherein 62Be methyl carbonyl or amino, R 63Be methyl, ethyl or phenyl methyl;
R 4Be selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl radical, the cyclobutene base, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, xenyl, morpholinyl, pyrrolidyl, piperazinyl, piperidyl, pyridyl, thienyl, isothiazolyl isoxazolyl, thiazolyl oxazolyl, pyrimidyl, quinolyl, isoquinolyl, imidazolyl, benzimidazolyl-, furyl, pyrazinyl, dihydro pyranyl, the dihydropyridine base, the dichloro furyl, THP trtrahydropyranyl, tetrahydrofuran base, benzofuryl, dihydro benzo furyl and benzodioxole base; R wherein 4Cycloalkyl, cycloalkenyl group, aryl and heterocyclic radical optionally replaced by one or more group, described group is independently from each other: methylthio group, methylsulfinyl, methyl sulphonyl, fluorine, chlorine, bromine, methyl, ethyl, sec.-propyl, the tertiary butyl, isobutyl-, ethynyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, methyl fluoride, difluoromethyl, amino, cyano group, nitro, dimethylamino and hydroxyl; Perhaps
Its pharmacologically acceptable salt or its tautomer.
Another kind of particularly preferred formula I compound is, wherein:
R 1Be hydrogen, methyl, ethyl, propargyl, hydroxyethyl, dimethylaminoethyl, diethyllaminoethyl or morpholinyl ethyl;
R 2Be selected from hydrogen, methyl, ethyl, propyl group, phenyl, trifluoromethyl, methoxycarbonyl ethyl, N, N-dimethylamino, N-phenyl amino, piperidyl, piperazinyl, pyridyl, N methyl piperazine base and piperazinyl amino; Phenyl wherein, piperidyl and pyridyl are optionally replaced by one or more group, and described group is independently from each other fluorine, chlorine, bromine, methyl, ethyl and trifluoromethyl;
R 3Be selected from pyridyl, pyrimidyl or quinolyl; R wherein 3Optionally replaced by one or more group, described group is independently from each other: fluorine, bromine, methyl, cyano group, methoxycarbonyl, aminocarboxyl, benzyl, styroyl, ethanoyl, hydroxyl, methoxyl group, dimethylamino, benzylamino, styroyl amino, amino methyl, amino, hydroxyl and methyl carbonyl;
R 4Be selected from phenyl, quinolyl, xenyl, pyridyl, thienyl, furyl, dihydro pyranyl, benzofuryl, dihydro benzo furyl and benzodioxole base; R wherein 4Cycloalkyl, cycloalkenyl group, aryl and heterocyclic radical optionally replaced by one or more group, described group is independently from each other: methylthio group, fluorine, chlorine, bromine, methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxyl; Perhaps
Its pharmacologically acceptable salt or tautomer.
The particularly preferred formula I compound of one class is, wherein:
R 1Be hydrogen or methyl;
R 2Be selected from hydrogen, methyl or ethyl;
R 3Be selected from pyridyl, pyrimidyl or quinolyl; R wherein 3Optionally replaced by one or more group, described group is independently from each other: fluorine, bromine, methyl, cyano group, methoxycarbonyl, aminocarboxyl, benzyl, styroyl, ethanoyl, hydroxyl, methoxyl group, dimethylamino, benzylamino, styroyl amino, amino methyl, amino, hydroxyl and methyl carbonyl;
R 4Be selected from phenyl, described phenyl is optionally replaced by one or more group, and described group is independently from each other: methylthio group, fluorine, chlorine, bromine, methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxyl; Perhaps
Its pharmacologically acceptable salt or tautomer.
Another particularly preferred formula I compound is, wherein:
R 1Be selected from hydrogen, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, isobutyl-, methyl fluoride, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, three chloroethyls, pentafluoroethyl group, seven fluoropropyls, the difluoro chloromethyl, dichlorofluoromethyl, two fluoro ethyls, two fluoropropyls, Dichloroethyl, two chloropropyls, vinyl, propenyl, ethynyl, propargyl, the 1-proyl, 2-propynyl, piperidyl, piperazinyl, morpholinyl, benzyl, phenylethyl, the morpholinyl methyl, the morpholinyl ethyl, the pyrrolidyl methyl, the piperazinyl methyl, piperidino methyl, pyridylmethyl, thienyl methyl, methoxymethyl, ethoxyl methyl, amino, methylamino, dimethylamino, phenyl amino, the methylamino methyl, dimethylamino methyl, the methylamino ethyl, dimethylaminoethyl, the ethylamino ethyl, diethyllaminoethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexyl methyl, hydroxymethyl, hydroxyethyl, mercapto methyl and methylthiomethyl;
R 2Structure with following formula:
Figure A9880736901071
Wherein: j is 0,1 or 2; M is 0; R 30And R 31Be independently from each other hydrogen and low alkyl group; R 32Be selected from hydrogen, low alkyl group, rudimentary phenylalkyl, rudimentary heterocyclic radical alkyl, lower alkoxy alkylidene group, aryloxy alkylidene group, aminoalkyl group, low-grade alkyl amino alkyl, rudimentary phenyl amino alkyl, lower alkylcarbonyl alkylidene group, rudimentary phenylcarbonyl group alkylidene group and rudimentary heterocyclic radical carbonylamino alkylidene group;
R 33Be selected from hydrogen, low alkyl group ,-C (O) R 35,-C (O) OR 35,-SO 2R 36,-C (O) NR 37R 38With-SO 2NR 39R 40
R wherein 35Be selected from low alkyl group, low-grade cycloalkyl, low-grade halogenated alkyl, low-grade alkenyl, be selected from phenyl, the aryl of xenyl and naphthyl, rudimentary heterocyclic radical, rudimentary phenylalkyl, rudimentary benzyl ring alkyl, the lower alkenyl ring alkylidene group, rudimentary heterocyclic radical alkylidene group, the low alkyl group phenylene, the low alkyl group heterocyclic radical, the phenyl phenylene, rudimentary phenyl heterocycles base, lower alkoxy, rudimentary alkenyloxy, the lower alkoxy alkylidene group, the lower alkoxyphenyl alkyl, the lower alkoxy phenylene, rudimentary phenoxy group alkylidene group, rudimentary phenyl alkoxyl group alkylidene group, rudimentary cycloalkyloxy alkylidene group, lower alkoxycarbonyl, rudimentary heterocyclic radical carbonyl, lower alkylcarbonyl oxygen base alkylidene group, lower alkylcarbonyl oxygen base phenylene, the lower alkoxycarbonyl alkylidene group, the lower alkoxycarbonyl phenylene, rudimentary phenyl carbalkoxy heterocyclic radical, the lower alkylcarbonyl heterocyclic radical, rudimentary phenylcarbonyl group oxygen base alkyl phenylene and lower alkylthio alkylidene group; The wherein said aryl of phenyl, xenyl and naphthyl, rudimentary heterocyclic radical, rudimentary phenylalkyl, low alkyl group phenylene, rudimentary phenyl heterocycles base, lower alkoxy phenylene, rudimentary phenoxy group alkylidene group, rudimentary cycloalkyloxy alkylidene group, lower alkoxycarbonyl alkylidene group and the lower alkylcarbonyl heterocyclic radical of being selected from optionally replaced by one or more group, and described group is independently from each other low alkyl group, halogen, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy, ketone group, amino, nitro and cyano group; Perhaps
R 35Be CHR 48R 49, R wherein 48Be phenyl sulfonyl amino or low alkyl group phenyl sulfonyl amino, R 49Be selected from rudimentary phenylalkyl, amino, low-grade alkyl amino and rudimentary Phenylalkylamino; Perhaps
R 35Be-NR 50R 51, R wherein 50Be low alkyl group, R 51It is the aryl that is selected from phenyl, xenyl and naphthyl;
R wherein 36Be selected from low alkyl group, low-grade halogenated alkyl, be selected from phenyl, the aryl of xenyl and naphthyl, rudimentary heterocyclic radical, the low-grade cycloalkyl alkylidene group, the low alkyl group phenylene, the low-grade alkenyl phenylene, the phenyl phenylene, rudimentary phenylalkyl, rudimentary phenyl alkenyl, rudimentary heterocyclic radical heterocyclic radical, the carboxyl phenylene, the lower alkoxy phenylene, the lower alkoxycarbonyl phenylene, the amino phenylene of lower alkylcarbonyl, lower alkylcarbonyl amino-heterocycles base, rudimentary phenylcarbonyl group aminoalkyl heterocyclic base, the low-grade alkyl amino phenylene, low-grade alkyl amino, the low-grade alkyl amino phenylene, low alkyl group alkylsulfonyl phenylene, low alkyl group alkylsulfonyl phenylalkyl and rudimentary phenyl sulfonyl heterocyclic radical; The wherein said aryl of phenyl, xenyl and naphthyl, rudimentary heterocyclic radical, low-grade cycloalkyl alkylidene group, rudimentary phenylalkyl, lower alkylcarbonyl amino-heterocycles base and the low alkyl group alkylsulfonyl phenylene of being selected from optionally replaced by one or more group, and described group is independently from each other: low alkyl group, halogen, hydroxyl, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy, ketone group, amino, nitro and cyano group;
R wherein 37Be selected from hydrogen and low alkyl group;
R wherein 38Be selected from hydrogen, low alkyl group, low-grade alkenyl, be selected from phenyl, the aryl of xenyl and naphthyl, rudimentary heterocyclic radical, rudimentary phenylalkyl, the low alkyl group phenylene, rudimentary benzyl ring alkyl, the phenyl phenylene, the low-grade cycloalkyl alkylidene group, rudimentary heterocyclic radical alkylidene group, low alkyl group heterocyclic radical alkylidene group, rudimentary phenylalkyl heterocyclic radical, the lower alkoxy alkylidene group, the lower alkoxy phenylene, rudimentary phenoxy group phenylene, phenylcarbonyl group, lower alkoxycarbonyl, the lower alkoxycarbonyl alkylidene group, the lower alkoxycarbonyl phenylene, the lower alkylcarbonyl carbonyl alkylen group, the low-grade alkyl amino alkylidene group, the low-grade alkyl amino phenylalkyl, the lower alkylcarbonyl amino alkylidenyl, the lower alkylthio phenylene, low alkyl group alkylsulfonyl phenylalkyl and rudimentary amino-sulfonyl phenylalkyl; The wherein said aryl of phenyl, xenyl and naphthyl, rudimentary heterocyclic radical, rudimentary phenylalkyl and the rudimentary heterocyclic radical alkylidene group of being selected from optionally replaced by one or more group, and described group is independently from each other low alkyl group, halogen, hydroxyl, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy, ketone group, amino, nitro and cyano group; Perhaps
R 38Be-CR 52R 53, R wherein 52Be lower alkoxycarbonyl, R 53It is the lower alkylthio alkylidene group; Perhaps
R 37And R 38The nitrogen-atoms that is connected with them lumps together the heterocycle that forms 4-8 unit;
R 39And R 40Have with claim 2 in R 26And R 27Identical definition; Perhaps
R 2Be selected from as next group group:
Figure A9880736901091
Wherein
K is the integer of 0-2;
R 56Be hydrogen or low alkyl group;
R 57Be hydrogen or low alkyl group;
R 58Be selected from hydrogen, low alkyl group, rudimentary phenylalkyl, the aryl that is selected from phenyl, xenyl and naphthyl, rudimentary heterocyclic radical, rudimentary heterocyclic radical alkyl, lower alkoxycarbonyl, low alkyl group alkylsulfonyl, rudimentary phenylalkyl alkylsulfonyl, rudimentary phenyl sulfonyl ,-C (O) R 59,-SO 2R 60With-C (O) NHR 61
R wherein 59Be selected from low alkyl group, low-grade halogenated alkyl, low-grade cycloalkyl, be selected from the aryl of phenyl, xenyl and naphthyl, rudimentary heterocyclic radical, low alkyl group phenylene, rudimentary phenylalkyl, low alkyl group heterocyclic radical, lower alkoxy, rudimentary alkenyloxy, rudimentary phenyl alkoxyl group, lower alkoxy alkylidene group, lower alkoxy phenylene, lower alkoxyphenyl alkyl; The wherein said aryl of phenyl, xenyl and naphthyl, rudimentary heterocyclic radical and the rudimentary phenylalkyl of being selected from optionally replaced by one or more group, and described group is independently from each other: low alkyl group, halogen, hydroxyl, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy, ketone group, amino, nitro and cyano group;
R wherein 60Be selected from low alkyl group, be selected from phenyl, xenyl and the aryl of naphthyl, rudimentary heterocyclic radical, low alkyl group phenylene, low alkyl group heterocyclic radical, rudimentary phenylalkyl, rudimentary heterocyclic radical heterocyclic radical, lower alkoxy phenylene, low-grade alkyl amino, low-grade alkyl amino phenylene, low alkyl group alkylsulfonyl phenylene and rudimentary phenyl sulfonyl heterocyclic radical; The wherein said aryl of phenyl, xenyl and naphthyl, rudimentary heterocyclic radical and the rudimentary phenylalkyl of being selected from optionally replaced by one or more group, and described group is independently from each other: low alkyl group, halogen, hydroxyl, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy, ketone group, amino, nitro and cyano group;
R wherein 61Be selected from low alkyl group, be selected from phenyl, aryl, low alkyl group phenylene and the lower alkoxy phenylene of xenyl and naphthyl; Wherein said aryl is optionally replaced by one or more group, and described group is independently from each other: low alkyl group, halogen, hydroxyl, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy, ketone group, amino, nitro and cyano group;
R 3Be selected from pyridyl, pyrimidyl and purine radicals; R wherein 3Optionally replaced by one or more group; described group is independently from each other methylthio group; methylsulfinyl; methyl sulphonyl; fluorine; chlorine; bromine; amino-sulfonyl; methyl; ethyl; sec.-propyl; the tertiary butyl; isobutyl-; cyano group; methoxycarbonyl; ethoxycarbonyl; aminocarboxyl; the methyl carbonylamino; trifluoromethyl; difluoromethyl; methyl fluoride; trichloromethyl; dichloromethyl; chloromethyl; hydroxyl; fluorophenyl methyl; the fluorophenyl ethyl; Chlorophenylmethyl; the chloro-phenyl-ethyl; the fluorophenyl vinyl; the chloro-phenyl-vinyl; the fluorophenyl pyrazolyl; the chloro-phenyl-pyrazolyl; carboxyl; methoxyl group; oxyethyl group; propyl group oxygen base; n-butoxy; methylamino; ethylamino; dimethylamino; diethylin; 2-methyl butyl amino; propargyl amino; amino methyl; amino-ethyl; N-methyl-N-phenyl amino; phenyl amino; diphenyl amino; benzylamino; styroyl amino; cyclopropyl amino; nitro; chlorosulfonyl; amino; the methyl carbonyl; methoxycarbonyl amino; ethoxycarbonyl amino; the p-methoxy-phenyl methylamino; N, N-dimethylaminoethyl amino; hydroxypropyl amino; hydroxyethyl amino; the imidazolyl ethylamino; the morpholinyl ethylamino; (1-ethyl-2-hydroxyl) ethylamino; piperidyl amino; pyridylmethyl amino; the phenyl methyl piperidyl amino; phenyl methyl amino; fluorophenyl methyl amino; the fluorophenyl ethylamino; the methylamino carbonyl; the ethylamino carbonyl; the methyl carbonyl; the p-methoxy-phenyl methylamino; diazanyl; 1-methyl diazanyl; or-NR 62R 63, R wherein 62Be methyl carbonyl or amino, R 63Be methyl, ethyl or phenyl methyl; With
R 4Be selected from hydrogen, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl radical, the cyclobutene base, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, xenyl, morpholinyl, pyrrolidyl, piperazinyl, piperidyl, pyridyl, thienyl, isothiazolyl isoxazolyl, thiazolyl oxazolyl, pyrimidyl, quinolyl, isoquinolyl, imidazolyl, benzimidazolyl-, furyl, pyrazinyl, dihydro pyranyl, the dihydropyridine base, the dihydrofuran base, THP trtrahydropyranyl, tetrahydrofuran base, benzofuryl, dihydro benzo furyl and benzodioxole base; R wherein 4Cycloalkyl, cycloalkenyl group, aryl and heterocyclic radical optionally replaced by one or more group, described group is independently from each other: methylthio group, methylsulfinyl, methyl sulphonyl, fluorine, chlorine, bromine, methyl, ethyl, sec.-propyl, the tertiary butyl, isobutyl-, ethynyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, methyl fluoride, difluoromethyl, amino, cyano group, nitro, dimethylamino and hydroxyl;
Or its pharmacologically acceptable salt or tautomer.
Another particularly preferred formula I compound is, wherein:
R 1Be hydrogen, methyl, ethyl, propargyl, hydroxyethyl, dimethyl aminoethyl, diethylamino ethyl or morpholinyl ethyl;
R 2Structure with following formula:
Wherein:
J is 0,1 or 2;
M is 0;
R 30Be hydrogen;
R 31Be selected from hydrogen and low alkyl group;
R 32Be selected from hydrogen and low alkyl group;
R 33Be selected from low alkyl group ,-C (O) 35,-C (O) OR 35,-SO 2R 36,-C (O) NR 37R 38With-SO 2NR 39R 40
R wherein 35Be selected from low alkyl group, low-grade cycloalkyl, phenyl, rudimentary heterocyclic radical, low alkyl group phenylene, lower alkoxy, rudimentary alkenyloxy, lower alkoxy alkylidene group, rudimentary phenoxy group alkylidene group and rudimentary phenyl alkoxyl group alkylidene group; Wherein said phenyl and rudimentary phenoxy group alkylidene group are optionally replaced by one or more groups that are independently from each other low alkyl group, halogen and low-grade halogenated alkyl;
R wherein 36Be selected from low alkyl group, phenyl, rudimentary heterocyclic radical, low alkyl group phenylene, phenyl phenylene, rudimentary phenylalkyl, low alkyl group heterocyclic radical, rudimentary heterocyclic radical heterocyclic radical, lower alkoxy phenylene and low-grade alkyl amino; Wherein said phenyl and rudimentary heterocyclic radical are optionally replaced by one or more group, and described group is independently from each other: low alkyl group, halogen, hydroxyl, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy, ketone group, amino, nitro and cyano group;
R wherein 37Be hydrogen;
R wherein 38Be selected from low alkyl group, phenyl and low alkyl group phenylene;
R wherein 39And R 40With the R in the claim 2 26And R 27Identical definition; Perhaps
R 2Be selected from as next group group:
Wherein
K is 0 or 1 integer;
R 56Be hydrogen;
R 57Be hydrogen;
R 58Be selected from-C (O) R 59With-SO 2R 60
R wherein 59Be selected from low alkyl group, low-grade cycloalkyl, phenyl, low alkyl group phenylene and lower alkoxy alkylidene group; Wherein said phenyl is optionally replaced by one or more group, and described group is independently from each other low alkyl group, halogen, hydroxyl, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy, ketone group, amino, nitro and cyano group;
R wherein 60Be selected from low alkyl group;
R 3Be selected from pyridyl, pyrimidyl or quinolyl; R wherein 3Optionally replaced by one or more group, described group is independently from each other fluorine, bromine, methyl, cyano group, methoxycarbonyl, aminocarboxyl, benzyl, styroyl, ethanoyl, hydroxyl, methoxyl group, dimethylamino, benzylamino, styroyl amino, amino methyl, amino, hydroxyl and methyl carbonyl;
R 4Be selected from phenyl, quinolyl, xenyl, pyridyl, thienyl, furyl, dihydro pyranyl, benzofuryl, dihydro benzo furyl and benzodioxole base; R wherein 4Cycloalkyl, cycloalkenyl group, aryl and heterocyclic radical optionally replaced by one or more group, described group is independently from each other: methylthio group, fluorine, chlorine, bromine, methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxyl;
Or its pharmacologically acceptable salt or tautomer.
Another particularly preferred formula I compound is, wherein:
R 1Be hydrogen or methyl;
R 3Be selected from pyridyl, pyrimidyl or quinolyl; R wherein 3Optionally replaced by one or more group, described group is independently from each other: fluorine, bromine, methyl, cyano group, methoxycarbonyl, aminocarboxyl, benzyl, styroyl, ethanoyl, hydroxyl, methoxyl group, dimethylamino, benzylamino, styroyl amino, amino methyl, amino, hydroxyl and methyl carbonyl;
R 4Be selected from phenyl, described phenyl is optionally replaced by one or more group, described group is independently from each other: methylthio group, fluorine, chlorine, bromine, methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxyl;
Or its pharmacologically acceptable salt or tautomer.
In one embodiment of the invention, formula I compound satisfies following one or more conditions:
R 1Be hydrogen or low alkyl group; Preferred R 1Be hydrogen or methyl; More preferably R 1Be hydrogen;
R 2Be hydrogen or low alkyl group; Preferred R 2Be hydrogen or methyl; More preferably R 2Be hydrogen;
R 3Be to replace or the unsubstituted pyridine base; Preferred this pyridyl is the 4-pyridyl; Perhaps
R 4Be to replace or unsubstituted phenyl; Preferred R 4The phenyl that is replaced by halogen.
In addition, work as R 3When being the pyrimidyl that replaces, preferably has a R at least 3Substituting group is to be connected on the carbon atom between two nitrogen-atoms of pyrimidine ring.
One group of particularly preferred formula I particular compound is made up of following compound, its tautomer and pharmacologically acceptable salt:
4-[5-(3-fluoro-4-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine;
4-[5-methyl-3-(2-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine;
4-[3-(4-fluorophenyl)-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-methyl-3-(4-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine;
4-[5-methyl-3-[4-(methylthio group) phenyl]-1H-pyrazoles-4-yl] pyridine;
4-[3-(4-chloro-phenyl-)-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-methyl-5-(3-aminomethyl phenyl) 1H-pyrazoles-4-yl] pyridine;
4-[5-(2, the 5-3,5-dimethylphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(1,3-benzodioxole-5-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-methyl-5-(4-Phenoxyphenyl)-1H-pyrazoles-4-yl] pyridine;
4-[5-[(1,1 '-xenyl)-the 4-yl]-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-methyl-5-[3-(Phenoxyphenyl)-1H-pyrazoles-4-yl] pyridine;
4-[3-methyl-5-[3-(phenyl methoxyl group) phenyl]-1H-pyrazoles-4-yl] pyridine;
4-[3-methyl-5-[2-(phenyl methoxyl group) phenyl]-1H-pyrazoles-4-yl] pyridine;
2-[3-methyl-4-(4-pyridyl)-1H-pyrazoles-4-yl] phenol;
3-[3-methyl-4-(4-pyridyl)-1H-pyrazoles 4-yl] phenol;
1-hydroxyl-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine;
5-(4-fluorophenyl)-N, N-dimethyl-4-(4-pyridyl)-1H-pyrazoles-3-amine;
5-(4-fluorophenyl)-N-phenyl-4-(4-pyridyl)-1H-pyrazoles-3 amine;
4-[5-(4-fluorophenyl)-3-phenyl-1H-pyrazoles-4-yl] pyridine;
4-[5-(3-aminomethyl phenyl)-3-(trifluoromethyl)-1H-pyrazoles-4-yl] pyridine;
4-[3-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazoles-5-yl] pyridine;
4-(5-cyclohexyl)-3-methyl isophthalic acid H-pyrazoles-4-yl) pyridine;
4-[5-(3-fluoro-5-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(3-aminomethyl phenyl)-3-propyl group-1H-pyrazoles-4-yl] pyridine;
4-[(3-methyl-5-phenyl-1H-pyrazoles-4-yl) methyl] pyridine;
4-[3,5-two (3-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine;
4-[4 methyl-2-(2-trifluorophenyl)-1H-pyrazoles-4-yl] pyridine;
4-[3-(2-chloro-phenyl-)-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-methyl-3-(2, the 4-3,5-dimethylphenyl)-1H-pyrazoles-4-yl] pyridine;
4-[5-(4-chloro-phenyl-)-1,3-dimethyl-1H-pyrazoles-4-yl] pyridine;
4-[3-(3-fluoro-2-aminomethyl phenyl)-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-(3, the 5-3,5-dimethylphenyl)-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-(3, the 5-Dimethoxyphenyl)-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-methyl-3-(3-nitrophenyl)-1H-pyrazoles-4-yl] pyridine;
N, N-dimethyl-4-[5-methyl-4-(4-pyridyl)-1H-pyrazole-3-yl] aniline;
4-[3-(2,3-Dihydrobenzofuranes-5-yl)-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-(4-bromophenyl)-5-methyl 1H-pyrazoles-4-yl] pyridine;
4-[3-(2-fluorophenyl)-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-(3-fluorophenyl)-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-methyl-5-[3-(trifluoromethyl) phenyl]-1H-pyrazoles-4-yl] pyridine;
4-(3-ethyl-4-phenyl-1H-pyrazoles-4-yl) pyridine;
4-[5-(3-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-ethyl-5-(3-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine;
4-[5-(3, the 4-difluorophenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(3-ethoxyl phenenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-methyl-5-[4-(trifluoromethyl) phenyl]-1H-pyrazoles-4-yl] pyridine;
4-[3-methyl-5-(3-thienyl)-1H-pyrazoles-4-yl] pyridine;
4-[5-(2,4 dichloro benzene base)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(3-chloro-4-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
3-(4-chloro-phenyl-)-4-(4-pyridyl)-1H-pyrazoles-5-ethyl propionate;
4-[3-(4-fluorophenyl)-1-methyl-pyrazoles-4-yl] pyridine;
5-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyrimidine-2-amine;
5-[3-methyl-5-(3-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyrimidine-2-amine;
5-[3-methyl-5-(2-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyrimidine-2-amine;
5-[5-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyrimidine-2-amine;
5-[5-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyrimidine-2-amine;
5-[5-(4-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyrimidine-2-amine;
5-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-amine;
4-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-amine;
4-[5-(3-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-amine;
4-[5-(2-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-amine;
4-[5-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-amine;
4-[5-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-amine;
4-[5-(4-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-amine;
5-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl]-the 2-methoxypyridine;
2-methoxyl group-5-[3-methyl-5-(3-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine;
2-methoxyl group-5-[5-(4-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl]-the 2-methoxypyridine;
2-methoxyl group-4-[3-methyl-5-(3-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine;
2-methoxyl group-4-[3-methyl-5-(2-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine;
4-[5-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl]-the 2-methoxypyridine;
4-[5-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl]-the 2-methoxypyridine;
2-methoxyl group-4-[3-methyl-5-(4-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine;
5-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-alcohol;
4-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-alcohol;
4-[5-(3-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-alcohol;
4-[5-(2-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-alcohol;
4-[5-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-alcohol;
4-[5-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-alcohol;
4-[5-(4-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-alcohol;
5-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-methylamine;
4-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-methylamine;
4-[5-(3-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-methylamine;
4-[5-(2-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-methylamine;
4-[5-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-methylamine;
4-[5-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-methylamine;
4-[5-(4-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-methylamine;
5-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-carboxamide;
4-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-carboxamide;
4-[5-(3-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-carboxamide;
4-[5-(2-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-carboxamide;
4-[5-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-carboxamide;
4-[5-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-carboxamide;
4-[5-(4-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-carboxamide;
4-[5-(3-fluoro-4-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(4-fluoro-3-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(4-chloro-3-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(2,3-Dihydrobenzofuranes-6-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(cumarone-6-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(3-fluoro-5-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(3-chloro-5-p-methoxy-phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(1-tetrahydrobenzene-1-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(1-1-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(5,6-dihydro-2H-pyrans-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-(5-cyclohexyl-3-methyl isophthalic acid H-pyrazoles-4-yl) pyridine;
4-[5-(4-methoxyl group-3-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(3-methoxyl group-4-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(3-methoxyl group-5-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(3-furyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
2-methyl-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine;
2-methoxyl group-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine;
4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine-2-methyl-formiate;
4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine-2-carboxamide;
1-[4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine-2-yl] ethyl ketone;
N, N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazoles-2-yl) pyridine-2-amine;
3-methyl-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine;
3-methoxyl group-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine;
4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) Nicotinicum Acidum methyl esters;
4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine-3-carboxamide;
1-[4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridin-3-yl] ethyl ketone;
3-bromo-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine;
N, N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazoles-2-yl) pyridine-3-amine;
2-methyl-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyrimidine;
4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyrimidine;
2-methoxyl group-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyrimidine;
4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyrimidine-2-amine;
N, N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyrimidine-2-amine;
4-(5,6-dihydro-2H-pyrans-4-yl)-3-methyl-5-phenyl-1H-pyrazoles;
3-methyl-5-phenyl-4-(3-thienyl)-1H-pyrazoles;
4-(3-furyl)-3-methyl-5-phenyl-1H-pyrazoles;
3-methyl-5-phenyl-4-(2-thienyl)-1H-pyrazoles;
4-(2-furyl)-3-methyl-5-phenyl-1H-pyrazoles;
4-(3-isothiazolyl)-3-methyl-5-phenyl-1H-pyrazoles;
4-(3-isoxazolyl)-3-methyl-5-phenyl-1H-pyrazoles;
4-(5-isothiazolyl)-3-methyl-5-phenyl-1H-pyrazoles;
4-(5-isoxazolyl)-3-methyl-5-phenyl-1H-pyrazoles;
3-methyl-5-phenyl-4-(5-thiazolyl)-1H-pyrazoles;
3-methyl-4-(5-oxazolyl)-5-phenyl-1H-pyrazoles;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] pyridine;
2-methyl-4-[3-(3-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine;
4-(1-methyl-3-phenyl-1H-pyrazoles-4-yl) pyridine;
4-(3-phenyl-1H-pyrazoles-4-yl) pyridine;
2-methyl-4-(3-phenyl-1H-pyrazoles-4-yl) pyridine;
4-[3-(3-chloro-phenyl-)-1-methyl-pyrazoles-4-yl] pyridine;
4-[3-(4-chloro-phenyl-)-1-methyl-pyrazoles-4-yl] pyridine;
4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4-yl] pyridine;
4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4-yl] pyridine;
4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4-yl]-the 2-picoline;
4-[3-(3-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-(3-fluorophenyl)-1H-pyrazoles-4-yl] pyridine;
4-[3-(3-chloro-phenyl-)-1-methyl-pyrazoles-4-yl]-the 2-picoline;
5-(4-chloro-phenyl-)-N-phenyl-4-(4-pyridyl)-1H-pyrazoles-3-amine;
5-(4-chloro-phenyl-)-N-methyl-4-(4-pyridyl)-1H-pyrazoles-3 amine;
5-(4-chloro-phenyl-)-N, N-dimethyl-4-(4-pyridyl)-1H-pyrazoles-3-amine dihydrate;
5-(3-fluorophenyl)-N, N-dimethyl-4-(4-pyridyl)-1H-pyrazoles-3-amine;
N, N-dimethyl-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-1H-pyrazoles-3-amine;
N-methyl-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-1H-pyrazoles-3-amine;
N-ethyl-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-1H-pyrazoles-3-amine;
N, N-diethyl-5-(3-aminomethyl phenyl)-4-(4-pyridyl)-1H-pyrazoles-3-amine;
5-(4-chloro-phenyl-)-N, N-diethyl-4-(4-pyridyl)-1H-pyrazoles-3-amine;
4-[5-(4-chloro-phenyl-)-4-(4-pyridyl)-1H-pyrazole-3-yl] morpholine;
5-(4-chloro-phenyl-)-N-propyl group-4-(4-pyridyl)-1H-pyrazoles-3-amine;
5-(4-chloro-phenyl-)-N-(phenyl methyl)-4-(4-pyridyl)-1H-pyrazoles-3-amine hydrate (2: 1);
5-(4-chloro-phenyl-)-N-(2-methoxy ethyl)-4-(4-pyridyl)-1H-pyrazoles-3-amine monohydrate;
1,1-dimethyl ethyl 4-[5-(4-chloro-phenyl-)-4-(4-pyridyl)-1H-pyrazole-3-yl]-1-piperazinecarboxylic acid ester;
1-[5-(4-chloro-phenyl-)-4-(4-pyridyl)-1H-pyrazole-3-yl] piperazine trihydrochloride salt;
1-[5-(4-chloro-phenyl-)-4-(4-pyridyl)-1H-pyrazole-3-yl]-the 4-methylpiperazine;
1,1-dimethyl ethyl 4-[5-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazole-3-yl]-1-piperazinecarboxylic acid ester;
1-[5-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazole-3-yl] piperazine trihydrochloride salt;
1-[5-(4-chloro-phenyl-)-4-(4-pyridyl)-1H-pyrazole-3-yl] piperazine;
N-[5-(4-chloro-phenyl-)-4-[2-(phenyl methyl) amino]-the 4-pyridyl]-the 1H-pyrazole-3-yl]-1,3-propylene diamine, tri hydrochloride;
1-[5-(4-chloro-phenyl-)-4-(4-pyridyl)-1H-pyrazole-3-yl]-4-(phenyl methyl) piperazine;
4-[3-(4-fluorophenyl)-5-(1-piperazinyl)-1H-pyrazoles-4-yl] pyrimidine, dihydrochloride;
1,1-dimethyl ethyl [3-[[5-(4-chloro-phenyl-)-4-(4-pyridyl)-1H-pyrazole-3-yl] amino] propyl group] carbamate;
The N-[5-[4-chloro-phenyl-)-and 4-(4-pyridyl)-1H-pyrazole-3-yl]-1,3-propylene diamine, tri hydrochloride monohydrate;
1,1-dimethyl ethyl [2-[[5-(4-chloro-phenyl-)-4-(4-pyridyl)-1H-pyrazole-3-yl] amino] ethyl] carbamate;
1,1-dimethyl ethyl 4-[5-(4-chloro-phenyl-)-1-(2-hydroxyethyl)-4-(4-pyridyl)-1H-pyrazole-3-yl]-1-piperazinecarboxylic acid ester;
1,1-dimethyl ethyl 4-[5-(4-fluorophenyl)-4-(4-pyrimidyl)-1H-pyrazole-3-yl]-1-piperazinecarboxylic acid ester;
1,1-dimethyl ethyl [3-[[5-(4-chloro-phenyl-)-4-(2-fluoro-4 pyridyl)-1H-pyrazole-3-yl] amino] propyl group] carbamate;
1-[5-(4-chloro-phenyl-)-4-(4-pyridyl)-1H-pyrazole-3-yl]-the 4-ethyl piperazidine;
N-[5-(4-chloro-phenyl-)-4-(4-pyridyl)-1H-pyrazole-3-yl]-1;
4-[3-(2, the 6-difluorophenyl)-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-(3-ethylphenyl)-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-(3-chloro-phenyl-)-5-ethyl-1H-pyrazoles-4-yl] pyridine;
4-(3-ethyl-5-(3-ethylphenyl)-1H-pyrazoles-4-yl] pyridine;
4-[3-(4-chloro-phenyl-)-5-(1-methylethyl)-1H-pyrazoles-4-yl] pyridine;
4-[3-cyclopropyl-5-(4-fluorophenyl)-1H-pyrazoles-4-yl] pyridine;
4-[3-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazoles-4-yl] pyridine;
4-[5-(cyclopropyl-3-(4-(fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
5-cyclopropyl-3-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazoles-1-ethanol;
3-(4-fluorophenyl)-5-(2-methoxyl group-4-pyridyl)-4-(4-pyridyl)-1H-pyrazoles-1-ethanol;
4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridyl)-1H-pyrazoles-5-yl]-2 (1H)-pyridones;
1-ethanoyl-4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridyl)-1H-pyrazoles-5-yl]-2 (1H)-pyridones;
2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4 pyridyl)-1H-pyrazoles-5-yl] the cyclopropane-carboxylic acid ethyl ester;
2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridyl)-1H-pyrazoles-5-yl] cyclopropane-carboxylic acid;
3-(4-fluorophenyl)-5-(4-imidazolyl)-4-(4-pyridyl)-1H-pyrazoles-1-ethanol;
4-[3-(4-chloro-3-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine;
5-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazoles-3-formic acid;
5-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazoles-3-methyl alcohol;
1-[[5-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazole-3-yl] carbonyl] piperazine;
1,1-dimethyl ethyl 4-[[5-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazole-3-yl] carbonyl]-1-piperazinecarboxylic acid ester;
4-(1,5-dimethyl-3-phenyl-1H-pyrazoles-4-yl) pyridine;
4-(1,3-dimethyl-5-phenyl-1H-pyrazoles-4-yl) pyridine;
4-[3-(4-chloro-phenyl-)-1,5-dimethyl-1H-pyrazoles-4-yl] pyridine;
4-[5-(4-chloro-phenyl-)-1,3-dimethyl-1H-pyrazoles-4-yl] pyridine;
4-[5-ethyl-1-methyl-3-(3-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine;
4-[3-ethyl-1-methyl-5-(3-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine;
4-[3-(4-chloro-phenyl-)-1-ethyl-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-(4-chloro-phenyl-)-2-ethyl-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] pyridine;
4-[3-(2-chloro-phenyl-)-1H-pyrazoles-4-yl] pyridine;
3-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazoles-1-ethanol;
3-(4-fluorophenyl)-4-(4-pyrimidyl)-1H-pyrazoles-1-ethanol;
4-[3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
2-[[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyridyl] amino]-the 1-butanols;
4-[5-bromo-3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyridine carbonitrile;
4-[2-[3-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazol-1-yl] ethyl] morpholine;
3-(4-fluorophenyl)-1-methyl-α-phenyl-4-(4-pyridyl)-1H-pyrazoles-5-methyl alcohol;
N-[5-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazole-3-yl]-4-morpholine ethamine;
4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4-yl)]-2 (1H)-pyridone hydrazones;
4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4-yl]-N-(phenyl methyl)-2-pyridine amine;
4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4-yl]-N-(phenylethyl)-2 pyridine amine;
4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4-yl]-N-ethyl-2-pyridine amine;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyridine carboxamide;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2-pyridine carboxylic acid methyl esters;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N-methyl-2-pyridine carboxamide;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyridine carboxylic acid;
4-[3-(3-fluorophenyl)-1H-pyrazoles-4-yl] pyridine;
4-[3-(1,3-benzodioxole-5-yl)-1H-pyrazoles-4-yl] pyridine;
4-[3-(3-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4-yl] pyridine;
4-[3-(1,3-benzodioxole-5-yl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-(4-chloro-phenyl-)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-(3-chloro-phenyl-)-1-methyl isophthalic acid H-pyrazoles-4-yl]-2-methyl-pyridine;
4-[5-(3-chloro-phenyl-)-1-methyl isophthalic acid H-pyrazoles-4-yl]-the 2-picoline;
4-[3-(3-chloro-phenyl-)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[5-(3-chloro-phenyl-)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
2-methyl-4-[1-methyl-3-(3-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine;
2-methyl-4-[1-methyl-5-(3-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine;
4-(3-phenyl-1H-pyrazoles-4-yl) pyridine;
4-[3-[3-(trifluoromethyl) phenyl]-1H-pyrazoles-4-yl] pyridine;
4-[1-methyl-3-[3-(trifluoromethyl) phenyl]-1H-pyrazoles-4-yl] pyridine;
4-[3-(3, the 4-difluorophenyl)-1H-pyrazoles-4-yl] pyridine;
4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4-yl]-2-fluorine pyridine;
4-[3-(4-bromophenyl)-1H-pyrazoles-4-yl] pyridine;
4-[3-(3, the 4-difluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-(4-bromophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
(E)-4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2-(2-phenyl vinyl) pyridine;
(S)-4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4-yl]-N-(2-methyl butyl)-2-pyridine amine;
4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4-yl]-the N-[(4-p-methoxy-phenyl) methyl]-2-pyridine amine;
N-[4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4-yl]-the 2-pyridyl]-the 2-pyridyl-methanamine;
N-[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyridyl]-the 2-pyridyl-methanamine;
2-fluoro-4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] pyridine;
4-[3-(4-iodophenyl)-1H-pyrazoles-4-yl] pyridine;
4-[3-(4-iodophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[1-methyl-3-[4-(trifluoromethyl) phenyl]-1H-pyrazoles-4-yl] pyridine;
N-[1-(4-fluorophenyl) ethyl]-4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2-pyridine amine;
The N-[(3-fluorophenyl) methyl]-4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2-pyridine amine;
4-[3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl]-2-(1-methyl diazanyl) pyridine;
2-fluoro-4-[3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-(3, the 4-difluorophenyl)-1H-pyrazoles-4-yl]-2-fluorine pyridine;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 3-picoline;
4-[3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl]-the 3-picoline;
4-[3-(3, the 4-difluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl]-2-fluorine pyridine;
3-(4-fluorophenyl)-N, N-dimethyl-4-(4-pyridyl)-1H-pyrazoles-1-ethamine;
2-[2-(4-fluorophenyl) ethyl]-4-[3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N-[1-(phenyl methyl)-4-piperidyl]-2-pyridine amine;
N '-[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2-pyridyl]-N, N-dimethyl-1;
2,4-two [3-(4-fluorophenyl)-1H-pyrazoles-4-yl] pyridine;
N-[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyridyl]-4-morpholine ethamine;
3-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-1H-pyrazoles-1-ethanol;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N-[2-(1H-imidazoles-1-yl) ethyl]-2-pyridine amine;
4-[2-[3-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-1H-pyrazol-1-yl] ethyl] morpholine;
(E)-3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl) vinyl]-the 4-pyridyl]-1H-pyrazoles-1-ethanol;
3-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-N, N-dimethyl-1H-pyrazoles-1-ethamine;
3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl) ethyl]-the 4-pyridyl]-1H-pyrazoles-1-ethanol;
4-[1-[2-(dimethylamino) ethyl]-3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N, N-dimethyl-2-pyridine amine;
4-[1-[2-(dimethylamino) ethyl]-3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the N-[(4-fluorophenyl) methyl]-2-pyridine amine;
3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl) ethyl]-the 4-pyridyl]-N, N-dimethyl-1H-pyrazoles-1-ethamine;
The N-[(4-fluorophenyl) methyl]-4-[3 (or 5)-(4-fluorophenyl)-1-[[2-(4-morpholinyl) ethyl]-1H-pyrazoles-4-yl]-2-pyridine amine;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N-4-piperidyl-2-pyridine amine;
N, N-diethyl-3-(4-fluorophenyl)-4-(2-fluoro-4-pyridyl)-1H-pyrazoles-1-ethamine;
4-[1-[2-(diethylin) ethyl]-3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the N-[(4-fluorophenyl) methyl]-2-pyridine amine;
2-[[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyridyl] amino] ethanol;
2-[[4-[3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl]-the 2-pyridyl] amino] ethanol;
3-[[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyridyl] amino]-the 1-propyl alcohol;
3-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl) methyl] amino)-the 4-pyridyl]-1H-pyrazoles-1-ethanol;
5-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl) methyl] amino]-the 4-pyridyl]-1H-pyrazoles-1-ethanol;
N, N diethyl-3-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazoles-1-ethamine;
The N-[(4-fluorophenyl) methyl]-4-[3-(4-fluorophenyl)-1-[2-(4-morpholinyl) ethyl]-1H-pyrazoles-4-yl]-2-pyridine amine;
N-[5-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazole-3-yl]-the 4-morpholine propylamine;
N '-[5-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazole-3-yl]-N, N-dimethyl-1,3-propylene diamine;
5-(4-fluorophenyl)-N-2-proyl-4-(4-pyridyl)-1H-pyrazoles-3-amine;
3-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl) methyl] amino]-the 4-pyridyl]-1H-pyrazoles-1-ethanol;
5-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl) methyl] amino]-the 4-pyridyl]-1H-pyrazoles-1-ethanol;
The 4-[3-[(4-fluorophenyl)-and 1H-pyrazoles-4-yl] quinoline;
N-[5-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazole-3-yl] glycine methyl ester;
N-[5-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazole-3-yl] glycine;
4-[3-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazoles-4-yl] pyridine;
4-[5-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazoles-4-yl] pyridine;
4,4 '-(1H-pyrazoles-3,4-two bases) two [pyridines];
4-[3-(3, the 4-dichlorophenyl)-1H-pyrazoles-4-yl] pyridine;
N-[5-(4-chloro-phenyl-)-4-(4-pyridyl)-1H-pyrazole-3-yl]-the 4-piperylhydrazine;
2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] pyrimidine;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2 (1H)-pyrimidone hydrazones;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N, N-dimethyl-2-PYRIMITHAMINE;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N-methyl-2-PYRIMITHAMINE;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N-(phenyl methyl)-2-PYRIMITHAMINE;
N-cyclopropyl-4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-PYRIMITHAMINE;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the N-[(4-p-methoxy-phenyl) methyl]-the 2-PYRIMITHAMINE;
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-PYRIMITHAMINE;
N-[4-[3-(4-fluorophenyl)-1H-pyrazoles-4 base]-the 2-pyrimidyl]-N-(phenyl methyl) ethanamide;
[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2-pyrimidyl] urethanum;
4-[3-(3-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyrimidine;
4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4-yl] pyrimidine;
4-[3-(3-fluorophenyl)-1H-pyrazoles-4-yl] pyrimidine; With
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] pyrimidine.
Among the formula I, the particularly preferred compound of another group is suc as formula shown in the IX:
Wherein:
Z represents carbon atom or nitrogen-atoms;
R 1Be selected from hydrogen, low alkyl group, rudimentary hydroxyalkyl, alkynyl of low-grade chain, rudimentary heterocyclic radical, rudimentary aralkyl, rudimentary aminoalkyl group and low-grade alkyl amino alkyl;
R 2Be selected from hydrogen, low alkyl group, be selected from phenyl, the aryl of xenyl and naphthyl, be selected from piperidyl, piperazinyl, imidazolyl, the 5-of pyridyl and morpholinyl or 6-unit heterocyclic radical, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxycarbonyl, low-grade alkyl amino, the low-grade alkyl amino alkyl, phenyl amino, rudimentary aralkyl, rudimentary aryl alkyl amino, the low-grade alkyl amino alkylamino, rudimentary aminoalkyl group, rudimentary aminoalkyl group amino, alkynyl of low-grade chain amino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkyl, rudimentary heterocyclic radical alkylamino, the low alkyl group heterocyclic radical, rudimentary carboxyl cycloalkyl, rudimentary carboxyalkyl amino, low-grade alkoxy alkyl amino, lower alkoxycarbonyl aminoalkyl group amino, rudimentary heterocyclic radical carbonyl, lower alkoxycarbonyl heterocyclic radical and lower alkoxycarbonyl heterocyclic radical carbonyl; Wherein aryl and heteroaryl are optionally replaced by one or more group, and described group is independently from each other: halogen, low alkyl group, ketone group, aralkyl, carboxyl, low-grade alkyl amino alkylamino, alkynyl of low-grade chain amino, rudimentary heterocyclic radical alkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; Perhaps
R 2Be-CR 54R 55, R wherein 54Be phenyl, R 55It is hydroxyl;
R 4Be selected from hydrogen, low-grade cycloalkyl, lower alkenyl ring, low-grade cycloalkyl dialkylene, 5-or 6-unit's heterocyclic radical and be selected from the aryl of phenyl, xenyl, naphthyl; R wherein 4Can optionally replaced by one or more group on the substituted position, described group is independently from each other halogen, low alkyl group, lower alkoxy, aryloxy, rudimentary aralkoxy, low-grade halogenated alkyl, lower alkylthio, low-grade alkyl amino, nitro, hydroxyl;
R 5Be selected from halogen, amino, cyano group, aminocarboxyl, low alkyl group, lower alkoxy, hydroxyl, rudimentary aminoalkyl group, rudimentary aralkyl, rudimentary aralkoxy, rudimentary aryl alkyl amino, lower alkoxycarbonyl, low-grade alkyl amino, lower alkylcarbonyl, the lower aryl alkenyl, the lower aryl heterocyclic radical, carboxyl, low-grade cycloalkyl amino, lower alkoxycarbonyl amino, the lower alkoxy aryl alkyl amino, the low-grade alkyl amino alkylamino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkylamino, rudimentary aralkyl heterocyclic radical amino, low-grade alkyl amino carbonylic, lower alkylcarbonyl, the lower alkoxy aryl alkyl amino, diazanyl and low alkyl group diazanyl or-NR 62R 63, R wherein 62Be lower alkylcarbonyl or amino, R 63Be low alkyl group or rudimentary phenylalkyl;
Or its pharmacologically acceptable salt or tautomer.
One group of preferred compound is by forming as shown in the formula the IX compound:
R 1Be selected from hydrogen, methyl, ethyl, hydroxyethyl and propargyl;
R 2Be selected from hydrogen, methyl, ethyl, propyl group, phenyl, trifluoromethyl, hydroxyethyl, the methoxycarbonyl ethyl, ethoxycarbonyl-ethyl, the N-methylamino, N, the N-dimethylamino, the N-ethylamino, N, the N-diethylamino, N-propyl group amino, the N-phenyl amino, amino methyl, amino-ethyl, aminoethylamino, amino propyl amino, propargyl amino, benzylamino, dimethylamino-propyl amino, morpholinyl propyl amino, the morpholinyl ethylamino, piperidyl, piperazinyl, imidazolyl, morpholinyl, pyridyl, the carboxyl methylamino, methoxy ethyl amino, (1, the 1-dimethyl) ethyl carbonyl, (1, the 1-dimethyl) ethyl carbonylamino propyl group amino, (1, the 1-dimethyl) ethyl carbonylamino ethylamino, piperazinyl carbonyl, 1,1-dimethyl ethyl piperazinyl carbonyl; Phenyl wherein, piperidyl, piperazinyl, imidazolyl, morpholinyl and pyridyl are optionally replaced by one or more group, described group is independently from each other: fluorine, chlorine, bromine, ketone group, methyl, ethyl, trifluoromethyl, benzyl, methoxyl group, methoxycarbonyl, ethoxycarbonyl and (1, the 1-dimethyl) ethoxycarbonyl;
R 4Be selected from cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, quinolyl, xenyl, pyridyl, thienyl, furyl, dihydro pyranyl, benzofuryl, dihydro benzo furyl and benzodioxole base; Wherein R4 is optionally replaced by one or more group, and described group is independently from each other methylthio group, fluorine, chlorine, bromine, methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxyl;
R 5Be selected from fluorine; chlorine; bromine; methyl; the fluorophenyl ethyl; the fluorophenyl vinyl; the fluorophenyl pyrazolyl; cyano group; methoxycarbonyl; aminocarboxyl; ethanoyl; the hydroxyl carboxyl; methoxyl group; methylamino; dimethylamino; 2-methyl butyl amino; ethylamino; dimethylaminoethyl amino; hydroxypropyl amino; hydroxyethyl amino; imidazolyl amino; the morpholinyl ethylamino; (1-ethyl-2-hydroxyl) ethylamino; piperidyl amino; pyridylmethyl amino; the phenyl methyl piperidyl amino; amino methyl; cyclopropyl amino; amino; hydroxyl; the methyl carbonyl; ethoxycarbonyl amino; the p-methoxy-phenyl methylamino; phenyl methyl amino; fluorophenyl methyl amino; the fluorophenyl ethylamino; the methylamino carbonyl; the methyl carbonyl; diazanyl and 1-methyl diazanyl, or-NR 62R 63, R wherein 62Be methyl carbonyl or amino, R 63Be methyl or benzyl;
Or its pharmacologically acceptable salt or tautomer.
Among the formula I, the particularly preferred compound of another group is as shown in the formula shown in the X:
Figure A9880736901291
Wherein
Z represents carbon atom or nitrogen-atoms;
R 1Be selected from low alkyl group, rudimentary hydroxyalkyl, alkynyl of low-grade chain, rudimentary aminoalkyl group and low-grade alkyl amino alkyl;
R 2Be selected from hydrogen, low alkyl group, be selected from phenyl, the aryl of xenyl and naphthyl, be selected from piperidyl, piperazinyl, imidazolyl, the 5-of pyridyl and morpholinyl or 6-unit heterocyclic radical, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxycarbonyl, low-grade alkyl amino, the low-grade alkyl amino alkyl, phenyl amino, rudimentary aralkyl, rudimentary aryl alkyl amino, the low-grade alkyl amino alkylamino, rudimentary aminoalkyl group, rudimentary aminoalkyl group amino, alkynyl of low-grade chain amino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkyl, rudimentary heterocyclic radical alkylamino, the low alkyl group heterocyclic radical, rudimentary carboxyl cycloalkyl, rudimentary carboxyalkyl amino, low-grade alkoxy alkyl amino, lower alkoxycarbonyl aminoalkyl group amino, rudimentary heterocyclic radical carbonyl, lower alkoxycarbonyl heterocyclic radical and lower alkoxycarbonyl heterocyclic radical carbonyl; Wherein aryl and heteroaryl are optionally replaced by one or more group, shown in group be independently from each other halogen, low alkyl group, ketone group, aralkyl, carboxyl, low-grade alkyl amino alkylamino, alkynyl of low-grade chain amino, rudimentary heterocyclic radical alkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; Perhaps
R 2Be-CR 54R 55, R wherein 54Be phenyl, R 55It is hydroxyl;
R 4Be selected from 5-or 6-unit heteroaryl, be selected from the aryl of phenyl, xenyl and naphthyl; R wherein 4Optionally replaced by one or more group, described group is independently from each other: halogen, low alkyl group, lower alkoxy, aryloxy, rudimentary aralkoxy, low-grade halogenated alkyl, lower alkylthio, low-grade alkyl amino, nitro, hydroxyl; With
R 5Be selected from halogen, amino, cyano group, aminocarboxyl, low alkyl group, lower alkoxy, hydroxyl, rudimentary aminoalkyl group, rudimentary aralkyl, rudimentary aralkoxy, rudimentary aryl alkyl amino, lower alkoxycarbonyl, low-grade alkyl amino, lower alkylcarbonyl, the lower aryl alkenyl, the lower aryl heterocyclic radical, carboxyl, low-grade cycloalkyl amino, lower alkoxycarbonyl amino, the lower alkoxy aryl alkyl amino, the low-grade alkyl amino alkylamino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkylamino, rudimentary aralkyl heterocyclic radical amino, low-grade alkyl amino carbonylic, lower alkylcarbonyl, the lower alkoxy aryl alkyl amino, diazanyl and low alkyl group diazanyl, or-NR 62R 63, R wherein 62Be lower alkylcarbonyl or amino, R 63Be low alkyl group or rudimentary phenylalkyl;
Or its pharmacologically acceptable salt or tautomer.
One group of preferred compound is made up of the compound as shown in the formula X:
R 1Be selected from methyl, ethyl, hydroxyethyl and propargyl;
R 2Be selected from methyl, ethyl, propyl group, phenyl, trifluoromethyl, hydroxyethyl, the methoxycarbonyl ethyl, ethoxycarbonyl-ethyl, the N-methylamino, N, the N-dimethylamino, the N-ethylamino, N, the N-diethylamino, N-propyl group amino, the N-phenyl amino, amino methyl, amino-ethyl, aminoethylamino, amino propyl amino, propargyl amino, benzylamino, piperidyl amino, dimethylaminoethyl amino, dimethylamino-propyl amino, morpholinyl propyl amino, the morpholinyl ethylamino, piperidyl, piperazinyl, imidazolyl, morpholinyl, pyridyl, the N methyl piperazine base, carboxymethylamino, methoxy ethyl amino, (1, the 1-dimethyl) ethyl carbonyl, (1, the 1-dimethyl) ethyl carbonylamino propyl group amino, (1, the 1-dimethyl) ethyl carbonylamino ethylamino, piperazinyl carbonyl and 1,1-dimethyl ethyl piperazinyl carbonyl; Phenyl wherein, piperidyl, piperazinyl, imidazolyl, morpholinyl and pyridyl are optionally replaced by one or more group, described group is independently from each other: fluorine, chlorine, bromine, ketone group, methyl, ethyl, trifluoromethyl, benzyl, methoxyl group, methoxycarbonyl, ethoxycarbonyl and (1, the 1-dimethyl) ethoxycarbonyl;
R 4Be selected from phenyl, quinolyl, xenyl, pyridyl, thienyl, furyl, dihydro pyranyl, benzofuryl, dihydro benzo furyl and benzodioxole base; R wherein 4Optionally replaced by one or more group, described group is independently from each other methylthio group, fluorine, chlorine, bromine, methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxyl;
R 5Be selected from fluorine; chlorine; bromine; methyl; the fluorophenyl ethyl; the fluorophenyl vinyl; the fluorophenyl pyrazolyl; cyano group; methoxycarbonyl; aminocarboxyl; ethanoyl; hydroxyl; carboxyl; methoxyl group; methylamino; dimethylamino; 2-methyl butyl amino; ethylamino; dimethylaminoethyl amino; hydroxypropyl amino; hydroxyethyl amino; propargyl amino; imidazolyl amino; the morpholinyl ethylamino; (1-ethyl-2-hydroxyl) ethylamino; piperidyl amino; pyridylmethyl amino; the phenyl methyl piperidyl amino; amino methyl; cyclopropyl amino; amino; hydroxyl; the methyl carbonyl; ethoxycarbonyl amino; the p-methoxy-phenyl methylamino; phenyl methyl amino; fluorophenyl methyl amino; the fluorophenyl ethylamino; the methylamino carbonyl; the methyl carbonyl; diazanyl and 1-methyl diazanyl, or-NR 62R 63, R wherein 62Be methyl carbonyl or amino, R 63Be methyl or benzyl;
Or its pharmacologically acceptable salt or tautomer.
Among the formula I, the particularly preferred compound of another group is as shown in the formula shown in the XI:
Figure A9880736901311
Wherein
Z represents carbon atom or nitrogen-atoms;
R 1Be selected from low alkyl group, rudimentary hydroxyalkyl, alkynyl of low-grade chain, rudimentary aminoalkyl group and low-grade alkyl amino alkyl;
R 2Be selected from hydrogen, low alkyl group, be selected from phenyl, the aryl of xenyl and naphthyl, be selected from piperidyl, piperazinyl, imidazolyl, the 5-of pyridyl and morpholinyl or 6-unit heterocyclic radical, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxycarbonyl, low-grade alkyl amino, the low-grade alkyl amino alkyl, phenyl amino, rudimentary aralkyl, rudimentary aryl alkyl amino, the low-grade alkyl amino alkylamino, rudimentary aminoalkyl group, rudimentary aminoalkyl group amino, alkynyl of low-grade chain amino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkyl, rudimentary heterocyclic radical alkylamino, the low alkyl group heterocyclic radical, rudimentary carboxyl cycloalkyl, rudimentary carboxyalkyl amino, low-grade alkoxy alkyl amino, lower alkoxycarbonyl aminoalkyl group amino, rudimentary heterocyclic radical carbonyl, lower alkoxycarbonyl heterocyclic radical and lower alkoxycarbonyl heterocyclic radical carbonyl; Wherein aryl and heteroaryl are optionally replaced by one or more group, and described group is independently from each other halogen, low alkyl group, ketone group, aralkyl, carboxyl, low-grade alkyl amino alkylamino, alkynyl of low-grade chain amino, rudimentary heterocyclic radical alkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; Perhaps
R 2Be-CR 54R 55, R wherein 54Be phenyl, R 55It is hydroxyl;
R 4Be selected from 5-or 6-unit heteroaryl and the aryl that is selected from phenyl, xenyl and naphthyl; R wherein 4Optionally replaced by one or more group, described group is independently from each other: halogen, low alkyl group, lower alkoxy, aryloxy, rudimentary aralkoxy, low-grade halogenated alkyl, lower alkylthio, low-grade alkyl amino, nitro, hydroxyl;
R 5Be selected from halogen, amino, cyano group, aminocarboxyl, low alkyl group, lower alkoxy, hydroxyl, rudimentary aminoalkyl group, rudimentary aralkyl, rudimentary aralkoxy, rudimentary aryl alkyl amino, lower alkoxycarbonyl, low-grade alkyl amino, lower alkylcarbonyl, the lower aryl alkenyl, the lower aryl heterocyclic radical, carboxyl, low-grade cycloalkyl amino, lower alkoxycarbonyl amino, the lower alkoxy aryl alkyl amino, the low-grade alkyl amino alkylamino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkylamino, rudimentary aralkyl heterocyclic radical amino, low-grade alkyl amino carbonylic, lower alkylcarbonyl, the lower alkoxy aryl alkyl amino, diazanyl and low alkyl group diazanyl, or-NR 62R 63, R wherein 62Be lower alkylcarbonyl or amino, R 63Be low alkyl group or rudimentary phenylalkyl;
Or its pharmacologically acceptable salt or tautomer.
One group of preferred compound is by forming as shown in the formula the XI compound:
R 1Be selected from methyl, ethyl, hydroxyethyl and propargyl;
R 2Be selected from methyl, ethyl, propyl group, phenyl, trifluoromethyl, hydroxyethyl, the methoxycarbonyl ethyl, ethoxycarbonyl-ethyl, the N-methylamino, N, the N-dimethylamino, the N-ethylamino, N, the N-diethylamino, N-propyl group amino, the N-phenyl amino, amino methyl, amino-ethyl, aminoethylamino, amino propyl amino, propargyl amino, benzylamino, dimethylamino-propyl amino, morpholinyl propyl amino, the morpholinyl ethylamino, piperidyl, piperazinyl, imidazolyl, morpholinyl, pyridyl, the carboxyl methylamino, methoxy ethyl amino, (1, the 1-dimethyl) ethyl carbonyl, (1, the 1-dimethyl) ethyl carbonylamino propyl group amino, (1, the 1-dimethyl) ethyl carbonylamino ethylamino, piperazinyl carbonyl, 1,1-dimethyl ethyl piperazinyl carbonyl; Phenyl wherein, piperidyl, piperazinyl, imidazolyl, morpholinyl and pyridyl are optionally replaced by one or more group, described group is independently from each other: fluorine, chlorine, bromine, ketone group, methyl, ethyl, trifluoromethyl, benzyl, methoxyl group, methoxycarbonyl, ethoxycarbonyl and (1, the 1-dimethyl) ethoxycarbonyl;
R 4Be selected from phenyl, quinolyl, xenyl, pyridyl, thienyl, furyl, dihydro pyranyl, benzofuryl, dihydro benzo furyl and benzodioxole base; R wherein 4Optionally replaced by one or more group, described group is independently from each other methylthio group, fluorine, chlorine, bromine, methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxyl;
R 5Be selected from fluorine; chlorine; bromine; methyl; the fluorophenyl ethyl; the fluorophenyl vinyl; the fluorophenyl pyrazolyl; cyano group; methoxycarbonyl; aminocarboxyl; ethanoyl; hydroxyl; carboxyl; methoxyl group; methylamino; dimethylamino; 2-methyl butyl amino; ethylamino; dimethylaminoethyl amino; hydroxypropyl amino; hydroxyethyl amino; imidazolyl amino; the morpholinyl ethylamino; (1-ethyl-2-hydroxyl) ethylamino; piperidyl amino; pyridylmethyl amino; the phenyl methyl piperidyl amino; amino methyl; cyclopropyl amino; amino; hydroxyl; the methyl carbonyl; ethoxycarbonyl amino; the p-methoxy-phenyl methylamino; phenyl methyl amino; fluorophenyl methyl amino; the fluorophenyl ethylamino; the methylamino carbonyl; the methyl carbonyl; diazanyl and 1-methyl diazanyl, or-NR 62R 63, R wherein 62Be methyl carbonyl or amino, R 63Be methyl or benzyl;
Or its pharmacologically acceptable salt or tautomer.
One group of preferred compound is by forming as shown in the formula the IX compound, wherein
Z represents carbon atom or nitrogen-atoms;
R 1Be selected from hydrogen, low alkyl group, rudimentary hydroxyalkyl, alkynyl of low-grade chain, rudimentary aminoalkyl group and low-grade alkyl amino alkyl;
R 2Be selected from hydrogen, low alkyl group, be selected from phenyl, the aryl of xenyl and naphthyl, be selected from piperidyl, piperazinyl, imidazolyl, the 5-of pyridyl and morpholinyl or 6-unit heterocyclic radical, low-grade halogenated alkyl, rudimentary hydroxyalkyl, lower alkoxycarbonyl, low-grade alkyl amino, the low-grade alkyl amino alkyl, phenyl amino, rudimentary aralkyl, rudimentary aryl alkyl amino, the low-grade alkyl amino alkylamino, rudimentary aminoalkyl group, rudimentary aminoalkyl group amino, alkynyl of low-grade chain amino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkyl, rudimentary heterocyclic radical alkylamino, the low alkyl group heterocyclic radical, rudimentary carboxyl cycloalkyl, rudimentary carboxyalkyl amino, low-grade alkoxy alkyl amino, lower alkoxycarbonyl aminoalkyl group amino, rudimentary heterocyclic radical carbonyl, lower alkoxycarbonyl heterocyclic radical and lower alkoxycarbonyl heterocyclic radical carbonyl; Wherein aryl and heteroaryl are optionally replaced by one or more group, and described group is independently from each other halogen, low alkyl group, ketone group, aralkyl, carboxyl, low-grade alkyl amino alkylamino, alkynyl of low-grade chain amino, rudimentary heterocyclic radical alkylamino, lower alkylcarbonyl and lower alkoxycarbonyl; Perhaps
R 2Be-CR 54R 65, R wherein 54Be phenyl, R 55It is hydroxyl;
R 4It is phenyl, this phenyl is optionally replaced by one or more group, and described group is independently from each other: halogen, low alkyl group, lower alkoxy, aryloxy, rudimentary aralkoxy, low-grade halogenated alkyl, lower alkylthio, low-grade alkyl amino, nitro, hydroxyl;
R 5Be selected from halogen, amino, cyano group, aminocarboxyl, low alkyl group, lower alkoxy, hydroxyl, rudimentary aminoalkyl group, rudimentary aralkyl, rudimentary aralkoxy, rudimentary aryl alkyl amino, lower alkoxycarbonyl, low-grade alkyl amino, lower alkylcarbonyl, the lower aryl alkenyl, the lower aryl heterocyclic radical, carboxyl, low-grade cycloalkyl amino, lower alkoxycarbonyl amino, the lower alkoxy aryl alkyl amino, the low-grade alkyl amino alkylamino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkylamino, rudimentary aralkyl heterocyclic radical amino, low-grade alkyl amino carbonylic, lower alkylcarbonyl, the lower alkoxy aryl alkyl amino, diazanyl and low alkyl group diazanyl, or-NR 62R 63, R wherein 62Be lower alkylcarbonyl or amino, R 63Be low alkyl group or rudimentary phenylalkyl;
Or its pharmacologically acceptable salt or tautomer.
One group of particularly preferred compound is made up of the compound as shown in the formula IX, wherein:
R 1Be selected from hydrogen, methyl, ethyl, hydroxyethyl and propargyl;
R 2Be selected from methyl, ethyl, propyl group, phenyl, trifluoromethyl, hydroxyethyl, the methoxycarbonyl ethyl, ethoxycarbonyl-ethyl, the N-methylamino, N, the N-dimethylamino, the N-ethylamino, N, the N-diethylamino, N-propyl group amino, the N-phenyl amino, amino methyl, amino-ethyl, aminoethylamino, amino propyl amino, propargyl amino, benzylamino, N-dimethylamino-propyl amino, morpholinyl propyl amino, the morpholinyl ethylamino, piperidyl, piperazinyl, imidazolyl, morpholinyl, pyridyl, carboxymethylamino, methoxy ethyl amino, (1, the 1-dimethyl) ethyl carbonyl, (1, the 1-dimethyl) ethyl carbonylamino propyl group amino, (1, the 1-dimethyl) ethyl carbonylamino ethylamino, piperazinyl carbonyl, 1,1-dimethyl ethyl piperazinyl carbonyl; Phenyl wherein, piperidyl, piperazinyl, imidazolyl, morpholinyl and pyridyl are optionally replaced by one or more group, described group is independently from each other: fluorine, chlorine, bromine, ketone group, methyl, ethyl, trifluoromethyl, benzyl, methoxyl group, methoxycarbonyl, ethoxycarbonyl and (1, the 1-dimethyl) ethoxycarbonyl;
R 4It is phenyl, this phenyl is optionally replaced by one or more group, and described group is independently from each other: methylthio group, fluorine, chlorine, bromine, methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxyl;
R 5Be selected from fluorine; chlorine; bromine; methyl; the fluorophenyl ethyl; the fluorophenyl vinyl; the fluorophenyl pyrazolyl; cyano group; methoxycarbonyl; aminocarboxyl; ethanoyl; hydroxyl; carboxyl; methoxyl group; methylamino; dimethylamino; 2-methyl butyl amino; ethylamino; dimethylaminoethyl amino; hydroxypropyl amino; hydroxyethyl amino; imidazolyl amino; the morpholinyl ethylamino; (1-ethyl-2-hydroxyl) ethylamino; piperidyl amino; pyridylmethyl amino; the phenyl methyl piperidyl amino; amino methyl; cyclopropyl amino; amino; hydroxyl; the methyl carbonyl; ethoxycarbonyl amino; the p-methoxy-phenyl methylamino; phenyl methyl amino; fluorophenyl methyl amino; the fluorophenyl ethylamino; the methylamino carbonyl; the methyl carbonyl; diazanyl and 1-methyl diazanyl, or-NR 62R 63, R wherein 62Be methyl carbonyl or amino, R 63Be methyl or benzyl;
Or its pharmacologically acceptable salt or tautomer.
Another is organized particularly preferred compound and is made up of the compound as shown in the formula IX, wherein:
Z represents carbon atom or nitrogen-atoms;
R 1Be selected from hydrogen, low alkyl group, rudimentary hydroxyalkyl and alkynyl of low-grade chain;
R 2Be selected from hydrogen and low alkyl group;
R 4Be selected from phenyl and benzodioxole base; Phenyl is wherein optionally replaced by one or more halogen group;
R 5Be selected from hydrogen, halogen and alkyl diazanyl;
Or its pharmacologically acceptable salt or tautomer.
Another group of particularly preferred compound is by forming as shown in the formula the IX compound, wherein:
Z represents carbon atom;
R 1Be selected from hydrogen, methyl, hydroxyethyl, propargyl;
R 2Be hydrogen;
R 4Be selected from phenyl and benzodioxole base; Phenyl is wherein optionally replaced by one or more group, and described group is independently from each other chlorine, fluorine and bromine;
R 5Be selected from hydrogen, fluorine and 1-methyl diazanyl;
Or its pharmacologically acceptable salt or its tautomer.
One group of particularly preferred compound is made up of the compound as shown in the formula IX, wherein:
Z represents carbon atom;
R 1Be selected from hydrogen and methyl;
R 2Be hydrogen; With
R 4Be selected from phenyl, this phenyl is optionally replaced by one or more group, and described group is independently from each other: chlorine, fluorine and bromine;
R 6Be selected from hydrogen and fluorine;
Or its pharmacologically acceptable salt or tautomer.
Term " hydrogen " is meant one hydrogen atom (H).This hydrogen group for example can be connected and form hydroxyl on the Sauerstoffatom, and perhaps two hydrogen groups can be connected and form methylene radical (CH on the carbon atom 2-).Term " alkyl "; no matter be independent use; still be used for other term as " haloalkyl ", " alkyl sulphonyl ", " alkoxyalkyl " and " hydroxyalkyl ", " cyano group alkyl " and " mercaptoalkyl ", include and contain 1 to about 20 or preferred 1 straight or branched group to about 12 carbon atoms.More preferably alkyl is to contain 1 " low alkyl group " to about 10 carbon atoms.First-selection contains 1 low alkyl group to about 6 carbon atoms.The example of described group comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, hexyl etc.Term " alkenyl " comprise contain at least one carbon-to-carbon double bond 2 to about 20 carbon atoms, preferred 2 straight or branched groups to about 12 carbon atoms.More preferably alkenyl is to contain 2 " low-grade alkenyls " to about 6 carbon atoms.The example of alkenyl comprises vinyl, allyl group, propenyl, butenyl and 4-methyl butene base.Term " alkenyl " and " low-grade alkenyl " comprise having " cis " and " trans " orientation, or are called the group of " E " and " Z " orientation.Term " alkynyl group " comprise contain at least one carbon-to-carbon three key 2 to about 20 carbon atoms, preferred 2 straight or branched groups to about 12 carbon atoms.More preferably alkynyl group is to contain 2 " alkynyl of low-grade chain " to about 6 carbon atoms.The example of alkynyl group comprises propargyl, 1-proyl, 2-propynyl, ethyl acetylene base, 2-butyne base and 1-pentynyl.Term " cycloalkyl " comprises and contains the 3 saturated carbon ring groups to about 12 carbon atoms.Term " cycloalkyl " comprises and contains the 3 saturated carbon ring groups to about 12 carbon atoms.Preferred cycloalkyl is to contain 3 " low-grade cycloalkyls " to about 8 carbon atoms.The example of described group comprises cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.Term " cycloalkyl alkylidene group " comprises the alkyl that is substituted by cycloalkyl.Preferred cycloalkyl alkylidene group is " the cycloalkyl alkylidene group " that contains the low alkyl group that is replaced by low-grade cycloalkyl defined above.The example of described group comprises cyclopropyl methyl, cyclobutylmethyl, cyclopentyl-methyl and cyclohexyl methyl.Term " cycloalkenyl group " comprises the undersaturated carbon ring group of the part that contains 3-12 carbon atom.The undersaturated carbon ring group of part that contains two two keys (can be conjugated also can be not conjugated) can be called " cycloalkyl dialkylene ".Preferred cycloalkenyl group is to contain 4 " lower alkenyl rings " to about 8 carbon atoms.The example of described group comprises cyclobutene base, cyclopentenyl and cyclohexenyl.Term " halogen " is meant fluorine, chlorine, bromine or iodine etc.Term " haloalkyl " comprises the group that wherein any one or a plurality of alkyl carbon atoms are replaced by the halogen of above definition.Specifically, comprise single haloalkyl, dihalo alkyl and multi-haloalkyl.For example, single haloalkyl can contain in iodine, bromine, chlorine or the fluorine atom any one at group.Dihalo can contain the two or more identical halogen atoms or the combination of different halogen atoms with multi-haloalkyl." low-grade halogenated alkyl " comprises the group that contains 1-6 carbon atom.The example of haloalkyl comprises methyl fluoride, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, trichloromethyl, pentafluoroethyl group, seven fluoropropyls, difluoro chloromethyl, dichlorofluoromethyl, two fluoro ethyls, two fluoropropyls, Dichloroethyl and two chloropropyls.Term " hydroxyalkyl " comprises and contains the 1 straight or branched alkyl to about 10 carbon atoms that any one in the described carbon atom all can be replaced by one or more hydroxyl.Preferred hydroxyalkyl is " the rudimentary hydroxyalkyl " that contains 1-6 carbon atom and one or more hydroxyls.The example of described group comprises hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl and hydroxyl hexyl.Term " alkoxyl group " and " alkyl oxy " comprise the oxy radical of straight or branched, contain 1 moieties to about 10 carbon atoms in this group.Preferred alkoxyl group is " lower alkoxy " that contains 1-6 carbon atom.The example of described group comprises methoxyl group, oxyethyl group, propoxy-, butoxy and tert.-butoxy.Term " alkoxyalkyl " comprises the alkyl group that contains one or more alkoxyl groups that are connected with alkyl, promptly forms monoalkoxy alkyl and dialkoxy alkyl." alkoxyl group " can also be replaced by one or more halogen atoms such as fluorine, chlorine or bromine, forms halogenated alkoxy.Term " aryl ", no matter separately use still is used in combination, and all refers to contain one, the carbocyclic aromatic system of two or three rings, and wherein, described ring can link together in the mode that hangs, and also can be condensed.Term " aryl " comprises aromatic groups such as phenyl, naphthyl, tetralyl, indane and xenyl.Aryl moiety can also be able to replaced by one or more substituting group substituted position, and described substituting group is independently from each other halogen; alkyl; alkenyl; alkynyl group; aryl; heterocyclic radical; alkylthio; arylthio; the alkylthio alkylidene group; the arylthio alkylidene group; alkyl sulphinyl; the alkyl sulphinyl alkylidene group; the aryl sulfonyl kia alkylidene group; alkyl sulphonyl; the alkyl sulphonyl alkylidene group; the aryl sulfonyl alkylidene group; alkoxyl group; aryloxy; aralkoxy; aminocarboxyl; alkyl amino-carbonyl; aromatic yl aminocarbonyl; carbalkoxy; aryloxy carbonyl; haloalkyl; amino; cyano group; nitro; alkylamino; arylamino; alkylamino alkylene; the arylamino alkylidene group; aminoalkyl group amino; hydroxyl; alkoxyalkyl; carboxyalkyl; alkoxycarbonyl alkyl; the aminocarboxyl alkylidene group; acyl group; carboxyl and aralkoxycarbonyl.That term " heterocyclic radical " comprises is saturated, part is undersaturated and undersaturatedly contain heteroatomic cyclic group, also can correspondingly be referred to as " Heterocyclylalkyl ", " heterocycloalkenyl " and " heteroaryl ", and heteroatoms wherein can be selected from nitrogen, sulphur and oxygen.The example of saturated heterocyclic group comprises the first monocyclic heterocycles group (for example pyrrolidyl, imidazolidyl, piperidino-(1-position only), piperazinyl etc.) of the saturated 3-6 that contains 1-4 nitrogen-atoms; The saturated 3-6 unit monocyclic heterocycles group (for example morpholinyl etc.) that contains 1-2 Sauerstoffatom and 1-3 nitrogen-atoms; The first monocyclic heterocycles group (for example thiazolidyl) of saturated 3-6 that contains 1-2 sulphur atom and 1-3 nitrogen-atoms.The example of the undersaturated heterocyclic group of part comprises dihydro-thiophene, dihydropyrane, dihydrofuran and thiazoline.Heterocyclic group can contain the nitrogen of 5 valencys, for example tetrazolium and pyridine group.Term " heteroaryl " comprises undersaturated heterocyclic group.The example of heteroaryl comprises the first monocyclic heterocycles group of the unsaturated 3-6 that contains 1-4 nitrogen-atoms, for example pyrryl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, (4H-1 for example, 2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl etc.), tetrazyl (for example 1H-tetrazyl, 2H-tetrazyl etc.) etc.; The unsaturated annelated heterocycles group that contains 1-5 nitrogen-atoms, for example indyl, pseudoindoyl, indolizine base, benzimidazolyl-, quinolyl, isoquinolyl, indazolyl, benzotriazole base, tetrazolo pyridazinyl (for example tetrazolo [1,5-b] pyridazinyl etc.) etc.; The first monocyclic heterocycles group of unsaturated 3-6 that contains a Sauerstoffatom, for example pyranyl, furyl etc.; The unsaturated 3-6 unit monocyclic heterocycles group that contains a sulphur atom, for example thienyl etc.; The unsaturated 3-6 monocyclic heterocycles group that contains 1-2 Sauerstoffatom and 1-3 nitrogen-atoms, Li such as oxazolyl, isoxazolyl, oxadiazole base (for example 1,2,4-oxadiazole base, 1,3,4-oxadiazole base, 1,2,5-oxadiazole base etc.) etc.; The unsaturated annelated heterocycles group (for example benzoxazolyl, Ben Bing oxadiazole base etc.) that contains 1-2 Sauerstoffatom and 1-3 nitrogen-atoms; The unsaturated 3-6 unit monocyclic heterocycles group that contains 1-2 sulphur atom and 1-3 nitrogen-atoms, for example thiazolyl, thiadiazolyl group (for example 1,2,4-thiadiazolyl group, 1,3,4-thiadiazolyl group, 1,2,5-thiadiazolyl group etc.) etc.; Contain the unsaturated annelated heterocycles group (for example benzothiazolyl, diazosulfide base etc.) of the nitrogen-atoms of 1-2 sulphur atom and 1-3 etc.Term " heterocycle " also comprises wherein heterocyclic group and aryl or group of naphthene base condensed group.The example of described fused bicyclic group comprises cumarone, thionaphthene etc.Described " heterocyclic radical " can have 1-3 substituting group, for example alkyl, hydroxyl, halogen, alkoxyl group, oxo, amino, alkylthio and alkylamino.Term " heterocyclic radical alkylidene group " comprises the alkyl group that heterocyclic radical replaces.More preferably the heterocyclic radical alkylidene group is " the rudimentary heterocyclic radical alkylidene group " that contains a 1-6 carbon atom and a heterocyclic group.Term " alkylthio " comprises and contains 1 group to the straight or branched alkyl of about 10 carbon atoms that is connected with bivalent sulfur atom.Preferred alkylthio is " lower alkylthio " that contains the alkyl of 1-6 carbon atom.The example of lower alkylthio is methylthio group, ethylmercapto group, rosickyite base, butylthio and own sulfenyl.Term " alkylthio alkylidene group " comprises and contains one by the group of bivalent sulfur atom with 1 alkylthio that is connected to the alkyl of about 10 carbon atoms.Preferred alkylthio alkylidene group is " the lower alkylthio alkylidene group " that contains the alkyl of 1-6 carbon atom.The example of described lower alkylthio alkylidene group comprises methylthiomethyl.Term " alkyl sulphinyl " comprise contain with divalence-S (=O)-1 group that group is connected to the straight or branched alkyl of about 10 carbon atoms.Preferred alkyl sulphinyl is " the low alkyl group sulfinyl " that contains the alkyl of 1-6 carbon atom.The example of described low alkyl group sulfinyl comprises methylsulfinyl, ethyl sulfinyl, butyl sulfinyl and hexyl sulfinyl.Term " alkylsulfonyl ", no matter be use separately or with other term as " alkyl sulphonyl ", " halosulfonyl groups " coupling, all be meant divalent group-SO 2-." alkyl sulphonyl " comprises the alkyl that is connected with alkylsulfonyl, and alkyl wherein as defined above.Preferred alkyl sulphonyl is " the low alkyl group alkylsulfonyl " that contains 1-6 carbon atom.The example of described low alkyl group alkylsulfonyl comprises methyl sulphonyl, ethylsulfonyl and sulfonyl propyl base." alkyl sulphonyl " can also be replaced by one or more halogen atoms such as fluorine, chlorine or bromine, forms halogenated alkyl sulfonyl.Term " halosulfonyl groups " comprises the halogen group that is connected with alkylsulfonyl.The example of described halosulfonyl groups comprises chlorosulfonyl and bromine alkylsulfonyl.Term " sulfamyl ", " amino-sulfonyl " and " sulfonamido " are meant NH 2O 2S-.Term " acyl group " is meant from the group that forms after organic acid is removed hydroxyl.The example of described acyl group comprises alkanoyl and aroyl.The example of described alkanoyl comprises formyl radical, ethanoyl, propionyl, butyryl radicals, isobutyryl, pentanoyl, isovaleryl, valeryl, caproyl, and the group that forms from succsinic acid, oxyacetic acid, glyconic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, glucuronic acid, toxilic acid, fumaric acid, pyruvic acid, amygdalic acid, pantothenic acid, beta-hydroxy-butanoic acid, tetrahydroxyadipic acid and galacturonic acid.No matter term " carbonyl " is to use separately or share as " carbalkoxy " with other term, all refer to-(C=O)-.No matter term " carboxyl " is to use separately or share as " carboxyalkyl " with other term, all refers to-CO 2H.Term " carboxyalkyl " comprises by the alkyl of carboxyl substituted.More preferably contain " the rudimentary carboxyalkyl " of low alkyl group defined above, and can on alkyl, be replaced by halogen.The example of described rudimentary carboxyalkyl comprises carboxymethyl, propyloic and carboxylic propyl group.Term " carbalkoxy " is meant the group that contains the alkoxyl group defined above that is connected with carbonyl by Sauerstoffatom.More preferably moieties contain 1-6 carbon atom " lower alkoxycarbonyl ".The example of described lower alkoxycarbonyl (ester) group comprises and replacing or unsubstituted methoxycarbonyl, ethoxycarbonyl, the third oxygen carbonyl, butoxy carbonyl and own oxygen carbonyl.Term " alkoxycarbonyl alkyl " comprises the alkyl that is replaced by the carbalkoxy of above definition.More preferably moieties contains 1-6 carbon atom " lower alkoxycarbonyl alkyl ".The example of described lower alkoxycarbonyl alkyl comprises and replacing or unsubstituted methoxycarbonyl methyl, ethoxycarbonylmethyl group, methoxycarbonyl ethyl and ethoxycarbonyl-ethyl.Term " alkyl-carbonyl " comprises and contains the alkyl defined herein that is connected with carbonyl, the group of hydroxyalkyl.The example of described group comprises and replacing or unsubstituted methyl carbonyl, ethyl carbonyl, propyl group carbonyl, butyl carbonyl, amyl group carbonyl, hydroxymethyl carbonyl, hydroxyethyl carbonyl.Term " aralkyl " comprises the alkyl that aryl replaces, for example benzyl, diphenyl methyl, trityl group, phenylethyl and diphenyl-ethyl.Aryl in the described aralkyl can also be replaced by one or more substituting group, and described substituting group is independently from each other halogen, alkyl, alkoxyl group, haloalkyl, halogenated alkoxy, amino and nitro.Term benzyl and phenyl methyl can exchange.Term " heterocyclic radical alkylidene group " comprises the alkyl (also can correspondingly be called Heterocyclylalkyl alkylidene group and heterocycloalkenyl alkylidene group) that the undersaturated heterocyclic group of saturated and part replaces, for example pyrrolidyl methyl; The alkyl (also can be called the heteroaryl alkylidene group) that heteroaryl replaces, for example pyridylmethyl, quinolyl methyl, thienyl methyl, furyl ethyl and quinolyl ethyl.Heteroaryl in the described heteroaralkyl can also be replaced by halogen, alkyl, alkoxyl group, haloalkyl and halogenated alkoxy.Term " aryloxy " comprises the aryl that is connected with other group by Sauerstoffatom.Term " aralkoxy " comprises the aralkyl that is connected with other group by Sauerstoffatom.Term " aminoalkyl group " comprises the alkyl that is replaced by amino.More preferably " rudimentary aminoalkyl group ".The example of described group comprises amino methyl, amino-ethyl etc.Term " alkylamino " refers to the amino that replaced by one or two alkyl.Preferred alkyl partly contains 1-6 carbon atom " low-grade alkyl amino ".Suitable low-grade alkyl amino can be mono-substituted N-alkylamino or dibasic N, N-alkylamino, for example N-methylamino, N-ethylamino, N, N-dimethylamino, N, N-diethylamino etc.Term " arylamino " refers to the amino that replaced by one or two aryl, for example N-phenyl amino." arylamino " can also partly be substituted at the aromatic ring of group.Term " aminocarboxyl " refers to formula-C (=O) NH 2Amide group.Term " alkyl amino-carbonyl " refers to the aminocarboxyl that replaced by one or two alkyl on amino nitrogen atom.Preferably " N-alkyl amino-carbonyl " and " N, N-dialkyl amino carbonyl "." the rudimentary N-alkyl amino-carbonyl " and " rudimentary N, N-dialkyl amino carbonyl " that more preferably contains the low alkyl group part of above definition.Term " alkyl-carbonyl-amino " comprises the amino that is replaced by an alkyl-carbonyl.Preferred alkyl-carbonyl-amino is to contain lower alkylcarbonyl defined above to be connected " lower alkylcarbonyl amino " on the amino.Term " alkylamino alkylene " is included in the group that is connected with one or more alkyl on the aminoalkyl group.
" hydrocarbon " as herein described part is organic compound or the group of only being made up of carbon and protium.These groups comprise alkyl, alkenyl, alkynyl group and aryl.These groups also comprise by alkyl, alkenyl, alkynyl group and the aryl of other aliphatic series or cyclic hydrocarbon group replacement, for example alkaryl, alkenyl aryl and alkynyl group aryl.Preferred these groups contain 1-20 carbon atom.
Heteroatoms substituted hydrocarbon radical as herein described is meant the hydrocarbyl portion that is replaced by other atom beyond at least one de-carbon, comprises the group that carbochain atom is wherein replaced by heteroatoms such as nitrogen, oxygen, sulphur or halogen atom.These substituting groups comprise lower alkoxy such as methoxyl group, oxyethyl group, butoxy; Halogen such as chlorine or fluorine; Ether; Acetal; Ketal; Ester; Heterocyclic group such as furyl or thienyl; Alkoxyl group; Hydroxyl; The hydroxyl of having protected; Acyl group; Acyloxy; Nitro; Cyano group; Amino and amido.
Other term that is used to describe the substituting group of pyrazoles ring but specifically defines in the text can define according to the mode identical with above definition.As mentioned above, more preferred substituents is the substituting group that contains " rudimentary " group.Unless otherwise defined, used term " rudimentary " is meant that each alkyl group of the pyrazoles ring substituents that contains one or more alkyl groups contains 1 to about 6 carbon atoms among the application; Each kiki alkenyl group that contains the pyrazoles ring substituents of one or more kiki alkenyl groups contains 2 to about 6 carbon atoms; Each the alkynyl group group that contains the pyrazoles ring substituents of one or more alkynyl group groups contains 2 to about 6 carbon atoms; Each cycloalkyl or the cycloalkenyl groups that contain the pyrazoles ring substituents of one or more cycloalkyl and/or cycloalkenyl group are respectively 3-8 unit's cycloalkyl or cycloalkenyl groups; Each aromatic yl group that contains the pyrazoles ring substituents of one or more aryl is a monocyclic aryl; Each heterocyclic group that contains the pyrazoles ring substituents of one or more heterocyclic groups is the heterocyclic group of 4-8 unit ring.
The present invention includes the tautomeric forms of formula I and IX compound.As described below, the pyrazole compound of formula I and I ' is equal on magnetic and structure owing to the proton tautomerism character of hydrogen.
Figure A9880736901421
The present invention also comprises the compound of formula I, the IX, X and the XI that contain one or more asymmetric carbons.It will be understood by those skilled in the art that the pyrazole compound of the present invention that has unsymmetrical carbon can exist with diastereomer, racemize or optically active form.So these forms include within the scope of the invention.More particularly, the present invention includes enantiomorph, diastereomer, racemic mixture and other mixture.
The present invention includes kinase mediated disease, inflammation and/or the arthritic pharmaceutical composition of disease, p38 that is used for the treatment of TNF mediation, said composition contains the formula I compound for the treatment of significant quantity or it treats acceptable salt or tautomer and at least a pharmaceutically acceptable carrier, assistant agent or thinner.
The present invention also comprises the pyrazole compound that can replace with the kinase whose ATP-binding site specificity of p38 bonded.Be not bound by any particular theory, the applicant infers that the pyrazole compound of these replacements can be in the following manner and the p38 kinase interactions.Because therefore the substituting group on the pyrazoles ring 3-position can form the hydrophobicity chamber near the kinase whose ATP-binding site of p38 in the p38 kinases around the 3-of binding site bit substituent.It is believed that this hydrophobicity chamber forms when the 3-bit substituent combines with the particular peptide sequence of enzyme.Specifically, be the Lys that is combined in p38 kinases ATP-binding site 52, Glu 69, Leu 73, Ile 82, Leu 84, Leu 101Side chain and Thr 103On the methyl of side chain (method of counting wherein is used for the method for counting of ERK-2 corresponding to routine).When the 3-bit substituent was aryl or heteroaryl, described aryl or heteroaryl can also be substituted.Infer that described ring substituents has hydroxylation or the further metabolism that is beneficial to the prevention ring.
Substituting group on the pyrazoles ring 4-position is the partial simulation thing of ATP VITAMIN B4 ring, although this substituting group might be further processed.It is the planar substituting group of end with suitable hydrogen bond receptor functional group that preferred this substituting group is one.Infer this receptor hydrogen can with Met 106The main chain N-H combination of residue, and this substituent one side contacts with body solvent (bulk solvent).
Replace in the 5-position of pyrazoles ring to have good tolerability and can make and render a service and the selectivity increase.Infer that this substituting group can stretch out along the direction of body solvent, and the suitable polar functionalities base of its end can with Asp 109Side chain interact, cause rendeing a service and optionally increasing.
Equally, on pyrazoles ring 1-or 2-position nitrogen-atoms, replace also to have good tolerability and can make and render a service to increase.Infer that the hydrogen substituting group that is connected on one of them theheterocyclic nitrogen atom is and Asp 165Bonded hydrogen.Nitrogen-atoms on the preferred 2-position and the carbon atom on the pyrazoles 3-position close with two bonds, and the nitrogen-atoms on the pyrazoles 1-position can be replaced by hydrogen or other substituting group.
Can replace the 5-bit substituent of pyrazoles and 1-or 2-bit substituent are selected to improve the physical properties of the pyrazole compound that replaces, particularly water-soluble and drug release characteristics.But preferably these substituent molecular weight all are lower than about 360 atomic mass units.More preferably these substituent molecular weight all are lower than about 250 atomic mass units.Still more preferably these substituent molecular weight summations are lower than about 360 atomic mass units.
A kind of pyrazole compound of particularly preferred replacement is made up of the compound as shown in the formula XII:
Wherein
R 1Be alkyl or the heterocyclic radical that the molecular weight alkyl that is lower than about 360 atomic mass units, heteroatoms replace;
R 2Be the alkyl or the heterocyclic radical that can replace at the kinase whose described ATP-binding site bonded alkyl of p38, heteroatoms with the p38 kinases;
R 3Be the alkyl that has the hydrogen bond receptor functional group, alkyl or the heterocyclic radical that heteroatoms replaces;
R 4Be alkyl or the heterocyclic radical that the molecular weight alkyl that is lower than about 360 atomic mass units, heteroatoms replace;
Condition is to work as R 4Be to contain the phenyl ring of 2-hydroxyl substituent and work as R 1When being hydrogen, R 3It or not the 2-pyridyl; Another condition is to work as R 4When being hydrogen, R 2Be selected from aryl, heterocyclic radical, unsubstituted cycloalkyl and cycloalkenyl group; Another condition is R 4It or not the methyl sulphonyl phenyl; Or
Its pharmacologically acceptable salt or its tautomer.
The pyrazole compound of one group of particularly preferred replacement is by forming as shown in the formula the XI compound, wherein:
R 1Be alkyl or the heterocyclic radical that the molecular weight alkyl that is lower than about 360 atomic mass units, heteroatoms replace;
R 2Be alkyl or the heterocyclic radical that alkyl, heteroatoms replace, wherein said group can with the Lys on the kinase whose described ATP-binding site of p38 52, Glu 69, Leu 73, Ile 82, Leu 84, Leu 101And Thr 103When side chain combination, described group are arranged in substantially and combine on ATP-binding site with the p38 kinases in the formed hydrophobicity chamber;
R 3Be alkyl or the heterocyclic radical that the alkyl that has the hydrogen bond receptor functional group, heteroatoms replace, this hydrogen can with the kinase whose Met of p38 106Main chain N-H combination;
R 4Be alkyl or the heterocyclic radical that the molecular weight alkyl that is lower than about 360 atomic mass units, heteroatoms replace.
The present invention also is included among the patient kinase mediated disease, inflammation and/or the arthritic method of disease, p38 of treatment TNF mediation, and this method comprises, the patient who suffers from or easily suffer from described disease is treated with the formula I compound for the treatment of significant quantity:
Figure A9880736901451
Wherein
R 1Be selected from hydrogen, alkyl, cycloalkyl, alkenyl, cycloalkenyl group, alkynyl group, aryl, heterocyclic group, the cycloalkyl alkylidene group, the cycloalkenyl group alkylidene group, the heterocyclic radical alkylidene group, haloalkyl, halogenated alkenyl, the halo alkynyl group, hydroxyalkyl, the hydroxyl alkenyl, the hydroxyl alkynyl group, aralkyl, aromatic yl alkenyl, aryl alkynyl chain, the aryl-heterocyclic base, carboxyl, carboxyalkyl, alkoxyalkyl, the alkenyloxy alkyl, the chain oxy-acetylene alkyl, aryloxy alkyl, the heterocyclic oxy group alkyl, the alkoxyl group alkoxyl group, mercaptoalkyl, the alkylthio alkylidene group, alkenyl sulfo-alkylidene group, the alkylthio alkenylene, amino, aminoalkyl group, alkylamino, alkenyl amino, chain alkynyl amino, arylamino, heterocyclic radical amino, alkyl sulphinyl, the alkenyl sulfinyl, the alkynyl group sulfinyl, aryl sulfonyl kia, the heterocyclic radical sulfinyl, alkyl sulphonyl, the alkenyl alkylsulfonyl, the alkynyl group alkylsulfonyl, aryl sulfonyl, the heterocyclic radical alkylsulfonyl, alkylamino alkylene, the alkyl sulphonyl alkylidene group, acyl group, the acyl-oxygen carbonyl, the carbalkoxy alkylidene group, the aryloxy carbonyl alkylidene group, heterocycle oxygen carbonyl alkylen group, the carbalkoxy arylidene, the aryloxy carbonyl arylidene, heterocycle oxygen carbonyl arylidene, the alkyl-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the heterocyclic radical carbonyl alkylen group, the alkyl-carbonyl arylidene, the aryl carbonyl arylidene, heterocyclic radical carbonyl arylidene, alkyl-carbonyl oxygen base alkylidene group, aryl carbonyl oxygen base alkylidene group, heterocyclic radical ketonic oxygen base alkylidene group, alkyl-carbonyl oxygen base arylidene, aryl carbonyl oxygen base arylidene and heterocyclic radical ketonic oxygen base arylidene; Perhaps
R 1Structure with following formula
Figure A9880736901461
Wherein:
I is the integer of 0-9;
R 25Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group;
R 26Be selected from hydrogen, alkyl, alkenyl, alkynyl group, cycloalkyl alkylidene group, aralkyl, carbalkoxy alkylidene group and alkylamino alkyl;
R 27Be selected from alkyl, cycloalkyl, alkynyl group, aryl, heterocyclic radical, aralkyl, the cycloalkyl alkylidene group, the cycloalkenyl group alkylidene group, the cycloalkyl arylidene, the cycloalkyl ring alkyl, the heterocyclic radical alkylidene group, alkyl arylene, alkyl aralkyl, the aralkyl arylidene, alkyl heterocyclic, the alkyl heterocyclic alkylidene group, the alkyl heterocyclic arylidene, the aralkyl heterocyclic radical, the alkoxyl group alkylidene group, the alkoxyl group arylidene, the alkoxy aromatic alkyl, the alkoxyl group heterocyclic radical, alkoxyl group alkoxyl group arylidene, the aryloxy arylidene, the aralkoxy arylidene, alkoxyl group heterocyclic radical alkylidene group, aryloxy alcoxyl base arylidene, the carbalkoxy alkylidene group, the carbalkoxy heterocyclic radical, carbalkoxy heterocyclic radical carbonyl alkylen group, aminoalkyl group, alkylamino alkylene, the aromatic yl aminocarbonyl alkylidene group, alkoxy aryl aminocarboxyl alkylidene group, the aminocarboxyl alkylidene group, the aromatic yl aminocarbonyl alkylidene group, the alkyl amino-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the carbalkoxy arylidene, the aryloxy carbonyl arylidene, alkyl aryloxy carbonyl arylidene, the aryl carbonyl arylidene, alkylaryl carbonyl arylidene, carbalkoxy heterocyclic radical arylidene, the alkoxycarbonyl alkoxy arylidene, heterocyclic radical carbonylic alkyl arylidene, the alkylthio alkylidene group, the cycloalkylthio alkylidene group, the alkylthio arylidene, the aromatic alkylthio arylidene, heterocyclic radical sulfo-arylidene, the arylthio alkyl arylidene, the arlysulfonylamino alkylidene group, the alkyl sulphonyl arylidene, the alkyl amino sulfonyl arylidene; Wherein said alkyl, cycloalkyl, aryl, heterocyclic radical, aralkyl, heterocyclic radical alkylidene group, alkyl heterocyclic arylidene, alkoxyl group arylidene, aryloxy arylidene, aromatic yl aminocarbonyl alkylidene group, aryloxy carbonyl arylidene, aryl carbonyl arylidene, alkylthio arylidene, heterocyclic radical sulfo-arylidene, arylthio alkyl arylidene and alkyl sulphonyl arylidene are optionally replaced by one or more group, and described group is independently from each other: alkyl, halogen, haloalkyl, alkoxyl group, ketone group, amino, nitro and cyano group; Perhaps
R 27Be-CHR 28R 29, R wherein 28Be carbalkoxy, R 29Be selected from aralkyl, aralkoxy alkylidene group, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, carbalkoxy alkylidene group, alkylthio alkylidene group and aromatic alkylthio alkylidene group; Wherein said aralkyl and heterocyclic group are optionally replaced by one or more groups that are independently from each other alkyl and nitro; Or
R 26And R 27Form heterocycle together with the nitrogen-atoms that they connected, wherein said heterocycle is optionally replaced by one or more groups that are independently from each other alkyl, aryl, heterocyclic radical, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, aryloxy alkylidene group, alkoxyl group arylidene, alkyl-aryloxy alkylidene group, alkyl-carbonyl, carbalkoxy, aralkoxycarbonyl, alkylamino and alkoxycarbonyl amido; Wherein said aryl, heterocyclic radical alkylidene group and aryloxy alkylidene group are optionally replaced by one or more group, and described group is independently from each other: halogen, alkyl and alkoxyl group;
R 2Be selected from hydrogen, halogen, alkyl, alkenyl, alkynyl group, aryl, heterocyclic radical, haloalkyl, hydroxyalkyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, alkylamino, alkenyl amino, chain alkynyl amino, arylamino, heterocyclic radical amino, the heterocyclic radical alkylamino, aryl alkyl amino, aminoalkyl group, aminoaryl, aminoalkyl group amino, the arylamino alkylidene group, alkylamino alkylene, the arylamino arylidene, the alkylamino arylidene, the alkylamino alkylamino, cycloalkyl, cycloalkenyl group, alkoxyl group, the heterocyclyloxy base, alkylthio, arylthio, the heterocyclic radical sulfo-, carboxyl, carboxyalkyl, the carboxyl cycloalkyl, the carboxyl cycloalkenyl group, carboxyalkyl amino, carbalkoxy, the heterocyclic radical carbonyl, alkoxycarbonyl alkyl, the carbalkoxy heterocyclic radical, carbalkoxy heterocyclic radical carbonyl, alkoxyalkyl amino, alkoxycarbonyl amido alkylamino and heterocyclic radical alkylsulfonyl; Aryl wherein, heterocyclic radical, the heterocyclic radical alkyl, cycloalkyl and cycloalkenyl group are optionally by one or more halogens that are independently from each other, ketone group, amino, alkyl, alkenyl, alkynyl group, aryl, heterocyclic radical, aralkyl, the heterocyclic radical alkyl, the epoxy group(ing) alkyl, amino (hydroxyalkyl) carboxyl, alkoxyl group, aryloxy, aralkoxy, haloalkyl, alkylamino, chain alkynyl amino, the alkylamino alkylamino, the heterocyclic radical alkylamino, alkyl-carbonyl, carbalkoxy, alkyl sulphonyl, the group of aryl sulfonyl and aralkyl alkylsulfonyl replaces; Perhaps
R 2Structure with following formula:
Figure A9880736901481
Wherein:
J is the integer of 0-8;
M is 0 or 1;
R 30And R 31Be independently from each other hydrogen, alkyl, aryl, heterocyclic radical, aralkyl, heterocyclic radical alkylidene group, aminoalkyl group, alkylamino alkyl, aminocarboxyl alkyl, alkoxyalkyl and alkyl-carbonyl oxygen base alkyl;
R 32Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group;
R 33Be selected from hydrogen, alkyl ,-C (O) R 35,-C (O) OR 35,-SO 2R 36,-C (O) NR 37R 38With-SO 2NR 39R 40, R wherein 35, R 36, R 37, R 38, R 39And R 40Be independently from each other the hydrocarbon and the heterocyclic radical of hydrocarbon, heteroatoms replacement;
R 34Be selected from hydrogen, alkyl, aminocarboxyl, alkyl amino-carbonyl and aromatic yl aminocarbonyl; Perhaps
R 2Be-CR 41R 42, R wherein 41Be aryl, R 42It is hydroxyl;
R 3Be selected from pyridyl, pyrimidyl, quinolyl, purine radicals,
Figure A9880736901482
R wherein 43Be selected from hydrogen, alkyl, aminoalkyl group, alkoxyalkyl, alkenyloxy alkyl and aryloxy alkyl;
R wherein 3Pyridyl; pyrimidyl; quinolyl and purine radicals are optionally replaced by one or more group, and described group is independently from each other: halogen; alkyl; aralkyl; aromatic yl alkenyl; the aryl-heterocyclic base; carboxyl; carboxyalkyl; alkoxyl group; aryloxy; alkylthio; arylthio; alkyl sulphinyl; aryl sulfonyl kia; alkyl sulphonyl; aryl sulfonyl; aralkoxy; the heterocyclic radical alkoxyl group; amino; alkylamino; alkenyl amino; chain alkynyl amino; cycloalkyl amino; cycloalkenyl group amino; arylamino; heterocyclic radical amino; aminocarboxyl; cyano group; hydroxyl; hydroxyalkyl; carbalkoxy; aryloxy carbonyl; heterocycle oxygen carbonyl; alkoxycarbonyl amido; the alkoxy aromatic alkylamino; amino sulfinyl; amino-sulfonyl; the alkylamino alkylamino; hydroxyalkyl amino; aryl alkyl amino; the heterocyclic radical alkylamino; aralkyl heterocyclic radical amino; nitro; alkyl amino-carbonyl; alkyl-carbonyl-amino; halosulfonyl groups; aminoalkyl group; haloalkyl; alkyl-carbonyl; diazanyl; the alkyl diazanyl; the aryl diazanyl or-NR 44R 45, R wherein 44Be alkyl-carbonyl or amino, R 45Be alkyl or aralkyl;
R 4Be selected from hydrogen, alkyl, alkenyl, alkynyl group, cycloalkyl, cycloalkenyl group, aryl and heterocyclic radical, wherein R 4Optionally replaced by one or more group, described group is independently from each other: halogen, alkyl, alkenyl, alkynyl group, aryl, heterocyclic radical, alkylthio, arylthio, the alkylthio alkylidene group, the arylthio alkylidene group, alkyl sulphinyl, the alkyl sulphinyl alkylidene group, the aryl sulfonyl kia alkylidene group, alkyl sulphonyl, the alkyl sulphonyl alkylidene group, the aryl sulfonyl alkylidene group, alkoxyl group, aryloxy, aralkoxy, aminocarboxyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, carbalkoxy, aryloxy carbonyl, haloalkyl, amino, cyano group, nitro, alkylamino, arylamino, alkylamino alkylene, the arylamino alkylidene group, aminoalkyl group amino and hydroxyl;
Condition is to work as R 4Be to contain the phenyl ring of 2-hydroxyl substituent and work as R 1When being hydrogen, R 3It or not the 2-pyridyl; Another condition is to work as R 4When being hydrogen, R 2Be selected from aryl, heterocyclic radical, unsubstituted cycloalkyl and cycloalkenyl group; Another condition is R 4It or not the methyl sulphonyl phenyl; Perhaps
Its pharmacologically acceptable salt or its tautomer.
Formula I compound also comprises its pharmacologically acceptable salt.Term " pharmacologically acceptable salt " comprises an alkali metal salt that is used to form free acid or free alkali or the common salt of additive salt.The character of salt is unimportant, as long as it is pharmaceutically useful.The suitable pharmaceutically acceptable acid additive salt of formula I compound can be from mineral acid or organic acid preparation.The example of described mineral acid is hydrochloric acid, Hydrogen bromide, hydroiodic acid HI, nitric acid, carbonic acid, sulfuric acid and phosphoric acid.Suitable organic acid can be selected from aliphatic series, cyclic aliphatic, aromatics, araliphatic, the organic acid of the carboxylic acid of heterocyclic radical and sulfonic acid class, the example of described acid is a formic acid, acetate, propionic acid, succsinic acid, oxyacetic acid, glyconic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, xitix, glucuronic acid, toxilic acid, fumaric acid, pyruvic acid, aspartic acid, L-glutamic acid, phenylformic acid, anthranilic acid, methylsulfonic acid, stearic acid, Whitfield's ointment, P-hydroxybenzoic acid, toluylic acid, amygdalic acid, pounce on acid, methylsulfonic acid, ethyl sulfonic acid, Phenylsulfonic acid, pantothenic acid, toluenesulphonic acids, the 2-ethylenehydrinsulfonic acid, Sulphanilic Acid, the cyclohexyl thionamic acid, alginic acid, beta-hydroxy-butanoic acid, tetrahydroxyadipic acid and galacturonic acid.The suitable pharmaceutically acceptable base addition salt of formula I compound comprises metal-salt and organic salt.Preferred metal-salt includes but are not limited to the salt of suitable basic metal (Ia family) salt, alkaline-earth metal (IIa family) salt and the acceptable metal of other physiology.Described salt can be from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc preparation.Preferred organic salt can comprise Trometamol, diethylamine, N, N '-dibenzyl-ethylenediamin, chloroprocaine, choline, diethanolamine, quadrol, meglumine (N-methylglucosamine) and PROCAINE HCL, PHARMA GRADE etc. from tertiary amine and quaternary ammonium salt preparation.So these salt all can make by the acid that will suit or the compound reaction of alkali and formula I-III from the compound of corresponding formula I-III by ordinary method.General synthetic method
Compound of the present invention can prepare according to the method for following reaction scheme I-XVIII, unless otherwise indicated, and R wherein 1, R 2, R 3, R 4, R 5And Ar 1All as to be defined in the compound of following formula I, IX, X and XI.
Scheme I
Reaction scheme I has provided by two lines synthesizing pyrazole 5.With pyridylmethyl ketone 1 and aldehyde 2 in the presence of alkali such as the piperidines, in solvent such as toluene or benzene, containing or do not containing the condensation that refluxes under the condition of acetate, generate α, β-undersaturated ketone 3.In route 1, ketone 3 at first is transformed into epoxide 4, for example at room temperature, in the presence of alkali such as sodium hydroxide, handle with superoxol.With epoxide 4 usefulness hydrazines in ethanol or other The suitable solvent, be up to handle in the temperature range of backflow and generating pyrazoles 5.In route 2, with ketone 3 directly with toluene sulfonyl hydrazide in acid as the condensation that refluxes in the presence of the acetate, generation pyrazoles 5.Perhaps, can isolate intermediate tosyl group hydrazone 6, in The suitable solvent such as ethylene glycol, in 25 ℃ to 150 ℃ temperature range, handle being converted into pyrazoles 5 then with alkali such as potassium hydroxide.
Scheme II
Figure A9880736901511
Scheme II has illustrated the synthetic of pyrazoles 12 of the present invention.With pyridine derivate 7 usefulness esters 8 alkali as two (TMS) sodium amide in the presence of, in The suitable solvent such as tetrahydrofuran (THF), handle to generate ketone 9.The halogen acid salt of ketone 9 or ketone 9 is handled formation α-Lu Daitong 10 (wherein X is a halogen) with halogenating agent such as bromine, N-bromosuccinimide or N-chlorosuccinimide in The suitable solvent such as acetate, methylene dichloride, methyl alcohol or its mixture.The example of suitable halogen acid salt comprises hydrochloride and hydrobromate.Halogenated ketone 10 and thiosemicarbazide 11 (R wherein 6And R 7Can be hydrogen, low alkyl group, phenyl, heterocyclic group etc., perhaps R 6And R 7Form selectivity and contain other heteroatomic heterocycle) reaction generation pyrazoles 12.The example that is used for the suitable solvent of this reaction is ethanol and dimethyl formamide.This reaction can contain or the condition of alkali-free or acid under, carry out in the temperature range in room temperature to 100 ℃.
The thiosemicarbazide that can not buy can be prepared by the following method by those skilled in the art usually: at first suitable amine and dithiocarbonic anhydride are reacted in the presence of alkali, handle with alkylating reagent such as methyl iodide then.The dithiocarbamic acid alkyl ester that forms is handled the required thiosemicarbazide of formation with hydrazine.This method also is recorded in E.Lieber and R.C.Orlowski, organic chemistry magazine, 22 volumes, 88 pages (1957).Another kind method is that hydrazine is joined in the thiocyanic ester of suitable replacement, referring to Y.Nomoto etc., and chemicals communication, 39 volumes, 86 pages (1991).The open source literature of Lieber and Nomoto is incorporated herein this paper as a reference.
Scheme III
Figure A9880736901521
Scheme II I has described the general type method by three kinds of route synthesizing pyrazoles 19.In route 1, ketone 13 and hydrazine 14 condensations are generated the hydrazides 16 that replaces, then itself and carboxylic acid halides or acid anhydrides 17 are reacted at low temperatures generation acyl group hydrazone 18.After temperature was heated to 200 ℃, acyl group hydrazone 18 was transformed into pyrazoles 19.In route 2, the reaction by ketone 13 and hydrazides 15 directly forms acyl group hydrazone 18, and described hydrazides 15 is by at room temperature reacting hydrazine and carboxylicesters to formation.Acyl group hydrazone 18 is generated pyrazoles 19 according to above method heating.In route 3, ketone 13 usefulness hydrazides 15 are handled directly generation pyrazoles 19 under the optimal temperature of room temperature to about 200 ℃ of scopes.Perhaps, this condensation reaction can or contain in the solvent of acetate at acid solvent such as acetate and carries out.
Scheme IV
Synthetic schemes IV has described the preparation of pyrazoles 19.
Plan V
Figure A9880736901532
The X=haloalkyl, alkyl
R 1＝Me，CH 2CH 2OH
R 4=cyclopropyl, 4-pyridyl, 4-imidazolyl
Reaction scheme V has described by hydrazone dianion and carboxylicesters cyclisation being prepared the two-step synthetic method of 4-pyridyl-5-aryl pyrazole compound 33 that 3-of the present invention replaces.In step 1, the pyridylmethyl ketone 31 that replaces (according to the description preparation among the following reaction scheme IX for example) is reacted generation ketone group hydrazone 32 with hydrazine in the presence of solvent such as alcoholic acid.The example of suitable hydrazine includes but are not limited to, phenylhydrazine and to the methoxyl group phenylhydrazine.In step 2, hydrazone 32 usefulness two normal alkali are handled the generation dianion as two (TMS) sodium amide in The suitable solvent such as tetrahydrofuran (THF).This reaction can be carried out under about 0 ℃ or lower temperature.In same step, dianion and ester such as iso methyl nicotinate, the condensation of cyclopropane-carboxylic acid methyl esters are generated required pyrazole compound 33.In some cases, may need the product of this step is generated required pyrazoles with dewatering agent such as mineral acid treatment.
Plan V I
Figure A9880736901551
Reaction scheme VI has described the another kind of synthetic method at 5 unsubstituted pyrazole compounds of ring.According to this method, at first heteroaryl methane is used highly basic such as hexamethyldisilane base Lithamide or lithium diisopropylamine to handle and generated heteroaryl methyl ketone 34.The example of suitable heteroaryl methane is 4-picoline, 4-methylpyrimidine, 2,4-lutidine, 2-chloro-4-methylpyrimidine, 2-chloro-4-picoline and 2-fluoro-4-picoline.The heteroaryl lithium methide compound of formation and the benzoic ether reaction of replacement are generated ketone 34.Suitable benzoic ether is parafluorobenzoic acid methyl esters and ethyl ester and Ethoforme and methyl esters.Ketone 34 and aminomethylene reagent such as dimethyl formamide dimethylacetal or tert.-butoxy two (dimethylamino) methane reaction are converted it into the aminomethylene derivative.With the hydrazine processing ketone 35 is changed into pyrazoles 36.
Change to this synthetic route can be synthesized 1 pyrazoles 38 that contains the nitrogen of replacement that is encircling by Stereoselective.At first ketone 34 and the suitable hydrazine reaction that replaces are converted it into hydrazone 37.The example of suitable hydrazine is N-methyl hydrazine and N-(2-hydroxyethyl) hydrazine.Hydrazone 37 and aminomethylene reagent react are generated pyrazoles 38.The example of suitable aminomethylene reagent comprises dimethyl formamide dimethylacetal and tert.-butoxy two (dimethylamino) methane.
R when pyrazole compound 36 and 38 3When substituting group has leaving group such as replaceable halogen, handle with amine subsequently and generate the amino heteroaryl derivative that replaces.The example of described amine comprises benzylamine, cyclopropylamine and ammonia.Also can be with leaving group with other nucleophilic reagent such as mercaptide and alkoxide displacement.Suitable commutable R 3The example of group includes but are not limited to 2-chloropyridine base and 2-bromopyridine base.
Plan V II
Figure A9880736901571
Reaction scheme VII has described and has worked as R 2=CH 3The time, prepare the method for derivative from pyrazoles 5 (according to reaction scheme 1 preparation).Pyrazoles 5 oxidations are generated carboxylic acid 39, then its reduction is generated methylol compound, or with itself and amine NR 10R 11(R wherein 10With 11Be independently from each other, for example hydrogen, alkyl and aryl, or the nitrogen-atoms that is connected with them lumps together and forms 4-8 unit ring, and this ring optionally contains one or more other heteroatomss that are selected from oxygen, nitrogen or sulphur) coupling forms acid amides 41, then with this reduction of amide generation sulfonamide derivatives 42.
Plan V III
Reaction scheme VIII has described from the method for pyrazoles 43 synthesizing pyrazoles 44 and 45.Can be with the theheterocyclic nitrogen atom alkylation of ordinary method with pyrazoles 43.The alkali (for example sodium hydride) that pyrazoles 43 usefulness are suitable is handled, and uses alkyl halide (for example methyl iodide) to handle the mixture that generates isomer 44 and 45 then.
Scheme IX
Reaction scheme IX has illustrated the synthetic of 3-aryl of the present invention-4-pyridyl-pyrazol compound.With phenylformic acid 46 and pyridine 47 reaction generation phenylbenzyl ketone 48 in the presence of highly basic such as basic metal hexamethyldisilane yl amino thing (preferred hexamethyldisilane base sodium amide or hexamethyldisilane base Lithamide), in The suitable solvent such as tetrahydrofuran (THF).Then that phenylbenzyl ketone 48 usefulness are excessive dimethyl formamide dimethylacetal is handled and is converted it into ketone 49.Then ketone 49 and hydrazine hydrate are reacted in The suitable solvent such as ethanol and generate pyrazoles 50.In reaction scheme IX, R 12Represent one or more be independently from each other above in R4 the substituent group of defined selectivity.Preferred R 12Be hydrogen, alkyl, halogen, trifluoromethyl, methoxyl group or cyano group, or the expression methylene-dioxy.
3-aryl of the present invention-4-pyrimidyl-pyrazole compound can be according to the mode of reaction scheme IX, by the corresponding pyrimidine of pyridine 47 usefulness is replaced synthesizing.Similarly, reaction scheme X to XVIII can be used for synthetic 3-aryl-4-pyrimidyl-pyrimidine compound corresponding to the 3-aryl-4-pyrimidyl-pyrazole compound shown in these reaction scheme.
Scheme X
Figure A9880736901611
Reaction scheme X has described a kind of of reaction scheme IX and has changed form, and this scheme can be used for synthesizing the 3-aryl-4-pyridyl-pyrazol compound that is further replaced on 1 nitrogen-atoms of pyrazoles ring.If phenylbenzyl ketone 48 (IX makes according to reaction scheme) is at first changed into hydrazone 51 with the hydrazine processing, hydrazone 51 usefulness dimethyl formamide dimethylacetals are handled generated product pyrazoles 52 then.
Reaction scheme XI to XVIII has described the further modification that can carry out reaction scheme IX, has a 3-aryl-4-pyridyl-pyrazol compound of different substituents with synthetic other.
Scheme XI
Scheme XII
In reaction scheme XII, X is chlorine, fluorine or bromine; R 13Be, for example hydrogen, alkyl, phenyl, aralkyl, heteroaralkyl, amino or alkylamino; R 20Be, for example hydrogen or alkyl.
Scheme XIII
Figure A9880736901631
Scheme XIV
Figure A9880736901632
Scheme XV
Figure A9880736901641
In reaction scheme XV, n is 1,2,3,4 or 5; R 14And R 15Be independently from each other, for example hydrogen, alkyl or aryl, or the nitrogen-atoms that is connected with them lumps together and forms 4-7 unit ring, and this ring also can contain one or more other heteroatomss that are selected from oxygen, nitrogen or sulphur.
Scheme XVI
Figure A9880736901642
In reaction scheme XVI, R 16Be selected from, for example hydrogen, alkyl and phenyl.
Scheme XVII
Figure A9880736901651
In reaction scheme XVII, R 17Be selected from, for example alkyl, phenylalkyl and heterocyclic radical alkyl.
Scheme XVIII
Figure A9880736901661
Wherein the 2-position of pyridine ring can be synthetic according to the method for describing among the reaction scheme XVIII by the compound of carboxyl or carboxy derivatives replacement.Raw material pyridyl pyrazoles 67 is transformed into 2-cyano derivative 68 by the following method: at first be converted into pyridine N-oxides with oxygenant such as metachloroperbenzoic acid reaction.Pyridine N-oxides is handled with the TMS prussiate, handled generating 2-cyano compound 68 then with dimethylcarbamyl chloride.Compound 68 and hydrogen peroxide reaction in the presence of suitable alkali are converted into methane amide 69.The example of suitable alkali comprises salt of wormwood and saleratus.Methane amide 69 and dimethyl formamide dimethylacetal reacted in methyl alcohol be converted into methyl esters 70.By saponification reaction ester 70 is transformed into carboxylic acid 71.Typical saponification reaction condition comprise with alkali such as sodium hydroxide or potassium hydroxide at The suitable solvent such as ethanol or second alcohol and water or first alcohol and water or suchlike solvent reaction.Can also be by under suitable temperature, handling the acid amides 72 that ester 70 is transformed into replacement with required amine such as methylamine.Temperature variation can be from room temperature to 180 ℃.In reaction scheme XVIII, R 18And R 19Be independently from each other, for example hydrogen, alkyl and aryl, or the nitrogen-atoms that is connected with them lumps together and forms 4-8 unit ring, and this ring can also contain one or more other heteroatomss that are selected from oxygen, nitrogen or sulphur.
Following examples comprise the detailed description of formula I, IX, X and XI compounds process for production thereof.These are described in detail all within the scope of the invention, and are used for illustrating general synthetic method described above, and described general synthetic method constitutes a part of the present invention.Providing these to describe in detail only for the purpose of description, is not to want to limit scope of the present invention.If not otherwise stated, all umbers are weight part, and temperature is degree centigrade.The NMR spectrum of all compounds is all consistent with its specified structure.Under some situation, specified structure confirms by Overhauser effect (NOE) experiment.
Used following abbreviation:
HCl-hydrochloric acid
MgSO 4-sal epsom
Na 2SO 4-sodium sulfate
NaIO 4-sodium periodate
NaHSO 3-sodium bisulfite
NaOH-sodium hydroxide
KOH-potassium hydroxide
P 2O 5-Vanadium Pentoxide in FLAKES
The Me-methyl
The Et-ethyl
MeOH-methyl alcohol
EtOH-ethanol
HOAc (or AcOH)-acetate
The EtOAc-ethyl acetate
H 2O-water
H 2O 2-hydrogen peroxide
CH 2Cl 2-methylene dichloride
K 2CO 3-salt of wormwood
KMnO 4-potassium permanganate
NaHMDS-hexamethyldisilane base sodium amide
The DMF-dimethyl formamide
EDC-1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride
The HOBT-1-hydroxybenzotriazole
The mCPBA-3-chloroperoxybenzoic acid
The Ts-tosyl group
TMSCN-TMS prussiate
Me 2NCOCl-N, the N-dimethylcarbamyl chloride
SEM-Cl-2-(TMS) ethoxyl methyl chlorine
H-hour
Hr-hour
Min-minute
The THF-tetrahydrofuran (THF)
The TLC-thin-layer chromatography
DSC-differential scanning calorimetry
The b.p.-boiling point
The m.p.-fusing point
Eq-equivalent, equivalent
The RT-room temperature
Example A-1
4-[5-[3-fluoro-4-methoxyphenyl]-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine The preparation of step 1:4-(3-fluoro-4-p-methoxy-phenyl)-3-pyridyl-3-butene-2-ketone
With 4-pyridyl acetone (1.0g, 7.4mmol), the 3-fluoro-is right-methoxybenzaldehyde (1.25g, 8.1mmol), and piperidines (0.13g, toluene 1.5mmol) (50ml) solution is heated to backflow.After 18 hours, with the reactant cool to room temperature, decompression moves down desolvates.Thick product (3.0g) produces lark solid product 4-(3-fluoro-4-methoxyphenyl)-3-pyridine-3-butene-2-ketone (1.60g, 80%) through chromatography (silica gel, 65: 35 ethyl acetate/hexane) purifying. Step 2:4-[5-(3-fluoro-4-methoxyphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] preparation of pyridine
To contain 3-pyridine-4-(3-fluoro-4-p-methoxy-phenyl)-3-butene-2-ketone (step 1) (and 0.99g, add in acetic acid solution 3.65mmol) (25ml) right-toluene sulfonyl hydrazide (0.68g, 3.65mol).Reaction solution is heated to and refluxed 6 hours, and acetate is removed from reaction solution through distillation.(2 * 100ml) wash the precipitation that produces, dry (Na with methylene dichloride (150ml) dilution, water 2SO 4), filter and concentrate.Thick product (1.5g) produces lark solid product 4-[5-(3-fluoro-4-methoxyphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl through chromatography (silica gel, ethyl acetate) purifying] pyridine (213mg, 20.7%): C 16H 14N 3OF.0.1H 2O analytical calculation value: C, 67.41; H, 5.02; N, 14.74. observed value: C, 67.37; H, 4.88; N, 14.35.
Example A-2
Figure A9880736901692
4-[3-methyl-5-phenyl-1H-pyrazoles-4-yl] pyridine The preparation of step 1:4-pyridine acetone
4-pyridine acetone is according to Ippolito etc., United States Patent (USP) 4,681, the method preparation on 944. The preparation of step 2:4-phenyl-3-(4-pyridine)-3-butene-2-ketone
Use-case A-1, step 1, ((1g 7.4mmol) uses phenyl aldehyde (790mg, 7.4mmol) condensation under refluxad to step 1) to 4-pyridine acetone in the benzene that contains piperidines (50mg) (15ml).Obtain required 4-phenyl-3-(4-pyridine)-3-butene-2-ketone crystal: 101-103 ℃ of .C of fusing point (m.p.) 15H 13NO (223.28) analytical calculation value: C, 80.69; H, 5.87; N, 6.27. observed value: C, 80.59; H, 5.79; N, 6.18. Step 3:4-phenyl-3-(4-pyridyl)-3, the preparation of 4-epoxy-2-butanone
Adopt example A-1, step 2, (1.25g, (230mg, 5.6mmol) handle with 30% aqueous hydrogen peroxide solution (1ml) down by existence at sodium hydroxide for methyl alcohol 7.6mmol) (20ml) solution with 4-phenyl-3-(4-pyridyl)-3-butene-2-ketone (step 2).Thick product obtains 4-phenyl-3-(4-pyridyl)-3,4-epoxy-2-butanone (270mg, 20%) through chromatography (silica gel, 1: 1 ethyl acetate/hexane) purifying.
Step 4:4-[3-methyl-5-phenyl-1H-pyrazoles-4-yl] preparation of pyridine
Adopt example A-1, step 3, with 4-phenyl-3-(4-pyridyl)-3, ((250mg, (50mg 1.5mmol) handles reflux 4 hours to ethanol 1mmol) (15ml) solution to step 3) to 4-epoxy-2-butanone with anhydrous hydrazine.Thick product is through chromatography (silica gel, 1: 1 acetone/hexane) purifying, and product is obtained the crystalline solid of 4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine (81mg, 35%) by recrystallization in ethyl acetate and the hexane: fusing point 212-214 ℃, and C 15H 13N 3(235.29) analytical calculation value: C, 76.57; H, 5.57; N, 17.86. measured value: C, 76.49; H, 5.42; N, 17.39.
Example A-3
Figure A9880736901701
4-[5-methyl-3-(2-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine The preparation of step 1:4-(2-aminomethyl phenyl)-3-(4-pyridine)-3-butene-2-ketone
To contain 4-pyridine acetone (example A-5, step 1) (0.75g, 5.56mmol), neighbour-toluic aldehyde (0.73g, 5.56mmol) and the toluene solution (50ml) of piperidines (100mg) be heated to backflow.The water that produces in the reaction is removed by the Dean-Stark steam trap.Behind the reflux 5 hours, reaction mixture at room temperature stirred 15 hours.Mixture is condensed into orange red oiliness resistates.Rough ketone obtains 4-(2-aminomethyl phenyl)-3-(4-pyridine)-3-butene-2-ketone: C through chromatography purification 16H 15NO (237.30) analytical calculation value: C, 80.98; H, 6.37; N, 5.90. measured value: C, 80.78; H, 6.61; N, 5.85. Step 2:4-(2-aminomethyl phenyl)-3-(4-pyridine)-3, the preparation of 4-epoxy-2-butanone
((1.0g in methyl ethanol 4.2mmol) (18ml) solution, adds H to step 1) to 4-(2-aminomethyl phenyl)-3-(4-pyridine)-3-butene-2-ketone 2O 2(30% weight percent) (0.95g, 8.4mmol) and sodium hydroxide (0.18g, 4.6mmol) aqueous solution (4ml).Reaction solution at room temperature stirred 70 hours.After removing methyl ethanol, add entry (25ml) and ethyl acetate (100ml) and stirred two-phase mixture 30 minutes.Water layer is washed with ethyl acetate (100ml) after the layering.Blended organic layer Na 2SO 4Drying, filtering and concentrating obtains oil.Separate from irreducible oil by chromatography and to obtain 4-(2-aminomethyl phenyl)-3-(4-pyridine)-3,4-epoxy-2-butanone. Step 3:4-[5-methyl-3-(2-aminomethyl phenyl)-1H-pyrazoles-4-yl] preparation of pyridine
With 4-(2-aminomethyl phenyl)-3-(4-pyridine)-3,4-epoxy-2-butanone (step 2) (0.11g, 0.434mmol) and hydrazine hydrate (0.043g, ethyl hexanol solution (50ml) 0.868mmol) are heated to and refluxed 20 hours.Resistates obtains 4-[5-methyl-3-(2-aminomethyl phenyl)-1H-pyrazoles-4-yl through chromatography purification after removing solvent] pyridine: C 16H 15N 3(249.32) analytical calculation value: C, 77.08; H, 6.06; N, 16.85. measured value: C, 76.66; H, 5.91, N, 16.84.
Example A-4
4-[5-methyl-3-(4-fluorophenyl)-1H-pyrazoles-4-yl] pyridine
Method according to example A-3 replaces neighbour-toluic aldehyde with right-fluorobenzaldehyde, makes title mixture: C 15H 12N 3F+0.1H 2O:(249.32) analytical calculation value: C, 70.63; H, 4.82; N, 16.47. measured value: C, 70.63; H, 4.78; N, 16.40.
Example A-5
Figure A9880736901721
4-[5-methyl-3-(4-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine
Method (smallish modification: in step 2 according to example A-3, the preparation of intermediate epoxide was finished at 0-10 ℃ in following 1 hour, reaction solution is stopped reaction by the water separation that contains 2 normal sodium bisulfites and ethyl acetate) and replace neighbour-toluic aldehyde with right-toluic aldehyde, separate title compound: C 16H 15N 3(249.32) analytical calculation value: C, 77.08; H, 6.06; N, 16.85. measured value: C, 76.97; H, 6.09; N, 16.90.
Example A-6
4-[5-methyl-3-[4-(methyl sulfenyl) phenyl]-1H-pyrazoles-4-yl] pyridine
Replace right-toluic aldehyde according to the method for example A-5 with 4-(methyl sulfenyl) phenyl aldehyde, make title compound: C 16H 15N 3S (281.38) analytical calculation value: C, 68.30; H, 5.37; N, 14.93. measured value: C, 68.34; H, 5.09; N, 14.78.
Example A-7
Figure A9880736901723
4-[3-(4-chloro-phenyl-)-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine
Replace right-toluic aldehyde according to the method for example A-5 with right-chlorobenzaldehyde, obtain title compound.C 15H 12N 3Cl (269.77) analytical calculation value: C, 66.79; H, 4.48; N, 15.58. measured value: C, 66.43; H, 4.44; N, 15.78.
Example A-8
4-[3-methyl-5-(3-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine
According to the method for example A-5 and with between-toluic aldehyde replaces right-toluic aldehyde, obtains title compound.C 16H 15N 3+ 0.2H 2O analytical calculation value: C, 75.98; H, 6.14; N, 16.61. measured value: C, 76.06; H, 6.05; N, 16.38.
Example A-9
Figure A9880736901732
4-[5-(2, the 5-3,5-dimethylphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine
According to the method for example A-5 with 2, the 5-dimethylbenzaldehyde replaces right-toluic aldehyde, obtains title compound: C 17H 17N 3+ 0.1H 2O analytical calculation value: C, 77.01; H, 6.54; N, 15.85. measured value: C, 76.96; H, 6.81; N, 15.51.
Example A-10
4-[5-(1,3-benzo dioxole-5-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine
4-pyridine acetone (1.5g, 12mmol), piperonylaldehyde (1.6g, 10.6mmol), acetate (110mg, 1.8mmol), and piperidines (110mg 1.3mmol) is dissolved in the toluene (30ml), and reflux is 2 hours in the flask that the Dean-Stark steam trap is housed.The solution cool to room temperature adds ethyl acetate and is settled out solid, collects (1.25g) on the filtering table.(348mg 1.81mmol) heated 1 hour reaction solution reflux 1 hour to this solid sample (500mg) under 80 ℃ in acetate (5ml) with right-toluene sulfonyl hydrazide.The reaction solution cool to room temperature, solvent evaporated.Resistates is dissolved in ethyl acetate, wet chemical with 5% and washing.Dry (MgSO 4) organic layer, evaporation obtains yellow solid after filtration, and this solid grinds with methylene dichloride, obtains 4-[5-(1,3-benzo dioxole-5-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine, collect (220mg, productive rate 42%) on the filter disc.C 16H 13N 3O 2Analytical calculation value: C, 68.81; H, 4.69; N, 15.04. measured value: C, 68.02; H, 4.54; N, 14.76.MS (M+H): 280 (base peaks).
Example A-11
4-[3-methyl-5-(4-phenoxy phenyl)-1H-pyrazoles-4-yl] pyridine
4-pyridine acetone (1.5g, 12mmol), 4-phenoxy benzaldehyde (92.1g, 10.6mmol), acetate (110mg, 1.8mmol), and piperidines (110mg 1.3mmol) is dissolved in toluene (30ml), and in the flask that the Dean-Stark steam trap is housed reflux 2 hours.The solution cool to room temperature adds ethyl acetate and is settled out solid, collects on the filter disc.(348mg, the solution of the ethylene glycol that contains potassium hydroxide (77mg) 1.81mmol) heated 0.5 hour down at 110 ℃ this solid sample (223mg) with right-toluene sulfonyl hydrazide.Step process obtains 4-[3-methyl-5-(4-phenoxy phenyl)-1H-pyrazoles-4-yl with example A-10] pyridine (100mg, productive rate 66%): analytical calculation C 21H 17N 3O+0.1H 2O:C, 76.62; H, 5.27; N, 12.76. actual measurement: C, 76.37; H, 5.19; N, 12.64.MS (M+H): 328 (base peaks).
Example A-12
Figure A9880736901742
4-[5-[(1,1 '-biphenyl)-the 4-yl]-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine
Utilize method prepare example A-10,, prepare 4-[5-[(1 with 4-formic acid biphenyl replacement piperonylaldehyde, 1 '-biphenyl)-the 4-yl]-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine is white solid: MS (M+H): 312 (base peaks).
Example A-13
Figure A9880736901751
4-[3-methyl-5-[3-(phenoxy phenyl)-1H-pyrazoles-4-yl] pyridine
Utilize the method for preparing example A-10, replace piperonylaldehyde, prepare 4-[3-methyl-5-[3-(phenoxy phenyl)-1H-pyrazoles-4-yl with the 3-phenoxy benzaldehyde] the pyridine white solid.
Example A-14
Figure A9880736901752
4-[3-methyl-5-[3-(phenyl methoxyl group) phenyl]-1H-pyrazoles-4-yl] pyridine
Utilize the method for preparing example A-10, replacing piperonylaldehyde is 3-benzyloxy phenyl aldehyde, prepares 4-[3-methyl-5-[3-(phenyl methoxyl group) phenyl]-1H-pyrazoles-4-yl] pyridine white solid: MS (M+H): 342 (base peaks).
Example A-15
Figure A9880736901753
4-[3-methyl-5-[2-(phenyl methoxyl group) phenyl]-1H-pyrazoles-4-yl] pyridine
Utilize method prepare example A-10, the replacement piperonylaldehyde is a 2-benzyloxy phenyl aldehyde, prepares 4-[3-methyl-5-[2-(phenyl methoxyl group) phenyl]-1H-pyrazoles-4-yl] pyridine is white solid: MS (M+H): 342 (base peaks).
Example A-16
Figure A9880736901761
2-[3-methyl-4-(4-pyridine)-1H-pyrazoles-4-yl] phenol
Utilize the method for preparing example A-10, replacing piperonylaldehyde is the 2-hydroxy benzaldehyde, prepares 2-[3-methyl-4-(4-pyridine)-1H-pyrazoles-4-yl] phenol: MS (M+H): 252 (base peaks).
Example A-17
3-[3-methyl-4-(4-pyridine)-1H-pyrazoles-4-yl] phenol
Utilize the method for preparing example A-10, replacing piperonylaldehyde is the 3-hydroxy benzaldehyde, prepares 3-[3-methyl-4-(4-pyridine)-1H-pyrazoles-4-yl] phenol: MS (M+H): 252 (base peaks).
Example A-18
Figure A9880736901763
1-hydroxyl-4-[3-methyl-5-phenyl-1H-pyrazoles-4-yl] the pyridine lush
To 4-[3-methyl-5-phenyl-1H-pyrazoles-4-yl] pyridine (example A-2) (2.06g, CH 8.76mmol) 2Cl 2(10ml) and in the mixing solutions of MeOH (20ml), add 3-chlorine benzoper acid (57-86%) (2.65g, 8.76mmol).Reaction solution at room temperature stirred 2 hours, used K 2CO 3(25%, 15mL) stopped reaction concentrates solution.The resistates that produces is separated in EtOAc (2.0L) and H 2Between the O (500ml).Organic layer is through separating H 2O (500ml) washes MgSO 4Drying, filtering and concentrating obtain 1-hydroxyl-4-[3-methyl-5-phenyl-1H-pyrazoles-4-yl] pyridine lush (1.12g, 54.5%): MS (M+H): 252 (base peaks).
Example A-19
5-(4-fluorophenyl)-N, N-dimethyl-4-(4-pyridine)-1H-pyrazoles-3-amine The preparation of step 1:1-fluoro-4-(4 '-pyridine ethanoyl) benzene
(18.6g 0.20mol), places more than 30 minutes to add the 4-picoline that is dissolved in anhydrous THF (200ml) at 0 ℃ in the solution of two (TMS) ammonification sodium (200ml, the THF of 1.0M).Reaction mixture is 0-10 ℃ of restir 30 minutes, and (16.8g, 0.10mol), control speed makes that temperature is not higher than 15 ℃ in the solution then its adding to be dissolved in the 4-fluorine ethyl benzoate of anhydrous THF (200ml).After the adding, the yellow suspension of generation at room temperature stirred 3 hours.Add entry (600ml), (3 * 200L) extract water with ethyl acetate.The blended organic layer is washed with salt, dried over mgso, also filtration.The filtrate vacuum concentration obtains 1-fluoro-4-(4 '-pyridine ethanoyl) benzene (19.9g, 92%) oil body, solidifies through placing: fusing point: 90-91 ℃; C 13H 10FNO analytical calculation value: C, 72.55; H, 4.68; N, 6.51. measured value: C, 72.07; H, 4.66; N, 6.62. The preparation of step 2:1-fluoro-4-(4 '-pyridinium tribromide ethanoyl) benzene
To 1-fluoro-4-(4 '-pyridine ethanoyl) benzene (step 1) (10.0g, dripping bromine in acetate 0.046mol) (200ml) solution (8.2g, acetate 0.052mol) (20ml) solution.Reaction mixture at room temperature stirs and spends the night, and except that after desolvating, resistates grinds with ethyl acetate.Form yellow solid, after filtration and dry air, 1-fluoro-4-(4 '-pyridinium tribromide ethanoyl) benzene (14.5g).This compound need not purifying and can be used for next step. Step 3:5-(4-fluorophenyl)-N, the preparation of N-dimethyl-4-(4-pyridine)-1H-pyrazoles-3-amine
Be dissolved in ethanol (10ml) 1-fluoro-4-(4 '-pyridinium tribromide ethanoyl) benzene (step 2) (3.8g, 0.01mol) and 4,4-dimethylamino-3-sulphur Urea,amino-(1.2g, mixture reflux 0.01mol) 30 minutes.During serpentinous solution cooling is fallen back (100ml).Water extracts with methylene dichloride (100ml).The blended organic phase is washed with salt, dried over mgso, filtering and concentrating.The resistates that produces obtains 5-(4-fluorophenyl)-N, the faint yellow solid of N-dimethyl-4-(4-pyridine)-1H-pyrazoles-3-amine (0.3g, 11%): fusing point: 245-247 ℃ .C with chromatography (silica gel, ethyl acetate) purifying 16H 15FN 4Analytical calculation value: C, 68.07; H, 5.36; N, 19.84. measured value: C, 68.00; H, 5.37; N, 19.61.
Example A-20
Figure A9880736901781
5-(4-fluorophenyl)-N-phenyl-4-(4-pyridyl)-1H-pyrazoles-3-amine
The preparation of 5-(4-fluorophenyl)-N-phenyl-4-(4-pyridyl)-1H-pyrazoles-3-amine is an identical method of utilizing example A-19 to describe: fusing point 218-219 ℃ .C 20H 15FN 4+ 0.1H 2O analytical calculation value: C, 72.33; H, 4.61; N, 16.87. measured value: C, 72.16; H, 4.56; N, 16.77.
Example A-21
Figure A9880736901782
4-[5-(4-fluorophenyl)-3-phenyl-1H-pyrazoles-4-yl] pyridine Step 1:1-fluoro-4-(4O-pyridine ethanoyl) benzene N-benzoyl hydrazone
(1.36g, (2.15g, 0.011mol), every adding part just drips a dense HCl to benzene to add 1-fluoro-4-(4 '-pyridine ethanoyl) in THF 0.01mol) (20ml) solution to benzoyl hydrazine.Reaction mixture at room temperature stirs and spends the night.Adularescent precipitation forms, white depositions after filtration, with ether wash with dry air after obtain 1-fluoro-4-(4 '-pyridine ethanoyl) benzene N-benzoyl hydrazone (2.90g, 79%), be cis and trans (ratio 1: 9) mixture of isomers. Step 2:4-[5-(4-fluorophenyl)-3-phenyl-1H-pyrazoles-4-yl] preparation of pyridine
1-fluoro-4-(4 '-the pyridine ethanoyl) benzene N-benzoyl hydrazone (step 1) (0.50g, 1.5mmol) logical N 2In 180 ℃ of heating 15 minutes, cooling then.The solid that produces obtains 4-[5-(4-fluorophenyl)-3-phenyl-1H-pyrazoles-4-yl with chromatography purification (silica gel, 1: 1 ethyl acetate/hexane)] pyridine (0.25g, 53%) is the lark solid: fusing point: 265-267 ℃ .C 20H 14FN 3+ 0.25H 2O analytical calculation value: C, 75.10; H, 4.57; N, 13.14. measured value: C, 74.98; H, 4.49; N, 12.87.
Example A-22
4-[5-(3-tolyl)-3-(trifluoromethyl)-1H-pyrazoles-4-yl] pyridine The preparation of step 1:3-(4 '-pyridine ethanoyl) toluene
3-(4 '-pyridine ethanoyl) toluene is used and example A-19, the described identical method preparation of step 1, and productive rate is 70%. Step 2: the preparation of trifluoroacetyl hydrazine
Trifluoroacetic Acid Ethyl Ester (14.2g, 0.10mol) and hydrazine (5.54g, 0.11mol) the mixed-liquor return heating of hydrate in ethanol (25ml) is 6 hours.Remove and desolvate, the resistates of generation drying under vacuum obtains trifluoroacetyl hydrazine (12.3g, 96%), for pure oil body, leaves standstill after coagulation. Step 3:4-[5-(3-tolyl)-3-(trifluoromethyl)-1H-pyrazoles-4-yl] preparation of pyridine
3-(4 '-the pyridine ethanoyl) (2.11g, 0.01mol) (1.0g, mixture 0.01mol) leads to N to toluene with trifluoroacetyl hydrazine (step 2) 2200 ℃ of heating 15 minutes.Crude product generates 4-[5-(3-tolyl)-3-(trifluoromethyl)-1H-pyrazoles-4-yl with chromatography (silica gel, 35: 65 ethyl acetate/hexane) purifying] pyridine (0.56g) is white solid: fusing point 237-239 ℃ .C 16H 12F 3N 3Analytical calculation value: C, 63.36; H, 3.99; N, 13.85. measured value: C, 63.6; H, 4.00; N, 13.70.
Example A-23
Figure A9880736901792
4-[3-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazoles-5-yl] pyridine
With 1-fluoro-4-(4 '-pyridine ethanoyl) benzene (1.0g, 4.6mmol) and the isonicotine hydrazine (0.63g, 4.6mmol) mixture heating up in THF (25ml) is evaporated to the dissolving dried.The solid that produces is heated to 140 ℃ earlier, phase transformation occurs, further is heated to 180 ℃ and makes fusing, and solid crystal wherein comes out.Reaction solution cools off rapidly, washes with 10%HCl (50ml) dilution and with chloroform.Water is settled out brown solid with bicarbonate neutralizes.Solid is handled purifying with activated carbon (Darco) in the MeOH that boils (100ml), filter also to concentrate, and obtains 4-[3-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazoles-5-yl] pyridine is the glossy brown solid: 304 ℃ of fusing points (DSC).Quality (MH +) 137 (100%).C 19H 13N 4F1/4H 2O analytical calculation value: C, 71.13; H, 4.24; N, 17.46. measured value: C, 70.88; H, 3.87; N, 17.38.
Example A-24
The 4-[5-cyclohexyl)-and 3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine The preparation of step 1:4-cyclohexyl-3 pyridines-3-butene-2-ketone
4-cyclohexyl-3 pyridines-3-butene-2-ketone is according to example A-1, the preparation of the method for step 1, with the 3-fluoro-right-methoxybenzaldehyde replaces with the hexanaphthene oxoethanoic acid. Step 2:4-[5-cyclohexyl)-and 3-methyl isophthalic acid H-pyrazoles-4-yl] preparation of pyridine
4-(5-cyclohexyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine is according to example A-1, and the preparation of the method for step 2 replaces with 4-cyclohexyl-3 pyridyl-3-butene-2-ketone (step 1): C with 4-(3-fluoro-4-methoxyphenyl)-3-pyridyl-3-butene-2-ketone 15H 19N 3Analytical calculation value: C, 73.56; H, 7.98; N, 17.16. measured value: C, 73.72; H, 7.91; N, 19.98.
Example A-25
Figure A9880736901802
4-[5-(3-fluoro-5-methoxyphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine
4-[5-(3-fluoro-5-methoxyphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] preparation of pyridine is according to example A-1, step 1 and 2 method, with the 3-fluoro-right-methoxybenzaldehyde replaces with between the 3-fluoro--methoxybenzaldehyde: C 16H 14N 3OF analytical calculation value: C, 67.83; H, 4.98; N, 14.83; N, 14.83. measured value: C, 67.68, H, 4.92; N, 14.92.
The example (26-55) of listing in table 1 below is according to method for preparing:
Following pyrazoles can prepare according to said process: example A-56 5-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyrimidine-2-amine; Example A-57 5-[3-methyl-5-(3-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyrimidine-2-amine; Example A-58 5-[3-methyl-5-(2-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyrimidine-2-amine; Example A-59 5-[5-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyrimidine-2-amine; Example A-60 5-[5-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyrimidine-2-amine; Example A-61 5-[5-(4-methoxyphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyrimidine-2-amine; Example A-62 5-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-amine; Example A-63 4-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-amine; Example A-64 4-[5-(3-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-amine; Example A-65 4-[5-(2-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-amine; Example A-66 4-[5-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-amine; Example A-67 4-[5-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-amine; Example A-68 4-[5-(4-methoxyphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-amine; Example A-69 5-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl]-the 2-pyridinyl methoxy; Example A-70 2-methoxyl group-5-[3-methyl-5-(3-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine; Example A-71 2-methoxyl group-5-[5-(4-methoxyphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine; Example A-72 4-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl]-the 2-pyridinyl methoxy; Example A-73 2-methoxyl group-4-[3-methyl-5-(3-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine; Example A-74 2-methoxyl group-4-[3-methyl-5-(2-aminomethyl phenyl)-1H-pyrazoles-4-yl] pyridine; Example A-75 4-[5-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl]-the 2-pyridinyl methoxy; Example A-76 4-[5-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl]-the 2-pyridinyl methoxy; Example A-77 2-methoxyl group-4-[3-methyl-5-(4-tolyl)-1H-pyrazoles-4-yl] pyridine; Example A-78 5-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-phenol; Example A-79 4-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-phenol; Example A-80 4-[5-(3-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-phenol; Example A-81 4-[5-(2-aminomethyl phenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-phenol; Example A-82 4-[5-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-phenol; Example A-83 4-[5-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-phenol; Example A-84 4-[5-(4-methoxyphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-phenol; Example A-85 5-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-methylamine; Example A-86 4-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-methylamine; Example A-87 4-[5-(3-tolyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-methylamine; Example A-88 4-[5-(2-tolyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-methylamine; Example A-89 4-[5-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-methylamine; Example A-90 4-[5-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-methylamine; Example A-91 4-[5-(4-methoxyphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-methylamine; Example A-92 5-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-Carboxylamide; Example A-93 4-[5-(3-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-Carboxylamide; Example A-94 4-[5-(3-tolyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-Carboxylamide; Example A-95 4-[5-(2-tolyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-Carboxylamide; Example A-96 4-[5-(4-chloro-phenyl-)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-Carboxylamide; Example A-97 4-[5-(4-fluorophenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-Carboxylamide; Example A-98 4-[5-(4-methoxyphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine-2-Carboxylamide; Example A-99 4-[5-(3-fluoro-4-methoxyphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine example A-100 4-[5-(4-fluoro-3-methoxyphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine; Example A-101 4-[5-(4-chloro-3-methoxyphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine; Example A-102 4-[5-(2,3-Dihydrobenzofuranes-6-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine; Example A-103 4-[5-(cumarone-6-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine; Example A-104 4-[5-(3-fluoro-5-methoxyphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine; Example A-105 4-[5-(3-chloro-5-methoxyphenyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine; Example A-106 4-[5-(1-tetrahydrobenzene-1-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine; Example A-107 4-[5-(1-1-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine; Example A-108 4-[5-(5,6-dihydro-2H-pyrans-4-yl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine; Example A-109 4-(5-cyclohexyl-3-methyl isophthalic acid H-pyrazoles-4-yl) pyridine; Example A-110 4-[5-(4-methoxyl group-3-tolyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine; Example A-111 4-[5-(3-methoxyl group-4-tolyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine; Example A-112 4-[5-(3-methoxyl group-5-tolyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine; Example A-113 4-[5-(3-furyl)-3-methyl isophthalic acid H-pyrazoles-4-yl] pyridine; Example A-114 2-methyl-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine; Example A-115 2-methoxyl group-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine; Example A-116 4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine-2-carboxylic acids methyl esters; Example A-117 4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine-2-Carboxylamide; Example A-118 1-[4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine-2-yl] ethyl ketone; Example A-119 N, N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazoles-2-yl) pyridine-2-amine; Example A-120 3-methyl-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine; Example A-121 3-methoxyl group-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine; Example A-122 4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine-3-carboxylic acid methyl esters; Example A-123 4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine-3-Carboxylamide; Example A-124 1-[4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridin-3-yl] ethyl ketone; Example A-125 3-bromo-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine; Example A-126 N, N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazoles-2-yl) pyridine-3-amine; Example A-127 2-methyl-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyrimidine; Example A-128 4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyrimidine; Example A-129 2-methoxyl group-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyrimidine; Example A-130 4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyrimidine-2-amine; Example A-131 N, N-dimethyl-4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyrimidine-2-amine; Example A-132 4-(5,6-dihydro-2H-pyrans-4-yl)-3-methyl-5-phenyl-1H-pyrazoles; Example A-133 3-methyl-5-phenyl-4-(3-thiophene)-1H-pyrazoles; Example A-134 4-(3-furyl)-3-methyl-5-phenyl-1H-pyrazoles; Example A-135 3-methyl-5-phenyl-4-(2-thiophene)-1H-pyrazoles; Example A-136 4-(2-furyl)-3-methyl-5-phenyl-1H-pyrazoles; Example A-137 4-(3-isothiazolyl)-3-methyl-5-phenyl-1H-pyrazoles; Example A-138 4-(3-isoxazolyl)-3-methyl-5-phenyl-1H-pyrazoles; Example A-139 4-(5-isothiazolyl)-3-methyl-5-phenyl-1H-pyrazoles; Example A-140 4-(5-isoxazolyl)-3-methyl-5-phenyl-1H-pyrazoles; Example A-141 3-methyl-5-phenyl-4-(5-thiazolyl)-1H-pyrazoles; Example A-142 3-methyl-4-(5-oxazolyl)-5-phenyl-1H-pyrazoles; Example A-143 2-methyl-4-[3-(3-tolyl)-1H-pyrazoles-4-yl] pyridine; Example A-144 4-(1-methyl-3-phenyl-1H-pyrazoles-4-yl) pyridine; Example A-145 4-(3-phenyl-1H-pyrazoles-4-yl) pyridine; Example A-146 2-methyl-4-(3-phenyl-1H-pyrazoles-4-yl) pyridine; Example A-147 4-[3-(3-chloro-phenyl-)-1-methyl-pyrazoles-4-yl] pyridine; Example A-148 4-[3-(4-chloro-phenyl-)-1-methyl-pyrazoles-4-yl] pyridine; Example A-149 4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4-yl] pyridine; Example A-150 4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4-yl] pyridine; Example A-151 4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4-yl]-the 2-picoline; Example A-152 4-[3-(3-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine; Example A-153 4-[3-(3-fluorophenyl)-1H-pyrazoles-4-yl] pyridine; With example A-154 4-[3-(3-chloro-phenyl-)-1-methyl-pyrazoles-4-yl]-the 2-picoline.
The compound of example A-155 to A-172 is according to above-mentioned chemical process (especially scheme II) synthetic, and by selecting corresponding initial reagent to illustrate with the example of illustrating in the past:
Example A-155
261 ℃ of 5-(4-chloro-phenyl-)-N-phenyl-4-(4-pyridine)-1H-pyrazoles-3-amine: DSC, C 20H 15ClN 4+ 0.25H 2O (MW 351.32) analytical calculation value: C, 68.38, H, 4.30, N, 15.95. measured value: C, 68.25, H, 4.41, N, 15.74.
Example A-156
Figure A9880736901872
260 ℃ of 5-(4-chloro-phenyl-)-N-methyl-4-(4-pyridine)-1H-pyrazoles-3-amine: DSC, C 15H 13ClN 4+ 0.125H 2O (MW 287.00) analytical calculation value: C, 62.77, H, 4.57, N, 19.52. measured value: C, 62.78, H, 4.33, N, 19.22.
Example A-157
5-(4-chloro-phenyl-)-N, N-dimethyl-4-(4-pyridine)-1H-pyrazoles-3-two hydration amine: DSC230 ℃, analytical calculation C 16H 15ClN 4+ 2H 2O (MW 334.81): C, 57.40, H, 4.52, N, 16.73. actual measurement: C, 57.72, H, 4.85, N, 16.54.
Example A-158
5-(3-fluorophenyl)-N, 227 ℃ of N-dimethyl-4-(4-pyridine)-1H-pyrazoles-3-amine: DSC, C 16H 15FN 4+ 0.125H 2O (MW 284.57) analytical calculation value: C, 67.53, H, 5.31, N, 19.69. measured value: C, 67.60, H, 5.20, N, 19.84.
Example A-159
Figure A9880736901882
N, 222 ℃ of N-dimethyl-5-(3-tolyl)-4-(4-pyridine)-1H-pyrazoles-3-amine: DSC, analytical calculation C 17H 18N 4+ 0.25H 2O (MW 282.86): C, 72.19, H, 6.41, N, 19.81. actual measurement: C, 71.99, H, 6.46, N, 19.90.
Example A-160
Figure A9880736901883
226 ℃ of N-methyl-5-(3-tolyl)-4-(4-pyridine)-1H-pyrazoles-3-amine: DSC, C 16H 16N 4+ 0.125H 2O (MW 266.58) analytical calculation value: C, 72.09, H, 6.05, N, 21.02. measured value: C, 72.12, H, 6.12, N, 20.83.
Example A-161
Figure A9880736901891
227 ℃ of N-ethyl-5-(3-tolyl)-4-(4-pyridine)-1H-pyrazoles-3-amine: DSC, C 17H 18N 4+ 0.125H 2O (MW 280.61) analytical calculation value: C, 72.77, H, 6.47, N, 19.97. measured value: C, 72.63, H, 6.40, N, 19.73.
Example A-162
Figure A9880736901892
N, 234 ℃ of N-diethyl-5-(3-tolyl)-4-(4-pyridine)-1H-pyrazoles-3-amine: DSC, C 19H 22N 4(MW 306.41) analytical calculation value: C, 74.48, H, 7.24, N, 18.29. measured value: C, 74.12, H, 7.18, N, 18.13.
Example A-163
Figure A9880736901893
5-(4-chloro-phenyl-)-N, N-diethyl-4-(4-pyridine)-1H-pyrazoles-3-amine: fusing point 260-261 ℃, C 18H 19ClN 4(MW 326.83) analytical calculation value: C, 66.15, H, 5.86, N, 17.14. measured value: C, 66.03, H, 5.72, N, 17.23.
Example A-164
Figure A9880736901901
4-[5-(4-chloro-phenyl-)-4-(4-pyridine)-1H-pyrazole-3-yl] 279 ℃ of morpholine: DSC, C 18H 17ClN 4O+0.25H 2O (MW 345.32) analytical calculation value: C, 62.61, H, 4.96, N, 16.23. measured value: C, 62.52, H, 4.77, N, 16.52.
Example A-165
Figure A9880736901902
244 ℃ of 5-(4-chloro-phenyl-)-N-propyl group-4-(4-pyridine)-1H-pyrazoles-3-amine: DSC, C 17H 17ClN 4+ 0.125H 2O (MW 315.06) analytical calculation value: C, 64.81, H, 5.44, N, 17.78. measured value: C, 64.94, H, 5.43, N, 17.78.
Example A-166
Be separated into 237 ℃ of 5-(4-chloro-phenyl-)-N-(phenmethyl)-4-(4-pyridine)-1H-pyrazoles-3-hydration amine (2: 1): DSC, C 21H 17ClN 4+ 0.5H 2O (MW 369.86) analytical calculation value: C, 68.20, H, 4.63, N, 15.15. measured value: C, 68.09, H, 4.55, N, 15.15.
Example A-167
Be separated into 223 ℃ of 5-(4-chloro-phenyl-) N-(2-methoxyethyl)-4-(4-pyridine)-1H-pyrazoles-3-one hydration amine: DSC, C 17H 17ClN 4O+H 2O (MW 346.82) analytical calculation value: C, 58.87, H, 4.94, N, 16.15. measured value: C, 58.59, H, 4.79, N, 16.02.
Example A-168
Figure A9880736901912
4-[5-(4-chloro-phenyl-)-4-(4-pyridine)-1H-pyrazole-3-yl]-1-piperazine-carboxylic acid 1,251 ℃ of 1-two methyl ethyl esters: DSC, C 23H 26ClN 5O (MW 439.95) analytical calculation value: C, 62.79, H, 5.96, N, 15.92. measured value: C, 62.40, H, 5.82, N, 15.82.
Example A-169
Figure A9880736901913
Be separated into 1-[5-(4-chloro-phenyl-)-4-(4-pyridine)-1H-pyrazole-3-yl] three piperazine chlorides: DSC99 ℃, C 18H 18ClN 4+ 3HCl (MW 449.21) analytical calculation value: C, 48.13, H, 4.71, N, 15.59. measured value: C, 47.76, H, 5.07, N, 15.51.
Example A-170
1-[5-(4-chloro-phenyl-)-4-(4-pyridine)-1H-pyrazole-3-yl]-the 4-methylpiperazine: fusing point 247-249 ℃, C 19H 20ClN 5+ 0.75H 2O (MW 367.33) analytical calculation value: C, 62.12, H, 5.49, N, 19.06. measured value: C, 62.45, H, 5.86, N, 19.32.
Example A-171
Figure A9880736901922
4-[5-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazole-3-yl]-1-piperazine-carboxylic acid 1,1-two methyl ethyl esters: fusing point 243-244 ℃, C 23H 26FN 5O 2+ 0.5CH 3CH 2CO 2CH 2CH 3(MW467.55) analytical calculation value: C, 64.22, H, 6.47, N, 14.98. measured value: C, 63.90, H, 6.61, N, 14.88.
Example A-172
1-[5-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazole-3-yl] three piperazine chlorides: fusing point 204-206 ℃, C 18H 18FN 5+ 3HCl+0.5H 2O (MW 441.77) analytical calculation value: C, 48.94, H, 4.79, N, 15.85. measured value: C, 48.66, H, 4.88, N, 15.50.
1-[5-(4-chloro-phenyl-)-4-(4-pyridine)-1H-pyrazole-3-yl] piperazine: fusing point 264-265 ℃, C 18H 18ClN 5+ 0.125H 2O (MW 342.08) analytical calculation value: C, 63.20, H, 5.30, N, 20.47. measured value: C, 63.04, H, 5.36, N, 20.33.
Select described other compound of chemical process synthetic of corresponding initial reagent further to comprise compound in the table 2 according to scheme II:
Table 2
Embodiment General step The microanalysis value ?DSC
Molecular formula C calculates C observation H calculates H observation N calculates N observation ?℃
??A-173 Scheme II ??C24H25ClN6·3HCl·1.5H2O ??50.63 ??50.58 ??4.96 ??5.03 ?14.76 ?14.68 ?182
??A-174 Scheme II ??C25H24ClN5·0.125H2O ??69.47 ??69.33 ??5.60 ??5.56 ?16.20 ?16.11 ?259
??A-175 Scheme II ??C17H17FN6·1.25H2O ??48.64 ??48.45 ??4.56 ??4.86 ?20.02 ?20.24 ?82
??A-176 Scheme II ??C22H26ClN5O2 ??61.75 ??61.57 ??6.12 ??6.04 ?16.37 ?16.34 ?217
??A-177 Scheme II ??C17H18ClN5·3HCl·H2O ??44.85 ??44.96 ??4.65 ??4.87 ?15.38 ?15.17 ?220
??A-178 Scheme II ??C21H24ClN5O2·0.125H2O ??60.61 ??60.51 ??5.81 ??5.81 ?16.83 ?16.64 ?232
??A-179 Scheme II ??C25H30ClN5O3 ??62.04 ??61.76 ??6.25 ??6.25 ?14.47 ?14.37 ?220
??A-180 Scheme II ??C22H25FN6O2·0.5H2O ??60.96 ??60.86 ??5.81 ??6.21 ?19.39 ?19.47 ?N.D.
??A-181 Scheme II ??C22H25ClFN5O2 ??59.26 ??58.98 ??5.65 ??5.55 ?15.71 ?15.36 ?210
??A-182 Scheme II ??C20H22ClN5·0.75H2O ??62.98 ??62.97 ??5.81 ??5.64 ?18.36 ?17.83 ?271
??A-183 Scheme II ??C16H19Cl4N5·3HCl ??45.41 ??45.37 ??4.53 ??4.74 ?120
Example A-173
N-[5-(4-chloro-phenyl-)-4-[2-(phenyl methyl)-amino]-the 4-pyridine]-the 1H-pyrazole-3-yl]-1,3-three hydrochloric acid propylene diamine
Example A-174
1-[5-(4-chloro-phenyl-)-4-(4-pyridine)-1H-pyrazole-3-yl]-4-(phenmethyl) piperazine
Example A-175
Be separated into 4-[3-(4-fluorophenyl)-5-(1-piperazinyl)-1H-pyrazoles-4-yl] two hydrochloric acid pyrimidines
Example A-176
Figure A9880736901951
[3-[[5-(4-chloro-phenyl-)-4-(4-pyridine)-1H-pyrazole-3-yl] amino] propyl group] carboxylamine 1,1-dimethyl ethyl ester
Example A-177
Figure A9880736901952
Be separated into N-[5-(4-chloro-phenyl-)-4-(4-pyridine)-1H-pyrazole-3-yl]-1, the single hydration three hydrochloric acid propylene diamine of 3-
Example A-178
Figure A9880736901953
[2-[[5-(4-chloro-phenyl-)-4-(4-pyridine)-1H-pyrazole-3-yl] amino] ethyl] carboxylamine 1,1-dimethyl ethyl ester
Example A-179
Figure A9880736901961
4-[5-(4-chloro-phenyl-)-1-(2-hydroxyethyl)-4-(4-pyridine)-1H-pyrazole-3-yl]-1-piperazine carboxylic acid 1,1-dimethyl ethyl ester
Example A-180
Figure A9880736901962
4-[5-(4-fluorophenyl)-4-(4-pyrimidine)-1H-pyrazole-3-yl]-1-piperidine carboxylic acid 1,1-dimethyl ethyl ester
Example A-181
[3-[[5-(4-chloro-phenyl-)-4-(2-fluoro-4-pyridine)-1H-pyrazole-3-yl] amino] propyl group] carboxylamine 1,1-dimethyl ethyl ester
Example A-182
Figure A9880736901971
1-[5-(4-chloro-phenyl-)-4-(4-pyridine)-1H-pyrazole-3-yl]-the 4-ethyl piperazidine
Example A-183
Figure A9880736901972
N-[5-(4-chloro-phenyl-)-4-(4-pyridine)-1H-pyrazole-3-yl]-1
The compound of example A-184 to A-189 is according to above-mentioned chemical process (especially scheme I and IV) synthetic, and by selecting corresponding initial reagent to illustrate with the example of illustrating in the past:
Example A-184
Figure A9880736901973
4-[3-(2, the 6-difluorophenyl)-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine: C 15H 11F 2N 3Analytical calculation value: C, 66.42, H, 4.09, N, 15.49. measured value: C, 66.20, H, 3.94, N, 15.16; 236.67 ℃ of fusing points.
Example A-185
4-[3-(3-ethylphenyl)-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine: C 17H 17N 3Analytical calculation value: C, 77.54, H, 6.51, N, 15.96. measured value: C, 77.16; H, 6.27; N, 15.69; Fusing point (DSC): 189.25 ℃.
Example A-186
4-[3-(3-chloro-phenyl-)-5-ethyl-1H-pyrazoles-4-yl] pyridine: C 16H 14ClN 30.1moleH 2O analytical calculation value: C, 67.15, H, 4.91, N, 14.33. measured value: C, 66.95, H, 5.00, N.14.36; DSC:176.18 ℃.
Example A-187
Figure A9880736901983
4-[3-methyl-5-(3-ethylbenzene base)-1H-pyrazoles-4-yl] pyridine: C 18H 19N 30.1mole H 2O analytical calculation value: C, 77.44, H, 6.93, N, 15.05. measured value: C, 77.39, H, 6.94, N, 14.93; Fusing point (DSC): 192.66 ℃.
Example A-188
Figure A9880736901991
4-[3-(4-chloro-phenyl-)-5-(1-methylethyl)-1H-pyrazoles-4-yl] pyridine, C 17H 16ClN 20.4M EtOAc analytical calculation value: C, 67.08, H, 5.81, N, 12.62. measured value: C, 67.40, H, 6.15, N, 12.34.
Example A-189
Figure A9880736901992
4-[3-cyclopropyl-5-(4-fluorophenyl)-1H-pyrazoles-4-yl] pyridine: C 17H 14FN 3Analytical calculation value: C, 73.1, H, 5.05, N, 15.04. measured value: C, 73.23; H, 4.89; N, 14.63; Fusing point: 239-240 ℃.
The compound of example A-190 is according to above-mentioned chemical process (especially scheme III) synthetic, and by selecting corresponding initial reagent to illustrate with the example of illustrating in the past:
Example A-190
4-[3-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazoles-4-yl] the same procedure preparation described by example A-22 of this compound of pyridine, 3-(4 '-pyridine ethanoyl) toluene is replaced with 1-fluoro-4-(4 '-pyridine ethanoyl) benzene (method of press example A-19 prepares).
C 15H 9F 4N 3Analytical calculation value: C, 58.64, H, 2.95, N, 13.68. measured value: C, 58.57; H, 3.07; N, 13.31; Fusing point (DSC): 281.94 ℃.
The compound of example A-191 to A-198 is to synthesize by selecting corresponding initial reagent according to above-mentioned chemical process (especially scheme I and IV):
Example A-191
Figure A9880736902001
4-[5-(cyclopropyl-3-(4-(fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine The preparation of step 1:1-(4-fluorophenyl)-2-4 (4-pyridine) ethyl ketone methyl hydrazone
Figure A9880736902002
1-(4-fluorophenyl)-2-(4-pyridine) ethyl ketone methyl hydrazone
To 4-fluoro benzoyl-4 '-pyridine methane (8.60g, 0.04mol) and methyl hydrazine (2.14g adds two vitriol oils in 50ml ethanolic soln 0.044mol).Reaction mixture at room temperature stirs and spends the night.Except that after desolvating, resistates is distributed in ethyl acetate and the water.Organic layer is washed with saturated sodium carbonate solution, with the salt washing, and dry on sal epsom.Filtrate concentrates, and crude product obtains 7.5g yellow solid (77% productive rate), 1-(4-fluorophenyl)-2-(4-pyridine) ethyl ketone methyl hydrazone with diethyl ester and hexane recrystallization.Step 2:4-[5-(cyclopropyl-3-(4-(fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] preparation of pyridine
0 ℃ of compound that drips step 1 preparation among the anhydrous THF that is dissolved in 10mL in the hexamethyl two silicon nitrogen sodium (sodium hexamethyldisilazide) (5.5mL, 1.0M is in THF) (0.67g, 0.0028mol).Dark brown solution stirred 30 minutes under this temperature.Add then the anhydrous THF be dissolved in 5ml cyclopropyl-carboxylic acid's methyl esters (0.34g, 0.0034mol).Reaction mixture is heated to room temperature and stirred 3 hours.Add entry and water ethyl acetate extraction.Organic layer is washed with salt, and dried over mgso is also filtered.Filtrate concentrates and uses chromatography purification (ethyl acetate/hexane/acetone on silica gel, 10: 9: 1) obtain the 0.45g product, 4-[5-(cyclopropyl-3-(4-(fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine, be faint yellow solid (55% productive rate), fusing point: 129-130 ℃; 1H NMR (CDCL 3): δ 8.53 (m, 2H), 7.32 (m, 2H), 7.14 (m, 2H), 6.97 (m, 2H), 4.00 (s, 3H), 1.83 (m, 1H), 0.95 (m, 2H), 0.36 (m, 2H); C 18H 16FN 3Analytical calculation value: C, 73.70; H, 5.50; N, 14.32. measured value: C, 73.63; H, 5.57; N, 14.08.
Example A-192
Figure A9880736902011
The preparation of 5-cyclopropyl-3-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazoles-1-ethanol step 1:1-(4-fluorophenyl)-2-(4-pyridine) ethyl ketone (2-hydroxyethyl) hydrazone
Figure A9880736902021
1-(4-fluorophenyl)-2-(4-pyridine) ethyl ketone (2-hydroxyethyl) hydrazone
80 ℃ to be equipped with hydroxyethylhydrazine (3.4g, add in flask 0.04mol) in batches 4-fluoro benzoyl-4 '-pyridine methane (8.6g, 0.04mol).Yellow oil body stirs under this temperature and spends the night.Cooled reaction solution is dissolved in the hot ethyl acetate and with the hexane grinding and obtains the 8.9g product, and 1-(4-fluorophenyl)-2-(4-pyridine) ethyl ketone (2-hydroxyethyl) hydrazone is yellow crystals (81%) fusing point: 122-123 ℃.Step 2:1-(4-fluorophenyl)-2-(4-pyridine) ethyl ketone [2-[[(1,1-dimethyl ethyl) dimetylsilyl] oxygen base] ethyl] preparation of hydrazone
Figure A9880736902022
1-(4-fluorophenyl)-2-(4-pyridine) ethyl ketone [2-[[(1,1-dimethyl ethyl) dimethyl methyl silicon
Alkyl] the oxygen base] ethyl] hydrazone
(2.73g, 0.01mol) (1.5g adds imidazoles in the DMF solution of 25ml 0.01mol) to 1-(4-fluorophenyl)-2-(4-pyridine) ethyl ketone (2-hydroxyethyl) hydrazone of preparation in batches with (1, the 1-dimethyl ethyl) dimethylsilane muriate in step 1.Reaction mixture at room temperature stirs and spends the night.Add entry and use ethyl acetate extraction, organic phase washes with water, wash with salt, dried over mgso is also filtered, filtrate concentrates and obtains the 3.8g crude product, 1-(4-fluorophenyl)-2-(4-pyridine) ethyl ketone [2-[[(1,1-dimethyl ethyl) dimetylsilyl] the oxygen base] ethyl] hydrazone, for need not purifying, yellow oil body can be directly used in next step.Step 3:5-cyclopropyl-1-[2-[[(1,1-dimethyl ethyl) dimethyl is silica-based] the oxygen base] ethyl]-3,4-phenylbenzene-1H-pyrazoles
Figure A9880736902031
5-cyclopropyl-1-[2-[[(1,1-dimethyl ethyl) dimethyl is silica-based] the oxygen base] ethyl]-3,4-two
Phenyl-1H-pyrazoles
0 ℃ of compound that in the solution of hexamethyl two silicon nitrogen sodium (4.2mL, 1.0M is in THF), is added drop-wise to step 2 preparation that is dissolved in the anhydrous THF of 10ml (0.78g, 0.002mol).Dark brown solution stirred 30 minutes under this temperature, add then the cyclopropyl-carboxylic acid's methyl esters be dissolved in the anhydrous THF of 5ml (0.27g, 0.0026mol).Reaction mixture is heated to room temperature and stirred 3 hours.Add entry and use the ethyl acetate extraction water.Organic layer is washed with salt, with dried over mgso and filtration.Filtrate concentrates and upward obtains the 0.30g product with chromatography purification, 5-cyclopropyl-1-[2-[[(1 at silica gel (ethyl acetate/hexane, 3: 7), the 1-dimethyl ethyl) dimethyl is silica-based] the oxygen base] ethyl]-3,4-phenylbenzene-1H-pyrazoles is faint yellow oil body (35% productive rate) 1H NMR (CDCl 3): δ 8.53 (m, 2H), 7.32 (m, 2H), 7.14 (d, J=5.6Hz, 2H), 6.97 (m, 2H), 4.47 (t, J=4.8Hz, 2H), 4.14 (t, J=4.8Hz, 2H), 1.93 (m, 1H), 0.95 (m, 2H), 0.87 (s, 9H), 0.41 (m, 2H); C 25H 32FN 3OSi analytical calculation value: C, 68.61; H, 7.37; N, 9.60. measured value: C, 68.39; H, 7.81; N, 9.23.Step 4:5-cyclopropyl-3-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazoles-1-alcoholic acid preparation
(0.27g at room temperature adds tetrabutyl fluoride amine (the 1.0M THF solution of 1.9ml) to the compound of preparing to step 3 in 5ml THF solution 0.00062mol).After one hour, add entry and use ethyl acetate extraction.Organic layer is washed with salt, dried over mgso, filtration.Filtrate concentrate and on silica gel (ethyl acetate/hexane, 9: 1) use chromatography purification, obtain the 0.16g product, 5-cyclopropyl-3-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazoles-1-ethanol is the lark solid, fusing point: 155-157 ℃; 1HNMR (CDCl 3): δ 8.53 (br s, 2H), 7.32 (m, 2H), 7.14 (d, J=5.6Hz, 2H), 6.97 (m, 2H), 4.42 (t, J=4.8Hz, 2H), 4.14 (t, J=4.8Hz, 2H), 1.83 (m, 1H), 0.93 (m, 2H), 0.35 (m, 2H); C 19H 18FN 3O analytical calculation value: C, 70.57; H, 5.61; N, 12.99. measured value: C, 70.46; H, 5.87; N, 12.84.Example A-193 3-(4-fluorophenyl)-5-(2-methoxyl group-4-pyridine)-4-(4-pyridine)-1H-pyrazoles-1-ethanol
0 ℃ of compound that in hexamethyldisilane (7.4ml is dissolved in the THF of 1.0M), drips preparation in the example A-192 step 2 that is dissolved in the anhydrous THF of 15ml (1.25g, 0.0034mol).Dark brown solution stirred 30 minutes under this temperature.Add then the anhydrous THF be dissolved in 5ml 4-(2-methoxyl group) pyridine carboxylic acid methyl esters (0.59g, 0.0035mol).Reaction mixture is heated to room temperature and stirred 3 hours.Add entry and use the ethyl acetate extraction water.Organic layer is washed with salt, and dried over mgso is also filtered.Filtrate concentrate and on silica gel (ethyl acetate/hexane, 1: 1) use chromatography purification, obtain the 0.28g product, 3-(4-fluorophenyl)-5-(2-methoxyl group-4-pyridine)-4-(4-pyridine)-1H-pyrazoles-1-ethanol is yellow solid, fusing point: 168-169 ℃; 1H NMR (CDCl 3): δ 8.42 (m, 2H), 8.20 (dd, J=0.7,5.2HZ, 1H), 7.37 (m, 2H), 7.02 (m, 2H), 6.95 (m, 2H), 6.71 (dd, J=1.4,5.2Hz, 1H), 6.66 (t, J=0.7Hz, 1H), 4.20 (m, 2H), 4.14 (m, 2H), 3.95 (s, 3H); C 22H 19FN 4O 2Analytical calculation value: C, 67.86; H, 4.91; N, 14.35. measured value: C, 67.46; H, 5.08; N, 14.03.
4-[1-[2-[[1,1-dimethyl ethyl] dimethyl is silica-based]-the oxygen base] ethyl]-3-(4-fluorophenyl-4-(4-pyridine)-1H-pyrazoles-5-yl)-2-methoxypyridine
Use the chromatography chromatography, with the form of yellow oil body also isolated second compound from above-mentioned reaction, 4-[1-[2-[[1, the 1-dimethyl ethyl] dimethyl silica gel]-the oxygen base] ethyl]-3-(4-fluorophenyl-4-(4-pyridine)-1H-pyrazoles-5-yl)-2-pyridinyl methoxy also separates from above-mentioned reaction, for. 1H?NMR(CDCl 3)：δ8.45(m，2H)，8.20(m，1H)，7.40(m，2H)，7.04(m，2H)，6.93(m，2H)，6.81(m，2H)，4.24(m，2H)，4.14(m，2H)，3.98(s，3H)，0.83(s，9H)，0.02(s，6H)。
Example A-194
Figure A9880736902051
4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridine)-1H-pyrazoles-5-yl]-2 (1H)-pyridones
To the 3-of 5ml acetate (4-fluorophenyl)-5-(2-methoxyl group-4-pyridine)-4-(4-pyridine)-1H-pyrazoles-1-ethanol (0.28g, 0.0006mol) the middle hydrogen bromide that adds 3ml 48%. reaction mixture reflux 3 hours. use water treatment refrigerative mixture subsequently, with oxyammonia alkalization and with ethyl acetate extraction refrigerative mixture. organic layer is washed with salt, dried over mgso is also filtered, and filtrate concentrates and at silica gel (MeOH/CH 2Cl 2/ NH 4OH, 5: 94: 1) go up and use chromatography purification, obtain the 0.07g product, 4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridine)-1H-pyrazoles-5-yl]-2 (1H)-pyridones, be yellow solid (32% productive rate), fusing point: 250-251 ℃, 1H NMR (DMSO-d6): δ 11.74 (s, 1H), 8.45 (d, J=5.0Hz, 2H), 7.35 (m, 3H), 7.16 (m, 2H), 7.03 (d, J=5.0Hz, 2H), 6.37 (s, 1H), 6.05 (d, J=5.2Hz, 1H), 5.0 (m, 1H), 4.13 (m, 2H), 3.81 (m, 2H); C 21H 17FN 4O 20.2 H 2O analytical calculation value: C, 66.06; H, 4.65; N, 14.67. measured value: C, 66.31; H, 4.49; N, 14.27.
Example A-195
1-ethanoyl-4-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridine)-1H-pyrazoles-5-yl]-
2 (1H)-pyridones
Form with yellow solid (38% productive rate) obtains, as an example the 1-ethanoyl-4-[3-of the by product of A-194 (4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridine)-1H-pyrazoles-5-yl]-2 (1H)-pyridones,, fusing point: 220-221 ℃; 1H NMR (CDCl 3): δ 8.50 (m, 2H), 7.339 (m, 3H), 7.02 (m, 4H), 6.59 (m, 1H) 6.08 (dd, J=1.4,5.2Hz, 1H), 4.52 (t, J=6.0Hz, 2H), 4.43 (t, J=6.0Hz, 2H), 2.04 (s, 3H); C 23H 19FN 4O 30.3H 2O analytical calculation value: C, 65.46; H, 4.63; N, 13.28. measured value: C, 65.09; H, 4.64; N, 12.99.
Example A-196 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridine)-1H-pyrazoles-5-yl] cyclopropyl-carboxylic acid's ethyl ester
At 0 ℃ to hexamethyl two silicon sodium (17.0ml, be dissolved among the THF of 1.0ml) drip the compound (1.37g of example A-192 step 1 preparation in the solution, 0.005mol) the anhydrous THF solution of 20ml. dark brown solution stirred 30 minutes in this temperature. add 1 of the anhydrous THF that is dissolved in 10ml then, 2-cyclopropyl diethyl dicarboxylate (1.12g, 0.006mol). reaction mixture is heated to room temperature and stirred 2 hours. add entry and water ethyl acetate extraction. and organic layer is washed with salt, dried over mgso is also filtered. and filtrate concentrates and in silica gel (ethyl acetate/hexane, 8: 2) go up and use chromatography purification, obtain the 0.18g product, 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridine)-1H-pyrazoles-5-yl] cyclopropyl-carboxylic acid's ethyl ester, be faint yellow oil body (35% productive rate) 1HNMR (CDCl 3): δ 8.55 (m, 2H), 7.32 (m, 2H), 7.11 (m, 2H), 6.97 (m, 2H), 4.38 (m, 2H), 4.16 (m, 4H), 2.47 (m, 1H), 1.53 (m, 2H), 1.26 (t, J=7.0Hz, 3H), (m, 2H), 0.90 (m, 2H); C 22H 22FN 3O 30.25H 2O analytical calculation value: C, 66.07; H, 5.67; N, 10.51 measured values: C, 65.89; H, 5.80; N, 9.95.
Example A-197
Figure A9880736902071
2-[3-(4-fluoropropyl)-1-(2-hydroxyethyl)-4-(4-pyridine)-1H-pyrazoles-5-yl] cyclopropyl-carboxylic acid
To 2-[3-(4-fluorophenyl)-1-(2-hydroxyethyl)-4-(4-pyridine)-1H-pyrazoles-5-yl according to example A-196 preparation] cyclopropyl-carboxylic acid's ethyl ester (0.21g, 0.0045mol) solution in add the sodium hydroxide (0.09g of 2ml, 0.0022mol) aqueous solution. reaction mixture refluxed stirred 6 hours. behind removal of solvents, resistates is dissolved among the 1N HCl of 10ml and stirred 30 minutes, with the sodium hydroxide of 1N pH to be adjusted to 5-6 and use ethyl acetate extraction then. organic layer is washed with salt, dried over mgso is also filtered. and filtrate concentrates, crude product obtains the 0.1g product with ethanol and ether recrystallization purifying, 2-[3-(4-fluoropropyl)-1-(2-hydroxyethyl)-4-(4-pyridine)-1H-pyrazoles-5-yl] cyclopropyl-carboxylic acid, be white solid (60% productive rate), fusing point: 253-255 ℃; 1H NMR (CD 3OD): δ 8.46 (m, 2H), 7.32 (m, 2H), 7.25 (m, 2H), 7.04 (m, 2H), 4.39 (t, J=5.0Hz, 2H), 4.03 (m, 2H), 2.60 (m, 1H), 1.51 (m, 2), 0.97 (m, 2H); C 20H 18FN 3O 3Analytical calculation value: C, 65.39; H, 4.94; N, 11.44. measured value: 64.92; H, 4.77; N, 11.20.
Example A-198
Figure A9880736902072
3-(4-fluorophenyl)-5-(4-imidazoles)-4-(4-pyridine)-1H-pyrazoles-1-ethanol step 1:1-[[2-(trimethyl silicon based) oxyethyl group] methyl]-1H-pyrroles-3-carboxylate methyl ester
Figure A9880736902073
1-[[2-(trimethyl silicon based) oxyethyl group] methyl]-1H-pyrroles-3-carboxylate methyl ester
At room temperature, (2.95g, 0.023mol) be added to DMF (dimethyl formamide) sodium hydride of 50mL (1.0g is 0.025mol) in the suspension in batches with 4-imidazolyl carboxylic acid methyl esters.Mixture at room temperature stirred 0.5 hour.Then with the time more than 5 minutes drip SEM-chlorine (4.17g, 0.025mol).Reaction mixture stirred after 4 hours, added water quick cooling.The water ethyl acetate extraction, organic layer is with salt washing, dried over mgso and filtration.Filtrate concentrates, crude product passes through silica gel chromatography purifying (ethyl acetate/hexane, 8: 2), obtains the mainly clarified oil of upright structure isomer of 4.0g.Step 2:4-[1-[2-[[(1,1-dimethyl ethyl) dimethyl is silica-based] oxygen] ethyl]-3-(4-fluorophenyl-5-[1-[[2-trimethyl silicane] oxyethyl group] methyl isophthalic acid H-imidazol-4 yl]-1H-pyrazoles-4-yl) preparation of pyridine.
Figure A9880736902081
4-[1-[2-[[(1,1-dimethyl ethyl) dimethyl is silica-based] oxygen] ethyl]-3-(4-fluorophenyl-5-[1-[[2-trimethyl silicane] oxyethyl group] methyl isophthalic acid H-imidazol-4 yl]-1H-pyrazoles-4-yl) pyridine
Under 0 ℃ of ar gas environment, (0.8g, the anhydrous THF of 10mL 0.002mol) (tetrahydrofuran (THF)) drips of solution is added in the THF solution (4.5mL, 1.0mol concentration) of hexamethyl two silicon sodium the compound that example A-192 step 2 is prepared.Dark brown solution stirred 30 minutes under this temperature.The compound (0.54g, the anhydrous THF solution of 5mL 0.0021mol) that add 1 preparation of this case step then.Reaction mixture is warming up to room temperature, stirs 1 hour.Add entry, the water ethyl acetate extraction.Organic layer salt water washing, dried over mgso and filtration.Filtrate concentrates, silica gel chromatography (ethyl acetate/hexane, 8: 2) purifying, obtains that 0.98g is lurid, putting for a long time can solidified oil production (productive rate 91%), fusing point: 79～80 ℃; 1H NMR (deuterochloroform): δ 8.48 (d, J=6.0Hz, 2H), 7.68 (d, J=1.3Hz, 1H), 7.38 (d, J=6.0Hz, 2H), 7.10 (m, 2H), 7.00 (m, 2H), 6.93 (d, J=1.3Hz, 1H), 5.25 (s, 2H), 4.53 (t, J=6.0Hz, 2H), 4.12 (t, J=6.0Hz, 2H), 3.84 (t, J=8.0Hz, 2H), 0.92 (t, J=8.0Hz, 2H), 0.84 (s, 9H), 0.021 (s, 18H); C 31H 44FN 5O 2Si 2Analytical calculation value: C, 62.70; H, 7.47; N, 11.79.Observed value: C, 62.98; H, 7.74; N, 11.88.Step 3:3-(4-fluorophenyl)-5-(4-imidazoles)-4-(4-pyridine)-1H-pyrazoles-1-alcoholic acid preparation
The tetrahydrofuran solution of 1.0M tetrabutyl fluoride amine is added to the compound of this case step 2 preparations, and (0.54g is in 10mL tetrahydrofuran solution 0.001mol).Mixture heating up is returned and is heated up in a steamer 3 hours, removes and desolvates, and residuum is distributed in ethyl acetate and the water.Organic layer salt water washing, dried over mgso and filtration.Filtrate concentrates, thick product is gone up purifying at silica gel (methylene chloride, 95: 5), obtains 0.22g white solid product, 3-(4-fluorophenyl)-5-(4-imidazoles)-4-(4-pyridine)-1H-pyrazoles-1-ethanol (productive rate 63%), fusing point: 227～228 ℃; 1H NMR (dimethyl sulfoxide (DMSO)-d 6): δ 8.45 (m, 2H), 7.83 (s, 1H), 7.35 (m, 2H), 7.15 (m, 4H), 7.09 (s, 1H), 5.20 (brs, 1H), 4.32 (s, 2H), 3.81 (m, 2H); C 19H 16FN 5O analytical calculation value: C, 65.32; H, 4.62; N, 20.05.Observed value: C, 64.98; H, 4.55; N, 19.79.
The chemical process that example A-199 compounds is narrated above (especially plan V I), it is synthetic to choose corresponding initial reagent.
Example A-199
Figure A9880736902091
4-[3-(4-chloro-3-tolyl)-1H-pyrazoles-4-yl] pyridine C 15H 22N 3Cl (269.74) analytical calculation value: C, 66.79; H, 4.48; N, 15.58.Observed value: C, 66.57; H, 4.15; N, 15.54.Fusing point (DSC): 198.17 ℃.
Example A-200 compound is by A-202, and according to the chemical process of narrating above (especially plan V II), it is synthetic to choose corresponding initial reagent.
Example A-200
Figure A9880736902092
5-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazoles-3-carboxylic acid
4-[3-(4-fluorophenyl)-5-methyl isophthalic acid H-pyrazoles-4-yl of pressing the described method preparation of example A-4 in water (7.5ml) and four butanols (10ml)] pyridine (5.83g, 24.0909mmol), (7.6916g, 48.18818mmol) mixture is heated back and heats up in a steamer 6 hours (or all run out of up to potassium permanganate) potassium permanganate.Mixture at room temperature stirs and spends the night, water (150mL) dilution then.Remove by filter the Manganse Dioxide in the mixture.Filtrate is used ethyl acetate extraction, removes unreacting material.Water layer 1N hcl acidifying increases to about 6 pH.Filter the white depositions of collection, washing and dry formation in vacuum chamber, obtain 5-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazoles-3-carboxylic acid (coming out) (2.9777g, 43.7%) with the monohydrate isolated in form.C 15H 10N 3FO 2H 2O (283+18) analytical calculation value: C, 59.80:H, 4.01; N, 13.95; Observed value: C, 59.48; H, 3.26; N, 13.65.Mass spectrum (MH +): 284 (base peaks)
Example A-201
Figure A9880736902101
5-(4-fluorobenzene)-4-(4-pyridine)-1H-pyrazoles-3-methyl alcohol
In nitrogen protection and return under the situation about heating up in a steamer; 1N lithium aluminum hydride tetrahydrofuran solution (4.0mL) is added drop-wise to monohydrate 5-(4-fluorophenyl)-4-(4-the pyridine)-1H-pyrazoles-3-carboxylic acid for preparing according to example A-200 with the time that surpasses 15 minutes, and (0.526g is in anhydrous tetrahydro furan 2.0mmol) (15mL) suspension.Form a kind of throw out.Mixture boiled kept 1 hour.Carefully add the lithium aluminum hydride of 4N potassium hydroxide aqueous solution (0.5mL) then with decomposing excessive.By hydrolytic action, the salt settling of white gets off.After finishing lithium aluminum hydride and adding, mixture heating up returned heat up in a steamer 15 minutes.Hot solution is filtered by Joachim B funnel suction, utilizes tetrahydrofuran (THF) (15ml) to return to heat up in a steamer 1 hour, carries out suction again and filter extract bottom product from throw out.Synthetic filtrate under reduced pressure concentrates.Filter residue is put in the ethyl acetate, water and salt water washing, and dried over mgso obtains thick product (0.45g).Thick product recrystallizing methanol obtains 5-(4-fluorobenzene)-4-(4-pyridine)-1H-pyrazoles-3-methyl alcohol (0.2808g, 56.5%).Fusing point (DSC): 260.26 ℃; C 15H 12N 3FO (269) analytical calculation value: C, 66.91; H, 4.49; N, 15.60; Observed value: C, 66.07; H, 4.63; N, 15.20.Mass spectrum (MH +): 270 (base peaks).
Example A-202
1-[[5-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazole-3-yl] carbonyl] piperazine step 1:4-[[5-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazole-3-yl] carbonyl]-1-piperazine carboxylic acid 1, the preparation of 1-two methyl/ethyls
Figure A9880736902112
Under 0 ℃ of nitrogen protection; with 1-(3-dimethylaminopropyl) 3-ethyl carbodiimide hydrochloride (0.6984g; 3.57mmol; Aldrich chemical company) joins monohydrate 5-(4-fluorophenyl)-4-(4-the pyridine)-1H-pyrazoles-3-carboxylic acid (0.9905g for preparing according to example A-200; 3.57mmol) and I-hydroxybenzotriazole (0.4824g, 3.57mmol) DMF (dimethyl sulfoxide (DMSO)) is (20ml) in the solution.Solution stirred 1 hour under 0 ℃ of nitrogen protection, then add 1-butoxy carbonyl piperazine (0.6585g, 3.5mmol), add again N-methylmorpholine (0.40mL, 3.6mmol).Reaction from 0 ℃ to stirred overnight at room temperature.After 19 hours, decompression removes down and desolvates, and the synthetic resistates is with ethyl acetate dilution, saturated sodium hydrogen carbonate solution, water and salt water washing, and uses dried over mgso.After the filtration, decompression removes down and desolvates, and obtains thick product by chromatography.4-[[5-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazole-3-yl] carbonyl]-1-piperazine carboxylic acid 1,1-dimethyl ethyl ester (1.2372g, 78.4%).C 24H 26N 5O 3F (451) analytical calculation value: C, 63.85; H, 5.80; N, 15.51; Observed value: C, 63.75; H, 5.71; N, 15.16.Mass spectrum (MH +): 452 (base peaks).Step 2:1-[[5-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazole-3-yl] carbonyl] piperazine two (trifluoroacetate), the preparation of monohydrate
Under room temperature, nitrogen protection, (0.1804g, 0.4mmol) methylene dichloride (1.0mL) and trifluoroacetic acid (0.3mL) mixing solutions stirred 2 hours the compound that step 1 is made.Removal of solvent under reduced pressure, trifluoroacetic acid is removed with methylene dichloride and methyl alcohol.Synthetic oily resistates dried overnight in vacuum chamber obtains 1-[[5-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazole-3-yl] carbonyl] piperazine (with two (trifluoroacetates), the isolated in form of a salt hydrate) (0.2400g, 100%) white solid.C 19H 18N 5OF2CF 3COOHH 2O (351+228+18) analytical calculation value: C, 46.24; H, 3.71; N, 11.72; Observed value: C, 45.87; H, 3.43; N, 11.45.Mass spectrum (MH +): 352 (base peaks).
The chemical process that example A-203 to A-206 compounds is narrated above (especially plan V III), synthetic by selecting corresponding initial reagent:
Example A-203
Figure A9880736902121
4-(1,5-dimethyl-3-phenyl-1H-pyrazoles-4-yl) pyridine
Figure A9880736902122
4-(1,3-dimethyl-5-phenyl-1H-pyrazoles-4-yl) pyridine
With 60% sodium hydride (41mg in the mineral oil (69mg), 0.00172mol) (cleaning with hexane in advance) dispersion joins 50mL4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine with the dioxan of 5mL (200mg is 0.00086mol) in the dioxan stirred solution of (pressing the method preparation of example A-2 narration).After three hours, (122mg, 0.00086mol) dioxan solution, mixture at room temperature stirred 20 hours to add the 10mL methyl iodide.Mixture simmer down to solid.Product is distributed between water (15mL) and the ethyl acetate (50mL).Organic layer with dried over mgso, filter, be condensed into solid.Product also separates with the radial chromatography purifying.Nuclear-magnetism (Overhauser effect test) shows that isolating first component of post (minor component) is 4-(1, a 3-dimethyl-5-phenyl-1H-pyrazoles-4-yl) pyridine, and isolating second component of post is 4-(1, a 5-dimethyl-3-phenyl-1H-pyrazoles-4-yl) pyridine
Main isomer (4-(1,5-dimethyl-3-phenyl-1H-pyrazoles-4-yl) pyridine): fusing point: 94～99 ℃.C 16H 15N 30.1MH 2O analytical calculation value: C, 77.08; H, 6.06; N, 16.85; Observed value: C, 76.59; H, 5.70; N, 16.62.
Example A-204
4-[3-(4-chloro-phenyl-)-1,5-dimethyl-1H-pyrazoles-4-yl] pyridine
Figure A9880736902132
4-[5-(4-chloro-phenyl-)-1,3-dimethyl-1H-pyrazoles-4-yl] pyridine (compound of example A-32)
4-[3-(4-chloro-phenyl-)-1,5-dimethyl-1H-pyrazoles-4-yl] pyridine and 4-[5-(4-chloro-phenyl-)-1,3-dimethyl-1H-pyrazoles-4-yl] pyridine is according to the described same steps as of example A-203, with 4-[3-(4-chloro-phenyl-)-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine (the method preparation of being narrated by example A-7) replaces the preparation of 4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine.
Main isomer 4-[3-(4-chloro-phenyl-)-1,5-dimethyl-1H-pyrazoles-4-yl] pyridine: C 16H 14N 3Cl (283.76) analytical calculation value: C, 67.72; H, 4.97; N, 14.81; Observed value: C, 67.45; H, 4.71; N, 14.63.Fusing point (DSC): 190.67 ℃.
Less important isomer 4-[5-(4-chloro-phenyl-)-1,3-dimethyl-1H-pyrazoles-4-yl] pyridine: fusing point: 82～88 ℃.C 16H 14N 3Cl (283.76) analytical calculation value: C, 67.72; H, 4.97; N, 14.81; Observed value: C, 67.56; H, 4.96; N, 14.73.
Example A-205
Figure A9880736902141
4-[5-ethyl-1-methyl-3-(3-tolyl)-1H-pyrazoles-4-yl] pyridine
Figure A9880736902142
4-[3-ethyl-1-methyl-5-(3-tolyl)-1H-pyrazoles-4-yl] pyridine
4-[5-ethyl-1-methyl-3-(3-tolyl)-1H-pyrazoles-4-yl] pyridine and 4-[3-ethyl-1-methyl-5-(3-tolyl)-1H-pyrazoles-4-yl] pyridine is according to the described same steps as of example A-203, by with 4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl] pyridine (the method preparation of being narrated by example A-45) replaces the preparation of 4-(3-methyl-5-phenyl-1H-pyrazoles-4-yl) pyridine.Main isomer (4-[5-ethyl-1-methyl-3-(3-tolyl)-1H-pyrazoles-4-yl] pyridine: C 18H 19NO 30.45MH 2O analytical calculation value: C, 75.73; H, 7.03; N, 14.77; Observed value: C, 76.03; H, 6.87; N, 14.28.Less important isomer (4-[3-ethyl-1-methyl-5-(3-tolyl)-1H-pyrazoles-4-yl] pyridine: C 18H 19NO 30.30MH 2O analytical calculation value: C, 76.46; H, 6.99; N, 14.86; Observed value: C, 76.58; H, 6.98; N, 14.63.
Example A-206 4-[3-(4-chloro-phenyl-)-1-ethyl-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine: C 17H 16N 3Cl (297.79) analytical calculation value: C, 68.57; H, 5.42; N, 14.11; Observed value: C, 68.33; H, 5.27; N, 14.08; Fusing point (DSC): 164.36 ℃.
Example A-207 4-[3-(4-chloro-phenyl-)-2-ethyl-5-methyl isophthalic acid H-pyrazoles-4-yl] pyridine: C 17H 16N 3Cl (297.79) analytical calculation value: C, 68.57; H, 5.42; N, 14.11; Observed value: C, 68.25; H, 5.36; N, 13.74; Fusing point (DSC): 156.46 ℃.
Example A-208 compound and A-209 compound prepare according to the chemical process of narrating above (especially scheme IX):
Example A-208
Figure A9880736902161
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] pyridine step 1:4-fluorophenyl-4 '-preparation of pyridine methane
With two (trimethyl silicane ammonia) lithium (600mL, 1M) join 20 ℃ of 4-picoline (32.6g under the constant temperature in mode stable, steam fast, 0.35mol) and the 4-ethyl fluoro benzoate (50.45g is in mixture 0.3mol), to guarantee not change envrionment temperature.Initial yellow solution is transformed into suspension, then stirs 2 hours.Add toluene (250mL), and mixture is cooled to 0 ℃.Under 0 ℃, use the concentrated hydrochloric acid chilling to reduce about pH value to 7 reaction mixture.Separate organic layer, carry out the extraction again of water layer with toluene (100mL).With organic layer drying (using sodium sulfate) and concentrated, obtain yellow solid, with hexane (200mL) development yellow solid, obtain pure phenylbenzyl ketone, 4-fluoro benzoyl-4 '-pyridine methane, productive rate 90% (58g). 1H NMR is consistent with object construction.Step 2:
Dimethylformamide dimethyl acetal (50mL) once is added to the phenylbenzyl ketone of step 1 preparation, and (30g, 0.14mols) in the suspension, mixture stirred 2 days at ambient temperature.Solution concentration is to doing, and the solid paste that obtains is modulated with hexane (150mL), and so that yellow solid to be provided, this yellow solid enough pure (pressing nucleus magnetic resonance determines) does not need repurity for next step use.Productive rate: 33.9g (90%). 1H NMR is consistent with object construction.Step 3:
(33.9g 0.1255mol) is dissolved in the 125mL ethanol vinyl-amine that step 2 is prepared, and is cooled to 0 ℃.(8.0g is anhydrous or the 16.0g hydration, 0.25mol) once to add hydrazine hydrate then.Fully stir the mixture, be warmed to envrionment temperature, the total overall reaction time is 3 hours.Enriched mixture is dissolved in the 200mL chloroform.After water (100mL) washing, the organic layer hcl as extraction agent of 150mL10%.Water layer was handled 10 minutes down at 70 ℃ with the 0.5g gac subsequently, use molecular sieve filtration, fully stirred and cooled off and carefully carry out neutralization reaction down to make pH be 7～8 (sodium hydroxide with 20%).Good off-white throw out after filtration, drying obtains 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] pyridine.Productive rate: 27.3g, (91%).Mass spectrum: m/z=240. 1H NMR is consistent with object construction.C 14H 10FN 3Analytical calculation value: C, 70.28; H, 4.21; N, 17.56; Observed value: C, 70.11; H, 4.33; N, 17.61.
Example A-209
4-[3-(2-chloro-phenyl-)-1H-pyrazoles-4-yl] pyridine
The same quadrat method that this compound adopts example A-208 to be narrated is utilized corresponding initial reagent preparation.C 14H 10ClN 3Analytical calculation value: C, 65.76; H, 3.94; N, 16.43; Observed value: C, 65.22; H, 3.91; N, 16.50.Fusing point (DSC): 208.46 ℃.
The compound of example A-210 and A-211 prepares according to the top chemical process of narrating (especially scheme X):
Example A-210
Figure A9880736902172
3-(4-fluorophenyl)-4-(4-pyridine) 1-hydrogen-pyrazoles-1-ethanol
In 500mL E Lunmeishi flask, with step 1 example A-208,4-fluorophenyl-4 '-(12.7g 0.059mol) mixes with the 90% hydroxyethylhydrazine ethanolic soln that contains 0.5mL acetate of 30mL for the phenylbenzyl ketone for preparing in the pyridine methane.Gentleness is evaporated small amount of sample after boiling (1 hour) under high vacuum, and uses 1H NMR detects to determine finishing of hydrazone formation.Be cooled to envrionment temperature, block reactant is solidified into yellow cake.(36mL 0.27mols), ℃ reaches mixture heating up to 80 at 10 minutes, and solid all dissolves under temperature, obtains clarifying yellow viscous solution to add DMF (dimethyl formamide) dimethylacetal then.Reaction mixture is slowly cooled to 25 ℃ immediately, stir and drip water (20mL) down, obtain muddy yellow oily suspension this moment.Extremely about 50～60 ℃ of this solution temperature, solution becomes clarifying yellow subsequently now.Stir down, slowly be cooled to envrionment temperature (can quicken this process) and produce a large amount of crystal if obtain crystal seed.After suction filters, wash and carry out drying, make 3-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazoles-faint yellow crystalline solid of 1-ethanol with 10% alcohol-water (50mL).As previously mentioned, add hot filtrate once more to clarification, cooling obtains addition product.From continue to place spend the night for the third time with the 4th time mother liquor, obtain remaining 3-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazoles-1-ethanol.Overall yield: { 12.3+3.3+0.4+0.4}=16.4g.(19.6％)。Mass spectrum, m/z=284. 1H NMR is consistent with object construction.C 16H 14FN 3O+H 2The analytical calculation value of O: C, 63.78; H, 5.35; N, 13.95; Observed value: C, 63.55; H, 5.07; N, 13.69.
Example A-211
3-(4-fluorophenyl)-4-(4-pyrimidyl)-1H-pyrazoles-1-ethanol
This compound is synthetic according to the same steps as that example A-210 is narrated, and just replaces being used for the 4-picoline of synthetic phenylbenzyl ketone with the 4-methylpyrimidine.
Example A-212 compound is according to the chemical process preparation of scheme XI.
Example A-212
4-[3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine
With in the example A-208 step 2 preparation vinyl-amine (5.0g 0.0185mol) is dissolved in the ethanol (75mL), is cooled to 0 ℃.Once add methyl hydrazine (1.7g, ethanolic soln 0.037mol) (75mL), and temperature remained on 0～10 ℃.After keeping 3 hours at ambient temperature, remove and desolvate, residuum is dissolved in methylene dichloride (150mL) and the water (100mL).Organic layer obtains slightly upright structure isomer mixture through separation, dry and concentrated, is shallow dark brown solid (the nuclear-magnetism result by title compound is 80: 20).Upright structure isomer mixture slightly is dissolved in 10% the hydrochloric acid (100mL), with methylene dichloride (100mL) washing, water layer is handled with gac (0.5g).Behind molecular sieve filtration, fully stir and cool off down, with sodium hydroxide (20%) neutralization solution to pH be 8.Light yellow precipitate is filtered, washed and drying.Solid (5g) is dissolved in the 10% heptane/toluene (70mL) of heat, slowly cooling at first drops to envrionment temperature, drops to 15 ℃ again.Scrape flask walls and cause crystallisation process.Continue after 2 hours, filter the solid that forms, with cold 50% toluene/heptane (25mL) washing, wash with hexane (25mL), drying obtains pure title compound again. 1H NMR confirms this structure (comprising the upright structure chemistry that adopts nuclear-magnetism Euclidean effect test).Productive rate: 2.1g (45%).Mass spectrum, m/z=254 (base peak).C 15H 12FN 3+ 0.2H 2The analytical calculation value of O: C, 70.15; H, 4.86; N, 16.4.Observed value: C, 70.18; H, 4.6; N, 16.47.
Example A-213 compound prepares according to the chemical process of scheme XII:
Example A-213
Figure A9880736902191
2-[[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyridyl] amino]-the 1-butanols
2-fluoro-pyridyl pyrazoles (0.2g, the same steps as of being narrated by example A-210 prepares, except replace being used for the 4-picoline of synthetic phenylbenzyl ketone with 2-fluoro-4-picoline) and (R, S)-uniform mixture of 2-amino-1-butanols (4 times mol amount, excessive) is heated to 210～220 ℃ and reaches 1.5 hours in the sealing phial.Carefully bottle is opened after being cooled to 100 ℃, added 5mL toluene and 5mL water, fully stirred 1 hour.Suction filters the solid that obtains, 2-[[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyridyl] amino]-the 1-butanols, use the 5mL water washing, again with toluene wash and dry.Productive rate: 190mg.(71％)。Mass spectrum, m/z=343. 1H NMR is consistent with object construction.
Example A-214 compound prepares according to the chemical process of scheme XIII:
Example A-214
Figure A9880736902201
4-[5-bromo-3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine
With bromine (19.5g 122.0mmol) joins 4-[3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] (2.7g, 10.67mmol) (press example A-212 preparation) acetate (30mL) and DMF (dimethyl formamide) are (13mL) in the solution for pyridine.Under 80 ℃, the solution heated overnight.The thin-layer chromatography Indicator Reaction finishes.Mixture slowly cools off with salt of wormwood (25g).When the pH value is 5 left and right sides, form throw out.Throw out water (50mL * 5) washing obtains 4-[5-bromo-3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine (1.24g, 35%): 174.38 ℃ of fusing points; Mass spectrum m/z=332,334; 1H NMR is consistent with object construction.C 15H 11N 3FBr0.2H 2The analytical calculation value of O: C, 53.66; H, 3.42; N, 12.51.Observed value: C, 53.58; H, 3.12; N, 12.43.℃
Example A-215 compound prepares according to the chemical process of scheme XIV:
Example A-215
Figure A9880736902202
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2-pyridine nitrile step 1:
3-chlorine peroxybenzoic acid (5.44g, 17.97mmol purity 57%) is joined 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-methyl alcohol (100mL) solution of 2-pyridine (press example A-208 preparation) in.Under 25 ℃, solution stirring is spent the night.Mixture is concentrated.Salt of wormwood is joined in the residuum.Form throw out, after filtration, water (30mL * 3) washes, and obtains corresponding oxynitride (3.764g, 81.66%).Step 2:
(0.3mL 2.25mmol) joins oxynitride (0.40g, dimethyl formamide 1.567mmol) (5mL) solution that step 1 prepares with the trimethylsilyl cyanide thing.Under 25 ℃, mixture was stirred 15 minutes, adding dimethyl methyl acyl chlorides (0.8mL, 8.69mmol).Stirred the mixture 2 hours.Thin-layer chromatography indication raw material is used up.With mixture in ethyl acetate: water (100mL: distribute 20mL).Organic layer with salt of wormwood (10%, 20mL), the washing of water (50mL), salt solution (50mL), use the magnesiumcarbonate drying, after filtration with concentrated 4-[3-(4-the fluorophenyl)-1H-pyrazoles-4-yl that obtains]-2-pyridine nitrile (0.23g, 56% productive rate): 209.22 ℃ of fusing points; Mass spectrum (chemi-ionization): m/z=265; 1H NMR is consistent with object construction.C 15H 9N 4F0.2H 2The analytical calculation value of O: C, 67.26; H, 3.54; N, 20.92.Observed value: C, 67.44; H, 3.40; N, 20.69.
Example A-216 compound prepares according to the chemical process of scheme XV:
Example A-216
Figure A9880736902211
4-[2-[3-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazol-1-yl] ethyl] morpholine step 1:
(10.0g 0.0353mol) is suspended in the pyridine (100mL), is cooled to 0 ℃ 3-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazoles-1-ethanol (pressing example A-210 preparation).Slowly add methylsulfonyl chloride, temperature remains on 0 ℃.After 10 ℃ stirring is spent the night down, add water coolant (100mL) and methylene dichloride (150mL) and make two-layer separating.With 100mL methylene dichloride aqueous layer extracted again, oil reservoir is dried, is concentrated into mashed prod.After the drying, obtain light brown cake under high vacuum, with ether (75mL) development, this merging thing obtains the milk yellow solid with drying after filtration, and its productive rate is 79% (10.1g). 1H NMR is consistent with object construction.This compound is used for step 2.Step 2:
(5.0g, (9.6g 0.11mol) in methyl alcohol (50mL) solution, heats back and heats up in a steamer 3～4 hours 0.0138mol) to be dissolved in the morpholine of 8 times of amounts with the methylsulfonyl salt of step 1 preparation.Sampling is done after nuclear-magnetism determines to react completely, and mixture is concentrated, and is dissolved in the methylene dichloride (150mL), and first water (100mL) is washed, and uses the salt pickling of 75mL5% again.The water layer pH value that neutralizes is 8, with methylene dichloride (100mL) extraction.Drying obtains light yellow pasty solid thing with concentrating, and with the development of 25mL ether, obtains solid.Obtain 4-[2-[3-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazol-1-yl with the toluene/hexane recrystallization] ethyl] the morpholine solid.Productive rate: 4.5g (86%).Mass spectrum, m/z=353. 1H NMR is consistent with object construction.C 20H 21FN 4The analytical calculation value of O: C, 68.16; H, 6.01; N, 15.90.Observed value: C, 68.20; H, 6.21; N, 15.80.
The compound of example A-217 prepares according to the chemical process of scheme XVI:
Example A-217
3-(4-fluorophenyl)-1-methyl-α-phenyl-4-(4-pyridyl)-1H-pyrazoles-5-methyl alcohol
With 4-[5-bromo-3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine (450mg, 1.35mmol) (by example A-214 prepare tetrahydrofuran (THF) (7mL) solution under nitrogen protection, join solid magnesium (60mg, 5mmol) in.Mixture heated 2 hours down at 40 ℃.Add phenyl aldehyde (1mL).Mixture heating up to 45 ℃ maintenance 2 hours.With hydrochloric acid (10mL, 1N) chilling, and wash with ethyl acetate.Alkalization acid solution layer, and use ethyl acetate extraction.Organic layer water, salt solution, wash, use dried over mgso, after filtration, concentrate and obtain resistates.Obtain title compound (59mg, productive rate 12%) with silicagel column purifying throw out.Mass spectrum: m/z=360 (M+1); 1H NMR is consistent with object construction.C 22H 18N 2The analytical calculation value of OF0.6EtOAC: C, 71.1; H, 5.6; N, 10.2.Observed value: C, 70.9; H, 5.47; N, 10.2.
The compound of example A-218 prepares by above-described chemical process (especially scheme XVII):
Example A-218
Nitrogen-[5-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazole-3-yl] morpholine ethamine
Press example A-208 step 1,4-fluorobenzoyl-4 '-(1.0g 0.0046mg) is dissolved among the 10Mldmf (dimethyl formamide), is cooled to-10 ℃ (dry ice-isopropyl acetone solution) for the raw material phenylbenzyl ketone for preparing in the pyridine methane.(0.62g, 0.0046mol), temperature remains on-10 ℃ once to add nitrogen-chloro-succinimide.After 5 minutes, under 0 ℃, once add thiosemicarbazide (0.0046mol), surpass 1 hour and slowly be warmed to envrionment temperature.After stirring is spent the night, under high vacuum, remove and desolvate, add entry and toluene (each 25mL), and fully stir.Isolate toluene layer, handling water layer (initial pH is 5.5) with acid carbonate, to make pH be 8.Filter the thin throw out that generates, and water, toluene and ether washing.Last development through ether (25mL) obtains the rice white solid, and nitrogen-[5-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazole-3-yl] morpholine ethamine refilters it with dry.Productive rate: 0.95g (56%).Mass spectrum m/z:368 (base peak).C 20H 22FN 5The analytical calculation value of O: C, 65.38; H, 6.04; N, 19.06.Observed value: C, 64.90; H, 5.92; N, 18.67.
Example A-219
4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4-yl]-2 (1H)-pyridone hydrazone step 1:(E)-2-(2-bromo-4-pyridine)-N, the preparation of N-dimethyl vinyl-amine
Figure A9880736902241
(1.0g 5.8mmol) is heated to 150 ℃ with two (dimethylamine) methane (5mL) of tert.-butoxy, keeps 16 hours with 4-methyl-2-bromopyridine.Press B.Adger et al, J.Chem.Soc., Perkin Trans.1, pp.2791-2796 (1988) is described, and the preparation 4-methyl-2 bromopyridine document is contained in this as a reference.Solvent evaporated is dissolved in throw out in the ethyl acetate, and washes with water.Use the dried over mgso organic layer, vacuumize to remove and desolvate, obtain (E)-2-(2-bromo-4-pyridine)-N of 1.0g, N-dimethyl vinyl-amine oily matter is used for step 2.Step 2:(Z)-2-(2-bromo-4-pyridine)-1-(3-chloro-phenyl-)-3-(dimethylamino)-2-propylene-1-ketone
(1.0g 4.4mmol) is dissolved in the methylene dichloride (15mL) with step 1 synthetic product.Under 0 ℃, add triethylamine (900mg, 8.8mmol), add afterwards the 3-chloro-benzoyl chloride (350mg, 4.5mmol).Mixture stirred 16 hours under nitrogen.Evaporating solvent under the vacuum is dissolved in throw out in the ether (25mL), adds the stirring of sal epsom (500mg) and silica gel (500mg) and refilters.Evaporate ether, with acetone and dichloromethane mixture as eluent, throw out is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, obtain the glassy product of 670mg, (Z)-and 2-(2-bromo-4-pyridine)-1-(3-chloro-phenyl-)-3-(dimethylamino)-2-propylene-1-ketone, this glassy mass need not be further purified and be used for step 3.Step 3:2-bromo-4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4-yl] pyridine
The product that step 2 is obtained (650mg, 1.8mmol) and a hydrazine hydrate (100mg) ethanol (10mL) solution return and heat up in a steamer 24 hours.Solvent evaporated, the mixture of using ethyl acetate and toluene are separated throw out as eluent in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, obtain 2-bromo-4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4-yl] pyridine (190mg, 31%) oily matter.C 14H 9BrClN 3The analytical calculation value: C, 50.25; H, 2.71; N, 12.56.Observed value: C, 50.10; H, 2.60; N, 12.40.
Obtain 4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4 base with ethyl acetate and the continuous wash-out of methanol mixture]-2 (1H)-pyridone hydrazone (190mg, 36%) crystalline solids.163～164 ℃ of fusing points; Mass spectrum (M+H)=286.C 14H 12N 5The analytical calculation value of Cl: C, 58.85; H, 4.23; N, 24.51.Observed value: C, 58.53; H, 4.28; N, 24.87.
Example A-220
Figure A9880736902252
4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4-yl]-nitrogen-(phenmethyl)-2-pyridine amine
(150mg, aniline 0.5mmol) (5mL) solution heated 6 hours down at 175 ℃ the bromopyridine compound that example A-219 step 3 is prepared.After the cooling, remove excessive aniline, ethyl acetate is joined in the resistates by molecular distillation.Wash organic phase with water, and after carrying out drying with sal epsom, vacuumize to remove and desolvate, with the mixture of ethyl acetate and toluene as eluent, throw out is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, obtain 4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4-yl]-nitrogen-(phenmethyl)-2-pyridine amine solid (110mg, 61%).179～180 ℃ of fusing points.C 21H 17ClN 4The analytical calculation value: C, 69.90; H, 4.75; N, 15.53.Observed value: C, 69.69; H, 4.81; N, 15.11.
Example A-221
Figure A9880736902261
4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4-yl]-nitrogen-(styroyl)-2-pyridine amine
Under nitrogen atmosphere, (250mg, phenylethylamine 0.75mmol) (5mL) solution heated 6 hours down at 175 ℃ the bromopyridine compound that example A-219 step 3 is prepared.Excessive amine distilled under high vacuum remove, throw out is dissolved in the ethyl acetate, and washes with water.Dried over mgso, remove desolvate after, with the mixture of ethyl acetate and toluene, throw out is separated in the enterprising circumstances in which people get things ready for a trip spectrum of silica gel, obtain 4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4-yl]-nitrogen-(styroyl)-2-pyridine amine solid (230mg, 81%), fusing point is 185～186 ℃.
C 22H 19ClN 4The analytical calculation value: C, 70.49; H, 5.11; N, 14.95.Observed value: C, 70.29; H, 5.15; N, 14.66.
Example A-222
Figure A9880736902262
4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4 base]-nitrogen-ethyl-2-pyridine amine
In sealed tube, (300mg, ethamine 0.9mmol) (3.5mL) and ethanol (5mL) solution heated 9 hours down at 150 ℃ the bromopyridine compound that example A-219 step 3 is prepared.Vacuumize to remove and desolvate,, on silica gel, resistates is carried out chromatographic separation, obtain 4-[3-(3-chloro-phenyl-)-1H-pyrazoles-4 base with 70 ethyl acetate/30 toluene]-nitrogen-ethyl-2-pyridine amine solid (125mg, 46%), 186～187 ℃ of fusing points.C 16H 15ClN 4The analytical calculation value: C, 64.32; H, 7.06; N, 18.75.Observed value: C, 64.42; H, 7.01; N, 18.45.
By selecting corresponding initial reagent, synthesize the compound of A-226-A-223 according to chemical process recited above (especially scheme XVIII):
Example A-223
Figure A9880736902271
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2-pyridine carboxy acid amides step 1:
Will between-the chlorine peroxybenzoic acid at room temperature once joins 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-(8.8g is in dichloromethane solution 0.037mol) for pyridine (method of press example A-208 narration prepares).Stir after 16 hours, remove and desolvate, handle resistates with saturated sodium bicarbonate.With throw out after filtration, dry air, obtain 8.2g white solid product (87%), fusing point: 207～209 ℃.Step 2:4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-preparation of 2-pyridine nitrile
At room temperature, with triethyl-silicane prussiate (2.5g, 0.025mol), again 5mLN, N-dimethylcarbamyl chloride (2.7g, 0.025mol) 5ml DFM (dimethyl formamide) solution join step 1 product (5.1g be in 20M1 DFM (dimethyl formamide) solution 0.02mol).After stirring is spent the night, reaction mixture is alkalized with the wet chemical of 200mL10%.The water layer ethyl acetate extraction.Organic layer also filters with salt water washing, dried over mgso.Concentrated filtrate with hexane development crude product and filtration, obtains 4.3g4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2-pyridine nitrile (90%) light yellow solid, fusing point: 238～239 ℃.Step 3:4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-preparation of 2-pyridine carboxy acid amides:
Under 0 ℃ with hydrogen peroxide (the 0.24mL30% aqueous solution, 1.7mmol) and salt of wormwood (0.04g, 0.4mmol) join 4-[3-(4-the fluorophenyl)-1H-pyrazoles-4-yl that makes by step 2]-(0.45g is in 10Ml DMSO (methyl-sulphoxide) solution 0.0017mol) for 2-pyridine nitrile.Mixture stirred 1 hour, made it be warmed to room temperature simultaneously.Add entry, filter the collecting precipitation thing, obtain 0.32g4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl through dry air]-2-pyridine carboxy acid amides white solid (productive rate 67%), fusing point: 230～231 ℃.C 15H 11FN 4The analytical calculation value of O: C, 63.83; H, 3.93; N, 19.85.Observed value: C, 63.42; H, 3.66; N, 19.58.
Example A-224
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-Pyridinecarboxylic Acid methyl esters is N, dinethylformamide dimethylacetal (3.67g, 0.03mol) be added drop-wise to 4-[3-(4-the fluorophenyl)-1H-pyrazoles-4-yl of the method preparation of being narrated by example A-223]-(2.9g is in 50mL methanol suspension 0.01mol) for 2-pyridine carboxy acid amides.Reaction mixture at room temperature stirs and spends the night, and heats back and heat up in a steamer 4 hours.After the cooling, filter and the collecting precipitation thing, obtain 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl through dry air]-2-Pyridinecarboxylic Acid methyl esters white solid (productive rate 69%), fusing point: 239～241 ℃.C 16H 12FN 3O 2The analytical calculation value: C, 64.64; H, 4.07; N, 14.13.Observed value: C, 64.36; H, 4.10; N, 14.27.
Example A-225
Figure A9880736902291
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N-methyl-2-pyridine carboxy acid amides
In sealed tube, methyl 4-[3-(4-the fluorophenyl)-1H-pyrazoles-4-yl that will prepare by the method that example A-224 is narrated]-(0.45g 1.5mmol) heated 16 hours down at 120 ℃ with 20mL methylamine (40% aqueous solution) mixture 2-Pyridinecarboxylic Acid salt.After the cooling, add entry, the water layer ethyl acetate extraction.Organic layer salt water washing, dried over mgso and filtration.Concentrating filter liquor obtains 0.4g4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N-methyl-2-pyridine carboxy acid amides white solid, fusing point: 88～89 ℃.C 16H 13FN 4O+0.4H 2The analytical calculation value of O: C, 63.32; H, 4.58; N, 18.46.Observed value: C, 63.10; H, 4.62; N, 18.35.
Example A-226
Figure A9880736902292
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2-Pyridinecarboxylic Acid
With 5mL sodium hydroxide (0.24g, 0.006mol) aqueous solution joins 4-[3-(4-the fluorophenyl)-1H-pyrazoles-4-yl of the method preparation that 10mL narrated by example A-224]-(0.90g is in ethanolic soln 0.003mol) for 2-Pyridinecarboxylic Acid salt.Reaction mixture heats back and heats up in a steamer 10 hours.Except that after desolvating, resistates is dissolved in water, making the pH value with the citric acid acidifying is 5.Then, the water ethyl acetate extraction, organic phase also concentrates with dried over mgso.Crude product is handled purifying with ether, obtains 0.62g4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2-Pyridinecarboxylic Acid white solid (productive rate 73%).Fusing point: 245 ℃ (dec.).C 15H 10FN 3O+0.2H 2The analytical calculation value of O: C, 62.80; H, 3.65; N, 14.65.Observed value: C, 62.77; H, 3.42; N, 14.58.
Disclose in the table 3 by one or more above-mentioned reaction scheme (other compound of the present invention of the preparation of scheme IX～XVIII) especially.The concrete synthetic schemes and the mass spectrum of every kind of compound and results of elemental analyses are also listed in the table 3.
Table 3
Embodiment General step ?MS Microanalysis
?M+1 The C calculated value The C observed value The H calculated value The H observed value The N calculated value The N observed value Add entry Add ethyl acetate
????A-227 ????IX ?240 ??69 ????69 ????4.3 ????4.6 ??17.2 ????16.8 ??0.25
????A-228 ????IX ?266 ??65.69 ????65.69 ????4.41 ????4.33 ??15.32 ????14.98
????A-229 ????XI ?254 ??70.6 ????70.6 ????4.8 ????4.5 ??16.5 ????16.3 ??0.1
????A-230 ????IX ?256 ??65.76 ????65.48 ????3.94 ????3.78 ??16.43 ????16.52
????A-231 ????XI ?280 ??64.18 ????63.95 ????4.39 ????4.31 ??13.86 ????13.90
????A-232 ????XI ?271 ??66.79 ????66.79 ????4.48 ????4.24 ??15.58 ????15.32
????A-233 ????XI ?284 ??66.9 ????66.8 ????5 ????5 ??14.6 ????14.9 ??0.2
????A-234 ????XI ?270 ??65.9 ????65.6 ????4.6 ????4.6 ??15.4 ????15.4 ??0.2
????A-235 ????XI ?264 ??77 ????76.7 ????6.5 ????6.5 ??15.8 ????15.7 ??0.1
????A-236 ????IX ?221 ??75.38 ????75.44 ????5.06 ????5.1 ??18.84 ????19 ??0.1
????A-237 ????IX ?290 ??61.52 ????61.67 ????3.58 ????3.51 ??14.35 ????14.32
????A-238 ????XI ?304 ??63.36 ????63.28 ????3.99 ????3.91 ??13.85 ????13.83
????A-239 ????IX ?258 ??65.37 ????65.39 ????3.53 ????3.52 ??16.33 ????16.31
????A-240 ????IX ?274 ??61.44 ????61.14 ????3.31 ????3.01 ??15.35 ????14.95
????A-241 ????IX ?300 ??56.02 ????55.99 ????3.36 ????3.26 ??14.00 ????14.01
????A-242 ????XI ?272 ??66.42 ????66.41 ????4.09 ????4.04 ??15.49 ????15.32
????A-243 ????XI ?314 ??57.34 ????57.22 ????3.85 ????3.68 ??13.37 ????13.27
????A-244 ????IX ?342 ??76.39 ????76.16 ????4.81 ????4.51 ??12.31 ????12.05 ??0.25
????A-245 ????XII ?341 ??64.89 ????64.65 ????6.36 ????6.17 ??15.93 ????15.82 ??0.6
????A-246 ????XII ?391 ??66.08 ????66.18 ????5.04 ????5.56 ??14.01 ????12.26 ??0.5
????A-247 ????XII ?362 ??64.46 ????64.16 ????4.65 ????4.34 ??18.79 ????18.65 ??0.6
????A-249 ????XII ?258 ??64.91 ????64.84 ????3.58 ????3.63 ??16.22 ????15.98 ??0.1
????A-250 ????IX ?348 ??48.44 ????48.07 ????2.9 ????2.82 ??12.1 ????12.01
????A-251 ????XI ?362 ??49.88 ????49.89 ????3.35 ????3.51 ??11.63 ????11.54
????A-252 ????XI ?304 ??63.36 ????63.34 ????3.99 ????3.96 ??13.85 ????13.81
????A-253 ????XII ?377 ??68.24 ????68.17 ????5 ????4.71 ??14.47 ????14.34 ????0.6
????A-254 ????XII ?363 ??66.31 ????66.12 ????4.77 ????4.31 ??14.73 ????14.6 ????1
????A-215 ????XIV ?265 ??67.3 ????67.4 ????3.5 ????3.4 ??20.9 ????20.7 ????0.2
????A-255 ????XII ?298 ??64.63 ????64.64 ????5.42 ????5.41 ??23.55 ????23.32
????A-256 ????XI ?272 ??66.42 ????66.58 ????4.09 ????4.26 ??15.49 ????14.78
????A-257 ????IX ?276 ??60.11 ????60.4 ????3.06 ????3.18 ??15.02 ????14.73 ????0.25
????A-258 ????IX ?254
????A-259 ????XI ?268 ??71.89 ????71.63 ????5.28 ????5.24 ??15.72 ????15.84
????A-260 ????X ?290 ??62.28 ????62.41 ????3.48 ????3.48 ??14.53 ????14.51
????A-261 ????X，XV ?311 ??69.26 ????69.2 ????6.2 ????6.25 ??17.95 ????17.89 ????0.1
????A-262 ????XI ?376 ??72.71 ????72.5 ????5.17 ????4.98 ??11.06 ????10.99 ????0.25
????A-263 ????XII ?428 ??70.81 ????70.59 ????6.28 ????6.45 ??15.88 ????15.08 ????0.75
????A-264 ????XII ?326 ??63.79 ????63.76 ????6.39 ????6.09 ??20.66 ????20.45 ????0.75
????A-265 ????IX ?400 ??66.18 ????66.77 ????4.1 ????4.23 ??16.78 ????15.83 ????1
????A-266 ????XII ?368 ??62.32 ????62.38 ????6.28 ????6.5 ??18.17 ????17.56 ????1
????A-267 ????XI ?302 ??62.66 ????62.85 ????4.47 ????4.34 ??13.7 ????13.53 ????0.4
????A-268 ????XII ?349 ??62.9 ????63.2 ????5.2 ????4.8 ??22.7 ????22.5 ????0.75 ????0.1
????A-269 ????XI，XV ?371 ??61.85 ????61.84 ????5.71 ????5.24 ??14.42 ????14.17 ????1
????A-270 ????XI，XV ?404 ??70.66 ????70.7 ????4.82 ????4.61 ??10.3 ????10.15 ????0.25
????A-271 ????XI，XV ?329 ??65.8 ????65.3 ????5.5 ????5.6 ??17.1 ????16.8
????A-272 ????XI ?406 ??69.95 ????70.13 ????5.35 ????5.28 ??10.14 ????9.89 ????0.5
????A-273 ????XI ?354 ??66.9 ????67.2 ????6.9 ????6.6 ??19.1 ????18.7 ????0.2 ????0.1
????A-274 ????XI，XII， ????XV ?434 ??63.6 ????63.1 ????6.3 ????5.8 ??14.4 ????14 ????2 ????0.2
????A-275 ????XI，XV ?433 ??70.44 ????70.74 ????6.18 ????6.3 ????12.64 ????12.05 ????0.6
????A-276 ????XI，XII， ????XV ?476 ??65.9 ????66.2 ????6.1 ????6.1 ????13.3 ????13.6 ????0.5 ???0.5
????A-277 ????XII ?338 ??61.11 ????63.02 ????6.48 ????6.39 ????18.75 ????16.61
????A-278 ????XI，XV ?357 ??64.2 ????63.8 ????6.5 ????6 ????15 ????14.8 ????1
????A-279 ????XI，XII， ????XV ?462 ??67.4 ????67.1 ????6.7 ????6.2 ????13.6 ????13.7 ????0.6 ???0.5
????A-280 ????XII ?299 ??61.27 ????61.47 ????5.37 ????5.11 ????17.86 ????17.21 ????0.9
????A-281 ????XII ?313 ??64.63 ????64.94 ????5.55 ????5.63 ????17.73 ????17.48 ????0.2
????A-282 ????XII ?313 ??64.63 ????64.81 ????5.55 ????5.43 ????17.73 ????17.38 ????0.3
????A-283 ????XI，XII ?407 ??67.2 ????67 ????5 ????5.2 ????13.6 ????13.2 ????0.25
????A-284 ????XI，XV ?339 ??70 ????70.3 ????6.9 ????6.9 ????16.3 ????16.2 ????0.25
????A-285 ????XI，XII， ????XV ?476 ??68.2 ????68.5 ????5.7 ????6.2 ????14.7 ????13.6
????A-286 ????XVII ?382 ??59.77 ????59.69 ????6.81 ????6.56 ????16.6 ????16.65 ????2.25
????A-287 ????XVII ?340 ??56.07 ????56.26 ????7.31 ????7.1 ????17.21 ????17.27 ????3.75
????A-288 ????XVII ?293 ??69.42 ????69.4 ????4.52 ????4.6 ????19.05 ????19.09 ????0.1
????A-289 ????XI，XII ?407 ??68 ????67.5 ????5 ????4.5 ????13.8 ????13.5
????A-290 ????XI，XII ?407 ??64 ????64.5 ????5.3 ????4.9 ????13 ????12.4 ????1.4
????A-291 ????IX ?290 ??74.7 ????74.9 ????4.2 ????4.2 ????14.5 ????14.5
????A-292 ????XVII ?326 ??61.22 ????61.46 ????4.77 ????4.53 ????16.8 ????16.97 ????0.4
????A-293 ????XVII ?313 ??55.75 ????55.98 ????4.85 ????4.02 ????16.25 ????16.37 ????1.8
????A-294 ????XI ?278 ??73.6 ????73.2 ????4.4 ????4.2 ????15.2 ????15
????A-295 ????XI ?278 ??67.9 ????67.7 ????4.9 ????4.3 ????14 ????13.7 ????1.3
????A-296 ????IX ??70.3 ????70.4 ????4.5 ????4.7 ????25.2 ????25.4
????A-297 ????IX ??57.9 ????57.7 ????3.1 ????2.9 ????14.5 ????14.5
Example A-227 4-[3-(3-fluorophenyl)-1H-pyrazoles-4-yl] pyridine
Example A-228
Figure A9880736902332
4-[3-(1,3-benzo dioxole-5 base)-1H-pyrazoles-4-yl] pyridine
Example A-229
Figure A9880736902333
4-[3-(3-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine
Example A-230 4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4 base] pyridine
Example A-231
Figure A9880736902342
4-[3-(1,3-benzo dioxole-5-yl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine
Example A-232
Figure A9880736902343
4-[3-(chloro-phenyl-)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine
Example A-233
Figure A9880736902351
4-[3-(3-chloro-phenyl-)-1-methyl isophthalic acid H-pyrazoles-4-yl]-2-picoline and 4-[5-(3-chloro-phenyl-)-1H-pyrazol-1-yl]-the 2-picoline
Example A-234
Figure A9880736902352
4-[3-(3-chloro-phenyl-)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine and 4-[5-(3-chloro-phenyl-)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine
Example A-235 2-methyl-4-[1-methyl-3 (or 5)-(3-tolyl)-1H-pyrazoles-4 base] pyridine
Example A-236
Figure A9880736902361
4-(3-phenyl-1H-pyrazoles-4-yl) pyridine
Example A-237 4-[3-[3-(trifluoromethyl) phenyl]-1H-pyrazoles-4-yl] pyridine
Example A-238 4-[1-methyl-3-[3-(trifluoromethyl) phenyl]-1H-pyrazoles-4-yl] pyridine
Example A-239 4-[3-(3, the 4-difluorophenyl)-1H-pyrazoles-4 base] pyridine
Example A-240
Figure A9880736902372
4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4 base]-2-fluorine pyridine
Example A-241 4-[3-(4-bromophenyl)-1H-pyrazoles-4-yl] pyridine
Example A-242 4-[3-(3, the 4-difluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine
Example A-243 4-[3-(4-bromophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine
Example A-244 (E)-4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2-(2-styroyl) pyridine
Example A-245 (S)-4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4 base]-N-(2-first butyl)-2-pyridine amine
Example A-246
Figure A9880736902392
4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4-yl]-the N-[(4-methoxyphenyl) methyl]-2-pyridine amine
Example A-247 N-[4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4-yl]-the 2-pyridine]-the 2-pyridyl-methanamine
Example A-248
Figure A9880736902401
N-[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyridine]-2-pyridyl-methanamine ultimate analysis calculated value: C, 41.12; H, 3.58; N, 9.22.Observed value: C, 41.74; H, 5.05; N, 11.11.
Example A-249
Figure A9880736902402
2-fluoro-4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] pyridine
Example A-250 4-[3-(4-iodine substituted phenyl)-1H-pyrazoles-4-yl] pyridine
Example A-251 4-[3-(4-iodine substituted phenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine
Example A-252
Figure A9880736902412
4-[1-methyl-3-[4-(trifluoromethyl) phenyl]-1H-pyrazoles-4-yl] pyridine
Example A-253
Figure A9880736902413
N-[1-(4-fluorophenyl) ethyl]-4-[3-(4-fluorophenyl)-1H-pyrazoles-4 base]-2-pyridine amine
Example A-254 The N-[(3-fluorophenyl) methyl]-4-[3-(4-fluorophenyl)-1H-pyrazoles-4 base]-2-pyridine amine
Example A-255 4-[3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl]-2-(1-methyl hydrazine) pyridine
Example A-256
Figure A9880736902423
2-fluoro-4-[3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] pyridine
Example A-257 4-[3-(3, the 4-difluorophenyl)-1H-pyrazoles-4-yl]-2-fluoro-pyridine
Example A-258
Figure A9880736902432
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 3-picoline
Example A-259 4-[3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl)-the 3-picoline
Example A-260 4-[3-(3, the 4-difluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl]-2-fluorine pyridine
Example A-261 3-(4-fluorophenyl)-N, N-dimethyl-4-(4-pyridine)-1H-pyrazoles-1-ethamine
Example A-262 2-[2-(4-fluorophenyl) ethyl]-4-[3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4 base] pyridine
Example A-263 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N-[1-(phenmethyl)-4-piperidines]-2-pyridine amine
Example A-264 N '-[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2-pyridine]-N, N-dimethyl-1,2-ethamine
Example A-265 2, two [3-(4-the fluorophenyl)-1H-pyrazoles-4-yl] pyridines of 4-
Example A-266
Figure A9880736902461
N-[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyridine]-4-morpholine ethamine
Example A-267
Figure A9880736902462
3-(4-fluorophenyl)-4-(2-fluoro-4-pyridine)-1H-pyrazoles-1-ethanol
Example A-268 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N-[2-(1H-imidazoles-1-yl) ethyl]-2-pyridine amine
Example A-269
Figure A9880736902471
4-[2-[3-(4-fluorophenyl)-4-(2-fluoro-4-pyridine)-1H-pyrazoles-1 base] ethyl] morpholine
Example A-270
Figure A9880736902472
(E)-3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl) vinyl]-the 4-pyridine]-1H-pyrazoles-1-ethanol
Example A-271
Figure A9880736902473
3-(4-fluorophenyl)-4-(2-fluoro-4-pyridine)-N, N-dimethyl-1H-pyrazoles-1-ethamine
Example A-272
Figure A9880736902481
3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl) ethyl]-the 4-pyridine]-1H-pyrazoles-1-ethanol
Example A-273 4-[1-[2-(dimethylamino) ethyl]-3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N, N-dimethyl-2-pyridine amine
Example A-274
Figure A9880736902483
4-[1-[2-(dimethylamino) ethyl]-3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the N-[(4-fluorophenyl) methyl]-2-pyridine amine
Example A-275 3-(4-fluorophenyl)-4-[2-[2-(4-fluorophenyl) ethyl]-the 4-pyridine]-N, N-dimethyl-1H-pyrazoles-1-ethamine
Example A-276
Figure A9880736902492
The N-[(4-fluorophenyl) methyl]-4-[3 (or 5)-(4-fluorophenyl)-1-[[2-(4-morpholine) ethyl]-the 1H-pyrazol-1-yl]-2-pyridine amine
Example A-277 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N-4-piperidines-2-pyridine amine
Example A-278
Figure A9880736902501
N, N-diethyl-3-(4-fluorophenyl)-4-(2-fluoro-4-pyridine)-1H-pyrazoles-1-ethamine
Example A-279 4-[1-[2-(diethylin) ethyl]-3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the N-[(4-fluorophenyl) methyl]-2-pyridine amine
Example A-280 2-[[4-[3-(4-(fluorophenyl)-1H-pyrazoles-4-yl)-2-pyridine] amino] ethanol
Example A-281
Figure A9880736902511
2-[[4-[3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl]-the 2-pyridine] amino] ethanol
Example A-282
Figure A9880736902512
3-[[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyridine] amino]-the 1-propyl alcohol
Example A-283
Figure A9880736902513
3 (or 5)-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl) methyl] amino]-the 4-pyridine]-1H-pyrazoles-1-ethanol
Example A-284
Figure A9880736902521
N, N-diethyl-3-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazoles-1-ethamine
Example A-285
Figure A9880736902522
The N-[(4-fluorophenyl) methyl]-4-[3-(4-fluorophenyl)-1-[2-(4-morpholinyl) ethyl]-1H-pyrazoles-4-yl]-2-pyridine amine
Example A-286
Figure A9880736902523
N-[5-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazole-3-yl]-the 4-morpholine propylamine
Example A-287
Figure A9880736902531
N '-[5-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazole-3-yl]-N, N-dimethyl-1,3-propylene diamine
Example A-288 5-(4-fluorophenyl)-N-2-proyl-4-(4-pyridine)-1H-pyrazoles-3-amine
Example A-289
Figure A9880736902533
3-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl) methyl] amino]-the 4-pyridine]-1H-pyrazoles-1-ethanol
Example A-290 5-(4-fluorophenyl)-4-[2-[[(4-fluorophenyl) methyl] amino]-the 4-pyridine]-1H-pyrazoles-1-ethanol
Example A-291 The 4-[3-[(4-fluorophenyl)-and 1H-pyrazoles-4-yl] quinoline
Example A-292
Figure A9880736902543
N-[5-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazole-3-yl] glycine methyl ester
Example A-293
Figure A9880736902551
N-[5-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazole-3-yl] glycine
Example A-294
Figure A9880736902552
4-[3-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazoles-4-yl] pyridine
Example A-295
Figure A9880736902553
4-[5-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazoles-4-yl] pyridine
Example A-296 4,4 '-(1H-pyrazoles-3,4-two bases) two [pyridines]
Example A-297
Figure A9880736902562
4-[3-(3, the 4-dichlorophenyl)-1H-pyrazoles-4-yl] pyridine
Example A-298
Figure A9880736902563
N-[5-(4-chloro-phenyl-)-4-(4-pyridine)-1H-pyrazole-3-yl]-the 4-piperylhydrazine
By selecting corresponding initial reagent, by the described chemical process of scheme I-XVIII, the pyrimidine substitution compound of synthetic example A-299-A-312:
Example A-299
Figure A9880736902571
2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] pyrimidine step 1;
Figure A9880736902572
Under room temperature, 40psi (pound/in2) pressure, with the Pa Er device with 2,6-two chloro-4-methylpyrimidines (5.0g, 0.031mol), triethylamine (6.23g, 0.062mol) and 100 milliliters of THF (tetrahydrofuran (THF)) solution of the mixture of the 5%Pd/C of catalytic amount carry out hydrogenation.After half an hour, filtering catalyst, concentrated filtrate.Crude product at the enterprising circumstances in which people get things ready for a trip spectrum of silica gel (ethyl acetate/hexane, 3: 7) purifying, is obtained the light yellow crystalline product of 2.36g (productive rate 50%); Fusing point: 47～49 ℃. The preparation of step: 2-(2-chloro-4-pyrimidine)-1-(4-fluorophenyl) ethyl ketone
Figure A9880736902573
2-(2-chloro-4-pyrimidine)-1-(4-fluorophenyl) ethyl ketone
(5.5g, THF 0.037mol) (tetrahydrofuran (THF)) solution slowly join under-78 ℃ in the solution (being made by butyllithium and Diisopropylamine in THF) of diisopropyl ammonification lithium the compound that step 1 is prepared, and continue more than 30 minute.After 1 hour, (7.62g, tetrahydrofuran solution 0.045mol), reaction mixture stir and spend the night, and temperature is to room temperature to add the 4-ethyl fluoro benzoate.Add entry, use the ethyl acetate extraction water.Organic layer salt water washing, dried over mgso and filtration.Concentrated filtrate, crude product is gone up by chromatography purification at silica gel (ethyl acetate/hexane, 3: 7), obtains 4.78g yellow solid (productive rate 51%), fusing point: 112～113 ℃.Step 3:(E)-preparation of 2-(2-chloro-4-pyrimidine)-3-(dimethyl amine)-1-(4-fluorophenyl)-2-propylene-1-ketone
Figure A9880736902581
(E)-preparation of 2-(2-chloro-4-pyrimidine)-3-(dimethylamino)-1-(4-fluorophenyl)-2-propylene-1-ketone
The dimethylformamide dimethyl acetal mixture of the compound of 100 milliliters of steps 2 preparation at room temperature stirred spend the night.Remove excessive dimethylformamide dimethyl acetal under the vacuum, obtain 4.5g Vandyke brown oily crude product, this product need not be further purified and be used.Step 4:2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] (0.82g, solution 0.014mol) at room temperature stirred 6 hours with the compound (4.4g) of step 3 preparation and hydrazine hydrate for the preparation of pyrimidine.Filter and collect yellow mercury oxide,, obtain 1.85g2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl through dry air] the pyrimidine yellow solid, fusing point: 204～205 ℃; The analytical calculation value of C13H8ClFN4: C, 56.84; H, 2.94; N, 20.40; Cl, 12.91.Observed value: C, 56.43; H, 2.76; N, 20.02; Cl, 12.97.
Example A-300
Figure A9880736902582
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2 (1H)-pyrimidone hydrazones
The ethanolic soln of the compound (1.5g) of example A-299 step 3 preparation and hydrazine hydrate (5 milliliters) heated back to heat up in a steamer spend the night.After the reaction mixture cooling, remove and desolvate.Resistates is distributed in ethyl acetate and the water, organic phase salt water washing, dried over mgso and filtration.Filtrate concentrates, and crude product carries out purifying with ethyl acetate and hexane recrystallization, obtains 0.5g light yellow solid product, 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2 (1H)-pyrimidone hydrazones (productive rate 38%), fusing point: 149～150 ℃; C 13H 11FN 6The analytical calculation value: C, 57.77; H, 4.01; N, 31.10.Observed value: C, 57.70; H, 4.31, N, 30.73.
Example A-301
Figure A9880736902591
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N, N-dimethyl-2-PYRIMITHAMINE step 1: preparation
(3.0g, 0.02mol) (10.45g, dimethyl formamide solution 0.06mol) stir down at 110 ℃ and spend the night the compound that 40 milliliters of example A-299 steps 2 are prepared with two (dimethylamino) methane of the tertiary butyl.Except that after desolvating, add entry, and use ethyl acetate extraction under the vacuum.Organic layer salt water washing, dried over mgso and filtration.Concentrated filtrate carries out purifying with ethyl acetate and hexane recrystallization, obtains 1.23g yellow solid (productive rate 32%), fusing point: 76～77 ℃; C 10H 16N 4The analytical calculation value: C, 62.47; H, 8.39; N, 29.14.Observed value: C, 62.19; H, 8.58; N, 29.02.Step 2:4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N, N-dimethyl-2-PYRIMITHAMINE
With the 4-fluorobenzoyl chloride be added drop-wise to 10 milliliters of these case step 1 preparation compound (1.2g, 0.0064mol) and triethylamine (0.65g is 0.0064mol) in the toluene solution.Mixture heating up is returned and is heated up in a steamer 10 hours, removes and desolvates.Resistates is distributed in ethyl acetate and the water.Organic layer also filters with salt water washing, dried over mgso.Filtrate concentrates, and crude product (1.6g) is dissolved in 50 milliliters of ethanol.(0.36g, 0.006mol) treatment soln are returned mixture heating up and are heated up in a steamer 2 hours with hydrazine hydrate.After removing ethanol, resistates is distributed in ethyl acetate and the water.Organic phase is also filtered with salt water washing, dried over mgso.Filtrate concentrates, and crude product is gone up at silica gel (ethyl acetate/hexane, 1: 1) and carried out purifying by chromatography, obtain the 0.6g yellow solid product, 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N, N-dimethyl-2-PYRIMITHAMINE, (productive rate 33%), fusing point: 155～156 ℃; C 15H 14FN 5The analytical calculation value: C, 63.59; H, 4.98; N, 24.72.Observed value: C, 63.32; H, 4.92; N, 24.31.
Example A-302
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N-methyl-2-PYRIMITHAMINE
In sealed tube, with 10 milliliters of 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazoles-4 bases according to example A-299 preparation] methylamine (40% aqueous solution) suspension of pyrimidine is 100 ℃ of following heated overnight.Then mixture is cooled to room temperature, throw out after filtration, dry air, obtain the 0.2g white solid product, 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N-methyl-2-PYRIMITHAMINE, (productive rate 68%), fusing point: 217～218 ℃; C 14H 12FN 5The analytical calculation value: C, 62.45; H, 4.49; N, 26.01.Observed value: C, 62.58; H, 4.36; N, 25.90.
Example A-303
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N-(phenmethyl)-2-PYRIMITHAMINE
This compound is by will be according to 2-chloro-4-[3-(4-the fluorophenyl)-1H-pyrazoles-4-yl of example A-299 preparation] pyrimidine in benzylamine, return heat up in a steamer spend the night synthetic.Product is a white solid product, 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-N-(phenmethyl)-2-PYRIMITHAMINE, its productive rate is 95%; Fusing point: 216～217 ℃; C 20H 16FN 5The analytical calculation value: C, 69.55; H, 4.67; N, 20.28.Observed value: C, 69.73; H, 4.69; N, 19.90.
Example A-304
N-cyclopropyl-4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-PYRIMITHAMINE
This compound is by under 50 ℃, at 2-chloro-4-[3-(4-the fluorophenyl)-1H-pyrazoles-4-yl of methanol solution according to example A-299 preparation] pyrimidine and excessive cyclopropylamine stir 12 hours synthetic.Product is a white solid product, N-cyclopropyl-4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-PYRIMITHAMINE, its productive rate is 26%; Fusing point: 203～204 ℃; C 16H 14FN 5The analytical calculation value: C, 65.07; H, 4.78; N, 23.71.Observed value: C, 64.42; H, 4.82; N, 23.58.
Example A-305
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the N-[(4-methoxyphenyl) methyl]-the 2-PYRIMITHAMINE
This compound is with 2-chloro-4-[3-(4-the fluorophenyl)-1H-pyrazoles-4-yl according to example A-299 preparation] pyrimidine in the 4-methoxybenzylamine by return heat up in a steamer spend the night synthetic.Obtain the rice white solid product, 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] the N-[(4-methoxyphenyl) methyl]-the 2-PYRIMITHAMINE, its productive rate is 80%; Fusing point: 183～185 ℃; C 21H 18FN 5The analytical calculation value of O: C, 67.19; H, 4.83; N, 18.66.Observed value: C, 67.01; H, 5.11; N, 18.93.
Example A-306
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-PYRIMITHAMINE
With 15 milliliters of 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yls according to example A-305 preparation]-the N-[(4-methoxyphenyl) methyl]-(0.35g, trifluoroacetic acid solution 0.00093mol) heats back heats up in a steamer 16 hours to the 2-PYRIMITHAMINE.Remove and desolvate, resistates is distributed in ethyl acetate and the 1N oxyammonia.Organic layer also filters with salt water washing, dried over mgso.Filtrate concentrates, and upward carries out purifying with chromatography at silica gel (ethyl acetate), obtains 0.14g light yellow solid product, 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-PYRIMITHAMINE, its productive rate is 59%, fusing point: 273～274 ℃; C 13H 10FN 3O0.25H 2The analytical calculation value of O: C, 60.11; H, 4.07; N, 26.96.Observed value: C, 60.15; H, 3.82; N, 26.38.
Example A-307
N-[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyrimidine]-N-(phenmethyl) ethanamide
With triethylamine (0.053g, 0.00052mol) join 10 milliliters of 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yls by example A-303 preparation]-N-(phenmethyl)-2-PYRIMITHAMINE (0.15g, 0.00043mol), DMAP (0.027g, 0.00022mol) and diacetyl oxide (0.066g is in tetrahydrofuran compound 0.00066mol).Solution at room temperature stirs and spends the night.Except that after desolvating, residuum is distributed in ethyl acetate and the water.Organic layer is with saturated sodium bicarbonate washing, salt water washing, dried over mgso and filtration.Filtrate concentrates, and crude product is developed with ether, obtains the 0.1g white solid product, N-[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyrimidine]-N-(phenmethyl) ethanamide (productive rate 60%), fusing point: 176～178 ℃; C 22H 18FN 5The analytical calculation value of O: C, 68.21; H, 4.68; N, 18.08.Observed value: C, 67.67; H, 4.85; N, 17.79.
Example A-308
Figure A9880736902631
[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2-pyrimidine] urethanum
Ethyl chloroformate is added drop-wise to 5 milliliters of 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yls by example A-306 preparation]-(0.26g is in pyridine suspension 0.001mol) for the 2-PYRIMITHAMINE.After adding, clear soln at room temperature stirred 6 hours.Add entry, the water ethyl acetate extraction.Organic layer also filters with salt water washing, dried over mgso.Filtrate concentrates, and crude product is developed with ether, obtains the 0.15g white solid product, ethyl [4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2-pyrimidine] carbamate (productive rate 46%), fusing point: 163～165 ℃; C 16H 14FN 5O 2The analytical calculation value: C, 58.71; H, 4.31; N, 21.04.Observed value: C, 59.22; H, 4.51; N, 21.66.
Example A-309
Figure A9880736902632
4-[3-(3-tolyl)-1H-pyrazoles-4-yl] pyrimidine
The same steps as preparation that this compound is narrated by example A-208 just replaces 4-fluorobenzoyl-4-pyridine methane with 1-methyl-3-(4 '-pyrimidine ethanoyl) benzene (method of being narrated by example A-19 step 1 by 4-methyl-pyrimidine and methyl 3-methyl benzoic acid ester prepares).C 14H 12N 4(236.27) analytical calculation value: C, 71.17; H, 5.12; N, 23.71.Observed value: C, 70.67; H, 5.26; N, 23.53.Fusing point (DSC): 151.67 ℃.
Example A-310
Figure A9880736902641
4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4-yl] pyrimidine
This compound is according to plan V I and the described chemical process of IX, replaces the pyridine starting raw material to prepare by selecting corresponding pyrimidine starting raw material.C 13H 9N 4Cl0.25H 2The ultimate analysis calculated value of O: C, 59.78; H, 3.67; N, 21.45.Observed value: C, 59.89; H, 3.32; N, 21.56.Fusing point (DSC): 218.17 ℃.
Example A-311
Figure A9880736902642
4-[3-(3-fluorophenyl)-1H-pyrazoles-4-yl] pyrimidine
This compound is according to plan V I and the described chemical process of IX, replaces the pyridine starting raw material to prepare by selecting corresponding pyrimidine starting raw material.C 13H 9N 4The ultimate analysis calculated value of F (240.24): C, 64.99; H, 3.78; N, 23.22.Observed value: C, 64.78; H, 3.75; N, 23.31.Fusing point (DSC): 168.58 ℃.
Example A-312
4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] pyrimidine
This compound is according to plan V I and the described chemical process of IX, replaces the pyridine starting raw material to prepare by selecting corresponding pyrimidine starting raw material.C 13H 9N 4The ultimate analysis calculated value of F (240.24): C, 64.99; H, 3.78; N, 23.32.Observed value: C, 64.94; H, 3.56; N, 23.44.Fusing point (DSC): 191.47 ℃.
Adopting one or more reaction scheme of stating among the application to restrain other compound that is equipped with includes, but is not limited to:
Figure A9880736902652
4-[3-(4-chloro-phenyl-)-5-(1-piperazine)-1H-pyrazoles-4-yl] pyrimidine
Figure A9880736902653
1-[5-(4-bromophenyl)-4-(4-pyridine)-1H-pyrazole-3-yl] piperazine
Figure A9880736902661
1-[4-(4-pyridine)-5-[4-(trifluoromethyl) phenyl]-the 1H-pyrazole-3-yl] piperazine 4-[5-(1-piperazine-4-(4-pyridine)-1H-pyrazole-3-yl) cyanobenzene
Figure A9880736902663
1-[5-(4-acetylenylbenzene)-4-(4-pyridine)-1H-pyrazole-3-yl] piperazine 5-(4-fluorophenyl)-4-(4-pyridine)-N-3-pyrrolidyl-1H-pyrazoles-3-amine
Figure A9880736902671
5-(4-chloro-phenyl-)-4-(4-pyridine)-N-3-pyrrolidyl-1H-pyrazoles-3-amine
Figure A9880736902672
N-[5-(4-fluorophenyl)-4-(4-pyridine)-1H-pyrazole-3-yl]-the 4-piperylhydrazine
Figure A9880736902673
3-(4-fluorophenyl)-5-(1-piperazine)-4-(4-pyridine)-1H-pyrazoles-1-ethanol
Figure A9880736902674
3-(4-chloro-phenyl-)-5-(1-piperazine)-4-(4-pyridine)-1H-pyrazoles-1 ethanol
Figure A9880736902681
The 4-[2-aminoethyl]-2-(4-fluorophenyl)-4,5,6,7-tetrahydrochysene-3-(4-pyridine) pyrazoles [1,5-a] pyrimidine-6-alcohol
Figure A9880736902682
The 4-[2-aminoethyl]-2-(4-chloro-phenyl-)-4,5,6,7-tetrahydrochysene-3-(4-pyridine) pyrazoles [1,5-a] pyrimidine-6-alcohol
Figure A9880736902683
3-(4-chloro-phenyl-)-4-(4-pyrimidine)-1H-pyrazoles-1-ethanol
Figure A9880736902684
5-(4-fluorophenyl)-4-(4-pyrimidine)-1H-pyrazoles-3-ethamine
Figure A9880736902691
5-(4-chloro-phenyl-)-4-(4-pyrimidine)-1H-pyrazoles-3-ethamine 4-[3-(4-fluorophenyl)-5-(4-piperidines)-1H-pyrazoles-4-yl] pyrimidine
Figure A9880736902693
4-[3-(4-chloro-phenyl-)-5-(4-piperidines)-1H-pyrazoles-4-yl] pyrimidine N-[4-] 3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyrimidine] ethanamide
Figure A9880736902701
N-[4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4-yl]-the 2-pyrimidine] ethanamide N-[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-2-pyrimidine propylamine
Figure A9880736902703
N-[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyrimidine] propylamine 6-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 1H-purine 6-[3-(4-chloro-phenyl-)-1H-pyrazolyl-4-yl]-the 1H-purine
Figure A9880736902712
N-[4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4-yl]-the 2-pyrimidyl]-N-(phenmethyl) ethanamide
Figure A9880736902713
N-[4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl]-the 2-pyrimidyl]-N-(phenmethyl) propionic acid amide
N-[4-[3-(4-chloro-phenyl-)-1H-pyrazolyl-4-yl]-the 2-pyrimidyl]-N-(phenmethyl) propionic acid amide
Biological assessment
The p38 kinase assays The clone of people p38a:
The coding region of people p38a cDNA from human monocyte cell line THP.1 isolating RNA through pcr amplification.First gang of cDNA be from total RNA with following method synthetic: 2 μ g RNA and 100ng random hexamer primer in 10 μ l reaction, by be heated to 70 ℃ 10 minutes, postposition 2 minutes on ice.Subsequently, add RNA enzyme 11 (Promega, MadisonWI), 50mM dNTP ' s 2 μ l, 5 * damping fluid, 4 μ l, 100mM DTT 2 μ l and Superscript II TMAMV reversed transcriptive enzyme 1 μ l (200U) is with synthetic cDNA.Random primer, dNTP and Superscript TMReagent is all available from the Gaithersburh of Life Technologies, Inc. (Life-Technologies), MA.Being reflected at 42 ℃ hatched 1 hour.The amplification of p38 cDNA goes into 5 μ l reversed transcriptive enzyme five equilibriums in the 100 μ lPCR reaction to finish, and the PCR reaction is composed as follows: distilled water 80 μ l, 50mM dNTP ' s 2 μ l, forward and reverse primer each 1 μ l (50pmol/ μ l), 10 * damping fluid, 10 μ l and Expand TM polysaccharase 1 μ l (Bao Ling Man).The PCR primer mixes amplification pulsating 5 ' and 3 ' end available from Genosys with Bam HI site.The sequence of forward and reverse primer is respectively 5 '-GATCGAGGATTCATGTCTCAGGAGAGGCCCA-3 ' and 5 '-GATCGAGGATTCTCAGGACTCCATCTCTTC-3 '.Pcr amplification is to carry out in DNA thermal cycler (Perkin Elmer), 94 ℃ 1 minute, 60 ℃ 1 minute, 68 ℃ 2 minutes, 30 times the circulation.After the amplification, unnecessary primer and uncorporated dNTP Wizard TMPCR prep (Promega) removes from the amplification segment, and digests with Bam HI (New England Biolabs).As T.Maniatis at molecular cloning: laboratory manual, described in the second edition (1989), the segment of Bam HI digestion combines with the pGEX 2T plasmid DNA (PhamaciaBiotech) that T-4 dna ligase and BamHI digest.According to manufacturers instruction, utilize ligation to transform into available from the chemically active intestinal bacteria DH10B of having of the Life-technologies cell.Use Promega Wizard TMThe micropreparation test kit is separated plasmid DNA from resulting bacterial clone.Contain the pulsating plasmid Prism of suitable Bam HI TM(Applied Biosystems Inc.) checks order in DNA thermal cycler (Perkin Elmer).The cDNA clone is accredited as coding two kinds of isoforms of people p38a (Lee et al.Nature 372,739).One of them clone contains the cDNA of p38a-2 (CSBP-2), is inserted into the cloning site of pGEX 2T, and 3 ' end of GST coding region is named as PMON35802.The cDNA clone of people's reports such as sequence that obtains from this clone and Lee is very identical.This expression plasmid can produce the fusion rotein of GST-p38a. The expression of people p38a:
The GST/p38a fusion rotein is that (Life Technoligies, Gibco-BRL) the plasmid pMON 35802 in expresses by DH10B strain intestinal bacteria.Bacterial strain is incubated overnight in containing the Luria Broth (LB) of 100mg/ml Ampicillin Trihydrate.The 10ml overnight culture inoculated among the fresh LB of 500ml in second day, put in 2 liters of flasks and grow, 37 ℃ of sustained oscillations reach 0.8 until culture 600nm absorbancy.Fusion rotein is abduction delivering by adding sec.-propyl b-D-thiogalactoside (IPTG) that final concentration is 0.05mM.Culture is at room temperature vibration 3 hours, centrifugal collecting cell.The cell precipitation stored frozen is until protein purification. The purifying of p38 kinases-α:
Except indicating the person, all chemical reagent are all available from Sigma Chemical Co..20 gram Bacillus coli cells precipitation 200mlPBS (140mM NaCl, 2.7mM KCl, the 10mM Na that from 51 liter vibration flask fermented product, collect 2HPO 4, 1.8mM KH 2PO 4, pH7.3) resuspended.Cell suspension is adjusted to 5mM DTT with 2M DTT, and the equivalent branch is gone in the Fu Shi conical tube of 5 50ml then.Cell with 1cm probe in supersound process (Ultrasonics modelW375) 3 times * 1 minute (pulse) on ice.The dissolved cellular constituent is removed through centrifugal (12,000 * g, 15 minutes), and limpid supernatant joins (Pharmacia) in gsh-agarose resin. Gsh-agarose affinity stratographic analysis:
50% glutathione agarose-PBS suspension 12ml adds in the limpid supernatant of 200ml, at room temperature, hatches 30 minutes with batchwise.Centrifugal collection resin (600 * g, 5 minutes), and wash 2 times with 150ml PBS/1%Triton X-100, wash 4 times with 40ml PBS then.For cracking from the GST-p38 fusion rotein goes out the p38 kinases, (Pharmacia, specific activity has hanged gsh-agarose resin again greater than the PBS 6ml of 7500 units/mg), mixes gently at room temperature 4 hours with containing 250 unit zymoplasm proteolytic enzyme.Centrifugal (600 * g, 5 minutes) remove gsh-agarose resin, and wash 2 times with 6ml PBS.PBS elutant and the digestion supernatant that contains the p38 kinase protein are mixed, and be adjusted into 0.3mM PMSF. Single Q anion-exchange chromatography is analyzed:
Zymoplasm cracked p38 kinases is further purified through the FPLC-anion-exchange chromatography.The sample that zymoplasm downcuts injects with buffer A equilibrated list Q HR10/10 (Pharmacia) anion-exchange column then with buffer A (25mM HEPES, pH7.5,25mM β-phospho-glycerol, 2mM DTT, 5% glycerine) dilution twice.Exchange column 160ml 0.1M-0.6MNaCl/ buffer A gradient (flow velocity 2ml/ branch) wash-out.Be collected in the p38 kinases elution peak at 200mM NaCl place, with Filtron 10 concentrating instruments (Filtron Corp.) simmer down to 3-4ml. Sephacrvl S100 analysed by gel filtration chromatography:
Use gel filtration chromatography (Pharmacia HiPrep 26/60 Sephacryl S100 post is with buffer B (50mMHEPES, pH7.5,50mM NaCl, 2mM DTT, 5% glycerine) balance) to carry out purifying again in spissated single Q-p38 kinases purifying sample.Albumen flow velocity from the post wash-out of buffer B with 0.5ml/min, and use the 280nm absorbance detection.Containing the kinase whose segment of p38 (detecting through the SDS-polyacrylamide gel electrophoresis) mixes and is chilled in-80 ℃.The typical purifying protein that obtains from 5 liters of intestinal bacteria oscillation and fermentation flasks is the 35mgp38 kinases.Vitro detection
Compound suppresses the ability of people p38 kinases α and estimates with two external experimental techniques.In first method, there is γ 32P-ATP ( 32P-ATP) under the situation, the biotinylated substrate PHAS-I of activated people p38 kinases α phosphorylation (insulin-induced, phosphorylation, to heat and the stable albumen of acid).PHAS-I is by biotinylation before experiment, thereby can catch phosphorylated substrate in experimentation.The p38 kinases is by the MKK6 activated.The detection of compound is carried out to 10 times of serial dilutions between the 0.001 μ M scope at 100 μ M with 1%DMSO.The concentration replicate(determination) of each inhibitor 3 times.
All are reflected in the 96 hole polypropylene boards carries out.Contain pH7.5 HEPES25mM in each reacting hole, 10mM magnesium acetate and the unlabelled ATP of 50 μ M.In experiment, activate for obtaining enough signal demand p38.With 1-2 μ g, final concentration is 1.5 μ M in the per 50 μ l reaction volumes of biotinylation PHAS-I.With 1 μ g, being equivalent to final concentration is 0.3 μ M in the per 50 μ l reaction volumes of activated people p38 kinases α.Add γ after the PHAS-I phosphorylation 32P-ATP. 32The P-ATP specific activity is 3000Ci/mmol, and per 50 μ l reaction volumes are with 1.2 μ Ci.Being reflected at 30 ℃ carried out 1 hour or spent the night.
After hatching, 20 μ l reaction mixtures be transferred on the filter plate of using the moistening heavy body streptavidin bag quilt of phosphate-buffered saline in advance (SAM-streptavidin-matrix, Promega).The reaction mixture that shifts can contact the streptavidin film 1-2min on the Promega plate.Mix having caught 32Behind the biotinylation PHAS-I of P, uncorporated for removing 32P-ATP, every hole is washed 3 times with 2M NaCl, and the 2M NaCl that contains 1% phosphorus washes 3 times, distillation washing 3 times, last 95% ethanol is washed 1 time.Filter plate is air-dry, adds 20 μ l scintillation solutions.The sealing counting.The result is displayed in Table 4.
The second method of using also is based on 33P-ATP exists down, and p38 kinases α induces EGFRP (egfr peptide, a 21mer) phosphorylation.The detection of compound is carried out to 10 times of serial dilutions between the 0.001 μ M scope at 100 μ M with 1%DMSO.Every kind of parallel detection of inhibitor concentration 3 times.Compound is estimated in the reaction volume of 50 μ l, wherein contains pH7.5 Hepes 25mM, 10mM magnesium acetate, 4% glycerine, 0.4% bovine serum albumin, 0.4mM DTT, the unlabelled ATP of 50 μ M, 25 μ g EGFRP (200 μ M) and 0.05 μ Ci γ 33P-ATP.Reaction starts by adding 0.09 μ g activated purifying people GST-p38 kinases α.Under the condition that 50 μ MATP exist, (5: 1, p38: MKK6) 30 ℃ of effects activated in 1 hour with GST-MKK6.After the incubated at room 60 minutes, add 150 μ l AG, 1 * 8 resin stopped reaction, this resin dissolves in 900mM sodium formiate damping fluid, pH3.0 (1 volume of resins is than two volume damping fluids).Mixture mixes 3 times with suction pipe, makes resin precipitated.The upper strata settled solution of cumulative volume 50 μ l is transferred to the micro plate (Microlite-2) from reaction tank.Add 150 μ l Microscint 40 then in each hole of micro plate, sealing mixes and counting.
Table 4Embodiment p38 kinases embodiment p38 kinases
IC50 (μ M) IC50 (μ M) 1 4.6 42 0.32 1.5 43＜0.18＜0.1 44＜0.116 3.8 45＜0.123 1.5 46＜0.125 2.6 47 3.226 0.7 48 1.828 0.3 50 2.333 2.5 51＜0.134 8.0 52 0.136 12.1 53 0.938 0.8 54 0.739 1.1 55 6.440 1.3 143＜0.1TNF cell detectsThe method of separation of human peripheral blood lymphocytes:
With people's whole blood collection in the Vacutainer pipe that contains as the EDTA of antithrombotics.Blood sample this (7ml) 5ml PMN cellular segregation liquid (Robbins Scientific) careful layering in the 15ml round bottom centrifuge tube.Sample at room temperature, in swinging open type centrifuge with 450-500 * centrifugal 30-35 of g speed minute.Remove the epipelagic zone cell after centrifugal, wash 3 times with no calcium or the PBS that do not have magnesium (w/o).Eccentric cell 400 * g under the room temperature, 10 minutes.With 2,000,000 cell/ml concentration has been hanged cell again with scavenger cell serum free medium (Gibco BRL).LPS stimulates people PBMs:
The PBM cell (0.1ml, 2,000,000/ml) in flat 96 hole micro plates, hatched jointly 1 hour with 0.1ml compound (10-0.41 μ M final concentration).With the DMSO dissolving, be diluted to final concentration with TCM then is 0.1%DMSO to compound earlier.Add 0.010mlLPS (Calbiochem, 20ng/ml final concentration).37 ℃ of overnight incubation.Shift out supernatant and detect TNF-α, IL1-b with the ELISA method.Detect vigor with MTS.After collecting the 0.1ml supernatant, in remaining 0.1ml cell, add 0.020ml MTS.Hatched 2-4 hour for 37 ℃, measure the O.D. value then at the 490-650nm place. U937 human tissue lymphoma cell line keeps and breaks up:
U937 cell (ATCC) is bred in RPMI 1640 substratum that contain 10% calf serum, 100IU/ml penicillin, 100 μ g/ml Streptomycin sulphates and 2mM glutamine (Gibco).Hatch with 20ng/ml phorbol 12-myristate 13-acetate (Sigma) and to make in the 100ml nutrient solution 50,000,000 cell induction in 24 hours to monocyte differentiation whole latter stage.Cell hangs again by centrifugal (200 * g, 5 minutes) washing and with the 100ml fresh medium.Collecting cell after 24-48 hour, centrifugal, hanged cell again with nutrient solution, concentration is 2,000,000 cell/ml. The generation of TNF behind the LPS stimulation U937 cell:
The U937 cell (0.1ml, 2,000,000/ml) in 96 hole micro plates, hatched 1 hour with 0.1ml compound (0.004-50 μ M, final concentration).Compound is the DMSO storing solution of 10mM, and in cell experiment, being diluted to the DMSO final concentration in nutrient solution is 0.1%.Add 0.02ml LPS (intestinal bacteria, final concentration are 100ng/ml) then.37 ℃ hatch 4 hours after, the TNF-α that is discharged in the nutrient solution carries out quantitatively with the ELISA method.Inhibition strength is expressed as IC50 (μ M).The results are shown in Table 5 for these TNF cell experiments.
Table 5 embodiment human body PBM detects the U937 cell detection
IC50(μM)???????????IC50((μM)
1???????????????????0.5
2???????????????????1.6????????????????0.578
4???????????????????0.1????????????????0.222
5??????????????????????????????????????0.274
7???????????????????0.2????????????????0.201
8???????????????????＜0.1
9???????????????????0.4
10??????????????????0.7????????????????1.687
12??????????????????8.5
13??????????????????4.8
14??????????????????1.2
17??????????????????1.1
19??????????????????0.3????????????????0.484
20?????????????????????????????????????1.089
21?????????????????????????????????????0.077
22??????????????????3.2
24??????????????????8.2
26??????????????????＜0.1??????????????0.029
27??????????????????2.7
28??????????????????0.1
29??????????????????2.2
30??????????????????2.6
31??????????????????0.8????????????????1.053
32?????????????????????????????????????2.696
33??????????????????0.4
34??????????????????0.5
35??????????????????0.7
36??????????????????1.4
37??????????????????1.5????????????????0.099
38??????????????????0.2????????????????0.208
39??????????????????0.7????????????????0.244
40??????????????????0.4
41??????????????????1.0
42??????????????????0.7
43??????????????????＜0.1??????????????0.243
44??????????????????0.4????????????????0.477
45??????????????????＜0.1??????????????0.04
46?????????????????????????????????????0.329
47?????????????????????????????????????2.359
48??????????????????2.2????????????????0.522
49??????????????????6.8
50??????????????????0.9
51?????????????????????????????????????0.074
54??????????????????0.2????????????????0.13
55??????????????????＜0.1??????????????0.228
143 0.301 rat experiments
The effect that new compound blocking-up TNF produces is also estimated with the rat model that LPS stimulates.In this model, adopt male Harlen Lewis rat (Sprague Dawley Co.).Every heavily about 300g of rat, experiment fasting in eve.Compound give typically 1-24 hour per os tube feed (although under a few cases, also using intraperitoneal, subcutaneous and intravenous administration) before LPS stimulates.Rat is injected 30 μ g/kg LPS (Salmonella typhi, Sigma Co.) through the tail vein.LPS stimulated after 1 hour, collected blood through the heart puncture.Serum sample is stored in-20 ℃ up to using (Biosource) quantitative assay TNF-α of enzyme linked immunological absorption experiment (" ELISA ").Other experimental details are set forth in Perretti, M., and et al., Br.J.pharmacol. (1993), 110,868-874, this literary composition is incorporated in the application's book as a reference.Mouse experiment The mouse model that LPS induces TNF-α to produce:
The BALB/c female mice tail vein injection 100ng of 10-12 week size is dissolved in 0.2ml brinish lipopolysaccharides (from S.Typhosa) and produces to induce TNF-α.Mouse is from the bloodletting of ball posterior vein hole after 1 hour, and the TNF concentration of free serum is carried out quantitative assay with ELISA in the blood clot.Typically, inject after LPS1 hour, serum TNF peak level scope is between 2-6ng/ml.
The compound of surveying at injection LPS preceding 1 hour or 6 hours, with 0.2ml 0.5% methylcellulose and 0.025% polysorbas20 suspendible aqueous solution form, the per os tube feed is given the fasting mouse.Experiment in 1 hour can the effect of assessing compound when the maximal plasma concentration level, but and the time length of 6 hours experiment assessing compounds effect.Effect depends on each time point, with respect to the lps injection mouse of only accepting media, and the percentage ratio that the serum TNF level suppresses.
Set forth in other results table 6 below that above-mentioned experiment obtains.The result of P38 experiment and U937 cell experiment is expressed as IC 50(μ m).Mouse-LPS experimental result is represented with inhibition percentage ratio.
Table 6
Example ??p38 1 ??p38 2 ?U937 ??mLPS ????mLPS ????mLPS
????8h ??6h?dose ??1h，30mpk
???A-212 ??0.49 ??0.74 ?0.0967 ????20 ????10 ????93
???A-208 ??0.104 ??0.049 ?0.1896 ????98 ????30 ????97
???A-227 ??0.06 ????96
???A-228 ??0.76 ??0.339 ?0.4173 ????32 ????30 ????92
???A-229 ??1.4 ?0.4622 ????76 ????91
???A-230 ??0.42 ??0.178 ????96
???A-231 ??0.174 ?0.3225 ????86 ????30 ????94
???A-232 ??0.048 ????96
???A-233 ??0.044 ????53
???A-234 ??0.103
???A-235 ??0.104 ????56
???A-236 ??0.237 ????94
???A-237 ??0.093 ?0.087 ????60
???A-238 ??0.177 ?0.4016
???A-239 ??0.034 ????51 ????30 ????87
???A-240 ??0.961 ????78 ????30 ????85
???A-241 ??0.338 ????79 ????30 ????87
???A-242 ??0.047 ????95 ????30 ????87
???A-243 ??0.729 ????82
???A-244 ??0.099
???A-245 ??＜.001 ?0.0337 ????65
???A-246 ??0.403 ??0.592 ?0.4952
???A-247 ??＜0.01 ?0.166
???A-249 ??0.432 ????73 ????30 ????86
???A-250 ??2.873
???A-251 ??0.637 ????32 ????87
???A-252 ??0.774 ?1.197 ????48 ????30 ????75
???A-253 ??＜.001 ?0.0044 ????61
???A-254 ??0.081 ?0.1411
???A-215 ??2.34 ?0.2976 ????38 ????30 ????80
???A-256 ??0.813 ?0.4562
???A-257 ??1.081 ??＜.01 ?0.5167
???A-213 ??0.22 ????57
???A-258 ??0.48 ?1.2083 ????68
???A-259 ??0.17 ?0.7574 ????62
???A-210 ??0.16 ?0.1983 ????85 ????30 ????93
???A-260 ??0.23 ?1.2821 ????47 ????30 ????79
???A-214 ??0.06 ?1.4006 ????70
???A-261 ??0.008 ?0.2542 ????48 ????30 ????92
???A-216 ??0.018 ?1.8287 ????27 ????30 ????91
???A-262 ??＜0.1 ?0.3267 ????45
???A-263 ??＜0.01 ??＜0.1 ?0.5434 ????49
Example ?p38 1 ??p38 2 ??U937 ??mLPS ????mLPS ????mLPS
????8h ??6h?dose ??1h，30mpk
??A-264 ??0.2594 ????61
??A-265 ??＜0.1 ??0.6016 ????32
??A-266 ??0.5393 ????0
??A-267 ??0.43 ??2.6681 ????80
??A-268 ??＜0.01 ??0.0074 ????11
??A-217 ?0.697 ??0.3486 ????9
??A-269 ??＞10uM ????51
??A-270 ??0.015 ??0.3466 ????53
??A-271 ??0.216 ??4.2144 ????68
??A-272 ?0.073 ??0.583 ????-8
??A-273 ?6.98 ??＞10 ????43
??A-274 ?＜0.1 ??0.92 ????21 ????30
??A-275 ?10.14 ?2 ??＞10
??A-276 ?0.176 ??0.45 ????-24 ????30
??A-277 ?0.026 ????33 ????30
??A-278 ?0.285 ??2.3 ????62 ????30
??A-279 ?0.005 ??0.7 ????64 ????30
??A-280 ?0.134 ????15 ????30
??A-281 ?0.053 ????22 ????30
??A-218 ?0.044 ????18 ????30
??A-282 ?0.045 ??0.0973 ????30 ????30
??A-283 ?＜0.1 ??0.7998 ????-20 ????30
??A-284 ?0.98 ??0.5088 ????-1
??A-285 ?＜0.1 ??0.1795 ????11 ????30
??A-286 ?0.057 ??0.09 ????29 ????30
??A-287 ?0.041 ??0.27 ????-24 ????30
??A-288 ?0.017 ??0.3 ????40 ????30
??A-289 ?＜0.1 ??0.14 ????44 ????30
??A-290 ??6.0191 ????4 ????30
??A-291 ?0.388 ??1.1309 ????36 ????30
??A-292 ?1.15 ??＞10
??A-293 ?0.73
??A-294 ?0.015 ??0.5 ????61 ????30
??A-295 ?7.66 ??＞10 ????94 ????30
??A-296 ?26
??A-297 ?0.52 ??0.17 ????89 ????30
1The result is based on the PHAS-I experimentation in p38 α in vitro tests 2P38 in vitro tests result is based on the EGFRP experimentation
The inducing and estimating of mouse arthritis due to the collagen:
Method described in the collagen autoimmune sacroiliitis that inducing mouse sacroiliitis is delivered at Annual Rev.Immunol.2:199 (1984) according to J.M.Stuart is carried out, and this literary composition is quoted in this application as a reference.Especially, injected and complete freund adjuvant (Sigma) blended chicken II Collagen Type VI (CII) 50 μ g (the Dr.Marie Griffiths by salt lake city You Ta university provides) by root of the tail portion by the 0th day, in the DBA/1 in 8-12 week male mice, induce sacroiliitis.Volumetric injection is 100 μ l.The 21st day, animal was used with incomplete freund adjuvant (100 μ l volume) blended 50 μ gCII and excites.The arthritic several times performance of animal per weekly check.Pawl animal rubescent or swelling then is designated as sacroiliitis.The scoring of sacroiliitis claw is according to the Gene Handling at II Collagen Type VI inductive mouse arthritis such as Wooley: influence the factor of disease susceptibility and the evidence of multiple MHC genes involved control, Trans.Proc., the method described in 15:180 (1983) one literary compositions is carried out.The scoring of seriousness adopts every claw 1-3 branch (maximum scores 12/ every mouse) to carry out.Any finger of animal or pawl show that rubescent or swelling is designated as 1 fen.Overall swelling in whole joint or deformity are designated as 2 fens.Ankylosis are designated as 3 fens.Animal estimated for 8 weeks.Use 8-10 animal for every group. The preparation of compound and administration:
The compound of on collagen-induced sacroiliitis mouse, testing for 0.5% methylcellulose (Sigma, St.Louis, MO), the suspension in 0.025% polysorbas20 (Sigma).The administration of compound suspension is amount twice per os tube feed every day with 0.1ml.The final evaluation that always lasted till the 56th day is used in beginning administration in the 20th day every day behind injection collagen.The scoring of sacroiliitis claw is by top described carrying out.Experimental result is listed in table 7.
Table 7
Compound Arthritic inhibition per-cent
A-210??????????????????????????58.5@15mpk
A-172??????????????????????????49.3@100mpk
A-189??????????????????????????51.6@30mpk
A-208??????????????????????????97.5@60mpk
A-208??????????????????????????75.0@60mpk
In this invention, also comprised one group of pharmacy composition that constitutes active compound of the present invention, and one or more are nontoxic, pharmacology acceptable carrier and/or thinner and/or adjuvant (to sum up becoming " carrier " material here), if desired, also have other activeconstituentss.Active compound of the present invention can be with any suitable administration, preferably being fit to the pharmacy composition form of this approach, and the preferred effective dose that satisfies the treatment needs.For example, active compound and composition can be oral, intravascular injection (IV), intraperitoneal injection, subcutaneous injection, intramuscularly (IM) or local topical.For oral, it can be for example tablet, hard or soft capsule, lozenge, accessible pulvis, suspension or liquid that pharmacy is formed.The pharmacy composition is preferably made the dosage unit form that contains the specified quantitative activeconstituents.The example of this dose unit is tablet and capsule.Activeconstituents also can drug administration by injection (IV, IM, subcutaneous or jet), salt solution for example during it is formed, and glucose or water can be used as appropriate carriers.In case of necessity, the pH of composition can be with suitable acid, alkali or damping fluid adjustment.Suitable swelling agent, disperse means, wetting agent or suspension agent comprise N.F,USP MANNITOL and PEG400, also can be included in the composition.A suitable parenteral is formed can also comprise the compound that is designed to the sterile solid material, is included in the lyophilized powder in the injection bottle.Before injection, can add aqueous solution dissolved compound.The therapeutic dose of application of active compound and be that treatment a kind of morbid state needed dosage depends on various factors with compound of the present invention and/or component, comprise the age, body weight, sex and receptor's medical condition, the severity of inflammation or inflammation related disease, route of administration and number of times and applied special compound, therefore changing can be very big.It approximately is 0.1-1000mg that pharmacy is formed the activeconstituents scope that can contain, preferably at 7.0-350mg.The about 0.01-100mg/ kg body weight of dosage every day, preferably in about 0.1-50mg/ kg body weight, only is in about 0.5-30mg/ kg body weight.The dosage of every day can divide and gives for 1-4 time.For the illness of skin, the external preparation of handy The compounds of this invention is to suffering from district one day with 2 to 4 times.For the illness of eye or other outside organization, as mouth and skin, gel, sprays, ointment or the emulsion of external application is preferably used in design, or suppository, activeconstituents that in total amount, comprises such as 0.075-30%w/w, preferably 0.2-20%w/w, preferably 0.4-15%w/w.When being designed to ointment, activeconstituents can be used and paraffin or the codissolved finish composition of water.Selection in addition is that activeconstituents can be designed to oil-in-water emulsion form.If desired, the water in the emulsion can comprise as the polyvalent alcohol of 30%w/w at least, as propylene glycol, butane-1,3-glycol, N.F,USP MANNITOL, sorbyl alcohol, glycerine,, polyethylene glycol and their mixture.External preparation may need to comprise a kind of compound that can strengthen absorption and make activeconstituents skin permeation or other site of action.The example of this skin penetration enhancer comprises methyl-sulphoxide and related analogs.Compound of the present invention can also be used the transcutaneous device administration.The passage of medication pond and porous-film or solid substrate variant can be realized topical preferably.For every kind of mode, promoting agent constantly is released into the saturable surface of adherence of promoting agent by a skim from medicine pond or tiny capsules, and this one side can contact with receptor's skin or mucous membrane.If promoting agent is by skin absorption, the flow that promoting agent discharges to the receptor is control and predefined.For tiny capsules, sealing agent also can be used as film.The transdermal passage can include adhesive systems, as acrylic latex, is dissolved in the compound of appropriate solvent system, and a polyester passage.The oil phase of latex of the present invention can constitute from known composition with known method.Though but instrument is made up of a kind of emulsifying agent mutually, the mixture of also at least a emulsifying agent and a kind of fat or a kind of oil or while and the mixture of fat with oil.Preferably a kind of hydrophilic emulsifying agent and a kind of lipophilic emulsifier as stablizer lump together.In a word, the emulsifying agent that adds or do not add stablizer has been formed so-called emulsifying wax, and wax has been formed so-called emulsification ointment main component with oil ﹠ fat, and this composition has formed the oily disperse phase of emulsion.Be applicable to that emulsifying agent of the present invention and emulsion stablizer comprise polysorbate60, Span80, whale Solsperse 2000 (cetostearylalcohol), tetradecyl alcohol, glycerol monostearate and sodium lauryl sulphate, and other.Select suitable oil or fat for preparation and be based on the needs that obtain the cosmetic characteristic, because active compound is low-down in the solubleness of the most of oil that are used for the pharmaceutical emulsifier type probably.Therefore emulsion should preferably non-oily, non-that be infected with flushable product, and certain denseness is arranged in order to avoid leak from test tube or other containers.Straight or branched, unit or double base alkyl ester all can be used as the mixture of propylene glycol diesters, sec.-propyl myristate, decyl oleate salt, sec.-propyl palmitate, butyl stearate, 2-palm acid ethyl polyhexamethylene or the branched ester of two-dissident diacid, different cetaceum stearic acid (iso cetyl stearate), coconut fatty acid.They can the independent or merging use according to required characteristic.In addition, dystectic liquid such as white soft wax and/or whiteruss or other mineral oil also can be used.The formulation that is fit to eye local application also comprises eye drop, and wherein activeconstituents is dissolved or suspended in the appropriate carriers, particularly the water solvent of activeconstituents.It is 0.5% to 20%, 0.5% to 10% better that anti-inflammatory activity constituent concentration in this formulation is preferably, particularly 1.5%w/w.For reaching therapeutic purpose, the active compound of this component invention adjuvants common and one or more suitable appointment medications mix.If oral administration administration, compound can with cellulose ester, Mierocrystalline cellulose alkyl ester, talcum powder, stearic acid, Magnesium Stearate, magnesium oxide, phosphoric acid and vitriolic sodium salt and calcium salt, gelatin, Sudan Gum-arabic, sodiun alginate, polyvinylpyrrolidone and/or the polyvinyl alcohol of lactose, sucrose, starch, paraffinic acid, then for making things convenient for administration to make tablet or capsule.This capsule or tablet can comprise a kind of controlled release form, as the distribution of active compound in the hydroxy propane methylcellulose gum.For the formulation of parenteral application can be aqua or nonaqueous solvent form etc. ooze sterile solution or suspension.These solution and suspension can wherein contain aforementioned one or more carriers or the thinner that is used for oral dosage form with sterilized powder or granules preparation.Compound may be dissolved in water, polyethylene glycol, glycol polypropylene, ethanol, Semen Maydis oil, Oleum Gossypii semen, peanut oil, sesame oil, phenylethyl alcohol, sodium-chlor and/or the various damping fluid.Other adjuvants and administering mode are widely known in pharmaceutical field.
The patent document of here listing is all quoted in this application as a reference.
Although this invention is addressed in many specific embodiments, the details of these embodiments can not be construed as all restrictions.
As preparation Embodiment B-i, the description of the synthetic method that is arranged in parallel of B-ii and B-iii compound
Option b-1 has been described and has been used for preparing the be arranged in parallel reaction unit of embodiment b-0001 to the B-1574 compound, also can be used for preparing the compound of Embodiment B-1575 to B-2269 by analogizing.Parallel reactor is carried out in the multicell reaction unit.Typical reaction unit can carry out 48 parallel reactors, and wherein each compound selective ground prepares in a reaction vessel B1.Each reaction vessel B1 is made by polypropylene or thermal glass, and contains a frit B2 in the bottom of container.Each reaction vessel is locking or is connecting through spiral through Leur-and linking to each other with reaction unit valve integrated board B3.The folding of each container value B4 is to realize by the position of control leur-lock or by the lever B5 that opens or closes in the line of valve integrated board.By on the position that valve is placed on out and through the flow of inert gas import valve B6 control rare gas element, thus the back-pressure of by-pass valve control integrated board below, can allow selectively solution discharge or remain in the container glass material above.The parallel reactor of carrying out in these parallel chambers can be undertaken by hatching on the temperature controlled shaking table that sheath is being arranged.The aluminium sheet of the band sheath through contacting with reaction unit cover B7 transmits the temperature that heat-conduction liquid can effectively be controlled reaction chamber.On oscillating table, the vertical track vibration by the orthostatic reaction device or can mix effectively to the lateral vibration of the reaction unit of lopsidedness.
In the process of reaction or during reaction terminating, functional resin is optionally joined among the reaction vessel B1.These functional resins can make the rapid purifying of the product in each reaction vessel.By opening vacuum valve B8 the reaction unit device is carried out vacuum filtration, the product of purifying is separated with the non-product component of resin absorption.Valve B8 is positioned at the bottom of reaction chamber B10, and B10 is containing the collection bottle stand B11 of four quadrants.Required product is independently obtaining among the receiving flask B9 with the filtrate form.From these receiving flasks, remove the product that solvent can obtain needs.
Option b-2 has been described before being filled into receiving flask B9 from Glass Containers B1, is purification reaction container product B 22, the various application of functional resin.Above-mentioned functional resin can be used as: 1) resin-bonded reagent B12 can produce resin binding reagents byproduct B13; 2) sorbent material of unnecessary liquid phase reaction thing B16 or B17 is respectively.Liquid phase reaction thing B16 and B17 contain inherent reactive functional group-rf1 and-rf2, complementary interaction functional group-Crf1 that can be by belonging to resin B 14 and B15 and-the chemo-selective adsorption takes place in Crf2; 3) adsorbent B 18 of liquid phase byproduct B19.Byproduct B19 contains molecular recognition function base-mr2, and it can the chemo-selective adsorption take place by the complementary function base on the resin B 18-Cmr2; 4) reaction quenching resin B 20 produces the resin B 21 of quenching.Resin B 20 contains functional group-Q, and the reaction of mediation product B 22 is quenched (such as prototropy) to form the separable form of required product B 22.When quenching, resin B 20 changes resin B 21 into, wherein-and q represents the useless functional group on the resin B 21; 5) adsorbent B 23 of the reagent B24 of chemical labeling and corresponding by product B25 thereof.The B24 of solubility contains difunctional chemical group ,-tag, and it is sluggish under reaction conditions, but can make the complementary function base-Ctag on B24 and the resin B 23 that adsorption takes place after the reaction.In addition, the soluble reaction by product B25 that forms in reaction process also contains same chemical functional base-tag, also can be adsorbed by resin B 23.In addition, the nucleophilic reagent of some reagent B16, particularly steric hindrance reagent and/or shortage electronics contains very weak adsorbable functional group (since it is so, rf1 is the weak functional group of adsorbability).These low absorbability reagent B16 can be in position by starting reagent B26 reaction changing into the stronger composition B27 of adsorptivity with absorption.B26 contains highly active complementary function base Crf 1, form B27 with the B16 reaction in position.The bifunctional molecule identification base that contains among the B26, mr also exists on the B27 of derivation in position.B26 and B27 all are adsorbed by the complementary molecule recognition function base on the resin B 28.By that analogy, some reactions contain weak adsorptivity by product B19, and are both like this, molecular recognition function base mr wherein 2Can not mediate on the resin B 18 the complementary function base to the direct absorption of B19.Use difunctional absorption and start the composition B30 that reagent B29 can be transformed into B19 easier absorption equally.The molecular recognition function base that the transfer that exists among the B30 comes, mr is easilier adsorbed by the complementary function base Cmr. on the resin B 31.In some reaction, multiple polymeric adsorbent can be used simultaneously to carry out purification reaction.Still can use simultaneously even contain the resin of inconsistent (interreaction) functional group, react fast than resin cross neutralization because these resins are removed the speed of liquid phase reaction thing, reagent or the by product of complementary function base from liquid phase.Similarly, it is faster than resin cross neutralization reaction to contain the quench speed of resin hardening liquid phase reaction thing, product or by product of functional group of reaction of interreaction or neutralization.
Option b 3 has been described and has been used to prepare the pattern automatic technique laboratory environment of example B0001 to the compound of Bxxxx.The chemicals of using in automatic laboratory are weighed at #1 station (robotics prepares the station), are dissolved or suspended in the solvent then.Therefore, the solvent of known volumetric molar concentration or suspension are to prepare for the use at other automatic workstations.Each chemical solution of bar code label also can be selected so that its identity can be discerned by bar code scanning in #1 station on this and other automatic workstations.
Be reflected on #2 and the #2 DUP pattern station initial.The #2DUP station is defined as the replica at #2 station, is used to increase automatic breadboard capacity.A reaction unit is installed in #2 or the #2DUP station.In addition, the shelf that contains reactant, reagent, solvent and paste resin also is installed on #2 or the #2DUP station.Under the control of a Chemoinformatics image file, by with reactant solution, reagent solution, solvent, and/or paste resin is transferred in each reaction unit container that is mounted and is started reaction.Solution, the quantitative transfer of suspension or solvent is finished by syringe, (one-up) barrier film perforation/Argon that one of this syringe control is one is except that gas bushing, the paste resin distribution sleeve in a wide hole, or with six roads (six-up) sleeve pipe of transfer capacity in six one rows' reaction vessels simultaneously.In chemical solution jump operation process, reaction unit and/or chemical solution frame can optionally be cooled to below the room temperature.After finishing chemical solution and solvent and shift at #2 or #2DUP station, reaction unit is installed in automatic station and begins to hatch.But preferably, after all capacity have shifted, take out reaction unit, and make it return to ambient temperature.The reaction unit off line is transferred in the vertical or edgewise vibration couveuse #5 station.
Weight/archives station #3 carries out the function that takes by weighing sky receiving flask weight (obtaining the gross weight of receiving flask) automatically, also carries out the function that takes by weighing the receiving flask weight (obtaining the gross weight of receiving flask) that filtering purified product is housed.The receiving flask that contains product is weighed at the #3 workstation after (gross weight mensuration), is dissolved in the organic solvent again at the #3 workstation to the receiving flask selectivity of product.Shift solvent with syringe, mounted (one-up) barrier film perforation/Argon together of this syringe control is removed gas bushing.According to the guidance and the record of Chemoinformatics system, each receiving flask that contains product is prepared into the solution of known volumetric molar concentration.These product solution are that follow-up reactions steps is installed on #2 or the #2DUP station then, or take the processing that performs an analysis on #7 or the #7DUP station.
Collecting frame is installed on the Savant automatic solvent #4 of evaporator station, #4DUP or the #4TRIP, can finish the rapid evaporation of solvent in the receiving flask that contains product, wherein #4DUP and #4TRIP are that double and triple bodies at #4 station are to increase the ability of removal solvent in the automatic laboratory.Commodity removal of solvents station is available from Savant company (#SC210A speedvac unit type is furnished with #RVT4104 type steam catcher and #VN100 steam net cryopump).
But #7 and #7DUP station execution analysis processing capacity.The #7DUP station is the repeat body at #7 station, to increase automatic breadboard capacity.The collecting frame that contains product is placed on arbitrary station.Then, each receiving flask that contains product solution of being made into known volumetric molar concentration by the guidance and the record of Chemoinformatics image file.Alternatively, this dissolved function also can be finished in the last process at #3 station by collecting bottle stand as previously mentioned.Under the control of Chemoinformatics image file, #7 or #7DUP station can be transferred to the aliquots containig in each product bottle and be used to carry out in the uniqueness and appraisable micro titer plate well of assay determination.
A this microtiter plate on #7 or #7DUP station prepares to be used for subsequently automatic HPLC/ mass spectrograph station #8 or #8DUP.The #8DUP station is the duplicating device at #8 station, to increase automatic breadboard analysis ability.#8 or #8DUP station are to link to each other with HP1100 MSD (G1946A) mass spectrograph available from (benchtop) LC/Mass spec equipment (HP1100 HPLC type) on the commercial platform of Hewlett-Packard (HewlettPackard); This equipment also is furnished with #G1322A type solvent vent fan, #G1312A type scale-of-two pump, #G1316A type column well heater and #G1315A type diode-array detector.Hewlett-Packard's equipment is connected (#215 of Gilson company self-actuated sampler) with commercially available self-actuated sampler.#8 or #8DUP station are by carrying out efficient liquid phase chromatographic analysis and follow pressure chemical ionization (APCI) to measure degree of purity of production and identity, or EFI mass spectrometry determining molecular weight.
Another microtiter plate on #7 or the #7DUP station is to prepare to be used in subsequently on the commercially available traffic probe Varian nuclear magnetic resonance spectrometer station #10 (Varian instrument traffic probe nucleus magnetic resonance, 300MHz are connected with commercially available Gilson 215 self-actuated samplers).Proton, 13-carbon, and/or 19-fluorine nmr spectrum is measured on this #10 station.
Other microtiter plates selectively are contained on #7 or the #7DUP station, are used for the collecting board that contains product of biological detection with preparation.Come the aliquots containig in the self-contained product collection bottle, under the control of Chemoinformatics image file, be transferred in these Biological Detection microtiter plates.The identity of each transfer product and amount are for Chemical Information System institute record, so that those do retrospective analysis to the biologist that product carries out Biological Detection.
Fourier-transform infrared line (FT-IR) spectrograph station #11 is used to analyze the identity of the organic functions group that chemistry connects on the resin.As mentioned above, resin contains the chemical functional base, as reagent, chemo-selective sequestrant or the quenchant of crude product in synthetic and the purification reaction apparatus container.Automatically laboratory applications is available from the FT-IR spectrograph commodity (#MagnaIR 560 types link to each other with the InspectIR microscope, to load and the location resin) of Nicolet Instruments.
Option b-3
Line between the pattern station is represented chemical shelf, reaction unit and/or is collected bottle stand and transfer to another pattern station from a pattern station.
The Chemlib IT system is the summation that operates in the software of the software of client's desktop and remote server.
The Chemlib IT system is that the data that flow process is handled in above-mentioned automatic laboratory can be supported and manage to client/server application software.This IT system can combine chemist and automatic compound experiment chamber, and can manage the data that produce in this process.
The software that operates in server stores the electronic data of all robotics units.This server is Silicon pattern I RIX platform v6.2, the database software Oracle7 v7.3.3.5.0 of operation storage data.Being connected to server from client terminal can be by Oracle TCP/IP adapter v2.2.2.1.0 and SQL *Net v2.2.2.1.0A provide agreement.SQL *Net is the Oracle socket, and it can allow the application program access Oracles data of database of client terminal.The desktop of client terminal is Microsoft's Window 95 systems.Chemlib IT system client software is made up of Omnis7 v3.5 and the visual C++ v5.0 of Microsoft.This structure of client terminal is formed promptly mentioned Chemlib here.Chemlib and server contact swap data are by OraclePL/SQL v2.3.3.4.0 agreement.These PL/SQL can set up one and Oracle SQL in the visit of Chemlib *The network plug-in that the Net driving mechanism connects, here the TCP/IP adapter can allow the data of access server.
One " storehouse " can be defined as the composite number in hole, and wherein every hole defines a kind of compound.Chemlib can define the storehouse in the pattern that is referred to as electrical form (electronic spreadsheet).Therefore, electrical form is the combination in n number hole, and these holes contain the required composition of compound that exists in synthetic each hole.
The chemist begins by the composition input electrical form that synthetic compound is required.The identity of these compositions and validity are defined in building blocks catalogue (the Building Block Catalog) pattern of Chemlib.The building blocks catalogue is the list directory of all reagent of showing to use in automatic laboratory, solvent, peripherals.On the basis for each compound selection component, we also show the quantity that each composition will be used.The amount of each composition can be by its volumetric molar concentration and capacity (μ l) or its solid-state form (mg) identification.Therefore a compound is being represented in a hole in electrical form, and this compound is to be assert by the amount of its composition and each composition.
For each compound in the electrical form, the assembling of these compositions or synthesize in the WS of Chemlib sequence pattern detailed description is arranged.Set synthesis step that WS sequence (Define WS Sequence) pattern recognition will carry out and any needs manually or the activity that off line is carried out from the automatic workstation on workstation automatically.We can assert from the composition of electrical form and the activity that should carry out this composition in automatic laboratory to utilize this pattern.In setting the WS sequence pattern, the chemist selects from a series of effort scales that will carry out in automatic laboratory, and with its order that will carry out they is gathered together.The Chemlib system obtains the activity that this group is assert, and utilizes the compositional data in the electrical form, converts these packings of orders and reformatting to automatic workstation used term.This machine term is stored in " in proper order " file on the common server, can be obtained by workstation automatically.
Automatically workstation synthesizes by described method in reaction unit equipment.Every hole in the electrical form is tracked and be mapped in a unique address of reaction unit equipment on the automatic workstation.Then, on automatic workstation in the reaction unit synthetic compound or product be loaded in the receiving flask.
Collection tube is taring at first, then, obtains its gross weight collected its product from reaction unit on automatic workstation after.These weight (tare weight and gross weight) are noted by tare weight/gross weight session pattern (Tare/Gross Session mod μ le).Subsequently, the output and the final quality of tare weight/gross weight session mode computation product or compound.
Preparation and screen display with the compound that performs an analysis are provided with mode declaration pattern specification by analyzing WS in Chemlib.Analysis WS is provided with pattern and identifies the dilution factor in every hole on the electrical form according to the output of compound and the volumetric molar concentration of needs.So just identify on automatic workstation, be transferred to special place on the MTP (microtiter plate) as the amount of analyzing and/or biology is measured, with μ l form.In the mass spectroscopy in every hole and high performance liquid phase outcome record and the Chemlib system of marking.
Dilution/file WS pattern is mapped to specific place, MX chamber by the hole with compound from electrical form and further identifies each compound, files with standing storage and as the part of registration process.
Communication between Chemlib and automatic workstation is undertaken by ascii text file.These files leave on the server by the Chemlib system, can be obtained by automatic workstation.Automatically the report of workstation generation also can be left on the server, and the Chemlib system can read the data of these files and record generation at this.Each automatic workstation is by Bohdan Automation Co., Ltd (Bohdan Atomation, the automatization hardware that Inc.) provides and a current Personal Computer composition that moves working group of Microsoft form 3.11 editions and Ethernet software of Illinois Mundelein.Automatically the workstation personal computer logs on network and makes one-way communication, only allows workstation to obtain file to server.Ground plan B4
At R 4Substitute the framework C-i that contains the primary amine functional group in the base, in the sterically defined reaction unit container that is arranged in parallel with excessive electrophilic reagent R J-Q reaction, wherein Q is that the group of chlorine, bromine or an acid active includes but not limited to N-hydroxy-succinamide.R J-Q comprises chloride of acid, alkyl chloroformate, SULPHURYL CHLORIDE, activatory carboxylicesters, activatory carbamate and isocyanate.Framework C-i and R JThe reaction of-Q, at room temperature exist tertiary amine groups and with polar proton inert solvent and/or halogenated solvent blended situation under be effective.Shown in option b-4, the product of Formula B-i is to come out with the isolated in form of purifying by the resin B 32 of adding the carbonyl functionalization, resin B 32 is adsorbed the adducts B35 that becomes resin-bonded with any unreacted primary amine framework C-i covalency, also can add the resin B 33 of primary amine functionalization, it can be from each reaction mixture covalency adsorb the electrophilic reagent R of any remnants J-Q becomes the adducts B34 of resin-bonded.Resin B 33 also can be by the absorption of transfer protons from liquid phase alkali-HQ HQ byproduct from reaction mixture.At incubated at room, filtration, rinsing resin mass, and concentrated filtrate, can make the product B-i of purifying can be from the adducts B32 of resin-bonded, B33, B34 filters out among B35 and the B36.
Figure A9880736902931
Option b-5 has specified the derivation of the framework C1 that contains primary amine, and the synthetic mode that can be arranged in parallel obtains required product B-i.In the synthetic reaction device that is arranged in parallel, single reaction product prepares in sterically defined mode in each many reaction units container.Dimethyl formamide (DMF) solution of the required framework C1 (limited volume) that contains primary amine joins in the reaction vessel, then adds the DMF solution of the N-methylmorphine of 4 times of metachemistry calculated amount.In each reaction vessel, add electrophilic reagent then: work as R J-Q adds 2 times of metachemistry calculated amount when being chloride of acid or alkyl chloroformate, or works as R JAdd 1.5 times of metachemistry calculated amount when-Q is SULPHURYL CHLORIDE, or work as R JWhen being isocyanate ,-Q adds 1.25 times of metachemistry calculated amount.Compare with the N-methylmorphine with not using excessive electrophilic reagent, using excessive electrophilic reagent and N-methylmorphine, can to make framework C1 be transformed into product B-0001-B-0048 rapider and/or more completely.Reaction mixture was hatched in envrionment temperature 2-3 hour.Each reaction vessel pack into then in a large number the amino-functionalization resin B 33 and the aldehyde functional resin B32 of (15-20 times of metachemistry calculated amount).Room temperature vertical oscillation 14-20 hour on the orbital oscillation device of the reaction vessel of resin fill makes the mixture in the container that contains resin obtain the suitableeest stirring.Excessive electrophilic reagent R J-Q and any unreacted framework amine C1 become insoluble adducts B34 and B37 respectively and remove from reaction medium.The N-methylmorphine hydrochlorinate salt that forms in reaction process in addition also is neutralized into the free alkali form of oneself by the Proton-Transfer Reactions with amino-functionalization resin B 33.The insoluble resin adduct B32 of simple filtration, B33, B34, B36 and B37, with ethylene dichloride rinsing resin mass, evaporated filtrate can obtain the product B-i of required purified form.
Figure A9880736902941
Option b-6 shows the overall synthetic method of the reaction that is arranged in parallel of relevant framework C-ii, at the R of C-ii 4Substitute in the body definition and contain the secondary amine functional group.Dress adds the electrophilic reagent RL-Q of the optional uniqueness of metachemistry calculated amount subsequently to contain the framework C-ii of secondary amine in each reaction vessel in each container, and wherein Q is chlorine, bromine or acid active group, includes, but are not limited to N-hydroxy-succinamide.R L-Q comprises Acibenzolar, activation carboxylamine and the isocyanate of chloride of acid, alkyl chloroformate, SULPHURYL CHLORIDE, carboxylic acid.C-ii and R LThere is the tertiary amine base room temperature in being reflected at of-Q or is effective under the situation of elevated temperature in the mixture of polar proton inert solvent and/or halogenated solvent.Liquid phase reaction proceed in each container, can provide crude mixture after, product B-ii is separated with purified form, this sepn process can be by adding isocyanate functional resin B38, the residual secondary amine framework C-ii of its covalency absorption becomes resin-bonded adducts B39, also can add primary amine functional resin B33, its covalency adsorbs electrophilic reagent R residual in each reactor L-Q becomes resin-bonded adducts B40.Resin B 33 also by in each container from the alkali-HQ transfer protons of liquid phase and chelating HQ by product becomes B36.After hatching with these resins simultaneously or successively, filtration, rinsing and concentrated filtrate make the product B-ii of purifying filter out from resin adduct B33, B36, B38, B39 and B40.
Option b-7 demonstration contains the conversion of the secondary amine of framework C-2 to required product B-ii.In the building-up reactions raw material that is arranged in parallel, each reaction product is that each leisure prepares in the reaction raw materials container more than 48.The dimethyl isobuty(roy)l chloride of framework C-2 (DMF) solution (limiting the quantity of) adds reaction vessel, adds the N-methylmorphine DMF solution of 4 times of metachemistry calculated amount subsequently.Add electrophilic reagent R then in each reaction vessel L-Q becomes ethylene dichloride (DCE) solution: work as R LWhen being chloride of acid or alkyl chloroformate ,-Q, works as R with 2.0 times of metachemistry calculated amount L-Q with 1.5 times of metachemistry calculated amount, works as R during for SULPHURYL CHLORIDE L-Q during for isocyanate with 1.25 times of metachemistry calculated amount.Reaction mixture was hatched 2-6 hour at ambient temperature.The amino-functionalization resin B 33 of the big excess of packing in each reaction vessel subsequently (15-20 times of metachemistry calculated amount) and the resin B 32 of isocyanate functionalization.The reaction raw materials of resin of packing into jolts on the device at track, under the envrionment temperature, vertically shakes 14-20 hour, makes resiniferous reaction mixture obtain best stirring.Excessive electrophilic reagent R L-Q and unreacted framework amine C-2 become insoluble adducts B40 and B39 respectively and remove from reaction medium.Resin B 33 also by in each container from the alkali-HQ transfer protons of liquid phase and chelating HQ by product becomes B36.After these resins are hatched,, the purified product solution in the collection tube is filtered out from resin adduct B33, B36, B38, B39 and B40 by filtering, use the solvent mixture rinsing of DMF and/or DCE.Concentrated filtrate can obtain the product B-ii of purifying.
Figure A9880736902961
Option b-8 shows the overall synthetic method of the reaction that is arranged in parallel of another relevant framework C-ii, at the R of C-ii 4Substitute in the body definition and contain the secondary amine functional group.Dress adds the electrophilic reagent R of the optional uniqueness of metachemistry calculated amount subsequently to contain the framework C-ii of secondary amine in each reaction vessel in each container L-Q.C-ii and R LThere is the tertiary amine base room temperature in being reflected at of-Q or is effective under the situation of elevated temperature in the mixture of polar proton inert solvent and/or halogenated solvent.
Compare with the N-methylmorphine with the electrophilic reagent without the metachemistry calculated amount, excessive electrophilic reagent and N-methylmorphine can be used for making framework quicker and/or more complete to the conversion of product B-ii.Reaction mixture was hatched 2-8 hour at ambient temperature.Adorn so that adsorbing reagent benzene sulphonyl isocyanate B41 to be arranged in each reaction vessel then.Reagent B41 is converted into C-ii the mixture B42 of original position derivation with residual secondary amine framework C-ii reaction.These reaction mixtures are hatched with the amino-functionalization resin B 33 of big excess (15-20 times of metachemistry calculated amount) subsequently, with liquid composition R L-Q, HQ, B41 and B42 adsorb respectively becomes the adducts of resin-bonded B40, B36, B44 and B43.Pack into resin reaction raw materials at ambient temperature, jolt at track and vertically to shake on the device 14-20 hour, make resiniferous reaction mixture obtain best stirring.Filter insoluble resin adducts B33, B36, B40, B43 and B44, can obtain to contain the filtrate of purified product B-ii subsequently with DMF and/or DCE rinsing container resin bed.Concentrated filtrate obtains purified product B-ii.
Figure A9880736902981
Option b-9 shows option b-8 method with framework C-2.The dimethyl isobuty(roy)l chloride of framework C-2 (DMF) solution (limiting the quantity of) adds reaction vessel, adds the N-methylmorphine DMF solution of 4 times of metachemistry calculated amount subsequently.Add electrophilic reagent R then in each reaction vessel L-Q becomes ethylene dichloride (DCE) solution: work as R LWhen being chloride of acid or alkyl chloroformate ,-Q, works as R with 2.0 times of metachemistry calculated amount L-Q with 1.5 times of metachemistry calculated amount, works as R during for SULPHURYL CHLORIDE L-Q during for isocyanate with 1.25 times of metachemistry calculated amount.Reaction mixture was hatched 2-6 hour at ambient temperature.After proceeding to the product mixtures that can provide thick in liquid phase reaction, be incorporated with the dichloroethane solution of adsorbing reagent benzene sulphonyl isocyanate B41 in each reaction vessel.Reagent B41 is converted into C-2 the mixture B45 of original position derivation with residual secondary amine framework C-2 reaction.These reaction mixtures are hatched with the amino-functionalization resin B 33 of big excess (15-20 times of metachemistry calculated amount) subsequently, with liquid composition R L-Q, HQ, B41 and B45 adsorb respectively becomes the adducts of resin-bonded B40, B36, B44 and B46.The reaction raw materials of resin of packing into jolts on the device at track, under the envrionment temperature, vertically shakes 20 hours, makes resiniferous reaction mixture obtain best stirring.Filter insoluble resin adducts B33, B36, B40, B44 and B46, can obtain to contain the filtrate of purified product B-ii subsequently with DCE rinsing container resin bed.Concentrated filtrate obtains purified product B-ii.
Figure A9880736902991
Another reaction raw materials synthetic group method that is arranged in parallel is shown in option b-10, is used to contain the deriving of framework C-iii of carboxylic acid.There is the carbodiimide reagent B48 of polymkeric substance combination, under the situation that in polar proton inert solvent and/or halogenated solvent mixture, has tertiary amine base to exist, the framework C-iii that free carboxylic acid function's base arranged the space guiding, in the reaction raw materials container that is arranged in parallel, with excessive selection different primary amine or secondary amine B47 reaction.Filter out each crude reaction product mixture from resin B 48 and B49 after, each reaction mixture is by the purifying with adsorbing reagent B50 (tetrafluoro is for Tetra hydro Phthalic anhydride) processing is arranged.Reagent B50 produces the original position derivation intermediate B 51 that contains carboxylic acid molecules recognition function base with residual excess amine B47 reaction.Subsequently, each reaction mixture is hatched with the primary amine functional resin B33 of 15-20 times of metachemistry calculated amount, and absorption B51, B50 and other residual sour framework C-iii make it to become respectively adducts B52, B53 and the B54 of resin-bonded.From the adducts of these resin-bonded, filter out liquid product B-iii and can obtain containing purified product B-iii filtrate with polar proton inert solvent and/or halogenated solvent rinsing resin bed.Concentrated filtrate can obtain the B-iii of purifying.
Figure A9880736903011
Option b-11 shows that will contain sour framework C-49 with parallel synthesis mode is converted into required amide product B-iii.The framework C-49 that limits the quantity of adds in each reaction vessel of the carbodiimide reagent B48 (5 times of metachemistry calculated amount) that contains the polymkeric substance combination with dimethyl isobuty(roy)l chloride solution form.The dimethyl isobuty(roy)l chloride solution of pyridine (4 times of metachemistry calculated amount) adds in this suspension, adds the dimethyl isobuty(roy)l chloride solution (1.5 times of metachemistry calculated amount) of excessive unit price amine B47 subsequently in each container.Then, the parallel reactor raw material jolts on the machine vertical the stirring 16-18 hour at track at ambient temperature, and filters to isolate liquid product from the reagent by product B49 of the reagent B48 of resin-bonded and resin-bonded.The solution that obtains (filtrate) contains the mixture of required amide product B-iii, and excessive amine B47 and other be unreacted to be contained sour framework C-49 and handle for Tetra hydro Phthalic anhydride B50 with tetrafluoro.B50 is converted into separately adsorbable half sour form B51 with the excess amine B47 in each filtrate container.After hatching in 2 hours, the amino-functionalization resin B 33 and the dichloroethane solution of excess add in each reaction vessel.Contain adducts B52, B53 and B55 that polyimide resin B33 is separately converted to its resin-bonded with B51, residual B50 and residual C-49.The reaction raw materials that adds resin jolts on the device at track, under the envrionment temperature, vertically shakes 16 hours, makes resiniferous reaction mixture obtain best stirring.Filter insoluble resin adducts B33, B52, B53 and B55, can obtain to contain the filtrate of purified product B-iii subsequently with dimethyl isobuty(roy)l chloride rinsing container resin bed.Concentrated filtrate obtains purified product B-iii.
Although option b-1 has been described to B-11 and has been used the chemical library technology that is arranged in parallel and prepare Formula B-i, B-ii and B-iii mixture, it is also noted that with the ordinary skill in the classical synthetic organic chemistry method, (in the traditional glass vessel, once prepare a mixture, and use such as the traditional way of chromatography and/or crystallization process and purify) in a conventional manner and also can prepare B-i, B-ii and B-iii.
The overall synthetic scheme C-1 that is depicted in of pyridine pyrazoles framework C-i, C-ii and C-iii.
Steps A: picoline is with alkali processing from-78 ℃ to 50 ℃ between 10 minutes to 3 hours, selects in n-butyllithium (n-BuLi), two-isopropylamine lithium (LDA), hexamethyl two silicon nitrogen lithiums (LiHMDS) [lithium hexamethyldisilazide], t-butoxide potassium (tBuOK) or the sodium hydride (NaH) of alkali from be dissolved in organic solvent such as tetrahydrofuran (THF) (THF), diethyl ether, t-butyl methyl ether, t-BuOH or dioxan but is not limited to these.Then in the picoline solution adding ester B56 solution that metal replaces.This reaction was taken place because of stirring in 30 minutes to 48 hours, and temperature range is-20 ℃ to 120 ℃ therebetween.Mixture is poured in the water and is used organic solvent extraction subsequently.In drying with after removing solvent, pyridine single ketones B57 comes out with thick solid isolated in form, and this thick solid can pass through crystallization process and/or chromatography purification.
Step B: the pyridine single ketones B57 solution that is dissolved in ether, THF, t-BuOH or dioxan added in the alkali 10 minutes to 3 hours, temperature-78 ℃ is to 50 ℃ therebetween, selects among n-BuLi, LDA, LiHMDS, tBuOK or the NaH of alkali from be dissolved in hexane, THF, diethyl ether, t-butyl methyl ether or t-BuOH but is not limited to these.Then, from R 4-CO 2The H deutero-adds in the B57 single ketones negatively charged ion with THF, ether or dioxan solution form through suitable alternate Acibenzolar or acyl halide, and temperature remains between-50 ℃ to 50 ℃ therebetween.Resulting mixture stirred under specified temp 5 minutes to 3 hours, and the pyridine diketone intermediate B 58 of generation does not need purifying promptly to can be used for step C.
Step C: the solution with water that contains pyridine diketone B58 is quenched, and uses from HOAc, H 2SO 4, HCl or HNO 3Middle inorganic or organic acid for adjusting pH of selecting is between 4 to 8.The temperature in this step remains on-20 ℃ between room temperature.Subsequently, hydrazine or hydrazine hydrate add in the mixture, and temperature remains on-20 ℃ to 40 ℃ effects 30 minutes to 3 hours therebetween.Then, mixture is poured in the water and is used organic solvent extraction.Obtain thick solid pyridine pyrazoles C-i or C-ii, this thick solid can pass through chromatography or crystallization process purifying.
Step D: in some cases, pyridine pyrazoles C-i or C-ii Q-C (R A)-(CH2) nCO 2The alkyl alkanisation, wherein Q is a halogen.C-i or C-ii handle between-20 ℃ to 150 ℃ temperature with alkali, and the reaction times, alkali was from being dissolved in NaH, NaOEt, KOtBu or the NEt such as THF, methylene dichloride, dioxan or DMF organic solvent between 30 minutes to 12 hours 3The middle selection.Then, the alkylation pyridine pyrazoles ester that obtains is hydrolyzed to acid with NaOH or LiOH processing in water/alcohol mixed solvent or THF/ water mixed solvent.If alkyl residue is the t-butyl, can select with the organic or inorganic acid treatment to remove ester function.Acidifying, obtaining with organic solvent extraction thereafter can be by the C-iii of chromatography or crystallization process purifying.In some cases, also form district's isomery alkylation product C-iv.Required C-iii can separate from C-iv by chromatogram purification or fractional crystallization.
Figure A9880736903051
The synthetic scheme C-2 that is depicted in of pyridine pyrazoles framework C-1.
Steps A:
Picoline adds in the THF solution of LiHMDS, at room temperature through 30 minutes to 1 hour.The solution that obtains is restir 30 minutes to 1 hour at room temperature.Solution adds pure ethyl then right-fluorobenzoic acid salt B60 room temperature 1-2 hour, at room temperature stirred the mixture 16-24 hour subsequently.Equal proportion water and ethyl acetate add reaction subsequently, and with extracting the funnel separating mixture.Organic layer drying, filtration and evaporation form the oily solid.Add hexane then, wash with solid filtering and with cold hexane, the pyridine single ketones B61 that obtains is used for step B.
Step B:
Pyridine single ketones B61 adds in the flask with the form of THF solution, and this flask keeps room temperature and the t-BuOK that is dissolved in the THF/t-BuOH cosolvent is housed.There is yellow mercury oxide to form and at room temperature continues and stirred 1-3 hour.After this, the glycine N-hydroxy-succinamide B62 of N-Cbz-protection dropwise adds with THF solution form, at room temperature puts 1-3 hour.This solution that comprises thick diketone B63 is directly used in step C.
Step C: handle from the solution with water that step B obtains, and regulate pH between 6 to 7 with acetic acid.Hydrazine hydrate dropwise adds in the mixture with aqueous solution form subsequently, room temperature underlying 30 minutes to 1 hour.Water and ethyl acetate add flask then, and mixture separates in separatory funnel thereafter.Organic layer drying, filtration and evaporation form thick oil, promptly produce the C-1Cbz of purifying through the chromatography silica gel purification.
Step D:
The Cbz protection group high pressure hydrogen and the Pd-C cracking in formaldehyde solution that contain among the mixture C-1Cbz.By filtering and concentrate acquisition amine C-1.
Number of C-v type pyridine pyrazoles framework prepares shown in scheme C-3.
Steps A: picoline was handled 10 minutes to 3 hours between-78 ℃ to 50 ℃ with alkali, and alkali is from being dissolved in organic solvent, as selection among the n-BuLi in THF, ether, t-BuOH or the dioxan, LDA, LiHMDS, tBuOK or the NaH but be not limited to these.The picoline solution of metal substitute adds carboxylic acid CbzNR then H-(CH 2) nCR F(R G)-CO 2H or BocNR H-(CH 2) nCR F(R G)-CO 2In the suitable activatory ester class solution of H, preferred N-hydroxy-succinamide B64, but be not limited to this.Be reflected at and stirred between-20 ℃ to 120 ℃ 30 minutes to 48 hours.Mixture is poured in the water and is used organic solvent extraction subsequently.In drying with after removing solvent, pyridine single ketones B65 comes out with thick solid isolated in form, and thick solid can pass through crystallization process and/or chromatography purification.
Step B: the pyridine single ketones B65 solution that is dissolved in ether, THF, t-BuOH or dioxan added in the alkali 10 minutes to 3 hours, temperature-78 ℃ is to 50 ℃ therebetween, selects among n-BuLi, LDA, LiHMDS, tBuOK or the NaH of alkali from be dissolved in hexane, THF, ether, dioxan or t-BuOH but is not limited to these.Negatively charged ion is precipitated as yellow solid sometimes.Through suitable alternate Acibenzolar, as N-hydroxy-succinamide B66, add in the single ketones negatively charged ion with THF, ether or dioxan solution form then, temperature remains between-50 ℃ to 50 ℃ therebetween.Resulting mixture stirred under specified temp 5 minutes to 3 hours, and the pyridine diketone intermediate B 67 of generation need not be further purified and promptly can be used for step C.
Step C: the solution with water that contains pyridine diketone B67 is quenched, and uses from HOAc, H 2SO 4, HCl or HNO 3Middle inorganic or organic acid for adjusting pH of selecting is between 4 to 8.The temperature in this step remains on-20 ℃ between room temperature.Subsequently, hydrazine or hydrazine hydrate add in the mixture, and maintain the temperature at-20 ℃ to 40 ℃ between 30 minutes to 3 hours.Then, mixture is poured in the water and is used organic solvent extraction.Obtain thick solid pyridine pyrazoles C-vBoc or C-vCbz, by chromatography or crystallization process purifying.
Step D:
Carboxylamine blocking group among C-vBoc or the C-vCbz is removed, and contains free primary amine (R with generation HBe hydrogen) or free secondary amine (R HBe not equal to hydrogen) framework C-v.The carboxylamine group of Boc protection was with trifluoroacetic acid (TFA)/methylene dichloride a few hours cracking at room temperature of 1: 1.Cbz carboxylamine blocking group high pressure hydrogen and Pd-C cracking in alcoholic solution.Resulting amine C-v is optionally crystallization or use chromatography purification subsequently.
The synthetic of framework C-vi finished shown in scheme C-4.
Steps A:
The pyridine pyrazoles B68 of Boc protection with the phenyl aldehyde in the methylene dichloride in room temperature, had under the condition of siccative processing 1-24 hour.Solvent evaporation then, resulting imines B69 is used for step B without being further purified.
Step B:
Pyridine pyrazole imine B69 is dissolved among the THF and in-78 ℃ to-20 ℃ temperature range and stirs in nitrogen.Such as the alkali of LDA, n-BuLi or LiHMDS dropwise in the mixture, and then stirred 10 minutes to 3 hours.The alkylating agent R of 2-5 a great deal of F-Q adds in the mixture subsequently and continues stirred for several hour.After this, mixture quenches with acid, makes it rise to room temperature, and stirred for several hour is finished until the cracking of Boc and imines functional group.PH is transferred to 12, and the mixture organic solvent extraction makes the dry and evaporation of organic solvent then.The crude pyridine pyrazoles separates and generation C-vi with recrystallize and/or chromatography.
Figure A9880736903101
The synthetic of framework C-vii that contains maleimide finished shown in scheme C-5.
The method that maleimide pyrazoles framework C-vii such as scheme C-5 are described is synthetic.Primary amine H 2N-R promptly substitutes with bromine, chlorine or triflate group on position 3 with the condensation reaction of maleic anhydride B70, has produced mixture B71.The maleimide derivatives B71 that forms reacts with acetophenone derivs B72 then, generates mixture B73 under the condition that has Pd (O) catalyzer and alkali.The methylene radical position of B73 is formed diketone derivative B76 by acid anhydrides B74 or activatory acid esters B75 acidylate subsequently.Diketone B76 generates required maleimide pyrazoles framework C-vii with the hydrazine condensation.
Scheme C-6 shows the synthetic of maleimide pyrazoles framework C-63, wherein R 4Be hydrogen.Synthetic from bromomaleic acid acid anhydride B77 with 2, the condensation reaction of 4-dimethyl benzyl amine in acetic acid and acetic anhydride begins, and produces intermediate B 78.There is catalyst P d in maleimide with the 4`-fluoro acetophenone then 2(dba) 3With handle under the condition of t-butoxide sodium, form acetyl fluoride benzophenone alternate maleimide B79.Produce a-ketone enamine B80 with two (tert-butoxybis) (dimethylamino) methane treatments B 79 of 3-fourth oxygen.A-ketone enamine B80 forms maleimide pyrazoles skeleton B81 with the hydrazine condensation.(CAN) selectively removes 2 with high cerium ammonium nitrate, 4-veratryl blocking group and obtain mixture C-63.
Figure A9880736903121
Scheme C-7 demonstration contains the framework C-64 of maleimide and synthesizing of C-65.These frameworks C-64 and C-65 are according to the group method synthetic shown in the scheme C-5, and are example to synthesize the pyrazoles B86 and the B87 that contain maleimide with N-hydroxy-succinamide class B82 and B83 respectively.Remove 2 with what CAN selected, the 4-veratryl uses trifluoroacetic acid (TFA) to remove the Boc blocking group subsequently, and produces framework C-64 and C-65.
Figure A9880736903131
Be used to prepare with the various functional resins of purifying parallel reactor mixture and have below adsorbing reagent is listed in more detail, comprise the reference of its commercial source or its preparation.B32
Figure A9880736903132
The polystyrene of 4-benzyloxy phenylcarbinol functionalization.Novabiochem cat.#01-64-0182B33 Report preparation according to D.L.Flynn etc.J.American Chemical Society (1997) 119, 4847-4881.B38
Figure A9880736903141
The polystyrene of methyl isocyanate functionalization.Novabiochem cat.#01-64-0169B48 The EDC of polymkeric substance combination is according to the report preparation of M.C.Desai etc.Tetrahedron Letters (1993) 34, 7685B41
Figure A9880736903143
The benzenesulfonyl isocyanate is bought from Aldrich chemical company.Cat#23,229-7B50
Figure A9880736903144
The 4-difluorophthalic anhydride is bought from Aldrich chemical company.Cat#33, the experimental procedure of 90l-6 from the parallel synthetic a series of amidess of framework C-1, carboxylamine class, ureas and sulfamido B-0001 to B-0048.
Example B-0001 to B-0048
In each reaction vessel (with the equipment of porous frit, the polypropylene syringe pipe of end closure) of parallel reactor device, add 200 μ L dimethyl formamides.The dimethyl formamide storing solution (0.1M, 500 μ L) that adds framework amine C-1 in each reaction vessel adds the dimethyl formamide storing solution (1.0M, 200 μ L) of N-methylmorphine again.The storing solution of various electrophilic reagents adds in the reaction vessel of adaptation subsequently: the dichloroethane solution 375 μ L of the 0.2M SULPHURYL CHLORIDE dichloroethane solution 313 μ L or the d of the 0.2M isocyanate dichloroethane solution 500 μ L or the c of 0.2M trichloromethane salt (chloroformates) a) the dichloroethane solution 500 μ L or the b of 0.2M chloride of acid))).Then, under mild nitrogen gas stream, parallel reactor device track at ambient temperature jolts (Labline Benchtop jolts machine), 200RPM, 2-3 hour.At this moment, each reaction vessel is handled with about 250mg versamid 900 B33 (4.0 milliequivalent N/ restrain resin) and about 100mg aldehyde resin B32 (2.9mmol/g resin).Each reaction vessel is with 1mL dimethyl formamide and the dilution of 1mL ethylene dichloride, and continues at ambient temperature that track jolts, 200RPM, 14-20 hour.Then, each reaction vessel is opened, and required liquid product is by filtering and be collected in the independent conical tube and from insoluble quenching separation of by-products.Each container is with twice of ethylene dichloride (1mL) rinsing and collect rinsing liquid.The solution of gained evaporate to dryness in Savant device (a kind of ultracentrifuge that the solvent grabber of high vacuum, temperature setting and the volatile solvent steam that condenses is arranged) then.The amine that is generated, carboxylamine, urea and sulfanilamide (SN) product are weighed and are identified subsequently.Below product amount that obtains with this method and analytical data are listed in.
Figure A9880736903161
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Figure A9880736903181
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Figure A9880736903191
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Figure A9880736903201
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Figure A9880736903211
With preparing Embodiment B-0049～B-1573 with the similar preparation process of above-mentioned determined Embodiment B 0001-B0048.
Figure A9880736903212
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Figure A9880736903213
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Figure A9880736903241
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Figure A9880736903251
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Figure A9880736903281
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Figure A9880736903311
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Figure A9880736903361
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Figure A9880736903371
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Figure A9880736903391
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Figure A9880736903421
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Figure A9880736903431
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Figure A9880736903451
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Figure A9880736903491
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Figure A9880736903511
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Figure A9880736903541
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Figure A9880736903571
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Figure A9880736903581
Figure A9880736903591
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Figure A9880736903592
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Figure A9880736903621
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Figure A9880736903631
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Figure A9880736903641
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Figure A9880736903651
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Figure A9880736903801
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Figure A9880736903861
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Figure A9880736903891
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Figure A9880736903901
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Figure A9880736903921
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Figure A9880736903961
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Figure A9880736903991
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Figure A9880736904001
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Figure A9880736904011
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Figure A9880736904032
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Figure A9880736904101
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Figure A9880736904111
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Figure A9880736904161
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Figure A9880736904171
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Figure A9880736904211
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Figure A9880736904221
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Figure A9880736904241
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Figure A9880736904251
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Figure A9880736904261
Figure A9880736904271
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Figure A9880736904291
Figure A9880736904301
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Figure A9880736904361
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Figure A9880736904381
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Figure A9880736904391
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Figure A9880736904411
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904421
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904431
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904441
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904461
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904471
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904491
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904511
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904561
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904571
Figure A9880736904581
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904591
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904601
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904611
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904621
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904631
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904641
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904651
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904691
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904701
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904711
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904721
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904751
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904761
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904801
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Figure A9880736904811
Mass spectrum mass spectrum embodiment R 2R J% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Figure A9880736904861
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Figure A9880736904871
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Figure A9880736904881
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Figure A9880736904911
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Figure A9880736904931
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Figure A9880736904941
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Figure A9880736904951
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Figure A9880736904971
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Figure A9880736905001
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Figure A9880736905021
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Figure A9880736905031
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Figure A9880736905051
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
Figure A9880736905071
Mass spectrum mass spectrum embodiment R 2R L% yield calculated value observed value
(M+H)
The proton nuclei magnetic data of the compound of choosing from Embodiment B-0001～B-1573 is listed in the table below.
The trade mark 1H NMR (solvent) dppm
?B-0120 (DMF-d7)d?8.53(bd，J＝4.99Hz，2H)，7.44-7.24(m，11H)，4.41(s，2H)，4.31(br， 2H)
?B-0224 (DMF-d7)d?8.56(bd，J＝4.98Hz，2H)，7.78-7.69(m，4H)，7.39-7.19(m，6H)， 4.23(br，2H)
?B-0235 (DMF-d7)d?8.47(br，2H)，7.91-7.75(m，3H)，7.57-7.53(m，1H)，7.38-7.34(m， 2H)，7.21-7.13(m，4H)，4.20(br，2H)
?B-0244 (CDCl3/CD3OD)d?8.38(d，J＝5.38Hz，1H)，7.62-7.32(m，9H)，7.04-6.95(m， 4H)，6.86-6.80(m，2H)，4.52(q，J＝6.96Hz，1H)，1.40(d，J＝6.88Hz，3H)
?B-0256 (DMF-d7)d?8.45(bd，J＝2.85，2H)，7.87(br?s，4H)，7.76-7.75(m，2H)，7.53- 7.33(m，5H)，7.18-7.13(br，4H)
?B-0426 (DMF-d7)，1.32(br，3H)，1.67(br，3H)，4.17(br，2H)，5.12(br，1H)，7.50(m，6H)， 3.77(m，2H)，13.54(br，1H).
?B-0438 (DMSO)，1.14(t，J＝6.9Hz，3H)，4.54(m，1H)，6.99(br，2H)，7.21(br，4H)， 7.45(s，1H)，7.61(q，J＝8.7Hz，2H)，8.52(d，J＝5.2Hz，2H).
?B-0466 (DMF-d7)，1.61(brd，J＝30.6Hz，3H)，4.61(br，1H)，7.25(m，6H)，7.65(m，3H)， 3.59(br，2H)13.34(brd，J＝34.8Hz，1H).
?B-0473 (CD3OD)，1.53(d，J＝7.2Hz，3H)，4.59(q，J＝7.2Hz，1H)，6.88(d，J＝4Hz， 1H)，7.09(m，3H)，7.15(dd，J＝4.4，1.6Hz，2H)，7.26(m，2H)，8.46(d，J＝6.0 Hz，2H).
?B-0477 (DMF)，1.80(br，3H)，2.35(s，1H)，4.98(br，1H)，7.38(m，6H)，7.85(m，2H)， 8.45(br，1H)，8.75(d，J＝6.0Hz，2H).
?B-0479 (Methanol-d4)，1.57(d，J＝5.6Hz，3H)，4.74(br，1H)，7.23(m，4H)，7.60(m，2H)， 7.81(m，4H)，8.67(br，2H).
?B-0487 (DMF)，1.78(s，3H)，2.76(br，6H)，4.85(br，1H)，7.42(br，2H)，7.54(br，2H)， 7.66(br，3H)，8.82(s，2H).
?B-0566 (CD3OD)，1.38(d，J＝7.2Hz，3H)，4.15(br，2H)，4.50(br，1H)，7.04(br，2H)， 7.18(br，2H)，7.30(m，7H)?8.45(m，2H).
?B-0569 (CD3OD)，1.56(br，3H)，4.66(q，J＝6.7Hz，1H)，7.17(m，8H)，7.56(m，2H)， 8.47(s，2H).
?B-0574 (Memanol-d4)，1.49(br，3H)，3.86(br，3H)，4.60(br，1H)，6.92(br，2H)，7.19(br， 2H)，7.31(br，2H)，7.76(m，4H)，8.60(br，2H).
?B-0639 (DMF-d7)，1.58(brd，J＝30.0Hz，3H)，4.62(br，1H)，7.25(m，6H)，7.60(m，4H)， 8.59(br，2H)，13.30(brd，J＝12.3Hz).
?B-0643 7.18(m，2H)，7.32(dd，J＝6.0，4.4Hz，1H)，7.70(dd，J＝9.0，5.8Hz，1H)， 8.43(dd，J＝4.8，3.2Hz，2H).
?B-0650 (CD3OD)，1.58(br，3H)，4.62(q，J＝6.6Hz，1H)，6.93(br，1H)，7.17(m，5H)， 7.31(br，2H)，8.51(br，2H).
?B-0656 (CDCl3/CD3OD)d?8.48(d，J＝5.30Hz，2H)，7.72-7.59(m，4H)，7.14-7.10(m， 2H)，7.03-6.97(m，4H)，4.60(q，J＝7.57Hz，1H)，1.43(d，J＝7.26Hz，3H)
?B-0663 (CD3OD)，1.52(d，J＝6.8Hz，3H)，3.75(s，3H)，7.21(m，2H)，7.42(m，2H)， 7.57(s，1H)，7.76(s，1H)，7.98(br，2H)，8.76(br，2H).
?B-1165 Hz，2H)，3.06(m，1H)，3.43(q，J＝6.1Hz，2H)，7.02(m，2H)，7.14(m，2H)， 7.41(m，2H)，8.59(d，J＝5.6Hz，2H).
?B-1169 ＝1.6Hz，1H)，7.04(t，J＝8.6Hz，2H)，7.14(m，2H)，7.36(m，2H)，8.39(d，J＝1.8 Hz，1H)，8.60(m，2H).
?B-1171 6.83(br，1H)，7.02(t，J＝8.7Hz，2H)，7.15(d，J＝5.6Hz，2H)，7.40(m，2H)， 8.59(d，J＝5.0Hz，2H).
The trade mark 1H NMR (solvent), dppm
B-1179 (CDCl3)，1.94(br，2H)，2.53(s，3H)，2.85(t，J＝6.2Hz，2H)，3.65(br，2H)， 5.15(br，1H)，7.04(m，3H)，7.22(m，3H)，7.41(br，4H)，8.60(br，2H).
B-1183 (CDCl3)，2.00(br，2H)，2.85(br，2H)，3.64(br，2H)，7.03(br，3H)，7.17(br，2H)， 7.36(br，2H)，7.66(br，2H)，8.60(br，2H)，8.77(br，2H).
B-1194 (DMSO)，1.76(br，2H)，2.66(br，2H)，2.91(br，2H)，4.30(s，2H)，7.18(br，5H)， 7.35(m，6H)，8.54(d，J＝5.8Hz，2H).
B-1200 DMSO)，1.17(br，3H)，1.76(br，2H)，2.71(br，2H)，2.97(br，4H)，7.18(br，4H)， 7.36(br，2H)，8.54(br，2H).
B-1206 (DMSO)，1.03(s，6H)，1.68(br，2H)，2.63(br，2H)，3.00(br，2H)，3.65(br，1H)， 5.69(m，2H)，7.16(br，4H)，7.35(br，2H)，8.54(br，2H).
B-1216 (DMSO)，1.75(m，2H)，2.14(s，6H)，2.66(br，2H)，3.10(br，2H)，7.04(br，3H)， 7.18(br，4H)，7.35(m，2H)，7.47(br，1H)，8.54(d，J＝4.8Hz，2H).
B-1226 (DMF)，1.25(br，3H)，2.01(br，2H)，3.35(br，4H)，6.20(s，1H)，6.30(s，1H)， 7.42(br，4H)，7.65(br，2H)，8.77(s，2H).
B-1360 (DMSO-d6)，1.80(br，4H)，2.82(br，1H)，2.94(br，1H)，3.10(br，1H)，3.60(br，1H)， 4.54(br，1H)，7.18(m，4H)，7.30(m，4H)，7.46(m，2H)，8.54(br，2H).
B-1361 (DMSO-d6)，0.99(br，6H)，1.73(br，4H)，2.89(br，2H)，3.03(m，1H)，4.04(br，2H)， 4.44(m，1H)，7.18(m，4H)，7.30(m，2H)，8.57(d，J＝4.64Hz，2H).
B-1363 (DMSO-d6)，1.78(br，4H)，2.01(s，3H)，2.89(br，1H)，3.05(br，1H)，3.34(br，1H)， 3.85(br，1H)，4.48(br，1H)，7.12(br，2H)，7.21(br，2H)，7.30(br，2H)，8.69(br，2H).
B-1364 (CDCl3)，0.78(dd，J＝3.0，2.9Hz，2H)，1.00(s，2H)，1.78(m，1H)，1.86(b，4H)， 2.64(m，1H)，2.99(m，1H)，3.16(m，1H)，4.33(br，1H)，4.70(br，1H)，6.99(m，2H)， 7.14(s，2H)，7.29(m，2H)，8.64(s，2H).
B-1368 (CDCl3)，1.89(s，4H)，2.65(m，1H)，2.96(m，1H)，3.06(m，1H)，3.43(s，3H)， 3.93(d，J＝13.2Hz，1H)，4.09(d，J＝13.5Hz，1H)，4.18(d，J＝13.5Hz，1H)， 4.68(d，J＝12.4Hz，1H)，7.60(m，2H)，7.12(s，2H)，7.26(m，2H)，8.63(s，2H).
With preparing Embodiment B-1574～B-2269 with the similar preparation process of above-mentioned determined Embodiment B 0001-B0048.
Prepare Embodiment B-1574～B-1597 embodiment R by framework C-27 2R L
Figure A9880736905131
Figure A9880736905141
Prepare Embodiment B-1598～B-1621 embodiment R by framework C-28 2R L
Figure A9880736905142
Embodiment R 2R L Embodiment R 2R L
Prepare Embodiment B-1622～B-1645 embodiment R by framework C-38 2R L
Figure A9880736905172
Embodiment R 2R L
Figure A9880736905181
Embodiment R 2R L
Figure A9880736905191
Figure A9880736905201
Prepare Embodiment B-1646～B-1669 embodiment R by framework C-39 2R L
Figure A9880736905202
Embodiment R 2R L
Figure A9880736905211
Embodiment R 2R L
Figure A9880736905221
Figure A9880736905231
Prepare Embodiment B-1670～B-1693 embodiment R by framework C-65 2R L
Figure A9880736905232
Embodiment R 2R L
Figure A9880736905241
Embodiment R 2R L
Figure A9880736905251
Prepare Embodiment B-1694～B-1717 embodiment R by framework C-66 2R L
Figure A9880736905262
Embodiment R 2R L
Figure A9880736905271
Embodiment R 2R L
Figure A9880736905281
Figure A9880736905291
Prepare Embodiment B-1718～B-1741 embodiment R by framework C-69 2R L Embodiment R 2R L
Figure A9880736905301
Embodiment R 2R L
Prepare Embodiment B-1742～B-1765 embodiment R by framework C-70 2R L Embodiment R 2R L
Figure A9880736905331
Embodiment R 2R L
Figure A9880736905351
Prepare Embodiment B-1766～B3-1789 embodiment R by framework C-71 2R L
Figure A9880736905352
Embodiment R 2R L Embodiment R 2R L
Figure A9880736905371
Prepare Embodiment B-1790～B-1813 embodiment R by framework C-72 2R L
Figure A9880736905382
Embodiment R 2R L
Figure A9880736905391
Embodiment R 2R L
Figure A9880736905401
Prepare Embodiment B-1814～B-1837 embodiment R by framework C-73 2R L
Figure A9880736905412
Embodiment R 2R L Embodiment R 2R L
Figure A9880736905441
Prepare Embodiment B-1838～B-1861 embodiment R by framework C-33 2R L
Figure A9880736905442
Embodiment R 2R L
Figure A9880736905451
Embodiment R 2R L
Figure A9880736905461
Prepare Embodiment B-1862～B-1885 embodiment R by framework C-45 2R L
Figure A9880736905472
Embodiment R 2R L
Figure A9880736905481
Embodiment R 2R L
Figure A9880736905491
By framework C～42 preparation Embodiment B-1886～B-1909 embodiment R 2R L Embodiment R 2R L
Figure A9880736905511
Embodiment R 2R L
Figure A9880736905521
Prepare Embodiment B-1910～B-1933 embodiment R by framework C-44 2R L
Figure A9880736905532
Embodiment R 2R L
Figure A9880736905541
Embodiment R 2R L
Figure A9880736905551
Prepare Embodiment B-1934～B-1957 embodiment R by framework C-41 2R L
Figure A9880736905562
Embodiment R 2R L
Figure A9880736905571
Embodiment R 2R L
Figure A9880736905581
Figure A9880736905591
Prepare Embodiment B-1958～B-1981 embodiment R by framework C-43 2R L
Figure A9880736905592
Embodiment R 2R L
Figure A9880736905601
Embodiment R 2R L
Figure A9880736905611
Figure A9880736905621
Prepare Embodiment B-1982～B-2005 embodiment R by framework C-30 2R L Embodiment R 2R L Embodiment R 2R L
Figure A9880736905641
Figure A9880736905651
Prepare Embodiment B-2006～B-2029 by framework C-60
Figure A9880736905652
Figure A9880736905661
Prepare Embodiment B-2030～B-2053 embodiment R by framework C-36 2R J
Figure A9880736905682
Embodiment R 2R J
Figure A9880736905691
Embodiment R 2R J
Figure A9880736905701
Prepare Embodiment B-2054～B-2077 embodiment R by framework C-34 2R J
Figure A9880736905712
Embodiment R 2R J Embodiment R 2R J
Figure A9880736905731
Prepare Embodiment B-2078～B-2101 embodiment R by framework C-57 2R J Embodiment R 2R J
Figure A9880736905751
Embodiment R 2R J
Figure A9880736905761
Prepare Embodiment B-2102～B-2125 embodiment R by framework C-52 2R J Embodiment R 2R J Embodiment R 2R J
Figure A9880736905791
Prepare Embodiment B-2126～B-2149 embodiment R by framework C-56 2R J
Figure A9880736905802
Embodiment R 2R J Embodiment R 2R J
Prepare Embodiment B-2150～B-2173 by framework C-32
Figure A9880736905832
Figure A9880736905851
Figure A9880736905861
Prepare Embodiment B-2174～B-2197 by framework C-64
Figure A9880736905862
Figure A9880736905871
Figure A9880736905891
Prepare Embodiment B-2198～B-2221 by framework C-22
Figure A9880736905892
Figure A9880736905901
Figure A9880736905911
Prepare Embodiment B-2222～B-2245 embodiment R by framework C-29 2R J
Figure A9880736905922
Embodiment R 2R J
Figure A9880736905931
Embodiment R 2R J
Figure A9880736905941
Figure A9880736905951
Prepare Embodiment B-2246～B-2269 by framework C-35
Figure A9880736905961
Figure A9880736905971
Embodiment B-2270～B-2317
In comprising a parallel reactor group of 48 sintering containers, each reaction vessel be equipped with the polymer B 48 (1.0mmol/g resin) that 250mg is bonding with the carbonization imide and the dimethyl formamide solution that contains sour framework C49 (0.1M, 500uL).(0.2M 1000uL) joins in each suspension, then adds a kind of special acid amides (0.2M, dimethyl formamide solution 37uL) with the dichloromethane solution of pyridine.At ambient temperature, with laboratory desk-top track shaker with 250 rev/mins of stirring reaction mixtures 16-20 hour.Reactant is filled in the Erlenmeyer flask, polymkeric substance 1.5mL dimethyl formamide and 2.0mL washed with dichloromethane.Filtrate is evaporated to dried in the Savant instrument, adds dimethyl formamide (350uL) and make the residuum dissolving in each Erlenmeyer flask.(1.0M, dimethyl formamide solution 150uL) are added in the Erlenmeyer flask of regrouping, and mixture was hatched 2 hours at ambient temperature with ptfe phthalic anhydride.Add in the reaction mixture in each Erlenmeyer flask then polyamine polymer B33 (4.0meq N/g resin, 250mg) and the 1.0mL methylene dichloride.At ambient temperature, shake mixture after 16 hours with 250 rev/mins speed, with the polypropylene washing organ pipe filtering mixt that has the porous filter plate with the track shaker.With dimethyl formamide (each 1.0mL) washing copolymer twice, filtrate and washings are collected Erlenmeyer flask.Filtrate is evaporated to dry doubling and weighs, the oily that obtains wanting or solid amide product B-2270～B-2317.In this way the analytical data of Zhi Bei product and productive rate are listed in the table below.
Figure A9880736905991
Figure A9880736906001
Figure A9880736906011
Figure A9880736906031
With preparing Embodiment B-2318～B-2461 with the similar preparation process of above-mentioned determined Embodiment B-2270～B-2317.
Figure A9880736906071
Figure A9880736906081
Figure A9880736906091
Figure A9880736906121
Figure A9880736906131
Figure A9880736906171
Figure A9880736906181
Figure A9880736906191
Figure A9880736906201
Figure A9880736906211
Figure A9880736906221
Embodiment C-1
5-aminomethyl-4-(4-pyridine)-3-(4-fluorophenyl) pyrazoles
Figure A9880736906231
1-(4-fluorophenyl)-2-(4-pyridine)--1-ethyl ketone.(40g 0.43mol) at room temperature, joins in the hexamethyldisilazane lithium solution (0.45mol, 450mL, the THF solution of 1.0M) (can be observed slight exothermic phenomenon) with more than 30 minutes times with the 4-picoline.With the solution stirring that obtains 1 hour.Again it is joined in the ethyl 4-fluorobenzoic acid salt (75.8g, 0.45mol, net weight) more than 1 hour consuming time.Mixture stirs spend the night (16 hours).Add entry (200mL), with ethyl acetate (2 * 200mL) extraction mixtures.Organic layer salt solution (1 * 200mL) washing, dried over mgso.Again after filtration, remove and desolvate, obtain the oily solid.In the oily solid, add hexane, filter the solid obtain, and with hexane (cold) washing.Yellow solid is separated (50g, 54%): 1H NMR (deuterochloroform) δ 8.58 (d, J=5.7Hz, 2H), 8.02 (dd, J=5.5,8.0,2H), 7.12～7.21 (m); LC/MS, tr=2.14 minute (5～95% acetyl nitriles/water, greater than 15 minutes, speed was 1mL/min, wavelength 254nm, 50 ℃ of temperature), M+H=216; C 23H 20N 4O 2F high resolution mass spectrum (M+H) analytical calculation value: 216.0825.Observed value: 216.0830 (Δ mmu=0.5).
N-carbobenzoxy-(Cbz)-5-aminomethyl-4-(4-pyridine)-3-(4-fluorophenyl) pyrazoles.3mL has in the round-bottomed flask of mechanical stirrer, nitrogen inlet and feed hopper, the THF solution of the 557mL that packs into (0.56mol) 1M potassium tert.-butoxide and 53mL (0.56mol) trimethyl carbinol.(60g 0.28mol) at room temperature is dissolved among the 600mLTHF, and joins in the mixture under stirring with ketone.There is yellow mercury oxide to form, mixture was stirred 1 hour.(128.6g 0.42mol) is dissolved among the 600mLTHF N-carbobenzoxy-(Cbz)-acid anhydride propylhomoserin N-hydroxy-succinamide, at room temperature is added drop-wise in the mixture with more than 1 hour time.With mixture restir 5 minutes, add 150mL water.Reach 6.7 with 70mL second acid for adjusting pH value.Add a hydrazine hydrate (41mL is dissolved in the 100mL water) by the filler funnel.Mixture was stirred 1 hour, with 500mL water and the dilution of 500mL ethyl acetate.Two-phase mixture is transferred in the removable funnel, two-phase is separated.(3 * 300mL) extract water layer with ethyl acetate.Organic layer obtains 157 red thick oily products through dried over sodium sulfate, filtration and evaporation.
Thick oil forms suspension in methylene dichloride, remove insolubles (DCU, the hydrazone class of single ketones) after filtration.Solution is divided into two parts.Every part is separated (Biotage 75L uses 3% ethanol/dichloromethane earlier, uses 6% ethanol/dichloromethane again) with chromatography.The fraction (from some pollutents of single ketones and hydrazone) that is fit in concentrating every part obtains yellow solid.Solid suspension is heated to boiling in ethyl acetate, kept 10 minutes.Solution is cooled to room temperature, and placement is spent the night.Filtering precipitate obtains 30g white solid (2 productive rate is 27%): 1H NMR (δ 13.36 of dimethyl formamide-d7) (s, 2H), 8.57 (d, J=5.4Hz, 2H); 19F NMR (δ-114.9 (m) of dimethyl formamide-d7) ,-116.8 (m) (split branch fluorine signal and come from the pyrazoles isomer); LC/MS, tr=3.52 minute (5～95% acetyl nitriles/water, time＞15min, speed 1mL/min, wavelength 254nm, 50 ℃ of temperature), M+H=403; C 23H 20N 4O 2F high resolution mass spectrum (M+H) analytical calculation value: 403.1570.Observed value: 403.1581 (Δ mmu=1.1).
5-aminomethyl-4-(4-pyridine)-3-(4-fluorophenyl) pyrazoles.In 1 liter of Parr bottle, add 7g2 (17.4mmol) and 180mL methyl alcohol and 90mLTHF, obtain settled solution.Use the purging with nitrogen gas Parr bottle, add 1.5g10%Pd/C (wet type Degussa E101).Parr bottle is pressurized to 40psi (H 2) and stir.After 5 hours, the hydrogen soakage is 5psi.Parr bottle is pressurized to 42psi again, and stirs and spend the night.Use the purging with nitrogen gas Parr bottle, filter by molecular sieve.(3 * 50mL) washing molecular sieves, concentrated filtrate obtains 4.5g rice white solid (94%) with methyl alcohol. 1H NMR 19F NMR (methyl-sulphoxide-d 6) δ 8.52 (d, J=4.63Hz, 2H), 7.36 (dd, J=5.64,8.1Hz, 2H), 7.16～7.30 (m, 4H), 36.79 (s, 2H); 19F NMR (methyl-sulphoxide-d 6) δ-114.56 (m); LC/MS, t r=1.21 minutes (5～95% acetyl nitriles/water, time＞15min, speed 1mL/min, wavelength 254nm, 50 ℃ of temperature), M+H=269m/z; C 15H 14N 4O 2F high resolution mass spectrum (M+H) analytical calculation value: 269.1202.Observed value: 269.1229 (Δ mmu=2.7).Following pyridine pyrazoles (C-2～C-21 sees Table C-1) is according to the experimental procedure preparation of the Embodiment C-1 narrated above.
Table C-1
Figure A9880736906251
Figure A9880736906261
Figure A9880736906271
?????????2.71(br，1H)，2.51(br， ???????????2H)，1.68(br，4H)
Following pyridine pyrazoles (C-22～C-40 sees Table C-2) is to adopt the experimental procedure of general scheme C-1 and C-2 and the above embodiments C-1 to prepare.
Table C-2
Figure A9880736906301
Figure A9880736906311
Embodiment C-49
Figure A9880736906322
Steps A
The pyrazoles that embodiment 4 obtains is made suspension in 52mL ethylene dichloride and 52mL2.5M sodium hydroxide.Tetrabutylphosphoniuhydroxide hydroxide amine (the 0.5mL1M aqueous solution) is joined in the mixture that is stirring.And the tert.-butyl bromide acetic ester (2.10g, 10.8mmol).Reaction mixture at room temperature stirred 4 hours.Pour mixture into 200mL methylene dichloride and 200mL water.Separate two-phase, water (1 * 100mL) and salt solution (1 * 100mL) washs organic phase.With dried over sodium sulfate and filter organic phase.Remove and desolvate, obtain the rice white solid.Develop solid with hexane, the solid that obtains by filtering separation carries out.Use the hexane wash solid, obtain 3.4g white solid (90%).
Step B
The hydrocarbylation pyrazoles that in dioxan, obtains with 57mL4NHCl treatment step A (3.7g, 10.1mmol).Solution at room temperature stirred 4 hours.Decompression removes down and desolvates, and residuum is dissolved among the THF.With propylene oxide (10.3mmol) treatment soln, and at room temperature stirred 1 hour.Remove and desolvate, remaining oil.Divide and remove residual solvent with ethanol several times.Solid with the ether development obtains by filtering to isolate Embodiment C-49 title compound, obtains 3.0g rice white solid (95%).The calculated value of mass spectrum: M+H: 312; Observed value: 312. 1H NMR (methyl-sulphoxide-d 6): 8.81 (d, J=6.4Hz, 2H), 7.73 (d, J=5.8Hz, 2H), 7.40 (m, 2H), 7.23 (t, J=8.5Hz, 1H), 5.16 (s, 2H), 2.40 (s, 3H).Embodiment C-50
Figure A9880736906331
According to the step of the foregoing description C-49, also by 4-[3-(4-fluorophenyl)-1 hydrogen-pyrazoles-4-yl] pyridine begins to prepare Embodiment C-50.The calculated value of mass spectrum: M+H: 298; Observed value: 298. 1H NMR (methyl-sulphoxide-d 6): 8.75 (d, J=6.4Hz, 2H), 8.68 (s, 1H), 7.78 (d, J=6.6Hz, 2H), 7.52 (dd, J=5.4,8.5Hz, 2H), 7.31 (t, J=8.9Hz, 2H), 5.16 (s, 2H).
Embodiment C-51
Figure A9880736906332
According to the method for describing among the scheme C-1, from the N-Boc-piperidyl analogue of Embodiment C-2, preparation Embodiment C-51.
Embodiment C-52 Steps A: use the alkaline purification picoline, alkali can be but be not limited to n-Butyl Lithium, LDA, hexamethyldisilazane lithium, tertiary butyl potassium or sodium hydride in organic solvent such as THF, ether, tertiary butyl alcohol or the dioxan, temperature continues 10 minutes～3 hours from-78 ℃～50 ℃.Then picoline solution is joined in N-Cbz-(L)-phenylalanine N-hydroxy-succinamide.Reactant can stir 30 minutes to 48 hours, and the whipping process range of temperature is-20 ℃～120 ℃.Then mixture is poured in the water, used organic solvent extraction.Dry with remove desolvate after, isolating can be by the thick solid of pyridine single ketones of crystallization or chromatography purification. Step B: ether, THF, tertiary butyl alcohol or the dioxan solution of pyridine single ketones are joined in a kind of alkali, alkali can be but be not limited to n-Butyl Lithium contained in hexane, THF, ether, dioxan or the tertiary butyl alcohol, LDA, hexamethyldisilazane lithium, tertiary butyl potassium or sodium hydride, temperature continues 10 minutes～3 hours from-78 ℃～50 ℃.THF, ether or the dioxan solution of malonaldehydic acid acid anhydride are joined in the single ketones negatively charged ion, and simultaneous temperature remains between-50 ℃～50 ℃.The mixture that stirring obtains under specified temperature 5 minutes to several hours.Synthetic pyridine diketone intermediate is used for step C, does not need purifying. Step C: water quenching contains the solution of pyridine diketone, and with a kind of organic or inorganic acid that is selected from acetic acid, sulfuric acid, hydrochloric acid or nitric acid the pH value is transferred to 4～8.In this step, temperature remains between-20 ℃～room temperature.Subsequently hydrazine or hydrazine hydrate are joined in the mixture, maintain the temperature at simultaneously between-20 ℃～40 ℃, kept 30 minutes～several hours.Then mixture is poured in the water, used organic solvent extraction.Obtain the thick solid of pyridine pyrazoles of N-Cbz-protection, with chromatography or this thick solid of crystallization process purifying. Step D:
Utilize the palladium carbon in pressurized hydrogen and the ethanol to decompose the CBZ blocking group, obtain framework C-52 with concentrating after filtration.
Figure A9880736906352
Produce the following compounds C-53～C-59 that shows among the C-3 according to the general step of above-mentioned preparation C-52.
Table C-3
Figure A9880736906353
Figure A9880736906361
Embodiment C-60 steps A:
Use dried reagent, exist under the room temperature under the situation of siccative, in methylene dichloride, with the pyridine pyrazoles of phenyl aldehyde treatments B oc protection, the time length is 1～24 hour.Then, the synthetic imines is used for step B, need be further purified solvent evaporation.
Figure A9880736906371
Step B;
Temperature-78 ℃～-20 ℃, under the nitrogen protection, the pyridine pyrazole imine is dissolved among the THF stirs.Drip a kind of alkali such as LDA, n-Butyl Lithium in the mixture, or the hexamethyldisilazane lithium, then the restir mixture is 10 minutes to 3 hours.Subsequently two normal methyl iodide are joined in the mixture, continue to stir several hours.The sour chilling of mixture, temperature be to room temperature, and stir and separated fully with imine up to Boc in several hours.PH is transferred to 12, use the organic solvent extraction mixture then, and drying and evaporating solvent.The crude pyridine pyrazoles obtains the C-60 of purifying again through crystallization or chromatogram purification.
Step B
Figure A9880736906372
1) alkali
2)Mel
3) acid, H 2O
Embodiment C-61
Method according to Embodiment C-60 narration prepares Embodiment C-61, and with 1,4-two bromo butane replace methyl iodide.
Embodiment C-62
Figure A9880736906381
Method according to Embodiment C-60 narration prepares Embodiment C-62, and with 1,3-two bromo butane replace methyl iodide.
Embodiment C-63
Synthesizing from bromomaleic acid acid anhydride B77 and 2 of Compound C-63, the condensation reaction of 4-dimethoxy benzylamine in acetic acid and acetic anhydride liquid begins.Pd in the catalyzer metering 2(dba) 3Exist down with 4 with uncle's fourth oxygen sodium '-acetyl fluoride benzene handles maleimide B78, forms the maleimide B79 of acetyl fluoride benzene replacement.Then, obtain a-ketone enamine B80 with two (dimethylamino) methane treatments B 79 of uncle's fourth oxygen.Concentrate a-ketone enamine B80 with hydrazine, form the maleimide pyrazoles B81 of N-protected.Decompose 2 with cerium ammonium nitrate, 4-veratryl group obtains title compound C-63.
Figure A9880736906391
Embodiment C-64 Method with scheme C-6 and C-7 narration prepares embodiment 64.
Embodiment C-65 Method with scheme C-6 and C-7 narration prepares embodiment 65.
Embodiment C-66
Figure A9880736906401
The synthetic embodiment 66 of method with scheme C-6 and C-7 narration uses N-2, and 4-veratryl-4-pyridine bromide ketone substitutes B78.
Embodiment C-67
The synthetic embodiment 67 of method with scheme C-6 and C-7 narration uses N-2, and 4-veratryl-4-pyridine bromide ketone substitutes B78, with N-Boc-glycyl N-hydroxy-succinamide B82.
Embodiment C-68
Figure A9880736906403
The synthetic embodiment 68 of method with scheme C-6 and C-7 narration uses N-2, and 4-veratryl-4-pyridine bromide ketone substitutes B78.
Embodiment C-69
Figure A9880736906411
Method with scheme C-6 and C-7 narration prepares embodiment 69, substitutes B83 with the N-Boc-nipecotylN-N-Hydroxysuccinimide.
Embodiment C-70
Figure A9880736906412
Method with scheme C-6 and C-7 narration prepares embodiment 70, substitutes B83 with the N-Boc-nipecotylN-N-Hydroxysuccinimide.
Embodiment C-71
Method with scheme C-6 and C-7 narration prepares embodiment 71, substitutes B78 with N-methyl-3-bromo maleimide.
Embodiment C-72
Figure A9880736906421
Method with scheme C-6 and C-7 narration prepares embodiment 72, replaces B78 with N-methyl-3-bromo maleimide, replaces B83 with the N-Boc-nipecotyl N-hydroxy-succinamide.
Embodiment C-73
Figure A9880736906422
Method with scheme C-6 and C-7 narration prepares embodiment 73, replaces B78 with N-methyl-3-bromo maleimide, replaces B83 with the N-Boc-nipecotyl N-hydroxy-succinamide.
The related biological data of the compound of Embodiment B-0001～B-1573 and Embodiment B-2270～B-2462 see the following form.
The inhibition data of external P38-alpha kinase are seen column:
" P38 alpha kinase IC 50, uM or % suppress @ concentration, (uM)
External in the human body U937 cell that LPS stimulates, measure the full cell analysis of the ability of compound inhibition TNF generation and see column:
" U937 cell IC 50, uM or % suppress @ concentration, and (uM) inhibition is subjected to the mouse interior evaluating of the TNF releasability of LPS stimulation to see column to compound:
" mouse LPS model, %TNF suppresses the @ dosage @ predose time " wherein dosage is that a mouthful tube feed amount is mg/kg (mpk), when predose time representation drops into this compound, is subjected to LPS to stimulate the preceding time.
Inhibition is subjected to the rat interior evaluating of the TNF releasability of LPS stimulation to see column to compound:
" rat LPS model, %TNF suppresses the @ dosage @ predose time " wherein dosage is that a mouthful tube feed amount is mg/kg (mpk), when predose time representation drops into this compound, is subjected to LPS to stimulate the preceding time.
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0001 ??53.0％@1.0uM ??40.0％@1.0uM
?B-0002 ??71.0％@1.0uM ??28.0％@10.0uM
?B-0003 ??70.0％@1.0uM ??76.0％10.0uM
?B-0004 ??80.0％@1.0uM ?????4.61uM
?B-0005 ??95.0％@1.0uM ?????2.97uM
?B-0006 ??82.0％@1.0uM ??80％@10.0uM
?B-0007 ??74.0％@1.0uM ??85.0％@10.0uM
?B-0008 ??42.0％@1.0uM ??65.0％@10.0uM
?B-0009 ????0.04uM ?????0.72uM
?B-0010 ????0.52uM ?????0.65uM
?B-0011 ????0.03uM ?????4.47uM
?B-0012 ??30.0％@1.0uM ??44.0％@1.0uM
?B-0013 ??70.0％@1.0uM ??84.0％@10.0uM
?B-0014 ??79.0％@1.0uM ??80.0％@10.0uM
?B-0015 ??82.0％@1.0uM ??80.0％@10.0uM
?B-0016 ??94.0％@1.0uM ?????3.98uM
?B-0017 ??56.0％@1.0uM ??79.0％@10.0uM
?B-0018 ??60.0％@1.0uM ??59.0％@10.0uM
?B-0019 ??84.0％@1.0uM ??100.0％@10.0uM
?B-0020 ??73.0％@1.0uM ??81.0％@10.0uM
?B-0021 ??68.0％@1.0uM ??76.0％@10.0uM
?B-0022 ??69.0％@1.0uM ??44.0@1.0uM
?B-0023 ??90.0％@1.0uM ??77.0％@10.0uM
?B-0024 ??94.0％@1.0uM ??52.0％@1.0uM
?B-0025 ??89.0％@1.0uM ??79.0％@10.0uM
?B-0026 ??96.0％@1.0uM ?????3.27uM
?B-0027 ??94.0％@1.0uM ?????11.0uM
?B-0028 ??69.0％@1.0uM ??45.0％@10.0uM
?B-0029 ??91.0％@1.0uM ??58.0％@10.0uM
?B-0030 ??92.0％@1.0uM ??75.0％@10.0uM
?B-0031 ??94.0％@1.0uM ??100.0％@10.0uM
?B-0032 ??94.0％@1.0uM ??78.0％@10.0uM
?B-0033 ??97.0％@1.0uM ?????10.0uM
?B-0034 ??95.0％@1.0uM ?????10.0uM
?B-0035 ??94.0％@1.0uM ?????10.0uM
?B-0036 ??92.0％@1.0uM ?????8.24uM
?B-0037 ??91.0％@1.0uM ??86.0％@10.0uM
?B-0038 ??71.0％@1.0uM ??84.0％@10.0uM
?B-0039 ??89.0％@1.0uM ??72.0％@10.0uM
?B-0040 ??93.0％@1.0uM ?????2.3uM
?B-0041 ??65.0％@1.0uM ??66.0％@10.0uM
?B-0042 ??94.0％@1.0uM ?????2.76uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0043 ????0.22uM ????0.54uM
?B-0044 ????0.14uM ????0.19uM
?B-0045 ??94.0％@1.0uM ????1.01uM
?B-0046 ??96.0％@1.0uM ??54.0％@1.0uM
?B-0047 ??94.0％@1.0uM ??74.0％@10.0uM
?B-0048 ??94.0％@1.0uM ?76.0％@10.0uM
?B-0049 ??88％@1.0uM ??33.0％@1.0uM
?B-0050 ??73％@1.0uM ??34.0％@1.0uM
?B-0051 ????3.3uM ????2.15uM ?47％@100mpk@-6h ?79％@3mpk@-4h
?B-0052 ??92％@1.0uM ??15.0％@1.0uM
?B-0053 ??95％@1.0uM ??34.0％@1.0uM
?B-0054 ??90％@1.0uM ??30.0％@1.0uM
?B-0055 ??93％@1.0uM ????＞1.0uM
?B-0056 ??96％@1.0uM ??21.0％@1.0uM
?B-0057 ??96％@1.0uM ??29.0％@1.0uM
?B-0058 ??79％@1.0uM ??18.0％@1.0uM
?B-0059 ??83％@1.0uM ??35.0％@1.0uM
?B-0060 ??73％@1.0uM ??22.0％@1.0uM
?B-0061 ??62％@1.0uM ??27.0％@1.0uM
?B-0062 ??94％@1.0uM ??36.0％@1.0uM
?B-0063 ??96％@1.0uM ??40.0％@1.0uM
?B-0064 ??90％@1.0uM ??4.0％@1.0uM
?B-0065 ??83％@1.0uM ??21.0％@1.0uM
?B-0066 ??94％@1.0uM ??28.0％@1.0uM
?B-0067 ??91％@1.0uM ??1.0％@1.0uM
?B-0068 ??72％@1.0uM ??22.0％@1.0uM
?B-0069 ??96％@1.0uM ??37.0％@1.0uM
?B-0070 ??92％@1.0uM ??30.0％@1.0uM
?B-0071 ??86％@1.0uM ??31.0％@1.0uM
?B-0072 ??77％@1.0uM ??32.0％@1.0uM
?B-0073 ??91％@1.0uM ??24.0％@1.0uM
?B-0074 ??92％@1.0uM ??42.0％@1.0uM
?B-0075 ??91％@1.0uM ??35.0％@1.0uM
?B-0076 ??58％@1.0uM ??21.0％@1.0uM
?B-0077 ????0.8uM ????10.0uM
?B-0078 ??80％@1.0uM ??20.0％@1.0uM
?B-0079 ??93％@1.0uM ??13.0％@1.0uM
?B-0080 ??73％@1.0uM ??73.0％@1.0uM
?B-0081 ??92％@1.0uM ??13.0％@1.0uM
?B-0082 ??47％@1.0uM ??27.0％@1.0uM
?B-0083 ????0.22uM ????6.51uM
?B-0084 ??56％@1.0uM ??30.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0085 ??83％@1.0uM ??21.0％@1.0uM
?B-0086 ??91％@1.0uM ??37.0％@1.0uM
?B-0087 ????0.55uM ????2.26uM ?38％@30mpk@-6h
?B-0088 ??96％@1.0uM ??9.0％@1.0uM
?B-0089 ????0.04uM ????3.33uM
?B-0090 ??98％@1.0uM ??52.0％@1.0uM
?B-0091 ??96％@1.0uM ??40.0％@1.0uM
?B-0092 ??97％@1.0uM ??34.0％@1.0uM
?B-0093 ????3.18uM ????1.25uM ?30％@30mpk@-6h
?B-0094 ??96％@1.0uM ??52.0％@1.0uM
?B-0095 ??98％@1.0uM ??38.0％@1.0uM
?B-0096 ??91％@1.0uM ??22.0％@1.0uM
?B-0097 ??72.0％@10.0uM ??38.0％@1.0uM
?B-0098 ??66.0％@10.0uM ??12.0％@1.0uM
?B-0099 ??43.0％@1.0uM ????＞1.0uM
?B-0100 ??75.0％@1.0uM ????5.0uM
?B-0101 ??71.0％@1.0uM ????2.11uM
?B-0102 ??81.0％@1.0uM ??15.0％@1.0uM
?B-0103 ??71.0％@1.0uM ??6.0％@1.0uM
?B-0104 ??56.0％@1.0uM ????2.78uM
?B-0105 ??78.0％@1.0uM ????5.0uM
?B-0106 ??62.0％@1.0uM ????5.0uM
?B-0107 ????0.27uM ????5.0uM
?B-0108 ??61.0％@1.0uM ????4.85uM
?B-0109 ??45.0％@1.0uM ??19.0％@1.0uM
?B-0110 ??66.0％@1.0uM ??13.0％@1.0uM
?B-0111 ??57.0％@1.0uM ????＞1.0uM
?B-0112 ??97.0％@1.0uM ????1.12uM
?B-0113 ??75.0％@1.0uM ??43.0％@1.0uM
?B-0114 ??45.0％@1.0uM ????3.92uM
?B-0115 ??47.0％@1.0uM ??2.0％@1.0uM
?B-0116 ??73.0％@1.0uM ??35.0％@1.0uM
?B-0117 ????0.46uM ????1.78uM ?30％@30mpk@-6h
?B-0118 ????1.18uM ????1.29uM
?B-0119 ??89.0％@10.0uM ????2.78uM
?B-0120 ????0.008uM ????0.21uM ?77％@100mpk@-6h ?70％@3mpk@-4h
?B-0121 ??79.0％@1.0uM ????1.22uM
?B-0122 ??79.0％@10.0uM ??2.0％@1.0uM
?B-0123 ??59.0％@1.0uM ????＞1.0uM
?B-0124 ??73.0％@1.0uM ??15.0％@1.0uM
?B-0125 ??70.0％@10.0uM ??17.0％@1.0uM
?B-0126 ??66.0％@1.0uM ????1.57uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0127 ??82.0％@1.0uM ????0.96uM
?B-0128 ??78.0％@1.0uM ????1.81uM
?B-0129 ??51.0％@1.0uM ??31.0％@1.0uM
?B-0130 ??69.0％@1.0uM ??58.0％@1.0uM
?B-0131 ??43.0％@1.0uM ??46.0％@1.0uM
?B-0132 ??76.0％@1.0uM ???8.0％@1.0uM
?B-0133 ??51.0％@1.0uM ??42.0％@1.0uM
?B-0134 ??60.0％@1.0uM ????2.17uM
?B-0135 ??78.0％@1.0uM ??58.0％@1.0uM
?B-0136 ??77.0％@1.0uM ??44.0％@1.0uM
?B-0137 ??41.0％@1.0uM ??37.0％@1.0uM
?B-0138 ??50.0％@1.0uM ??32.0％@1.0uM
?B-0139 ??54.0％@10.0uM ??17.0％@1.0uM
?B-0140 ???67％@10.0uM ???9.0％@1.0uM
?B-0141 ??78.0％@1.0uM ??10.0％@1.0uM
?B-0142 ??86.0％@1.0uM ??12.0％@1.0uM
?B-0143 ??42.0％@1.0uM ????3.63uM
?B-0144 ??86.0％@1.0uM ??43.0％@1.0uM
?B-0145 ??54.0％@10.0uM ??12.0％@1.0uM
?B-0146 ??77.0％@10.0uM ??28.0％@1.0uM
?B-0147 ??44.0％@1.0uM ??22.0％@1.0uM
?B-0148 ??51.0％@1.0uM ????＞1.0uM
?B-0149 ????1.15uM ????10.0uM
?B-0150 ?27.0％@10.0uM ??35.0％@1.0uM
?B-0151 ??43.0％@1.0uM ??30.0％@1.0uM
?B-0152 ??51.0％@1.0uM ??24.0％@1.0uM
?B-0153 ??57.0％@1.0uM ??21.0％@1.0uM
?B-0154 ?65.0％@10.0uM ??14.0％@1.0uM
?B-0155 ?40.0％@10.0uM ??26.0％@1.0uM
?B-0156 ?42.0％@10.0uM ??13.0％@1.0uM
?B-0157 ?48.0％@10.0uM ???9.0％@1.0uM
?B-0158 ?58.0％@10.0uM ??39.0％@1.0uM
?B-0159 ?54.0％@10.0uM ???5.0％@1.0uM
?B-0160 ?59.0％@10.0uM ??26.0％@1.0uM
?B-0161 ?72.0％@10.0uM ??13.0％@1.0uM
?B-0162 ??23％@1.0uM ????2.05uM
?B-0163 ?20.0％@10.0uM ??10.0％@1.0uM
?B-0164 ?37.0％@10.0uM ??20.0％@1.0uM
?B-0165 ?70.0％@10.0uM ??19.0％@1.0uM
?B-0166 ?45.0％@10.0uM ??37.0％@1.0uM
?B-0167 ??40.0％@1.0uM ??37.0％@1.0uM
?B-0168 ??44％@1.0uM ????2.36uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0169 ??43.0％@1.0uM ?21.0％@1.0uM
?B-0170 ??43.0％@1.0uM ?30.0％@1.0uM
?B-0171 ?61.0％@10.0uM ?21.0％@1.0uM
?B-0172 ?16.0％@10.0uM ?11.0％@1.0uM
?B-0173 ?33.0％@10.0uM ?48.0％@1.0uM
?B-0174 ?54.0％@10.0uM ?43.0％@1.0uM
?B-0175 ?41.0％@10.0uM ?31.0％@1.0uM
?B-0176 ??50.0％@1.0uM ?30.0％@1.0uM
?B-0177 ?70.0％@10.0uM ?27.0％@1.0uM
?B-0178 ?12.0％@10.0uM ?35.0％@1.0uM
?B-0179 ?27.0％@10.0uM ?37.0％@1.0uM
?B-0180 ?34.0％@10.0uM ?23.0％@1.0uM
?B-0181 ??5.0％@1.0uM ??2.0％@1.0uM
?B-0182 ?39.0％@10.0uM ?40.0％@1.0uM
?B-0183 ?12.0％@10.0uM ?34.0％@1.0uM
?B-0184 ?66.0％@10.0uM ?17.0％@1.0uM
?B-0185 ?65.0％@10.0uM ?25.0％@1.0uM
?B-0186 ??40.0％@1.0uM ?25.0％@1.0uM
?B-0187 ??4.0％@10.0uM ?14.0％@1.0uM
?B-0188 ?70.0％@10.0uM ?35.0％@1.0uM
?B-0189 ?42.0％@10.0uM ??9.0％@1.0uM
?B-0190 ?59.0％@10.0uM ?31.0％@1.0uM
?B-0191 ??40.0％@1.0uM ?29.0％@1.0uM
?B-0192 ?12.0％@10.0uM ?47.0％@1.0uM
?B-0193 ????0.54uM ???6％@1.0uM
?B0194 ????1.31uM ??22％@1.0uM
?B-0195 ????1.03uM ??55％@1.0uM
?B-0196 ????2.24uM ????＞1.0uM
?B-0197 ????2.0uM ??14％@1.0uM
?B-0198 ????1.2uM ???2％@1.0uM
?B-0199 ????1.34uM ???3％@1.0uM
?B-0200 ????1.31uM ??16％@1.0uM
?B-0201 ????0.29uM ??59％@1.0uM
?B-0202 ????0.55uM ????2.26uM
?B-0203 ????0.16uM ??65％@1.0uM
?B-0204 ????0.21uM ??48％@1.0uM
?B-0205 ????0.096uM ??54％@1.0uM
?B-0206 ????5.76uM ??14％@1.0uM
?B-0207 ????0.12uM ??52％@1.0uM
?B-0208 ????0.067uM ????＞1.0uM
?B-0209 ????0.29uM ???8％@1.0uM
?B-0210 ????0.057uM ??67％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0211 ????0.25uM ??30％@1.0uM
?B-0212 ????0.12uM ??28％@1.0uM
?B-0213 ????0.31uM ??39％@1.0uM
?B-0214 ????0.16uM ??50％@1.0uM
?B-0215 ????0.11uM ??51％@1.0uM
?B-0216 ????0.56uM ????＞1.0uM
?B-0217 ????0.55uM ????＞1.0uM
?B-0218 ????0.53uM ??18％@1.0uM
?B-0219 ????0.91uM ??18％@1.0uM
?B-0220 ????0.13uM ??40％@1.0uM
?B-0221 ????2.4uM ????＞1.0uM
?B-0222 ????0.4uM ??29.0％@1.0uM
?B-0223 ????0.2uM ??1.0％@1.0uM
?B-0224 ????＜0.1uM ??93.0％@1.0uM
?B-0225 ????0.047uM ??37.0％@1.0uM
?B-0226 ????0.074uM ??20.0％@1.0uM
?B-0227 ????0.045uM ??1.0％@1.0uM
?B-0228 ????0.15uM ??44.0％@1.0uM
?B-0229 ????＜0.1uM ??61.0％@1.0uM
?B-0230 ????0.041uM ??30.0％@1.0uM
?B-0231 ????0.055uM ??40.0％1.0uM
?B-0232 ????0.048uM ??24.0％@1.0uM
?B-0233 ????0.095uM ??43.0％@1.0uM
?B-0234 ????0.11uM ??68.0％@1.0uM
?B-0235 ????1.31uM ??90.0％@1.0uM
?B-0236 ????0.077uM ??46.0％@1.0uM
?B-0237 ????0.13uM ??60.0％@1.0uM
?B-0238 ????0.47uM ??82.0％@1.0uM
?B-0239 ????5.73uM ??84.0％@1.0uM
?B-0240 ????0.2uM ??70.0％@1.0uM
?B-0241 ????0.1uM ??45.0％@1.0uM
?B-0242 ????＜0.1uM ??78.0％@1.0uM
?B-0243 ????0.039uM ??53.0％@1.0uM
?B-0244 ????0.02uM ??57.0％@1.0uM
?B-0245 ????0.13uM ??24.0％@1.0uM
?B-0246 ????＜0.1uM ????＞1.0uM
?B-0247 ????0.082uM ??75.0％@1.0uM
?B-0248 ????＜0.1uM ??11.0％@1.0uM
?B-0249 ????＜0.1uM ??75.0％@1.0uM
?B-0250 ????0.28uM ??36.0％@1.0uM
?B-0251 ????0.31uM ??1.0％@1.0uM
?B-0252 ????0.041uM ??54.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0253 ????0.061uM ??74.0％@1.0uM
?B-0254 ????0.12uM ??59.0％@1.0uM
?B-0255 ????0.32uM ??68.0％@1.0uM
?B-0256 ????＜0.1uM ??88.0％@1.0uM
?B-0257 ????1.71uM ??11.0％@1.0uM
?B-0258 ????0.37uM ??63.0％@1.0uM
?B-0259 ????0.35uM ??58.0％@1.0uM
?B-0260 ????0.56uM ??23.0％@1.0uM
?B-0261 ????0.49uM ??23.0％@1.0uM
?B-0262 ????0.41uM ??89.0％@1.0uM
?B-0263 ????0.62uM ??64.0％@1.0uM
?B-0264 ????0.14uM ??18.0％@1.0uM
?B-0265 ????0.92uM ??24.0％@1.0uM
?B-0266 ????0.25uM ??24.0％@1.0uM
?B-0267 ????0.48uM ??11.0％@1.0uM
?B-0268 ????3.39uM ??19.0％@1.0uM
?B-0269 ????9.81uM ??19.0％@1.0uM
?B-0270 ????5.79uM ??13.0％@1.0uM
?B-0271 ????7.55uM ??12.0％@1.0uM
?B-0272 ????1.81uM ??48.0％@1.0uM
?B-0273 ????5.03uM ??13.0％@1.0uM
?B-0274 ????2.68uM ??25.0％@1.0uM
?B-0275 ????2.67uM ??33.0％@1.0uM
?B-0276 ????1.25uM ??26.0％@1.0uM
?B-0277 ????0.68uM ??34.0％@1.0uM
?B-0278 ????1.26uM ??36.0％@1.0uM
?B-0279 ????1.39uM ??33.0％@1.0uM
?B-0280 ????0.86uM ??18.0％@1.0uM
?B-0281 ????7.37uM ??24.0％@1.0uM
?B-0282 ????0.75uM ??38.0％@1.0uM
?B-0283 ????6.66uM ??29.0％@1.0uM
?B-0284 ????0.083uM ??65.0％@1.0uM
?B-0285 ????4.57uM ??29.0％@1.0uM
?B-0286 ????0.33uM ??50.0％@1.0uM
?B-0287 ????4.0uM ??22.0％@1.0uM
?B-0288 ????4.46uM ??26.0％@1.0uM
?B-0289 ????0.15uM ??55.0％@1.0uM
?B-0290 ????0.66uM ??44.0％@1.0uM
?B-0291 ????1.33uM ??20.0％@1.0uM
?B-0292 ????0.22uM ??28.0％@1.0uM
?B-0293 ????0.66uM ??53.0％@1.0uM
?B-0294 ????0.68uM ??45.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0295 ????0.82uM ??45.0％@1.0uM
?B-0296 ????8.03uM ??36.0％@1.0uM
?B-0297 ????0.78uM ??30.0％@1.0uM
?B-0298 ????0.58uM ??48.0％@1.0uM
?B-0299 ????0.87uM ??54.0％@1.0uM
?B-0300 ????0.78uM ??32.0％@1.0uM
?B-0301 ????0.19uM ??50.0％@1.0uM
?B-0302 ????4.02uM ??24.0％@1.0uM
?B-0303 ????0.22uM ??10.0％@1.0uM
?B-0304 ????0.56uM ??28.0％@1.0uM
?B-0305
?B-0306
?B-0307
?B-0308
?B-0309
?B-0310
?B-0311
?B-0312
?B-0313
?B-0314
?B-0315
?B-0316
?B-0317
?B-0318
?B-0319
?B-0320
?B-0321
?B-0322
?B-0323
?B-0324
?B-0325
?B-0326
?B-0327
?B-0328
?B-0329
?B-0330
?B-0331
?B-0332
?B-0333
?B-0334
?B-0335
?B-0336
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0337
?B-0338
?B-0339
?B-0340
?B-0341
?B-0342
?B-0343
?B-0344
?B-0345
?B-0346
?B-0347
?B-0348
?B-0349
?B-0350
?B-0351
?B-0352
?B-0353 ????1.37uM ????55％@1.0uM
?B-0354 ????1.0uM ????0.66uM ?51％@30mpk@-6h ?54％@3mpk@-4h
?B-0355 ????0.75uM ??40.0％@1.0uM
?B-0356 ????0.66uM ??24.0％@1.0uM
?B-0357 ????1.46uM ????0.66uM
?B-0358 ????0.37uM ??17.0％@1.0uM
?B-0359 ????0.45uM ??47.0％@1.0uM
?B-0360 ????1.6uM ??19.0％@1.0uM
?B-0361 ????0.33uM ??46.0％@1.0uM
?B-0362 ????0.52uM ??27.0％@1.0uM
?B-0363 ????4.67uM ??25.0％@1.0uM
?B-0364 ????1.44uM ??27.0％@1.0uM
?B-0365 ????0.96uM ??27.0％@1.0uM
?B-0366 ????0.7uM ??46.0％@1.0uM
?B-0367 ????1.0uM ??23.0％@1.0uM
?B-0368 ????1.0uM ????0.64uM ?37％@30mpk@-6h
?B-0369 ????0.16uM ??57.0％@1.0uM
?B-0370 ????0.65uM ??28.0％@1.0uM
?B-0371 ????0.49uM ??28.0％@1.0uM
?B-0372 ????0.35uM ??29.0％@1.0uM
?B-0373 ????0.45uM ??18.0％@1.0uM
?B-0374 ????1.38uM ??12.0％@1.0uM
?B-0375 ????1.0uM ??19.0％@1.0uM
?B-0376 ????2.99uM ??12.0％@1.0uM
?B-0377 ????1.29uM ??36.0％@1.0uM
?B-0378 ????1.1uM ??36.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0379 ????0.53uM ??24.0％@1.0uM
?B-0380 ????1.41uM ??32.0％@1.0uM
?B-0381 ????0.22uM ??47.0％@1.0uM
?B-0382 ????0.41uM ??32.0％@1.0uM
?B-0383 ????1.43uM ??10.0％@1.0uM
?B-0384 ????4.02uM ??16.0％@1.0uM
?B-0385 ????0.057uM ????0.9uM ?30％@30mpk@-6h ??0％@3mpk@-4h
?B-0386 ????0.13uM ??54.0％@1.0uM
?B-0387 ????0.41uM ??52.0％@1.0uM
?B-0388 ????＜0.1uM ??36.0％@1.0uM
?B-0389 ????0.01uM ????0.05uM ??62％@3mpk@-4h
?B-0390 ????0.089uM ??55.0％@1.0uM
?B-0391 ????0.86uM ??18.0％@1.0uM
?B-0392 ????0.13uM ??57.0％@1.0uM
?B-0393 ????0.043uM ??66.0％@1.0uM
?B-0394 ????0.13uM ??45.0％@1.0uM
?B-0395 ????0.087uM ??48.0％@1.0uM
?B-0396 ????0.097uM ????0.44uM
?B-0397 ????0.17uM ??41.0％@1.0uM
?B-0398 ????0.054uM ??66.0％@1.0uM
?B-0399 ????0.14uM ??39.0％@1.0uM
?B-0400 ????0.16uM ??25.0％@1.0uM
?B-0401 ????0.46uM ??52.0％@1.0uM
?B-0402 ????0.14uM ????1.51uM
?B-0403 ????1.77uM ????2.42uM
?B-0404 ????0.31uM ??48.0％@1.0uM
?B-0405 ????0.79uM ??30.0％@1.0uM
?B-0406 ????0.54uM ??35.0％@1.0uM
?B-0407 ????0.76uM ??27.0％@1.0uM
?B-0408 ????0.5uM ??50.0％@1.0uM
?B-0409 ????0.53uM ??30.0％@1.0uM
?B-0410 ????0.38uM ??44.0％@1.0uM
?B-0411 ????0.62uM ??50.0％@1.0uM
?B-0412 ????0.24uM ??48.0％@1.0uM
?B-0413 ????0.18uM ??55.0％@1.0uM
?B-0414 ????2.54uM ??25.0％@1.0uM
?B-0415 ????0.42uM ??43.0％@1.0uM
?B-0416 ????0.32uM ??34.0％@1.0uM
?B-0417 ????0.91uM ??28.0％@1.0uM
?B-0418 ????0.22uM ??27.0％@1.0uM
?B-0419 ????0.85uM ??41.0％21.0uM
?B-0420 ????0.83uM ??49.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0421 ????0.46uM ??57.0％@1.0uM
?B-0422 ????＜0.1uM ??40.0％@1.0uM
?B-0423 ????0.18uM ??33.0％@1.0uM
?B-0424 ????0.083uM ??32.0％@1.0uM
?B-0425 ????0.26uM ??54.0％@1.0uM
?B-0426 ????0.055uM ????0.74uM ?41％@3mpk@-4h
?B-0427 ????0.63uM ??39.0％@1.0uM
?B-0428 ????0.99uM ??27.0％@1.0uM
?B-0429 ????0.27uM ??45.0％@1.0uM
?B-0430 ????0.29uM ??75.0％@1.0uM
?B-0431 ????0.21uM ??64.0％@1.0uM
?B-0432 ????＜0.1uM ??89.0％@1.0uM
?B-0433 ????＜0.1uM ??92.0％@1.0uM
?B-0434 ????0.12uM ??65.0％@1.0uM
?B-0435 ????0.3uM ??61.0％@1.0uM
?B-0436 ????1.11uM ??71.0％@1.0uM
?B-0437 ????0.58uM ??59.0％@1.0uM
?B-0438 ????＜0.1uM ??91.0％@1.0uM
?B-0439 ????2.12uM ??65.0％@1.0uM
?B-0440 ????0.66uM ??63.0％@1.0uM
?B-0441 ????0.8uM ??58.0％@1.0uM
?B-0442 ????＜0.1uM ??91.0％@1.0uM
?B-0443 ????2.01uM ??71.0％@1.0uM
?B-0444 ????1.01uM ??51.0％@1.0uM
?B-0445 ????＜0.1uM ??83.0％@1.0uM
?B-0446 ????0.78uM ??80.0％@1.0uM
?B-0447 ????0.19uM ??71.0％@1.0uM
?B-0448 ????0.4uM ??79.0％@1.0uM
?B-0449 ????0.83uM ??81.0％@1.0uM
?B-0450 ????0.26uM ??81.0％@1.0uM
?B-0451 ????0.071uM ??83.0％@1.0uM ?42％@30mpk@-6h
?B-0452 ????0.7uM ??75.0％@1.0uM
?B-0453 ????0.47uM ??75.0％@1.0uM
?B-0454 ????0.11uM ??80.0％@1.0uM
?B-0455 ????＜0.1uM ??95.0％@1.0uM ??36％@3mpk％-4h
?B-0456 ????1.81uM ??67.0％@1.0uM
?B-0457 ????0.089uM ??81.0％@1.0uM
?B-0458 ????0.033uM ??70.0％@1.0uM
?B-0459 ????0.099uM ??76.0％@1.0uM
?B-0460 ????0.061uM ??92.0％@1.0uM
?B-0461 ????0.025uM ??96.0％@1.0uM
?B-0462 ????＜0.1uM ??97.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0463 ????0.052uM ??95.0％@1.0uM
?B-0464 ????＜0.1uM ??91.0％@1.0uM
?B-0465 ????0.084uM ??98.0％@1.0uM
?B-0466 ????＜0.1uM ??98.0％@1.0uM ??0％@3mpk@-4h
?B-0467 ????＜0.1uM ??77.0％@1.0uM
?B-0468 ????0.031uM ??93.0％@1.0uM
?B-0469 ????0.056uM ??92.0％@1.0uM
?B-0470 ????0.063uM ??92.0％@1.0uM
?B-0471 ????0.027uM ??97.0％@1.0uM
?B-0472 ????0.19uM ??54.0％@1.0uM
?B-0473 ????0.004uM ??95.0％@1.0uM
?B-0474 ????0.024uM ??86.0％@1.0uM
?B-0475 ????0.21uM ??74.0％@1.0uM
?B-0476 ????0.56uM ??69.0％@1.0uM
?B-0477 ????1.48uM ??96.0％@1.0uM
?B-0478 ????0.034uM ??87.0％@1.0uM
?B-0479 ????0.031uM ??90.0％@1.0uM ??15％@3mpk@-4h
?B-0480 ????0.12uM ??88.0％@1.0uM
?B-0481 ????0.014uM ??95.0％@1.0uM ??56％@3mpk@-4h
?B-0482 ????0.97uM ??68.0％@1.0uM
?B-0483 ????0.57uM ??68.0％@1.0uM
?B-0484 ????0.28uM ??62.0％@1.0uM
?B-0485 ????0.04uM ??95.0％@1.0uM
?B-0486 ????0.24uM ??80.0％@1.0uM
?B-0487 ????0.11uM ??89.0％@1.0uM ??54％@3mpk@-4h
?B-0488 ????0.62uM ??88.0％@1.0uM
?B-0489 ????0.3uM ??80.0％@1.0uM
?B-0490 ????0.91uM ??74.0％@1.0uM
?B-0491 ????0.43uM ??66.0％@1.0uM
?B-0492 ????0.069uM ??42.0％@1.0uM
?B-0493 ????0.3uM ??36.0％@1.0uM
?B-0494 ????0.13uM ??30.0％@1.0uM
?B-0495 ????0.12uM ??25.0％@1.0uM
?B-0496 ????0.83uM ??16.0％@1.0uM
?B-0497 ????0.44uM ??31.0％@1.0uM
?B-0498 ????0.33uM ??11.0％@1.0uM
?B-0499 ????0.39uM ??37.0％@1.0uM
?B-0500 ????0.26uM ??41.0％@1.0uM
?B-0501 ????0.049uM ??52.0％@1.0uM
?B-0502 ????0.065uM ??48.0％@1.0uM
?B-0503 ????0.16uM ??73.0％@1.0uM
?B-0504 ????0.4uM ??43.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0505 ????0.28uM ??44.0％@1.0uM
?B-0506 ????0.94uM ??43.0％@1.0uM
?B-0507 ????0.18uM ??75.0％@1.0uM
?B-0508 ????2.0uM ??48.0％@1.0uM
?B-0509 ????0.1uM ??86.0％@1.0uM
?B-0510 ????0.69uM ??61.0％@1.0uM
?B-0511 ????0.007uM ??90.0％@1.0uM
?B-0512 ????1.0uM ??53.0％@1.0uM
?B-0513 ????0.72uM ??52.0％@1.0uM
?B-0514 ????0.14uM ??87.0％@1.0uM
?B-0515 ????0.42uM ??61.0％@1.0uM
?B-0516 ????0.37uM ??84.0％@1.0uM
?B-0517 ????0.094uM ??52.0％@1.0uM
?B-0518 ????0.11uM ??64.0％@1.0uM
?B-0519 ????0.043uM ??87.0％@1.0uM
?B-0520 ????0.4uM ??67.0％@1.0uM
?B-0521 ????1.37uM ??52.0％@1.0uM
?B-0522 ????0.15uM ??75.0％@1.0uM
?B-0523 ????0.19uM ??83.0％@1.0uM
?B-0524 ????0.4uM ??77.0％@1.0uM
?B-0525 ????0.16uM ??76.0％@1.0uM
?B-0526 ????0.031uM ??87.0％@1.0uM
?B-0527 ????1.09uM ??63.0％@1.0uM
?B-0528 ????0.14uM ??70.0％@1.0uM
?B-0529 ????0.11uM ??73.0％@1.0uM
?B-0530 ????5.53uM ??45.0％@1.0uM
?B-0531 ????0.5uM ??48.0％@1.0uM
?B-0532 ????0.45uM ????1.01uM ?41％@30mpk@-6h
?B-0533 ????1.23uM ??47.0％@1.0uM
?B-0534 ????0.41uM ??54.0％@1.0uM
?B-0535 ????0.44uM ????0.87uM
?B-0536 ????0.46uM ????0.15uM
?B-0537 ????3.44uM ??51.0％@1.0uM
?B-0538 ????1.13uM ??45.0％@1.0uM
?B-0539 ????2.84uM ??21.0％@1.0uM
?B-0540 ????3.62uM ??54.0％@1.0uM
?B-0541 ????3.24uM ??28.0％@1.0uM
?B-0542 ????1.55uM ??50.0％@1.0uM
?B-0543 ????1.56uM ??43.0％@1.0uM
?B-0544 ????1.12uM ??27.0％@1.0uM
?B-0545 ????1.06uM ??41.0％@1.0uM
?B-0546 ????1.04uM ??18.0％@1.0uM
?B-0547 ????1.24uM ??21.0％@1.0uM
?B-0548 ????1.77uM ??28.0％@1.0uM
?B-0549 ????2.22uM ??22.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0550 ????2.41uM ??14.0％@1.0uM
?B-0551 ????1.08uM ??56.0％@1.0uM
?B-0552 ????0.13uM ??46.0％@1.0uM
?B-0553 ????1.44uM ??47.0％@1.0uM
?B-0554 ????2.58uM ??20.0％@1.0uM
?B-0555 ????1.87uM ??34.0％@1.0uM
?B-0556 ????0.49uM ??39.0％@1.0uM
?B-0557 ????1.37uM ??32.0％@1.0uM
?B-0558 ????0.85uM ??33.0％@1.0uM
?B-0559 ????0.53uM ??49.0％@1.0uM
?B-0560 ????2.57uM ??31.0％@1.0uM
?B-0561 ????2.07uM ??40.0％@1.0uM
?B-0562 ????0.22uM ????0.3uM ??5％@3mpk@-4h
?B-0563 ????0.18uM ????0.13uM
?B-0564 ????0.82uM ??58％@1.0uM
?B-0565 ????0.23uM ????0.59uM
?B-0566 ????＜0.1uM ????0.17uM ??0％@3mpk@-4h
?B-0567 ????0.14uM ????0.28uM
?B-0568 ????1.22uM ??46.0％@1.0uM
?B-0569 ????0.15uM ????0.26uM
?B-0570 ????0.27uM ??46.0％@1.0uM
?B-0571 ????0.38uM ??44.0％@1.0uM
?B-0572 ????0.27uM ??41.0％@1.0uM
?B-0573 ????0.36uM ????1.7uM
?B-0574 ????0.13uM ????0.66uM ??37％@3mpk@-4h
?B-0575 ????0.032uM ????0.17uM
?B-0576 ????0.068uM ????0.39uM ??65％@3mpk@-4h
?B-0577 ????0.091uM ??66.0％@1.0uM
?B-0578 ????1.88uM ??47.0％@1.0uM
?B-0579 ????0.11uM ??79.0％@1.0uM
?B-0580 ????2.23uM ????0.84uM
?B-0581 ????0.26uM ????2.17uM
?B-0582 ????1.03uM ??37.0％@1.0uM
?B-0583 ????3.93uM ??26.0％@1.0uM
?B-0584 ????0.66uM ??54.0％@1.0uM
?B-0585 ????0.83uM ??79.0％@1.0uM ?50％@30mpk@-6h
?B-0586 ????0.81uM ??51.0％@1.0uM
?B-0587 ????6.84uM ??38％@1.0uM
?B-0588 ????12.8uM ??42％@1.0uM
?B-0589 ????1.71uM ??42％@1.0uM
?B-0590 ????1.57uM ????38.0uM
?B-0591 ????3.59uM ??29.0％@1.0uM
?B-0592 ????1.62uM ??45.0％@1.0uM
?B-0593 ????1.22uM ??36.0％@1.0uM
?B-0594 ????- ??41.0％@1.0uM
?B-0595 ????2.42uM ??22.0％@1.0uM
?B-0596 ????20.0uM ??41.0％@1.0uM
?B-0597 ????1.68uM ??63.0％@1.0uM
?B-0598 ????2.12uM ??50.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0599 ????4.16uM ??21.0％@1.0uM
?B-0600 ????0.002uM ??28.0％@1.0uM
?B-0601 ????0.089uM ????1.31uM ??43％@3mpk％-4h
?B-0602 ????0.97uM ??61.0％@1.0uM
?B-0603 ????0.09uM ??51.0％@1.0uM
?B-0604 ????0.3uM ??20.0％@1.0uM
?B-0605 ????0.18uM ??47.0％@1.0uM
?B-0606 ????0.17uM ??53.0％@1.0uM
?B-0607 ????2.79uM ??70.0％@1.0uM
?B-0608 ????0.059uM ??73.0％@1.0uM
?B-0609 ????＜0.1uM ??87.0％@1.0uM
?B-0610 ????＜0.1uM ??88.0％@1.0uM
?B-0611 ????0.65uM ??60.0％@1.0uM
?B-0612 ????0.16uM ??60.0％@1.0uM
?B-0613 ????0.17uM ??76.0％@1.0uM
?B-0614 ????0.76uM ??70.0％@1.0uM ??0％@3mpk@-4h
?B-0615 ????0.08uM ??83.0％@1.0uM
?B-0616 ????0.38uM ??87.0％@1.0uM
?B-0617 ????0.045uM ??92.0％@1.0uM
?B-0618 ????0.37uM ??80.0％@1.0uM
?B-0619 ????＜0.1uM ??88.0％@1.0uM
?B-0620 ????1.59uM ??58.0％@1.0uM
?B-0621 ????0.36uM ??68.0％@1.0uM
?B-0622 ????0.076uM ??78.0％@1.0uM
?B-0623 ????0.12uM ??76.0％@1.0uM
?B-0624 ????0.085uM ??54.0％@1.0uM
?B-0625 ????0.023uM ??88.0％@1.0uM
?B-0626 ????＜0.1uM ??85.0％@1.0uM
?B-0627 ????0.25uM ??69.0％@1.0uM
?B-0628 ????0.023uM ??72.0％@1.0uM
?B-0529 ????0.2uM ??79.0％@1.0uM
?B-0630 ????0.06uM ??77.0％@1.0uM
?B-0631 ????0.065uM ??81.0％@1.0uM
?B-0632 ????＜0.1uM ??79.0％@1.0uM
?B-0633 ????0.6uM ??80.0％@1.0uM
?B-0634 ????0.6uM ??40.0％@1.0uM
?B-0635 ????0.15uM ??55.0％@1.0uM
?B-0636 ????＜0.1uM ??86.0％@1.0uM
?B-0637 ????0.11uM ??92.0％@1.0uM
?B-0638 ????0.25uM ??89.0％@1.0uM
?B-0639 ????0.051uM ??93.0％@1.0uM ??50％@3mpk@-4h
?B-0640 ????0.36uM ??94.0％@1.0uM
?B-0641 ????0.58uM ??65.0％@1.0uM
?B-0642 ????0.49uM ??90.0％@1.0uM
?B-0643 ????0.069uM ??85.0％@1.0uM ??0％@3mpk@-4h
?B-0644 ????0.058uM ??89.0％@1.0uM
?B-0645 ????0.58uM ??80.0％@1.0uM
?B-0646 ????0.26uM ??94.0％@1.0uM
?B-0647 ????1.61uM ??76.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0648 ????＜0.1uM ??83.0％@1.0uM
?B-0649 ????0.83uM ??39.0％@1.0uM
?B-0650 ????0.006uM ??95.0％@1.0uM ??8％@3mpk@-4h
?B-0651 ????1.78uM ??81.0％@1.0uM
?B-0652 ????0.19uM ??83.0％@1.0uM
?B-0653 ????2.01uM ??74.0％@1.0uM
?B-0654 ????5.97uM ??78.0％@1.0uM
?B-0655 ????1.25uM ??76.0％@1.0uM
?B-0656 ????0.007uM ??95.0％@1.0uM ??28％@3mpk@-4h
?B-0657 ????0.17uM ??83.0％@1.0uM
?B-0658 ????1.14uM ??91.0％@1.0uM
?B-0659 ????2.64uM ??87.0％@1.0uM
?B-0660 ????0.088uM ??92.0％@1.0uM
?B-0661 ????＜0.1uM ??90.0％@1.0uM
?B-0662 ????＜0.1uM ??95.0％@1.0uM
?B-0663 ????0.88uM ??74.0％@1.0uM
?B-0664 ????0.39uM ??80.0％@1.0uM
?B-0665 ????0.47uM ??72.0％@1.0uM
?B-0666 ????0.17uM ??73.0％@1.0uM
?B-0667 ????0.83uM ??75.0％@1.0uM
?B-0668 ????0.27uM ??78.0％@1.0uM
?B-0669 ????0.89uM ??34.0％@1.0uM
?B-0670 ????3.15uM ??32.0％@1.0uM
?B-0671 ????6.38uM ??36.0％@1.0uM
?B-0672 ????6.59uM ??32.0％@1.0uM
?B-0673 ????8.54uM ??48.0％@1.0uM
?B-0674 ????2.81uM ??42.0％@1.0uM
?B-0675 ????5.42uM ??3.0％@1.0uM
?B-0676 ????2.09uM ??22.0％@1.0uM
?B-0677 ????1.63uM ??25.0％@1.0uM
?B-0678 ????0.38uM ??52.0％@1.0uM
?B-0679 ????0.062uM ??45.0％@1.0uM
?B-0680 ????0.42uM ??67.0％@1.0uM
?B-0681 ????1.96uM ??17.0％@1.0uM
?B-0682 ????0.76uM ??39.0％@1.0uM
?B-0683 ????13.0uM ??32.0％@1.0uM
?B-0684 ????0.54uM ??68.0％@1.0uM
?B-0685 ????15.4uM ??33.0％@1.0uM
?B-0686 ????0.42uM ??59.0％@1.0uM
?B-0687 ????10.1uM ??15.0％@1.0uM
?B-0688 ????0.66uM ??58.0％@1.0uM
?B-0689 ????14.6uM ??27.0％@1.0uM
?B-0690 ????27.1uM ??36.0％@1.0uM
?B-0691 ????0.16uM ??48.0％@1.0uM
?B-0692 ????0.38uM ??29.0％@1.0uM
?B-0693 ????0.39uM ??28.0％@1.0uM
?B-0694 ????0.62uM ??21.0％@1.0uM
?B-0695 ????0.23uM ??32.0％@1.0uM
?B-0696 ????0.085uM ??35.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0697 ????0.45uM ??44.0％@1.0uM
?B-0698 ????2.33uM ??43.0％@1.0uM
?B-0699 ????0.34uM ??31.0％@1.0uM
?B-0700 ????0.24uM ??56.0％@1.0uM
?B-0701 ????0.39uM ??45.0％@1.0uM
?B-0702 ????0.036uM ??39.0％@1.0uM
?B-0703 ????0.12uM ??39.0％@1.0uM
?B-0704 ????2.19uM ??29.0％@1.0uM
?B-0705 ????0.44uM ??21.0％@1.0uM
?B-0706 ????0.44uM ??32.0％@1.0uM
?B-0707 ????1.7uM
?B-0708 ????2.1uM
?B-0709 ????0.84uM
?B-0710 ????1.99uM
?B-0711 ????1.99uM
?B-0712 ????2.9uM
?B-0713 ????4.3uM
?B-0714 ????3.7uM
?B-0715 ????3.2uM
?B-0716 ????4.6uM
?B-0717 ????4.3uM
?B-0718 ????1.4uM
?B-0719 ????3.4uM
?B-0720 ????1.3uM
?B-0721 ????3.8uM
?B-0722 ????0.07uM ????＞1.0uM
?B-0723 ????0.47uM
?B-0724 ????0.06uM ??17.0％@1.0uM
?B-0725 ????9.7uM
?B-0726 ????1.4uM
?B-0727 ????0.51uM
?B-0728 ????20.0uM
?B-0729 ????0.87uM
?B-0730 ????0.25uM ??11.0％@1.0uM
?B-0731 ????0.87uM ????＞1.0uM
?B-0732 ????14.0uM
?B-0733 ????32.0uM
?B-0734 ????0.92uM
?B-0735 ????1.0uM
?B-0736 ????26.0uM
?B-0737 ????2.6uM
?B-0738 ????2.7uM
?B-0739 ????4.1uM
?B-0740 ????4.4uM
?B-0741 ????26.0uM
?B-0742 ????2.2uM
?B-0743 ????1.2uM
?B-0744 ????23.0uM
?B-0745 ????6.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0746 ????0.01uM ??22.0％@1.0uM
?B-0747 ????1.1uM
?B-0748 ????1.2uM
?B-0749 ????4.4uM
?B-0750 ????0.92uM
?B-0751 ????1.6uM
?B-0752 ????0.33uM
?B-0753 ????0.37uM
?B-0754 ????0.55uM
?B-0755 ????2.3uM
?B-0756 ????0.94uM
?B-0757 ????0.54uM ??16.0％@1.0uM
?B-0758 ????1.5uM
?B-0759 ????0.3uM
?B-0760 ????0.01uM ??13.0％@1.0uM
?B-0761 ????＜0.1uM
?B-0762 ????0.13uM ??5.0％@1.0uM
?B-0763 ????0.015uM ??17.0％@1.0uM
?B-0764 ????0.67uM ??26.0％@1.0uM
?B-0765 ????0.3uM ??29.0％@1.0uM
?B-0766 ????0.95uM
?B-0767 ????0.08uM
?B-0768 ????1.4uM
?B-0769 ????12.7uM
?B-0770 ????2.3uM
?B-0771 ????0.5uM
?B-0772 ????0.8uM
?B-0773 ????14.0uM
?B-0774 ????1.5uM
?B-0775 ????0.6uM ????＞1.0uM
?B-0776 ????0.9uM ????＞1.0uM
?B-0777 ????21.0uM
?B-0778 ????51.0uM
?B-0779 ????0.5uM
?B-0780 ????1.1uM
?B-0781 ????48.0uM
?B-0782 ????22.0uM
?B-0783 ????8.0uM
?B-0784 ????7.0uM
?B-0785 ????23.0uM
?B-0786 ????24.0uM
?B-0787 ????1.5uM
?B-0788 ????1.2uM
?B-0789 ????33.0uM
?B-0790 ????1.0uM ??4.0％@1.0uM
?B-0791 ????0.3uM ????＞1.0uM
?B-0792 ????1.1uM
?B-0793 ????0.3uM
?B-0794 ????2.9uM ??2.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0795 ????1.9uM ??11.0％@1.0uM
?B-0796 ????1.4uM
?B-0797 ????1.04uM ???????-
?B-0798 ????1.73uM ???????-
?B-0799 ??????- ????＞1.0uM
?B-0800 ????1.01uM ????＞1.0uM
?B-0801 ????0.67uM ????＞1.0uM
?B-0802 ??????- ????＞1.0uM
?B-0803 ????0.057uM ??53.0％@1.0uM
?B-0804 ????0.3uM ??32.0％@1.0uM
?B-0805 ????0.71uM ????＞1.0uM
?B-0806 ????3.28uM ????＞1.0uM
?B-0807 ????10.8uM ???????-
?B-0808 ????3.09uM ????＞1.0uM
?B-0809 ????1.22uM ??7.0％@1.0uM
?B-0810 ????1.11uM ????＞1.0uM
?B-0811 ????2.79uM ????2.0％@1.0uM
?B-0812 ????2.12uM ????＞1.0uM
?B-0813 ????3.02uM ????＞1.0uM
?B-0814 ??????- ????＞1.0uM
?B-0815 ????2.11uM ????＞1.0uM
?B-0816 ????3?46uM ????＞1.0uM
?B-0817 ????3.07uM ??33.0％@1.0uM
?B-0818 ????4.97uM ????＞1.0uM
?B-0819 ????1.08uM ????＞1.0uM
?B-0820 ????1.64uM ??3.0％@1.0uM
?B-0821 ????1?44uM ???????-
?B-0822 ????1.33uM ???????-
?B-0823 ????2.39uM ????＞1.0uM
?B-0824 ????3.41uM ???????-
?B-0825 ??????- ???????-
?B-0826 ????1.74uM ???????-
?B-0827 ????15.6uM ???????-
?B-0828 ????7.9uM ???????-
?B-0829 ????0.61uM ??65.0％@1.0uM
?B-0830 ????0.54uM ??34.0％@1.0uM
?B-0831 ????0.9uM ????＞1.0uM
?B-0832 ????1.49uM ???????-
?B-0833 ????0.95uM ??23.0％@1.0uM
?B-0834 ????1.25uM ???????-
?B-0835 ??????- ???????-
?B-0836 ????1.24uM ???????-
?B-0837 ????1.96uM ????＞1.0uM
?B-0838 ????3.1uM ???????-
?B-0839 ????4.3uM ???????-
?B-0840 ????0.63uM ??47.0％@1.0uM
?B-0841 ????0.32uM ??36.0％@1.0uM
?B-0842 ????0.74uM ??63.0％@1.0uM
?B-0843 ????0.61uM ????＞1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0844 ????0.4uM ??25.0％@1.0uM
?B-0845 ????1.78uM ???????-
?B-0846 ????1.8uM ???????-
?B-0847 ????0.73uM ??21.0％@1.0uM
?B-0848 ????1.56uM ???????-
?B-0849 ????1.25uM ???????-
?B-0850 ????1.81uM ???????-
?B-0851 ????0.91uM ??39.0％@1.0uM
?B-0852 ????1.02uM ???????-
?B-0853 ???????- ??38.0％@1.0uM
?B-0854 ???????- ??25.0％@1.0uM
?B-0855 ???????- ??8.0％@1.0uM
?B-0856 ???????- ??38.0％@1.0uM
?B-0857 ????6.25uM ???????-
?B-0858 ????2.1uM ??48.0％@1.0uM
?B-0859 ????39.5uM ???????-
?B-0860 ????38.1uM ???????-
?B-0861 ????1.32uM ??12.0％@1.0uM
?B-0862 ????2.15uM ??4.0％@1.0uM
?B-0863 ????0.81uM ??25.0％@1.0uM
?B-0864 ????0.39uM ??40.％@1.0uM
?B-0865 ????0.66uM ??46.0％@1.0uM
?B-0866 ????1.38uM ??28.0％@1.0uM
?B-0867 ????0.62uM ????＞1.0uM
?B-0868 ????3.28uM ??8.0％@1.0uM
?B-0869 ????4.19uM ????＞1.0uM
?B-0870 ????3.13uM ????＞1.0uM
?B-0871 ????1.9uM ????＞1.0uM
?B-0872 ????3.13uM ??3.0％@1.0uM
?B-0873 ????6.92uM ????＞1.0uM
?B-0874 ????1.92uM ????＞1.0uM
?B-0875 ????2.13uM ????8％@1.0uM
?B-0876 ????0.89uM ????＞1.0uM
?B-0877 ????1.17uM ??13.0％@1.0uM
?B-0878 ????0.65uM ??19.0％@1.0uM
?B-0879 ????0.87uM ??1.0％@1.0uM
?B-0880 ????0.15uM ??40.0％@1.0uM
?B-0881 ????1.36uM ????＞1.0uM
?B-0882 ????1.48uM ??9％@1.0uM
?B-0883 ????1.06uM ????＞1.0uM
?B-0884 ????1.89uM ???????-
?B-0885
?B-0886
?B-0887
?B-0888
?B-0889
?B-0890
?B-0891
?B-0892
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0893
?B-0894
?B-0895
?B-0896
?B-0897
?B-0898
?B-0899
?B-0900
?B-0901
?B-0902
?B-0903
?B-0904
?B-0905
?B-0906
?B-0907
?B-0908
?B-0909
?B-0910
?B-0911
?B-0912
?B-0913
?B-0914
?B-0915
?B-0916
?B-0917
?B-0918
?B-0919
?B-0920
?B-0921
?B-0922
?B-0923
?B-0924
?B-0925
?B-0926
?B-0927
?B-0928
?B-0929
?B-0930
?B-0931
?B-0932
?B-0933 ??47.0％@1.0uM ??37.0％@1.0uM
?B-0934 ??67.0％@1.0uM ??36.0％@1.0uM
?B-0935 ??69.0％@1.0uM ??54.0％@1.0uM
?B-0936 ??69.0％@1.0uM ????＞1.0uM
?B-0937 ??64.0％@1.0uM ????1.74uM
?B-0938 ??51.0％@1.0uM ??29.0％@1.0uM
?B-0939 ??78.0％@1.0uM ??14.0％@1.0uM
?B-0940 ??56.0％@1.0uM ??22.0％@1.0uM
?B-0941 ??81.0％@1.0uM ??25.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0942 ??82.0％@1.0uM ??2.0％@1.0uM
?B-0943 ??63.0％@10.0uM ??24.0％@1.0uM
?B-0944 ??45.0％@1.0uM ??27.0％@1.0uM
?B-0945 ??96.0％@1.0uM ????0.93uM
?B-0946 ??76.0％@1.0uM ??31.0％@1.0uM
?B-0947 ??69.0％@1.0uM ??34.0％@1.0uM
?B-0948 ??68.0％@1.0uM ????1.81uM
?B-0949 ??90.0％@1.0uM ??17.0％@1.0uM
?B-0950 ??81.0％@1.0uM ????0.58uM
?B-0951 ??82.0％@1.0uM ??20.0％@1.0uM
?B-0952 ??44.0％@1.0uM ??21.0％@1.0uM
?B-0953 ??63.0％@1.0uM ??25.0％@1.0uM
?B-0954 ??62.0％@1.0uM ????0.52uM
?B-0955 ??49.0％@1.0uM ????0.54uM
?B-0956 ??56.0％@1.0uM ????1.33uM
?B-0957 ??79.0％@1.0uM ??22.0％@1.0uM
?B-0958 ??74.0％@1.0uM ????0.38uM
?B-0959 ??83.0％@1.0uM ??39.0％@1.0uM
?B-0960 ??48.0％@1.0uM ??4.0％@1.0uM
?B-0961 ??79.0％@1.0uM ??23.0％@1.0uM
?B-0962 ??85.0％@1.0uM ????2.71uM
?B-0963 ??76.0％@1.0uM ??39.0％@1.0uM
?B-0964 ??94.0％@1.0uM ????5.0uM
?B-0965 ??74.0％@1.0uM ????1.1uM
?B-0966 ??50.0％@1.0uM ??5.0％@1.0uM
?B-0967 ??80.0％@1.0uM ??29.0％@1.0uM
?B-0968 ??35.0％@1.0uM ??26.0％@1.0uM
?B-0969 ??63.0％@1.0uM ??35.0％@1.0uM
?B-0970 ??76.0％@10.0uM ????0.88uM
?B-0971 ??61.0％@1.0uM ??39.0％@1.0uM
?B-0972 ??85.0％@1.0uM ??2.0％@1.0uM
?B-0973 ??66.0％@10.0uM ??48.0％@1.0uM
?B-0974 ??57.0％@1.0uM ??47.0％@1.0uM
?B-0975 ??82.0％@1.0uM ??32.0％@1.0uM
?B-0976 ??79.0％@1.0uM ??36.0％@1.0uM
?B-0977 ??60.0％@1.0uM ??26.0％@1.0uM
?B-0978 ??59.0％@1.0uM ??36.0％@1.0uM
?B-0979 ??56.0％@10.0uM ??23.0％@1.0uM
?B-0980 ??68.0％@1.0uM ??31.0％@1.0uM
?B-0981 ??62.0％@1.0uM ??57.0％@1.0uM
?B-0982 ??65.0％@1.0uM ??23.0％@1.0uM
?B-0983 ??75.0％@1.0uM ????0.8uM
?B-0984 ??60.0％@1.0uM ??51.0％@1.0uM
?B-0985 ??86.0％@1.0uM ????0.75uM
?B-0986 ??70.0％@1.0uM ??71.0％@1.0uM
?B-0987 ??78.0％@1.0uM ??79.0％@1.0uM
?B-0988 ??72.0％@1.0uM ??65.0％@1.0uM
?B-0989 ??85.0％@1.0uM ????0.85uM
?B-0990 ??- ??26.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-0991 ??58.0％@1.0uM ??33.0％@1.0uM
?B-0992 ??77.0％@1.0uM ??45.0％@1.0uM
?B-0993 ??57.0％@1.0uM ??73.0％@1.0uM
?B-0994 ??55.0％@1.0uM ??43.0％@1.0uM
?B-0995 ??53.0％@1.0uM ??14.0％@1.0uM
?B-0996 ??54.0％@1.0uM ??27.0％@1.0uM
?B-0997 ??69.0％@1.0uM ??22.0％@1.0uM
?B-0998 ??67.0％@1.0uM ??25.0％@1.0uM
?B-0999 ??61.0％@1.0uM ??24.0％@1.0uM
?B-1000 ??55.0％@1.0uM ??42.0％@1.0uM
?B-1001 ??63.0％@1.0uM ??31.0％@1.0uM
?B-1002 ??70.0％@1.0uM ??41.0％@1.0uM
?B-1003 ??74.0％@1.0uM ??29.0％@1.0uM
?B-1004 ??79.0％@1.0uM ??45.0％@1.0uM
?B-1005 ??58.0％@1.0uM ??23.0％@1.0uM
?B-1006 ??69.0％@1.0uM ??38.0％@1.0uM
?B-1007 ??52.0％@1.0uM ??34.0％@1.0uM
?B-1008 ??54.0％@1.0uM ??23.0％@1.0uM
?B-1009 ??80.0％@1.0uM ??55.0％@1.0uM
?B-1010 ??75.0％@1.0uM ????1.0uM
?B-1011 ??72.0％21.0uM ??17.0％@1.0uM
?B-1012 ??- ??20.0％@1.0uM
?B-1013 ??85.0％@1.0uM ??7.0％@1.0uM
?B-1014 ??88.0％@1.0uM ??20.0％@1.0uM
?B-1015 ??77.0％@1.0uM ??34.0％@1.0uM
?B-1016 ??58.0％@1.0uM ??10.0％@1.0uM
?B-1017 ??96.0％@1.0uM ??58.0％@1.0uM
?B-1018 ??88.0％@1.0uM ??34.0％@1.0uM
?B-1019 ??82.0％@1.0uM ??66.0％@1.0uM
?B-1020 ??87.0％@1.0uM ??36.0％@1.0uM
?B-1021 ??82.0％@1.0uM ??35.0％@1.0uM
?B-1022 ??84.0％@1.0uM ??53.0％@1.0uM
?B-1023 ??93.0％@1.0uM ??70.0％@1.0uM
?B-1024 ??89.0％@1.0uM ??57.0％@1.0uM
?B-1025 ??61.0％@1.0uM ??23.0％@1.0uM
?B-1026 ??87.0％@1.0uM ??53.0％@1.0uM
?B-1027 ??58.0％@1.0uM ??18.0％@1.0uM
?B-1028 ??70.0％@1.0uM ??17.0％@1.0uM
?B-1029 ??69.0％@1.0uM ??54.0％@1.0uM
?B-1030 ??76.0％@1.0uM ??60.0％@1.0uM
?B-1031 ??69.0％@1.0uM ??42.0％@1.0uM
?B-1032 ??76.0％@1.0uM ??37.0％@1.0uM
?B-1033 ??86.0％@1.0uM ??34.0％@1.0uM
?B-1034 ??66.0％@1.0uM ??39.0％@1.0uM
?B-1035 ??75.0％@1.0uM ??52.0％@1.0uM
?B-1036 ??68.0％@1.0uM ??68.0％@1.0uM
?B-1037 ??- ??41.0％@1.0uM
?B-1038 ??57.0％@1.0uM ????0.57uM
?B-1039 ??- ????1.33uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-1040 ??72.0％@1.0uM ????0.38uM
?B-1041 ??70.0％@1.0uM ??73.0％@1.0uM
?B-1042 ??79.0％@1.0uM ??12.0％@1.0uM
?B-1043 ??64.0％@1.0uM ??53.0％@1.0uM
?B-1044 ??94.0％@1.0uM ????0.93uM
?B-1045 ??78.0％@1.0uM ??25.0％@1.0uM
?B-1046 ??72.0％@1.0uM ??66.0％@1.0uM
?B-1047 ??72.0％@1.0uM ??58.0％@1.0uM
?B-1048 ??67.0％@1.0uM ??19.0％@1.0uM
?B-1049 ??67.0％@1.0uM ??65.0％@1.0uM
?B-1050 ???????- ????0.54uM
?B-1051 ??68.0％@1.0uM ??41％@1.0uM
?B-1052 ??69.0％@1.0uM ??66％@1.0uM
?B-1053 ??78.0％@1.0uM ????0.4uM
?B-1054 ??79.0％@1.0uM ??55.0％@1.0uM
?B-1055 ??89.0％@1.0uM ??63.0％@1.0uM
?B-1056 ??89.0％@1.0uM ????0.76uM
?B-1057 ??85.0％@1.0uM ????0.72uM
?B-1058 ????0.66uM ??43.0％@1.0uM
?B-1059 ????0.18uM ??24.0％@1.0uM
?B-1060 ????0.11uM ??32.0％@1.0uM
?B-1061 ????0.03uM ??19.0％@1.0uM
?B-1062 ????＜0.1uM ??26.0％@1.0uM
?B-1063 ????0.16uM ??44.0％@1.0uM
?B-1064 ????0.39uM ??50.0％@1.0uM
?B-1065 ????0.56uM ??40.0％@1.0uM
?B-1066 ????＜0.1uM ??39.0％@1.0uM
?B-1067 ????1.6uM ??32.0％@1.0uM
?B-1068 ????0.48uM ??24.0％@1.0uM
?B-1069 ????0.22uM ??27.0％@1.0uM
?B-1070 ????＜0.1uM ??44.0％@1.0uM
?B-1071 ????＜0.1uM ??48.0％@1.0uM
?B-1072 ????0.38uM ??28.0％@1.0uM
?B-1073 ????＜0.1uM ??21.0％@1.0uM
?B-1074 ????0.23uM ??33.0％@1.0uM
?B-1075 ????0.03uM ??29.0％@1.0uM
?B-1076 ????0.08uM ??31.0％@1.0uM
?B-1077 ????＜0.1uM ??38.0％@1.0uM
?B-1078 ????0.26uM ??48.0％@1.0uM
?B-1079 ????＜0.1uM ??40.0％@1.0uM
?B-1080 ????0.19uM ??28.0％@1.0uM
?B-1081 ????＜0.1uM ??37.0％@1.0uM
?B-1082 ????＜0.1uM ??54.0％@1.0uM
?B-1083 ????＜0.1uM ??23.0％@1.0uM
?B-1084 ????0.43uM ??29.0％@1.0uM
?B-1085 ????＜0.1uM ??29.0％@1.0uM
?B-1086 ????＜0.1uM ??42.0％@1.0uM
?B-1087 ????0.05uM ??32.0％@1.0uM
?B-1088 ????0.73uM ??49.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-1089 ????＜0.1uM ??39.0％@1.puM
?B-1090 ????＜0.1uM ??90.0％@1.0uM
?B-1091 ????＜0.1uM ??73.0％@1.0uM
?B-1092 ????0.27uM ??85.0％@1.0uM
?B-1093 ????0.33uM ??36.0％@1.0uM
?B-1094 ????0.013uM ??69.0％@1.0uM
?B-1095 ????＜0.1uM ??70.0％@1.0uM
?B-1096 ????＜0.1uM ??32.0％@1.0uM
?B-1097 ????＜0.1uM ??44.0％@1.07uM
?B-1098 ????＜0.1uM ??82.0％@1.0uM
?B-1099 ????0.26uM ??74.0％@1.0uM
?B-1100 ????0.22uM ??56.0％@1.0uM
?B-1101 ????0.026uM ??82.0％@1.0uM
?B-1102 ????0.035uM ??83.0％@1.0uM
?B-1103 ????0.094uM ??90.0％@1.0uM
?B-1104 ????0.12uM ??69.0％@1.0uM
?B-1105 ????＜0.1uM ??84.0％@1.0uM
?B-1106 ????＜0.1uM ??86.0％@1.0uM
?B-1107 ????0.057uM ??84.0％@1.0uM
?B-1108 ????0.22uM ??81.0％@1.0uM
?B-1109 ????0.054uM ??80.0％@1.0uM
?B-1110 ????0.47uM ??64.0％@1.0uM
?B-1111 ????0.19uM ??64.0％@1.0uM
?B-1112 ????0.58uM ??43.0％@1.0uM
?B-1113 ????＜0.1uM ??72.0％@1.0uM
?B-1114 ????0.069uM ??51.0％@1.0uM
?B-1115 ????0.024uM ??89.0％@1.0uM
?B-1116 ????0.41uM ??81.0％@1.0uM
?B-1117 ????0.13uM ??73.0％@1.0uM
?B-1118 ????0.33uM ??91.0％@1.0uM
?B-1119 ????0.35uM ??80.0％@1.0uM
?B-1120 ????0.47uM ??9.0％@1.0uM
?B-1121 ????3.58uM ??29.0％@1.0uM
?B-1122 ????1.84uM ??32.0％@1.0uM
?B-1123 ????2.93uM ??27.0％@1.0uM
?B-1124 ????1.49uM ??52.0％@1.0uM
?B-1125 ????0.56uM ??41.0％@1.0uM
?B-1126 ????1.5uM ????＞1.0uM
?B-1127 ????0.71uM ??7.0％@1.0uM
?B-1128 ????2.55uM ??26.0％@1.0uM
?B-1129 ????1.07uM ??46.0％@1.0uM
?B-1130 ????0.5uM ??29.0％@1.0uM
?B-1131 ????0.076uM ??34.0％@1.0uM
?B-1132 ????0.72uM ??11.0％@1.0uM
?B-1133 ????0.38uM ??33.0％@1.0uM
?B-1134 ????1.71uM ??33.0％@1.0uM
?B-1135 ????0.23uM ??38.0％@1.0uM
?B-1136 ????1.17uM ??40.0％@1.0uM
?B-1137 ????0.038uM ??35.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-1138 ????1.82uM ????＞1.0uM
?B-1139 ????0.041uM ??29.0％@1.0uM
?B-1140 ????1.68uM ??39.0％@1.0uM
?B-1141 ????2.47uM ??32.0％@1.0uM
?B-1142 ????0.11uM ??37.0％@1.0uM
?B-1143 ????0.17uM ??40.0％@1.0uM
?B-1144 ????0.44uM ??72.0％@1.0uM
?B-1145 ????1.07uM ??71.0％@1.0uM
?B-1146 ????0.47uM ??61.0％@1.0uM
?B-1147 ????0.095uM ??53.0％@1.0uM
?B-1148 ????0.43uM ??61.0％@1.0uM
?B-1149 ????1.55uM ??48.0％@1.0uM
?B-1150 ????0.47uM ??75.0％@1.0uM
?B-1151 ????0.32uM ??72.0％@1.0uM
?B-1152 ????0.73uM ??53.0％@1.0uM
?B-1153 ????2.22uM ??52.0％@1.0uM
?B-1154 ????0.085uM ??46.0％@1.0uM
?B-1155 ????3.22uM ??30.0％@1.0uM
?B-1156 ????0.27uM ??78.0％@1.0uM
?B-1157 ????0.26uM ??66.0％@1.0uM
?B-1158 ??74％@1.0uM ????0.68uM ?53％@30mpk@-6h
?B-1159 ??66.0％@1.0uM ????1.03uM ?60％@30mpk@-6h
?B-1160 ??79.0％@1.0uM ????0.38uM
?B-1161 ??64.0％21.0uM ????0.93uM ?40％@30mpk@-6h ?45％@3mpk@-4h
?B-1162 ??79.0％@1.0uM ????0.59uM ?40％@30mpk@-6h
?B-1163 ??74.0％@1.0uM ????0.37uM
?B-1164 ???????- ????0.35uM
?B-1165 ??66.0％@1.0uM ????0.99uM
?B-1166 ??77.0％@1.0uM ????0.39uM ?50％@30mpk@-6h ?50％@3mpk@-4h
?B-1167 ??70.0％@1.0uM ????1.06uM
?B-1168 ??66.0％@1.0uM ????0.63uM
?B-1169 ??80.0％@1.0uM ????0.11uM
?B-1170 ??82.0％@1.0uM ????0.57uM
?B-1171 ??78.0％@1.0uM ????0.23uM
?B-1172 ??68.0％@1.0uM ????1.95uM
?B-1173 ??65.0％@1.0uM ??62％@1.0uM
?B-1174 ??80.0％@1.0uM ????0.86uM
?B-1175 ??72.0％@1.0uM ????1.83uM
?B-1176 ??67.0％@1.0uM ??67.0％@1.0uM
?B-1177 ??70.0％@1.0uM ????1.16uM
?B-1178 ??92.0％@1.0uM ????1.61uM
?B-1179 ??86.0％@1.0uM ????0.41uM
?B-1180 ??78.0％@1.0uM ????0.53uM
?B-1181 ??79.0％@1.0uM ??66％@1.0uM
?B-1182 ??72.0％@1.0uM ????0.65uM
?B-1183 ??77.0％@1.0uM ????0.2uM
?B-1184 ??69.0％@1.0uM ????0.63uM
?B-1185 ??71.0％@1.0uM ????0.79uM
?B-1186 ??83.0％@1.0uM ??60％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-1187 ??76.0％@1.0uM ????1.89uM
?B-1188 ???????- ??36.0％@1.0uM
?B-1189 ??68.0％@1.0uM ????0.83uM
?B-1190 ??78.0％@1.0uM ??62.0％@1.0uM
?B-1191 ??74.0％@1.0uM ??57.0％@1.0uM
?B-1192 ??84.0％@1.0uM ????0.47uM
?B-1193 ??69.0％@1.0uM ??65.0％@1.0uM
?B-1194 ??87.0％@1.0uM ????0.58uM
?B-1195 ??52.0％@1.0uM ??60.0％@1.0uM
?B-1196 ??74.0％@1.0uM ??68.0％@1.0uM
?B-1197 ??77.0％@1.0uM ??45.0％@1.0uM
?B-1198 ??92.0％@1.0uM ????0.46uM
?B-1199 ??87.0％@1.0uM ??49.0％@1.0uM
?B-1200 ??95.0％@1.0uM ????0.64uM
?B-1201 ??84.0％@1.0uM ????0.51uM
?B-1202 ??71.0％@1.0uM ??58.0％@1.0uM
?B-1203 ??84.0％@1.0uM ??58.0％@1.0uM
?B-1204 ??68.0％@1.0uM ??59.0％@1.0uM
?B-1205 ??74.0％@1.0uM ??46.0％@1.0uM
?B-1206 ??81.0％@1.0uM ????0.34uM
?B-1207 ??90.0％@1.0uM ??58.0％@1.0uM
?B-1208 ??82.0％@1.0uM ??51.0％@1.0uM
?B-1209 ??86.0％@1.0uM ??55.0％@1.0uM
?B-1210 ??82.0％@1.0uM ??57.0％@1.0uM
?B-1211 ??88.0％@1.0uM ??59.0％@1.0uM
?B-1212 ??90.0％@1.0uM ??57.0％@1.0uM
?B-1213 ??84.0％@1.0uM ????0.62uM
?B-1214 ??76.0％@1.0uM ??58.0％@1.0uM
?B-1215 ??86.0％@1.0uM ????0.23uM
?B-1216 ??88.0％@1.0uM ????0.18uM
?B-1217 ??87.0％@1.0uM ????0.46uM
?B-1218 ??88.0％@1.0uM ??76.0％@1.0uM
?B-1219 ??85.0％@1.0uM ??37.0％@1.0uM
?B-1220 ??81.0％@1.0uM ??53.0％@1.0uM
?B-1221 ??82.0％@1.0uM ??44.0％@1.0uM
?B-1222 ??65.0％@1.0uM ??9.0％@1.0uM
?B-1223 ??80.0％@1.0uM ??61.0％@1.0uM
?B-1224 ??82.0％@1.0uM ??74.0％@1.0uM
?B-1225 ??89.0％@1.0uM ??73.0％@1.0uM
?B-1226 ??89.0％@1.0uM ????0.18uM
?B-1227 ??83.0％@1.0uM ????0.22uM
?B-1228 ??90.0％@1.0uM ????0.72uM
?B-1229 ??87.0％@1.0uM ????0.65uM
?B-1230 ??90.0％@1.0uM ????0.25uM
?B-1231 ??94.0％@1.0uM ????0.56uM
?B-1232 ??81.0％@1.0uM ??54.0％@1.0uM
?B-1233 ??85.0％@1.0uM ????0.36uM
?B-1234 ??89.0％@1.0uM ????0.49uM
?B-1235 ????0.04uM ??76.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-1236 ????0.1uM ??53.0％@1.0uM
?B-1237 ????0.22uM ??39.0％@1.0uM
?B-1238 ????0.14uM ??16.0％@1.0uM
?B-1239 ????＜0.1uM ??38.0％@1.0uM
?B-1240 ????＜0.1uM ??59.0％@1.0uM
?B-1241 ????0.04uM ??81.0％@1.0uM
?B-1242 ????0.08uM ??83.0％@1.0uM
?B-1243 ????0.04uM ??47.0％@1.0uM
?B-1244 ????0.26uM ??44.0％@1.0uM
?B-1245 ????0.49uM ??42.0％@1.0uM
?B-1246 ????0.27uM ??40.0％@1.0uM
?B-1247 ????＜0.1uM ??58.0％@1.0uM
?B-1248 ????＜0.1uM ??68.0％@1.0uM
?B-1249 ????0.24uM ??60.0％@1.0uM
?B-1250 ????0.14uM ??18.0％@1.0uM
?B-1251 ????0.41uM ??38.0％@1.0uM
?B-1252 ????0.17uM ??46.0％@1.0uM
?B-1253 ????0.15uM ??57.0％@1.0uM
?B-1254 ????0.16uM ??68.0％@1.0uM
?B-1255 ????12.9uM ??75.0％@1.0uM
?B-1256 ????0.12uM ??41.0％@1.0uM
?B-1257 ????1.48uM ??40.0％@1.0uM
?B-1258 ????0.07uM ??56.0％@1.0uM
?B-1259 ????＜0.1uM ????0.48uM
?B-1260 ????0.11uM ??48.0％@1.0uM
?B-1261 ????0.74uM ??44.0％@1.0uM
?B-1262 ????＜0.1uM ??63.0％@1.0uM
?B-1263 ????1.05uM ??57.0％@1.0uM
?B-1264 ????0.32uM ??47.0％@1.0uM
?B-1265 ????0.43uM ??51.0％@1.0uM
?B-1266 ????＜0.1uM ??58.0％@1.0uM
?B-1267 ????＜0.1uM ??73.0％@1.0uM
?B-1268 ????＜0.1uM ??79.0％@1.0uM
?B-1269 ????0.46uM ??84.0％@1.0uM
?B-1270 ????0.47uM ??83.0％@1.0uM
?B-1271 ????0.13uM ??74.0％@1.0uM
?B-1272 ????0.014uM ??38.0％@1.0uM
?B-1273 ????＜0.1uM ??36.0％@1.0uM
?B-1274 ????＜0.1uM ??41.0％@1.0uM
?B-1275 ????＜0.1uM ??50.0％@1.0uM
?B-1276 ????0.062uM ??11.0％@1.0uM
?B-1277 ????＜0.1uM ??47.0％@1.0uM
?B-1278 ????0.12uM ??85.0％@1.0uM
?B-1279 ????＜0.1uM ??79.0％@1.0uM
?B-1280 ????0.039uM ??83.0％@1.0uM
?B-1281 ????＜0.1uM ??85.0％@1.0uM
?B-1282 ????＜0.1uM ??75.0％@1.0uM
?B-1283 ????＜0.1uM ??64.0％@1.0uM
?B-1284 ????＜0.1uM ??75.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-1285 ????0.057uM ??80.0％@1.0uM
?B-1286 ????0.15uM ??78.0％21.0uM
?B-1287 ????0.25uM ??55.0％@1.0uM
?B-1288 ????0.15uM ??74.0％@1.0uM
?B-1289 ????0.73uM ??35.0％@1.0uM
?B-1290 ????0.26uM ??75.0％@1.0uM
?B-1291 ????0.097uM ??55.0％@1.0uM
?B-1292 ????0.01uM ??74.0％@1.0uM
?B-1293 ????0.31uM ??48.0％@1.0uM
?B-1294 ????0.013uM ??54.0％@1.0uM
?B-1295 ????0.079uM ??74.0％@1.0uM
?B-1296 ????0.038uM ??48.0％@1.0uM
?B-1297 ????0.02uM ????＞1.0uM
?B-1298 ????0.055uM ??20.0％@1.0uM
?B-1299 ????0.091uM ????＞1.0uM
?B-1300 ????0.071uM ??18.0％@1.0uM
?B-1301 ????0.12uM ??15.0％@1.0uM
?B-1302 ????0.023uM ??11.0％@1.0uM
?B-1303 ????0.08uM ????＞1.0uM
?B-1304 ????0.11uM ??10.0％@1.0uM
?B-1305 ????0.64uM ??9.0％@1.0uM
?B-1306 ????0.11uM ????＞1.0uM
?B-1307 ????0.009uM ??16.0％@1.0uM
?B-1308 ????＜0.1uM ????＞1.0uM
?B-1309 ????0.045uM ????＞1.0uM
?B-1310 ????0.12uM ??11.0％@1.0uM
?B-1311 ????0.05uM ??57.0％@1.0uM
?B-1312 ????0.35uM ????＞1.0uM
?B-1313 ????0.035uM ??37.0％@1.0uM
?B-1314 ????0.045uM ??24.0％@1.0uM
?B-1315 ????0.055uM ??12.0％@1.0uM
?B-1316 ????0.026uM ??36.0％@1.0uM
?B-1317 ????0.019uM ??9.0％@1.0uM
?B-1318 ????＜0.1uM ??1.0％@1.0uM
?B-1319 ????0.24uM ????＞1.0uM
?B-1320 ????0.047uM ??43.0％@1.0uM
?B-1321 ????0.47uM ??66.0％@1.0uM
?B-1322 ????0.12uM ??87.0％@1.0uM
?B-1323 ????0.013uM ??85.0％@1.0uM
?B-1324 ????0.16uM ??83.0％@1.0uM
?B-1325 ????0.27uM ??95.0％@1.0uM
?B-1326 ????0.092uM ??84.0％@1.0uM
?B-1327 ????0.13uM ??65.0％@1.0uM
?B-1328 ????0.032uM ??86.0％@1.0uM
?B-1329 ????0.66uM ??54.0％@1.0uM
?B-1330 ????0.053uM ??85.0％@1.0uM
?B-1331 ????0.004uM ??85.0％@1.0uM
?B-1332 ????0.007uM ??81.0％@1.0uM
?B-1333 ????0.45uM ??76.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-1334 ????0.13uM ??73.0％@1.0uM
?B-1335 ????0.097uM ??63.0％@1.0uM
?B-1336 ????0.072uM ??83.0％@1.0uM
?B-1337 ????0.4uM ??90.0％@1.0uM
?B-1338 ????0.18uM ??73.0％@1.0uM
?B-1339 ????0.12uM ??67.0％@1.0uM
?B-1340 ????0.043uM ??63.0％@1.0uM
?B-1341 ????0.42uM ??52.0％@1.0uM
?B-1342 ????0.25uM ??59.0％@1.0uM
?B-1343 ????0.065uM ??83.0％@1.0uM
?B-1344 ????0.014uM ??86.0％@1.0uM
?B-1345 ????0.27uM ??73.0％@1.0uM
?B-1346 ????0.043uM ??86.0％@1.0uM
?B-1347 ????0.021uM ??84.0％@1.0uM
?B-1348 ????0.009uM ??69.0％@1.0uM
?B-1349 ????0.037uM ??86.0％@1.0uM
?B-1350 ????0.019uM ??78.0％@1.0uM
?B-1351 ????0.068uM ??78.0％@1.0uM
?B-1352 ????0.013uM ??76.0％@1.0uM
?B-1353 ????0.062uM ??80.0％@1.0uM
?B-1354 ????0.013uM ??83.0％@1.0uM
?B-1355 ????0.07uM ??75.0％@1.0uM
?B-1356 ????0.059uM ??91.0％@1.0uM
?B-1357 ????0.18uM ??84.0％@1.0uM
?B-1358 ????0.16uM ??76.0％@1.0uM
?B-1359 ????0.005 ??84.0％@1.0uM
?B-1360 ????0.11 ????0.15uM ??54％@3mpk@-4h
?B-1361 ????0.03 ????0.29uM
?B-1362 ????0.003 ????0.29uM
?B-1363 ????0.009 ????0.28uM ?51.0％@30pmk@- ????6H ??53％@3mpk@-4h
?B-1364 ????0.009 ????0.27uM ??53.0％@30mpk@- ????6.0H ??17％@3mpk@-4h
?B-1365 ????0.17 ??88.0％@1.0uM
?B-1366 ????0.04 ????0.27uM
?B-1367 ????＜0.1 ????0.22uM
?B-1368 ????0.031 ????0.33uM ?44.0％@30mpk@-
?B-1369 ????＜0.1 ????0.29uM
?B-1370 ????＜0.1 ????0.77uM
?B-1371 ????0.06 ??83.0％@1.0uM
?B-1372 ????＜0.1 ????0.41uM ?48.0％@30mpk@-
?B-1373 ????0.016 ????0.17uM
?B-1374 ????＜0.1 ????0.28uM
?B-1375 ????0.01 ????0.25uM
?B-1376 ????0.009 ????0.26uM ?3.0％@30mpk@-6H
?B-1377 ????0.12 ????5.0uM
?B-1378 ????0.02 ????1.04uM
?B-1379 ????＜0.1 ????0.092uM
?B-1380 ????＜0.1 ????0.26uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-1381 ????0.055 ????0.73uM
?B-1382 ????＜0.1 ????0.44uM
?B-1383 ????0.0012 ????0.15uM
?B-1384 ????0.57 ????0.37uM
?B-1385 ????＜0.1 ????0.11uM
?B-1386 ????＜0.1 ????0.25uM
?B-1387 ????＜0.1 ????0.1uM
?B-1388 ????0.57 ????1.38uM
?B-1389 ????0.06 ????0.57uM
?B-1390 ????＜0.1 ??71.0％@1.0uM
?B-1391 ????0.016uM ??82.0％@1.0uM
?B-1392 ????0.059uM ??82.0％@1.0uM
?B-1393 ????3.17uM ??80.0％@1.0uM
?B-1394 ????0.32uM ??78.0％@1.0uM
?B-1395 ????1.48 ??61.0％@1.0uM
?B-1396 ????1.55 ??73.0％@1.0uM
?B-1397 ????0.92 ??85.0％@1.0uM
?B-1398 ????0.67 ??83.0％@1.0uM
?B-1399 ????0.14 ??74.0％@1.0uM
?B-1400 ????0.024 ??83.0％@1.0uM
?B-1401 ????0.033 ??75.0％@1.0uM
?B-1402 ????0.12 ??76.0％@1.0uM
?B-1403 ????4.54 ??71％@1.0uM
?B-1404 ????0.6 ??70％@1.0uM
?B-1405 ????0.28 ??70％@1.0uM
?B-1406 ????1.39 ??56.0％@1.0uM
?B-1407 ????0.4 ??71.0％@1.0uM
?B-1408 ????0.27 ??69.0％@1.0uM
?B-1409 ????＜0.1 ??72.0％@1.0uM
?B-1410 ????＜0.1 ??69％@1.0uM
?B-1411 ????＜0.1 ??81.0％@1.0uM
?B-1412 ????0.097 ??80.0％@1.0uM
?B-1413 ????0.016 ??78.0％@1.0uM
?B-1414 ????0.025 ??83.0％@1.0uM
?B-1415 ????1.41 ??79.0％@1.0uM
?B-1416 ????0.14 ??81.0％@1.0uM
?B-1417 ????0.069 ??69.0％@1.0uM
?B-1418 ????1.01 ??82.0％@1.0uM
?B-1419 ????0.3 ??84.0％@1.0uM
?B-1420 ????＜0.1 ??82.0％@1.0uM
?B-1421 ????0.014 ??75.0％@1.0uM
?B-1422 ????0.58 ??68.0％@1.0uM
?B-1423 ????1.58 ??84.0％@1.0uM
?B-1424 ????0.86 ??76.0％@1.0uM
?B-1425 ????0.09 ??83.0％@1.0uM
?B-1426 ????0.19 ??80.0％@1.0uM
?B-1427 ????＜0.1 ??84.0％@1.0uM
?B-1428 ????＜0.1 ??86.0％@1.0uM
?B-1429 ????＜0.1 ??87.0％@1.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-1430 ????0.75uM ??35.0％@1.0uM
?B-1431 ????0.36uM ??58.0％@1.0uM
?B-1432 ????0.11uM ??51.0％@1.0uM
?B-1433 ????0.26uM ??21.0％@1.0uM
?B-1434 ????0.19uM ??28.0％@1.0uM
?B-1435 ????1.8uM ??45.0％@1.0uM
?B-1436 ????1.0uM ??20.0％@1.0uM
?B-1437 ????0.3uM ??23.0％@1.0uM
?B-1438 ????2.01uM ??27.0％@1.0uM
?B-1439 ????1.7uM ??17.0％@1.0uM
?B-1440 ????0.87uM ??3.0％@1.0uM
?B-1441 ????1.95uM ??66.0％@1.0uM
?B-1442 ????1.54uM ??18.0％@1.0uM
?B-1443 ????0.014uM ??83.0％@1.0uM
?B-1444 ????0.3uM ??24.0％@1.0uM
?B-1445 ????0.43uM ??27.0％@1.0uM
?B-1446 ????0.77uM ??36.0％@1.0uM
?B-1447 ????0.5uM ??34.0％@1.0uM
?B-1448 ????1.43uM ??22.0％@1.0uM
?B-1449 ????1.61uM ??50.0％@1.0uM
?B-1450 ????2.1uM ??49.0％@1.0uM
?B-1451 ????2.88uM ??50％@1.0uM
?B-1452 ????2.41uM ??47.0％@1.0uM
?B-1453 ????2.53uM ??49.0％@1.0uM
?B-1454 ????1.6uM ??12.0％@1.0uM
?B-1455 ????1.21uM ??8.0％@1.0uM
?B-1456 ????1.29uM ????＞1.0uM
?B-1457 ????0.43uM ??43.0％@1.0uM
?B-1458 ????0.95uM ??65.0％@1.0uM
?B-1459 ????0.67uM ??46.0％@1.0uM
?B-1460 ????0.96uM ??29.0％@1.0uM
?B-1461 ????0.4uM ??39.0％@1.0uM
?B-1462 ????0.22uM ??50.0％@1.0uM
?B-1463 ????2.34uM ??26.0％@1.0uM
?B-1464 ????1.18uM ??27.0％@1.0uM
?B-1465 ????3.23uM ??31.0％@1.0uM
?B-1466 ????1.69uM ????＞1.0uM
?B-1467 ????1.22uM ??1.0％@1.0uM
?B-1468 ????1.61uM ??10.0％@1.0uM
?B-1469 ????0.37uM ??14.0％@1.0uM
?B-1470 ????0.6uM ??28.0％@1.0uM
?B-1471 ????0.85uM ??25.0％@1.0uM
?B-1472 ????0.93uM ??12.0％@1.0uM
?B-1473 ????1.24uM ??14.0％@1.0uM
?B-1474 ????1.23uM ??31.0％@1.0uM
?B-1475 ????2.1uM ??24.0％@1.0uM
?B-1476 ????0.047uM ??42.0％@1.0uM
?B-1477 ????2.5uM ??34.0％@1.0uM
?B-1478
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
B-1479
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-2270 ????0.72uM ??31％@10.0uM
?B-2271 ????0.93uM ??38％@10.0uM
?B-2272 ????0.26uM ?53.0％@10.0uM
?B-2273 ????1.92uM ?39.0％@10.0uM
?B-2274 ????0.26uM ?59.0％@10.0uM
?B-2275 ????2.16uM ?53.0％@10.0uM
?B-2276 ????11.5uM ?37.0％@10.0uM
?B-2277 ????14.9uM ?44.0％@10.0uM
?B-2278 ????0.8uM ?51.0％@10.0uM
?B-2279 ????0.32uM ?36.0％@10.0uM
?B-2280 ????0.4uM ?57.0％@10.0uM
?B-2281 ????0.81uM ?60.0％@10.0uM
?B-2282 ????0.91uM ?41.0％@10.0uM
?B-2283 ????0.04uM ?53.0％@10.0uM
?B-2284 ????4.61uM ?62.0％@10.0uM
?B-2285 ????2.29uM ?49.0％@10.0uM
?B-2286 ????0.017uM ????0.78uM ?25％@30mpk@-1h
?B-2287 ????2.56uM ?61.0％@10.0uM
?B-2288 ????6.51uM ?46.0％@10.0uM
?B-2289 ????3.0uM ?30.0％@10.0uM
?B-2290 ????2.37uM ?59.0％@10.0uM
?B-2291 ????0.019uM ??41％@10.0uM
?B-2292 ????8.82uM ?57.0％@10.0uM
?B-2293 ????2.11uM ?56.0％@10.0uM
?B-2294 ????1.68uM ?50.0％@10.0uM
?B-2295 ????1.79uM ?56.0％@10.0uM
?B-2296 ????17.3uM ?63.0％@10.0uM
?B-2297 ????3.59uM ?57.0％@10.0uM
?B-2298 ????0.29uM ????4.22uM
?B-2299 ????1.97uM ?62.0％@10.0uM
?B-2300 ????0.07uM ?43.0％@10.0uM
?B-2301 ????0.18uM ?44.0％@10.0uM
?B-2302 ????1.0uM ?58.0％@1.0uM
?B-2303 ????0.011uM ?54.0％@10.0uM
?B-2304 ????1.41uM ?50.0％@10.0uM
?B-2305 ????0.54uM ?60.0％@10.0uM
?B-2306 ????5.88uM ?39.0％@10.0uM
?B-2307 ????2.29uM ?69.0％@10.0uM
?B-2308 ????0.66uM ?56.0％@10.0uM
?B-2309 ????0.29uM ?47.0％@10.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-2310 ????0.12uM ????1.2uM ?50％@30mpk@-6h
?B-2311 ????7.18uM ??60％@10.0uM
?B-2312 ????2.93uM ?43.0％@10.0uM
?B-2313 ????42.3uM ?58.0％@10.0uM
?B-2314 ????11.0uM ?66.0％@10.0uM
?B-2315 ????0.49uM ?36.0％@10.0uM
?B-2316 ????0.46uM ?58.0％@10.0uM
?B-2317 ????1.0uM ?60.0％@10.0uM
?B-2318 ?73.0％@10.0uM ?25.0％@10.0uM
?B-2319 ?75.0％@10.0uM ?40.0％@10.0uM
?B-2320 ?44.0％@10.0uM ?35.0％@10.0uM
?B-2321 ?69.0％@10.0uM ?27.0％@10.0uM
?B-2322 ?76.0％@10.0uM ?38.0％@10.0uM
?B-2323 ?69.0％@10.0uM ?46.0％@10.0uM
?B-2324 ?58.0％@10.0uM ?36.0％@10.0uM
?B-2325 ?60.0％@10.0uM ?51.0％@10.0uM
?B-2326 ?76.0％@10.0uM ?33.0％@10.0uM
?B-2327 ?76.0％@10.0uM ?23.0％@10.0uM
?B-2328 ?65.0％@10.0uM ?28.0％@10.0uM
?B-2329 ?72.0％@10.0uM ?53.0％@10.0uM
?B-2330 ?81.0％@10.0uM ?37.0％@10.0uM
?B-2331 ?74.0％@10.0uM ?44.0％@10.0uM
?B-2332 ?70.0％@10.0uM ?47.0％@10.0uM
?B-2333 ?58.0％@10.0uM ?36.0％@10.0uM
?B-2334 ?81.0％@10.0uM ?45.0％@10.0uM
?B-2335 ?82.0％@10.0uM ?50.0％@10.0uM
?B-2336 ?48.0％@10.0uM ?35.0％@10.0uM
?B-2337 ?46.0％@10.0uM ?59.0％@10.0uM
?B-2338 ?73.0％@10.0uM ?50.0％@10.0uM
?B-2339 ?84.0％@10.0uM ????＞10.0uM
?B-2340 ?35.0％@10.0uM ?12.0％@10.0uM
?B-2341 ?75.0％@10.0uM ?50.0％@10.0uM
?B-2342 ?83.0％@10.0uM ?46.0％@10.0uM
?B-2343 ?43.0％@10.0uM ?27.0％@10.0uM
?B-2344 ?71.0％@10.0uM ?50.0％@10.0uM
?B-2345 ?64.0％@10.0uM ?38.0％@10.0uM
?B-2346 ?45.0％@10.0uM ?48.0％@10.0uM
?B-2347 ?49.0％@10.0uM ?50.0％@10.0uM
?B-2348 ?76.0％@10.0uM ?48.0％@10.0uM
?B-2349 ?75.0％@10.0uM ?27.0％@10.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-2350 ?38.0％@10.0uM ?56.0％@10.0uM
?B-2351 ?77.0％@10.0uM ?1.0％@10.0uM
?B-2352 ?37.0％@10.0uM ?19.0％@10.0uM
?B-2353 ?38.0％@10.0uM ?33.0％@10.0uM
?B-2354 ?65.0％@10.0uM ?25.0％@10.0uM
?B-2355 ?84.0％@10.0uM ?50.0％@10.0uM
?B-2356 ?77.0％@10.0uM ?45.0％@10.0uM
?B-2357 ?47.0％@10.0uM ?41.0％@10.0uM
?B-2358 ?17.0％@10.0uM ?52.0％@10.0uM
?B-2359 ?76.0％@10.0uM ?35.0％@10.0uM
?B-2360 ?45.0％@10.0uM ????＞10.0uM
?B-2361 ?19.0％@10.0uM ?46.0％@10.0uM
?B-2362 ?60％@100.0uM ?39.0％@10.0uM
?B-2363 ?44.0％@10.0uM ?1.0％@10.0uM
?B-2364 ?47.0％@10.0uM ?4.0％@10.0uM
?B-2365 ?82.0％@10.0uM ?43.0％@10.0uM
?B-2366 ?70.0％@10.0uM ?59.0％@10.0uM
?B-2367 ?46.0％@10.0uM ?40.0％@1.0uM
?B-2368 ?65.0％@10.0uM ?55.0％@10.0uM
?B-2369 ?32.0％@10.0uM ????＞10.0uM
?B-2370 ?73％@100.0uM ?20.0％@10.0uM
?B-2371 ?54.0％@10.0uM ?36.0％@10.0uM
?B-2372 ?55.0％@100.0uM ????＞10.0uM
?B-2373 ?50.0％@100.0uM ??6％@10.0uM
?B-2374 ?35.0％@10.0uM ?20.0％@10.0uM
?B-2375 ?62.0％@100.0uM ????＞10.0uM
?B-2376 ?32.0％@10.0uM ?17.0％@10.0uM
?B-2377 ?34.0％@10.0uM ?17.0％@10.0uM
?B-2378 ?48.0％@10.0uM ?61.0％@10.0uM
?B-2379 ?73.0％@100.0uM ?45.0％@1.0uM
?B-2380 ?81％@100.0uM ?53.0％@10.0uM
?B-2381 ?68％@100.0uM ?2.0％@10.0uM
?B-2382 ?51.0％@10.0uM ?24.0％@10.0uM
?B-2383 ?63.0％@10.0uM ?35.0％@10.0uM
?B-2384 ?49％@100.0uM ?10.0％@10.0uM
?B-2385 ?79.0％@10.0uM ?19.0％@10.0uM
?B-2386 ?38.0％@10.0uM ?19.0％@10.0uM
?B-2387 ?50.0％@100.0uM ????＞10.0uM
?B-2388 ?42.0％@10.0uM ?24.0％@10.0uM
?B-2389 ?39.0％@10.0uM ?29.0％@10.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-2390 ?34.0％@10.0uM ?27.0％@1.0uM
?B-2391 ?40.0％@10.0uM ?59.0％@10.0uM
?B-2392 ?63.0％@10.0uM ?46.0％@10.0uM
?B-2393 ?43.0％@10.0uM ????＞10.0uM
?B-2394 ?37.0％@10.0uM ?22.0％@10.0uM
?B-2395 ?32.0％@10.0uM ?28.0％@10.0uM
?B-2396 ?75.0％@10.0uM ????＞10.0uM
?B-2397 ?83.0％@10.0uM ?22.0％@10.0uM
?B-2398 ?55％@100.0uM ?10.0％@10.0uM
?B-2399 ?69.0％@10.0uM ?18.0％@10.0uM
?B-2400 ?60.0％@10.0uM ?40.0％@10.0uM
?B-2401 ?78.0％@10.0uM ?44.0％@10.0uM
?B-2402 ?43.0％@10.0uM ?52.0％@10.0uM
?B-2403 ?72％@100.0uM ?52.0％@10.0uM
?B-2404 ?58％@100.0uM ?52.0％@10.0uM
?B-2405 ?47％@100.0uM ????＞10.0uM
?B-2406 ?45.0％@10.0uM ?24.0％@10.0uM
?B-2407 ?47％@100.0uM ?27.0％@10.0uM
?B-2408 ?39.0％@10.0uM ?10.0％@10.0uM
?B-2409 ?78.0％@10.0uM ?26.0％@10.0uM
?B-2410 ?33.0％@10.0uM ?32.0％@10.0uM
?B-2411 ?26％@100.0uM ?13.0％@10.0uM
?B-2412 ?40.0％@10.0uM ?31.0％@10.0uM
?B-2413 ?75.0％@10.0uM ?37.0％@10.0uM
?B-2414 ?86.0％@10.0uM ?38.0％@10.0uM
?B-2415 ?94.0％@10.0uM ?50.0％@10.0uM
?B-2416 ?85.0％@10.0uM ?43.0％@1.0uM
?B-2417 ?83.0％@10.0uM ?18.0％@10.0uM
?B-2418 ?88.0％@10.0uM ?34.0％@10.0uM
?B-2419 ?86.0％@10.0uM ?66.0％@10.0uM
?B-2420 ?70.0％@10.0uM ?34.0％@10.0uM
?B-2421 ?89.0％210.0uM ?38.0％@10.0uM
?B-2422 ?90.0％@10.0uM ?17.0％@10.0uM
?B-2423 ?85.0％@10.0uM ????＞10.0uM
?B-2424 ?86.0％@10.0uM ?43.0％@10.0uM
?B-2425 ?79.0％@10.0uM ?42.0％@10.0uM
?B-2426 ?88.0％@10.0uM ?53.0％@1?0.0uM
?B-2427 ?87.0％@10.0uM ?59.0％@10.0uM
?B-2428 ?82.0％@10.0uM ?50.0％@10.0uM
?B-2429 ?92.0％@10.0uM ?32.0％@10.0uM
Embodiment P38 alpha kinase IC50, uM or % suppress @ concentration (uM) U937 cell IC50, uM or % suppress @ concentration (uM) Mouse LPS model %TNF suppresses the @ dosage @ predose time Rat LPS model % suppresses the @ dosage @ predose time
?B-2430 ?90.0％@10.0uM ?61.0％@10.0uM
?B-2431 ?85.0％210.0uM ?68.0％@10.0uM
?B-2432 ?86.0％210.0uM ?40.0％@10.0uM
?B-2433 ?94.0％@10.0uM ?84.0％@10.0uM
?B-2434 ?92.0％@10.0uM ?63.0％@10.0uM
?B-2435 ?84.0％@10.0uM ?4.0％@10.0uM
?B-2436 ?80.0％@10.0uM ?54.0％@10.0uM
?B-2437 ?82.0％@10.0uM ?41.0％@10.0uM
?B-2438 ?75.0％@10.0uM ?40.0％@10.0uM
?B-2439 ?81.0％@10.0uM ?44.0％@10.0uM
?B-2440 ?77.0％@10.0uM ?78.0％@10.0uM
?B-2441 ?86.0％@10.0uM ?46.0％@10.0uM
?B-2442 ?86.0％@10.0uM ????＞10.0uM
?B-2443 ?84.0％@10.0uM ?44.0％@10.0uM
?B-2444 ?89.0％@10.0uM ?7.0％@10.0uM
?B-2445 ?94.0％@10.0uM ?15.0％@10.0uM
?B-2446 ?90.0％@10.0uM ?28.0％@10.0uM
?B-2447 ?94.0％@10.0uM ????＞10.0uM
?B-2448 ?75.0％@10.0uM ?30.0％@10.0uM
?B-2449 ?86.0％@10.0uM ?42.0％@10.0uM
?B-2450 ?87.0％@10.0uM ?46.0％@1.0uM
?B-2451 ?87.0％@10.0uM ?45.0％@10.0uM
?B-2452 ?89.0％@10.0uM ?33.0％@10.0uM
?B-2453 ?91.0％@10.0uM ????＞10.0uM
?B-2454 ?88.0％@10.0uM ?40.0％@10.0uM
?B-2455 ?87.0％@10.0uM ?54.0％@10.0uM
?B-2456 ?86.0％@10.0uM ?53.0％@10.0uM
?B-2457 ?90.0％@10.0uM ?18.0％@10.0uM
?B-2458 ?83.0％@10.0uM ?36.0％@10.0uM
?B-2459 ?82.0％@10.0uM ?81.0％@10.0uM
?B-2460 ?80.0％@10.0uM ?79.0％@10.0uM
?B-2461 ?67.0％@10.0uM ?59.0％@10.0uM

Claims (139)

1, a kind of molecular formula is the compound of I: Wherein
R 1Be selected from the hydrogen base, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclic radical, the cycloalkyl alkylidene group, the cycloalkenyl alkylidene group, the heterocyclic radical alkylidene group, haloalkyl, halogenated alkenyl, the halo alkynyl, hydroxyalkyl, the hydroxyl alkenyl, the hydroxyl alkynyl, aralkyl, aralkenyl, aromatic yl polysulfide yl, the aryl-heterocyclic base, carboxyl, carboxyalkyl, alkoxyalkyl, the alkenyloxy alkyl, the alkynyloxy group alkyl, aryloxy alkyl, the heterocyclic oxy group alkyl, the alkoxyl group alkoxyl group, mercaptoalkyl, the alkylthio alkylidene group, alkenyl sulfo-alkylidene group, the alkylthio alkylene group, amino, aminoalkyl group, alkylamino, alkenyl amino, alkynyl amino, arylamino, heterocyclic radical amino, the alkyl sulfinyl, the alkenyl sulfinyl, the alkynyl sulfinyl, the aryl sulfinyl, the heterocyclic radical sulfinyl, alkyl sulphonyl, the alkenyl alkylsulfonyl, the alkynyl alkylsulfonyl, aryl sulfonyl, the heterocyclic radical alkylsulfonyl, alkylamino alkylene, the alkyl sulphonyl alkylidene group, acyl group, the acyloxy carbonyl, the alkoxy carbonyl alkylidene group, the aryloxycarbonyl alkylidene group, the heterocyclic oxy group carbonyl alkylen group, the alkoxy carbonyl arylidene, the aryloxycarbonyl arylidene, heterocyclic oxy group carbonyl arylidene, the alkyl-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the heterocyclic radical carbonyl alkylen group, the alkyl-carbonyl arylidene, the aryl carbonyl arylidene, heterocyclic radical carbonyl arylidene, the alkyl carbonyl oxy alkylidene group, the aryl-carbonyl oxygen alkylidene group, heterocyclic radical carbonyl oxygen base alkylidene group, the alkyl carbonyl oxy arylidene, the aryl-carbonyl oxygen arylidene, with heterocyclic radical carbonyl oxygen base arylidene; Perhaps
R 1Molecular formula be Wherein:
I is 0～9 integer;
R 25Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group; With
R 26Be selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl alkylidene group, aralkyl, alkoxy carbonyl alkylidene group and alkylamino alkyl; With
R 27Be selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclic radical, aralkyl, the cycloalkyl alkylidene group, the cycloalkenyl alkylidene group, the cycloalkyl arylidene, the cycloalkyl ring alkyl, the heterocyclic radical alkylidene group, alkyl arylene, alkyl aralkyl, the aralkyl arylidene, alkyl heterocyclic, the alkyl heterocyclic alkylidene group, the alkyl heterocyclic arylidene, the aralkyl heterocyclic radical, the alkoxyl group alkylidene group, the alkoxyl group arylidene, the alkoxy aromatic alkyl, the alkoxyl group heterocyclic radical, alkoxyl group alkoxyl group arylidene, the aryloxy arylidene, the aralkoxy arylidene, alkoxyl group heterocyclic radical alkylidene group, aryloxy alcoxyl base arylidene, the alkoxy carbonyl alkylidene group, the alkoxy carbonyl heterocyclic radical, alkoxy carbonyl heterocyclic radical carbonyl alkylen group, aminoalkyl group, alkylamino alkylene, the aromatic yl aminocarbonyl alkylidene group, alkoxy aryl aminocarboxyl alkylidene group, the aminocarboxyl alkylidene group, the aromatic yl aminocarbonyl alkylidene group, the alkyl amino-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the alkoxy carbonyl arylidene, the aryloxycarbonyl arylidene, alkyl-aryloxy carbonyl arylidene, the aryl carbonyl arylidene, alkyl-aryloxy carbonyl arylidene, the aryl carbonyl arylidene, alkylaryl carbonyl arylidene, alkoxy carbonyl heterocyclic radical arylidene, alkoxy carbonyl alkoxyl group arylidene, heterocyclic radical carbonylic alkyl arylidene, the alkylthio alkylidene group, cycloalkyl sulfo-alkylidene group, the alkylthio arylidene, aralkyl sulfo-arylidene, heterocyclic radical sulfo-arylidene, aryl alkylthio arylidene, the arlysulfonylamino alkylidene group, the alkyl sulphonyl arylidene, the alkyl amino sulfonyl arylidene; Wherein said alkyl, cycloalkyl, aryl, heterocyclic radical, aralkyl, the heterocyclic radical alkylidene group, the alkyl heterocyclic arylidene, the alkoxyl group arylidene, the aryloxy arylidene, the aromatic yl aminocarbonyl alkylidene group, the aryloxycarbonyl arylidene, the aryl carbonyl arylidene, the alkylthio arylidene, heterocyclic radical sulfo-arylidene, aryl alkylthio arylidene and alkyl sulphonyl arylidene are by one or more alkyl that are independently selected from, halogen, haloalkyl, alkoxyl group, ketone group, amino, the group of nitro and cyano group at random replaces; Perhaps
R 27Be-CHR 28R 29, R wherein 28Be alkoxy carbonyl, R 29Be selected from aralkyl, alkoxy aryl alkylidene group, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, alkoxy carbonyl alkylidene group, alkylthio alkylidene group and aralkyl sulfo-alkylidene group, wherein said aralkyl and heterocyclic radical are at random replaced by one or more groups that are independently selected from alkyl and nitro; Or
R 26And R 27Connected nitrogen-atoms forms heterocyclic radical, wherein said heterocyclic radical is at random replaced by one or more groups, and this group is independently selected from alkyl, aryl, heterocyclic radical, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, aryloxy alkylidene group, alkoxyl group arylidene, alkyl-aryloxy alkylidene group, alkyl-carbonyl, alkoxy carbonyl, aromatic alkoxy carbonyl, alkylamino and alkoxycarbonyl amino; Wherein said aryl, heterocyclic radical alkylidene group and aryloxy alkylidene group are at random replaced by one or more groups that are independently selected from halogen, alkyl and alkoxyl group; With
R 2Be selected from the hydrogen base, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, haloalkyl, hydroxyalkyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, alkylamino, alkenyl amino, alkynyl amino, arylamino, heterocyclic radical amino, the heterocyclic radical alkylamino, aryl alkyl amino, aminoalkyl group, aminoaryl, aminoalkyl group amino, the arylamino alkylidene group, alkylamino alkylene, the arylamino arylidene, the alkylamino arylidene, the alkylamino alkylamino, cycloalkyl, cycloalkenyl, alkoxyl group, heterocyclic oxy group, alkylthio, arylthio, the sulfo-heterocyclic radical, carboxyl, carboxyalkyl, the carboxyl cycloalkyl, the carboxyl cycloalkenyl, carboxyalkyl amino, alkoxy carbonyl, the heterocyclic radical carbonyl, alkoxy carbonyl alkyl, the alkoxy carbonyl heterocyclic radical, alkyl-carbonyl heterocyclic radical carbonyl, alkoxyalkyl amino, the alkoxycarbonyl amino alkylamino, with the heterocyclic radical alkylsulfonyl, aryl wherein, heterocyclic radical, the heterocyclic radical alkyl, cycloalkyl and cycloalkenyl are at random replaced by one or more groups, and described group is independently selected from halogen, ketone group, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, aralkyl, the heterocyclic radical alkyl, epoxy alkyl, amino (hydroxyalkyl) carboxyl, alkoxyl group, aryloxy, alkoxy aryl, haloalkyl, alkylamino, alkynyl amino, alkylamino alkynes amino, the heterocyclic radical alkylamino, alkyl-carbonyl, alkoxy carbonyl, aryl sulfonyl, with the aralkyl alkylsulfonyl; Or
R 2Molecular formula be:
Figure A9880736900041
Wherein
J is 0～8 integer; And
M is 0 or 1;
R 30And R 31Be independently selected from hydrogen, alkyl, aryl, heterocyclic radical, aralkyl, heterocyclic radical alkylidene group, aminoalkyl group, alkylamino alkyl, aminocarboxyl alkyl, alkoxyalkyl and alkyl-carbonyl oxyalkyl; With
R 32Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group;
R 33Be selected from hydrogen, alkyl ,-C (O) R 35,-C (O) OR 35,-SO 2R 36,-C (O) NR 37R 38, and SO 2NR 39R 40, R wherein 35, R 36, R 37, R 38, R 39And R 40Be independently selected from hydrocarbon, assorted hydrocarbon and the heterocyclic radical that replaces; And
R 34Be selected from hydrogen, alkyl, aminocarboxyl, alkyl amino-carbonyl and aromatic yl aminocarbonyl; Or
R 2Be CR 41R 42, R wherein 41Be aryl, R 42It is hydroxyl; With
R 3Be selected from pyridyl, pyrimidyl, quinolyl, purine radicals,
R wherein 43Be selected from hydrogen, alkyl, aminoalkyl group, alkoxyalkyl, alkenyloxy alkyl and aryloxy alkyl; With
Wherein said R 3Pyridyl; pyrimidyl; quinolyl; the purine radicals group is at random replaced by one or more groups, and these groups are independently selected from halogen; alkyl; aralkyl; aralkenyl; the aryl-heterocyclic base; carboxyl; carboxyalkyl; alkoxyl group; aryloxy; alkylthio; arylthio; the alkyl sulfinyl; the aryl sulfinyl; alkyl sulphonyl; aryl sulfonyl; aralkoxy; the heterocyclic radical alkoxyl group; amino; alkylamino; alkenyl amino; alkynyl amino; cycloalkyl amino; cycloalkenyl amino; arylamino; heterocyclic radical amino; aminocarboxyl; cyano group; hydroxyl; hydroxyalkyl; alkoxy carbonyl; aryloxycarbonyl; the heterocyclic oxy group carbonyl; alkoxycarbonyl amino; the alkoxy aromatic alkylamino; amino sulfinyl; amino-sulfonyl; the alkylamino alkylamino; hydroxyalkyl amino; aryl alkyl amino; the heterocyclic radical alkylamino; aralkyl heterocyclic radical amino; nitro; alkyl amino-carbonyl; alkyl-carbonyl-amino; halosulfonyl groups; aminoalkyl group; haloalkyl; alkyl-carbonyl; diazanyl; the alkyl diazanyl; the aryl diazanyl; or-NR 44R 45, R wherein 44Be alkyl-carbonyl or amino, R 45Be alkyl or aralkyl; With
R 4Be selected from hydrogen base, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclic radical, wherein R 4At random replaced by one or more groups, this group is independently selected from halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, alkylthio, arylthio, the alkylthio alkylidene group, aryl sulfo-alkylidene group, the alkyl sulfinyl, alkyl sulfinyl alkylidene group, aryl sulfinyl alkylidene group, alkyl sulphonyl, the alkyl sulphonyl alkylidene group, the aryl sulfonyl alkylidene group, alkoxyl group, aryloxy, aralkoxy, aminocarboxyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkoxy carbonyl, aryloxycarbonyl, haloalkyl, amino, cyano group, nitro, alkylamino, arylamino, alkylamino alkylene, the arylamino alkylidene group, aminoalkyl group amino, and hydroxyl;
Work as R 4Be when containing the phenyl ring of a 2-hydroxyl substituent and work as R 1When being the hydrogen base, the R that provides 3It or not the 2-pyridyl; Work as R in addition 4When being the hydrogen base, the R that further provides 2Be selected from aryl, heterocyclic radical, the cycloalkyl that is unsubstituted and cycloalkenyl; The R that further provides 4It or not the alkylsulfonyl phenyl; Or
Acceptable salt or its isomer on the pharmacology.
2, compound as claimed in claim 1, wherein
R 1Be selected from hydrogen base, low alkyl group, low-grade cycloalkyl, low-grade alkenyl, low-grade alkynyl, rudimentary heterocyclic radical, low-grade cycloalkyl alkylidene group, low-grade halogenated alkyl, rudimentary hydroxyalkyl, rudimentary aralkyl, low-grade alkoxy alkyl, rudimentary mercaptoalkyl, low alkyl group sulfo-alkylidene group, amino, low-grade alkyl amino, lower aryl amino, low-grade alkyl amino alkylidene group and rudimentary heterocyclic radical alkylidene group; Or
R 1Molecular formula be Wherein:
I is 0,1 or 2; With
R 25Be selected from hydrogen, low alkyl group, rudimentary phenylalkyl, rudimentary heterocyclic radical alkyl, lower alkoxy alkylidene group, rudimentary phenoxy group alkylidene group, rudimentary aminoalkyl group, low-grade alkyl amino alkyl, rudimentary phenoxy group aminoalkyl group, lower alkylcarbonyl alkylidene group, rudimentary phenyloxycarbonyl alkylidene group and rudimentary heterocyclic radical carbonylamino alkylidene group; With
R 26Be selected from hydrogen, low alkyl group, low-grade alkenyl, low-grade alkynyl, low-grade cycloalkyl alkylidene group, rudimentary phenylalkyl, elementary alkoxy carbonyl alkylidene group and low-grade alkyl amino alkyl; With
R 27Be selected from low alkyl group, low-grade cycloalkyl, low-grade alkynyl, be selected from phenyl, the aryl of biphenyl and naphthyl, rudimentary heterocyclic radical, rudimentary phenylalkyl, the low-grade cycloalkyl alkylidene group, rudimentary cycloalkenyl alkylidene group, the low-grade cycloalkyl arylidene, the low-grade cycloalkyl cycloalkyl, rudimentary heterocyclic radical alkylidene group, the low alkyl group phenylene, the low alkyl group phenylalkyl, rudimentary phenylalkyl phenylene, the low alkyl group heterocyclic radical, low alkyl group heterocyclic radical alkylidene group, low alkyl group heterocyclic radical phenylene, rudimentary benzene alkyl heterocycle base, the lower alkoxy alkylidene group, the lower alkoxy phenylene, the lower alkoxyphenyl alkyl, the lower alkoxy heterocyclic radical, lower alkoxy alkoxyl group phenylene, rudimentary phenoxy group phenylene, rudimentary phenyl alkoxyl group phenylene, lower alkoxy heterocyclic radical alkylidene group, rudimentary phenoxy alkoxy phenylene, the elementary alkoxy carbonyl alkylidene group, the elementary alkoxy carbonyl heterocyclic radical, elementary alkoxy carbonyl heterocyclic radical carbonyl alkylen group, rudimentary aminoalkyl group, the low-grade alkyl amino alkylidene group, rudimentary phenyl amino carbonyl alkylen group, lower alkoxyphenyl aminocarboxyl alkylidene group, rudimentary aminocarboxyl alkylidene group, lower aryl aminocarboxyl alkylidene group, the low-grade alkyl amino carbonylic alkylidene group, rudimentary phenylcarbonyl group alkylidene group, the elementary alkoxy carbonyl phenylene, rudimentary phenyloxycarbonyl phenylene, low alkyl group phenyloxycarbonyl phenylene, rudimentary phenylcarbonyl group phenylene, low alkyl group phenylcarbonyl group phenylene, elementary alkoxy carbonyl heterocyclic radical phenylene, elementary alkoxy carbonyl alkoxyl group phenylene, rudimentary heterocyclic radical carbonylic alkyl phenylene, low alkyl group sulfo-alkylidene group, low-grade cycloalkyl sulfo-alkylidene group, low alkyl group sulfo-phenylene, rudimentary benzene alkylthio phenylene, rudimentary heterocyclic radical sulfo-phenylene, rudimentary phenyl alkylthio phenylene, rudimentary phenyl sulfonyl amino alkylidene group, low alkyl group alkylsulfonyl phenylene, low-grade alkyl amino alkylsulfonyl phenylene; Wherein said low alkyl group, low-grade cycloalkyl, be selected from phenyl, the aryl of xenyl and naphthyl, rudimentary heterocyclic radical, rudimentary benzene alkyl, rudimentary heterocyclic radical alkylidene group, low alkyl group heterocyclic radical phenylene, the lower alkoxy phenylene, rudimentary phenoxy group phenylene, rudimentary phenyl amino carbonyl alkylen group, rudimentary phenyloxycarbonyl phenylene, rudimentary phenylcarbonyl group phenylene, low alkyl group sulfo-phenylene, rudimentary heterocyclic radical sulfo-phenylene, rudimentary phenyl alkylthio phenylene and alkyl sulphonyl phenylene are at random replaced by one or more groups, and this group is independently selected from low alkyl group, halogen, low-grade halogenated alkyl, lower alkoxy, ketone group, amino, nitro and cyano group; Perhaps
R 27Be-CHR 46R 47, R wherein 46Be elementary alkoxy carbonyl, R 47Be selected from rudimentary benzene alkyl, rudimentary phenyl alkoxyl group alkylidene group, rudimentary heterocyclic radical alkylidene group, low alkyl group heterocyclic radical alkylidene group, elementary alkoxy carbonyl alkylidene group, low alkyl group sulfo-alkylidene group and rudimentary phenylalkyl sulfo-alkylidene group, wherein said phenylalkyl and heterocyclic radical are at random replaced by one or more groups that are independently selected from low alkyl group and nitro; Or
R 26And R 27Connected nitrogen-atoms forms 4-8 unit ring heterocycle, wherein said heterocycle is at random replaced by one or more groups, and this group is independently selected from low alkyl group, is selected from phenyl, aryl, heterocyclic radical, heterocyclic radical alkylidene group, low alkyl group heterocyclic radical alkylidene group, rudimentary phenoxy group alkylidene group, lower alkoxy phenylene, lower alkylcarbonyl, elementary alkoxy carbonyl, rudimentary phenyl oxygen base carbonyl, low-grade alkyl amino and the elementary alkoxy carbonyl amino of xenyl and naphthyl; The wherein said aryl of phenyl, xenyl and naphthyl, rudimentary heterocyclic radical alkylidene group and the rudimentary phenoxy group alkylidene group of being selected from random replaced by one or more groups that are independently selected from halogen, low alkyl group and lower alkoxy; With
R 2Be selected from the hydrogen base, halogen, low alkyl group, be selected from phenyl, the aryl of xenyl and naphthyl, low-grade halogenated alkyl, rudimentary hydroxyalkyl, 5-or 6-unit heterocyclic radical, the low alkyl group heterocyclic radical, rudimentary heterocyclic radical alkyl, low-grade alkyl amino, low-grade alkynyl amino, phenyl amino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkylamino, rudimentary Phenylalkylamino, rudimentary aminoalkyl group, rudimentary aminoalkyl group amino, the low-grade alkyl amino alkylamino, low-grade cycloalkyl, low-grade alkenyl, the elementary alkoxy carbonyl alkyl, rudimentary cycloalkenyl, rudimentary carboxyalkyl amino, elementary alkoxy carbonyl, rudimentary heterocyclic radical carbonyl, the elementary alkoxy carbonyl heterocyclic radical, elementary alkoxy carbonyl heterocyclic radical carbonyl, alkoxy carbonyl alkyl, low-grade alkoxy alkyl amino, elementary alkoxy carbonyl aminoalkyl group amino, rudimentary heterocyclic radical alkylsulfonyl, rudimentary heterocyclic oxy group and rudimentary heterocycle sulfenyl, aryl wherein, heterocyclic radical, the heterocyclic radical alkyl, cycloalkyl and cycloalkenyl are replaced arbitrarily by one or more groups, and described group is independently selected from halogen, ketone group, low alkyl group, low-grade alkynyl, phenyl, 5-or 6-unit heterocyclic radical, rudimentary phenylalkyl, rudimentary heterocyclic radical alkyl, rudimentary epoxy alkyl, carboxyl, lower alkoxy, rudimentary aryloxy, rudimentary phenyl alkoxyl group, low-grade halogenated alkyl, low-grade alkyl amino, the low-grade alkyl amino alkylamino, low-grade alkynyl amino, rudimentary amino (hydroxyalkyl), rudimentary heterocyclic radical alkylamino, lower alkylcarbonyl, elementary alkoxy carbonyl, rudimentary phenylalkyl alkylsulfonyl, and phenyl sulfonyl; Or
R 2Molecular formula be:
Figure A9880736900081
Wherein
J is 0,1 or 2; And
M is 0;
R 30And R 31Be independently selected from hydrogen, alkyl, aryl, heterocyclic radical, aralkyl, heterocyclic radical alkylidene group, aminoalkyl group, alkylamino alkyl, aminocarboxyl alkyl, alkoxyalkyl and alkyl-carbonyl oxyalkyl; With
R 32Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group; With
R 33Be selected from hydrogen, alkyl ,-C (O) R 35,-C (O) OR 35,-SO 2R 36,-C (O) NR 37R 38, and-SO 2NR 39R 40
R wherein 35Be selected from alkyl, cycloalkyl, haloalkyl, alkenyl, aryl, heterocyclic radical, aralkyl, cycloalkyl aryl, the cycloalkenyl alkylidene group, the heterocyclic radical alkylidene group, the alkyl alkylidene group, alkyl heterocyclic, the aryl arylidene, the aryl-heterocyclic base, alkoxyl group, alkenyloxy, the alkoxyl group alkylidene group, the alkoxy aromatic alkyl, the alkoxyl group arylidene, the aryloxy alkylidene group, the alkoxy aryl alkylidene group, the cycloalkyloxy alkylidene group, alkoxy carbonyl, the heterocyclic radical carbonyl, the alkyl carbonyl oxy alkylidene group, the alkyl carbonyl oxy arylidene, the alkoxy carbonyl alkylidene group, the alkoxy carbonyl arylidene, the aryl-alkoxy carbonyl heterocyclic radical, the alkyl-carbonyl heterocyclic radical, the aryl-carbonyl oxygen alkyl arylene, with the alkylthio alkylidene group; Wherein said aryl, heterocyclic radical, aralkyl, alkyl arylene, aryl-heterocyclic base, alkoxyl group arylidene, aryloxy alkylidene group, cycloalkyloxy alkylidene group, alkoxy carbonyl alkylidene group and alkyl-carbonyl heterocyclic radical are at random replaced by one or more groups, and this group is independently selected from alkyl, halogen, haloalkyl, alkoxyl group, halogenated alkoxy, ketone group, amino, nitro and cyano group; Or
R 35Be CHR 48R 49, R wherein 48Be arlysulfonylamino or alkylaryl sulfuryl amino, R 49Be selected from aralkyl, amino, alkylamino and aryl alkyl amino; Or
R 35For-NR 50R 51, R wherein 50Be alkyl, R 51It is aryl; With
R wherein 36Be selected from alkyl, haloalkyl, aryl, heterocyclic radical, heterocyclic radical alkyl alkylidene group, alkyl arylene, the alkenyl arylidene, the aryl arylidene, aralkyl, aromatic yl alkenyl, the heterocyclic radical heterocyclic radical, the carbonyl arylidene, the alkoxyl group arylidene, the alkoxy carbonyl arylidene, the alkyl-carbonyl-amino arylidene, the alkyl-carbonyl-amino heterocyclic radical, the aryl-amino-carbonyl alkyl heterocyclic, the alkylamino arylidene, alkylamino, the alkylamino arylidene, the alkyl sulphonyl arylidene, the alkyl sulphonyl aralkyl, with the arylsulfonylheterocyamines base, wherein said aryl, heterocyclic radical, the cycloalkyl alkylidene group, aralkyl, the alkyl-carbonyl-amino heterocyclic radical, at random replaced by one or more groups with the alkyl sulphonyl arylidene, this group is independently selected from alkyl, halogen, hydroxyl, haloalkyl, alkoxyl group, halogenated alkoxy, ketone group, amino, nitro, and cyano group; With
R wherein 37Be selected from hydrogen and alkyl; With
R wherein 38Be selected from hydrogen, alkyl, alkenyl, aryl, heterocyclic radical, aralkyl, alkyl arylene, cycloalkyl aryl, the aryl arylidene, the cycloalkyl alkylidene group, the heterocyclic radical alkylidene group, the alkyl heterocyclic alkylidene group, the aralkyl heterocyclic radical, the alkoxyl group alkylidene group, the alkoxyl group arylidene, the aryloxy arylidene, aryl carbonyl, alkoxy carbonyl, the alkoxy carbonyl alkylidene group, the alkoxy carbonyl arylidene, the alkyl-carbonyl carbonyl alkylen group, alkylamino alkylene, the alkylamino aralkyl, the alkyl-carbonyl-amino alkylidene group, the alkylthio arylidene, the alkyl sulphonyl aralkyl, with the amino-sulfonyl aralkyl, wherein said aryl, heterocyclic radical, aralkyl and heterocyclic radical alkylidene group are at random replaced by one or more groups, and this group is independently selected from alkyl, halogen, hydroxyl, haloalkyl, alkoxyl group, halogenated alkoxy, ketone group, amino, nitro, and cyano group; Or
R 38Be-CR 52R 53, R wherein 52Be alkoxy carbonyl, R 53It is the alkylthio alkylidene group; Or
R 37And R 38Connected nitrogen-atoms forms heterocycle together; With
R 39And R 40With the R in the claim 1 25And R 27Has identical definition; Or
R 2Be-CR 41R 42, R wherein 41Be phenyl, R 42It is hydroxyl; Or
R 2Be selected from following groups:
Figure A9880736900101
Wherein
K is 0～3 integer; With
R 56Be hydrogen or low alkyl group; With
R 57Be hydrogen or low alkyl group; Or
R 56And R 57Form the low-grade alkylidene bridge; With
R 58Be selected from hydrogen, alkyl, aralkyl, aryl, heterocyclic radical, heterocyclic radical alkyl, alkoxy carbonyl, alkyl sulphonyl, aralkyl alkylsulfonyl, aryl sulfonyl ,-C (O) R 59,-SO 2R 60, and-C (O) NHR 61
R wherein 59Be selected from alkyl, haloalkyl, cycloalkyl, aryl, heterocyclic radical, alkyl arylene, aralkyl, alkyl heterocyclic, alkoxyl group, alkenyloxy, alkoxy aryl, alkoxyl group alkylidene group, alkoxyl group arylidene, alkoxy aromatic alkyl, wherein said aryl, heterocyclic radical and aralkyl are at random replaced by one or more groups, and this group is independently selected from alkyl, halogen, hydroxyl, haloalkyl, alkoxyl group, halogenated alkoxy, ketone group, amino, nitro and cyano group; With
R wherein 60Be selected from alkyl, aryl, heterocyclic radical, alkyl arylene, alkyl heterocyclic, aralkyl, heterocyclic radical heterocyclic radical, alkoxyl group arylidene, alkylamino, alkylamino arylidene, alkyl sulphonyl arylidene and arylsulfonylheterocyamines base, wherein said aryl, heterocyclic radical and aralkyl are at random replaced by one or more groups, and this group is independently selected from alkyl, halogen, hydroxyl, haloalkyl, alkoxyl group, halogenated alkoxy, ketone group, amino, nitro and cyano group; With
R wherein 61Be selected from alkyl, aryl, alkyl arylene and alkoxyl group arylidene, wherein said aryl is at random replaced by one or more groups, and this group is independently selected from alkyl, halogen, hydroxyl, haloalkyl, alkoxyl group, halogenated alkoxy, ketone group, amino, nitro and cyano group; With
R 3Be selected from pyridyl, pyrimidyl, quinolyl, purine radicals and
Figure A9880736900111
R wherein 43Be selected from hydrogen, low alkyl group, rudimentary aminoalkyl group, low-grade alkoxy alkyl, rudimentary alkenyloxy alkyl and rudimentary aryloxy alkyl; With
Wherein said R 3Pyridyl; pyrimidyl; quinolyl; the purine radicals group is at random replaced by one or more groups, and described group is independently selected from lower alkylthio; the low alkyl group alkylsulfonyl; amino-sulfonyl; halogen; low alkyl group; rudimentary aralkyl; rudimentary phenyl alkenyl; rudimentary phenyl heterocycles base; carboxyl; the low alkyl group sulfinyl; cyano group; the lower alkoxy carboxyl; aminocarboxyl; lower alkylcarbonyl amino; low-grade halogenated alkyl; hydroxyl; lower alkoxy; amino; low-grade cycloalkyl amino; low-grade alkyl amino; low-grade alkenyl amino; low-grade alkynyl amino; rudimentary aminoalkyl group; arylamino; rudimentary aryl alkyl amino; nitro; halosulfonyl groups; lower alkylcarbonyl; elementary alkoxy carbonyl amino; the lower alkoxyphenyl alkylamino; the low-grade alkyl amino alkylamino; rudimentary hydroxyalkyl amino; rudimentary heterocyclic radical amino; rudimentary heterocyclic radical alkylamino; rudimentary phenylalkyl heterocyclic radical amino; low-grade alkyl amino carbonylic; the lower alkoxyphenyl alkylamino; diazanyl; the low alkyl group diazanyl; or-NR 44R 45, R wherein 44Be lower alkylcarbonyl or amino, R 45Be low alkyl group or rudimentary phenylalkyl; With
R 4Be selected from hydrogen base, low-grade cycloalkyl, rudimentary cycloalkenyl, the aryl that is selected from phenyl, xenyl and naphthyl and 5-or 6-unit heterocyclic radical, wherein R 4Low-grade cycloalkyl, rudimentary cycloalkenyl, aryl and 5-10 unit heterocyclic radical at random replaced by one or more groups, this group is independently selected from lower alkylthio, low alkyl group alkylsulfonyl, low alkyl group sulfinyl, halogen, low alkyl group, low-grade alkynyl, lower alkoxy, rudimentary aryloxy, rudimentary aralkoxy, rudimentary heterocyclic radical, low-grade halogenated alkyl, amino, cyano group, nitro, low-grade alkyl amino and hydroxyl; Or
Acceptable salt or its isomer on the pharmacology.
3, compound as claimed in claim 2, wherein
R 1Be selected from the hydrogen base, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, isobutyl-, methyl fluoride, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl group, seven fluoropropyls, the difluoro chloromethyl, dichlorofluoromethyl, two fluoro ethyls, two fluoropropyls, Dichloroethyl, two chloropropyls, vinyl, propenyl, ethynyl, propargyl, the 1-proyl, 2-propynyl, send the pyridine base, piperazinyl, morpholinyl, benzyl, phenylethyl, the morpholinyl methyl, the morpholinyl ethyl, the pyrrolidyl methyl, the piperazinyl methyl, piperidino methyl, pyridylmethyl, thienyl methyl, methoxymethyl, ethoxyl methyl, amino, methylamino, dimethylamino, phenyl amino, the methylamino methyl, dimethylaminomethyl, the methylamino ethyl, dimethyl aminoethyl, the ethylamino ethyl, the diethylamino ethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexyl methyl, hydroxymethyl, hydroxyethyl, mercapto methyl, with the methyl methylthio group; With
R 2Be selected from the hydrogen base, chloro, fluorine-based, bromo, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, isobutyl-, phenyl, xenyl, methyl fluoride, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl group, seven fluoropropyls, the difluoro chloromethyl, dichlorofluoromethyl, two fluoro ethyls, two fluoropropyls, Dichloroethyl, two chloropropyls, methylol, hydroxyethyl, pyridyl, isothiazolyl isoxazolyl, thienyl, thiazolyl oxazolyl, pyrimidyl, the chinol base, isoquinolyl, imidazolyl, benzimidazolyl-, furyl, pyrazinyl, piperidyl, piperazinyl, morpholinyl, the N methyl piperazine base, the methoxycarbonyl ethyl, the ethoxy carbonyl ethyl, the N-methylamino, N, the N-dimethylamino, the N-ethylamino, N, the N-diethylamino, N-n-propyl group amino, N, the N-dimethylamino, N-methyl-N-phenyl amino, the N-phenyl amino, piperidyl amino, the N-benzylamino, N-propargyl amino, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl radical, the cyclobutene base, cyclopentenyl, cyclohexenyl, cyclohexadienyl, amino methyl, amino-ethyl, aminoethylamino, amino propyl amino, N, N-dimethyl aminoethyl amino, N, N-dimethylaminopropyl amino, the morpholinyl ethylamino, morpholinyl propyl amino, the carboxyl methylamino, methoxy ethyl amino, methoxycarbonyl, ethoxy carbonyl, propoxycarbonyl, 1,1-dimethyl ethoxy carbonyl, 1, the amino ethylamino of 1-dimethyl ethoxy carbonyl, 1, amino third amino of 1-dimethyl ethoxy carbonyl, piperazinyl carbonyl, with 1,1-dimethyl ethoxy carbonyl piperazinyl carbonyl; Wherein said aryl, heteroaryl, cycloalkyl and cycloalkenyl are at random replaced by one or more groups, that this group is independently selected from is fluorine-based, chloro, bromo, ketone group, methyl, ethyl, sec.-propyl, the tertiary butyl, isobutyl-, benzyl, carboxyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, methyl fluoride, difluoromethyl, dimethylamino, methoxycarbonyl, ethoxy carbonyl and 1,1-dimethyl ethyl carbonyl; Or
R 2Be-CR 54R 55, R wherein 54Be phenyl, R 55It is hydroxyl; With
R 3Be selected from pyridyl, pyrimidyl and purine radicals; R wherein 3Replaced arbitrarily by one or more groups; this group is independently selected from methylthio group; methyl sulfinyl; the horizontal acyl group of methyl; fluorine-based; chloro; bromo; amino horizontal acyl group; methyl; ethyl; sec.-propyl; the tertiary butyl; isobutyl-; cyano group; methoxycarbonyl; ethoxy carbonyl; aminocarboxyl; the methyl carbonyl amino; trifluoromethyl; difluoromethyl; methyl fluoride; trichloromethyl; dichloromethyl; chloromethyl; hydroxyl; fluorophenyl methyl; the fluorophenyl ethyl; Chlorophenylmethyl; the chloro-phenyl-ethyl; the fluorophenyl vinyl; the chloro-phenyl-vinyl; the fluorophenyl imidazolyl; the chloro-phenyl-imidazolyl; carboxyl; methoxyl group; oxyethyl group; propoxy-; the n-butoxy; methylamino; ethylamino; dimethylamino; diethylin; 2-methyl butyl amino; propargyl amino; amino methyl; amino-ethyl; N-methylbenzene amino; phenyl amino; diphenylamino; benzylamino; styroyl amino; cyclopropyl amino; nitro; chlorosulfonyl; amino; the methyl carbonyl; methoxycarbonyl amino; ethoxy carbonyl amino; the p-methoxy-phenyl methylamino; N, N-dimethyl aminoethyl amino; hydroxypropyl amino; hydroxyethyl amino; the imidazolyl ethylamino; the morpholinyl ethylamino; (1-ethyl-2-hydroxyl) ethylamino; piperidyl amino; the pyridyl methylamino-; the phenyl methyl piperidyl amino; phenyl methyl amino; fluorophenyl methyl amino; the fluorophenyl ethylamino; the methylamino carbonyl; the ethylamino carbonyl; the methyl carbonyl; the p-methoxy-phenyl methylamino-; diazanyl; 1-methyl-diazanyl; or-NR 44R 45, R wherein 44Be methyl carbonyl or amino, R 45Be methyl, ethyl or phenmethyl; With
R 4Be selected from the hydrogen base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl radical, the cyclobutene base, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, xenyl, morpholinyl, pyrrolidyl, piperazinyl, piperidyl, pyridyl, thienyl, isothiazolyl isoxazolyl, thiazolyl oxazolyl, pyrimidyl, the chinol base, isoquinolyl, imidazolyl, benzimidazolyl-, furyl, pyrazinyl, the dihydroxyl pyranyl, the dihydroxy-pyridine base, the dihydroxyl furyl, the tetrahydroxy pyranyl, the tetrahydroxy furyl, cumarone, dihydroxyl benzo furans, with benzo dioxolyl, wherein R 4Described cycloalkyl, cycloalkenyl, aryl and heterocyclic radical at random replaced by one or more groups, this group is independently selected from methylthio group, methyl sulfinyl, methyl sulphonyl, fluorine-based, chloro, bromo, methyl, ethyl, sec.-propyl, the tertiary butyl, isobutyl-, ethynyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, methyl fluoride, difluoromethyl, amino, cyano group, nitro, dimethylamino and carboxyl; Or
Acceptable salt or its isomer on the pharmacology.
4, compound as claimed in claim 3, wherein
R 1Be hydrogen base, methyl, ethyl, propargyl, carboxy ethyl, dimethylaminoethyl, diethylamino ethyl or morpholinyl ethyl;
R 2Be selected from hydrogen base, methyl, ethyl, propyl group, phenyl, trifluoromethyl, methoxycarbonyl ethyl, N, N-dimethylamino, N-phenyl amino, piperidyl, piperazinyl, pyridyl, N methyl piperazine base and piperazinyl amino; Wherein said phenyl, piperidyl and pyridyl are replaced arbitrarily by one or more groups, and that this group is independently selected from is fluorine-based, chloro, bromo, methyl, ethyl and trifluoromethyl;
R 3Be selected from pyridyl, pyrimidyl or quinolyl; R wherein 3At random replaced by one or more groups, that this group is independently selected from is fluorine-based, bromo, methyl, cyano group, methoxycarbonyl, aminocarboxyl, benzyl, styroyl, ethanoyl, hydroxyl, methoxyl group, dimethylamino, benzyl amino, styroyl amino, amino methyl, amino, hydroxyl and methyl carbonyl;
R 4Be selected from phenyl, chinol base, xenyl, pyridyl, thienyl, furyl, dihydro pyranyl, benzofuryl, dihydro benzo furyl and benzo dioxolyl; R wherein 4Cycloalkyl, cycloalkenyl, aryl and heterocyclic radical at random replaced by one or more groups, this group is independently selected from methylthio group, fluorine-based, chloro, bromo, methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxyl; Or
Acceptable salt or its isomer on the pharmacology.
5, compound as claimed in claim 4, wherein
R 1Be hydrogen base or methyl;
R 2Be selected from hydrogen base, methyl or ethyl;
R 3Be selected from pyridyl, pyrimidyl or quinolyl; R wherein 3At random replaced by one or more groups, that this group is selected from is fluorine-based, bromo, methyl, cyano group, methoxycarbonyl, aminocarboxyl, benzyl, styroyl, ethanoyl, hydroxyl, methoxyl group, dimethylamino, benzyl amino, styroyl amino, amino methyl, amino, hydroxyl and methyl carbonyl;
R 4Be selected from phenyl, this phenyl can at random be replaced by one or more groups, and this group is selected from methylthio group, fluorine-based, chloro, bromo, methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxyl; Or acceptable salt or its isomer on the pharmacology.
6, compound as claimed in claim 2, wherein
R 1Be selected from the hydrogen base, methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, isobutyl-, methyl fluoride, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, three chloroethyls, pentafluoroethyl group, seven fluoropropyls, the difluoro chloromethyl, dichlorofluoromethyl, two fluoro ethyls, two fluoropropyls, Dichloroethyl, two chloropropyls, vinyl, propenyl, ethynyl, propargyl, the 1-proyl, 2-propynyl, piperidyl, piperazinyl, morpholinyl, benzyl, phenylethyl, the morpholinyl methyl, the morpholinyl ethyl, the pyrrolidyl methyl, the piperazinyl methyl, piperidino methyl, pyridylmethyl, thienyl methyl, methoxymethyl, ethoxyl methyl, amino, methylamino, dimethylamino, phenylamino, the methylamino methyl, dimethylamino methyl, the methylamino ethyl, dimethylaminoethyl, the ethylamino ethyl, the diethylamino ethyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclohexyl methyl, hydroxymethyl, hydroxyethyl, mercapto methyl, with the methyl thiomethyl; With
R 2Molecular formula be:
Figure A9880736900151
Wherein:
J is 0,1 or 2; With
M is 0; With
R 30And R 31Be independently selected from hydrogen and low alkyl group;
R 32Be selected from hydrogen, low alkyl group, rudimentary benzene alkyl, rudimentary heterocyclic radical alkyl, lower alkoxy alkylidene group, aryloxy alkylidene group, aminoalkyl group, low-grade alkyl amino alkyl, rudimentary phenylamino alkyl, lower alkylcarbonyl alkylidene group, rudimentary phenylcarbonyl group alkylidene group and rudimentary heterocyclic radical carbonylamino alkylidene group;
R 33Be selected from hydrogen, low alkyl group ,-C (O) R 35,-C (O) OR 35,-SO 2R 36,-C (O) NR 37R3 8, and-SO 2NR 39R 40
R wherein 35Be selected from low alkyl group, low-grade cycloalkyl, low-grade halogenated alkyl, low-grade alkenyl, be selected from phenyl, the aryl of xenyl and naphthyl, rudimentary heterocyclic radical, rudimentary benzene alkyl, rudimentary phenyl ring alkyl, rudimentary cycloalkenyl alkylidene group, rudimentary heterocyclic radical alkylidene group, the low alkyl group phenylene, the low alkyl group heterocyclic radical, the phenyl phenylene, rudimentary phenyl heterocycles base, lower alkoxy, rudimentary alkenyloxy, the lower alkoxy alkylidene group, the lower alkoxy benzene alkyl, the lower alkoxy phenylene, rudimentary phenoxy group alkylidene group, rudimentary phenyl alkoxyl group alkylidene group, rudimentary cycloalkyloxy alkylidene group, elementary alkoxy carbonyl, rudimentary heterocyclic radical carbonyl, low alkyl group carbonyl oxygen base alkylidene group, low alkyl group carbonyl oxygen base phenylene, the elementary alkoxy carbonyl alkylidene group, the elementary alkoxy carbonyl phenylene, rudimentary phenyl alkoxy carbonyl heterocyclic radical, the lower alkylcarbonyl heterocyclic radical, rudimentary phenyl carbonyl oxygen base alkyl phenylene, with low alkyl group sulfo-alkylidene group; Wherein be selected from the described aryl of phenyl, xenyl and naphthyl, rudimentary heterocyclic radical, rudimentary benzene alkyl, low alkyl group phenylene, rudimentary phenyl heterocycles base, lower alkoxy phenylene, rudimentary phenoxy group alkylidene group, rudimentary cycloalkyloxy alkylidene group, elementary alkoxy carbonyl alkylidene group and lower alkylcarbonyl heterocyclic radical and at random replaced by one or more groups, this group is independently selected from low alkyl group, halogen, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy, ketone group, amino, nitro and cyano group; Or
R 35Be CHR 48R 49, R wherein 48Be phenylsulfonamido or low alkyl group benzenesulfonyl amino, R 49Be selected from rudimentary benzene alkylamino, low-grade alkyl amino and rudimentary benzene alkylamino; Or
R 35For-NR 50R 51, R wherein 50Be low alkyl group, R 51Be selected from the aryl of phenyl, xenyl and naphthyl; With
R wherein 36Be selected from low alkyl group, low-grade halogenated alkyl, be selected from phenyl, the aryl of xenyl and naphthyl, rudimentary heterocyclic radical, the low-grade cycloalkyl alkylidene group, the low alkyl group phenylene, the low-grade alkenyl phenylene, the phenyl phenylene, rudimentary benzene alkyl, rudimentary phenyl alkenyl, rudimentary heterocyclic radical heterocyclic radical, the carbonyl phenylene, the lower alkoxy phenylene, the elementary alkoxy carbonyl phenylene, the amino phenylene of lower alkylcarbonyl, lower alkylcarbonyl amino-heterocycles base, rudimentary phenylcarbonyl group aminoalkyl heterocyclic base, rudimentary phenyl amino phenylene, low-grade alkyl amino, the low-grade alkyl amino phenylene, low alkyl group alkylsulfonyl phenylene, low alkyl group alkylsulfonyl benzene alkyl, with rudimentary phenyl sulfonyl heterocyclic radical, wherein be selected from phenyl, the described aryl of xenyl and naphthyl, rudimentary heterocyclic radical, the low-grade cycloalkyl alkylidene group, rudimentary benzene alkyl, lower alkylcarbonyl amino-heterocycles base, at random replaced by one or more groups with low alkyl group alkylsulfonyl phenylene, this group is independently selected from low alkyl group, halogen, hydroxyl, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy, ketone group, amino, nitro, and cyano group; With
R wherein 37Be selected from hydrogen and low alkyl group; With
R wherein 38Be selected from hydrogen, low alkyl group, low-grade alkenyl, be selected from phenyl, the aryl of xenyl and naphthyl, rudimentary heterocyclic radical, rudimentary benzene alkyl, the low alkyl group phenylene, rudimentary benzyl ring alkyl, rudimentary phenyl phenylene, the low-grade cycloalkyl alkylidene group, rudimentary heterocyclic radical alkylidene group, low alkyl group heterocyclic radical alkylidene group, rudimentary benzene alkyl heterocycle base, the lower alkoxy alkylidene group, the lower alkoxy phenylene, rudimentary phenoxy group phenylene, phenylcarbonyl group, elementary alkoxy carbonyl, the elementary alkoxy carbonyl alkylidene group, the elementary alkoxy carbonyl phenylene, the lower alkylcarbonyl carbonyl alkylen group, the low-grade alkyl amino alkylidene group, low-grade alkyl amino benzene alkyl, the lower alkylcarbonyl amino alkylidenyl, the low-grade alkyl sulphur phenylene, low alkyl group alkylsulfonyl benzene alkyl, with rudimentary amino-sulfonyl benzene alkyl, wherein be selected from phenyl, the described aryl of xenyl and naphthyl, rudimentary heterocyclic radical, rudimentary benzene alkyl and rudimentary heterocyclic radical alkylidene group are at random replaced by one or more groups, and this group is independently selected from low alkyl group, halogen, hydroxyl, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy, ketone group, amino, nitro, and cyano group; Or
R 38Be-CR 52R 53, R wherein 52Be elementary alkoxy carbonyl, R 53It is low alkyl group sulfo-alkylidene group; Or
R 37And R 38Connected nitrogen-atoms forms 4-8 unit ring heterocycle together; With
R 39And R 40With the R in the claim 2 25And R 27Has identical definition; Or
R 2Be selected from following groups:
Figure A9880736900171
Wherein
K is 0～2 integer; With
R 56Be hydrogen or low alkyl group; With
R 57Be hydrogen or low alkyl group; Or
R 58Be selected from hydrogen, low alkyl group, rudimentary benzene alkyl, the aryl that is selected from phenyl, xenyl and naphthyl, rudimentary heterocyclic radical, rudimentary heterocyclic radical alkyl, elementary alkoxy carbonyl, low alkyl group alkylsulfonyl, rudimentary benzene alkyl sulphonyl, rudimentary phenyl sulfonyl ,-C (O) R 59,-SO 2R 60, and-C (O) NHR 61
R wherein 59Be selected from low alkyl group, low-grade halogenated alkyl, low-grade cycloalkyl, be selected from phenyl, the aryl of xenyl and naphthyl, rudimentary heterocyclic radical, the low alkyl group phenylene, rudimentary phenylalkyl, the low alkyl group heterocyclic radical, lower alkoxy, rudimentary alkenyloxy, rudimentary phenyl alkoxyl group, the lower alkoxy alkylidene group, the lower alkoxy phenylene, the lower alkoxyphenyl alkyl, wherein be selected from phenyl, the described aryl of xenyl and naphthyl, rudimentary heterocyclic radical and rudimentary benzene alkyl are at random replaced by one or more groups, and this group is independently selected from low alkyl group, halogen, hydroxyl, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy, ketone group, amino, nitro, and cyano group; With
R wherein 60Be selected from low alkyl group, be selected from phenyl, the aryl of xenyl and naphthyl, rudimentary heterocyclic radical, the low alkyl group phenylene, the low alkyl group heterocyclic radical, rudimentary benzene alkyl, rudimentary heterocyclic radical heterocyclic radical, the lower alkoxy phenylene, low-grade alkyl amino, the low-grade alkyl amino phenylene, low alkyl group alkylsulfonyl phenylene, with rudimentary phenyl sulfonyl heterocyclic radical, wherein be selected from phenyl, the described aryl of xenyl and naphthyl, rudimentary heterocyclic radical, replaced arbitrarily by one or more groups with rudimentary benzene alkyl, this group is independently selected from low alkyl group, halogen, hydroxyl, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy, ketone group, amino, nitro, and cyano group; With
R wherein 61Be selected from low alkyl group, be selected from phenyl, aryl, low alkyl group phenylene and the lower alkoxy phenylene of xenyl and naphthyl, wherein said aryl is replaced arbitrarily by one or more groups, and this group is independently selected from low alkyl group, halogen, hydroxyl, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy, ketone group, amino, nitro and cyano group; With
R 3Be selected from pyridyl, pyrimidyl and purine radicals; R wherein 3Replaced arbitrarily by one or more groups; this group is independently selected from methylthio group; methyl sulfinyl; methyl sulphonyl; fluorine-based; chloro; bromo; amino-sulfonyl; methyl; ethyl; sec.-propyl; the tertiary butyl; isobutyl-; cyano group; methoxycarbonyl; ethoxy carbonyl; aminocarboxyl; the methyl carbonylamino; trifluoromethyl; difluoromethyl; methyl fluoride; trichloromethyl; dichloromethyl; chloromethyl; hydroxyl; fluorophenyl methyl; the fluorophenyl ethyl; Chlorophenylmethyl; the chloro-phenyl-ethyl; the fluorophenyl vinyl; the chloro-phenyl-vinyl; the fluorophenyl imidazolyl; the chloro-phenyl-imidazolyl; carboxyl; methoxyl group; oxyethyl group; propoxy-; the n-butoxy; methylamino; ethylamino; dimethylamino; diethylin; 2-methyl butyl amino; propargyl amino; amino methyl; amino-ethyl; N-methyl-N-phenylamino; phenyl amino; diphenylamino; benzylamino; styroyl amino; cyclopropyl amino; nitro; chlorosulfonyl; amino; the methyl carbonyl; methoxycarbonyl amino; ethoxy carbonyl amino; the p-methoxy-phenyl methylamino; N, N-dimethylaminoethyl amino; hydroxypropyl amino; hydroxyethyl amino; the imidazolyl ethylamino; the morpholinyl ethylamino; (1-ethyl-2-hydroxyl) ethylamino; piperidyl amino; pyridylmethyl amino; the phenyl methyl piperidyl amino; phenyl methyl amino; fluorophenyl methyl amino; the fluorophenyl ethylamino; the methylamino carbonyl; the ethylamino carbonyl; the methyl carbonyl; the p-methoxy-phenyl methylamino-; diazanyl; 1-methyl diazanyl; or-NR 44R 45, R wherein 44Be methyl carbonyl or amino, R 45Be methyl, ethyl or phenmethyl; With
R 4Be selected from the hydrogen base, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropenyl radical, the cyclobutene base, cyclopentenyl, cyclohexenyl, cyclohexadienyl, phenyl, xenyl, morpholinyl, pyrrolidyl, piperazinyl, piperidyl, pyridyl, thienyl, isothiazolyl isoxazolyl, thiazolyl oxazolyl, pyrimidyl, the chinol base, isoquinolyl, imidazolyl, benzimidazolyl-, furyl, pyrazinyl, dihydro pyranyl, the dihydropyridine base, the dihydrofuran base, THP trtrahydropyranyl, tetrahydrofuran base, cumarone, Dihydrobenzofuranes, with benzo dioxolyl, wherein R 4Described cycloalkyl, cycloalkenyl, aryl and heterocyclic radical at random replaced by one or more groups, this group is independently selected from methylthio group, methyl sulfinyl, the horizontal acyl group of methyl, fluorine-based, chloro, bromo, methyl, ethyl, sec.-propyl, the tertiary butyl, isobutyl-, vinyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, methyl fluoride, difluoromethyl, amino, cyano group, nitro, dimethylamino and carboxyl; Or acceptable salt or its isomer on the pharmacology.
7, compound as claimed in claim 6, wherein
R 1Be hydrogen base, methyl, ethyl, propargyl,, hydroxyethyl, dimethylaminoethyl, diethyllaminoethyl or morpholinyl ethyl;
R 2Molecular formula be: Wherein:
J is 0,1 or 2; With
M is 0; With
R 30Be hydrogen; With
R 31Be selected from hydrogen and low alkyl group; With
R 32Be selected from hydrogen, low alkyl group; With
R 33Be selected from low alkyl group ,-C (O) R 35,-C (O) OR 35,-SO 2R 36,-C (O) NR 37R 38, and-SO 2NR 39R 40
R wherein 35Be selected from low alkyl group, low-grade cycloalkyl, phenyl, rudimentary heterocyclic radical, low alkyl group phenylene, lower alkoxy, rudimentary alkenyloxy, lower alkoxy alkylidene group, rudimentary phenoxy group alkylidene group and rudimentary benzene alkoxyl group alkylidene group, wherein said phenyl and rudimentary phenoxy group alkylidene group are at random replaced by one or more groups, and this group is independently selected from low alkyl group, halogen and low-grade halogenated alkyl; With
R wherein 36Be selected from low alkyl group, phenyl, rudimentary heterocyclic radical, low alkyl group phenylene, phenyl phenylene, rudimentary phenylalkyl, low alkyl group heterocyclic radical, rudimentary heterocyclic radical heterocyclic radical, lower alkoxy phenylene and low-grade alkyl amino; Wherein said phenyl and rudimentary heterocyclic radical are replaced arbitrarily by one or more groups, and this group is independently selected from low alkyl group, halogen, hydroxyl, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy, ketone group, amino, nitro and cyano group; With
R wherein 37Be hydrogen; With
R wherein 38Be selected from low alkyl group, phenyl and low alkyl group phenylene;
R 39And R 40With the R in the claim 2 26And R 27Has identical definition; Or
R 2Be selected from following groups:
Figure A9880736900201
Wherein
K is 0 or 1 integer; With
R 56Be hydrogen; With
R 57Be hydrogen; Or
R 58Be selected from-C (O) R 59With-SO 2R 60
R wherein 59Be selected from low alkyl group, low-grade cycloalkyl, phenyl, low alkyl group phenylene and lower alkoxy alkylidene group, wherein said phenyl group is replaced arbitrarily by one or more groups, and this group is independently selected from low alkyl group, halogen, hydroxyl, low-grade halogenated alkyl, lower alkoxy, elementary halogenated alkoxy, ketone group, amino, nitro and cyano group; With
R wherein 60Be selected from low alkyl group; With
R 3Be selected from pyridyl, pyrimidyl and quinolyl; R wherein 3At random replaced by one or more groups, that this group is independently selected from is fluorine-based, bromo, methyl, cyano group, methoxycarbonyl, aminocarboxyl, benzyl, styroyl, ethanoyl, hydroxyl, methoxyl group, dimethylamino, benzylamino, styroyl amino, amino methyl, amino, hydroxyl and methyl carbonyl; With
R 4Be selected from phenyl, chinol base, xenyl, pyridyl, thienyl, furyl, dihydro pyranyl, benzofuryl, dihydro benzo furyl and benzo dioxolyl, wherein R 4Described cycloalkyl, cycloalkenyl, aryl and heterocyclic radical at random replaced by one or more groups, this group is independently selected from methylthio group, fluorine-based, chloro, bromo, methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxyl; Or
Acceptable salt or its isomer on the pharmacology.
8, compound as claimed in claim 7, wherein
R 1Be hydrogen base or methyl; With
R 3Be selected from pyridyl, pyrimidyl or quinolyl, wherein R 3Replaced arbitrarily by one or more groups, that this group is independently selected from is fluorine-based, bromo, methyl, cyano group, methoxycarbonyl, aminocarboxyl, benzyl, styroyl, ethanoyl, hydroxyl, methoxyl group, dimethylamino, benzylamino, styroyl amino, amino methyl, amino, hydroxyl and methyl carbonyl; With
R 4Be selected from phenyl, this phenyl is at random replaced by one or more groups, and this group is independently selected from methylthio group, fluorine-based, chloro, bromo, methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxyl; Or
Acceptable salt or its isomer on the pharmacology.
9, compound as claimed in claim 1, wherein R 1It is the hydrogen base.
10, compound as claimed in claim 2, wherein R 1It is the hydrogen base.
11, compound as claimed in claim 3, wherein R 1It is the hydrogen base.
12, compound as claimed in claim 6, wherein R 1It is the hydrogen base.
13, compound as claimed in claim 3, wherein R 1Be methyl or ethyl.
14, compound as claimed in claim 6, wherein R 1Be methyl or ethyl.
15, compound as claimed in claim 2, wherein R 2It is the hydrogen base.
16, compound as claimed in claim 3, wherein R 2It is the hydrogen base.
17, compound as claimed in claim 2, wherein R 4It is the phenyl that replaces arbitrarily.
18, compound as claimed in claim 3, wherein R 4It is the phenyl that replaces arbitrarily.
19, compound as claimed in claim 6, wherein R 4It is the phenyl that replaces arbitrarily.
20, compound as claimed in claim 2, wherein R 1And R 2Independently be selected from hydrogen base, methyl and ethyl.
21, compound as claimed in claim 3, wherein R 1And R 2Independently be selected from hydrogen base, methyl and ethyl.
22, compound as claimed in claim 2, wherein R 1And R 2Independently be selected from hydrogen base, methyl and ethyl; R 4It is the phenyl that replaces arbitrarily.
23, compound as claimed in claim 3, wherein R 1And R 2Independently be selected from hydrogen base, methyl and ethyl; R 4It is the phenyl that replaces arbitrarily.
24, a kind of compound with claim 1 of molecular formula IX,
Figure A9880736900231
Wherein Z represents a carbon atom or a nitrogen-atoms; With
R 1Be selected from hydrogen base, low alkyl group, rudimentary hydroxyalkyl, low-grade alkynyl, rudimentary heterocyclic radical, rudimentary aralkyl, rudimentary aminoalkyl and low-grade alkyl amino alkyl; With
R 2Be selected from the hydrogen base, low alkyl group, be selected from phenyl, the aryl of xenyl and naphthyl, be selected from piperidyl, piperazinyl, imidazolyl, the 5-of pyridyl and morpholinyl or 6-unit heterocyclic radical, low-grade halogenated alkyl, rudimentary hydroxyalkyl, elementary alkoxy carbonyl, low-grade alkyl amino, the lower alkyl amino alkyl, phenyl amino, rudimentary aralkyl, rudimentary aryl alkyl amino, the low-grade alkyl amino alkylamino, rudimentary aminoalkyl group, rudimentary aminoalkyl group amino, low-grade alkynyl amino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkyl, rudimentary heterocyclic radical alkylamino, the low alkyl group heterocyclic radical, rudimentary carboxyl cycloalkyl, rudimentary carboxyalkyl amino, low-grade alkoxy alkyl amino, elementary alkoxy carbonyl aminoalkyl group amino, rudimentary heterocyclic radical carbonyl, the elementary alkoxy carbonyl heterocyclic radical, with elementary alkoxy carbonyl heterocyclic radical carbonyl, wherein aryl and heterocyclic radical are at random replaced by one or more groups, and this group is independently selected from halogen, low alkyl group, ketone group, aralkyl, carboxyl, the low-grade alkyl amino alkylamino, low-grade alkynyl amino, rudimentary heterocyclic radical alkylamino, lower alkylcarbonyl and elementary alkoxy carbonyl; Or
R 2Be-CR 54R 55, R wherein 54Be phenyl, R 55It is hydroxyl; With
R 4Be selected from hydrogen base, low-grade cycloalkyl, rudimentary cycloalkenyl, low-grade cycloalkyl diethyl, 5-or 6-unit's heterocyclic radical and be selected from the aryl of phenyl, xenyl, naphthyl; R wherein 4At random replaced by one or more groups in commutable position, this group is independently selected from halogen, low alkyl group, lower alkoxy, aryloxy, rudimentary aralkoxy, low-grade halogenated alkyl, lower alkylthio, low-grade alkyl amino, nitro, hydroxyl; With
R 5Be selected from halogen, amino, cyano group, aminocarboxyl, low alkyl group, lower alkoxy, hydroxyl, rudimentary aminoalkyl group, rudimentary aralkyl, rudimentary aralkyl oxy, rudimentary aryl alkyl amino, elementary alkoxy carbonyl, low-grade alkyl amino, lower alkylcarbonyl, rudimentary aralkenyl, the lower aryl heterocyclic radical, carboxyl, low-grade cycloalkyl amino, elementary alkoxy carbonyl amino, the lower alkoxy aryl alkyl amino, the low-grade alkyl amino alkylamino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkylamino, rudimentary aralkyl heterocyclic radical amino, low-grade alkyl amino carbonylic, lower alkylcarbonyl, the lower alkoxy aryl alkyl amino, diazanyl and low alkyl group diazanyl, or-NR 62R 63, R wherein 62Be lower alkylcarbonyl or amino, R 63Be low alkyl group or rudimentary benzene alkyl; Or acceptable salt or its isomer on the pharmacology.
25, as the compound of claim 24, wherein
R 1Be selected from hydrogen base, methyl, ethyl, hydroxyethyl and propargyl; With
R 2Be selected from the hydrogen base, methyl, ethyl, propyl group, phenyl, trifluoromethyl, hydroxyethyl, the methoxycarbonyl ethyl, the ethoxy carbonyl ethyl, the N-methylamino, N, the N-dimethylamino, the N-ethylamino, N, the N-diethylamino, N-propyl group amino, the N-phenyl amino, amino methyl, amino-ethyl, aminoethylamino, amino propyl amino, propargyl amino, benzylamino, dimethylaminopropyl amino, morpholinyl third amino, the morpholinyl ethylamino, piperidyl, piperazinyl, imidazolyl, morpholinyl, pyridyl, the carboxyl methylamino, methoxy ethyl amino (1, the 1-dimethyl) B carbonyl, (1, the 1-dimethyl) ethyl carbonylamino third amino, (1, the 1-dimethyl) ethyl carbonylamino ethylamino, piperazinyl carbonyl, 1,1-dimethyl-ethyl piperazidine base carbonyl; Wherein said phenyl, piperidyl, piperazinyl, imidazolyl, morpholinyl and pyridyl are at random replaced by one or more groups, that this group is independently selected from is fluorine-based, chloro, bromo, ketone group, methyl, ethyl, trifluoromethyl, benzyl, methoxyl group, methoxycarbonyl and (1, the 1-dimethyl) ethoxy carbonyl; Or
R 4Be selected from cyclohexyl, cyclohexenyl, cyclohexadienyl, phenyl, chinol base, xenyl, pyridyl, thienyl, furyl, dihydro pyranyl, benzofuryl, dihydro benzo furyl and benzo dioxolyl; R wherein 4At random replaced by one or more groups, this group is independently selected from methylthio group, fluorine-based, chloro, bromo, methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxyl; With
R 5Be selected from fluorine-based; chloro; bromo; methyl; the fluorobenzene ethyl; the fluorophenethyl thiazolinyl; the fluorophenyl pyrazolyl; cyano group; methoxycarbonyl; aminocarboxyl; ethanoyl; hydroxyl; carboxyl; methoxyl group; methylamino-; dimethylamino; 2-methyl butyl amino; ethylamino; the dimethylamino ethylamino; hydroxypropyl amino; the hydroxyl ethylamino; imidazolyl amino; the morpholinyl ethylamino; (1-ethyl-2-hydroxyl) ethylamino; piperidyl amino; the pyridyl methylamino-; the phenmethyl piperidyl amino; aminomethyl; cyclopropyl amino; amino; hydroxyl; the methyl carbonyl; ethoxy carbonyl amino; the methoxyphenyl methylamino-; phenmethyl amino; the fluorophenyl methylamino-; the fluorophenyl ethylamino; amino-carbonyl; the methyl carbonyl; diazanyl and 1-methyl diazanyl, or-NR 62R 63, R wherein 62Be methyl carbonyl or amino, R 63Be methyl or benzyl; Perhaps acceptable salt or its isomer on the pharmacology.
26, as the compound of claim 24, R wherein 1It is the hydrogen base.
27, as the compound of claim 25, R wherein 1It is the hydrogen base.
28, as the compound of claim 24, R wherein 1It is low alkyl group.
29, as the compound of claim 25, R wherein 1It is low alkyl group.
30, as the compound of claim 24, R wherein 2It is the hydrogen base.
31, as the compound of claim 25, R wherein 2It is the hydrogen base.
32, as the compound of claim 24, R wherein 1And R 2Be independently selected from hydrogen base, methyl and ethyl.
33, as the compound of claim 25, R wherein 1And R 2Be independently selected from hydrogen base, methyl and ethyl.
34, as the compound of claim 25, wherein Z represents a carbon atom.
35, a kind of compound with claim 1 of molecular formula X, Wherein
Z represents a carbon atom or a nitrogen-atoms; With
R 1Be selected from low alkyl group, rudimentary hydroxyalkyl, low-grade alkynyl, rudimentary aminoalkyl group and low-grade alkyl amino alkyl; With
R 2Be selected from the hydrogen base, low alkyl group, be selected from phenyl, the aryl of xenyl and naphthyl, be selected from piperidyl, piperazinyl, imidazolyl, the 5-of pyridyl and morpholinyl or 6-unit heterocyclic radical, low-grade halogenated alkyl, rudimentary hydroxyalkyl, elementary alkoxy carbonyl, low-grade alkyl amino, the low-grade alkyl amino alkyl, phenylamino, rudimentary aralkyl, rudimentary aryl alkyl amino, the low-grade alkyl amino alkylamino, rudimentary aminoalkyl, rudimentary aminoalkyl group amino, low-grade alkynyl amino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkyl, rudimentary heterocyclic radical alkylamino, the low alkyl group heterocyclic radical, rudimentary carboxyl cycloalkyl, rudimentary carboxyalkyl amino, low-grade alkoxy alkyl amino, elementary alkoxy carbonyl aminoalkyl group amino, rudimentary heterocyclic radical carbonyl, the elementary alkoxy carbonyl heterocyclic radical, with elementary alkoxy carbonyl heterocyclic radical carbonyl; Wherein aryl and heterocyclic radical are at random replaced by one or more groups, and this group is independently selected from halogen, low alkyl group, ketone group, aralkyl, carboxyl, low-grade alkyl amino alkylamino, low-grade alkynyl amino, rudimentary heterocyclic radical alkylamino, lower alkylcarbonyl and elementary alkoxy carbonyl; Or
R 2Be-CR 54R 55, R wherein 54Be phenyl, R 55It is hydroxyl; With
R 4Be selected from 5-or 6-unit's heterocyclic radical and be selected from the aryl of phenyl, xenyl and naphthyl; R wherein 4At random replaced by one or more groups, this group is independently selected from halogen, low alkyl group, lower alkoxy, aryloxy, rudimentary aralkoxy, low-grade halogenated alkyl, lower alkylthio, low-grade alkyl amino, nitro, hydroxyl; With
R 5Be selected from halogen, amino, cyano group, aminocarboxyl, low alkyl group, lower alkoxy, hydroxyl, rudimentary aminoalkyl group, rudimentary aralkyl, rudimentary aralkoxy, rudimentary aryl alkyl amino, elementary alkoxy carbonyl, low-grade alkyl amino, lower alkylcarbonyl, rudimentary aralkenyl, the lower aryl heterocyclic radical, carboxyl, low-grade cycloalkyl amino, elementary alkoxy carbonyl amino, the lower alkoxy aryl alkyl amino, the low-grade alkyl amino alkylamino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkylamino, rudimentary aralkyl heterocyclic radical amino, low-grade alkyl amino carbonylic, lower alkylcarbonyl, the lower alkoxy aryl alkyl amino, diazanyl, with the low alkyl group diazanyl, or-NR 62R 63, R wherein 62Be lower alkylcarbonyl or amino, R 63Be low alkyl group or rudimentary benzene alkyl; Perhaps acceptable salt or its isomer on the pharmacology.
36, as the compound of claim 35, wherein
R 1Be selected from methyl, ethyl, hydroxyethyl and propargyl; With
R 2Be selected from methyl, ethyl, propyl group, phenyl, trifluoromethyl, hydroxyethyl, the methoxycarbonyl ethyl, the ethoxy carbonyl ethyl, the N-methylamino-, N, the N-dimethylamino, the N-ethylamino, N, the N-diethylin, N-third amino, the N-phenyl amino, amino methyl, amino-ethyl, amino ethylamino, amino third amino, propargyl amino, benzylamino, piperidyl amino, the dimethylamino ethylamino, dimethylamino third amino, morpholinyl third amino, the morpholinyl ethylamino, pyridyl, piperazinyl, imidazolyl, morpholinyl, pyridyl, the N methyl piperazine base, the carboxyl methylamino-, the methoxyl group ethylamino, (1, the 1-dimethyl) ethyl carbonyl, (1, the 1-dimethyl) ethyl carbonylamino third amino, (1, the 1-dimethyl) ethyl carbonylamino ethylamino, piperazinyl carbonyl and 1,1-dimethyl-ethyl piperazidine base carbonyl; Wherein said phenyl, piperidyl, piperazinyl, imidazolyl, morpholinyl and pyridyl are at random replaced by one or more groups, that this group is independently selected from is fluorine-based, chloro, bromo, ketone group, methyl, ethyl, trifluoromethyl, benzyl, methoxyl group, methoxycarbonyl, ethoxy carbonyl and (1, the 1-dimethyl) ethoxy carbonyl; With
R 4Be selected from phenyl, chinol base, xenyl, pyridyl, thienyl, furyl, dihydro pyranyl, benzofuryl, dihydro benzo furyl and benzo dioxolyl; R wherein 4Can at random be replaced by one or more groups, this group is independently selected from methylthio group, fluorine-based, chloro, bromo, methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxyl; With
R 5Be selected from fluorine-based; chloro; bromo; methyl; the fluorobenzene ethyl; the fluorophenethyl thiazolinyl; the fluorophenyl pyrazolyl; cyano group; methoxycarbonyl; aminocarboxyl; ethanoyl; hydroxyl; carboxyl; methoxyl group; methylamino-; dimethylamino; 2-methyl butyl amino; ethylamino; the dimethylamino ethylamino; hydroxyl third amino; the hydroxyl ethylamino; propargyl amino; imidazolyl amino; the morpholinyl ethylamino; (1-ethyl-2-hydroxyl) ethylamino; piperidyl amino; the pyridyl methylamino-; the phenmethyl piperidyl amino; amino methyl; cyclopropylamino; amino; hydroxyl; the methyl carbonyl; ethoxy carbonyl amino; the p-methoxy-phenyl methylamino-; the phenyl methylamino-; the fluorophenyl methylamino-; the fluorophenyl ethylamino; amino-carbonyl; the first carbonyl; diazanyl; with 1-methyl diazanyl, or-NR 62R 63, R wherein 62Be first carbonyl or amino, R 63Be methyl or benzyl; Or
Acceptable salt or its isomer on the pharmacology.
37, as the compound of claim 35, R wherein 1It is low alkyl group.
38, as the compound of claim 36, R wherein 1It is low alkyl group.
39, as the compound of claim 35, R wherein 2It is the hydrogen base.
40, as the compound of claim 36, R wherein 2It is the hydrogen base.
41, as the compound of claim 35, R wherein 1Be methyl or ethyl, R 2Be selected from hydrogen base, methyl and ethyl.
42, as the compound of claim 36, R wherein 1Be methyl or ethyl, R 2Be selected from hydrogen base, methyl and ethyl.
43, as the compound of claim 35, wherein Z represents a carbon atom.
44, a kind of compound with claim 1 of chemical formula XI Wherein Z represents a carbon atom or a nitrogen-atoms; With
R 1Be selected from low alkyl group, rudimentary hydroxyalkyl, low-grade alkynyl, rudimentary aminoalkyl group and low-grade alkyl amino alkyl; With
R 2Be selected from the hydrogen base, low alkyl group, be selected from the aryl of phenylbiphenylyl and naphthyl, be selected from piperidyl, piperazinyl, imidazolyl, the 5-of pyridyl and morpholinyl or 6-unit heterocyclic radical, low-grade halogenated alkyl, rudimentary hydroxyalkyl, elementary alkoxy carbonyl, low-grade alkyl amino, the lower alkyl amino alkyl, phenyl amino, rudimentary aralkyl, rudimentary aryl alkyl amino, the low-grade alkyl amino alkylamino, rudimentary aminoalkyl group, rudimentary aminoalkyl group amino, low-grade alkynyl amino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkyl, rudimentary heterocyclic radical alkylamino, the low alkyl group heterocyclic radical, rudimentary carboxyl heterocyclic radical, rudimentary carboxyalkyl amino, the lower alkoxy alkylamino, elementary alkoxy carbonyl aminoalkyl group amino, rudimentary heterocyclic radical carbonyl, the elementary alkoxy carbonyl heterocyclic radical, with elementary alkoxy carbonyl heterocyclic radical carbonyl; Wherein aryl and heterocyclic radical are at random replaced by one or more groups, and this group is independently selected from halogen, low alkyl group, ketone group, aralkyl, carboxyl, lower alkyl amino alkylamino, low-grade alkynyl amino, rudimentary heterocyclic radical alkylamino, lower alkylcarbonyl and elementary alkoxy carbonyl; Or
R 2Be-CR 54R 55, R wherein 54Be phenyl, R 55It is hydroxyl; With
R 4Be selected from 5-or 6-unit's heterocyclic radical and be selected from the aryl of phenyl, xenyl and naphthyl; R wherein 4At random replaced by one or more groups, this group is independently selected from halogen, low alkyl group, lower alkoxy, aryloxy, rudimentary aralkoxy, low-grade halogenated alkyl, lower alkylthio, low-grade alkyl amino, nitro, hydroxyl; With
R 5Be selected from halogen, amino, cyano group, aminocarboxyl, low alkyl group, lower alkoxy, hydroxyl, rudimentary aminoalkyl group, rudimentary aralkyl, rudimentary aralkoxy, rudimentary aryl alkyl amino, elementary alkoxy carbonyl, low-grade alkyl amino, lower alkylcarbonyl, rudimentary aralkenyl, the lower aryl heterocyclic radical, carboxyl, low-grade cycloalkyl amino, elementary alkoxy carbonyl amino, the lower alkoxy aryl alkyl amino, the low-grade alkyl amino alkylamino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkylamino, rudimentary aralkyl heterocyclic radical amino, low-grade alkyl amino carbonylic, lower alkylcarbonyl, the lower alkoxy aryl alkyl amino, diazanyl, with the low alkyl group diazanyl, or-NR 62R 63, R wherein 62Be lower alkylcarbonyl or amino, R 63Be low alkyl group or rudimentary benzene alkyl; Perhaps acceptable salt or its isomer on the pharmacology.
45, as the compound of claim 44, wherein
R 1Be selected from methyl, ethyl, hydroxyethyl and propargyl; With
R 2Be selected from methyl, ethyl, propyl group, phenyl, trifluoromethyl, hydroxyethyl, the methoxycarbonyl ethyl, the ethoxy carbonyl ethyl, the N-methylamino-, N, the N-dimethylamino, the N-ethylamino, N, the N-diethylin, N-third amino, the N-phenyl amino, amino methyl, amino-ethyl, amino ethylamino, amino third amino, propargyl amino, benzylamino, dimethylamino third amino, morpholinyl third amino, the morpholinyl ethylamino, piperidyl, piperazinyl, imidazolyl, morpholinyl, pyridyl, carboxymethylamino, the methoxyl group ethylamino, (1, the 1-dimethyl) ethyl carbonyl, (1, the 1-dimethyl) ethyl carbonylamino third amino, (1, the 1-dimethyl) ethyl carbonylamino ethylamino, piperazinyl carbonyl and 1,1-dimethyl-ethyl piperazidine base carbonyl; Wherein said phenyl, piperidyl, piperazinyl, imidazolyl, morpholinyl and pyridyl are at random replaced by one or more groups, that this group is independently selected from is fluorine-based, chloro, bromo, ketone group, methyl, ethyl, trifluoromethyl, benzyl, methoxyl group, methoxycarbonyl, ethoxy carbonyl and (1, the 1-dimethyl) ethoxy carbonyl; With
R 4Be selected from phenyl, chinol base, xenyl, pyridyl, thienyl, furyl, dihydro pyranyl, benzofuryl, dihydro benzo furyl and benzo dioxolyl; R wherein 4Can at random be replaced by one or more groups, this group is independently selected from methylthio group, fluorine-based, chloro, bromo, methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxyl; With
R 5Be selected from fluorine-based; chloro; bromo; methyl; the fluorobenzene ethyl; the fluorophenethyl thiazolinyl; the fluorophenyl pyrazolyl; cyano group; methoxycarbonyl; aminocarboxyl; ethanoyl; hydroxyl; carboxyl; methoxyl group; methylamino-; dimethylamino; 2-methyl butyl amino; ethylamino; the dimethylamino ethylamino; hydroxyl third amino; the hydroxyl ethylamino; imidazolyl amino; the morpholinyl ethylamino; (1-ethyl-2-hydroxyl) ethylamino; piperidyl amino; the pyridyl methylamino-; the phenmethyl piperidyl amino; amino methyl; cyclopropylamino; amino; hydroxyl; the methyl carbonyl; ethoxy carbonyl amino; the p-methoxy-phenyl methylamino-; the phenyl methylamino-; the fluorophenyl methylamino-; the fluorophenyl ethylamino; amino-carbonyl; the methyl carbonyl; diazanyl; with 1-methyl diazanyl, or-NR 62R 63, R wherein 62Be first carbonyl or amino, R 63Be methyl or benzyl; Or
Acceptable salt or its isomer on the pharmacology.
46, as the compound of claim 44, R wherein 1It is low alkyl group.
47, as the compound of claim 45, R wherein 1It is low alkyl group.
48, as the compound of claim 44, R wherein 2It is the hydrogen base.
49, as the compound of claim 45, R wherein 2It is the hydrogen base.
50, as the compound of claim 44, R wherein 1Be methyl or ethyl, R 2Be selected from hydrogen base, methyl and ethyl.
51, as the compound of claim 45, R wherein 1Be methyl or ethyl, R 2Be selected from hydrogen base, methyl and ethyl.
52, as the compound of claim 44, wherein Z represents a carbon atom.
53, a kind of compound with claim 1 of molecular formula IX, Wherein Z represents a carbon atom or a nitrogen-atoms; With
R 1Be selected from hydrogen base, low alkyl group, rudimentary hydroxyalkyl, low-grade alkynyl, rudimentary aminoalkyl group and low-grade alkyl amino alkyl; With
R 2Be selected from the hydrogen base, low alkyl group, be selected from the aryl of phenylbiphenylyl and naphthyl, be selected from piperidyl, piperazinyl, imidazolyl, the 5-of pyridyl and morpholinyl or 6-unit heterocyclic radical, low-grade halogenated alkyl, rudimentary hydroxyalkyl, elementary alkoxy carbonyl, low-grade alkyl amino, the lower alkyl amino alkyl, phenyl amino, rudimentary aralkyl, rudimentary aryl alkyl amino, the low-grade alkyl amino alkylamino, rudimentary aminoalkyl group, rudimentary aminoalkyl group amino, low-grade alkynyl amino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkyl, rudimentary heterocyclic radical alkylamino, the low alkyl group heterocyclic radical, rudimentary carboxyl heterocyclic radical, rudimentary carboxyalkyl amino, low-grade alkoxy alkyl amino, elementary alkoxy carbonyl aminoalkyl group amino, rudimentary heterocyclic radical carbonyl, the elementary alkoxy carbonyl heterocyclic radical, with elementary alkoxy carbonyl heterocyclic radical carbonyl; Wherein aryl and heterocyclic radical are at random replaced by one or more groups, and this group is independently selected from halogen, low alkyl group, ketone group, aralkyl, carboxyl, low-grade alkyl amino alkylamino, low-grade alkynyl amino, rudimentary heterocyclic radical alkylamino, lower alkylcarbonyl and elementary alkoxy carbonyl; Or
R 2Be-CR 54R 55, R wherein 54Be phenyl, R 55It is hydroxyl; With
R 4It is phenyl, described phenyl is at random replaced by one or more groups, and this group is independently selected from halogen, low alkyl group, lower alkoxy, aryloxy, rudimentary aralkoxy, low-grade halogenated alkyl, lower alkylthio, low-grade alkyl amino, nitro, hydroxyl; With
R 5Be selected from halogen, amino, cyano group, aminocarboxyl, low alkyl group, lower alkoxy, hydroxyl, rudimentary aminoalkyl group, rudimentary aralkyl, rudimentary aralkoxy, rudimentary aryl alkyl amino, elementary alkoxy carbonyl, low-grade alkyl amino, lower alkylcarbonyl, rudimentary aralkenyl, the lower aryl heterocyclic radical, carboxyl, low-grade cycloalkyl amino, elementary alkoxy carbonyl amino, the lower alkoxy aryl alkyl amino, the low-grade alkyl amino alkylamino, rudimentary heterocyclic radical amino, rudimentary heterocyclic radical alkylamino, rudimentary aralkyl heterocyclic radical amino, low-grade alkyl amino carbonylic, lower alkylcarbonyl, the lower alkoxy aryl alkyl amino, diazanyl, with the low alkyl group diazanyl, or-NR 62R 63, R wherein 62Be lower alkylcarbonyl or amino, R 63Be low alkyl group or rudimentary benzene alkyl; Perhaps
Acceptable salt or its isomer on the pharmacology.
54, as the compound of claim 53, wherein
R 1Be selected from hydrogen base, methyl, ethyl, hydroxyethyl and propargyl; With
R 2Be selected from methyl, ethyl, propyl group, phenyl, trifluoromethyl, hydroxyethyl, the methoxycarbonyl ethyl, the ethoxy carbonyl ethyl, the N-methylamino-, N, the N-dimethylamino, the N-ethylamino, N, the N-diethylin, N-third amino, the N-phenyl amino, amino methyl, amino-ethyl, aminoethylamino, amino propyl amino, propargyl amino, benzylamino, dimethylamino third amino, morpholinyl third amino, piperidyl, piperazinyl, imidazolyl, morpholinyl, pyridyl, the carboxyl methylamino-, the methoxyl group ethylamino, (1, the 1-dimethyl) ethyl carbonyl, (1, the 1-dimethyl) ethyl carbonylamino third amino, (1, the 1-dimethyl) ethyl carbonylamino ethylamino, piperazinyl carbonyl and 1,1-dimethyl-ethyl piperazidine base carbonyl; Wherein said phenyl, piperidyl, piperazinyl, imidazolyl, morpholinyl and pyridyl are replaced arbitrarily by one or more groups, that this group is independently selected from is fluorine-based, chloro, bromo, ketone group, methyl, ethyl, trifluoromethyl, benzyl, methoxyl group, methoxycarbonyl, ethoxy carbonyl and (1, the 1-dimethyl) ethoxy carbonyl; With
R 4It is phenyl, described phenyl is replaced arbitrarily by one or more groups, and this group is independently selected from methylthio group, fluorine-based, chloro, bromo, methyl, ethyl, methoxyl group, oxyethyl group, phenoxy group, benzyloxy, trifluoromethyl, nitro, dimethylamino and hydroxyl; With
R 5Be selected from fluorine-based; chloro; bromo; methyl; the fluorobenzene ethyl; the fluorophenethyl thiazolinyl; the fluorophenyl pyrazolyl; cyano group; methoxycarbonyl; aminocarboxyl; ethanoyl; hydroxyl; carboxyl; methoxyl group; methylamino-; dimethylamino; 2-methyl butyl amino; ethylamino; the dimethylamino ethylamino; hydroxyl third amino; the hydroxyl ethylamino; imidazolyl amino; the morpholinyl ethylamino; (1-ethyl-2-hydroxyl) ethylamino; piperidyl amino; the pyridyl methylamino-; the phenmethyl piperidyl amino; amino methyl; cyclopropylamino; amino; hydroxyl; the methyl carbonyl; ethoxy carbonyl amino; the p-methoxy-phenyl methylamino-; phenyl methyl amino; the fluorophenyl methylamino-; the fluorophenyl ethylamino; amino-carbonyl; the methyl carbonyl; diazanyl; with 1-methyl diazanyl, or-NR 62R 63, R wherein 62Be first carbonyl or amino, R 63Be methyl or benzyl; Or
Acceptable salt or its isomer on the pharmacology.
55, as the compound of claim 53, R wherein 1Be hydrogen base or low alkyl group.
56, as the compound of claim 54, R wherein 1Be hydrogen base or low alkyl group.
57, as the compound of claim 53, R wherein 1It is the hydrogen base.
58, as the compound of claim 54, R wherein 1It is the hydrogen base.
59, as the compound of claim 53, R wherein 2It is the hydrogen base.
60, as the compound of claim 54, R wherein 2It is the hydrogen base.
61, as the compound of claim 53, R wherein 4The phenyl that is replaced by one or more fluorine-based, chloros or bromo.
62, as the compound of claim 54, R wherein 4The phenyl that is replaced by one or more fluorine-based, chloros or bromo.
63, as the compound of claim 53, R wherein 1And R 2Be independently selected from hydrogen base, methyl and ethyl.
64, as the compound of claim 54, R wherein 1And R 2Be independently selected from hydrogen base, methyl and ethyl.
65, as the compound of claim 53, wherein Z represents a carbon atom.
66, a kind of compound with claim 1 of molecular formula IX,
Figure A9880736900341
Wherein
Z represents a carbon atom or a nitrogen-atoms; With
R 1Be selected from hydrogen base, low alkyl group, rudimentary hydroxyalkyl and low-grade alkynyl; With
R 2Be selected from hydrogen base and low alkyl group;
R 4Be selected from phenyl and benzo dioxolyl; Wherein phenyl is at random replaced by one or more halogen groups;
R 5Be selected from hydrogen base, halogen and alkyl diazanyl; Or acceptable salt or its isomer on the pharmacology.
67, as the compound of claim 66, wherein
Z represents a carbon atom; With
R 1Be selected from hydrogen base, methyl, hydroxyethyl and propargyl; With
R 2It is the hydrogen base;
R 4Be selected from phenyl and benzo dioxolyl; Wherein phenyl is at random replaced by one or more groups, and this group is independently selected from chloro, fluorine-based and bromo; With
R 5Be selected from hydrogen base, fluorine-based and 1-methyl diazanyl; Or acceptable salt or its isomer on the pharmacology.
68, as the compound of claim 67, wherein
Z represents a carbon atom; With
R 1Be selected from hydrogen base and methyl; With
R 2It is the hydrogen base;
R 4Be selected from phenyl, this phenyl is at random replaced by one or more groups, and this group is independently selected from chloro, fluorine-based and bromo; With
R 5Be selected from hydrogen base and fluorine-based; Or acceptable salt or its isomer on the pharmacology.
69, A compound as claimed in claim 1, selected from the following compounds, their isomers Bodies and their pharmacologically acceptable salt thereof: 4 - [5 - (3 - fluoro-4 - methoxy-phenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyridine; 4 - [5 - methyl - 3 - (2 - methylphenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 (4 - fluorophenyl) -5 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - methyl - 3 - (4 - methylphenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [5 - methyl - 3 - [4 - (methylthio) phenyl]-1H-pyrazol-4 - yl] pyridine; 4 - [3 (4 - chlorophenyl) -5 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - methyl-5 - (3 - methylphenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (2,5 - dimethylphenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (1,3 - benzodioxol-penten-5 - yl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - methyl-5 - (4 - phenoxy-phenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [5 - [(1,1 '- biphenyl)-4 - yl] -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - methyl-5 - [3 - (phenoxy-phenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - methyl-5 - [3 - (phenylmethoxy) phenyl]-1H-pyrazol-4 - yl] pyridine; 4 - [3 - methyl-5 - [2 - (phenylmethoxy) phenyl]-1H-pyrazol-4 - yl] pyridine; 2 - [3 - methyl - 4 - (4 - pyridyl) -1 H-pyrazol-4 - yl] phenol; 3 - [3 - methyl - 4 - (4 - pyridyl)-1H-pyrazol-4 - yl] phenol; 1 - hydroxy - 4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyridinium; 5 - (4 - fluorophenyl)-N, N-dimethyl-4 - (4 - pyridyl)-1H-pyrazol-3 - amine; 5 - (4 - fluorophenyl)-N-phenyl-4 - (4 - pyridyl)-1H-pyrazol-3 - amine; 4 - [5 - (4 - fluorophenyl) -3 - phenyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (3 - methylphenyl) -3 - (trifluoromethyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (4 - fluorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-5 - yl] pyridine; 4 - (5 - cyclohexyl) -3 - methyl-1H-pyrazol-4 - yl) pyridine; 4 - [5 - (4 - fluoro-5 - methoxy-phenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (3 - methylphenyl) -3 - propyl-1H-pyrazol-4 - yl] pyridine; 4 - [(3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) methyl] pyridine; 4 - [3,5 - bis (3 - methylphenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [4 - methyl - 2 - (2 - trifluoromethyl-phenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (2 - chlorophenyl) -5 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - methyl - 3 - (2,4 - dimethylphenyl)-1H-pyrazol-4 - yl] pyridine; 4 [5 - (4 - chlorophenyl) -1,3 - dimethyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (3 - fluoro-2 - methylphenyl) -5 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (3,5 - dimethylphenyl) -5 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (3,5 - dimethoxyphenyl) -5 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - methyl - 3 - (3 - nitrophenyl)-1H-pyrazol-4 - yl] pyridine; N, N-dimethyl-4 - [5 - methyl - 4 - (4 - pyridyl)-1H-pyrazol-3 - yl] aniline; 4 - [3 - (2,3 - dihydro-benzofuran-5 - yl) -5 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (4 - bromophenyl) -5 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (2 - fluorophenyl) -5 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (3 - bromophenyl) -5 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - methyl-5 - [3 - (trifluoromethyl) phenyl]-1H-pyrazol-4 - yl] pyridine; 4 - (3 - ethyl-4 - phenyl-1H-pyrazol-4 - yl) pyridine; 4 - [5 - (3 - methoxy-phenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - ethyl-5 - (3 - methyl-phenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (3,4 - difluorophenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (3 - ethoxy-phenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - methyl-5 - [4 - (trifluoromethyl) phenyl]-1H-pyrazol-4 - yl] pyridine; 4 - [3 - methyl-5 - (3 - thienyl)-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (2,4 - dichlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (3 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (3 - chloro - methoxy-phenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; Of ethyl 3 - (4 - chlorophenyl) -4 - (4 - pyridyl)-1H-pyrazole-5-propanoate; 4 - [3 - (4 - fluorophenyl) -1 - methyl - pyrazol-4 - yl] pyridine; 5 - [5 - (3 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] pyrimidin-2 - amine; 5 - [3 - methyl-5 - (3 - methylphenyl)-1H-pyrazol-4 - yl] pyrimidin-2 - amine; 5 - [3 - methyl-5 - (2 - methylphenyl)-1H-pyrazol-4 - yl] pyrimidin-2 - amine; 5 - [5 - (4 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] pyrimidin-2 - amine; 5 - [5 - (4 - fluorophenyl) -3 - methyl-1H-pyrazol-4 - yl] pyrimidin-2 - amine; 5 - [5 - (4 - methoxyphenyl) -3 - methyl-1H-pyrazol-4 - yl] pyrimidin-2 - amine; 5 - [5 - (3 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridin-2 - amine; 4 - [5 - (3 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridin-2 - amine; 4 - [5 - (3 - methyl-phenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridin-2 - amine; 4 - [5 - (2 - methylphenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridin-2 - amine; 4 - [5 - (4 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridin-2 - amine; 4 - [5 - (4 - fluorophenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridin-2 - amine; 4 - [5 - (4 - methoxyphenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridin-2 - amine; 5 - [5 - (3 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] -2 - methoxypyridine; 2 - methoxy-5 - [3 - methyl-5 - (3 - methyl-phenyl)-1H-pyrazol-4 - yl] pyridine; 2 - methoxy-5 - [5 - (4 - methoxyphenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (3 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] -2 - methoxypyridine; 2 - methoxy - 4 - [3 - methyl-5 - (3 - methyl-phenyl)-1H-pyrazol-4 - yl] pyridine; 2 - methoxy - 4 - [3 - methyl-5 - (2 - methyl-phenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (4 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] -2 - methoxypyridine; 4 - [5 - (4 - fluorophenyl) -3 - methyl-1H-pyrazol-4 - yl] -2 - methoxypyridine; 2 - methoxy - 4 - [3 - methyl-5 - (4 - methylphenyl) -1 H-pyrazol-4 - yl] pyridine; 5 - [5 - (3 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridin-2 - ol; 4 - [5 - (3 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridin-2 - ol; 4 - [5 - (3 - methyl-phenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridin-2 - ol; 4 - [5 - (2 - methylphenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridin-2 - ol; 4 - [5 - (4 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridin-2 - ol; 4 - [5 - (4 - fluorophenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridin-2 - ol; 4 - [5 - (4 - methoxyphenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridin-2 - ol; 5 - [5 - (3 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridin-2 - amine; 4 - [5 - (3 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridin-2 - amine; 4 - [5 - (3 - methyl-phenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridin-2 - amine; 4 - [5 - (2 - methylphenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridin-2 - amine; 4 - [5 - (4 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridin-2 - amine; 4 - [5 - (4 - fluorophenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridin-2 - amine; 4 - [5 - (4 - methoxyphenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridin-2 - amine; 5 - [5 - (3 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridine-2 - carboxylic acid amide; 4 - [5 - (3 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridine-2 - carboxylic acid amide; 4 - [5 - (3 - methyl-phenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridine-2 - carboxylic acid amide; 4 - [5 - (2 - methylphenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridine-2 - carboxylic acid amide; 4 - [5 - (4 - chlorophenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridine-2 - carboxylic acid amide; 4 - [5 - (4 - fluorophenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridine-2 - carboxylic acid amide; 4 - [5 - (4 - methoxyphenyl) -3 - methyl-1H-pyrazol-4 - yl] - pyridine-2 - carboxylic acid amide; 4 - [5 - (3 - fluoro-4 - methoxy-phenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (4 - fluoro-3 - methoxy-phenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (4 - chloro-3 - methoxy-phenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (2,3 - dihydro-benzofuran-6 - yl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (benzofuran-6 - yl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (3 - fluoro-5 - methoxy-phenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (3 - chloro-5 - methoxy-phenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (1 - cyclohexen-1 - yl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (1,3 - cyclohexadiene-1 - yl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (5,6 - dihydro-2H-pyran-4-yl - yl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - (5 - cyclohexyl-3 - methyl-1H-pyrazol-4 - yl) pyridine; 4 - [5 - (4 - methoxy-3 - methyl-phenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (3 - methoxy - 4 - methyl-phenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (3 - methoxy-5 - methyl-phenyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (3 - furyl) -3 - methyl-1H-pyrazol-4 - yl] pyridine; 2 - methyl -4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyridine; 2 - methoxy - 4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyridine; Methyl 4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyridine-2 - carboxylate; 4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyridine-2 - carboxylic acid amide; 1 - [4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyridin-2 - yl] ethanone; N, N-dimethyl-4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyridin-2 - amine; 3 - methyl - 4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyridine; 3 - methoxy - 4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyridine; Methyl 4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyridine-3 - carboxylate; 4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyridine-3 - carboxamide; 1 - [4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyridin-3 - yl] ethanone; 3 - bromo -4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyridine; N, N-dimethyl-4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyridin-3 - amine; 2 - methyl -4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyrimidine; 4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyrimidine; 2 - methoxy - 4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyrimidine; 4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyrimidin-2 - amine; N, N-dimethyl-4 - (3 - methyl-5 - phenyl-1H-pyrazol-4 - yl) pyrimidine-3 - amine; 4 - (5,6 - dihydro-2H-pyran-4-yl - yl) -3 - methyl-5 - phenyl-1H-pyrazole; 3 - methyl-5 - phenyl-4 - (3 - thienyl)-1H-pyrazole; 4 - (3 - furyl) -3 - methyl-5 - phenyl-1H-pyrazole; 3 - methyl-5 - phenyl-4 - (2 - thienyl)-1H-pyrazole; 4 - (2 - furyl) -3 - methyl-5 - phenyl-1H-pyrazole; 4 - (3 - isothiazolyl) -3 - methyl-5 - phenyl-1H-pyrazole; 4 - (3 - isoxazolyl) -3 - methyl-5 - phenyl-1H-pyrazole; 4 - (5 - isothiazolyl) -3 - methyl-5 - phenyl-1H-pyrazole; 4 - (5 - isoxazolyl) -3 - methyl-5 - phenyl-1H-pyrazole; 3 - methyl-5 - phenyl-4 - (5 - thiazolyl)-1H-pyrazole; 3 - methyl - 4 - (5 - oxazolyl)-5 - phenyl-1H-pyrazole; 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] pyridine; 2 - methyl -4 - [3 - (3 - methyl-phenyl)-1H-pyrazol-4 - yl] pyridine; 4 - (1 - methyl - 3 - phenyl-1H-pyrazol-4 - yl) pyridine; 4 - (3 - phenyl-1H-pyrazol-4 - yl) pyridine; 2 - methyl -4 - (3 - phenyl-1H-pyrazol-4 - yl) pyridine; 4 - [3 - (3 - chlorophenyl) -1 - methyl - pyrazol-4 - yl] pyridine; 4 - [3 - (4 - chlorophenyl) -1 - methyl - pyrazol-4 - yl] pyridine; 4 - [3 - (3 - chlorophenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (4 - chlorophenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (3 - chlorophenyl)-1H-pyrazol-4 - yl] -2 - methyl-pyridine; 4 - [3 - (3 - fluorophenyl) -1 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (3 - fluorophenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (3 - chlorophenyl) -1 - methyl - pyrazol-4 - yl] -2 - methyl-pyridine; 5 - (4 - chlorophenyl)-N-phenyl-4 - (4 - pyridyl)-1H-pyrazol-3 - amine; 5 - (4 - chlorophenyl)-N-methyl-4 - (4 - pyridyl)-1H-pyrazol-3 - amine; 5 - (4 - chlorophenyl)-N, N-dimethyl-4 - (4 - pyridyl)-1H-pyrazole-3 - amine dihydrate; 5 - (3 - fluorophenyl)-N, N-dimethyl-4 - (4 - pyridyl)-1H-pyrazol-3 - amine; N, N-dimethyl-5 - (3 - methylphenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - amine; N-methyl-5 - (3 - methylphenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - amine; N-ethyl-5 - (3 - methylphenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - amine; N, N-diethyl-5 - (3 - methylphenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - amine; 5 - (4 - chlorophenyl)-N, N-diethyl-4 - (4 - pyridyl)-1H-pyrazol-3 - amine; 4 - [5 - (4 - chlorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl] morpholine; 5 - (4 - chlorophenyl)-N-propyl-4 - (4 - pyridyl)-1H-pyrazol-3 - amine; 5 - (4 - chlorophenyl)-N-(phenylmethyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - amine hydrate (2:1); 5 - (4 - chlorophenyl)-N-(2 - methoxy-ethyl) -4 - (4 - pyridyl)-1H-pyrazole-3 - amine monohydrate; 1,1 - dimethyl-ethyl-4 - [5 - (4 - chlorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl]-1 - piperazine carboxylic acid Triazine; 1 - [5 - (4 - chlorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl] piperazine trihydrochloride; 1 - [5 - (4 - chlorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl] -4 - methylpiperazine; 1,1 - dimethyl-ethyl-4 - [5 - (4 - fluorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl]-1 - piperazine carboxylic acid Triazine; 1 - [5 - (4 - fluorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl] piperazine trihydrochloride; 1 - [5 - (4 - chlorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl]-piperazine; N-[5 - (4 - chlorophenyl) -4 - [2 - (phenylmethyl) amino]-4-pyridinyl]-1H-pyrazol-3 - yl] -1,3 - malonic Amine trihydrochloride; 1 - [5 - (4 - chlorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl] -4 - (phenylmethyl) piperazine; 4 - [3 - (4 - fluorophenyl) -5 - (1 - piperazinyl)-1H-pyrazol-4 - yl] pyrimidine dihydrochloride; 1,1 - dimethylethyl - [3 - [5 - (4 - chlorophenyl) -4 - (4 - pyridyl) -1 H-pyrazol-3 - yl] amino] propyl] Carbamate; N-[5 - (4 - chlorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl] -1,3 - propanediamine, trihydrochloride Monohydrate; 1,1 - dimethylethyl - [2 - [[5 - (4 - chlorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl] amino] ethyl Yl] carbamate; 1,1 - dimethylethyl 4 - [5 - (4 - chlorophenyl) -1 - (2 - hydroxyethyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - Yl]-1 - carboxylic acid-piperazine; 1,1 - dimethylethyl 4 - [5 - (4 - fluorophenyl) -4 - (4 - pyrimidinyl)-1H-pyrazol-3 - yl]-1 - piperazine carboxylic acid Triazine; 1,1 - dimethylethyl - [3 - [[5 - (4 - chlorophenyl) -4 - (2 fluoro-4 - pyridinyl)-1H-pyrazol-3 - yl] amino] Propyl] carbamate; 1 - [5 - (4 - chlorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl] -4 - ethyl-piperazine; N-[5 - (4 - chlorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl] -1,2 - ethanediamine; 4 - [3 - (2,6 - difluorophenyl) -5 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (3 - ethyl-phenyl) -5 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (3 - chlorophenyl) -5 - ethyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - ethyl-5 - (3 - ethylphenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (4 - chlorophenyl) -5 - (1 - methylethyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - cyclopropyl-5 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (4 - fluorophenyl) -5 - (trifluoromethyl)-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (cyclopropyl-3 - (4 - (fluorophenyl) -1 - methyl-1H-pyrazol-4 - yl] pyridine; 5 - cyclopropyl-3 - (4 - fluorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-1 - ethanol; 3 - (4 - fluorophenyl) -5 - (2 - methoxy - 4 - pyridyl) -4 - (4 - pyridyl)-1H-pyrazol-1 - ethanol; 4 - [3 - (4 - fluorophenyl) -1 - (2 - hydroxyethyl) -4 - (4 - pyridyl)-1H-pyrazol-5 - yl] -2 (1H) - pyridine Ketone; 1 - acetyl-4 - [3 - (4 - fluorophenyl) -1 - (2 - hydroxyethyl) -4 - (4 - pyridyl)-1H-pyrazol-5 - yl] - 2 (1H) - pyridone; Of ethyl 2 - [3 - (4 - fluorophenyl) -1 - (2 - hydroxyethyl) -4 - (4 - pyridyl)-1H-pyrazol-5 - yl] cyclopropane Carboxylic acid esters; 2 - [3 - (4 - fluorophenyl) -1 - (2 - hydroxyethyl) -4 - (4 - pyridyl)-1H-pyrazol-5 - yl] butyric acid ring; 3 - (4 - fluorophenyl) -5 - (4 - imidazolyl) -4 - (4 - pyridyl)-1H-pyrazol-1 - ethanol; 4 - [3 - (4 - chloro-3 - methylphenyl)-1H-pyrazol-4 - yl] pyridine; 5 - (4 - fluorophenyl) -4 - (4 - pyridyl)-1H-pyrazole-3 - carboxylic acid; 5 - (4 - fluorophenyl) -4 - (4 - pyridyl)-1H-pyrazole-3 - methanol; 1 - [[5 - (4 - fluorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl] carbonyl] piperazine; 1,1 - dimethylethyl 4 - [[5 - (4 - fluorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl] carbonyl] -1 - Piperazine carboxylic acid ester; 4 - (1,5 - dimethyl-3 - phenyl-1H-pyrazol-4 - yl) pyridine; 4 - (1,3 - dimethyl-5 - phenyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (4 - chlorophenyl) -1,5 - dimethyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (4 - chlorophenyl) -1,3 - dimethyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - ethyl-1 - methyl - 3 - (3 - methylphenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - ethyl-1 - methyl -5 - (3 - methylphenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (4 - chlorophenyl) -1 - ethyl-5 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (4 - chlorophenyl) -2 - ethyl-5 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (2 - chlorophenyl)-1H-pyrazol-4 - yl] pyridine; 3 - (4 - fluorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-1 - ethanol; 3 - (4 - fluorophenyl) -4 - (4 - pyrimidinyl)-1H-pyrazol-1 - ethanol; 4 - [3 - (4 - fluorophenyl) -1 - methyl-1H-pyrazol-4 - yl] pyridine; ² - [[4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - pyridinyl] amino] -1 - butanol; 4 - [5 - bromo-3 - (4 - fluorophenyl) -1 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - pyridinecarbonitrile; 4 - [2 - [3 - (4 - fluorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-1 - yl] ethyl] morpholine; 3 - (4 - fluorophenyl) -1 - methyl-α-phenyl-4 - (4 - pyridyl)-1H-pyrazol-5 - methanol; N-[5 - (4 - fluorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl] -4 - morpholino-ethylamine; 4 - [3 - (3 - chlorophenyl)-1H-pyrazol-4 - yl] -2 (1H) - pyridinone hydrazone; 4 - [3 - (3 - chlorophenyl)-1H-pyrazol-4 - yl]-N-(phenylmethyl) -2 - pyridinamine; 4 - [3 - (3 - chlorophenyl)-1H-pyrazol-4 - yl]-N-(phenylethyl) -2 - pyridinamine; 4 - [3 - (3 - chlorophenyl)-1H-pyrazol-4 - yl]-N-ethyl-2 - pyridyl amine; 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - pyridinecarboxamide; Methyl 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - pyridine carboxylate; 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl]-N-methyl-2 - pyridine carboxamide; 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - pyridinecarboxylic acid; 4 - [3 - (3 - fluorophenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (1,3 - benzodioxol-penten-5 - yl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (3 - fluorophenyl) -1 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (3 - chlorophenyl) -1 H-pyrazol-4 - yl] pyridine; 4 - [3 - (1,3 - benzodioxol-penten-5 - yl) -1 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (3-4 chlorophenyl) -1 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (3 - chlorophenyl) -1 - methyl-1H-pyrazol-4 - yl] -2 - methyl-pyridine; 4 - [5 - (3 - chlorophenyl) -1 - methyl-1H-pyrazol-4 - yl] -2 - methyl-pyridine; 4 - [3 - (3 - chlorophenyl) -1 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (3 - chlorophenyl) -1 - methyl-1H-pyrazol-4 - yl] pyridine; 2 - methyl -4 - [1 - methyl - 3 - (3 - methylphenyl)-1H-pyrazol-4 - yl] pyridine; 2 - methyl -4 - [1 - methyl -5 - (3 - methylphenyl)-1H-pyrazol-4 - yl] pyridine; 4 - (3 - phenyl-1H-pyrazol-4 - yl) pyridine; 4 - [3 - [3 - (trifluoromethyl) phenyl]-1H-pyrazol-4 - yl] pyridine; 4 - [1 - methyl - 3 - [3 - (trifluoromethyl) phenyl]-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (3,4 - difluorophenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (4 - chlorophenyl)-1H-pyrazol-4 - yl] -2 - fluoro-pyridine; 4 - [3 - (4 - bromophenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (3,4 - difluorophenyl) -1 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (4 - bromophenyl) -1 - methyl-1H-pyrazol-4 - yl] pyridine; (E) -4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - (2 - styrene-yl) pyridine; (S) -4 - [3 - (4 - chlorophenyl)-1H-pyrazol-4 - yl]-N-(2 - methylbutyl) - 2 - pyridyl amine; 4 - [3 - (4 - chlorophenyl)-1H-pyrazol-4 - yl]-N-[(4 - methoxy - phenyl) methyl] -2 - pyridinamine; N-[4 - [3 - (4 - chlorophenyl)-1H-pyrazol-4 - yl] -2 - pyridinyl]-2 - pyridine carboxamide; N-[4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - pyridinyl]-2 - pyridine carboxamide; 2 - fluoro-4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (4 - iodo-phenyl)-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (4 - iodo-phenyl) -1 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [1 - methyl - 3 - (4 - trifluoromethyl) phenyl]-1H-pyrazol-4 - yl] pyridine; N-[1 - (4 - fluorophenyl) ethyl] -4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - pyridinamine; N-[(3 - fluorophenyl) methyl] -4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - pyridinamine; 4 - [3 - (4 - fluorophenyl) -1 - methyl-1H-pyrazol-4 - yl] -2 - (1 - methylhydrazino) pyridine; 2 - fluoro-4 - [3 - (4 - fluorophenyl) -1 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (3,4 - difluorophenyl)-1H-pyrazol-4 - yl] -2 - fluoro - pyridine; 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -3 - methyl pyridine; 4 - [3 - (4 - fluorophenyl) -1 - methyl-1H-pyrazol-4 - yl] -3 - methyl - pyridine; 4 - [3 - (3,4 - difluorophenyl) -1 - methyl-1H-pyrazol-4 - yl] -2 - fluoro-pyridine; 3 - (4 - fluorophenyl)-N, N-dimethyl-4 - (4 - pyridyl)-1H-pyrazol-1 - amine; 2 - [2 - (4 - fluorophenyl) ethyl] -4 - [3 - (4 - fluorophenyl) -1 - methyl-1H-pyrazol-4 - yl] pyridine; 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl]-N-[1 - (phenylmethyl) -4 - piperidinyl] -2 - pyridinamine; N'-[4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - pyridinyl]-N, N-dimethyl-1 ,2 diamine; 2,4 - bis [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] pyridine; N-[4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - pyridinyl] -4 - morpholino-ethylamine; 3 - (4 - fluorophenyl) -4 - (2 - fluoro-4 - pyridinyl)-1H-pyrazol-1 - ethanol; 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl]-N-[2 - (1H-imidazol-1 - yl) ethyl] -2 - pyridinamine; 4 - [2 - [3 - (4 - fluorophenyl) -4 - (2 - fluoro-4 - pyridinyl)-1H-pyrazol-1 - yl] ethyl] morpholine; (E) -3 - (4 - fluorophenyl) -4 - [2 - [2 - (4 - fluorophenyl) ethenyl] -4 - pyridinyl]-1H-pyrazol-1 - B Alcohol; 3 - (4 - fluorophenyl) -4 - (2 - fluoro-4 - pyridinyl)-N, N-dimethyl-1H-pyrazol-1 - amine; 3 - (4 - fluorophenyl) -4 - [2 - [2 - (4 - fluorophenyl) ethyl] -4 - pyridinyl]-1H-pyrazol-1 - ethanol; 4 - [1 - [2 - (dimethylamino) ethyl] -3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl]-N, N-dimethyl-2 - pyrazol Piperidine amine; 4 - [1 - [2 - (dimethylamino) ethyl] -3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl]-N-[(4 - fluorophenyl) methyl Yl] -2 - pyridinamine; 3 - (4 - fluorophenyl) -4 - [2 - [2 - (4 - fluorophenyl) ethyl] -4 - pyridinyl]-N, N-dimethyl-1H-pyrazole - 1 - ethylamine; N-[(4 - fluorophenyl) methyl] -4 - [3 (or 5) - (4 - fluorophenyl) -1 - [[2 - (4 - morpholinyl) ethyl]-1H- topiramate -4 - yl] -2 - pyridinamine; 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl]-N-4-piperidyl 2 - pyridyl amine; N, N-diethyl-3 - (4 - fluorophenyl) -4 - (2 - fluoro-4 - pyridinyl)-1H-pyrazol-1 - amine; 4 - [1 - [2 - (diethylamino) ethyl] -3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl]-N-[(4 - fluorophenyl) methyl Yl] -2 - pyridinamine; ² - [[4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - pyridinyl] amino] ethanol; ² - [[4 - [3 - (4 - fluorophenyl) -1 - methyl-1H-pyrazol-4 - yl] -2 - pyridinyl] amino] ethanol; 3 - [[4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - pyridinyl] amino] -1 - propanol; 3 - (4 - fluorophenyl) -4 - [2 - [[(4 - fluorophenyl) methyl] amino] -4 - pyridinyl]-1H-pyrazol-1 - ethanol; 5 - (4 - fluorophenyl) -4 - [2 - [[(4 - fluorophenyl) methyl] amino] -4 - pyridinyl]-1H-pyrazol-1 - ethanol; N, N-diethyl-3 - (4 - fluorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-1 - amine; N-[(4 - fluorophenyl) methyl] -4 - [3 - (4 - fluorophenyl) -1 - [2 - (4 - morpholinyl) ethyl]-1H-pyrazol-4 - Yl] -2 - pyridinamine; N-[5 - (4 - fluorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl] -4 - morpholino-propylamine; N'-[5 - (4 - fluorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl]-N, N-dimethyl-1 ,3 - propylamine; 5 - (4 - fluorophenyl)-N-2-propynyl-4 - (4 - pyridyl)-1H-pyrazol-3 - amine; 3 - (4 - fluorophenyl) -4 - [2 [[(4 - fluorophenyl) methyl] amino] -4 - pyridinyl]-1H-pyrazol-1 - ethanol; 5 - (4 - fluorophenyl) -4 - [2 [[(4 - fluorophenyl) methyl] amino] -4 - pyridinyl]-1H-pyrazol-1 - ethanol; 4 - [3 - [(4 - fluorophenyl)-1H-pyrazol-4 - yl] quinoline; N-[5 - (4 - fluorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl]-acetate; N-[5 - (4 - fluorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl]-amino acid; 4 - [3 - (4 - fluorophenyl) -1 - (2 - propynyl)-1H-pyrazol-4 - yl] pyridine; 4 - [5 - (4 - fluorophenyl) -1 - (2 - propynyl)-1H-pyrazol-4 - yl] pyridine; 4,4 '- (1H-pyrazol-3 ,4 - United yl) bis [pyridine]; 4 - [3 - (3,4 - dichlorophenyl)-1H-pyrazol-4 - yl] pyridine; N-[5 - (4 - chlorophenyl) -4 - (4 - pyridyl)-1H-pyrazol-3 - yl] -4 - piperazine amine; 2 - chloro-4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] pyrimidine; 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 (1H) - pyrimidinone hydrazone; 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl]-N, N-dimethyl-2 - pyrimidinamine; 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl]-N-methyl-2 - pyrimidinamine; 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl]-N-(phenylmethyl) -2 - pyrimidinamine; N-cyclopropyl-4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - pyrimidinamine; 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl]-N-[(4 - methoxyphenyl) methyl-2 - pyrimidinamine; 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - pyrimidinamine; N-[4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - pyrimidinyl]-N-(phenylmethyl) acetamide; Ethyl [4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] -2 - pyrimidinyl] carbamate; 4 - [3 - (3 - methylphenyl)-1H-pyrazol-4 - yl] pyrimidine; 4 - [3 - (4 - chlorophenyl)-1H-pyrazol-4 - yl] pyrimidine; 4 - [3 - (3 - fluorophenyl)-1H-pyrazol-4 - yl] pyrimidine; and 4 - [3 - (4 - fluorophenyl)-1H-pyrazol-4 - yl] pyrimidine. ...
70, compound as claimed in claim 1, be selected from comprise following compounds, they isomer and their pharmacology on acceptable salt:
Figure A9880736900461
Figure A9880736900471
Figure A9880736900481
Figure A9880736900501
Figure A9880736900511
Figure A9880736900531
71, compound as claimed in claim 1 is 4-[5-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazoles-4-yl] acceptable salt or its isomer on pyridine or its pharmacology.
72, compound as claimed in claim 1 is 4-[3-(4-fluorophenyl)-1-(2-propynyl)-1H-pyrazoles-4-yl] acceptable salt or its isomer on pyridine or its pharmacology.
73, compound as claimed in claim 1 is acceptable salt or its isomer on 3-(4-fluorophenyl)-4-(4-pyridyl)-1H-pyrazoles-1-ethanol or its pharmacology.
74, compound as claimed in claim 1 is 4-[3-(4-fluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl]-2-(1-methyl diazanyl) pyridine or its pharmacology on acceptable salt or its isomer.
75, compound as claimed in claim 1 is 1-[5-(4-chloro-phenyl-)-4-(4-pyridyl)-1H-pyrazole-3-yl] acceptable salt or its isomer on piperazine or its pharmacology.
76, compound as claimed in claim 1 is 4-[3-cyclopropyl-5-(4-fluorophenyl)-1H-pyrazoles-4-yl] acceptable salt or its isomer on pyridine or its pharmacology.
77, compound as claimed in claim 1 is 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] acceptable salt or its isomer on pyridine or its pharmacology.
78, compound as claimed in claim 1 is 1-[5-(4-chloro-phenyl-)-4-(4-pyridyl)-1H-pyrazole-3-yl]-4-methylpiperazine or its pharmacology on acceptable salt or its isomer.
79, compound as claimed in claim 1 is 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] acceptable salt or its isomer on pyrimidine or its pharmacology.
80, compound as claimed in claim 1, be 2-fluorine-based-4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] acceptable salt or its isomer on pyridine or its pharmacology.
81, compound as claimed in claim 1 is 4-[3-(3, the 4-difluorophenyl)-1-methyl isophthalic acid H-pyrazoles-4-yl] acceptable salt or its isomer on pyridine or its pharmacology.
82, compound as claimed in claim 1 is 4-[3-(4-bromophenyl)-1H-pyrazoles-4-yl] acceptable salt or its isomer on pyridine or its pharmacology.
83, compound as claimed in claim 1 is 4-[3-(4-chloro-phenyl-)-1H-pyrazoles-4-yl]-2-fluorine pyridine or its pharmacology on acceptable salt or its isomer.
84, compound as claimed in claim 1 is 4-[3-(1,3-benzo dioxolyl-5-yl)-1-methyl isophthalic acid H-pyrazoles-4-yl] acceptable salt or its isomer on pyridine or its pharmacology.
85, compound as claimed in claim 1 is 4-[3-(3-fluorophenyl) 1-methyl isophthalic acid H-pyrazoles-4-yl] acceptable salt or its isomer on pyridine or its pharmacology.
86, compound as claimed in claim 1 is 4-[3-(3-fluorophenyl)-1-methyl-pyrazoles-4-yl] acceptable salt or its isomer on pyridine or its pharmacology.
87, compound as claimed in claim 1 is acceptable salt or its isomer on 5-(4-fluorophenyl)-N-2-proyl-4-(4-pyridine)-1H-pyrazoles-3-amine or its pharmacology.
88, a kind of alternative pyrazoles that specifically is attached on the kinase whose ATP of the p38 juncture.
89, as the compound of claim 88, molecular formula is:
Figure A9880736900561
Wherein
R 1Be that molecular weight is approximately less than the alkyl of 360 atomic mass units, assorted substituted hydrocarbon radical or heterocyclic group; With
R 2Be at described p38 kinase whose ATP juncture and p38 kinases bonded alkyl, assorted substituted hydrocarbon radical or heterocyclic group; With
R 3Be the alkyl with hydrogen bond receptor functionality, assorted substituted hydrocarbon radical or heterocyclic group; With
R 4Be that molecular weight is approximately less than the alkyl of 360 atomic mass units, assorted substituted hydrocarbon radical or heterocyclic group;
Work as R 4Be when containing the phenyl ring of a 2-hydroxyl substituent, and work as R 1When being the hydrogen base, the R that provides 3It or not the 2-pyridyl; Work as R 4When being the hydrogen base, the R that further provides 2Be selected from aryl, heterocyclic radical, unsubstituted cycloalkyl and cycloalkenyl; The R that further provides 4It or not the methyl sulphonyl phenyl; Or
Acceptable salt and isomer thereof on the pharmacology
90, as the compound of claim 89, R wherein 2Be alkyl, assorted substituted hydrocarbon radical or heterocyclic radical group, this group is at p38 kinase whose described ATP juncture and Lys 52, Glu 69, Leu 73, Ile 82, Leu 84, Leu 101And Thr 103The side chain combination, in described cohesive process, described group is arranged in securely by the p38 kinases in the hydrophobic nature cavity that the ATP juncture forms.
91, as the compound of claim 89, R wherein 3Be the alkyl with hydrogen bond receptor functionality, assorted substituted hydrocarbon radical or heterocyclic radical group, the hydrogen of this hydrogen bond receptor functionality and the kinase whose Met of p38 106The combination of N-H major key.
92, as the compound of claim 89, R wherein 1Be that molecular weight is approximately less than the alkyl of 250 atomic mass units, alkyl or the heterocyclic radical group that heterocyclic radical replaces.
93, as the compound of claim 89, R wherein 4Be that molecular weight is approximately less than the alkyl of 250 atomic mass units, assorted substituted hydrocarbon radical or heterocyclic radical group.
94, as the compound of claim 89, wherein
R 1Be that molecular weight is approximately less than the alkyl of 360 atomic mass units, assorted substituted hydrocarbon radical or heterocyclic radical group; With
R 2Be alkyl, assorted substituted hydrocarbon radical or heterocyclic group, wherein said heterocyclic group is at p38 kinase whose described ATP juncture and Lys 52, Glu 69, Leu 73, Ile 82, Leu 84, Leu 101And Thr 103The side chain combination, described in conjunction with actual procedure in, described group is arranged in securely by the p38 kinases in the hydrophobic nature cavity that the ATP juncture forms;
R 3Be the alkyl with hydrogen bond receptor functionality, assorted substituted hydrocarbon radical or heterocyclic radical group, the hydrogen of this hydrogen bond receptor functionality and the kinase whose Met of p38 106The combination of N-H major key;
R 4Be that molecular weight is approximately less than the alkyl of 360 atomic mass units, assorted substituted hydrocarbon radical or heterocyclic radical group.
95, as the compound of claim 94, R wherein 1And R 4Be independently selected from alkyl, assorted substituted hydrocarbon radical and heterocyclic group, and the binding molecule amount is approximately less than 360 atomic mass units.
96, a kind of medicinal compositions comprises a kind of compound for the treatment of significant quantity, and described compound is selected from the compound of claim 1; Or acceptable salt on its pharmacology.
97, as the medicinal compositions of claim 96, wherein said compound is selected from the compound of claim 3; Or acceptable salt on its pharmacology.
98, as the medicinal compositions of claim 96, wherein said compound is selected from the compound of claim 4; Or acceptable salt on its pharmacology.
99, as the medicinal compositions of claim 96, wherein said compound is selected from the compound of claim 5; Or acceptable salt on its pharmacology.
100, as the medicinal compositions of claim 96, wherein said compound is selected from the compound of claim 6; Or acceptable salt on its pharmacology.
101, a kind of medicinal compositions comprises a kind of compound for the treatment of significant quantity, and described compound is selected from the compound of claim 24; Or acceptable salt on its pharmacology.
102, as the medicinal compositions of claim 101, wherein said compound is selected from the compound of claim 25; Or acceptable salt on its pharmacology.
103, a kind of medicinal compositions comprises a kind of compound for the treatment of significant quantity, and described compound is selected from the compound of claim 25; Or acceptable salt on its pharmacology.
104, as the medicinal compositions of claim 103, wherein said compound is selected from the compound of claim 36; Or acceptable salt on its pharmacology.
105, a kind of medicinal compositions comprises a kind of compound for the treatment of significant quantity, and described compound is selected from the compound of claim 44; Or acceptable salt on its pharmacology.
106, as the medicinal compositions of claim 105, wherein said compound is selected from the compound of claim 45; Or acceptable salt on its pharmacology.
107, a kind of medicinal compositions comprises a kind of compound for the treatment of significant quantity, and described compound is selected from the compound of claim 53; Or acceptable salt on its pharmacology.
108, as the medicinal compositions of claim 107, wherein said compound is selected from the compound of claim 54; Or acceptable salt on its pharmacology.
109, a kind of medicinal compositions comprises a kind of compound for the treatment of significant quantity, and described compound is selected from the compound of claim 66; Or acceptable salt on its pharmacology.
110, a kind of medicinal compositions comprises a kind of compound for the treatment of significant quantity, and described compound is selected from the compound of claim 69; Or acceptable salt on its pharmacology.
111, as the medicinal compositions of claim 110, wherein said compound is 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] acceptable salt and isomer thereof on pyridine or its pharmacology.
112, a kind of disease mediated method of TNF for the treatment of, described method comprise the patient who suffers from or suffer from easily this disease with the compounds for treating of the molecular formula I of treatment significant quantity, R wherein 1Be selected from the hydrogen base, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclic radical, the cycloalkyl alkylidene group, the cycloalkenyl alkylidene group, the heterocyclic radical alkylidene group, haloalkyl, halogenated alkenyl, the halo alkynyl, hydroxyalkyl, the hydroxyl alkenyl, the hydroxyl alkynyl, aralkyl, aralkenyl, aromatic yl polysulfide yl, the aryl-heterocyclic base, carboxyl, carboxyalkyl, alkoxyalkyl, the alkenyloxy alkyl, the alkynyloxy group alkyl, aryloxy alkyl, the heterocyclic oxy group alkyl, the alkoxyl group alkoxyl group, mercaptoalkyl, the alkylthio alkylidene group, alkenyl sulfo-alkylidene group, the alkylthio alkylene group, amino, aminoalkyl group, alkylamino, alkenyl amino, alkynyl amino, arylamino, heterocyclic radical amino, the alkyl sulfinyl, the alkenyl sulfinyl, the alkynyl sulfinyl, the aryl sulfinyl, the heterocyclic radical sulfinyl, alkyl sulphonyl, the alkenyl alkylsulfonyl, the alkynyl alkylsulfonyl, aryl sulfonyl, the heterocyclic radical alkylsulfonyl, alkylamino alkylene, the alkyl sulphonyl alkylidene group, acyl group, the acyloxy carbonyl, the alkoxy carbonyl alkylidene group, the aryloxycarbonyl alkylidene group, the heterocyclic oxy group carbonyl alkylen group, the alkoxy carbonyl arylidene, the aryloxycarbonyl arylidene, heterocyclic oxy group carbonyl arylidene, the alkyl-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the heterocyclic radical carbonyl alkylen group, the alkyl-carbonyl arylidene, the aryl carbonyl arylidene, heterocyclic radical carbonyl arylidene, the alkyl carbonyl oxy alkylidene group, the aryl-carbonyl oxygen alkylidene group, heterocyclic radical carbonyl oxygen base alkylidene group, the alkyl carbonyl oxy arylidene, the aryl-carbonyl oxygen arylidene, heterocyclic radical carbonyl oxygen base arylidene; Perhaps
R 1Molecular formula be
Figure A9880736900601
Wherein:
I is 0～9 integer;
R 25Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group; With
R 26Be selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl alkylidene group, aralkyl, alkoxy carbonyl alkylidene group and alkylamino alkyl; With
R 27Be selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclic radical, aralkyl, the cycloalkyl alkylidene group, the cycloalkenyl alkylidene group, the cycloalkyl arylidene, the cycloalkyl ring alkyl, the heterocyclic radical alkylidene group, alkyl arylene, alkyl aralkyl, the aralkyl arylidene, alkyl heterocyclic, the alkyl heterocyclic alkylidene group, the alkyl heterocyclic arylidene, the aralkyl heterocyclic radical, the alkoxyl group alkylidene group, the alkoxyl group arylidene, the alkoxy aromatic alkyl, the alkoxyl group heterocyclic radical, alkoxyl group alkoxyl group arylidene, the aryloxy arylidene, the aralkoxy arylidene, alkoxyl group heterocyclic radical alkylidene group, aryloxy alcoxyl base arylidene, the alkoxy carbonyl alkylidene group, the alkoxy carbonyl heterocyclic radical, alkoxy carbonyl heterocyclic radical carbonyl alkylen group, aminoalkyl group, alkylamino alkylene, the aromatic yl aminocarbonyl alkylidene group, alkoxy aryl aminocarboxyl alkylidene group, the aminocarboxyl alkylidene group, the aromatic yl aminocarbonyl alkylidene group, the alkyl amino-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the alkoxy carbonyl arylidene, the aryloxycarbonyl arylidene, alkyl-aryloxy carbonyl arylidene, the aryl carbonyl arylidene, alkyl-aryloxy carbonyl arylidene, the aryl carbonyl arylidene, alkylaryl carbonyl arylidene, alkoxy carbonyl heterocyclic radical arylidene, alkoxy carbonyl alkoxyl group arylidene, heterocyclic radical carbonylic alkyl arylidene, the alkylthio alkylidene group, cycloalkyl sulfo-alkylidene group, the alkylthio arylidene, aralkyl sulfo-arylidene, heterocyclic radical sulfo-arylidene, aryl alkylthio arylidene, the arlysulfonylamino alkylidene group, the alkyl sulphonyl arylidene, the alkyl amino sulfonyl arylidene; Wherein said alkyl, cycloalkyl, the aryl-heterocyclic base, aralkyl, the heterocyclic radical alkylidene group, the alkyl heterocyclic arylidene, the alkoxyl group arylidene, the aryloxy arylidene, the aromatic yl aminocarbonyl alkylidene group, the aryloxycarbonyl arylidene, the aryl carbonyl arylidene, the alkylthio arylidene, heterocyclic radical sulfo-arylidene, aryl alkylthio arylidene and alkyl sulphonyl arylidene are by one or more alkyl that are independently selected from, halogen, haloalkyl, alkoxyl group, ketone group, amino, the group of nitro and cyano group at random replaces; Perhaps
R 27Be-CHR 28R 29, R wherein 28Be alkoxy carbonyl, R 29Be selected from aralkyl, aralkoxy alkylidene group, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, alkoxy carbonyl alkylidene group, alkylthio alkylidene group and aralkyl sulfo-alkylidene group, wherein said aralkyl and heterocyclic radical are at random replaced by one or more groups that are independently selected from alkyl and nitro; Or
R 26And R 27Connected nitrogen-atoms forms heterocyclic radical together, wherein said heterocyclic radical is at random replaced by one or more groups, and this group is independently selected from alkyl, aryl, heterocyclic radical, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, aryloxy alkylidene group, aryloxy arylidene, alkyl-aryloxy alkylidene group, alkyl-carbonyl, alkoxy carbonyl, aryloxycarbonyl, alkylamino and alkoxycarbonyl amino; Wherein said aryl, heterocyclic radical alkylidene group and aryloxy alkylidene group are at random replaced by one or more groups that are independently selected from halogen, alkyl and alkoxyl group; With
R 2Be selected from the hydrogen base, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, haloalkyl, hydroxyalkyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, alkylamino, alkenyl amino, alkynyl amino, arylamino, heterocyclic radical amino, the heterocyclic radical alkylamino, aryl alkyl amino, aminoalkyl group, aminoaryl, aminoalkyl group amino, the arylamino alkylidene group, alkylamino alkylene, the arylamino arylidene, the alkylamino arylidene, the alkylamino alkylamino, cycloalkyl, cycloalkenyl, alkoxyl group, heterocyclic oxy group, alkylthio, arylthio, the sulfo-heterocyclic radical, carboxyl, carboxyalkyl, the carboxyl cycloalkyl, the carboxyl cycloalkenyl, carboxyalkyl amino, alkoxy carbonyl, the heterocyclic radical carbonyl, alkoxy carbonyl alkyl, the alkoxy carbonyl heterocyclic radical, alkoxy carbonyl heterocyclic radical carbonyl, alkoxyalkyl amino, alkoxyl group carboxyamino alkylamino, with the heterocyclic radical alkylsulfonyl, aryl wherein, heterocyclic radical, the heterocyclic radical alkyl, cycloalkyl and cycloalkenyl are at random replaced by one or more groups, and described group is independently selected from halogen, ketone group, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, aralkyl, the heterocyclic radical alkyl, epoxy alkyl, amino (hydroxyalkyl) carboxyl, alkoxyl group, aryloxy, alkoxy aryl, haloalkyl, alkylamino, alkynyl amino, alkylamino alkynes amino, the heterocyclic radical alkylamino, alkyl-carbonyl, alkoxy carbonyl, alkyl sulphonyl, aryl sulfonyl and aralkyl alkylsulfonyl; Or
R 2Molecular formula be:
Figure A9880736900621
Wherein
J is 0～8 integer; And
M is 0 or 1;
R 30And R 31Be independently selected from hydrogen, alkyl, aryl, heterocyclic radical, aralkyl, heterocyclic radical alkylidene group, aminoalkyl group, alkylamino alkyl, aminocarboxyl alkyl, alkoxyalkyl and alkyl-carbonyl oxyalkyl; With
R 32Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group;
R 33Be selected from hydrogen, alkyl ,-C (O) R 35,-C (O) OR 35,-SO 2R 36,-C (O) NR 37R 38, and SO 2NR 39R 40, R wherein 35, R 36, R 37, R 38, R 39And R 40Be independently selected from hydrocarbon, assorted hydrocarbon and the heterocyclic radical of replacing; And
R 34Be selected from hydrogen, alkyl, aminocarboxyl, alkyl amino-carbonyl and aromatic yl aminocarbonyl; Or
R 2Be CR 41R 42, R wherein 41Be aryl, R 42It is hydroxyl; With
R 3Be selected from pyridyl, pyrimidyl, quinolyl, purine radicals,
R wherein 43Be selected from hydrogen, alkyl, aminoalkyl group, alkoxyalkyl, alkenyloxy alkyl and aryloxy alkyl; With
Wherein said R 3Pyridyl; pyrimidyl; quinolyl; the purine radicals group is at random replaced by one or more groups, and these groups are independently selected from halogen; alkyl; aralkyl; aralkenyl; the aryl-heterocyclic base; carboxyl; carboxyalkyl; alkoxyl group; aryloxy; alkylthio; arylthio; the alkyl sulfinyl; the aryl sulfinyl; alkyl sulphonyl; aryl sulfonyl; aralkoxy; the heterocyclic radical alkoxyl group; amino; alkylamino; alkenyl amino; alkynyl amino; cycloalkyl amino; cycloalkenyl amino; arylamino; heterocyclic radical amino; aminocarboxyl; cyano group; hydroxyl; hydroxyalkyl; alkoxy carbonyl; aryloxycarbonyl; the heterocyclic oxy group carbonyl; alkoxycarbonyl amino; the alkoxy aromatic alkylamino; amino sulfinyl; amino-sulfonyl; the alkylamino alkylamino; hydroxyalkyl amino; aryl alkyl amino; the heterocyclic radical alkylamino; aralkyl heterocyclic radical amino; nitro; alkyl amino-carbonyl; alkyl-carbonyl-amino; halosulfonyl groups; aminoalkyl group; haloalkyl; alkyl-carbonyl; diazanyl; the alkyl diazanyl; the aryl diazanyl; or-NR 44R 45, R wherein 44Be alkyl-carbonyl or amino, R 45Be alkyl or aralkyl; With
R 4Be selected from hydrogen base, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclic radical, wherein R 4At random replaced by one or more groups, this group is independently selected from halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, alkylthio, arylthio, the alkylthio alkylidene group, aryl sulfo-alkylidene group, the alkyl sulfinyl, alkyl sulfinyl alkylidene group, aryl sulfinyl alkylidene group, alkyl sulphonyl, the alkyl sulphonyl alkylidene group, the aryl sulfonyl alkylidene group, alkoxyl group, aryloxy, aralkoxy, aminocarboxyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkoxy carbonyl, aryloxycarbonyl, haloalkyl, amino, cyano group, nitro, alkylamino, arylamino, alkylamino alkylene, the arylamino alkylidene group, aminoalkyl group amino and hydroxyl;
Work as R 4Be when containing the phenyl ring of a 2-hydroxyl substituent and work as R 1When being the hydrogen base, the R that provides 3It or not the 2-pyridyl; Work as R in addition 4When being the hydrogen base, the R that further provides 2Be selected from aryl, heterocyclic radical, the cycloalkyl that is unsubstituted and cycloalkenyl; The R that further provides 4It or not the alkylsulfonyl phenyl; Or acceptable salt or its isomer on the pharmacology.
113, a kind of method for the treatment of the kinase mediated disease of p38, described method comprises the patient who suffers from or suffer from easily this disease with the compounds for treating of the molecular formula I of significant quantity,
Figure A9880736900641
Wherein
R 1Be selected from the hydrogen base, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclic radical, the cycloalkyl alkylidene group, the cycloalkenyl alkylidene group, the heterocyclic radical alkylidene group, haloalkyl, halogenated alkenyl, the halo alkynyl, hydroxyalkyl, the hydroxyl alkenyl, the hydroxyl alkynyl, aralkyl, aralkenyl, aromatic yl polysulfide yl, the aryl-heterocyclic base, carboxyl, carboxyalkyl, alkoxyalkyl, the alkenyloxy alkyl, the alkynyloxy group alkyl, aryloxy alkyl, the heterocyclic oxy group alkyl, the alkoxyl group alkoxyl group, mercaptoalkyl, the alkylthio alkylidene group, alkenyl sulfo-alkylidene group, the alkylthio alkylene group, amino, aminoalkyl group, alkylamino, alkenyl amino, alkynyl amino, arylamino, heterocyclic radical amino, the alkyl sulfinyl, the alkenyl sulfinyl, the alkynyl sulfinyl, the aryl sulfinyl, the heterocyclic radical sulfinyl, alkyl sulphonyl, the alkenyl alkylsulfonyl, the alkynyl alkylsulfonyl, aryl sulfonyl, the heterocyclic radical alkylsulfonyl, alkylamino alkylene, the alkyl sulphonyl alkylidene group, acyl group, the acyloxy carbonyl, the alkoxy carbonyl alkylidene group, the aryloxycarbonyl alkylidene group, the heterocyclic oxy group carbonyl alkylen group, the alkoxy carbonyl arylidene, the aryloxycarbonyl arylidene, heterocyclic oxy group carbonyl arylidene, the alkyl-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the heterocyclic radical carbonyl alkylen group, the alkyl-carbonyl arylidene, the aryl carbonyl arylidene, heterocyclic radical carbonyl arylidene, the alkyl carbonyl oxy alkylidene group, the aryl-carbonyl oxygen alkylidene group, heterocyclic radical carbonyl oxygen base alkylidene group, the alkyl carbonyl oxy arylidene, the aryl-carbonyl oxygen arylidene, heterocyclic radical carbonyl oxygen base arylidene; Perhaps
R 1Molecular formula be Wherein:
I is 0～9 integer;
R 25Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group; With
R 26Be selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl alkylidene group, aralkyl, alkoxy carbonyl alkylidene group and alkylamino alkyl; With
R 27Be selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclic radical, aralkyl, the cycloalkyl alkylidene group, the cycloalkenyl alkylidene group, the cycloalkyl arylidene, the cycloalkyl ring alkyl, the heterocyclic radical alkylidene group, alkyl arylene, alkyl aralkyl, the aralkyl arylidene, alkyl heterocyclic, the alkyl heterocyclic alkylidene group, the alkyl heterocyclic arylidene, the aralkyl heterocyclic radical, the alkoxyl group alkylidene group, the alkoxyl group arylidene, the alkoxy aromatic alkyl, the alkoxyl group heterocyclic radical, alkoxyl group alkoxyl group arylidene, the aryloxy arylidene, the aralkoxy arylidene, alkoxyl group heterocyclic radical alkylidene group, aryloxy alcoxyl base arylidene, the alkoxy carbonyl alkylidene group, the alkoxy carbonyl heterocyclic radical, alkoxy carbonyl heterocyclic radical carbonyl alkylen group, aminoalkyl group, alkylamino alkylene, the aromatic yl aminocarbonyl alkylidene group, alkoxy aryl aminocarboxyl alkylidene group, the aminocarboxyl alkylidene group, the aromatic yl aminocarbonyl alkylidene group, the alkyl amino-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the alkoxy carbonyl arylidene, the aryloxycarbonyl arylidene, alkyl-aryloxy carbonyl arylidene, the aryl carbonyl arylidene, alkyl-aryloxy carbonyl arylidene, the aryl carbonyl arylidene, alkylaryl carbonyl arylidene, alkoxy carbonyl heterocyclic radical arylidene, alkoxy carbonyl alkoxyl group arylidene, heterocyclic radical carbonylic alkyl arylidene, the alkylthio alkylidene group, cycloalkyl sulfo-alkylidene group, the alkylthio arylidene, aralkyl sulfo-arylidene, heterocyclic radical sulfo-arylidene, aryl alkylthio arylidene, the arlysulfonylamino alkylidene group, the alkyl sulphonyl arylidene, the alkyl amino sulfonyl arylidene; Wherein said alkyl, cycloalkyl, the aryl-heterocyclic base, aralkyl, the heterocyclic radical alkylidene group, the alkyl heterocyclic arylidene, the alkoxyl group arylidene, the aryloxy arylidene, the aromatic yl aminocarbonyl alkylidene group, the aryloxycarbonyl arylidene, the aryl carbonyl arylidene, the alkylthio arylidene, heterocyclic radical sulfo-arylidene, aryl alkylthio arylidene and alkyl sulphonyl arylidene are by one or more alkyl that are independently selected from, halogen, haloalkyl, alkoxyl group, ketone group, amino, the group of nitro and cyano group at random replaces; Perhaps
R 27Be-CHR 28R 29, R wherein 28Be alkoxy carbonyl, R 29Be selected from aralkyl, aralkoxy alkylidene group, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, alkoxy carbonyl alkylidene group, alkylthio alkylidene group and aralkyl sulfo-alkylidene group, wherein said aralkyl and heterocyclic radical are at random replaced by one or more groups that are independently selected from alkyl and nitro; Or
R 26And R 27Connected nitrogen-atoms forms heterocyclic radical together, wherein said heterocyclic radical is at random replaced by one or more groups, and this group is independently selected from alkyl, aryl, heterocyclic radical, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, aryloxy alkylidene group, epoxy group(ing) arylidene, alkyl-aryloxy alkylidene group, alkyl-carbonyl, alkoxy carbonyl, aryloxycarbonyl, alkylamino and alkoxycarbonyl amino; Wherein said aryl, heterocyclic radical alkylidene group and aryloxy alkylidene group are at random replaced by one or more groups that are independently selected from halogen, alkyl and alkoxyl group; With
R 2Be selected from the hydrogen base, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, haloalkyl, hydroxyalkyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, alkylamino, alkenyl amino, alkynyl amino, arylamino, heterocyclic radical amino, the heterocyclic radical alkylamino, aryl alkyl amino, aminoalkyl group, aminoaryl, aminoalkyl group amino, the arylamino alkylidene group, alkylamino alkylene, the arylamino arylidene, the alkylamino arylidene, the alkylamino alkylamino, cycloalkyl, cycloalkenyl, alkoxyl group, heterocyclic oxy group, alkylthio, arylthio, the sulfo-heterocyclic radical, carboxyl, carboxyalkyl, the carboxyl cycloalkyl, the carboxyl cycloalkenyl, carboxyalkyl amino, alkoxy carbonyl, the heterocyclic radical carbonyl, alkoxy carbonyl alkyl, alkoxyl group base heterocyclic radical, alkoxy carbonyl heterocyclic radical carbonyl, alkoxyalkyl amino, alkoxyl group carboxyamino alkylamino, with the heterocyclic radical alkylsulfonyl, aryl wherein, heterocyclic radical, the heterocyclic radical alkyl, cycloalkyl and cycloalkenyl are at random replaced by one or more groups, and described group is independently selected from halogen, ketone group, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, aralkyl, the heterocyclic radical alkyl, epoxy alkyl, amino (hydroxyalkyl) carboxyl, alkoxyl group, aryloxy, alkoxy aryl, haloalkyl, alkylamino, alkynyl amino, the alkylamino alkylamino, the heterocyclic radical alkylamino, alkyl-carbonyl, alkoxy carbonyl, alkyl sulphonyl, aryl sulfonyl, with the aralkyl alkylsulfonyl; Or
R 2Molecular formula be:
Figure A9880736900661
Wherein
J is 0～8 integer; And
M is 0 or 1;
R 30And R 31Be independently selected from hydrogen, alkyl, aryl, heterocyclic radical, aralkyl, heterocyclic radical alkylidene group, aminoalkyl group, alkylamino alkyl, aminocarboxyl alkyl, alkoxyalkyl and alkyl-carbonyl oxygen base alkyl; With
R 32Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group;
R 33Be selected from hydrogen, alkyl ,-C (O) R 35,-C (O) OR 35,-SO 2R 36,-C (O) NR 37R 38, and-SO 2NR 39R 40, R wherein 35, R 36, R 37, R 38, R 39And R 40Be independently selected from hydrocarbon, assorted hydrocarbon and the heterocyclic radical of replacing; And
R 34Be selected from hydrogen, alkyl, aminocarboxyl, alkyl amino-carbonyl and aromatic yl aminocarbonyl; Or
R 2Be-CR 41R 42, R wherein 41Be aryl, R 42It is hydroxyl; With
R 3Be selected from pyridyl, pyrimidyl, quinolyl, purine radicals,
Figure A9880736900671
R wherein 43Be selected from hydrogen, alkyl, aminoalkyl group, alkoxyalkyl, alkenyloxy alkyl and aryloxy alkyl; With
Wherein said R 3Pyridyl; pyrimidyl; quinolyl; the purine radicals group is at random replaced by one or more groups, and these groups are independently selected from halogen; alkyl; aralkyl; aralkenyl; the aryl-heterocyclic base; carboxyl; carboxyalkyl; alkoxyl group; aryloxy; alkylthio; arylthio; the alkyl sulfinyl; the aryl sulfinyl; alkyl sulphonyl; aryl sulfonyl; alkoxy aryl; the heterocyclic radical alkoxyl group; amino; alkylamino; alkenyl amino; alkynyl amino; cycloalkyl amino; cycloalkenyl amino; arylamino; heterocyclic radical amino; aminocarboxyl; cyano group; hydroxyl; hydroxyalkyl; alkoxy carbonyl; aryloxycarbonyl; the heterocyclic oxy group carbonyl; alkoxycarbonyl amino; the alkoxy aromatic alkylamino; amino sulfinyl; amino-sulfonyl; the alkylamino alkylamino; hydroxyalkyl amino; aryl alkyl amino; the heterocyclic radical alkylamino; aralkyl heterocyclic radical amino; nitro; alkyl amino-carbonyl; alkyl-carbonyl-amino; halosulfonyl groups; aminoalkyl group; haloalkyl; alkyl-carbonyl; diazanyl; the alkyl diazanyl; the aryl diazanyl; or-NR 44R 45, R wherein 44Be alkyl-carbonyl or amino, R 45Be alkyl or aralkyl; With
R 4Be selected from hydrogen base, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclic radical, wherein R 4At random replaced by one or more groups, this group is independently selected from halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, alkylthio, arylthio, the alkylthio alkylidene group, aryl sulfo-alkylidene group, the alkyl sulfinyl, alkyl sulfinyl alkylidene group, aryl sulfinyl alkylidene group, alkyl sulphonyl, the alkyl sulphonyl alkylidene group, the aryl sulfonyl alkylidene group, alkoxyl group, aryloxy, aralkoxy, aminocarboxyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkoxy carbonyl, aryloxycarbonyl, haloalkyl, amino, cyano group, nitro, alkylamino, arylamino, alkylamino alkylene, the arylamino alkylidene group, aminoalkyl group amino, and hydroxyl;
Work as R 4Be when containing the phenyl ring of a 2-hydroxyl substituent and work as R 1When being the hydrogen base, the R that provides 3It or not the 2-pyridyl; Work as R in addition 4When being the hydrogen base, the R that further provides 2Be selected from aryl, heterocyclic radical, the cycloalkyl that is unsubstituted and cycloalkenyl; The R that further provides 4It or not the alkylsulfonyl phenyl; Or acceptable salt or its isomer on the pharmacology.
114, a kind of method for the treatment of inflammation, described method comprises the patient who suffers from inflammation with the compounds for treating of the molecular formula I of significant quantity,
Figure A9880736900681
Wherein
R 1Be selected from the hydrogen base, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclic radical, the cycloalkyl alkylidene group, the cycloalkenyl alkylidene group, the heterocyclic radical alkylidene group, haloalkyl, halogenated alkenyl, the halo alkynyl, hydroxyalkyl, the hydroxyl alkenyl, the hydroxyl alkynyl, aralkyl, aralkenyl, aromatic yl polysulfide yl, the aryl-heterocyclic base, carboxyl, carboxyalkyl, alkoxyalkyl, the alkenyloxy alkyl, the alkynyloxy group alkyl, aryloxy alkyl, the heterocyclic oxy group alkyl, the alkoxyl group alkoxyl group, mercaptoalkyl, the alkylthio alkylidene group, alkenyl sulfo-alkylidene group, the alkylthio alkylene group, amino, aminoalkyl group, alkylamino, alkenyl amino, alkynyl amino, arylamino, heterocyclic radical amino, the alkyl sulfinyl, the alkenyl sulfinyl, the alkynyl sulfinyl, the aryl sulfinyl, the heterocyclic radical sulfinyl, alkyl sulphonyl, the alkenyl alkylsulfonyl, the alkynyl alkylsulfonyl, aryl sulfonyl, the heterocyclic radical alkylsulfonyl, alkylamino alkylene, the alkyl sulphonyl alkylidene group, acyl group, the acyloxy carbonyl, the alkoxy carbonyl alkylidene group, the aryloxycarbonyl alkylidene group, the heterocyclic oxy group carbonyl alkylen group, the alkoxy carbonyl arylidene, the aryloxycarbonyl arylidene, heterocyclic oxy group carbonyl arylidene, the alkyl-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the heterocyclic radical carbonyl alkylen group, the alkyl-carbonyl arylidene, the aryl carbonyl arylidene, heterocyclic radical carbonyl arylidene, the alkyl carbonyl oxy alkylidene group, the aryl-carbonyl oxygen alkylidene group, heterocyclic radical carbonyl oxygen base alkylidene group, the alkyl carbonyl oxy arylidene, the aryl-carbonyl oxygen arylidene, heterocyclic radical carbonyl oxygen base arylidene; Perhaps
R 1Molecular formula be
Figure A9880736900691
Wherein:
I is 0～9 integer;
R 25Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group; With
R 26Be selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl alkylidene group, aralkyl, alkoxy carbonyl alkylidene group and alkylamino alkyl; With
R 27Be selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclic radical, aralkyl, the cycloalkyl alkylidene group, the cycloalkenyl alkylidene group, the cycloalkyl arylidene, the cycloalkyl ring alkyl, the heterocyclic radical alkylidene group, alkyl arylene, alkyl aralkyl, the aralkyl arylidene, alkyl heterocyclic, the alkyl heterocyclic alkylidene group, the alkyl heterocyclic arylidene, the aralkyl heterocyclic radical, the alkoxyl group alkylidene group, the alkoxyl group arylidene, the alkoxy aromatic alkyl, the alkoxyl group heterocyclic radical, alkoxyl group alkoxyl group arylidene, the aryloxy arylidene, the aralkoxy arylidene, alkoxyl group heterocyclic radical alkylidene group, aryloxy alcoxyl base arylidene, the alkoxy carbonyl alkylidene group, the alkoxy carbonyl heterocyclic radical, alkoxy carbonyl heterocyclic radical carbonyl alkylen group, aminoalkyl group, alkylamino alkylene, the aromatic yl aminocarbonyl alkylidene group, alkoxy aryl aminocarboxyl alkylidene group, the aminocarboxyl alkylidene group, the aromatic yl aminocarbonyl alkylidene group, the alkyl amino-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the alkoxy carbonyl arylidene, the aryloxycarbonyl arylidene, alkyl-aryloxy carbonyl arylidene, the aryl carbonyl arylidene, alkyl-aryloxy carbonyl arylidene, the aryl carbonyl arylidene, alkylaryl carbonyl arylidene, alkoxy carbonyl heterocyclic radical arylidene, alkoxy carbonyl alkoxyl group arylidene, heterocyclic radical carbonylic alkyl arylidene, the alkylthio alkylidene group, cycloalkyl sulfo-alkylidene group, the alkylthio arylidene, aralkyl sulfo-arylidene, heterocyclic radical sulfo-arylidene, aryl alkylthio arylidene, the arlysulfonylamino alkylidene group, the alkyl sulphonyl arylidene, the alkyl amino sulfonyl arylidene; Wherein said alkyl, cycloalkyl, the aryl-heterocyclic base, aralkyl, the heterocyclic radical alkylidene group, the alkyl heterocyclic arylidene, the alkoxyl group arylidene, the aryloxy arylidene, the aromatic yl aminocarbonyl alkylidene group, the aryloxycarbonyl arylidene, the aryl carbonyl arylidene, the alkylthio arylidene, heterocyclic radical sulfo-arylidene, aryl alkylthio arylidene and alkyl sulphonyl arylidene are by one or more alkyl that are independently selected from, halogen, haloalkyl, alkoxyl group, ketone group, amino, the group of nitro and cyano group at random replaces; Perhaps
R 27Be-CHR 28R 29, R wherein 28Be alkoxy carbonyl, R 29Be selected from aralkyl, aralkoxy alkylidene group, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, alkoxy carbonyl alkylidene group, alkylthio alkylidene group and aralkyl sulfo-alkylidene group, wherein said aralkyl and heterocyclic radical are at random replaced by one or more groups that are independently selected from alkyl and nitro; Or
R 26And R 27Connected nitrogen-atoms forms heterocyclic radical together, wherein said heterocyclic radical is at random replaced by one or more groups, and this group is independently selected from alkyl, aryl, heterocyclic radical, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, aryloxy alkylidene group, aryloxy arylidene, alkyl-aryloxy alkylidene group, alkyl-carbonyl, alkoxy carbonyl, aryloxycarbonyl, alkylamino and alkoxycarbonyl amino; Wherein said aryl, heterocyclic radical alkylidene group and aryloxy alkylidene group are at random replaced by one or more groups that are independently selected from halogen, alkyl and alkoxyl group; With
R 2Be selected from the hydrogen base, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, haloalkyl, hydroxyalkyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, alkylamino, alkenyl amino, alkynyl amino, arylamino, heterocyclic radical amino, the heterocyclic radical alkylamino, aryl alkyl amino, aminoalkyl group, aminoaryl, aminoalkyl group amino, the arylamino alkylidene group, alkylamino alkylene, the arylamino arylidene, the alkylamino arylidene, the alkylamino alkylamino, cycloalkyl, cycloalkenyl, alkoxyl group, heterocyclic oxy group, alkylthio, arylthio, the sulfo-heterocyclic radical, carboxyl, carboxyalkyl, the carboxyl cycloalkyl, the carboxyl cycloalkenyl, carboxyalkyl amino, alkoxy carbonyl, the heterocyclic radical carbonyl, alkoxy carbonyl alkyl, the alkoxy carbonyl heterocyclic radical, alkoxy carbonyl heterocyclic radical carbonyl, alkoxyalkyl amino, alkoxyl group carboxyamino alkylamino, with the heterocyclic radical alkylsulfonyl, aryl wherein, heterocyclic radical, the heterocyclic radical alkyl, cycloalkyl and cycloalkenyl are at random replaced by one or more groups, and described group is independently selected from halogen, ketone group, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, aralkyl, the heterocyclic radical alkyl, epoxy alkyl, amino (hydroxyalkyl) carboxyl, alkoxyl group, aryloxy, alkoxy aryl, haloalkyl, alkylamino, alkynyl amino, the alkylamino alkylamino, the heterocyclic radical alkylamino, alkyl-carbonyl, alkoxy carbonyl, alkyl sulphonyl, aryl sulfonyl, with the aralkyl alkylsulfonyl; Or
R 2Molecular formula be: Wherein
J is 0～8 integer; And
M is 0 or 1;
R 30And R 31Be independently selected from hydrogen, alkyl, aryl, heterocyclic radical, aralkyl, heterocyclic radical alkylidene group, aminoalkyl group, alkylamino alkyl, aminocarboxyl alkyl, alkoxyalkyl and alkyl-carbonyl oxygen base alkyl; With
R 32Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group;
R 33Be selected from hydrogen, alkyl ,-C (O) R 35,-C (O) OR 35,-SO 2R 36,-C (O) NR 37R 38, and-SO 2NR 39R 40, R wherein 35, R 36, R 37, R 38, R 39And R 40Be independently selected from hydrocarbon, assorted hydrocarbon and the heterocyclic radical of replacing; And
R 34Be selected from hydrogen, alkyl, aminocarboxyl, alkyl amino-carbonyl and aromatic yl aminocarbonyl; Or
R 2Be-CR 41R 42, R wherein 41Be aryl, R 42It is hydroxyl; With
R 3Be selected from pyridyl, pyrimidyl, quinolyl, purine radicals,
Figure A9880736900712
R wherein 43Be selected from hydrogen, alkyl, aminoalkyl group, alkoxyalkyl, alkenyloxy alkyl and aryloxy alkyl; With
Wherein said R 3Pyridyl; pyrimidyl; quinolyl; the purine radicals group is at random replaced by one or more groups, and these groups are independently selected from halogen; alkyl; aralkyl; aralkenyl; the aryl-heterocyclic base; carboxyl; carboxyalkyl; alkoxyl group; aryloxy; alkylthio; arylthio; the alkyl sulfinyl; the aryl sulfinyl; alkyl sulphonyl; aryl sulfonyl; alkoxy aryl; the heterocyclic radical alkoxyl group; amino; alkylamino; alkenyl amino; alkynyl amino; cycloalkyl amino; cycloalkenyl amino; arylamino; heterocyclic radical amino; aminocarboxyl; cyano group; hydroxyl; hydroxyalkyl; alkoxy carbonyl; aryloxycarbonyl; the heterocyclic oxy group carbonyl; alkoxycarbonyl amino; the alkoxy aromatic alkylamino; amino sulfinyl; amino-sulfonyl; the alkylamino alkylamino; hydroxyalkyl amino; aryl alkyl amino; the heterocyclic radical alkylamino; aralkyl heterocyclic radical amino; nitro; alkyl amino-carbonyl; alkyl-carbonyl-amino; halosulfonyl groups; aminoalkyl group; haloalkyl; alkyl-carbonyl; diazanyl; the alkyl diazanyl; the aryl diazanyl; or-NR 44R 45, R wherein 44Be alkyl-carbonyl or amino, R 45Be alkyl or aralkyl; With
R 4Be selected from hydrogen base, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclic radical, wherein R 4At random replaced by one or more groups, this group is independently selected from halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, alkylthio, arylthio, the alkylthio alkylidene group, aryl sulfo-alkylidene group, the alkyl sulfinyl, alkyl sulfinyl alkylidene group, aryl sulfinyl alkylidene group, alkyl sulphonyl, the alkyl sulphonyl alkylidene group, the aryl sulfonyl alkylidene group, alkoxyl group, aryloxy, aralkoxy, aminocarboxyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkoxy carbonyl, aryloxycarbonyl, haloalkyl, amino, cyano group, nitro, alkylamino, arylamino, alkylamino alkylene, the arylamino alkylidene group, aminoalkyl group amino, and hydroxyl;
Work as R 4Be when containing the phenyl ring of a 2-hydroxyl substituent and work as R 1When being the hydrogen base, the R that provides 3It or not the 2-pyridyl; Work as R in addition 4When being the hydrogen base, the R that further provides 2Be selected from aryl, heterocyclic radical, the cycloalkyl that is unsubstituted and cycloalkenyl; The R that further provides 4It or not the alkylsulfonyl phenyl; Or acceptable salt or its isomer on the pharmacology.
115, a kind of method of treatment of arthritis, described method comprise with the compounds for treating of the molecular formula I of significant quantity suffering from or suffer from easily arthritic patient, Wherein
R 1Be selected from the hydrogen base, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclic radical, the cycloalkyl alkylidene group, the cycloalkenyl alkylidene group, the heterocyclic radical alkylidene group, haloalkyl, halogenated alkenyl, the halo alkynyl, hydroxyalkyl, the hydroxyl alkenyl, the hydroxyl alkynyl, aralkyl, aralkenyl, aromatic yl polysulfide yl, the aryl-heterocyclic base, carboxyl, carboxyalkyl, alkoxyalkyl, the alkenyloxy alkyl, the alkynyloxy group alkyl, aryloxy alkyl, the heterocyclic oxy group alkyl, the alkoxyl group alkoxyl group, mercaptoalkyl, the alkylthio alkylidene group, alkenyl sulfo-alkylidene group, the alkylthio alkylene group, amino, aminoalkyl group, alkylamino, alkenyl amino, alkynyl amino, arylamino, heterocyclic radical amino, the alkyl sulfinyl, the alkenyl sulfinyl, the alkynyl sulfinyl, the aryl sulfinyl, the heterocyclic radical sulfinyl, alkyl sulphonyl, the alkenyl alkylsulfonyl, the alkynyl alkylsulfonyl, aryl sulfonyl, the heterocyclic radical alkylsulfonyl, alkylamino alkylene, the alkyl sulphonyl alkylidene group, acyl group, the acyloxy carbonyl, the alkoxy carbonyl alkylidene group, the aryloxycarbonyl alkylidene group, the heterocyclic oxy group carbonyl alkylen group, the alkoxy carbonyl arylidene, the aryloxycarbonyl arylidene, heterocyclic oxy group carbonyl arylidene, the alkyl-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the heterocyclic radical carbonyl alkylen group, the alkyl-carbonyl arylidene, the aryl carbonyl arylidene, heterocyclic radical carbonyl arylidene, the alkyl carbonyl oxy alkylidene group, the aryl-carbonyl oxygen alkylidene group, heterocyclic radical carbonyl oxygen base alkylidene group, the alkyl carbonyl oxy arylidene, the aryl-carbonyl oxygen arylidene, heterocyclic radical carbonyl oxygen base arylidene; Perhaps
R 1Molecular formula be Wherein:
I is 0～9 integer;
R 25Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group; With
R 26Be selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl alkylidene group, aralkyl, alkoxy carbonyl alkylidene group and alkylamino alkyl; With
R 27Be selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclic radical, aralkyl, the cycloalkyl alkylidene group, the cycloalkenyl alkylidene group, the cycloalkyl arylidene, the cycloalkyl ring alkyl, the heterocyclic radical alkylidene group, alkyl arylene, alkyl aralkyl, the aralkyl arylidene, alkyl heterocyclic, the alkyl heterocyclic alkylidene group, the alkyl heterocyclic arylidene, the aralkyl heterocyclic radical, the alkoxyl group alkylidene group, the alkoxyl group arylidene, the alkoxy aromatic alkyl, the alkoxyl group heterocyclic radical, alkoxyl group alkoxyl group arylidene, the aryloxy arylidene, the aralkoxy arylidene, alkoxyl group heterocyclic radical alkylidene group, aryloxy alcoxyl base arylidene, the alkoxy carbonyl alkylidene group, the alkoxy carbonyl heterocyclic radical, alkoxy carbonyl heterocyclic radical carbonyl alkylen group, aminoalkyl group, alkylamino alkylene, the aromatic yl aminocarbonyl alkylidene group, alkoxy aryl aminocarboxyl alkylidene group, the aminocarboxyl alkylidene group, the aromatic yl aminocarbonyl alkylidene group, the alkyl amino-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the alkoxy carbonyl arylidene, the aryloxycarbonyl arylidene, alkyl-aryloxy carbonyl arylidene, the aryl carbonyl arylidene, alkyl-aryloxy carbonyl arylidene, the aryl carbonyl arylidene, alkylaryl carbonyl arylidene, alkoxy carbonyl heterocyclic radical arylidene, alkoxy carbonyl alkoxyl group arylidene, heterocyclic radical carbonylic alkyl arylidene, the alkylthio alkylidene group, cycloalkyl sulfo-alkylidene group, the alkylthio arylidene, aralkyl sulfo-arylidene, heterocyclic radical sulfo-arylidene, aryl alkylthio arylidene, the arlysulfonylamino alkylidene group, the alkyl sulphonyl arylidene, the alkyl amino sulfonyl arylidene; Wherein said alkyl, cycloalkyl, the aryl-heterocyclic base, aralkyl, the heterocyclic radical alkylidene group, the alkyl heterocyclic arylidene, the alkoxyl group arylidene, the aryloxy arylidene, the aromatic yl aminocarbonyl alkylidene group, the aryloxycarbonyl arylidene, the aryl carbonyl arylidene, the alkylthio arylidene, heterocyclic radical sulfo-arylidene, aryl alkylthio arylidene and alkyl sulphonyl arylidene are by one or more alkyl that are independently selected from, halogen, haloalkyl, alkoxyl group, ketone group, amino, the group of nitro and cyano group at random replaces; Perhaps
R 27Be-CHR 28R 29, R wherein 28Be alkoxy carbonyl, R 29Be selected from aralkyl, aralkoxy alkylidene group, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, alkoxy carbonyl alkylidene group, alkylthio alkylidene group and aralkyl sulfo-alkylidene group, wherein said aralkyl and heterocyclic radical are at random replaced by one or more groups that are independently selected from alkyl and nitro; Or
R 26And R 27Connected nitrogen-atoms forms heterocyclic radical together, wherein said heterocyclic radical is at random replaced by one or more groups, and this group is independently selected from alkyl, aryl, heterocyclic radical, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, aryloxy alkylidene group, aryloxy arylidene, alkyl-aryloxy alkylidene group, alkyl-carbonyl, alkoxy carbonyl, aryloxycarbonyl, alkylamino and alkoxycarbonyl amino; Wherein said aryl, heterocyclic radical alkylidene group and aryloxy alkylidene group are at random replaced by one or more groups that are independently selected from halogen, alkyl and alkoxyl group; With
R 2Be selected from the hydrogen base, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, haloalkyl, hydroxyalkyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, alkylamino, alkenyl amino, alkynyl amino, arylamino, heterocyclic radical amino, the heterocyclic radical alkylamino, aryl alkyl amino, aminoalkyl group, aminoaryl, aminoalkyl group amino, the arylamino alkylidene group, alkylamino alkylene, the arylamino arylidene, the alkylamino arylidene, the alkylamino alkylamino, cycloalkyl, cycloalkenyl, alkoxyl group, heterocyclic oxy group, alkylthio, arylthio, the sulfo-heterocyclic radical, carboxyl, carboxyalkyl, the carboxyl cycloalkyl, the carboxyl cycloalkenyl, carboxyalkyl amino, alkoxy carbonyl, the heterocyclic radical carbonyl, alkoxy carbonyl alkyl, the alkoxy carbonyl heterocyclic radical, alkoxy carbonyl heterocyclic radical carbonyl, alkoxyalkyl amino, alkoxyl group carboxyamino alkylamino, with the heterocyclic radical alkylsulfonyl, aryl wherein, heterocyclic radical, the heterocyclic radical alkyl, cycloalkyl and cycloalkenyl are at random replaced by one or more groups, and described group is independently selected from halogen, ketone group, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, aralkyl, the heterocyclic radical alkyl, epoxy alkyl, amino (hydroxyalkyl) carboxyl, alkoxyl group, aryloxy, alkoxy aryl, haloalkyl, alkylamino, alkynyl amino, the alkylamino alkylamino, the heterocyclic radical alkylamino, alkyl-carbonyl, alkoxy carbonyl, alkyl sulphonyl, aryl sulfonyl, with the aralkyl alkylsulfonyl; Or
R 2Molecular formula be:
Figure A9880736900751
Wherein
J is 0～8 integer; And
M is 0 or 1;
R 30And R 31Be independently selected from hydrogen, alkyl, aryl, heterocyclic radical, aralkyl, heterocyclic radical alkylidene group, aminoalkyl group, alkylamino alkyl, aminocarboxyl alkyl, alkoxyalkyl and alkyl-carbonyl oxygen base alkyl; With
R 32Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group;
R 33Be selected from hydrogen, alkyl ,-C (O) R 35,-C (O) OR 35,-SO 2R 36,-C (O) NR 37R 38, and-SO 2NR 39R 40, R wherein 35, R 36, R 37, R 38, R 39And R 40Be independently selected from hydrocarbon, assorted hydrocarbon and the heterocyclic radical of replacing; And
R 34Be selected from hydrogen, alkyl, aminocarboxyl, alkyl amino-carbonyl and aromatic yl aminocarbonyl; Or
R 2Be-CR 41R 42, R wherein 41Be aryl, R 42It is hydroxyl; With
R 3Be selected from pyridyl, pyrimidyl, quinolyl, purine radicals,
Figure A9880736900761
R wherein 43Be selected from hydrogen, alkyl, aminoalkyl group, alkoxyalkyl, alkenyloxy alkyl and aryloxy alkyl; With
Wherein said R 3Pyridyl; pyrimidyl; quinolyl; the purine radicals group is at random replaced by one or more groups, and these groups are independently selected from halogen; alkyl; aralkyl; aralkenyl; the aryl-heterocyclic base; carboxyl; carboxyalkyl; alkoxyl group; aryloxy; alkylthio; arylthio; the alkyl sulfinyl; the aryl sulfinyl; alkyl sulphonyl; aryl sulfonyl; alkoxy aryl; the heterocyclic radical alkoxyl group; amino; alkylamino; alkenyl amino; alkynyl amino; cycloalkyl amino; cycloalkenyl amino; arylamino; heterocyclic radical amino; aminocarboxyl; cyano group; hydroxyl; hydroxyalkyl; alkoxy carbonyl; aryloxycarbonyl; the heterocyclic oxy group carbonyl; alkoxycarbonyl amino; the alkoxy aromatic alkylamino; amino sulfinyl; amino-sulfonyl; the alkylamino alkylamino; hydroxyalkyl amino; aryl alkyl amino; the heterocyclic radical alkylamino; aralkyl heterocyclic radical amino; nitro; alkyl amino-carbonyl; alkyl-carbonyl-amino; halosulfonyl groups; aminoalkyl group; haloalkyl; alkyl-carbonyl; diazanyl; the alkyl diazanyl; the aryl diazanyl; or-NR 44R 45, R wherein 44Be alkyl-carbonyl or amino, R 45Be alkyl or aralkyl; With
R 4Be selected from hydrogen base, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclic radical, wherein R 4At random replaced by one or more groups, this group is independently selected from halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, alkylthio, arylthio, the alkylthio alkylidene group, aryl sulfo-alkylidene group, the alkyl sulfinyl, alkyl sulfinyl alkylidene group, aryl sulfinyl alkylidene group, alkyl sulphonyl, the alkyl sulphonyl alkylidene group, the aryl sulfonyl alkylidene group, alkoxyl group, aryloxy, aralkoxy, aminocarboxyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkoxy carbonyl, aryloxycarbonyl, haloalkyl, amino, cyano group, nitro, alkylamino, arylamino, alkylamino alkylene, the arylamino alkylidene group, aminoalkyl group amino, and hydroxyl;
Work as R 4Be when containing the phenyl ring of a 2-hydroxyl substituent and work as R 1When being the hydrogen base, the R that provides 3It or not the 2-pyridyl; Work as R in addition 4When being the hydrogen base, the R that further provides 2Be selected from aryl, heterocyclic radical, the cycloalkyl that is unsubstituted and cycloalkenyl; The R that further provides 4It or not the alkylsulfonyl phenyl; Or acceptable salt or its isomer on the pharmacology.
116, a kind of method for the treatment of the kinase mediated disease of p38, described method comprises the patient who suffers from or suffer from easily this disease with the compounds for treating of the molecular formula I of significant quantity,
Figure A9880736900771
Wherein Z represents a carbon atom or a nitrogen-atoms; And R 1Be selected from hydrogen base, low alkyl group.Rudimentary hydroxyalkyl and low-grade alkynyl; And R 2Be selected from hydrogen base and low alkyl group; And R 4Be selected from phenyl and benzo dioxolyl; Wherein benzene is replaced arbitrarily by one or more halogen groups; And R 5Be selected from hydrogen base halogen and alkyl diazanyl; Or acceptable salt or its isomer on the pharmacology.
117, as the method for claim 112, disease mediated bone resorption, graft versus host reaction, atherosclerosis, sacroiliitis, osteoarthropathy, rheumatoid arthritis, gout, psoriatic, local inflammation morbid state, adult respiratory distress syndrome, asthma, chronic pneumonia, heart reperfusion injury, kidney reperfusion injury, thrombus, glomerulonephritis, Crohn disease, ulcerative colitis, enteritis and the cachectic disease of being selected from of TNF wherein.
118, as the method for claim 112, wherein TNF is disease mediated is inflammation.
119, as the method for claim 112, wherein TNF is disease mediated is sacroiliitis.
120, as the method for claim 112, wherein TNF is disease mediated is asthma.
121, as the method for claim 112, wherein compound is 4-[3-(4-fluorophenyl)-1H-pyrazoles-4-yl] acceptable salt or its isomer on pyridine or its pharmacology.
122, as the method for claim 112, wherein compound is 1-[5-(4-chloro-phenyl-)-4-(4-pyridyl)-1H-pyrazole-3-yl]-4-methylpiperazine or its pharmacology on acceptable salt or its isomer.
123, as the method for claim 113, wherein disease is that the p38 alpha kinase is disease mediated.
124, as the method for claim 113, wherein the kinase mediated disease of p38 is selected from bone resorption, graft versus host reaction, atherosclerosis, sacroiliitis, osteoarthropathy, rheumatoid arthritis, gout, psoriatic, local inflammation morbid state, adult respiratory distress syndrome, asthma, chronic pneumonia, heart reperfusion injury, kidney reperfusion injury, thrombus, glomerulonephritis, Crohn disease, ulcerative colitis, enteritis and emaciation disease.
125, as the method for claim 113, wherein the kinase mediated disease of p38 is an inflammation.
126, as the method for claim 113, the kinase mediated disease sacroiliitis of p38 wherein.
127, as the method for claim 113, wherein the kinase mediated disease of p38 is an asthma.
128, as the method for claim 116, wherein disease is that the p38 alpha kinase is disease mediated.
129, as the method for claim 116, wherein the kinase mediated disease of p38 is selected from bone resorption, graft versus host reaction, atherosclerosis, sacroiliitis, osteoarthropathy, rheumatoid arthritis, gout, psoriatic, local inflammation morbid state, adult respiratory distress syndrome, asthma, chronic pneumonia, heart reperfusion injury, kidney reperfusion injury, thrombus, glomerulonephritis, Crohn disease, ulcerative colitis, enteritis and cachectic disease.
130, as the method for claim 116, wherein the kinase mediated disease of p38 is an inflammation.
131, as the method for claim 116, wherein the kinase mediated disease of p38 is a sacroiliitis.
132, as the method for claim 116, wherein the kinase mediated disease of p38 is an asthma.
133, a kind of method for preparing the pyrazoles of molecular formula I, Wherein
R 1Be selected from the hydrogen base, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclic radical, the cycloalkyl alkylidene group, the cycloalkenyl alkylidene group, the heterocyclic radical alkylidene group, haloalkyl, halogenated alkenyl, the halo alkynyl, hydroxyalkyl, the hydroxyl alkenyl, the hydroxyl alkynyl, aralkyl, aralkenyl, aromatic yl polysulfide yl, the aryl-heterocyclic base, carboxyl, carboxyalkyl, alkoxyalkyl, the alkenyloxy alkyl, the alkynyloxy group alkyl, aryloxy alkyl, the heterocyclic oxy group alkyl, the alkoxyl group alkoxyl group, mercaptoalkyl, the alkylthio alkylidene group, alkenyl sulfo-alkylidene group, the alkylthio alkylene group, amino, aminoalkyl group, alkylamino, alkenyl amino, alkynyl amino, arylamino, heterocyclic radical amino, the alkyl sulfinyl, the alkenyl sulfinyl, the alkynyl sulfinyl, the aryl sulfinyl, the heterocyclic radical sulfinyl, alkyl sulphonyl, the alkenyl alkylsulfonyl, the alkynyl alkylsulfonyl, aryl sulfonyl, the heterocyclic radical alkylsulfonyl, alkylamino alkylene, the alkyl sulphonyl alkylidene group, acyl group, the acyloxy carbonyl, the alkoxy carbonyl alkylidene group, the aryloxycarbonyl alkylidene group, the heterocyclic oxy group carbonyl alkylen group, the alkoxy carbonyl arylidene, the aryloxycarbonyl arylidene, heterocyclic oxy group carbonyl arylidene, the alkyl-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the heterocyclic radical carbonyl alkylen group, the alkyl-carbonyl arylidene, the aryl carbonyl arylidene, heterocyclic radical carbonyl arylidene, the alkyl carbonyl oxy alkylidene group, the aryl-carbonyl oxygen alkylidene group, heterocyclic radical carbonyl oxygen base alkylidene group, the alkyl carbonyl oxy arylidene, the aryl-carbonyl oxygen arylidene, heterocyclic radical carbonyl oxygen base arylidene; Perhaps
R 1Molecular formula be
Figure A9880736900801
Wherein:
I is 0～9 integer;
R 25Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group; With
R 26Be selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl alkylidene group, aralkyl, alkoxy carbonyl alkylidene group and alkylamino alkyl; With
R 27Be selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclic radical, aralkyl, the cycloalkyl alkylidene group, the cycloalkenyl alkylidene group, the cycloalkyl arylidene, the cycloalkyl ring alkyl, the heterocyclic radical alkylidene group, alkyl arylene, alkyl aralkyl, the aralkyl arylidene, alkyl heterocyclic, the alkyl heterocyclic alkylidene group, the alkyl heterocyclic arylidene, the aralkyl heterocyclic radical, the alkoxyl group alkylidene group, the alkoxyl group arylidene, the alkoxy aromatic alkyl, the alkoxyl group heterocyclic radical, alkoxyl group alkoxyl group arylidene, the aryloxy arylidene, the aralkoxy arylidene, alkoxyl group heterocyclic radical alkylidene group, aryloxy alcoxyl base arylidene, the alkoxy carbonyl alkylidene group, the alkoxy carbonyl heterocyclic radical, alkoxy carbonyl heterocyclic radical carbonyl alkylen group, aminoalkyl group, alkylamino alkylene, the aromatic yl aminocarbonyl alkylidene group, alkoxy aryl aminocarboxyl alkylidene group, the aminocarboxyl alkylidene group, the aromatic yl aminocarbonyl alkylidene group, the alkyl amino-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the alkoxy carbonyl arylidene, the aryloxycarbonyl arylidene, alkyl-aryloxy carbonyl arylidene, the aryl carbonyl arylidene, alkyl-aryloxy carbonyl arylidene, the aryl carbonyl arylidene, alkylaryl carbonyl arylidene, alkoxy carbonyl heterocyclic radical arylidene, alkoxy carbonyl alkoxyl group arylidene, heterocyclic radical carbonylic alkyl arylidene, the alkylthio alkylidene group, cycloalkyl sulfo-alkylidene group, the alkylthio arylidene, aralkyl sulfo-arylidene, heterocyclic radical sulfo-arylidene, aryl alkylthio arylidene, the arlysulfonylamino alkylidene group, the alkyl sulphonyl arylidene, the alkyl amino sulfonyl arylidene; Wherein said alkyl, cycloalkyl, the aryl-heterocyclic base, aralkyl, the heterocyclic radical alkylidene group, the alkyl heterocyclic arylidene, the alkoxyl group arylidene, the aryloxy arylidene, the aromatic yl aminocarbonyl alkylidene group, the aryloxycarbonyl arylidene, the aryl carbonyl arylidene, the alkylthio arylidene, heterocyclic radical sulfo-arylidene, aryl alkylthio arylidene and alkyl sulphonyl arylidene are by one or more alkyl that are independently selected from, halogen, haloalkyl, alkoxyl group, ketone group, amino, the group of nitro and cyano group at random replaces; Perhaps
R 27Be-CHR 28R 29, R wherein 28Be alkoxy carbonyl, R 29Be selected from aralkyl, aralkoxy alkylidene group, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, alkoxy carbonyl alkylidene group, alkylthio alkylidene group and aralkyl sulfo-alkylidene group, wherein said aralkyl and heterocyclic radical are at random replaced by one or more groups, and described group is independently selected from alkyl and nitro; Or
R 26And R 27Connected nitrogen-atoms forms heterocyclic radical together, wherein said heterocyclic radical is at random replaced by one or more groups, and this group is independently selected from alkyl, aryl, heterocyclic radical, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, aryloxy alkylidene group, aryloxy arylidene, alkyl-aryloxy alkylidene group, alkyl-carbonyl, alkoxy carbonyl, aryloxycarbonyl, alkylamino and alkoxycarbonyl amino; Wherein said aryl, heterocyclic radical alkylidene group and aryloxy alkylidene group are at random replaced by one or more groups that are independently selected from halogen, alkyl and alkoxyl group; With
R 2Be selected from the hydrogen base, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, haloalkyl, hydroxyalkyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, alkylamino, alkenyl amino, alkynyl amino, arylamino, heterocyclic radical amino, the heterocyclic radical alkylamino, aryl alkyl amino, aminoalkyl group, aminoaryl, aminoalkyl group amino, the arylamino alkylidene group, alkylamino alkylene, the arylamino arylidene, the alkylamino arylidene, the alkylamino alkylamino, cycloalkyl, cycloalkenyl, alkoxyl group, heterocyclic oxy group, alkylthio, arylthio, the sulfo-heterocyclic radical, carboxyl, carboxyalkyl, the carboxyl cycloalkyl, the carboxyl cycloalkenyl, carboxyalkyl amino, alkoxy carbonyl, the heterocyclic radical carbonyl, alkoxy carbonyl alkyl, alkoxyl group base heterocyclic radical, alkoxy carbonyl heterocyclic radical carbonyl, alkoxyalkyl amino, alkoxyl group carboxyamino alkylamino, with the heterocyclic radical alkylsulfonyl, aryl wherein, heterocyclic radical, the heterocyclic radical alkyl, cycloalkyl and cycloalkenyl are at random replaced by one or more groups, and described group is independently selected from halogen, ketone group, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, aralkyl, the heterocyclic radical alkyl, epoxy alkyl, amino (hydroxyalkyl) carboxyl, alkoxyl group, aryloxy, alkoxy aryl, haloalkyl, alkylamino, alkynyl amino, alkylamino alkynes amino-heterocycles base alkylamino, alkyl-carbonyl, alkoxy carbonyl, alkyl sulphonyl, aryl sulfonyl, with the aralkyl alkylsulfonyl; Or
R 2Molecular formula be:
Figure A9880736900821
Wherein
J is 0～8 integer; And
M is 0 or 1;
R 30And R 31Be independently selected from hydrogen, alkyl, aryl, heterocyclic radical, aralkyl, heterocyclic radical alkylidene group, aminoalkyl group, alkylamino alkyl, aminocarboxyl alkyl, alkoxyalkyl and alkyl-carbonyl oxygen base alkyl; With
R 32Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group;
R 33Be selected from hydrogen, alkyl ,-C (O) R 35,-C (O) OR 35,-SO 2R 36,-C (O) NR 37R 38, and-SO 2NR 39R 40, R wherein 35, R 36, R 37, R 38, R 39And R 40Be independently selected from hydrocarbon, assorted hydrocarbon and the heterocyclic radical that replaces; And
R 34Be selected from hydrogen, alkyl, aminocarboxyl, alkyl amino-carbonyl and aromatic yl aminocarbonyl; Or
R 2Be-CR 41R 42, R wherein 41Be aryl, R 42It is hydroxyl; With
R 3Be selected from pyridyl, pyrimidyl, quinolyl, purine radicals, R wherein 43Be selected from hydrogen, alkyl, aminoalkyl group, alkoxyalkyl, alkenyloxy alkyl and aryloxy alkyl; With
Wherein said R 3Pyridyl; pyrimidyl; quinolyl; the purine radicals group is at random replaced by one or more groups, and these groups are independently selected from halogen; alkyl; aralkyl; aralkenyl; the aryl-heterocyclic base; carboxyl; carboxyalkyl; alkoxyl group; aryloxy; alkylthio; arylthio; the alkyl sulfinyl; the aryl sulfinyl; alkyl sulphonyl; aryl sulfonyl; alkoxy aryl; the heterocyclic radical alkoxyl group; amino; alkylamino; alkenyl amino; alkynyl amino; cycloalkyl amino; cycloalkenyl amino; arylamino; heterocyclic radical amino; aminocarboxyl; cyano group; hydroxyl; hydroxyalkyl; alkoxy carbonyl; aryloxycarbonyl; the heterocyclic oxy group carbonyl; alkoxycarbonyl amino; the alkoxy aromatic alkylamino; amino sulfinyl; amino-sulfonyl; the alkylamino alkylamino; hydroxyalkyl amino; aryl alkyl amino; the heterocyclic radical alkylamino; aralkyl heterocyclic radical amino; nitro; alkyl amino-carbonyl; alkyl-carbonyl-amino; halosulfonyl groups; aminoalkyl group; haloalkyl; alkyl-carbonyl; diazanyl; the alkyl diazanyl; the aryl diazanyl; or-NR 44R 45, R wherein 44Be alkyl-carbonyl or amino, R 45Be alkyl or aralkyl; With
R 4Be selected from hydrogen base, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclic radical, wherein R 4At random replaced by one or more groups, this group is independently selected from halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, alkylthio, arylthio, the alkylthio alkylidene group, aryl sulfo-alkylidene group, the alkyl sulfinyl, alkyl sulfinyl alkylidene group, aryl sulfinyl alkylidene group, alkyl sulphonyl, the alkyl sulphonyl alkylidene group, the aryl sulfonyl alkylidene group, alkoxyl group, aryloxy, aralkoxy, aminocarboxyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkoxy carbonyl, aryloxycarbonyl, haloalkyl, amino, cyano group, nitro, alkylamino, arylamino, alkylamino alkylene, the arylamino alkylidene group, aminoalkyl group amino, and hydroxyl; Or acceptable salt or its isomer on the pharmacology, described method comprises and generates acylhydrazone and condensation to form the step of substituted pyrazolecarboxylic.
134, as the method for claim 133, wherein acylhydrazone is generated by ketone and the reaction of acyl group hydrazides.
135, as the method for claim 133, wherein condensation is to carry out under about 25～200 ℃ temperature.
136, a kind of method for preparing the pyrazoles of molecular formula I,
Figure A9880736900841
Wherein
R 1Be selected from the hydrogen base, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclic radical, the cycloalkyl alkylidene group, the cycloalkenyl alkylidene group, the heterocyclic radical alkylidene group, haloalkyl, halogenated alkenyl, the halo alkynyl, hydroxyalkyl, the hydroxyl alkenyl, the hydroxyl alkynyl, aralkyl, aralkenyl, aromatic yl polysulfide yl, the aryl-heterocyclic base, carboxyl, carboxyalkyl, alkoxyalkyl, the alkenyloxy alkyl, the alkynyloxy group alkyl, aryloxy alkyl, the heterocyclic oxy group alkyl, the alkoxyl group alkoxyl group, mercaptoalkyl, the alkylthio alkylidene group, alkenyl sulfo-alkylidene group, the alkylthio alkylene group, amino, aminoalkyl group, alkylamino, alkenyl amino, alkynyl amino, arylamino, heterocyclic radical amino, the alkyl sulfinyl, the alkenyl sulfinyl, the alkynyl sulfinyl, the aryl sulfinyl, the heterocyclic radical sulfinyl, alkyl sulphonyl, the alkenyl alkylsulfonyl, the alkynyl alkylsulfonyl, aryl sulfonyl, the heterocyclic radical alkylsulfonyl, alkylamino alkylene, the alkyl sulphonyl alkylidene group, acyl group, the acyloxy carbonyl, the alkoxy carbonyl alkylidene group, the aryloxycarbonyl alkylidene group, the heterocyclic oxy group carbonyl alkylen group, the alkoxy carbonyl arylidene, the aryloxycarbonyl arylidene, heterocyclic oxy group carbonyl arylidene, the alkyl-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the heterocyclic radical carbonyl alkylen group, the alkyl-carbonyl arylidene, the aryl carbonyl arylidene, heterocyclic radical carbonyl arylidene, the alkyl carbonyl oxy alkylidene group, the aryl-carbonyl oxygen alkylidene group, heterocyclic radical carbonyl oxygen base alkylidene group, the alkyl carbonyl oxy arylidene, the aryl-carbonyl oxygen arylidene, heterocyclic radical carbonyl oxygen base arylidene; Perhaps
R 1Molecular formula be
Figure A9880736900842
Wherein:
I is 0～9 integer;
R 25Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group; With
R 26Be selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl alkylidene group, aralkyl, alkoxy carbonyl alkylidene group and alkylamino alkyl; With
R 27Be selected from alkyl, cycloalkyl, alkynyl, aryl, heterocyclic radical, aralkyl, the cycloalkyl alkylidene group, the cycloalkenyl alkylidene group, the cycloalkyl arylidene, the cycloalkyl ring alkyl, the heterocyclic radical alkylidene group, alkyl arylene, alkyl aralkyl, the aralkyl arylidene, alkyl heterocyclic, the alkyl heterocyclic alkylidene group, the alkyl heterocyclic arylidene, the aralkyl heterocyclic radical, the alkoxyl group alkylidene group, the alkoxyl group arylidene, the alkoxy aromatic alkyl, the alkoxyl group heterocyclic radical, alkoxyl group alkoxyl group arylidene, the aryloxy arylidene, the aralkoxy arylidene, alkoxyl group heterocyclic radical alkylidene group, aryloxy alcoxyl base arylidene, the alkoxy carbonyl alkylidene group, the alkoxy carbonyl heterocyclic radical, alkoxy carbonyl heterocyclic radical carbonyl alkylen group, aminoalkyl group, alkylamino alkylene, the aromatic yl aminocarbonyl alkylidene group, alkoxy aryl aminocarboxyl alkylidene group, the aminocarboxyl alkylidene group, the aromatic yl aminocarbonyl alkylidene group, the alkyl amino-carbonyl alkylidene group, the aryl carbonyl alkylidene group, the alkoxy carbonyl arylidene, the aryloxycarbonyl arylidene, alkyl-aryloxy carbonyl arylidene, the aryl carbonyl arylidene, alkyl-aryloxy carbonyl arylidene, the aryl carbonyl arylidene, alkylaryl carbonyl arylidene, alkoxy carbonyl heterocyclic radical arylidene, alkoxy carbonyl alkoxyl group arylidene, heterocyclic radical carbonylic alkyl arylidene, the alkylthio alkylidene group, cycloalkyl sulfo-alkylidene group, the alkylthio arylidene, aralkyl sulfo-arylidene, heterocyclic radical sulfo-arylidene, aryl alkylthio arylidene, the arlysulfonylamino alkylidene group, the alkyl sulphonyl arylidene, the alkyl amino sulfonyl arylidene; Wherein said alkyl, cycloalkyl, the aryl-heterocyclic base, aralkyl, the heterocyclic radical alkylidene group, the alkyl heterocyclic arylidene, the alkoxyl group arylidene, the aryloxy arylidene, the aromatic yl aminocarbonyl alkylidene group, the aryloxycarbonyl arylidene, the aryl carbonyl arylidene, the alkylthio arylidene, heterocyclic radical sulfo-arylidene, aryl alkylthio arylidene and alkyl sulphonyl arylidene are by one or more alkyl that are independently selected from, halogen, haloalkyl, alkoxyl group, ketone group, amino, the group of nitro and cyano group at random replaces; Or
R 27Be-CHR 28R 29, R wherein 28Be alkoxy carbonyl, R 29Be selected from aralkyl, aralkoxy alkylidene group, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, alkoxy carbonyl alkylidene group, alkylthio alkylidene group and aralkyl sulfo-alkylidene group, wherein said aralkyl and heterocyclic radical are at random replaced by one or more groups, and described group is independently selected from alkyl and nitro; Or
R 26And R 27Connected nitrogen-atoms forms heterocyclic radical together, wherein said heterocyclic radical is at random replaced by one or more groups, and this group is independently selected from alkyl, aryl, heterocyclic radical, heterocyclic radical alkylidene group, alkyl heterocyclic alkylidene group, aryloxy alkylidene group, aryloxy arylidene, alkyl-aryloxy alkylidene group, alkyl-carbonyl, alkoxy carbonyl, aryloxycarbonyl, alkylamino and alkoxycarbonyl amino; Wherein said aryl, heterocyclic radical alkylidene group and aryloxy alkylidene group are at random replaced by one or more groups that are independently selected from halogen, alkyl and alkoxyl group; With
R 2Be selected from the hydrogen base, halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, haloalkyl, hydroxyalkyl, aralkyl, alkyl heterocyclic, the heterocyclic radical alkyl, alkylamino, alkenyl amino, alkynyl amino, arylamino, heterocyclic radical amino, the heterocyclic radical alkylamino, aryl alkyl amino, aminoalkyl group, aminoaryl, aminoalkyl group amino, the arylamino alkylidene group, alkylamino alkylene, the arylamino arylidene, the alkylamino arylidene, the alkylamino alkylamino, cycloalkyl, cycloalkenyl, alkoxyl group, heterocyclic oxy group, alkylthio, arylthio, the sulfo-heterocyclic radical, carboxyl, carboxyalkyl, the carboxyl cycloalkyl, the carboxyl cycloalkenyl, carboxyalkyl amino, alkoxy carbonyl, the heterocyclic radical carbonyl, alkoxy carbonyl alkyl, the alkoxy carbonyl heterocyclic radical, alkoxy carbonyl heterocyclic radical carbonyl, alkoxyalkyl amino, alkoxyl group carboxyamino alkylamino, with the heterocyclic radical alkylsulfonyl, aryl wherein, heterocyclic radical, the heterocyclic radical alkyl, cycloalkyl and cycloalkenyl are at random replaced by one or more groups, and described group is independently selected from halogen, ketone group, amino, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, aralkyl, the heterocyclic radical alkyl, epoxy alkyl, amino (hydroxyalkyl) carboxyl, alkoxyl group, aryloxy, alkoxy aryl, haloalkyl, alkylamino, alkynyl amino, alkylamino alkynes amino-heterocycles base alkylamino, alkyl-carbonyl, alkoxy carbonyl, alkyl sulphonyl, aryl sulfonyl, with the aralkyl alkylsulfonyl; Or
R 2Molecular formula be;
Figure A9880736900861
Wherein
J is 0～8 integer; And
M is 0 or 1;
R 30And R 31Be independently selected from hydrogen, alkyl, aryl, heterocyclic radical, aralkyl, heterocyclic radical alkenyl, aminoalkyl group, alkylamino alkyl, aminocarboxyl alkyl, alkoxyalkyl and alkyl-carbonyl oxygen base alkyl; With
R 32Be selected from hydrogen, alkyl, aralkyl, heterocyclic radical alkyl, alkoxyl group alkylidene group, aryloxy alkylidene group, aminoalkyl group, alkylamino alkyl, arylamino alkyl, alkyl-carbonyl alkylidene group, aryl carbonyl alkylidene group and heterocyclic radical carbonylamino alkylidene group;
R 33Be selected from hydrogen, alkyl ,-C (O) R 35,-C (O) OR 35,-SO 2R 36,-C (O) NR 37R 38, and-SO 2NR 39R 40, R wherein 35, R 36, R 37, R 38, R 39And R 40Be independently selected from hydrocarbon, assorted hydrocarbon and the heterocyclic radical of replacing; And
R 34Be selected from hydrogen, alkyl, aminocarboxyl, alkyl amino-carbonyl and aromatic yl aminocarbonyl; Or
R 2Be CR 41R 42, R wherein 41Be aryl, R 42It is hydroxyl; With
R 3Be selected from pyridyl, pyrimidyl, quinolyl, purine radicals,
R wherein 43Be selected from hydrogen, alkyl, aminoalkyl group, alkoxyalkyl, alkenyloxy alkyl and aryloxy alkyl; With
Wherein said R 3Pyridyl; pyrimidyl; quinolyl; the purine radicals group is at random replaced by one or more groups, and these groups are independently selected from halogen; alkyl; aralkyl; aralkenyl; the aryl-heterocyclic base; carboxyl; carboxyalkyl; alkoxyl group; aryloxy; alkylthio; arylthio; the alkyl sulfinyl; the aryl sulfinyl; alkyl sulphonyl; aryl sulfonyl; alkoxy aryl; the heterocyclic radical alkoxyl group; amino; alkylamino; alkenyl amino; alkynyl amino; cycloalkyl amino; cycloalkenyl amino; arylamino; heterocyclic radical amino; aminocarboxyl; cyano group; hydroxyl; hydroxyalkyl; alkoxy carbonyl; aryloxycarbonyl; the heterocyclic oxy group carbonyl; alkoxycarbonyl amino; the alkoxy aromatic alkylamino; amino sulfinyl; amino-sulfonyl; the alkylamino alkylamino; hydroxyalkyl amino; aryl alkyl amino; the heterocyclic radical alkylamino; aralkyl heterocyclic radical amino; nitro; alkyl amino-carbonyl; alkyl-carbonyl-amino; halosulfonyl groups; aminoalkyl group; haloalkyl; alkyl-carbonyl; diazanyl; the alkyl diazanyl; the aryl diazanyl; or-NR 44R 45, R wherein 44Be alkyl-carbonyl or amino, R 45Be alkyl or aralkyl; With
R 4Be selected from hydrogen base, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl and heterocyclic radical, wherein R 4At random replaced by one or more groups, this group is independently selected from halogen, alkyl, alkenyl, alkynyl, aryl, heterocyclic radical, alkylthio, arylthio, the alkylthio alkylidene group, aryl sulfo-alkylidene group, the alkyl sulfinyl, alkyl sulfinyl alkylidene group, aryl sulfinyl alkylidene group, alkyl sulphonyl, the alkyl sulphonyl alkylidene group, the aryl sulfonyl alkylidene group, alkoxyl group, aryloxy, aralkoxy, aminocarboxyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, alkoxy carbonyl, aryloxycarbonyl, haloalkyl, amino, cyano group, nitro, alkylamino, arylamino, alkylamino alkylene, the arylamino alkylidene group, aminoalkyl group amino, and hydroxyl; Or the acceptable salt of its pharmacology or its isomer, described method comprises with the acyl group hydrazides handles replacement ketone to obtain the step of pyrazoles.
137, as the method for claim 136, wherein this method is carried out in acid solvent.
138, as the method for claim 137, wherein acid solvent is an acetate.
139, as the method for claim 137, wherein acid solvent is the organic solvent that contains a kind of acid.
CN98807369A 1997-05-22 1998-05-22 Substituted pyrazoles as P38 kinase inhabitors Pending CN1264377A (en)

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