CN106518767A - Substituted benzopyrazole diarylurea compound, preparation method and medical application thereof - Google Patents

Substituted benzopyrazole diarylurea compound, preparation method and medical application thereof Download PDF

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Publication number
CN106518767A
CN106518767A CN201510574993.8A CN201510574993A CN106518767A CN 106518767 A CN106518767 A CN 106518767A CN 201510574993 A CN201510574993 A CN 201510574993A CN 106518767 A CN106518767 A CN 106518767A
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group
tert
methyl
pyrazoles
indazole
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Inventor
钟武
李松
朱殿玺
李行舟
周辛波
王晓奎
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Institute of Pharmacology and Toxicology of AMMS
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Institute of Pharmacology and Toxicology of AMMS
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles

Abstract

A substituted benzopyrazole diarylurea compound, a preparation method and medical application thereof relate to a compound as shown in the general formula I, or isomer, medicinal salt and a solvate thereof. The invention also relates to a composition containing the compound as shown in the general formula I or the isomer, medicinal salt and solvate thereof and a pharmaceutically acceptable carrier, an excipient or a diluent. The invention also relates to application of the compound as shown in the general formula I or the isomer, medicinal salt and solvate thereof in overcoming inflammation, inflammatory diseases, tumor and acute lung injury caused by suffocating gas or irritant gas, especially to application of the compound as shown in the general formula I or the isomer, medicinal salt and solvate thereof in P38 MAPK pathway-related diseases or symptoms.

Description

Replace benzopyrazoles diaryl urea compound, its preparation method and its medical usage
Technical field
The present invention relates to logical formula (I) replaces benzopyrazoles diaryl urea compound as the purposes for struvite and tumprigenicity medicine.
Background technology
Mitogen-activated kinase (MAPKs) is one kind of intracellular protein kinase, belong to serine/threonine kinase series, numerous functional processes such as gene expression, cell propagation and death can be participated in as intracellular numerous priming reactions and the regulation medium of functional response.P38 MAPK signal paths are the important composition members of MAPK families, its activation is the result of numerous Pro-inflammatory Cytokines and pressure factor effect, not only very important effect is played in numerous Intracellular signals feedback procedures including inflammatory cell proliferation and differentiation with amplification, and participate in the process of stress.The document for having many correlations describes the related properties of p38 MAPK and the application in disease research and prospect.
P38 MAPK were considered as originally the associated proteins (CSBP) of the anti-inflammatory drug for playing inhibitory action by cytokine, found by Han etc. in an experiment in 1993 first, the gene for having been cloned p38 MAPK by Han etc. first in mouse liver cell in 1994, it is the albumen of the 38KD that coding is made up of 360 aminoacid, plays important adjustment effect in the biosynthetic process of inflammatory cytokine.
The p38 MAPK families having now been found that include four types：P 38 alpha, p38 β, p38 γ and p38 δ.Different p38 MAPK hypotypes are adjusted in tissue distribution, upstream kinases, downstream effects substrate and reaction to extracellular stimulus are all had nothing in common with each other, and the p38 MAPK of different subtype also have different degrees of similarity in structure.P 38 alpha and p38 β suffer from extensive expression in various in-vivo tissues, they contain 74% identical aminoacid sequence simultaneously, and they are all specific expressed, p38 γ have 64% amino acid identity with p 38 alpha, p38 γ are then mainly expressed in skeletal muscle, and p38 δ are then relatively common in small intestinal, lung tissue, adrenal gland, prostate etc..Due to p 38 alpha and β parts of body distribution than wide, thus be primarily directed to the suppression of p 38 alpha and β for the inhibitor of p38 MAPK.Many evidences show that p38 MAPK approach shows important effect in inflammation disease and cancer.Effects of the p38 MAPK in these relevant diseases is summarized, while also show the inhibitor of p38 MAPK with the potential value as treatment meanss.
Our creativeness have invented brand-new replacement benzopyrazoles diaryl urea compound as P38 MAPK inhibitor, inhibitory action of this kind of compound in vitro to P38 MAPK paths have rated by high flux screening, it was found that nearly all embodiment Compound cellular activity is better than the P38 inhibitor SB203580 that document is generally acknowledged with P38 α enzymatic activitys, the positive control drug SB203580 of wherein COMPOUNDS EXAMPLE 3 and document report compares, TNF-α inhibitory activity strengthens 400 times, and P38 α enzyme inhibition activities strengthen 10 times.In addition compare with positive control drug BIRB-796, embodiment 2 and embodiment 31 are significantly improved to P38 α enzyme selectivities.
The present invention report with highly active P38 MAPK micromolecular inhibitors, to overcome a difficult problem for inflammation, inflammation related disease and tumor disease, the acute lung injury disease that particularly asphyxiating gass or irritative gass are caused, the clinical treatment for this kind of disease provide new medicinal strategies.
Present invention aim at providing the new diaryl urea compound of a class as the purposes for struvite and tumprigenicity medicine.
The content of the invention
1. the present invention relates to the content of logical formula (I) compound or its isomer
Wherein：
Ar1For C6-C10Aromatic carbocyclic, including but not limited to phenyl ring, substituted benzene ring, cyclo-octatetraene etc.；Or C3-C10The nonaromatic heterocycles of saturation insatiable hunger, including but not limited to Pentamethylene., hexamethylene, cyclopentenes, cyclohexene, cyclohexadiene；C5-C10Aromatic heterocycle, including one or more be selected from O, the hetero atom of N, S, including but not limited to imidazoles, pyrazoles, furan, thiophene, thiazole, azoles, pyrazine, pyrimidine, indole, quinoline etc.；Or C5-C8Single heterocycle or C8-C11Double heterocycles, including one or more be selected from O, the hetero atom of N, S, including but not limited to tetrahydrofuran, Tetramethylene sulfide, piperidines etc.；Wherein Ar1Independently and selectively by one or more R1Replaced；
R1It is independently
(1)C1-C10The direct-connected or branched paraffin of saturation, described alkyl partly or entirely can be substituted with halogen atoms, and selectively can be replaced by 1-3 phenyl, naphthalene nucleus or following hetero atom：Quinolyl, isoquinolyl, pyrimidine radicals, pyrazinyl, piperazinyl, pyrrole radicals, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl；Above-mentioned phenyl, naphthalene nucleus or heterocycle selectively can be replaced by 0-5 following radicals：Halogen, C1-C6Direct-connected or branched alkyl, C2-C6Direct-connected or branched-chain alkene, C1-C6Direct-connected or branched alkoxy, C2-C6Direct-connected or alkenyloxy, halogen, trifluoromethyl, trifluoromethoxy, acetyl group, aroyl, methoxycarbonyl group, carbethoxyl group, benzenesulfonyl, hydroxyl, amino, single or double C1-C4Substituted sulfoamido, cyano group, nitro；
(2)C3-C10Cycloalkyl and cycloalkenyl group, the group partly or entirely can be optionally substituted by halogen, or selectively by 1-3 C1-C6Direct-connected or branched alkyl or C1-C6Alkoxyl replaces；1-3 methylene of above-mentioned cycloalkyl or cycloalkenyl group can selectively by O, NH, S, SO, SO2, carbonyl, methylol replace；0-5 following substituent group of above-mentioned cycloalkyl or cycloalkenyl group：Halogen, C1-C6Direct-connected or branched alkyl or C1-C6Alkoxyl；
(3)C3-C10Undersaturated direct-connected or branched-chain alkenyl, described alkyl partly or entirely can be optionally substituted by halogen, and selectively by 1-3 C1-C6Direct-connected or branched alkyl, phenyl, naphthyl or following heterocyclic substituted：Quinolyl, isoquinolyl, pyrimidine radicals, pyrazinyl, piperazinyl, pyrrole radicals, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl；Above-mentioned phenyl, naphthalene nucleus or heterocycle selectively can be replaced by 0-5 following radicals：Halogen, C1-C6Direct-connected or branched alkyl, C2-C6Direct-connected or branched-chain alkene, C1-C6Direct-connected or branched alkoxy, C2-C6Direct-connected or alkenyloxy, halogen, trifluoromethyl, trifluoromethoxy, acetyl group, aroyl, methoxycarbonyl group, carbethoxyl group, benzenesulfonyl, hydroxyl, amino, single or double C1-C4Substituted sulfoamido, cyano group, nitro；
(4) halogen, nitro, hydroxyl, amino, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, and various monosubstituted or disubstituted amino-compound；
R1It is independently C1-C10The direct-connected of saturation, side chain and cycloalkane, halogen substiuted；
R2It is independently C1-C10The direct-connected of saturation, side chain and cycloalkane, described alkyl partly or entirely can be substituted with halogen atoms, and phenyl ring or substituted benzene ring replace；
On the other hand, the present invention provides the Pharmaceutical composition of the logical formula (I) compound medicine of inclusion compound, and which contains at least one logical formula (I) compound or pharmaceutically acceptable salt thereof, solvate, one or more pharmaceutical carrier of one-level or excipient.
On the other hand, the invention further relates to the method for preparing logical formula (I) compound or its pharmaceutical salts or solvate.
Another further aspect, the present invention relates to logical formula (I) compound is used for treating or preventing the pharmaceutical usage of the disease that cytokine (TNF-α, IL-1 etc.) is mediated.
At another aspect, the present invention provides logical formula (I) compound to be used for treating or preventing cytokine (TNF-α, IL-1 etc.) disease that mediates, risk factor or disease method, including the subject or the compounds of this invention of prevention effective dose that give this needs.The disease that heretofore described cytokine (TNF-α, IL-1 etc.) is mediated, risk factor or disease include following disease：Rheumatoid arthritiss, chronic pulmonary obstruction, the acute lung injury that asphyxiating gass or irritative gass are caused, arthritic psoriasises, conjunctivo-urethro-synovial syndrome, gout, osteoarthritis, traumatic arthritiss, acute synovitis, poker back, gouty disease and other joint diseases, septicemia, septic shock, myelodysplastic syndrome, toxic shock, brain malaria, meningitiss, local hemorrhage apoplexy, osteoporosises, congestive heart failure, coronary artery bypass graft (CAB), glomerulonephritiss, chronic renal failure, diabetes, diabetic retinopathy, Crohn disease, ulcerative colitiss, muscle deterioration, eczema, contact dermatitis, psoriasiss, conjunctivitis, auxiliary treatment of cancer etc..
In an embodiment of the invention, the invention provides leading to formula (I) compound and its pharmaceutical salts or solvate,
Wherein：
Ar1For phenyl ring, substituted benzene ring etc.；C5-C10Aromatic heterocycle, including one or more be selected from O, the hetero atom of N, S, including but not limited to imidazoles, pyrazoles, furan, thiophene, thiazole, azoles, pyrazine, pyrimidine, indole, quinoline etc.；Including the aromatic heterocycle that aryl replaces, the such as pyrazoles of phenyl replacement, imidazoles etc.；
R1It is independently H or halogen atom；
R2It is independently C1-C10The direct-connected of saturation, side chain and cycloalkane, described alkyl partly or entirely can be substituted with halogen atoms, and phenyl ring or substituted benzene ring replace；
In a preferred embodiment of the present invention, the invention provides leading to formula (I) compound and its pharmaceutical salts or solvate,
Wherein：
Ar1For isopropyl phenyl ring, 2- 4-Chlorobenzotrifluorides, the 3- tert-butyl group -1- p-methylphenyl pyrazoles, the 3- tert-butyl group -1- p-nitrophenyl pyrazoles, the 3- tert-butyl group -1- p-fluorophenyl pyrazoles, the 3- tert-butyl group -1- Phenylpyrazoles replace；
R1It is independently H or F atom；
R2It is independently ethyl, 2- chloroethyls, cyclopenta, cyclohexyl, cyclopropyl, isopropyl, rubigan, an aminomethyl phenyl replace；
Currently preferred compound includes：
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- ethyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- ethyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-fluorophenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- ethyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- ethyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- (2- chloroethyls) -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-fluorophenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- (2- chloroethyls) -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- (2- chloroethyls) -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- (2- chloroethyls) -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- isopropyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- isopropyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- isopropyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } the phenoxy group }-N- tert-butyl group -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } the phenoxy group }-N- tert-butyl group -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles] urea } methyl } the phenoxy group }-N- tert-butyl group -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-fluorophenyl -1H- pyrazoles] urea } methyl } the phenoxy group }-N- tert-butyl group -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- cyclohexyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- cyclohexyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- cyclohexyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- cyclopenta -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- cyclopenta -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- cyclopenta -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- cyclopenta -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- cyclopenta -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- cyclohexyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- cyclohexyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- isopropyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- isopropyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } -4- the fluorophenoxies }-N- tert-butyl group -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } -4- the fluorophenoxies }-N- tert-butyl group -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- ethyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- ethyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- (2- chloroethyls) -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- (2- chloroethyls) -1H- indazole -1- amide
5- { the fluoro- 2- of 4- { [3- (3- isopropyls) urea] methyl } phenoxy group }-N- (2- chloroethyls) -1H- indazole -1- amide
5- { 2- { [3- (3- isopropyls) urea] methyl } phenoxy group }-N- ethyl -1H- indazole -1- amide
5- { 2- { { 3- [4- chloro- 3- (trichloromethyl) phenyl] urea groups } methyl } phenoxy group }-N- ethyl -1H- indazole -1- amide
5- { 2- { { 3- [4- chloro- 3- (trichloromethyl) phenyl] urea groups } methyl } phenoxy group }-N- (2 chloroethyl) -1H- indazole -1- amide
And its officinal salt or solvate.
The invention provides the preparation method of logical formula (I) compound and its pharmaceutical salts.
R1=CH3, NO2, F, H
R2=H, F
R2=H, F R3=ethyl, 2- chloroethyls, isopropyl, the tert-butyl group, cyclopenta, cyclohexyl
Substituted phenylhydrazine A and cyano group pinacolone B obtains intermediate C in 8 hours in 80 DEG C of alcohol refluxs；Intermediate C, E, G obtain intermediate D, F, H by reacting 12 hours in 0 DEG C of tetrahydrofuran solution with trichloroethyl chloroformate.
Substituted adjacent cyano group fluorobenzene I and 3- methyl-PAP J reacts 4 hours in 90 DEG C of DMSO solutions and obtains intermediate K；Intermediate K and amyl nitrite, acetic anhydride 90 DEG C of back flow reaction in toluene solution obtain intermediate L in 8 hours；Intermediate L obtains intermediate M in 1 hour by lithium aluminium hydride reduction in 65 DEG C of tetrahydrofuran solutions.
Intermediate D, F, H and intermediate M, S react 1 hour in 100 DEG C of DMSO solutions and obtain intermediate N；The room temperature reaction 4h in dichloromethane obtains logical formula (I) compound O to last intermediate N with the isocyanates for replacing.
Another further aspect, the present invention provides a kind of acute lung injury disease medicament compositionss for overcoming inflammation, inflammation related disease, tumor and asphyxiating gass or irritative gass to cause, which includes the compound of above-mentioned Formulas I, or they isomer, pharmaceutically acceptable salt, solvate or N- oxides, and at least one pharmaceutically acceptable carrier.
Another further aspect, the present invention provides a kind of pharmaceutical composition, which includes the compound of above-mentioned Formulas I, or they isomer, pharmaceutically acceptable salt, solvate or N- oxides, additionally comprise the acute lung injury disease medicament compositionss for overcoming inflammation, inflammation related disease, tumor and asphyxiating gass or irritative gass to cause one or more, which includes the compound of above-mentioned Formulas I, and at least one pharmaceutically acceptable carrier.
Another further aspect, the present invention provides the compound of above-mentioned Formulas I, or they isomer, pharmaceutically acceptable salt, solvate or N- oxides, they are used as the acute lung injury disease medicament for overcoming inflammation, inflammation related disease, tumor and asphyxiating gass or irritative gass to cause.
Another further aspect, the present invention provides a kind of method of the acute lung injury disease for overcoming inflammation, inflammation related disease, tumor and asphyxiating gass or irritative gass to cause, which includes to the experimenter compound of the above-mentioned Formulas I for giving therapeutically effective amount, or they isomer, pharmaceutically acceptable salt, solvate or N- oxides, and one or more other anti-inflammatory drug is optionally given in combination.
Another further aspect, the present invention provides the purposes of the compound or their isomer, pharmaceutically acceptable salt, solvate or N- oxides of above-mentioned Formulas I in medicine is prepared, and wherein described medicine is used for the acute lung injury disease for overcoming inflammation, inflammation related disease, tumor and asphyxiating gass or irritative gass to cause.
Now the term for describing the present invention occurred in present specification and claims is defined as follows.For specific term, if implication defined herein is inconsistent with the implication that those skilled in the art are generally understood that, it is defined by implication defined herein；If do not defined in this application, which has the implication that those skilled in the art are generally understood that.
Term " alkyl " used in the present invention refers to straight or branched univalent saturated hydrocarbon radical.“C1-C10Alkyl " refers to the straight or branched alkyl with 1～10 carbon atom, such as methyl, ethyl, propyl group, isopropyl, normal-butyl, sec-butyl, the tert-butyl group, amyl group, 2- amyl groups, isopentyl, neopentyl, hexyl, 2- hexyls, 3- hexyls, 3- methyl amyls, heptyl and octyl group etc..Term " C1-C6Alkyl " means the straight or branched alkyl with 1～6, i.e., 1,2,3,4,5 or 6 carbon atoms, typically methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, amyl group and hexyl etc..Similarly, term " C1-C3Alkyl " means the straight or branched alkyl with 1,2 or 3 carbon atoms, i.e. methyl, ethyl, n-pro-pyl and isopropyl.Alkyl in the present invention is preferably C1-C6Alkyl, more preferably C1-C3Alkyl.
Term " halogen " used in the present invention refers to fluorine, chlorine, bromine and atomic iodine.
Term " aromatic radical " used in the present invention refers to the optionally substituted monocyclic or bicyclic hydrocarbons loop systems comprising at least one unsaturated aromatic ring, preferably with 6～10, i.e., the aryl of 6,7,8,9 or 10 carbon atoms.The example of the aromatic radical in the present invention includes phenyl, naphthyl, 1,2,3,4- tetralyls, indyl and indenyl etc..Aromatic radical in the present invention can be by following substituent group：C1-C6Alkyl, C1-C6Alkoxyl, itrile group, halogen, hydroxyl, amino, nitro, list (C1-C6) alkyl amino, two (C1-C6) alkyl amino, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Haloalkyl or C1-C6Halogenated alkoxy.
Term " fragrant heterocyclic radical " used in the present invention refers to the heteroatomic optionally substituted monocyclic or bicyclic unsaturated aromatic ring system comprising at least one independently selected from N, O or S, it is preferred that having 5～10, i.e., 5, the fragrant heterocyclic radical of 6,7,8,9 or 10 atoms.The example of " fragrant heterocyclic radical " includes but is not limited to thienyl, pyridine radicals, thiazolyl, isothiazolyl, furyl, pyrrole radicals, triazolyl, imidazole radicals, triazine radical, di azoly, oxazolyl, isoxazolyl, pyrazolyl, imidazoles ketone group, azoles, thiazole ketone group, tetrazole radical, thiadiazolyl group, benzimidazolyl, benzoxazolyl group, benzothiazolyl, tetrahydrochysene triazolo pyridyl, tetrahydrochysene triazolopyrimidinyl, benzofuranyl, benzothienyl, thianaphthenyl, indyl, isoindolyl, pyriconyl, pyridazinyl, pyrazinyl, pyrimidine radicals, quinolyl, phthalazinyl, quinoxalinyl, quinazolyl, imidazopyridyl, azoles pyridine radicals, thiazolopyridinyl, Imidazopyridazine base, azoles pyridazinyl, thiazole pyridazinyl, pteridyl, furazanyl, benzotriazole base, Pyrazolopyridine base and purine radicals etc..Heteroaryl in the present invention can be by following substituent group：C1-C6Alkyl, C1-C6Alkoxyl, itrile group, halogen, hydroxyl, amino, nitro, list (C1-C6) alkyl amino, two (C1-C6) alkyl amino, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Haloalkyl or C1-C6Halogenated alkoxy.
Term " cycloalkyl " used in the present invention refers to the saturated carbon ring group of 3,4,5,6,7,8,9 or 10 carbon atoms.The cycloalkyl can be monocyclic or multi-ring fused system, and can condense on aromatic ring.The example of these groups includes cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl etc..The cycloalkyl of this paper can be unsubstituted, or in one or more commutable positions by suitable substituent group.For example, the cycloalkyl in the present invention can optionally by following substituent group：C1-C6Alkyl, C1-C6Alkoxyl, itrile group, halogen, hydroxyl, amino, nitro, list (C1-C6) alkyl amino, two (C1-C6) alkyl amino, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Haloalkyl or C1-C6Halogenated alkoxy.
Term " heterocyclic radical " used in the present invention is referred to comprising at least one and most four heteroatomic optionally substituted monocyclic and bicyclic saturations independently selected from N, O or S, fractional saturation or undersaturated ring system, it is preferred that having 4～10,5,6 or 7 circle heterocycles bases of i.e. 4,5,6,7,8,9 or 10 atoms, condition are the rings of the heterocyclic radical without two adjacent O or S atom.Preferred heterocyclic radical includes but is not limited to pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, piperidyl, morpholinyl or piperazinyl etc..Heterocyclic radical in the present invention can be by following substituent group：C1-C6Alkyl, C1-C6Alkoxyl, itrile group, halogen, hydroxyl, amino, nitro, list (C1-C6) alkyl amino, two (C1-C6) alkyl amino, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Haloalkyl or C1-C6Halogenated alkoxy.
Term " aryl alkyl " used in the present invention refers to the alkyl as defined above replaced by one or more aryl as defined above.Preferred aryl alkyl is aryl-C1-C3Alkyl.The example of the aryl alkyl in the present invention includes benzyl and phenylethyl etc..
Term " fragrant heterocyclic radical alkyl " used in the present invention refers to the alkyl as defined above replaced by fragrant heterocyclic radical as defined above.Preferred fragrant heterocyclic radical alkyl is 5- or 6- unit's heteroaryl-C1-C3- alkyl.The example of the heteroaryl alkyl in the present invention includes pyridyl-ethyl group etc..
Term " cycloheteroalkylalkyl " used in the present invention refers to the alkyl as defined above replaced by heterocyclic radical as defined above.Preferred cycloheteroalkylalkyl is 5 or 6 circle heterocycles base-C1-C3- alkyl.The example of the cycloheteroalkylalkyl in the present invention includes Pentamethylene oxide. ylmethyl.
Term " pharmaceutically acceptable salt " used in the present invention means acceptable in pharmacy and the compounds of this invention of the required pharmacological activity with parent compound salt.This kind of salt includes：The salt of the sour addition formed with mineral acid or with organic acid, described mineral acid such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc.；Described organic acid such as acetic acid, propanoic acid, caproic acid, cyclopentyl propionic acid, glycolic, acetone acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, LOMAR PWA EINECS 246-676-2, camphorsulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid etc.；Or the salt formed when replacing by metal ion, such as alkali metal ion or alkaline-earth metal ions in acid proton present on parent compound；Or the coordination compound formed with organic base, described organic base such as ethanolamine, diethanolamine, triethanolamine, N-METHYL-ALPHA-L-GLUCOSAMINE etc..
Term " solvate " used in the present invention means the material that the compounds of this invention is combined to form with acceptable solvent in pharmacy.In pharmacy, acceptable solvent includes water, ethanol, acetic acid etc..Solvate includes the solvate of the solvate and non stoichiometric amounts of stoichiometric amount, preferably hydrate.The compound of the present invention can use water or the crystallization of various organic solvents or recrystallization, in this case it is possible to form various solvates.
The pharmaceutical composition of the present invention includes the formula compound of formula I or the pharmaceutically acceptable carrier that its isomer, pharmaceutically acceptable salt or hydrate and one or more are suitable of effective dose.Here pharmaceutical carrier is included but is not limited to：Ion-exchanger, aluminium oxide, aluminium stearate, lecithin, serum albumin such as Human Albumin, buffer substance such as phosphate, glycerol, sorbic acid, potassium sorbate, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium Chloride, zinc salt, cabosil, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, Polyethylene Glycol, sodium carboxymethyl cellulose, polyacrylate, Cera Flava, lanoline.
The pharmaceutical composition of the compounds of this invention can be applied with following any-mode：Orally, spraying suction, rectal application, nasal cavity applied medicine, buccal medication, local application, non-bowel medication, such as subcutaneous, vein, intramuscular, intraperitoneal, intrathecal, in ventricle, with intracranial injection or input in breastbone, or by a kind of explant reservoir medication.Wherein preferably orally, intraperitoneal or intravenous administration mode.
When oral medication, the compounds of this invention can be made into arbitrarily oral acceptable dosage form, including but not limited to tablet, capsule, aqueous solution or water slurry.Wherein, tablet using carrier generally comprise Lactose and corn starch, can also add lubricant such as magnesium stearate in addition.Capsule preparations using diluent generally comprise Lactose and dried corn starch.Active component is then typically used in mixed way by aqueous suspension preparation with suitable emulsifying agent and suspending agent.If desired, can also add some sweeting agents, aromatic or coloring agent in above oral dosage form.
When local application, particularly treat Local out dressing easy to reach and suffer from face or organ, during such as eyes, skin or lower intestinal tract nervous system disease, the compounds of this invention can be made by different topical preparations forms according to different suffer from face or organ, be described as follows：
When eye local application, the compounds of this invention can be configured to the dosage form of a kind of micronized suspension or solution, using the Sterile Saline that carrier is isotonic certain pH, can wherein add also can not adding preservative agent such as zephiran chloride alkoxide.For ophthalmically acceptable, also compound can be made ointment such as vaseline paste.
When topical application, the compounds of this invention can be made into appropriate ointment, lotion or cream formulation form, and wherein active component is suspended or dissolved in one or more carrier.The carrier that ointment formulation can be used is included but is not limited to：Mineral oil, Albolene, white vaseline, Propylene Glycol, polyethylene glycol oxide, polypropylene oxide, emulsifing wax and water；The carrier that lotion or cream can be used is included but is not limited to：Mineral oil, sorbitan monostearate, polysorbate60, cetyl ester wax, hexadecene are fragrant and mellow, 2- octyldodecanols, benzyl alcohol and water.
The compounds of this invention can be with aseptic injection preparation form medication, including aseptic injection water or oil suspension or aseptic injectable solution.Wherein, the carrier and solvent that can be used includes water, Ringer's mixture and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilizing also is used as solvent or suspension media, such as monoglyceride or two glyceride.
Specific embodiment
Following specific embodiment is the preferred embodiments of the invention, and which should not be construed as constituting any restriction to the present invention.
The fusing point of compound is determined by RY-1 melting point apparatus, the non-calibration of thermometer.Mass spectrum is determined by Micromass ZabSpec high resolution mass spectrometers (resolution 1000).1H NMR are determined by JNM-ECA-400 SUPERCONDUCTING NMRs instrument, operating frequency1H NMR 400MHz,13C NMR 100MHz。
Embodiment
Embodiment 15-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- ethyl -1H- indazole -1- amide
100mL ethanol, (30mmol) pivaloyl group acetonitrile, (33.63mmol) 4- procarbazines is added in 250mL eggplant type bottles; the lower Deca 3.6mL concentrated hydrochloric acid of stirring; it is heated to reflux 8 hours, cools down, concentration; residue adjusts pH10-11 with dilute sodium hydroxide; extracted three times with ethyl acetate, anhydrous sodium sulfate drying, concentration; solid with ethyl acetate/the petroleum ether for obtaining is recrystallized to give white crystal C, yield 80.3%.The 5- tert-butyl groups -2- p-methylphenyls -3- amino-pyrazols (3.5mmolC) is placed in 100ml three-necked bottles, dissolved with 30ml tetrahydrofurans, three-necked bottle is placed in into cryostat and is cooled to -20 DEG C, 2.9g sodium bicarbonate is dividedly in some parts under stirring, after 15min, dropwise Deca trichloroethyl chloroformate (3.5mmol), control solution temperature is less than 0 DEG C, after completion of dropping, continue stirring 30min, then heat to 0 DEG C of reaction 12h. reaction and finish, mixture is filtered, filtering residue ethyl acetate rinse, filtrate concentration, yield 85%.
The fluoro- benzene eyeball I of 7.9g 2- are dissolved in 50ml DMSO, are dividedly in some parts 27g potassium carbonate.Mixed liquor is stirred at room temperature 30min.Weigh 4.78 g3- methyl-PAP J and add reactant liquor, mixed liquor is heated to into 90 DEG C, react 12h.Reaction is finished.Reactant liquor pours 200ml frozen water into, is placed in refrigerator, after 3h, takes out, and has yellow solid K to separate out, filters, is dried.Yield 93%.0.8g 2- (4- amine -3- methylphenoxy) cyanophenyl K is dissolved in 30ml dry toluenes, sequentially adds 1.14g acetic anhydride and 0.3g sodium acetates.Mixed liquor is placed in oil bath, is heated to 80 DEG C, is added dropwise over 0.6g amyl nitrite, reacts 8h, and reaction is finished, reacting liquid filtering, and concentration, with column chromatography for separation product L, yield 80%.Weigh in 0.35g tetrahydrochysene lithium aluminiums addition 15ml anhydrous tetrahydro furans; reaction bulb is placed in ice bath; weigh 0.8g 2- ((1- acetyl group -1H- indazole -5- bases) epoxide) the molten 10ml anhydrous tetrahydro furans of cyanophenyl L; solution dropwise instills the suspension of tetrahydrochysene lithium aluminium; after completion of dropping, 65 DEG C are refluxed 1h.Reaction is finished, and adds ethanol to produce to bubble-free, filter in mixed liquor, and concentration, with column chromatography for separation product M, yield 73%.
20mL dimethyl sulfoxides are added in 50mL there-necked flasks, add compound 0.5mmol2,2,2- trichloroethyls-(the 3- tert-butyl group -1- (4- methylphenyls) -1H- pyrazoles -5- bases) amide D, add compound 2- ((1H- indazole -5- bases) epoxide) benzene methanamine M 0.5mmol, Deca 0.5ml triethylamine enters reaction, heats 80 DEG C and reacts 1 hour.Cooling, pours in 150ml water, is extracted 3 times with ethyl acetate, and organic layer saturated sodium-chloride is washed 3 times, and anhydrous sodium sulfate drying overnight, is concentrated, column chromatography for separation product N, yield 58%.Take in intermediate N 0.5mmol addition 50ml single port bottles, dissolved with 20ml DCM and 1ml DMSO mixed solvents, the ethyl isocyanate of 2.5mmol is added in reactant liquor, room temperature reaction 4h, reactant liquor are poured in 50ml water, dichloromethane extraction 3 times, anhydrous sodium sulfate drying is overnight, concentration, column chromatography for separation obtain end-product 0, yield 81%.
1H-NMR (400MHz, DMSO-d6)
δ：9.05 (t, 1H), 8.77 (s, 1H), 8.57 (s, 1H), 8.30 (d, 2H), 7.81 (d, 2H), 7.71 (d, 1H), 7.30 (m, 2H), 7.22 (m, 1H), 7.15 (m, 1H), 6.99 (m, 2H), 6.93 (d, 1H), 6.29 (s, 1H), 4.26 (d, 2H), 3.31 (m, 2H), 2.39 (s, 3H), 1.27 (s, 9H), 1.16 (t, 3H). (M+H)+：566.Mp：171-173℃.
Embodiment 25-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- ethyl -1H- indazole -1- amide
Using the method for embodiment 1, paranitrophenylhydrazine is changed to procarbazine by therein, white solid is obtained.
1H-NMR (400MHz, DMSO-d6)
δ：9.05 (t, 1H), 8.77 (s, 1H), 8.57 (s, 1H), 8.30 (d, 2H), 7.81 (d, 2H), 7.71 (d, 1H), 7.30 (m, 2H), 7.22 (m, 1H), 7.15 (m, 1H), 6.99 (m, 2H), 6.93 (d, 1H), 6.29 (s, 1H), 4.26 (d, 2H), 3.31 (m, 2H), 1.27 (s, 9H), 1.16 (t, 3H). (M+H)+：597.Mp：156-158℃.
Embodiment 35-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-fluorophenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- ethyl -1H- indazole -1- amide
Using the method for embodiment 1, procarbazine is changed to therein to fluorine phenylhydrazine, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：9.06 (t, 1H), 8.77 (s, 1H), 8.28 (s, 1H), 7.71 (d, 2H), 7.49 (d, 2H), 7.29 (m, 4H), 7.23 (m, 1H), 7.20 (m, 1H), 6.90 (m, 3H), 4.25 (d, 2H), 3.30 (m, 2H), 1.23 (s, 9H), 1.14 (t, 3H). (M+H)+：570.Mp：166-168℃.
Embodiment 45-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- ethyl -1H- indazole -1- amide
Using the method for embodiment 1, phenylhydrazine is changed to procarbazine by therein, white solid is obtained.
1H-NMR (400MHz, DMSO-d6)
δ：9.04 (t, 1H), 8.74 (s, 1H), 8.34 (s, 1H), 7.61 (d, 2H), 7.49 (d, 2H), 7.45 (m, 1H) 7.26 (m, 4H), 7.19 (m, 1H), 7.10 (m, 1H), 6.92 (m, 3H), 4.20 (d, 2H), 3.30 (m, 2H), 1.24 (s, 9H), 1.13 (t, 3H). (M+H)+：552.Mp：171-173℃.
Embodiment 55-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- (2- chloroethyls) -1H- indazole -1- amide
Using the method for embodiment 1, phenylhydrazine is changed to procarbazine by therein, ethyl isocyanate is changed to 2- chloroethyl isocyanates, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：9.01 (t, 1H), 8.71 (s, 1H), 8.24 (s, 1H), 7.60 (d, 2H), 7.41 (d, 2H), 7.40 (m, 1H) 7.23 (m, 4H), 7.14 (m, 1H), 7.10 (m, 1H), 6.92 (m, 3H), 4.20 (d, 2H), 3.53 (m, 2H), 3.30 (m, 2H), 1.24 (s, 9H). (M+H)+：586.Mp：182-184℃.
Embodiment 65-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-fluorophenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- (2- chloroethyls) -1H- indazole -1- amide
Using the method for embodiment 1, procarbazine is changed to therein to fluorine phenylhydrazine, ethyl isocyanate is changed to 2- chloroethyl isocyanates, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：9.13 (t, 1H), 8.75 (s, 1H), 8.22 (s, 1H), 7.71 (d, 1H), 7.45 (m, 2H), 7.27 (m, 4H), 7.25 (m, 1H), 7.20 (m, 1H), 6.97 (m, 3H), 6.13 (s.1H), 4.21 (d, 2H), 3.70 (m, 2H), 3.53 (m, 2H), 1.20 (s, 9H). (M+H)+：604.Mp：199-201℃.
Embodiment 75-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- (2- chloroethyls) -1H- indazole -1- amide
Using the method for embodiment 1, ethyl isocyanate is changed to 2- chloroethyl isocyanates, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.95 (m, 2H), 8.21 (s, 1H), 7.31 (m, 7H), 7.22 (m, 2H), 6.91 (m, 3H), 6.20 (s, 1H), 4.25 (d, 2H), 3.72 (d, 2H), 2.39 (s, 3H), 1.14 (s, 9H). (M+H)+：600.Mp：166-169℃.
Embodiment 85-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- isopropyl -1H- indazole -1- amide
Using the method for embodiment 1, ethyl isocyanate is changed to isopropyl isocyanate, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.75 (m, 2H), 8.20 (s, 1H), 7.32 (m, 7H), 7.21 (m, 2H), 6.95 (m, 3H), 6.21 (s, 1H), 4.27 (d, 2H), 4.00 (m, 1H), 2.39 (s, 3H), 1.25 (d, 6H), 1.19 (s, 9H). (M+H)+：580.Mp：183-185℃.
Embodiment 95-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- isopropyl -1H- indazole -1- amide
Using the method for embodiment 1, phenylhydrazine is changed to procarbazine by therein, ethyl isocyanate is changed to isopropyl isocyanate, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.79 (m, 2H), 8.29 (s, 1H), 7.72 (d, 1H), 7.45 (m, 4H), 7.25 (m, 5H), 6.91 (m, 3H), 6.27 (s, 1H), 4.31 (d, 2H), 4.02 (m, 1H), 1.24 (d, 6H), 1.19 (s, 9H). (M+H)+：56 6.Mp：172-175℃.
Embodiment 105-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- isopropyl -1H- indazole -1- amide
Using the method for embodiment 1, paranitrophenylhydrazine is changed to procarbazine by therein, ethyl isocyanate is changed to isopropyl isocyanate, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.73 (m, 2H), 8.60 (s, 1H), 8.29 (m, 3H), 7.81 (m, 2H), 7.70 (d, 1H), 7.27 (m, 4H), 7.25 (m, 1H), 7.20 (m, 1H), 6.33 (s.1H), 4.25 (d, 2H), 4.02 (m, 1H), 1.24 (d, 6H), 1.18 (s, 9H). (M+H)+：611.Mp：177-180℃.
Embodiment 115-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- the tert-butyl group -1H- indazole -1- amide
Using the method for embodiment 1, paranitrophenylhydrazine is changed to procarbazine by therein, ethyl isocyanate is changed to t-butylisocyanate, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.73 (m, 2H), 8.60 (s, 1H), 8.29 (m, 3H), 7.81 (m, 2H), 7.70 (d, 1H), 7.27 (m, 4H), 7.25 (m, 1H), 7.20 (m, 1H), 6.33 (s.1H), 4.25 (d, 2H), 1.24 (s, 9H), 1.18 (s, 9H). (M+H)+：625.Mp：166-168℃.
Embodiment 125-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- the tert-butyl group -1H- indazole -1- amide
Using the method for embodiment 1, wherein will be changed to t-butylisocyanate by ethyl isocyanate, obtain white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.75 (m, 2H), 8.20 (s, 1H), 7.32 (m, 7H), 7.21 (m, 2H), 6.95 (m, 3H), 6.21 (s, 1H), 4.27 (d, 2H), 4.00 (m, 1H), 2.39 (s, 3H), 1.25 (d, 6H), 1.23 (s, 9H), 1.19 (s, 9H). (M+H)+：594.Mp：181-183℃.
Embodiment 135-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- the tert-butyl group -1H- indazole -1- amide
Using the method for embodiment 1, phenylhydrazine wherein will be changed to procarbazine, ethyl isocyanate is changed to t-butylisocyanate, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.79 (m, 2H), 8.29 (s, 1H), 7.72 (d, 1H), 7.45 (m, 4H), 7.25 (m, 5H), 6.91 (m, 3H), 6.27 (s, 1H), 4.30 (d, 2H), 1.24 (d, 9H), 1.19 (s, 9H). (M+H)+：580.Mp：190-192℃.
Embodiment 145-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-fluorophenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- the tert-butyl group -1H- indazole -1- amide
Using the method for embodiment 1, wherein procarbazine will be changed to fluorine phenylhydrazine, ethyl isocyanate is changed to t-butylisocyanate, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：9.13 (t, 1H), 8.75 (s, 1H), 8.22 (s, 1H), 7.71 (d, 1H), 7.45 (m, 2H), 7.27 (m, 4H), 7.25 (m, 1H), 7.20 (m, 1H), 6.97 (m, 3H), 6.13 (s.1H), 4.21 (d, 2H), 1.24 (s, 9H), 1.18 (s, 9H). (M+H)+：598.Mp：188-190℃.
Embodiment 155-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-fluorophenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- cyclohexyl -1H- indazole -1- amide
Using the method for embodiment 1, wherein procarbazine will be changed to fluorine phenylhydrazine, ethyl isocyanate is changed to cyclohexyl isocyanate, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.75 (m, 2H), 8.20 (s, 1H), 7.32 (m, 7H), 7.21 (m, 2H), 6.95 (m, 3H), 6.21 (s, 1H), 4.27 (d, 2H), 3.68 (m, 1H), 1.25 (d, 6H), 1.59 (m, 10H) 1.19 (s, 9H). (M+H)+：624.Mp：172-174℃.
Embodiment 165-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- cyclohexyl -1H- indazole -1- amide
Using the method for embodiment 1, wherein will be changed to cyclohexyl isocyanate by ethyl isocyanate, obtain white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.75 (m, 2H), 8.20 (s, 1H), 7.32 (m, 7H), 7.21 (m, 2H), 6.95 (m, 3H), 6.21 (s, 1H), 4.27 (d, 2H), 3.68 (m, 1H), 2.39 (s, 3H), 1.25 (d, 6H), 1.59 (m, 6H), 1.19 (s, 9H), 0.85 (m, 4H). (M+H)+：620.Mp：134-136℃.
Embodiment 175-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- cyclohexyl -1H- indazole -1- amide
Using the method for embodiment 1, paranitrophenylhydrazine wherein will be changed to procarbazine, ethyl isocyanate is changed to cyclohexyl isocyanate, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.72 (m, 2H), 8.21 (s, 1H), 7.29 (m, 7H), 7.21 (m, 2H), 6.95 (m, 3H), 6.21 (s, 1H), 4.27 (d, 2H), 3.68 (m, 1H), 1.59 (m, 6H), 1.19 (s, 9H), 0.85 (m, 4H). (M+H)+：651.Mp：172-174℃.
Embodiment 185-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- cyclohexyl -1H- indazole -1- amide
Using the method for embodiment 1, phenylhydrazine wherein will be changed to procarbazine, ethyl isocyanate is changed to cyclohexyl isocyanate, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.79 (m, 2H), 8.29 (s, 1H), 7.72 (d, 1H), 7.45 (m, 4H), 7.25 (m, 5H), 6.91 (m, 3H), 6.27 (s, 1H), 4.31 (d, 2H), 4.02 (m, 1H), 1.24 (m, 6H), 1.19 (s, 9H), 0.84 (m, 4H). (M+H)+：606.Mp：167-169℃.
Embodiment 195-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- cyclopenta -1H- indazole -1- amide
Using the method for embodiment 1, phenylhydrazine wherein will be changed to procarbazine, ethyl isocyanate is changed to cyclopenta isocyanates, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.78 (m, 2H), 8.23 (s, 1H), 7.73 (d, 1H), 7.40 (m, 4H), 7.25 (m, 5H), 6.91 (m, 3H), 6.27 (s, 1H), 4.31 (d, 2H), 4.08 (m, 1H), 1.24 (m, 8H), 1.19 (s, 9H). (M+H)+：592.Mp：158-160℃.
Embodiment 205-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- cyclopenta -1H- indazole -1- amide
Using the method for embodiment 1, paranitrophenylhydrazine wherein will be changed to procarbazine, ethyl isocyanate is changed to cyclopenta isocyanates, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.72 (m, 2H), 8.21 (s, 1H), 7.29 (m, 7H), 7.21 (m, 2H), 6.95 (m, 3H), 6.21 (s, 1H), 4.27 (d, 2H), 3.68 (m, 1H), 1.90 (m, 2H), 1.69 (m, 4H), 1.53 (m, 2H), 1.25 (s, 9H). (M+H)+：637.Mp：173-175℃.
Embodiment 215-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles) urea) methyl) phenoxy group】- N- cyclopenta -1H- indazole -1- amide
Using the method for embodiment 1, wherein will be changed to cyclopenta isocyanates by ethyl isocyanate, obtain white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.81 (m, 2H), 8.27 (s, 1H), 7.29 (m, 7H), 7.21 (m, 2H), 6.95 (m, 3H), 6.21 (s, 1H), 4.27 (d, 2H), 3.68 (m, 1H), 2.34 (s, 3H) 1.90 (m, 2H), 1.69 (m, 4H), 1.53 (m, 2H), 1.25 (s, 9H). (M+H)+：606.Mp：166-168℃.
Embodiment 225-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles) urea) methyl) -4- fluorophenoxies】- N- cyclopenta -1H- indazole -1- amide
Using the method for embodiment 1, wherein the fluoro- 2- cyano group fluorobenzene of 4- will be changed to by 2- cyano group fluorobenzene, ethyl isocyanate is changed to cyclopenta isocyanates, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.86 (d, 1H), 8.76 (s, 1H), 8.28 (s, 1H), 7.74 (d, 1H), 7.33 (m, 2H), 7.22 (m, 3H), 7.03 (m, 5H), 6.21 (s, 1H), 4.25 (d, 2H), 4.18 (m, 1H), 2.34 (s, 3H), 1.90 (m, 2H), 1.69 (m, 4H), 1.53 (m, 2H), 1.25 (s, 9H). (M+H)+：624.Mp：171-173℃.
Embodiment 235-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles) urea) methyl) -4- fluorophenoxies】- N- cyclopenta -1H- indazole -1- amide
Using the method for embodiment 1, wherein will be changed to the fluoro- 2- cyano group fluorobenzene of 4- by 2- cyano group fluorobenzene, be changed to paranitrophenylhydrazine to procarbazine, ethyl isocyanate will be changed to cyclopenta isocyanates, and will obtain white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.79 (d, 1H), 8.76 (s, 1H), 8.28 (s, 1H), 7.74 (d, 1H), 7.33 (m, 2H), 7.22 (m, 3H), 7.03 (m, 5H), 6.21 (s, 1H), 4.25 (d, 2H), 4.18 (m, 1H), 1.90 (m, 2H), 1.69 (m, 4H), 1.53 (m, 2H), 1.25 (s, 9H). (M+H)+：655.Mp：172-174℃.
Embodiment 245-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles) urea) methyl) -4- fluorophenoxies】- N- cyclohexyl -1H- indazole -1- amide
Using the method for embodiment 1, wherein will be changed to the fluoro- 2- cyano group fluorobenzene of 4- by 2- cyano group fluorobenzene, be changed to paranitrophenylhydrazine to procarbazine, ethyl isocyanate will be changed to cyclohexyl isocyanate, obtain white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.78 (d, 1H), 8.74 (s, 1H), 8.28 (s, 1H), 7.74 (d, 1H), 7.33 (m, 2H), 7.22 (m, 3H), 7.03 (m, 5H), 6.21 (s, 1H), 4.25 (d, 2H), 4.18 (m, 1H), 1.53 (m, 6H), 1.25 (s, 9H), 0.85 (m, 4H). (M+H)+：669.Mp：163-165℃.
Embodiment 255-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles) urea) methyl) -4- fluorophenoxies】- N- cyclohexyl -1H- indazole -1- amide
Using the method for embodiment 1, wherein the fluoro- 2- cyano group fluorobenzene of 4- will be changed to by 2- cyano group fluorobenzene, ethyl isocyanate is changed to cyclohexyl isocyanate, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.77 (d, 1H), 8.74 (s, 1H), 8.28 (s, 1H), 7.74 (d, 1H), 7.33 (m, 2H), 7.22 (m, 3H), 7.03 (m, 5H), 6.21 (s, 1H), 4.25 (d, 2H), 4.18 (m, 1H), 2.45 (s, 3H), 1.53 (m, 6H), 1.25 (s, 9H), 0.95 (m, 4H). (M+H)+：638.Mp：171-173℃.
Embodiment 265-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles) urea) methyl) -4- fluorophenoxies】- N- isopropyl -1H- indazole -1- amide
Using the method for embodiment 1, wherein the fluoro- 2- cyano group fluorobenzene of 4- will be changed to by 2- cyano group fluorobenzene, ethyl isocyanate is changed to isopropyl isocyanate, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.77 (d, 1H), 8.74 (s, 1H), 8.26 (s, 1H), 7.74 (d, 1H), 7.33 (m, 2H), 7.22 (m, 3H), 7.03 (m, 5H), 6.21 (s, 1H), 4.25 (d, 2H), 4.18 (m, 1H), 3.69 (s, 1H), 2.45 (s, 3H), 1.27 (m, 6H), 1.25 (s, 9H). (M+H)+：598.Mp：163-165℃.
Embodiment 275-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles) urea) methyl) -4- fluorophenoxies】- N- isopropyl -1H- indazole -1- amide
Using the method for embodiment 1, wherein will be changed to the fluoro- 2- cyano group fluorobenzene of 4- by 2- cyano group fluorobenzene, be changed to paranitrophenylhydrazine to procarbazine, ethyl isocyanate will be changed to cyclohexyl isocyanate, obtain white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.77 (d, 1H), 8.74 (s, 1H), 8.28 (s, 1H), 7.74 (d, 1H), 7.33 (m, 2H), 7.22 (m, 3H), 7.03 (m, 5H), 6.21 (s, 1H), 4.25 (d, 2H), 4.16 (m, 1H), 1.26 (m, 6H), 1.25 (s, 9H). (M+H)+：629.Mp：153-155℃.
Embodiment 285-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles) urea) methyl) -4- fluorophenoxies】- N- the tert-butyl group -1H- indazole -1- amide
Using the method for embodiment 1, wherein will be changed to the fluoro- 2- cyano group fluorobenzene of 4- by 2- cyano group fluorobenzene, be changed to paranitrophenylhydrazine to procarbazine, ethyl isocyanate will be changed to t-butylisocyanate, obtain white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.77 (d, 1H), 8.74 (s, 1H), 8.28 (s, 1H), 7.74 (d, 1H), 7.33 (m, 2H), 7.22 (m, 3H), 7.03 (m, 5H), 6.21 (s, 1H), 4.25 (d, 2H), 1.41 (s, 9H), 1.25 (s, 9H). (M+H)+：643.Mp：179-181℃.
Embodiment 295-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles) urea) methyl) -4- fluorophenoxies】- N- the tert-butyl group -1H- indazole -1- amide
Using the method for embodiment 1, wherein the fluoro- 2- cyano group fluorobenzene of 4- will be changed to by 2- cyano group fluorobenzene, ethyl isocyanate is changed to t-butylisocyanate, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.76 (d, 1H), 8.74 (s, 1H), 8.28 (s, 1H), 7.74 (d, 1H), 7.33 (m, 2H), 7.22 (m, 3H), 7.03 (m, 5H), 6.21 (s, 1H), 4.25 (d, 2H), 2.45 (s, 3H), 1.41 (s, 9H), 1.25 (s, 9H). (M+H)+：612.Mp：151-153℃.
Embodiment 305-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles) urea) methyl) -4- fluorophenoxies】- N- ethyl -1H- indazole -1- amide
Using the method for embodiment 1, wherein will be changed to the fluoro- 2- cyano group fluorobenzene of 4- by 2- cyano group fluorobenzene, paranitrophenylhydrazine is changed to procarbazine, white solid is obtained.
1H-NMR (400MHz, DMSO-d6)
δ：9.02 (d, 1H), 8.74 (s, 1H), 8.28 (s, 1H), 7.74 (d, 1H), 7.33 (m, 2H), 7.22 (m, 3H), 7.03 (m, 5H), 6.21 (s, 1H), 4.25 (d, 2H), 3.30 (m, 2H), 1.25 (s, 9H), 1.13 (t, 3H). (M+H)+：615.Mp：148-151℃.
Embodiment 315-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles) urea) methyl) -4- fluorophenoxies】- N- ethyl -1H- indazole -1- amide
Using the method for embodiment 1, wherein will be changed to the fluoro- 2- cyano group fluorobenzene of 4- by 2- cyano group fluorobenzene, obtain white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.77 (d, 1H), 8.74 (s, 1H), 8.28 (s, 1H), 7.74 (d, 1H), 7.33 (m, 2H), 7.22 (m, 3H), 7.03 (m, 5H), 6.21 (s, 1H), 4.25 (d, 2H), 3.30 (m, 2H), 2.45 (s, 3H), 1.25 (s, 9H), 1.15 (t, 3H). (M+H)+：584.Mp：166-169℃.
Embodiment 325-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles) urea) methyl) -4- fluorophenoxies】- N- (2- chloroethyls) -1H- indazole -1- amide
Using the method for embodiment 1, wherein will be changed to the fluoro- 2- cyano group fluorobenzene of 4- by 2- cyano group fluorobenzene, procarbazine will be changed to fluorine phenylhydrazine, ethyl isocyanate will be changed to 2- chloroethyl isocyanates, obtain white solid.
1H-NMR (400MHz, DMSO-d6)
δ：9.12 (d, 1H), 8.84 (s, 1H), 8.28 (s, 1H), 7.74 (d, 1H), 7.33 (m, 2H), 7.22 (m, 3H), 7.03 (m, 5H), 6.21 (s, 1H), 4.25 (d, 2H), 3.81 (t, 2H), 3.60 (m, 2H), 3.30 (m, 2H), 1.25 (s, 9H), 1.13 (t, 3H). (M+H)+：618.Mp：184-186℃.
Embodiment 335-【2- ((3- (- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles) urea) methyl) -4- fluorophenoxies】- N- (2- chloroethyls) -1H- indazole -1- amide
Using the method for embodiment 1, wherein will be changed to the fluoro- 2- cyano group fluorobenzene of 4- by 2- cyano group fluorobenzene, be changed to paranitrophenylhydrazine to procarbazine, ethyl isocyanate will be changed to 2- chloroethyl isocyanates, and will obtain white solid.
1H-NMR (400MHz, DMSO-d6)
δ：9.18 (d, 1H), 8.78 (s, 1H), 8.28 (s, 1H), 7.74 (d, 1H), 7.33 (m, 2H), 7.22 (m, 3H), 7.03 (m, 5H), 6.21 (s, 1H), 4.25 (d, 2H), 3.81 (t, 2H), 3.60 (m, 2H), 3.30 (m, 2H), 1.25 (s, 9H). (M+H)+：649.Mp：164-166℃.
Embodiment 345-【The fluoro- 2- of 4- ((3- (3- isopropyls) urea) methyl) phenoxy group】- N- (2- chloroethyls) -1H- indazole -1- amide
Using the method for embodiment 1, wherein the fluoro- 2- cyano group fluorobenzene of 4- will be changed to by 2- cyano group fluorobenzene, with 3- isopropyl anilines as raw material, ethyl isocyanate is changed to 2- chloroethyl isocyanates, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.58 (m, 2H), 8.18 (s, 1H), 8.03 (s, 1H), 7.84 (s, 1H), 7.53 (m, 1H), 7.42 (m, 2H), 7.03 (m, 5H), 6.21 (s, 1H), 4.25 (d, 2H), 3.81 (t, 2H), 3.60 (m, 2H), 2.97 (m, 1H), 1.25 (d, 6H). (M+H)+：524.Mp：192-194℃.
Embodiment 355-【2- ((3- (3- isopropyls) urea) methyl) phenoxy group】- N- ethyl -1H- indazole -1- amide
Using the method for embodiment 1, wherein will be changed to the fluoro- 2- cyano group fluorobenzene of 4- by 2- cyano group fluorobenzene, with 3- isopropyl anilines as raw material, obtain white solid.
1H-NMR (400MHz, DMSO-d6)
δ：8.58 (m, 2H), 8.18 (s, 1H), 8.03 (s, 1H), 7.84 (s, 1H), 7.53 (m, 1H), 7.42 (m, 2H), 7.03 (m, 5H), 6.21 (s, 1H), 4.25 (d, 2H), 3.04 (m, 2H), 2.97 (m, 1H), 1.20 (d, 6H), 1.05 (t, 3H). (M+H)+：490.Mp：182-184℃.
Embodiment 365-【2- ((3- (4- chloro- 3- (trichloromethyl) phenyl) urea groups) methyl) phenoxy group】- N- ethyl -1H- indazole -1- amide
Using the method for embodiment 1, wherein will be changed to the fluoro- 2- cyano group fluorobenzene of 4- by 2- cyano group fluorobenzene, with 3- trifluoromethyl -4- chloroanilines as raw material, obtain white solid.
1H-NMR (400MHz, DMSO-d6)
δ：9.12 (m, 2H), 9.03 (s, 1H), 8.03 (s, 1H), 7.74 (s, 1H), 7.53 (m, 1H), 7.42 (m, 2H), 7.03 (m, 4H), 6.21 (s, 1H), 4.25 (d, 2H), 3.81 (t, 2H), 3.03 (m, 3H), 1.19 (t, 2H). (M+H)+：550.Mp：177-180℃.
Embodiment 375-【2- ((3- (4- chloro- 3- (trichloromethyl) phenyl) urea groups) methyl) phenoxy group】- N- (2 chloroethyl) -1H- indazole -1- amide
Using the method for embodiment 1, wherein the fluoro- 2- cyano group fluorobenzene of 4- will be changed to by 2- cyano group fluorobenzene, with 3- trifluoromethyl -4- chloroanilines as raw material, ethyl isocyanate is changed to 2- chloroethyl isocyanates, obtains white solid.
1H-NMR (400MHz, DMSO-d6)
δ：9.15 (m, 2H), 9.06 (s, 1H), 8.06 (s, 1H), 7.74 (s, 1H), 7.53 (m, 1H), 7.42 (m, 2H), 7.03 (m, 4H), 6.21 (s, 1H), 4.25 (d, 2H), 3.81 (t, 2H), 3.23 (m, 2H). (M+H)+：584.Mp：156-158℃.
Embodiment 38P38-MAPK inhibitor is screened using GFP-MAPKAPk2_BHK cell models
Experiment material and method
Instrument：1000 living cells imaging systems of IN Cell Analyzer (GE companies of the U.S.)
Cell strain：The bhk cell strain (GE companies of the U.S.) of expression GFP-MAPKAPk2 fusion protein
Cell culture fluid：The F12 culture fluid of G418 containing 1mg/ml and 10%FBS
Analysis culture fluid：The F12 culture fluid of HEPES containing 10mM, 0.2%BSA
Fixative：12% formalin (PBS matches somebody with somebody, 3 ×)
Dyeing liquor：PBS containing 1 μM of Hoechst 33342 (Invitrogen companies of the U.S.)
The preparation of compound：
Agonist Anisomycin DMSO are made into 10mM mother solutions, are made into 300nM working solutions with analysis culture fluid.
Compound DMSO is made into 30mM mother solutions, it is that 300nM Anisomycin are made into 1 × working solution with agonist, initial screening with 0.3 μM, 3 μM and 10 μM three final concentrations, secondary screening according to compound activity by gradient respectively from final concentration 0.1nM, 0.3nM, 1nM, 3nM, 10nM, 30nM, 0.1 μM, 0.3 μM, 1 μM, 3 μM, 10 μM in continuous seven concentration do dose-effect relationship.Positive compound MOL-p38-001 does dose-effect relationship from 0.3 μM and 3 μM conduct control of final concentration simultaneously in secondary screening.
Compareed using the analysis culture fluid containing 0.3 ‰ DMSO of final concentration as Control, using the 300nM Anisomycin containing 0.3 ‰ DMSO of final concentration as agonist control.
Experimental procedure：
The bhk cell of stable expression GFP-MAPKAPk2 fusion protein, 37 DEG C of 5% CO2 are incubated in the F12 culture fluid of G418 containing 1mg/ml and 10%FBS.According in the saturating Tissue Culture Plate in 2.0 × 104/100 μ l/ holes Zhong Yu96 holes black bottom of cell, 37 DEG C of 5% CO2 cultivates 18-24h.Prepare agonist and compound working solutions.Cell is washed once with 100 μ l/ holes analysis culture fluid, adds 100 μ l/ holes compound working solutions, experiment to set Control controls and agonist control, parallel 3 hole of repetition of each concentration of compound.37 DEG C of 5% CO2 of cell is incubated 90min, adds 3 × fixative, the 50 μ l/ holes of room temperature pre-warm to mix, is incubated at room temperature 20min.200 μ l/ holes of cell dyeing liquor are washed three times, and stay in room temperature dyeing 1hr in 200 μ l/ holes dyeing liquors.Cell is measured in 1000 living cells imaging systems of IN Cell Analyzer.Condition determination is：20 times of object lens, excitation wavelength Ex=460nm, launch wavelength Em=535nm, exposure 300ms detection nucleus passage blue-fluorescences；Excitation wavelength Ex=475nm, launch wavelength Em=535nm, exposure 1000ms detection Cytoplasm passage green fluorescence GFP are continuously taken pictures per 5, the hole visual field.Using 1000 Nuclear Trafficking Analysis Module software analysis cell nuclear translocations of GE companies IN Cell Analyzer, the activity that compound suppresses nuclear translocation is calculated.
Compound suppression ratio (%)=(compound treated cells nuclear translocation-agonists treated cells nuclear translocation)/(Control control treatments cell nuclear translocation-agonists treated cells nuclear translocation) × 100%
Embodiment 39Drug screening is carried out in lipopolysaccharide-induced peripheral blood lymphocytes TNF-α test experience
Fresh blood is collected and is separated with PBMC
1. blood sampling person's contact volunteer, gathers enough fresh bloods and is stored in heparin sodium blood taking tube.
2. shift in SepMate separating pipes of the blood of DPBS contrast dilutions extremely added with 15ml Lymphoprep separating liquids,
3. room temperature 1200g is centrifuged 30 minutes, stops centrifugation without brake.
4. tunica albuginea layer (comprising PBMC) is suctioned out, and DPBS is washed twice.
5. with the resuspended PBMC of 1640 culture medium containing 10% calf serum, cell counting.
The TNF-α release experiment of LPS inductions
1.PBMC bed boards according to plan plus the compound that diluted, are cultivated one hour in 37 degree cell culture incubators per 80,000, hole cell.
2. add LPS to stimulate cell.Final concentration of 10ng/ml.37 degree of cell culture incubator overnight incubations.
3. centrifuging and taking supernatant, detects the TNF-α content in cell conditioned medium according to TNF-α ELISA kit step.
4.FlexStation3 reads absorbance, and deriving data carries out statistical computation IC50.
Embodiment 40Inhibition test SCREENED COMPOUND of the medicine to p 38 alpha enzyme
1. p 38 alpha buffer of the concentration for 500ng/ml is prepared.
2. diluted for continuous 2 times for 500ng/ml kinase buffer solution using concentration, dilute 16 points.
3. take in p 38 alpha buffer solution 384 orifice plates of addition that 5uL diluted.
4. 0.8uM GFP-ATF2 and 180uM ATP mixed solution 1ml are prepared.
5. in each aerial GFP-ATF2 and ATP mixed solution for adding 5uL, starting reaction.
6. incubated at room temperature is sealed 1 hour.
7. ATF-2 antibody 1ml are prepared.
8. the antibody of 10ul, mix homogeneously are added in each hole.
9. seal, incubated at room temperature 30 minutes.
10. on instrument read TR-FRET signals.
11. add 2ul compound 0.5%DMSO solution, 3 times of each hole to dilute, 11 concentration, and 2 repetitions (3333,1111,370,123,41,13.7,4.57,1.52,0.51,0.17,0.056).
12. addition 4uL p 38 alphas are in each hole.
13. incubated at room temperature 15 minutes.
14. add 4uL GFP-ATF2 and ATP mixed solutions, provocative reaction.
15. incubated at room temperature 1 hour.
16. each hole add 10uL antibody.
17. incubated at room temperature 30 minutes.
TR-FRET signals are read on 18. instruments, calculate IC50Value.
Embodiment 41Compound is tested to the Selective depression of p 38 alpha/β/gamma/delta enzyme
1. p 38 alpha/β/gamma/delta buffer of the concentration for 500ng/ml is prepared.
2. diluted for continuous 2 times for 500ng/ml kinase buffer solution using concentration, dilute 16 points.
3. take in p 38 alpha buffer solution 384 orifice plates of addition that 5uL diluted.
4. 0.8uM GFP-ATF2 and 180uM ATP mixed solution 1ml are prepared.
5. in each aerial GFP-ATF2 and ATP mixed solution for adding 5uL, starting reaction.
6. incubated at room temperature is sealed 1 hour.
7. ATF-2 antibody 1ml are prepared.
8. the antibody of 10ul, mix homogeneously are added in each hole.
9. seal, incubated at room temperature 30 minutes.
10. on instrument read TR-FRET signals.
11. add 2ul compound 0.5%DMSO solution, 3 times of each hole to dilute, 11 concentration, and 2 repetitions (3333,1111,370,123,41,13.7,4.57,1.52,0.51,0.17,0.056).
12. addition 4uL p 38 alphas are in each hole.
13. incubated at room temperature 15 minutes.
14. add 4uL GFP-ATF2 and ATP mixed solutions, provocative reaction.
15. incubated at room temperature 1 hour.
16. each hole add 10uL antibody.
17. incubated at room temperature 30 minutes.
TR-FRET signals are read on 18. instruments, calculate IC50Value.

Claims (12)

1. formula (I) compound or its isomer are led to,
Wherein：
Ar1For C6-C10Aromatic carbocyclic, including but not limited to phenyl ring, substituted benzene ring, cyclo-octatetraene etc.；Or C3-C10The nonaromatic heterocycles of saturation insatiable hunger, including but not limited to Pentamethylene., hexamethylene, cyclopentenes, cyclohexene, cyclohexadiene；C5-C10Aromatic heterocycle, including one or more be selected from O, the hetero atom of N, S, including but not limited to imidazoles, pyrazoles, furan, thiophene, thiazole, azoles, pyrazine, pyrimidine, indole, quinoline etc.；Or C5-C8Single heterocycle or C8-C11Double heterocycles, including one or more be selected from O, the hetero atom of N, S, including but not limited to tetrahydrofuran, Tetramethylene sulfide, piperidines etc.；Wherein Ar1Independently and selectively by one or more R1Replaced；
R1It is independently
(1)C1-C10The direct-connected or branched paraffin of saturation, described alkyl partly or entirely can be substituted with halogen atoms, and selectively can be replaced by 1-3 phenyl, naphthalene nucleus or following hetero atom：Quinolyl, isoquinolyl, pyrimidine radicals, pyrazinyl, piperazinyl, pyrrole radicals, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl；Above-mentioned phenyl, naphthalene nucleus or heterocycle selectively can be replaced by 0-5 following radicals：Halogen, C1-C6Direct-connected or branched alkyl, C2-C6Direct-connected or branched-chain alkene, C1-C6Direct-connected or branched alkoxy, C2-C6Direct-connected or alkenyloxy, halogen, trifluoromethyl, trifluoromethoxy, acetyl group, aroyl, methoxycarbonyl group, carbethoxyl group, benzenesulfonyl, hydroxyl, amino, single or double C1-C4Substituted sulfoamido, cyano group, nitro；
(2)C3-C10Cycloalkyl and cycloalkenyl group, the group partly or entirely can be optionally substituted by halogen, or selectively by 1-3 C1-C6Direct-connected or branched alkyl or C1-C6Alkoxyl replaces；1-3 methylene of above-mentioned cycloalkyl or cycloalkenyl group can selectively by O, NH, S, SO, SO2, carbonyl, methylol replace；0-5 following substituent group of above-mentioned cycloalkyl or cycloalkenyl group：Halogen, C1-C6Direct-connected or branched alkyl or C1-C6Alkoxyl；
(3)C3-C10Undersaturated direct-connected or branched-chain alkenyl, described alkyl partly or entirely can be optionally substituted by halogen, and selectively by 1-3 C1-C6Direct-connected or branched alkyl, phenyl, naphthyl or following heterocyclic substituted：Quinolyl, isoquinolyl, pyrimidine radicals, pyrazinyl, piperazinyl, pyrrole radicals, furyl, thienyl, pyrazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl；Above-mentioned phenyl, naphthalene nucleus or heterocycle selectively can be replaced by 0-5 following radicals：Halogen, C1-C6Direct-connected or branched alkyl, C2-C6Direct-connected or branched-chain alkene, C1-C6Direct-connected or branched alkoxy, C2-C6Direct-connected or alkenyloxy, halogen, trifluoromethyl, trifluoromethoxy, acetyl group, aroyl, methoxycarbonyl group, carbethoxyl group, benzenesulfonyl, hydroxyl, amino, single or double C1-C4Substituted sulfoamido, cyano group, nitro；
(4) halogen, nitro, hydroxyl, amino, carboxyl, cyano group, trifluoromethyl, trifluoromethoxy, and various monosubstituted or disubstituted amino-compound；
R1It is independently H or F atom；
R2It is independently C1-C10The direct-connected of saturation, side chain and cycloalkane, described alkyl partly or entirely can be substituted with halogen atoms, and phenyl ring or substituted benzene ring replace.
2. formula (I) compound or its isomer are led to,
Wherein：
Ar1For phenyl ring, substituted benzene ring etc.；C5-C10Aromatic heterocycle, including one or more be selected from O, the hetero atom of N, S, including but not limited to imidazoles, pyrazoles, furan, thiophene, thiazole, azoles, pyrazine, pyrimidine, indole, quinoline etc.；Including the aromatic heterocycle that aryl replaces, the such as pyrazoles of phenyl replacement, imidazoles etc.；
R1It is independently H or halogen atom；
R2It is independently C1-C10The direct-connected of saturation, side chain and cycloalkane, described alkyl partly or entirely can be substituted with halogen atoms, and phenyl ring or substituted benzene ring replace.
3. formula (I) compound or its isomer are led to,
Wherein：
Ar1For isopropyl phenyl ring, 2- 4-Chlorobenzotrifluorides, the 3- tert-butyl group -1- p-methylphenyl pyrazoles, the 3- tert-butyl group -1- p-nitrophenyl pyrazoles, the 3- tert-butyl group -1- p-fluorophenyl pyrazoles, the 3- tert-butyl group -1- Phenylpyrazoles replace；
R1It is independently H or F atom；
R2It is independently ethyl, 2- chloroethyls, cyclopenta, cyclohexyl, cyclopropyl, isopropyl, rubigan, an aminomethyl phenyl replace.
4. the compound of the claim with following structures or its isomer：
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- ethyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- ethyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-fluorophenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- ethyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- ethyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- (2- chloroethyls) -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-fluorophenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- (2- chloroethyls) -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- (2- chloroethyls) -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- (2- chloroethyls) -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- isopropyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- isopropyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- isopropyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } the phenoxy group }-N- tert-butyl group -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } the phenoxy group }-N- tert-butyl group -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles] urea } methyl } the phenoxy group }-N- tert-butyl group -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-fluorophenyl -1H- pyrazoles] urea } methyl } the phenoxy group }-N- tert-butyl group -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- cyclohexyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- cyclohexyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- cyclohexyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- phenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- cyclopenta -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- cyclopenta -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } phenoxy group }-N- cyclopenta -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- cyclopenta -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- cyclopenta -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- cyclohexyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- cyclohexyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- isopropyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- isopropyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } -4- the fluorophenoxies }-N- tert-butyl group -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } -4- the fluorophenoxies }-N- tert-butyl group -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- ethyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- ethyl -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-methylphenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- (2- chloroethyls) -1H- indazole -1- amide
5- { 2- { { 3- [- 5 base of 3- (tert-butyl group) -1- p-nitrophenyl -1H- pyrazoles] urea } methyl } -4- fluorophenoxies }-N- (2- chloroethyls) -1H- indazole -1- amide
5- { the fluoro- 2- of 4- { [3- (3- isopropyls) urea] methyl } phenoxy group }-N- (2- chloroethyls) -1H- indazole -1- amide
5- { 2- { [3- (3- isopropyls) urea] methyl } phenoxy group }-N- ethyl -1H- indazole -1- amide
5- { 2- { { 3- [4- chloro- 3- (trichloromethyl) phenyl] urea groups } methyl } phenoxy group }-N- ethyl -1H- indazole -1- amide
5- { 2- { { 3- [4- chloro- 3- (trichloromethyl) phenyl] urea groups } methyl } phenoxy group }-N- (2 chloroethyl) -1H- indazole -1- amide
And its officinal salt or solvate.
5. the invention provides the preparation method of logical formula (I) compound and its pharmaceutical salts.
R1=CH3, NO2, F, H
R2=H, F
R2=H, F R3=ethyl, 2- chloroethyls, isopropyl, the tert-butyl group, cyclopenta, cyclohexyl
Substituted phenylhydrazine A and cyano group pinacolone B obtains intermediate C in 8 hours in 80 DEG C of alcohol refluxs；Intermediate C, E, G obtain intermediate D, F, H by reacting 12 hours in 0 DEG C of tetrahydrofuran solution with trichloroethyl chloroformate.
Substituted adjacent cyano group fluorobenzene I and 3- methyl-PAP J reacts 4 hours in 90 DEG C of DMSO solutions and obtains intermediate K；Intermediate K and amyl nitrite, acetic anhydride 90 DEG C of back flow reaction in toluene solution obtain intermediate L in 8 hours；Intermediate L obtains intermediate M in 1 hour by lithium aluminium hydride reduction in 65 DEG C of tetrahydrofuran solutions.
Intermediate D, F, H and intermediate M, S react 1 hour in 100 DEG C of DMSO solutions and obtain intermediate N；The room temperature reaction 4h in dichloromethane obtains logical formula (I) compound O to last intermediate N with the isocyanates for replacing.
6. another further aspect, the present invention provides a kind of pharmaceutical composition of the acute lung injury for overcoming inflammation, inflammation related disease, tumor and asphyxiating gass or irritative gass to cause, which includes the compound of above-mentioned Formulas I, or they isomer, pharmaceutically acceptable salt, solvate or N- oxides, and at least one pharmaceutically acceptable carrier.
7. another further aspect, the present invention provides a kind of pharmaceutical composition, which includes the compound of above-mentioned Formulas I, or they isomer, pharmaceutically acceptable salt, solvate or N- oxides, additionally comprise the pharmaceutical composition of the acute lung injury for overcoming inflammation, inflammation related disease, tumor and asphyxiating gass or irritative gass to cause one or more, which includes the compound of above-mentioned Formulas I, and at least one pharmaceutically acceptable carrier.
8. another further aspect, the present invention provides the compound of above-mentioned Formulas I, or they isomer, pharmaceutically acceptable salt, solvate or N- oxides, they are used as the medicines for the acute lung injury disease for overcoming inflammation, inflammation related disease, tumor and asphyxiating gass or irritative gass to cause.
9. another further aspect, the present invention provides a kind of disease method for treating the acute lung injury that inflammation, inflammation related disease, tumor and asphyxiating gass or irritative gass are caused, which includes to the experimenter compound of the above-mentioned Formulas I for giving therapeutically effective amount, or they isomer, pharmaceutically acceptable salt, solvate or N- oxides, and one or more other anti-inflammatory drug is optionally given in combination.
10. another further aspect, the present invention provides the purposes of the compound or their isomer, pharmaceutically acceptable salt, solvate or N- oxides of above-mentioned Formulas I in medicine is prepared, and wherein described medicine is used for treating the acute lung injury disease that experimenter especially overcomes inflammation, inflammation related disease, tumor and asphyxiating gass or irritative gass to cause.
11. terms for describing the present invention that now will occur in present specification and claims are defined as follows.For specific term, if implication defined herein is inconsistent with the implication that those skilled in the art are generally understood that, it is defined by implication defined herein；If do not defined in this application, which has the implication that those skilled in the art are generally understood that.
Term " alkyl " used in the present invention refers to straight or branched univalent saturated hydrocarbon radical.“C1-C10Alkyl " refers to the straight or branched alkyl with 1～10 carbon atom, such as methyl, ethyl, propyl group, isopropyl, normal-butyl, sec-butyl, the tert-butyl group, amyl group, 2- amyl groups, isopentyl, neopentyl, hexyl, 2- hexyls, 3- hexyls, 3- methyl amyls, heptyl and octyl group etc..Term " C1-C6Alkyl " means the straight or branched alkyl with 1～6, i.e., 1,2,3,4,5 or 6 carbon atoms, typically methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, amyl group and hexyl etc..Similarly, term " C1-C3 alkyl " means the straight or branched alkyl with 1,2 or 3 carbon atoms, i.e. methyl, ethyl, n-pro-pyl and isopropyl.Alkyl in the present invention is preferably C1-C6Alkyl, more preferably C1-C3Alkyl.
Term " halogen " used in the present invention refers to fluorine, chlorine, bromine and atomic iodine.
Term " aromatic radical " used in the present invention refers to the optionally substituted monocyclic or bicyclic hydrocarbons loop systems comprising at least one unsaturated aromatic ring, preferably with 6～10, i.e., the aryl of 6,7,8,9 or 10 carbon atoms.The example of the aromatic radical in the present invention includes phenyl, naphthyl, 1,2,3,4- tetralyls, indyl and indenyl etc..Aromatic radical in the present invention can be by following substituent group：C1-C6Alkyl, C1-C6Alkoxyl, itrile group, halogen, hydroxyl, amino, nitro, list (C1-C6) alkyl amino, two (C1-C6) alkyl amino, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Haloalkyl or C1-C6Halogenated alkoxy.
Term " fragrant heterocyclic radical " used in the present invention refers to the heteroatomic optionally substituted monocyclic or bicyclic unsaturated aromatic ring system comprising at least one independently selected from N, O or S, it is preferred that having 5～10, i.e., 5, the fragrant heterocyclic radical of 6,7,8,9 or 10 atoms.The example of " fragrant heterocyclic radical " includes but is not limited to thienyl, pyridine radicals, thiazolyl, isothiazolyl, furyl, pyrrole radicals, triazolyl, imidazole radicals, triazine radical, di azoly, oxazolyl, isoxazolyl, pyrazolyl, imidazoles ketone group, azoles, thiazole ketone group, tetrazole radical, thiadiazolyl group, benzimidazolyl, benzoxazolyl group, benzothiazolyl, tetrahydrochysene triazolo pyridyl, tetrahydrochysene triazolopyrimidinyl, benzofuranyl, benzothienyl, thianaphthenyl, indyl, isoindolyl, pyriconyl, pyridazinyl, pyrazinyl, pyrimidine radicals, quinolyl, phthalazinyl, quinoxalinyl, quinazolyl, imidazopyridyl, azoles pyridine radicals, thiazolopyridinyl, Imidazopyridazine base, azoles pyridazinyl, thiazole pyridazinyl, pteridyl, furazanyl, benzotriazole base, Pyrazolopyridine base and purine radicals etc..Heteroaryl in the present invention can be by following substituent group：C1-C6Alkyl, C1-C6Alkoxyl, itrile group, halogen, hydroxyl, amino, nitro, list (C1-C6) alkyl amino, two (C1-C6) alkyl amino, C2-C6 thiazolinyls, C2-C6Alkynyl, C1-C6Haloalkyl or C1-C6Halogenated alkoxy.
Term " cycloalkyl " used in the present invention refers to the saturated carbon ring group of 3,4,5,6,7,8,9 or 10 carbon atoms.The cycloalkyl can be monocyclic or multi-ring fused system, and can condense on aromatic ring.The example of these groups includes cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl etc..The cycloalkyl of this paper can be unsubstituted, or in one or more commutable positions by suitable substituent group.For example, the cycloalkyl in the present invention can optionally by following substituent group：C1-C6Alkyl, C1-C6Alkoxyl, itrile group, halogen, hydroxyl, amino, nitro, list (C1-C6) alkyl amino, two (C1-C6) alkyl amino, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Haloalkyl or C1-C6Halogenated alkoxy.
Term " heterocyclic radical " used in the present invention is referred to comprising at least one and most four heteroatomic optionally substituted monocyclic and bicyclic saturations independently selected from N, O or S, fractional saturation or undersaturated ring system, it is preferred that having 4～10,5,6 or 7 circle heterocycles bases of i.e. 4,5,6,7,8,9 or 10 atoms, condition are the rings of the heterocyclic radical without two adjacent O or S atom.Preferred heterocyclic radical includes but is not limited to pyrrolidinyl, tetrahydrofuran base, dihydrofuran base, tetrahydro-thienyl, piperidyl, morpholinyl or piperazinyl etc..Heterocyclic radical in the present invention can be by following substituent group：C1-C6Alkyl, C1-C6Alkoxyl, itrile group, halogen, hydroxyl, amino, nitro, list (C1-C6) alkyl amino, two (C1-C6) alkyl amino, C2-C6Thiazolinyl, C2-C6Alkynyl, C1-C6Haloalkyl or C1-C6Halogenated alkoxy.
Term " aryl alkyl " used in the present invention refers to the alkyl as defined above replaced by one or more aryl as defined above.Preferred aryl alkyl is aryl-C1-C3Alkyl.The example of the aryl alkyl in the present invention includes benzyl and phenylethyl etc..
Term " fragrant heterocyclic radical alkyl " used in the present invention refers to the alkyl as defined above replaced by fragrant heterocyclic radical as defined above.Preferred fragrant heterocyclic radical alkyl is 5- or 6- unit's heteroaryl-C1-C3- alkyl.The example of the heteroaryl alkyl in the present invention includes pyridyl-ethyl group etc..
Term " cycloheteroalkylalkyl " used in the present invention refers to the alkyl as defined above replaced by heterocyclic radical as defined above.Preferred cycloheteroalkylalkyl is 5 or 6 circle heterocycles base-C1-C3- alkyl.The example of the cycloheteroalkylalkyl in the present invention includes Pentamethylene oxide. ylmethyl.
Term " pharmaceutically acceptable salt " used in the present invention means acceptable in pharmacy and the compounds of this invention of the required pharmacological activity with parent compound salt.This kind of salt includes：The salt of the sour addition formed with mineral acid or with organic acid, described mineral acid such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc.；Described organic acid such as acetic acid, propanoic acid, caproic acid, cyclopentyl propionic acid, glycolic, acetone acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, benzenesulfonic acid, LOMAR PWA EINECS 246-676-2, camphorsulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid etc.；Or the salt formed when replacing by metal ion, such as alkali metal ion or alkaline-earth metal ions in acid proton present on parent compound；Or the coordination compound formed with organic base, described organic base such as ethanolamine, diethanolamine, triethanolamine, N-METHYL-ALPHA-L-GLUCOSAMINE etc..
Term " solvate " used in the present invention means the material that the compounds of this invention is combined to form with acceptable solvent in pharmacy.In pharmacy, acceptable solvent includes water, ethanol, acetic acid etc..Solvate includes the solvate of the solvate and non stoichiometric amounts of stoichiometric amount, preferably hydrate.The compound of the present invention can use water or the crystallization of various organic solvents or recrystallization, in this case it is possible to form various solvates.
The pharmaceutical composition of the present invention includes the formula compound of formula I or the pharmaceutically acceptable carrier that its isomer, pharmaceutically acceptable salt or hydrate and one or more are suitable of effective dose.Here pharmaceutical carrier is included but is not limited to：Ion-exchanger, aluminium oxide, aluminium stearate, lecithin, serum albumin such as Human Albumin, buffer substance such as phosphate, glycerol, sorbic acid, potassium sorbate, the partial glyceride mixtures of saturated vegetable fatty acid, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, Sodium Chloride, zinc salt, cabosil, magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, Polyethylene Glycol, sodium carboxymethyl cellulose, polyacrylate, Cera Flava, lanoline.
The pharmaceutical composition of 12. the compounds of this invention can be applied with following any-mode：Orally, spraying suction, rectal application, nasal cavity applied medicine, buccal medication, local application, non-bowel medication, such as subcutaneous, vein, intramuscular, intraperitoneal, intrathecal, in ventricle, with intracranial injection or input in breastbone, or by a kind of explant reservoir medication.Wherein preferably orally, intraperitoneal or intravenous administration mode.
When oral medication, the compounds of this invention can be made into arbitrarily oral acceptable dosage form, including but not limited to tablet, capsule, aqueous solution or water slurry.Wherein, tablet using carrier generally comprise Lactose and corn starch, can also add lubricant such as magnesium stearate in addition.Capsule preparations using diluent generally comprise Lactose and dried corn starch.Active component is then typically used in mixed way by aqueous suspension preparation with suitable emulsifying agent and suspending agent.If desired, can also add some sweeting agents, aromatic or coloring agent in above oral dosage form.
When local application, particularly treat Local out dressing easy to reach and suffer from face or organ, during such as eyes, skin or lower intestinal tract nervous system disease, the compounds of this invention can be made by different topical preparations forms according to different suffer from face or organ, be described as follows：
When eye local application, the compounds of this invention can be configured to the dosage form of a kind of micronized suspension or solution, using the Sterile Saline that carrier is isotonic certain pH, can wherein add also can not adding preservative agent such as zephiran chloride alkoxide.For ophthalmically acceptable, also compound can be made ointment such as vaseline paste.
When topical application, the compounds of this invention can be made into appropriate ointment, lotion or cream formulation form, and wherein active component is suspended or dissolved in one or more carrier.The carrier that ointment formulation can be used is included but is not limited to：Mineral oil, Albolene, white vaseline, Propylene Glycol, polyethylene glycol oxide, polypropylene oxide, emulsifing wax and water；The carrier that lotion or cream can be used is included but is not limited to：Mineral oil, sorbitan monostearate, polysorbate60, cetyl ester wax, hexadecene are fragrant and mellow, 2- octyldodecanols, benzyl alcohol and water.
The compounds of this invention can be with aseptic injection preparation form medication, including aseptic injection water or oil suspension or aseptic injectable solution.Wherein, the carrier and solvent that can be used includes water, Ringer's mixture and isotonic sodium chlorrde solution.In addition, the fixed oil of sterilizing also is used as solvent or suspension media, such as monoglyceride or two glyceride.
CN201510574993.8A 2015-09-11 2015-09-11 Substituted benzopyrazole diarylurea compound, preparation method and medical application thereof Pending CN106518767A (en)

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US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels
US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels

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US11834441B2 (en) 2019-12-06 2023-12-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11919887B2 (en) 2019-12-06 2024-03-05 Vertex Pharmaceuticals Incorporated Substituted tetrahydrofurans as modulators of sodium channels
US11767337B2 (en) 2020-02-18 2023-09-26 Gilead Sciences, Inc. Antiviral compounds
US11697666B2 (en) 2021-04-16 2023-07-11 Gilead Sciences, Inc. Methods of preparing carbanucleosides using amides
US11827627B2 (en) 2021-06-04 2023-11-28 Vertex Pharmaceuticals Incorporated N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels

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